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PocketMEDICINE

Fifth Edition

Edited byMARC S. SABATINE, MD, MPHASSOCIATE PROFESSOR OF

MEDICINE

HARVARD MEDICAL SCHOOL

The MassachusettsGeneral HospitalHandbook of InternalMedicine

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Pocket medicine (Sabatine)Pocket medicine / [edited by]

Marc S. Sabatine. — Fifth edition.p. ; cm.

Preceded by Pocket medicine /edited by Marc S. Sabatine. 4th ed.c2011.

Includes bibliographical

references and index.ISBN-13: 978-1-4511-8237-8ISBN-10: 1-4511-8237-6ISBN-13: 978-1-4511-8887-5ISBN-10: 1-4511-8887-0I. Sabatine, Marc S., editor of

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CONTENTS

Contributing AuthorsForewordPreface

CARDIOLOGYNeal A. Chatterjee, Ada Stefanescu,

William J. Hucker, David M.Dudzinski, Marc S. Sabatine,Michelle O’Donoghue

ElectrocardiographyChest PainNoninvasive Evaluation of CADCoronary Angiography andRevascularization

Acute Coronary SyndromesPA Catheter and Tailored TherapyHeart FailureCardiomyopathiesValvular Heart DiseasePericardial DiseaseHypertensionAortic AneurysmsAcute Aortic SyndromesArrhythmiasAtrial FibrillationSyncopeIntracardiac DevicesCardiac Risk Assessment forNoncardiac SurgeryPeripheral Artery Disease

PULMONARYQIan J. Barbash, Kathryn A. Hibbert,

Atul MalhotraDyspneaPulmonary Function TestsAsthmaAnaphylaxisChronic Obstructive PulmonaryDiseaseHemoptysisBronchiectasisSolitary Pulmonary NoduleObstructive Sleep ApneaInterstitial Lung DiseasePleural EffusionVenous ThromboembolismPulmonary Hypertension

Respiratory FailureMechanical VentilationAcute Respiratory DistressSyndromeSepsis

GASTROENTEROLOGYZachary A. Zator, Andrew S. de

Lemos, Lawrence S. FriedmanEsophageal and Gastric DisordersGastrointestinal BleedingDiarrhea, Constipation and IleusDiverticular DiseaseInflammatory Bowel DiseaseIntestinal IschemiaPancreatitisAbnormal Liver Tests

HepatitisAcute Liver FailureCirrhosisHepatic Vascular DiseaseAscitesBiliary Tract Disease

NEPHROLOGYAndrew S. Allegretti, Andrew L.

Lundquist, Hasan BazariAcid-Base DisturbancesSodium and Water HomeostasisPotassium HomeostasisRenal FailureGlomerular DiseaseUrinalysisNephrolithiasis

HEMATOLOGY-ONCOLOGYAndrew M. Brunner, Sheheryar K.

Kabraji, Mark M. Awad, Andrew J.Aguirre, Daniel J. DeAngelo, DavidP. Ryan

AnemiaDisorders of HemostasisPlatelet DisordersCoagulopathiesHypercoagulable StatesDisorders of LeukocytesTransfusion TherapyMyelodysplastic SyndromesMyeloproliferative NeoplasmsLeukemiaLymphomaPlasma Cell Dyscrasias

Hematopoietic Stem CellTransplantationLung CancerBreast CancerProstate CancerColorectal CancerChemotherapy Side EffectsPancreatic TumorsOncologic EmergenciesCancer of Unknown Primary Site

INFECTIOUS DISEASESAna A. Weil, Emily P. Hyle, Nesli

BasgozPneumoniaFungal InfectionsInfections in Immunosuppressed

HostsUrinary Tract InfectionsSoft Tissue and Bone InfectionsInfections of the Nervous SystemBacterial EndocarditisTuberculosisHIV/AIDSTick-Borne DiseasesFever Syndromes

ENDOCRINOLOGYKelly B. Lauter, Marc N. Wein,

Michael MannstadtPituitary DisordersThyroid DisordersAdrenal DisordersCalcium Disorders

Diabetes MellitusLipid Disorders

RHEUMATOLOGYZachary S. Wallace, Eli Miloslavsky,

Robert P. FridayArthritis—OverviewRheumatoid ArthritisAdult Onset Still’s Disease &Relapsing PolychondritisCrystal Deposition ArthritidesSeronegative SpondyloarthritisInfectious Arthritis & BursitisConnective Tissue DiseasesSystemic Lupus ErythematosusVasculitisIgG4-Related Disease

CryoglobulinemiaAmyloidosis

NEUROLOGYMichael P. Bowley, Todd M.

Herrington, Eyal Y. Kimchi, SarahWahlster, Tracey A. Cho

Change in Mental StatusSeizuresAlcohol WithdrawalStrokeWeakness & NeuromuscularDysfunctionHeadacheBack and Spinal Cord Disease

CONSULTS

Kiran H. Lagisetty, Jennifer F. Tseng,Katherine T. Chen, Stella K. Kim

Surgical IssuesOb/Gyn IssuesOphthalmic Issues

APPENDIXICU Medications & Treatment of

Hypotension/ShockAntibioticsFormulae and Quick Reference

ABBREVIATIONS

INDEX

PHOTO INSERTS

RadiologyEchocardiography & CoronaryAngiographyPeripheral Blood Smears &LeukemiasUrinalysis

ACLS

CONTRIBUTING AUTHORS

Andrew J. Aguirre, MD, PhDHematology-Oncology Fellow,

Dana-Farber/PartnersCancerCareHematology/Oncology Program

Andrew S. Allegretti, MDInternal Medicine Resident,

Massachusetts General Hospital

Mark M. Awad, MD, PhDHematology-Oncology Fellow,

Dana-Farber/Partners

CancerCareHematology/Oncology Program

Ian J. Barbash, MDInternal Medicine Resident,


Nesli Basgoz, MDAssociate Chief and Clinical

Director, Infectious DiseaseDivision, Massachusetts GeneralHospital

Associate Professor of Medicine,Harvard Medical School

Hasan Bazari, MDClinical Director, Nephrology Unit,

Massachusetts General HospitalProgram Director, Internal

Medicine Residency,Massachusetts General Hospital


Michael P. Bowley, MD, PhDNeurology Resident, Partners

Neurology Residency

Andrew M. Brunner, MDInternal Medicine Resident,


Neal A. Chatterjee, MDInternal Medicine Resident,


Katherine T. Chen, MD, MPHAssociate Professor of Obstetrics,

Gynecology, and ReproductiveScience

Associate Professor of MedicalEducation

Vice-Chair of Ob/Gyn Education,Career Development, andMentorship

Icahn School of Medicine at MountSinai, New York

Tracey A. Cho, MDAssociate Program Director,

Partners-Harvard Neurology

ResidencyAssistant Professor of Neurology,

Harvard Medical SchoolAssistant Neurologist,


Andrew S. de Lemos, MDTransplant Hepatology Fellow,


Daniel J. DeAngelo, MD, PhDAdult Leukemia Program, Dana-

Farber Cancer Institute &Brigham and Women’s Hospital


David M. Dudzinski, MD, JDCardiology Fellow, Massachusetts

General Hospital

Robert P. Friday, MD, PhDAttending Physician, Rheumatology

Unit, Massachusetts GeneralHospital

Associate Director, RheumatologyFellowship Program,Massachusetts General Hospital

Instructor in Medicine, HarvardMedical School

Lawrence S. Friedman, MDAnton R. Fried, MD, Chair,

Department of Medicine,

Newton-Wellesley HospitalAssistant Chief of Medicine,

Massachusetts General HospitalProfessor of Medicine, Harvard

Medical SchoolProfessor of Medicine, Tufts

University School of Medicine

Todd M. Herrington, MD, PhDNeurology Resident, Partners

Neurology Residency

Kathryn A. Hibbert, MDPulmonary and Critical Care

Fellow, Harvard Medical School

William J. Hucker, MD, PhD

Cardiology Fellow, MassachusettsGeneral Hospital

Emily P. Hyle, MDAssistant in Medicine, Infectious

Disease Division, MassachusettsGeneral Hospital

Instructor in Medicine, HarvardMedical School

Sheheryar K. Kabraji, BM, BChInternal Medicine Resident,


Stella K. Kim, MDDirector, Clinical Research in

Opthalmology

Director, Opthalmology ResidencyRotation Program

Associate Professor ofOpthalmology

UT MD Anderson Cancer Center

Eyal Y. Kimchi, MD, PhDNeurology Resident, Partners

Neurology Residency

Kiran H. Lagisetty, MDSurgical Resident, Beth Israel

Deaconess Medical Center

Kelly B. Lauter, MD, PhDInternal Medicine Resident,


Andrew L. Lundquist, MDNephrology Fellow, BWH/MGH

Joint Nephrology FellowshipProgram

Atul Malhotra, MDAssociate Physician, Divisions of

Pulmonary & Critical Care andSleep Medicine, Brigham andWomen’s Hospital


Michael Mannstadt, MDAttending Physician, Endocrine

Unit, Massachusetts GeneralHospital

Assistant Professor of Medicine,Harvard Medical School

Eli Miloslavsky, MDRheumatology Fellow,


Michelle O’Donoghue, MD, MPHInvestigator, TIMI Study Group and

Associate Physician,Cardiovascular Division, Brighamand Women’s Hospital

Affiliate Physician, CardiologyDivision, Massachusetts GeneralHospital

Assistant Professor of Medicine,Harvard Medical School

David P. Ryan, MDClinical Director, Massachusetts

General Hospital Cancer CenterChief of Hematology/Oncology,

Massachusetts General HospitalAssociate Professor of Medicine,

Harvard Medical School

Marc S. Sabatine, MD, MPHChairman, TIMI Study Group and

Physician, CardiovascularDivision, Brigham and Women’sHospital

Affiliate Physician, CardiologyDivision, Massachusetts GeneralHospital

Associate Professor of Medicine,

Harvard Medical School

Ada Stefanescu, MD, CMInternal Medicine Resident,


Jennifer F. Tseng, MD, MPHChief, Division of Surgical

Oncology, Beth Israel DeaconessMedical Center

Associate Professor of Surgery,Harvard Medical School

Sarah Wahlster, MDNeurology Resident, Partners

Neurology Residency

Zachary S. Wallace, MDInternal Medicine Resident,


Ana A. Weil, MD, MPHInternal Medicine Resident,


Marc N. Wein, MD, PhDEndocrinology Fellow,


Zachary A. Zator, MDInternal Medicine Resident,


FOREWORD

To the 1st Edition

It is with the greatest enthusiasmthat I introduce Pocket Medicine. Inan era of information glut, it willlogically be asked, “Why anothermanual for medical houseo cers?” Yet, despite enormousinformation readily available inany number of textbooks, or at thepush of a key on a computer, it isoften that the harried house o ceris less helped by the description ofdi erential diagnosis and therapies

than one would wish.Pocket Medicine is the joint

venture between house sta andfaculty expert in a number ofmedical specialties. Thiscollaboration is designed toprovide a rapid but thoughtfulinitial approach to medicalproblems seen by house o cerswith great frequency. Questionsthat frequently come from facultyto the house sta on rounds, manyhours after the initial interactionbetween patient and doctor, havebeen anticipated and importantpathways for arriving at diagnosesand initiating therapies are

presented. This approach willfacilitate the evidence-basedmedicine discussion that will followthe workup of the patient. Thiswell-conceived handbook shouldenhance the ability of everymedical house o cer to properlyevaluate a patient in a timelyfashion and to be stimulated tothink of the evidence supportingthe diagnosis and the likelyoutcome of therapeuticintervention. Pocket Medicine willprove to be a worthy addition tomedical education and to the careof our patients.

DENNIS A. AUSIELLO, MDPhysician-in-Chief, Massachusetts

General HospitalJackson Professor of Clinical

Medicine, Harvard Medical School

PREFACE

To my parents, Matt and LeeSabatine, to their namesake

grandchildren Matteo and Natalie,and to my wife Jennifer

Written by residents, fellows andattendings, the mandate for PocketMedicine was to provide, in aconcise a manner as possible, thekey information a clinician needsfor the initial approach to andmanagement of the most commoninpatient medical problems.

The tremendous response to the

previous editions suggests we wereable to help ll an important needfor clinicians. With this fifth editioncome several major improvementsincluding a thorough updating ofevery topic, the addition of severalnew topics (including treatment ofanaphylaxis, approach to inpatientnutritional issues, chemotherapyside e ects, and workup of a feverin a recent traveler), and inclusionof additional photomicrographs.We have also added a new sectionon Consults in which non-internalmedicine specialists provide expertguidance in terms of establishing adi erential diagnosis for common

presenting symptoms and initiatingan evaluation in anticipation ofcalling a consult. As always, wehave incorporated key referencesto the most recent high-tier reviewsand important studies publishedright up to the time Pocket Medicinewent to press. We welcome anysuggestions for furtherimprovement.

Of course medicine is far too vasta eld to ever summarize in atextbook of any size. Longmonographs have been devoted tomany of the topics discussedherein. Pocket Medicine is meantonly as a starting point to guide

one during the initial phases ofdiagnosis and management untilone has time to consult morede nitive resources. Although therecommendations herein are asevidence-based as possible,medicine is both a science and anart. As always, sound clinicaljudgement must be applied toevery scenario.

I am grateful for the support ofthe house o cers, fellows, andattendings at the MassachusettsGeneral Hospital. It is a privilegeto work with such aknowledgeable, dedicated, andcompassionate group of physicians.

I always look back on my timethere as Chief Resident as one ofthe best experiences I have everhad. I am grateful to severaloutstanding clinical mentors,including Hasan Bazari, LarryFriedman, Nesli Basgoz, MortSwartz, Eric Isselbacher, Bill Dec,Mike Fifer, and Roman DeSanctis,as well as the late Charlie McCabeand Peter Yurchak.

This edition would not have beenpossible without the help of twoindividuals in the TIMI StudyGroup Chairman’s O ce. MelindaCuerda, my academic coordinator,was an invaluable resource for this

edition. She shepherded everyaspect of the project from start to

nish, with an incredible eye todetail to ensure that each page ofthis book was the very best it couldbe. Pamela Melhorn, my executiveassistant, expertly manages theChairman’s O ce, miraculouslycoordinating the complex clinical,research, and educational missions.

Lastly, special thanks to myparents for their perpetualencouragement and love and, ofcourse, to my wife, Jennifer Tseng,who, despite being a surgeon, ismy closest advisor, my best friendand the love of my life.

I hope that you nd PocketMedicine useful throughout thearduous but incredibly rewardingjourney of practicing medicine.

MARC S. SABATINE, MD, MPH

ELECTROCARDIOGRAPHY

Approach (a systematic approachis vital)• Rate (? tachy, brady) and

rhythm (? relationshipbetween P and QRS)

• Intervals (PR, QRS, QT) andaxis (? LAD or RAD)

• Chamber abnormality (? LAAand/or RAA, ? LVH and/orRVH)

• QRST changes (? Q waves, poorR-wave progression V1–V6, ST↑/↓ or T-wave Δs)

Figure 1-1 QRS axis

Left axis deviation (LAD)• Definition: axis beyond –30° (S

> R in lead II)• Etiologies: LVH, LBBB, inferior

MI, WPW• Left anterior fascicular block:

LAD (–45 to –90°) and qR inaVL and QRS <120 msec andno other cause of LAD (eg,

IMI)

Right axis deviation (RAD)• Definition: axis beyond +90° (S

> R in lead I)• Etiologies: RVH, PE, COPD

(usually not > +110°), septaldefects, lateral MI, WPW

• Left posterior fascicular block:RAD (90–180°) and rS in I &aVL and qR in III & aVF andQRS <120 msec and no othercause of RAD

Prolonged QT interval (NEJM2008;358:169;www.torsades.org)• QT measured from beginning of

QRS complex to end of T wave(measure longest QT)

• QT varies w/ HR → correct w/Bazett formula: QTc =QT/√RR (in sec), formula

http://www.torsades.org

inaccurate at very high andlow HR (nl QTc <440 msec and <460 msec )

• QT prolongation a/w ↑ risk TdP(esp. >500 msec); performbaseline/serial ECGs if usingQT prolonging meds, no estabguidelines for stopping Rx ifQT prolongs

• Etiologies:Antiarrhythmics: class Ia

(procainamide,disopyramide), class III(amiodarone, sotalol)

Psych drugs: antipsychotics(phenothiazines,

haloperidol, atypicals), Li, ?SSRI, TCA

Antimicrobials: macrolides,quinolones, azoles,pentamidine, atovaquone,atazanavir

Other: antiemetics(droperidol, 5-HT3

antagonists), alfuzosin,methadone, ranolazine

Electrolyte disturbances:hypoCa (nb, hyperCa a/w ↓QT), ? hypoK, ? hypoMg

Autonomic dysfxn: ICH (deepTWI), stroke, carotidendarterectomy, neck

dissectionCongenital (long QT

syndrome): K, Na, Cachannelopathies (Circ2013;127:126)

Misc: CAD, CMP, bradycardia,high-grade AVB,hypothyroidism,hypothermia, BBB

Left ventricular hypertrophy(LVH) (Circ 2009;119:e251)• Etiologies: HTN, AS/AI, HCMP,

coarctation of aorta• Criteria (all w/ Se <50%, Sp

>85%; accuracy affected byage, sex, race, BMI)Romhilt-Estes point-score

system: 4 points =probable, 5 points =definite ↑ Amplitude (any ofthe following): largest R or Sin limb leads ≥20 mm or Sin V1 or V2 ≥30 mm or R inV5 or V6 ≥30 mm (3 points)ST displacement opposite to

QRS deflection: w/o dig (3points); w/ dig (1 point)

LAA (3 points); LAD (2

points); QRS duration≥90 msec (1 point)Intrinsicoid deflection

(QRS onset to peak ofR) in V5 or V6 ≥50 msec(1 point)

Sokolow-Lyon: S in V1 + R inV5 or V6 ≥35 mm or R inaVL ≥11 mm

Cornell: R in aVL + S in V3

>28 mm in men or >20mm in women

If LAD/LAFB, S in III + max(R+S) in precordium ≥30mm

Right ventricular hypertrophy(RVH) (Circ 2009;119:e251)• Etiologies: cor pulmonale,

congenital (tetralogy, TGA, PS, ASD, VSD), MS, TR

• Criteria (all tend to beinsensitive, but highly specific,except in COPD)R > S in V1 or R in V1 ≥7

mm, S in V5 or V6 ≥7 mm,drop in R/S ratio acrossprecordium

RAD ≥ +110° (LVH + RAD orprominent S in V5 or V6 →biventricular hypertrophy)

Ddx of dominant R wave in V1or V2• Ventricular enlargement: RVH

(RAD, RAA, deep S waves in I,V5, V6); HCMP

• Myocardial injury: posterior MI(anterior Rw = posterior Qw;often with IMI)

• Abnormal depolarization: RBBB(QRS >120 msec, rSR′); WPW(↓ PR, Δ wave, ↑ QRS)

• Other: dextroversion; Duchennemuscular dystrophy; leadmisplacement; nl variant

Poor R wave progression (PRWP)(Am Heart J 2004;148:80)

• Definition: loss of anterior forcesw/o frank Q waves (V1–V3); Rwave in V3 ≤3 mm

• Possible etiologies (nonspecific):old anteroseptal MI (usually

w/ R wave V3 ≤1.5 mm, ±persistent ST ↑ or TWI V2 &V3) cardiomyopathy

LVH (delayed RWP withprominent left precordialvoltage), RVH, COPD (whichmay also have RAA, RAD,limb lead QRS amplitude≤5, SISIISIII w/ R/S ratio <1in those leads)

LBBB; WPW; clockwiserotation of the heart; leadmisplacement; PTX

Pathologic Q waves• Definition: ≥30 msec (≥20 msec

V2–V3) or >25% height of Rwave in that QRS complex

• Small (septal) q waves in I, aVL,V5 & V6 are nl, as can beisolated Qw in III, aVR, V1

• “Pseudoinfarct” pattern may beseen in LBBB, infiltrative dis.,HCMP, COPD, PTX, WPW

ST elevation (STE) (NEJM2003;349:2128; Circ

2009;119:e241 & e262)• Acute MI (upward convexity ±

TWI) or prior MI withpersistent STE

• Coronary spasm (Prinzmetal’sangina; transient STE in acoronary distribution)

• Myopericarditis (diffuse,upward concavity STE; a/w PR↓; Tw usually upright)

• HCMP, Takotsubo CMP,ventricular aneurysm,cardiac contusion

• Pulmonary embolism (occ. STEV1–V3; typically associatedTWI V1–V4, RAD, RBBB)

• Repolarization abnormalitiesLBBB (↑ QRS duration, STE

discordant from QRScomplex)dx of STEMI in setting of

LBBB: ≥1 mm STEconcordant w/ QRS (Se73%, Sp 92%), STD ≥1mm V1–V3 (Se 25%, Sp96%) or STE ≥5 mmdiscordant w/ QRS (Se31%, Sp 92%) (“Sgarbossacriteria,” NEJM1996;334:481)

LVH (↑ QRS amplitude);Brugada syndrome (rSR′,

downsloping STE V1–V2)Hyperkalemia (↑ QRS

duration, tall Ts, no Ps)• aVR: STE >1 mm a/w ↑ mort in

STEMI; STE aVR > V1 a/w leftmain disease

• Early repolarization: mostoften seen in V2–V5 & in youngadults (Ann Emerg Med2012;60:45)J point ↑ 1–4 mm; notch in

downstroke of R wave;upward concavity of ST;large Tw;

ratio of STE / T waveamplitude <25%; pattern

may disappear with exercise? early repol in inf leads may

be a/w ↑ risk of VF (NEJM2009;361:2529; Circ2011;124:2208)

ST depression (STD)• Myocardial ischemia (± Tw

abnl) or acute true posteriorMI (V1–V3)

• Digitalis effect (downsloping ST± Tw abnl, does not correlatew/ dig levels)

• Hypokalemia (± U wave)• Repolarization abnl in a/w LBBB

or LVH (usually in leads V5,V6, I, aVL)

T wave inversion (TWI;generally ≥1 mm; deep if ≥5mm) (Circ 2009;119:e241)• Ischemia or infarct; Wellens’ sign

(deep early precordial TWI) →proximal LCA lesion

• Myopericarditis; CMP(Takotsubo, ARVC, apicalHCM); MVP; PE (esp. if TWIV1–V4)

• Repolarization abnl in a/wLVH/RVH (“strain pattern”),BBB

• Posttachycardia or postpacing• Electrolyte, digoxin, PaO2,

PaCO2, pH or core

temperature disturbances• Intracranial bleed (“cerebral T

waves,” usually w/ ↑ QT)• Normal variant in children (V1–

V4) and leads in which QRScomplex predominantly

Low voltage• QRS amplitude (R + S) <5 mm

in all limb leads & <10 mm inall precordial leads

• Etiologies: COPD (precordialleads only), pericardialeffusion, myxedema, obesity,pleural effusion, restrictive orinfiltrative CMP, diffuse CAD

CHEST PAIN

Initial approach• Focused history: quality &

severity of pain; location &radiation; provoking &palliating factors; intensity atonset; duration, frequency &pattern; setting in which itoccurred; associated sx; cardiachx and risk factors

• Targeted exam: VS (includingBP in both arms), cardiacgallops, murmurs or rubs; signsof vascular disease (carotid orfemoral bruits, ↓ pulses), signsof heart failure; lung &abdominal exam; chest wallexam for reproducibility of

pain• 12-lead ECG: obtain w/in 10

min; c/w priors & obtain serialECGs; consider posterior leads(V7–V9) to reveal posterior MIif hx c/w ACS but ECGunrevealing or ST ↓ V1–V4

• Cardiac biomarkers (Tn ± CK-MB): ✓ Tn at baseline & 3–6 hafter sx onset troponin:>95% Se, 90% Sp; level>99th %ile w/ rise & fall inapprop. setting is dx of MIdetectable 1–6 h after injury,peaks 24 h, may remainelevated for 7–10 d in STEMI

high-sens. Tn: 98% Se, 90% Spw/in 3 h of admit, 90% Sew/in 1 h ( JAMA2011;306:2684)Causes for ↑ Tn other than ACS

(= “type 1 MI”): (1) Supply-demand mismatch not due toΔ in CAD (= “type 2 MI”;eg, ↑↑ HR, shock, HTN crisis,spasm, HCM, severe AS), (2)non-ischemic injury(myocarditis/toxic CMP,cardiac contusion) or (3)multifactorial (PE, sepsis,severe HF, renal failure,Takotsubo, infilt dis.) (Circ2012;126:2020)

CK-MB: less Se & Sp (skel.muscle, tongue, diaphragm,intestine, uterus, prostate),useful for dx of post-PCI/CABG MI or MI if Tnalready elevated

• CXR; other imaging (echo, PECTA, etc.) as indicated basedon H&P and initial testing

• If low prob of ACS (eg, ECG &Tn) & stable → noninvasivefxnal or imaging test

• Coronary CT angio (CCTA): NPV98% for signif CAD, but PPV35% for ACS; helpful to r/oCAD if low-intermed prob ofACS. CCTA vs. noninv. fxnal

test for ischemia → ↓ time todx & LOS, but ↑ prob ofcath/PCI, contrast exposure &↑ radiation (NEJM2012;366:1393 & 367:299;JACC 2013;61:880). “Tripler/o” CT angiogram for CAD,PE, AoD.

NONINVASIVE EVALUATION OFCAD

Stress testing (Circ2007;115:1464; JACC2012;60:1828)• Indications: dx CAD, evaluate Δ

in clinical status in Pt w/known CAD, risk stratify s/pACS, evaluate exercisetolerance, localize ischemia

(imaging required)• Contraindications (Circ

2002;106:1883; &2012;126:2465)Absolute: AMI w/in 48 h,

high-risk UA, acute PE,severe sx AS, uncontrolledHF, uncontrolledarrhythmias,myopericarditis, acute aorticdissection

Relative: left main CAD, modvalvular stenosis, severeHTN, HCMP, high-degreeAVB, severe electrolyte abnl

• Exercise: standard Bruce (↑speed & incline q3min),

modified Bruce (begins w/otreadmill incline), submax (if<3 wk post-MI) or sx-limited;holdnitrates/βB/CCB/ranolazine iftrying to dx CAD, but givewhen assessing if Pt ischemicon meds

• Pharmacologic: if unable toexer., low exer. tol, or recentMI. Se & Sp exercise.Preferred if LBBB (requiresimaging since ECG notinterpretable). Coronaryvasodilators (will reveal CAD,but not tell you if Pt ischemic):regadenoson, dipyridamole or

adenosine (may precipitatebradycardia andbronchospasm).Chronotropes/inotropes (morephysiologic): dobutamine (mayprecipitate tachyarrhythmias).

• Imaging: used if uninterpretableECG (paced, LBBB, resting ST ↓>1 mm, dig., LVH, WPW),after indeterminate ECG test,pharmacologic tests, orlocalization of ischemiaSPECT (eg, 99mTc-sestamibi),

PET (rubidium-82; usuallyw/ pharm test), echo, MRI

Test results

• HR (must achieve ≥85% of maxpred HR [220-age] for exer.test to be dx), BP response,peak double product (HR ×BP; nl >20k), HR recovery(HRpeak – HR1 min later; nl >12)

• Max exercise capacity achieved(METS or min)

• Occurrence of symptoms (atwhat level of exertion andsimilarity to presenting sx)

• ECG Δs: downsloping or horizontalST ↓ (≥1 mm) 60–80 ms afterQRS predictive of CAD (butdoes not localize ischemicterritory); however, STE highlypredictive & localizes

• Duke treadmill score = exercisemin – (5 × max ST dev) – (4× angina index) [0 none, 1nonlimiting, 2 limiting]; score≥5 → <1% 1-y mort; –10 to+ 4 → 2–3%; ≤ –11 → ≥5%

• Imaging: radionuclide defects orechocardiographic regionalwall motion abnormalitiesreversible defect = ischemia;

fixed defect = infarct;transient isch dilation =severe CAD

false : breast → ant “defect”and diaphragm → inf“defect”

false may be seen if

balanced (eg, 3VD) ischemia(global ↓ perfusion w/oregional Δs)

High-risk test results (PPV ~50%for LM or 3VD, ∴ considercoronary angio)• ECG: ST ↓ ≥2 mm or ≥1 mm in

stage 1 or in ≥5 leads or ≥5min in recovery; ST ↑; VT

• Physiologic: ↓ or fail to ↑ BP, <4METS, angina during exercise,Duke score ≤ –11; ↓ EF

• Radionuclide: ≥1 lg or ≥2 mod.reversible defects, transient LVcavity dilation, ↑ lung uptake

Myocardial viability (Circ

2008;117:103; Eur Heart J2011;31:2984 & 2011;32:810)• Goal: identify hibernating

myocardium that could regainfxn after revascularization

• Options: MRI (Se ~95%, Sp~85%), PET (Se ~90%, Sp~65%), dobutamine stressecho (Se ~80%, Sp ~80%);

SPECT/rest-redistribution(Se ~85%, Sp ~70%)

In Pts w/ LV dysfxn, viabil.doesn’t predict ↑ CABGbenefit vs. med Rx (NEJM2011;364:1617)

CT & MR coronary angio (NEJM

2008;369:2324; Circ2010;121:2509; Lancet2012;379:453)• Image quality best at slower &

regular HR (? give bB ifpossible, goal HR 55–60)

• Calcium generates artifact for CTangiography

• MRI: angiography, perfusion, LVfxn, enhancement (early =microvasc obstr; late = MI)

Coronary artery calcium score(CACS; Circ 2010;122:e584; NEJM2012;366:294; JAMA 2012;308:788)• Quantifies extent of calcium; thus

estimates plaque burden (but

not % coronary stenosis)• ? Risk strat. (<100 = low; >300

= high) in asx Pts w/intermed risk (10–20% 10-yrisk)

• ? Value as screening test to r/oCAD in sx Pt (CACS <100 →3% probability of signif CAD;but interpretation affected byage, gender)

CORONARY ANGIOGRAPHYAND REVASCULARIZATION

Indications for coronaryangiography in stable CAD orasx Pts• CCS class III–IV angina despite

medical Rx or angina +systolic dysfxn

• High-risk stress test findings (seeprior topic)

• Uncertain dx after noninvasivetesting (& compelling need todetermine dx), occupationalneed for definitive dx (eg,pilot) or inability to undergononinvasive testing

• Systolic dysfxn with unexplainedcause

• Survivor of SCD, polymorphicVT, sustained monomorphic VT

• Suspected spasm ornonatherosclerotic cause ofischemia (eg, anomalouscoronary)

Precath checklist• Document peripheral arterial

exam (radial, femoral, DP, PTpulses; bruits); NPO >6 h

• ✓ CBC, PT, & Cr; give IVF (±bicarb, ± acetylcysteine; see“CIAKI”); blood bank sample

• ASA 325 mg × 1; consider clopi

600 mg ≥2–6 h before PCI or,if ACS, ticagrelor pre- or peri-PCI or prasugrel peri-PCI;cangrelor (IV P2Y12 inhib) ↓peri-PCI ischemic events vs.clopi w/o preload (NEJM2013;368:1303); considerstatin preRx (Circ2011;123:1622)

Coronary revascularization instable CAD (Circ 2011;124:e574)• Optimal med Rx (OMT) should be

initial focus if stable, w/ocritical anatomy, & w/o ↓ EF

• PCI: ↓ angina more quickly c/wOMT; does not ↓ D/MI (NEJM

2007;356:1503); in Pts w/ ≥1stenosis w/ FFR ≤0.8 (seebelow), ↓ urg revasc c/w OMT(NEJM 2012;367:991); may benoninferior to CABG inunprotected left main dis.(NEJM 2011;364:1718)

• CABG: in older studies, ↓ mort.c/w OMT if 3VD, LM, 2VD w/critical prox LAD, esp. if ↓ EF;more recently, if EF <35% ↓CV death vs. OMT (NEJM2011;364:1607) insufficientevidence to support routineviability assessment (NEJM2011;364:1617) in diabetics w/≥2VD, ↓ D/MI, but ↑ stroke

c/w PCI (NEJM2012;367:2375)

• If revasc deemed necessary, PCI iflimited # of discrete lesions, nlEF, no DM, poor operativecandidate; CABG if extensiveor diffuse disease, ↓ EF, DM orvalvular disease; if 3VD/LM:CABG ↓ D/MI & revasc buttrend toward ↑ stroke c/w PCI(Lancet 2013;381:629);SYNTAX score II helps identifyPts who benefit most fromCABG (Lancet 2013;381:639)

PCI• Balloon angioplasty (POBA):

effective, but c/b dissection &elastic recoil & neointimalhyperplasia → restenosis; nowreserved for small lesions & ?some SVG lesions

• Bare metal stents (BMS): ↓elastic recoil → 33–50% ↓restenosis & repeat revasc (to~10% by 1 y) c/w POBA;requires ASA lifelong & P2Y12

inhib × ≥4 wk• Drug-eluting stents (DES): ↓

neointimal hyperplasia →~75% ↓ restenosis, ~50% ↓repeat revasc (to <5% by 1y), no ↑ D/MI c/w BMS (NEJM2013;368:254); next

generation DES may ↓ repeatrevasc & stent thrombosis;require P2Y12 inhib ≥1 y (Circ2007;115:813)

• Radial access ↓ vasc. complic. vs.femoral, but no ∆ D/MI/CVA(Lancet 2011;377:1409)

• Fractional flow reserve [FFR;ratio of max flow (induced byIV or IC adenosine) distal vs.proximal to a stenosis] guidedPCI (<0.8) → ↓ # stents & ↓D/MI/revasc (NEJM2009;360:213)

Post-PCI complications• Postprocedure ✓ vascular access

site, distal pulses, ECG, CBC,Cr

• Bleedinghematoma/overt bleeding:

manual compression,reverse/stop anticoag

retroperitoneal bleed: may p/w↓ Hct ± back pain; ↑ HR & ↓BP late; Dx w/ abd/pelvicCT (I–); Rx: reverse/stopanticoag (d/winterventionalist),IVF/PRBC/plts as required

if bleeding uncontrolled,consult performinginterventionalist or surgery

• Vascular damage (~1% of dx

angio, ~5% of PCI; Circ2007;115:2666)pseudoaneurysm: triad of pain,

expansile mass, systolicbruit; Dx: U/S; Rx (if pain or>2 cm): manual or U/S-directed compression,thrombin injection orsurgical repair

AV fistula: continuous bruit;Dx: U/S; Rx: surgical repair

LE ischemia (emboli,dissection, clot): cool,mottled extremity, ↓ distalpulses; Dx: pulse volumerecording (PVR), angio; Rx:percutaneous or surgical

repair• Peri-PCI MI: >5× ULN of

Tn/CK-MB + either sx orECG/angio Δs; Qw MI in <1%

• Renal failure: contrast-inducedmanifests w/in 24 h, peaks 3–5 d (see “CIAKI”)

• Cholesterol emboli syndrome(typically in middle-aged &elderly and w/ Ao atheroma)renal failure (late and

progressive, eos in urine);mesenteric ischemia (abdpain, LGIB, pancreatitis);intact distal pulses butlivedo pattern and toenecrosis

• Stent thrombosis: mins to yrsafter PCI, typically p/w AMI.Due to mech prob. (stentunderexpansion orunrecognized dissection,typically presents early) or d/cof antiplt Rx (esp. if d/c bothASA & P2Y12 inhib; JAMA2005;293:2126). Risk of latestent thrombosis may be higherwith DES than BMS ( JACC2006;48:2584).

• In-stent restenosis: mos afterPCI, typically p/w gradual ↑angina (10% p/w ACS). Due tocombination of elastic recoiland neointimal hyperplasia; ↓

w/ DES vs. BMS.

ACUTE CORONARYSYNDROMES

Ddx (causes of myocardialischemia/infarction other thanatherosclerotic plaque rupture)• Nonatherosclerotic coronary

artery diseaseSpasm: Prinzmetal’s variant,

cocaine-induced (6% of CP+ cocaine use r/i for MI)

Dissection: spontaneous(vasculitis, CTD,pregnancy), aortic dissectionwith retrograde extension(usually involving RCA →IMI) or mechanical(catheter, surgery, trauma)

Embolism: endocarditis,prosthetic valve, muralthrombus, AF, myxoma;thrombosis

Vasculitis: Kawasakisyndrome, Takayasuarteritis, PAN, Churg-Strauss,SLE, RA

Congenital: anomalous originfrom aorta or PA,

myocardial bridge(intramural segment)

• Fixed CAD but ↑ myocardial O2

demand (eg, ↑ HR, anemia,AS) → “demand” ischemia

• Myocarditis; Takatsubo/stressCMP; toxic CMP; cardiaccontusion

Clinical manifestations ( JAMA2005;294:2623)• Typical angina: retrosternal

pressure/pain/tightness ±radiation to neck, jaw or armsprecip. by exertion, relieved by

rest or NTG; in ACS, new-onset, crescendo or at rest

• Associated symptoms: dyspnea,diaphoresis, N/V, palpitationsor lightheadedness

• Many MIs (~20% in older series)are initially unrecognized b/csilent or atypical sx

Physical exam• Signs of ischemia: S4, new MR

murmur 2° pap. muscle dysfxn,paradoxical S2, diaphoresis

• Signs of heart failure: ↑ JVP,crackles in lung fields, S3,HoTN, cool extremities

• Signs of other areas ofatherosclerotic disease: carotid

or femoral bruits, ↓ distalpulses

Diagnostic studies• ECG: ST ↓/↑, TWI, new LBBB,

hyperacute Tw. Qw/PRWPmay suggest prior MI, ∴ CAD✓ ECG w/in 10 min ofpresentation, with any Δ in sxand at 6–12 h; compare w/baselinedx of STEMI if old LBBB: ≥1

mm STE concordant w/ QRS(Se 73%, Sp 92%), STD ≥1mm V1–V3 (Se 25%, Sp 96%)or STE ≥5 mm discordantw/ QRS (Se 31%, Sp 92%)

• Cardiac biomarkers (Tnpreferred, or CK-MB): ✓ Tn atbaseline & 3–6 h after sx onset;a rise to >99th %ile inapprop. clinical setting dx ofMI (see “Chest Pain”); nb, inPts w/ ACS & ↓ CrCl, ↑ Tn stillportends poor prognosis(NEJM 2002;346:2047)

• If low prob, stress test, CTangio or rest perfusionimaging to r/o CAD (see“Chest Pain”)

• TTE (new wall motion abnl)suggestive of ACS; coronaryangio gold standard for CAD

Prinzmetal’s (variant) angina• Coronary spasm → transient STE

usually w/o MI (but MI, AVB,VT can occur)

• Pts usually young, smokers, ±other vasospastic disorders (eg,migraines, Raynaud’s)

• Angiography → nonobstructiveCAD, focal spasm w/

hyperventilation, acetylcholine• Treatment: high-dose CCB,

nitrates (+SL NTG prn), ? a-blockers; d/c smoking

• Cocaine-induced vasospasm: useCCB, nitrates, ASA; ? avoid bB,but data weak and labetalolappears safe (Archives2010;170:874; Circ2011;123:2022)

Approach to triage• If hx and initial ECG &

biomarkers non-dx, repeatECG & biomarkers 3–6 h later

• If remain nl and low likelihoodof ACS, search for alternativecauses of chest pain

• If remain nl, have ruled out MI,but if suspicion for ACS basedon hx, then still need to r/o UAw/ stress test to assess forinducible ischemia (or CTA tor/o CAD);if low risk (age ≤70; � prior

CAD, CVD, PAD; � restangina) can do as outPt

w/in 72 h (0% mortality,<0.5% MI, Ann Emerg Med2006;47:427)

if not low risk, admit andinitiate Rx for possible ACSand consider stress test orcath

Coronary angiography (Circ2007;116:e148 & 2012;126:875)• Conservative strategy =

selective angiography. MedicalRx with pre-d/c stress test;angio only if recurrentischemia or strongly ETT.Indicated for: low TIMI risk

score, Pt or physicianpreference in absence of high-risk features, low-risk women(JAMA 2008;300:71).

• Invasive strategy = routineangiography w/in 72 hImmediate (w/in 2 h) if:

refractory/recurrentischemia, hemodynamic orelectrical instability

Early (w/in 24 h) if: Tn, ST Δ,TRS ≥3, GRACE risk score>140 (NEJM2009;360:2165)

Delayed (ie, acceptable anytimew/in 72 h) if: diabetes, EF<40%, GFR <60, post-MI

angina, PCI w/in 6 mo,prior CABG or high-riskstress results

32% ↓ rehosp for ACS,nonsignif 16% ↓ MI, no Δ inmortality c/w cons. (JAMA2008;300:71)

↑ peri-PCI MI counterbalancedby ↓↓ in spont. MI

Mortality benefit seen in somestudies, likely only if cons.strategy w/ low rate ofangio

Figure 1-2 Approach toUA/NSTEMI

STEMI

Requisite STE (at J point)• ≥2 contiguous leads w/ ≥1 mm

(except for V2–V3: ≥2 mm in and ≥1.5 mm in )

• New or presumed new LBBB

Reperfusion (“time is muscle”)• Immediate reperfusion (ie,

opening occluded culpritcoronary artery) is critical

• In PCI-capable hospital, goalshould be primary PCI w/in90 min of 1st medical contact

• In non-PCI-capable hospital,consider transfer to PCI-

capable hospital (see below),o/w fibrinolytic therapyw/in 30 min of hospitalpresentation

• Do not let decision regardingmethod of reperfusion delaytime to reperfusion

Primary PCI (NEJM 2007;356:47)• Indic: STE + sx <12 h; ongoing

ischemia 12–24 h after sxonset; shock regardless of time

• Superior to lysis: 27% ↓ death,65% ↓ reMI, 54% ↓ stroke,95% ↓ ICH (Lancet2003;361:13)

• Thrombus aspiration during

angio prior to stenting ↓mortality (Lancet2008;371:1915)

• Do not intervene on nonculpritlesions; risk stratify w/imaging stress (Circ2011;124:e574)

• Transfer to center for 1° PCI mayalso be superior to lysis (NEJM2003;349:733), see below

Fibrinolysis

• Indic: STE/LBBB + sx <12 h;benefit if sx >12 h less clear;reasonable if persist. sx & STE

• Mortality ↓ ~20% in anterior MIor LBBB and ~10% in IMI c/w� reperfusion Rx

• Prehospital lysis (ie, ambulance):further 17% ↓ in mortality( JAMA 2000;283:2686)

• ~1% risk of ICH; high-riskgroups include elderly (~2% if>75 y), women, low wt

• Although age not contraindic., ↑risk of ICH in elderly (>75 y)makes PCI more attractive

Nonprimary PCI• Facilitated PCI: upstream lytic,

GPI or GPI + ½ dose lyticbefore PCI offers no benefit

• Rescue PCI if shock, unstable,failed reperfusion or persistentsx (NEJM 2005;353:2758)

• Routine angio ± PCI w/in 24 hof successful lysis: ↓D/MI/revasc (Lancet

2004;364:1045) and w/in 6 h↓ reMI, recurrent ischemia, &HF compared to w/in 2 wk(NEJM 2009;360:2705);∴ if lysed at non-PCI capable

hospital, consider transfer toPCI-capable hospital ASAP esp.if high-risk presentation (eg,anterior MI, inferior MI w/ lowEF or RV infarct, extensiveSTE or LBBB, HF, ↓ BP or ↑HR)

• Late PCI (median day 8) ofoccluded infarct-related artery:no benefit (NEJM2006;355:2395)

LV failure (~25%)• Diurese to achieve PCWP 15–20

→ ↓ pulmonary edema, ↓myocardial O2 demand

• ↓ Afterload → ↑ stroke volume &CO, ↓ myocardial O2 demand

can use IV NTG ornitroprusside (risk ofcoronary steal) → short-acting ACEI

• Inotropes if HF despite diuresis &↓ afterload; use dopamine,dobutamine or milrinone

• Cardiogenic shock (~7%) =MAP <60 mmHg, CI <2L/min/m2, PCWP >18 mmHg;inotropes, mech support [eg,VAD, IABP (trial w/o benefitNEJM 2012;367:1287)] to keepCI >2; pressors to keep MAP>60; if not done already,coronary revasc (NEJM1999;341:625)

IMI complications (Circ1990;81:401; NEJM1994;330:1211; JACC2003;41:1273)• Heart block (~20%, occurs

because RCA typically suppliesAV node)40% on present., 20% w/in 24

h, rest by 72 h; high-gradeAVB can develop abruptly

Rx: atropine, epi,aminophylline (100 mg/min× 2.5 min), temp wire

• RV infarct (30–50%, but only ½of those clinically signif).HoTN; ↑ JVP, Kussmaul’s; 1mm STE in V4R; RA/PCWP

≥0.8; RV dysfxn on TTE; proxRCA occl.Rx: optimize preload (RA goal

10–14, BHJ 1990;63:98); ↑contractility (dobutamine);maintain AV synchrony(pacing as necessary);reperfusion (NEJM1998;338:933); mechanicalsupport (IABP or RVAD);pulmonary vasodilators (eg,inhaled NO)

Mechanical complications(incid. <1% for each; typicallyoccur a few days post-MI)• Free wall rupture: ↑ risk w/

lysis, large MI, ↑ age, , HTN;p/w PEA or hypoTN,pericardial sx, tamponade; Rx:volume resusc., ?pericardiocentesis, inotropes,surgery

• VSD: large MI in elderly; AMI →apical VSD, IMI → basalseptum; 90% w/ harsh murmur±thrill (NEJM 2002;347:1426);

Rx: diuretics, vasodil.,inotropes, IABP, surgery,perc. closure

• Papillary muscle rupture: morecommon after inf MI (PM pap.muscle supplied by PDA alone)

than ant MI (AL pap. musclesupplied by diags & OMs);50% w/ new murmur, rarely athrill, ↑ v wave in PCWPtracing; asymmetricpulmonary edema. Rx:diuretics, vasodilators, IABP,surgery.

Arrhythmias post-MI• Treat as per ACLS for unstable or

symptomatic bradycardias &tachycardias

• AF (10–16% incidence): β-blocker or amio, ± digoxin(particularly if HF), heparin

• VT/VF: lido or amio × 6–24 h,

then reassess; ↑ βB as tol.,replete K & Mg, r/o ischemia;early monomorphic (<48 h

post-MI) does not carry badprognosis

• Accelerated idioventricularrhythm (AIVR): slow VT(<100 bpm), often seen aftersuccessful reperfusion;

typically self-terminates anddoes not require treatment

• May consider backuptranscutaneous pacing (TP)if: 2° AVB type I, BBB

• Backup TP or initiatetransvenous pacing if: 2° AVBtype II; BBB + AVB

• Transvenous pacing (TV) if: 3°AVB; new BBB + 2° AVB typeII; alternating LBBB/RBBB(can bridge w/ TP until TV,which is best accomplishedunder fluoroscopic guidance)

Prognosis• In registries, in-hospital mortality

is 6% w/ reperfusion Rx (lytic

or PCI) and ~20% w/o• Predictors of mortality: age, time

to Rx, anterior MI or LBBB,heart failure (Circ2000;102:2031)

PREDISCHARGE CHECKLIST ANDLONG-TERM POST-ACS

MANAGEMENT

Risk stratification• Stress test if anatomy undefined;

consider stress if signif residualCAD post-PCI of culprit

• Assess LVEF prior to d/c; EF ↑~6% in STEMI over 6 mo( JACC 2007;50:149)

Medications (barringcontraindications)• Aspirin: 81 mg daily• P2Y12 inhib (eg, clopi, prasugrel

or ticagrelor): ≥12 mo if stent(min 1 mo after BMS); some

PPIs interfere w/biotransformation of clopi and∴ plt inhibition, but noconvincing impact on clinicaloutcomes (Lancet2009;374:989; NEJM2010;363:1909); use w/PPIs ifh/o GIB or multiple GIB riskfactors ( JACC 2010;56:2051)

• β-blocker: 23% ↓ mortality afterMI

• Statin: high-intensity lipid-lowering (eg, atorvastatin 80mg, NEJM 2004;350:1495)

• ACEI: lifelong if HF, ↓ EF, HTN,DM; 4–6 wk or at least untilhosp. d/c in all STEMI

? long-term benefit in CADw/o HF (NEJM2000;342:145 &2004;351:2058; Lancet2003;362:782)

• Aldosterone antag: 15% ↓ deathif EF <40% & either DM or s/sof HF (NEJM 2003;348:1309)

• Nitrates: standing ifsymptomatic; SL NTG prn forall

• Oral anticoagulants: if warfarinneeded in addition toASA/clopi (eg, AF or LVthrombus), target INR 2–2.5. ?stop ASA if at high bleedingrisk on triple Rx (Lancet

2013;381:1107). Low-doserivaroxaban (2.5 mg bid) inaddition to ASA & clopi → 16%↓ D/MI/stroke and 32% ↓ all-cause death, but ↑ majorbleeding and ICH (NEJM2012;366:9).

ICD (NEJM 2008;359:2245)• If sust. VT/VF >2 d post-MI not

due to reversible ischemia• Indicated in 1° prevention of SCD

if post-MI w/ EF ≤30–40%(NYHA II–III) or ≤30–35%(NYHA I); need to wait ≥40 dafter MI (NEJM 2004;351:2481& 2009;361:1427)

Risk factors and lifestylemodifications (Circ2011;124:2458)• Low chol. (<200 mg/d) & fat

(<7% saturated) diet; LDLgoal <70 mg/dL; ? Ω;-3 FA

• BP <140/90 mmHg; smokingcessation

• If diabetic, tailor HbA1c goalbased on Pt (avoid TZDs if HF)

• Exercise (30–60 min 5–7 ×/wk);cardiac rehab; BMI goal 18.5–24.9 kg/m2

• Influenza vaccination (Circ2006;114:1549); screen fordepression

PA CATHETER AND TAILOREDTHERAPY

Rationale• Cardiac output (CO) = SV × HR;

SV depends on LV end-diastolicvolume (LVEDV)∴ manipulate LVEDV tooptimize CO while minimizingpulmonary edema

• Balloon at tip of catheter inflated→ floats into “wedge”position. Column of bloodextends from tip of catheter,through pulmonary circulation,to a point just proximal to LA.Under conditions of no flow,

PCWP LA pressure LVEDP,which is proportional toLVEDV.

• Situations in which these basicassumptions fail:(1) Catheter tip not in West

lung zone 3 (and ∴ PCWP= alveolar pressure ≠ LApressure); clues include lackof a & v waves and if PAdiastolic pressure < PCWP

(2) PCWP > LA pressure (eg,mediastinal fibrosis,pulmonary VOD, PVstenosis)

(3) Mean LA pressure >LVEDP (eg, MR, MS)

(4) Δ LVEDP-LVEDVrelationship (ie, abnlcompliance, ∴ “nl” LVEDPmay not be optimal)

Indications ( JACC 1998;32:840& Circ 2009;119:e391)• Diagnosis and evaluation

Ddx of shock (cardiogenic vs.distributive; esp. if trial ofIVF failed or is high risk)and of pulmonary edema(cardiogenic vs. not; esp. iftrial of diuretic failed or ishigh risk)

Evaluation of CO, intracardiacshunt, pulmonary HTN, MR,

tamponadeEvaluation of unexplained

dyspnea (PAC duringprovocation w/ exercise,vasodilator)

• Therapeutics (Circ2006;113:1020)Tailored therapy to optimize

PCWP, SV, SvO2 in heartfailure (incl end-stage) orshock

Guide to vasodilator therapy(eg, inhaled NO, nifedipine)in pulm HTN, RV infarction

Guide to perioperativemanagement in some high-

risk Pts, pretransplantation• Contraindications

Absolute: right-sidedendocarditis, thrombus/massor mechanical valve; PE

Relative: coagulopathy(reverse), recent PPM or ICD(place under fluoroscopy),LBBB (~5% risk of RBBB →CHB, place under fluoro),bioprosthetic R-sided valve

Efficacy concerns (NEJM2006;354:2213; JAMA2005;294:1664)• No benefit to routine PAC use in

high-risk surgery, sepsis, ARDS

• No benefit in decompensated HF( JAMA 2005;294:1625);untested in cardiogenic shock

• But: ~½ of CO & PCWP clinicalestimates incorrect; CVP &PCWP not well correl.; ∴ usePAC to (a) answerhemodynamic ? and thenremove, or (b) managecardiogenic shock

Placement• Insertion site: R internal

jugular or L subclavian veinsfor “anatomic” flotation intoPA

• Inflate balloon (max 1.5 mL)

when advancing and tomeasure PCWP

• Use resistance to inflation andpressure tracing to avoidoverinflation & risk of PArupture

• Deflate the balloon whenwithdrawing and at all othertimes

• CXR should be obtained afterplacement to assess forcatheter position and PTX

• If catheter cannot be successfullyfloated (typically if severe TRor RV dilatation) or if anotherrelative contraindicationexists, consider fluoroscopic

guidance

Complications• Central venous access:

pneumo/hemothorax (~1%),arterial puncture (ifinadvertent cannulation w/dilation → surgical/endovasceval), air embolism, thoracicduct injury

• Advancement: atrial orventricular arrhythmias (3%VT; 20% NSVT and >50%PVC), RBBB (5%), catheterknotting, cardiacperforation/tamponade, PArupture

• Maintenance: infection (esp. ifcatheter >3 d old), thrombus,pulm infarction (≤1%),valve/chordae damage, PArupture/pseudoaneurysm (esp.w/ PHT), balloon rupture

Intracardiac pressures• Transmural pressure ( preload)

= measured intracardiacpressure – intrathoracicpressure

• Intrathoracic pressure (usuallyslightly ) is transmitted tovessels and heart

• Always measure intracardiacpressure at end-expiration,

when intrathoracic pressureclosest to 0 (“high point” inspont. breathing Pts; “lowpoint” in Pts on pressurevent.)

• If ↑ intrathoracic pressure (eg,PEEP), measured PCWPoverestimates true transmuralpressures. Can approx bysubtracting ~½ PEEP (× ¾ toconvert cm H2O to mmHg).

• PCWP: LV preload best estimatedat a wave; risk of pulmonaryedema from avg PCWP

Cardiac output• Thermodilution: saline injected

in RA. Δ in temp over timemeasured at thermistor (in PA)is integrated and is 1/CO.Inaccurate if ↓ CO, sev TR orshunt.

• Fick method: O2 consumption (O2) (L/min) = CO (L/min) ×∆ arteriovenous O2 content∴ CO = O2 / C(a-v)O2

O2 ideally measured (esp. if ↑metab demands), but freqestimated (125 mL/min/m2)

C(a-v)O2 = [10×1.36 mLO2/g of Hb × Hb g/dL ×(SaO2–SvO2)]. SvO2 is key

variable that Δs.If SVO2 >80%, consider if the

PAC is “wedged” (ie, pulmvein sat), L→R shunt,impaired O2 utilization(severe sepsis, cyanide,carbon monoxide), ↑↑ FiO2.

Tailored therapy in cardiogenicshock (Circ 2009;119:e391)• Goals: optimize both MAP and

CO while ↓ risk of pulmonaryedemaMAP = CO × SVR; CO = HR

× SV (which depends onpreload, afterload andcontractility)

pulmonary edema when PCWP

>20–25 (↑ levels may betolerated in chronic HF)

• Optimize preload = LVEDV LVEDP LAP PCWP (NEJM1973;289:1263)goal PCWP ~14–18 in acute

MI, ≤14 in acutedecompensated HF

optimize in individual Pt bymeasuring SV w/ differentPCWP to create Starlingcurve

↑ by giving NS (albumin w/oclinical benefit over NS;PRBC if significant anemia)

↓ by diuresis (qv),ultrafiltration or dialysis if

refractory to diuretics• Optimize afterload wall stress

during LV ejection = [(~SBP× radius) / (2 × wall thick.)]and ∴ ∝ MAP and ∝ SVR =(MAP – CVP / CO); goals:MAP >60, SVR 800–1200MAP >60 & SVR ↑:

vasodilators (eg,nitroprusside, NTG, ACEI,hydral.) or wean pressors

MAP <60 & SVR ↑ (& ∴ CO↓): temporize w/ pressorsuntil can ↑ CO (see below)

MAP <60 & SVR low/nl (& ∴inappropriate vasoplegia):vasopressors (eg,

norepineph-rine [a, b],dopamine [D, a, b],phenylephrine [a] orvasopressin [V1] ifrefractory)

• Optimize contractility ∝ COfor given preload & afterload;goal CI = (CO / BSA) >2.2if too low despite optimal

preload & vasodilators (asMAP permits): inotropes: eg, dobutamine(mod inotrope & mildvasodilator) or milrinone(strong inotrope &vasodilator, incl pulm), both

proarrhythmic, or epi(strong inotrope & pressor)

mechanical support devices: eg,IABP, percutaneous orsurgical VAD (left-sided,right-sided or both) or ECMO(Circ 2011;123:533)

HEART FAILURE

Definitions (Braunwald’s HeartDisease, 9th ed., 2012)• Failure of heart to pump blood

forward at sufficient rate tomeet metabolic demands ofperipheral tissues, or ability todo so only at abnormally highcardiac filling pressures

• Low output (↓ cardiac output) vs.high output (↑ stroke volume± ↑ cardiac output)

• Left-sided (pulmonary edema) vs.right-sided (↑ JVP,hepatomegaly, peripheraledema)

• Backward (↑ filling pressures,congestion) vs. forward(impaired systemic perfusion)

• Systolic (inability to expelsufficient blood) vs. diastolic(failure to relax and fillnormally)

• Reduced (HFrEF) vs. preserved(HFpEF) left ventricularejection fraction

• Some degree of systolic anddiastolic dysfxn, may occurregardless of ejection fraction

Figure 1-3 Approach to left-sided heart failure

History• Low output: fatigue, weakness,

exercise intolerance, Δ MS,anorexia

• Congestive: left-sided →dyspnea, orthopnea,

paroxysmal nocturnal dyspnearight-sided → peripheraledema, RUQ discomfort,bloating, satiety

Functional classification (NewYork Heart Association class)• Class I: no sx w/ ordinary

activity; class II: sx w/ordinary activity; class III: sxw/ minimal activity; class IV:sx at rest

Physical exam (“2-minute”hemodynamic profile; JAMA1996;275:630 & 2002;287:628)• Congestion (“dry” vs. “wet”)

↑ JVP (~80% of the time JVP

>10 → PCWP >22; J HeartLung Trans 1999;18:1126) hepatojugular reflux: >4 cm↑ in JVP for ≥15 sec w/abdominal pressure Se/Sp73/87% for RA >8 andSe/Sp 55/83% for PCWP>15 (AJC 1990;66:1002)

Abnl Valsalva response: squarewave (↑ SBP w/ strain), noovershoot (no ↑ BP afterstrain)

S3 (in Pts w/ HF → ~40% ↑risk of HF hosp. or pumpfailure death; NEJM2001;345:574)

rales, dullness at base 2°pleural effus. (often absent inchronic HF due to lymphaticcompensation) ±hepatomegaly, ascites andjaundice, peripheral edema

• Perfusion (“warm” vs. “cold”)narrow pulse pressure (<25%

of SBP) → CI <2.2 (91% Se,83% Sp; JAMA1989;261:884)

soft S1 (↓ dP/dt), pulsusalternans, cool & paleextremities, ↓ UOP, muscleatrophy

• ± Other: Cheyne-Stokes resp.,

abnl PMI (diffuse, sustained orlifting depending on cause ofHF), S4 (diast. dysfxn),murmur (valvular dis., ↑ MVannulus, displaced papillarymuscles)

Evaluation for the presence ofheart failure• CXR (see Radiology insert): pulm

edema, pleural effusions ±cardiomegaly, cephalization,Kerley B-lines

• BNP/NT-proBNP can help excludeHF; levels ↑ w/ age, ↓ w/obesity, ↓ renal fxn, AF

• Evidence of ↓ organ perfusion: ↑

Cr, ↓ Na, abnl LFTs• Echo (see inserts): ↓ EF & ↑

chamber size → systolicdysfxn; hypertrophy, abnl MVinflow, abnl tissue Doppler →? diastolic dysfxn; abnl valvesor pericardium; estimate RVSP

• PA catheterization: ↑ PCWP, ↓CO and ↑ SVR (in low-outputfailure)

Evaluation of the causes of heartfailure• ECG: evidence for CAD, LVH,

LAE, heart block or lowvoltage (? infiltrativeCMP/DCMP)

• Coronary angio (or noninvasiveimaging, eg, CT angio); if noCAD, w/u for CMP

Precipitants of acute heartfailure• Dietary indiscretion or

medical nonadherence(~40% of cases)

• Myocardial ischemia orinfarction (~10–15% ofcases); myocarditis

• Renal failure (acute,progression of CKD, orinsufficient dialysis) → ↑preload

• Hypertensive crisis (incl. from

RAS), worsening AS → ↑ left-sided afterload

• Drugs (bB, CCB, NSAIDs, TZDs),chemo (anthracyclines,trastuzumab), or toxins(EtOH)

• Arrhythmias; acute valvulardysfxn (eg, endocarditis), esp.mitral or aortic regurgitation

• COPD or PE → ↑ right-sidedafterload; anemia, systemicinfection, thyroid disease

Treatment of acutedecompensated heart failure• Assess degree of congestion &

adequacy of perfusion

• For congestion: “LMNOP”Lasix IV w/ monitoring of

UOP; total daily dose 2.5×usual daily PO dose → ↑UOP, but transient ↑ in renaldysfxn vs. 1× usual dose; �clear diff between cont gttvs. q12h dosing (NEJM2011;364:797)

Morphine (↓ sx, venodilator, ↓afterload)

Nitrates (venodilator)Oxygen ± noninvasive vent (↓

sx, ↑ PaO2; no ∆ mortality;see “MechanicalVentilation”)

Position (sitting up & legsdangling over side of bed →↓ preload)

• For low perfusion, see below• Adjustment of oral meds

ACEI/ARB: hold if HoTN,consider Δ to hydralazine &nitrates if renal

decompensationβB: reduce dose by at least ½

if mod HF, d/c if severe HFand/or need inotropes

Treatment of advanced heartfailure (Circ 2009;119:e391)• Consider PAC if not resp to Rx,

unsure re: vol status, HoTN, ↑Cr, need inotropes

• Tailored Rx w/ PAC (qv); goalsof MAP >60, CI >2.2 (MVO2

>60%), SVR <800, PCWP<18

• IV vasodilators: NTG,nitroprusside (risk of coronarysteal if CAD; prolonged use →

cyanide/thiocyanate toxicity);nesiritide (rBNP) not rec forroutine use (NEJM2011;365:32)

• Inotropes (properties in additionto ↑ inotropy listed below)dobutamine: vasodilation at

doses ≤5 µg/kg/min; mild ↓PVR; desensitization overtime

dopamine: splanchnic vasodil.→ ↑ GFR & natriuresis;vasoconstrictor at ≥5µg/kg/min

milrinone: prominent systemic& pulmonary vasodilation; ↓dose by 50% in renal failure

• Ultrafiltration: similar wt lossto aggressive diuresis, but ↑renal failure (NEJM2012:367:2296)

• Mechanical circulatorysupport (Circ 2011;123:533)Intra-aortic balloon pump

(IABP): inflates in diastole &deflates in systole to ↓impedance to LV ejection ofblood, ↓ myocardial O2

demand & ↑ coronaryperfusion

ventricular assist device (LVAD± RVAD): as bridge torecovery (NEJM2006;355:1873) or

transplant (some temporarytypes can be placedpercutaneously = PVAD), oras destination therapy (45–50% ↓ mort. vs. med Rx;NEJM 2009;361:2241)

• Cardiac transplantation: 15–20%mort. in 1st y, median survival10 y

• Utility of BNP-guided Rx remainsdebated (Circ 2013;301:500 &509)

• Implantable PA pressure sensorin NYHA III → ~30% ↓ risk ofhosp (Lancet 2011;377:658)

Heart failure with preserved EF(HFpEF; “Diastolic HF”) (Circ2011;124:e540)• Epidemiology: ~½ of Pts w/ HF

have normal or only min.impaired systolic fxn (EF≥40%); risk factors for HFpEFincl ↑ age, , DM, AF.Mortality to those w/systolic dysfxn.

• Etiologies (impaired relaxationand/or ↑ passive stiffness):ischemia, prior MI, LVH,HCMP, infiltrative CMP,RCMP, aging, hypothyroidism

• Precipitants of pulmonaryedema: volume overload (poorcompliance of LV → sensitiveto even modest ↑ in volume);ischemia (↓ relaxation);tachycardia (↓ filling time indiastole), AF (loss of atrialboost to LV filling); HTN (↓afterload → ↓ stroke volume)

• Dx w/ clinical s/s of HF w/preserved systolic fxn. Dxsupported by evidence of diastdysfxn:(1) echo: abnl MV inflow (E/A

reversal and Δs in E wavedeceleration time) & ↓myocardial relax. (↑ isovol

relax. time & ↓ early diastoletissue Doppler vel)

(2) exercise-induced ↑ PCWP(± ↓ response chronotropic& vasodilator reserve)

• Treatment: diuresis for voloverload, BP control,prevention of tachycardia andischemia;no benefit to: ACEI/ARB

(NEJM 2008;359:2456),PDE5 inhib ( JAMA2013;309:1268)

spironolactone improves LVfxn, but not sx ( JAMA2013;309:781)

combined ARB/neprilysin

(neutral endopeptidase)inhib under study (Lancet2012;380:1387)

CARDIOMYOPATHIES

Diseases with mechanical and/orelectrical dysfunction of the

myocardium

DILATED CARDIOMYOPATHY(DCMP)

Definition and epidemiology(Circ 2006;113:1807)• Ventricular dilatation and ↓

contractility ± ↓ wallthickness

• Incidence: 5–8/100,000/yr;prevalence: 1/2500. Mostcommon reason for hearttransplant.

Etiologies (NEJM 2000;342:1077;Circ Res 2012;111:131)• Ischemia/infarct: systolic

dysfxn & dilation due to poorremodeling post-MI

• Valvular disease: systolic dysfxndue to chronic volumeoverload in MR & AI

• Familial (~25%): mutations incytoskeletal, nuclear andfilament proteins (NEJM1992;362:77)

• Idiopathic (~25%): ?undiagnosed infectious,alcoholic or genetic cause

• Infectious myocarditis (10–15%, autoimmune response;Lancet 2012;379:738)Viruses (parvoB19 & HHV6 >

coxsackie, adeno, echo,CMV, HCV): from subacute(dilated LV, mild–mod

dysfxn) to fulminant(nondil., thick, edematousLV, sev dysfxn)

Bacterial, fungal, rickettsial,TB, Lyme (mild myocarditis,often with AVB)

HIV: ~8% of asx HIV ; due toHIV, other virus orantiretrovirals; HIV alsoassociated w/ prematureCAD (Circ 2008;118:e36;Heart 2009;95:1193)

Chagas: apical aneurysm ±thrombus, RBBB,megaesophagus/colon(NEJM 1993;329:639)

• Toxic: alcohol (5%) typ. 7–8

drinks/d × >5 y, butvariable; cocaine; XRT (usuRCMP);anthracyclines (risk ↑ >550

mg/m2, may manifest late),cyclophosphamide,trastuzumab

• Infiltrative (5%): often mix ofDCMP + RCMP (qv) withthickened wallamyloidosis, sarcoidosis,

hemochromatosis, tumor• Autoimmune: collagen vasc. dis.

(3%): PM, SLE, scleroderma,PAN, RA, Wegener’s;peripartum (last month → 5 mo

postpartum; JACC

2011;58:659): ~1:3000 preg.↑ risk w/ multiparity, ↑ age,Afr Am; stnd HF Rx except ifpreg then select drugs basedon safety; ? bromocriptine to↓ prolactin; ~½ normalizeEF; even if nl EF ~30%recur w/ next preg

Idiopathic giant cellmyocarditis (GCM): avg age42 y, fulminant, VT (NEJM1997;336:1860)

Eosinophilic (variableperipheral eos):hypersensitivity (mild HF) oracute necrotizingeosinophilic myocarditis

(ANEM; STE, effusion,severe HF)

• Stress-induced (Takotsubo =apical ballooning): mimics MI(pain, ± STE & ↑ Tn; deepTWI & ↑ QT); mid/apexdyskinesis; ? Rx w/ bB, ACEI;usu. improves over wks (JAMA2011;306:277)

• Tachycardia: likelihood ∝rate/duration; often resolvesw/ rate cntl (Circ2005;112:1092)

• Arrhythmogenic rightventricular cardiomyopathy(ARVC): fibrofattyreplacement of RV → dilation

(dx w/ MRI); ECG: ± RBBB,TWI V1–V3, e wave; risk VT(Lancet 2009;373:1289)

• Metab/other: hypothyroid.,acromegaly, pheo, OSA,thiamine, selenium orcarnitine defic

Clinical manifestations• Heart failure: both congestive &

poor forward flow sx; signs ofL- & R-sided HFdiffuse, laterally displaced

PMI, S3, ± MR or TR(annular dilat., displacedpap. muscle)

• Embolic events (~10%),

supraventricular/ventriculararrhythmias, & palpitations

• Chest pain can be seen w/ someetiologies (eg, myocarditis)

Diagnostic studies and workup• CXR: moderate to marked

cardiomegaly, ± pulmonaryedema & pleural effusions

• ECG: may see PRWP, Q waves orBBB; low-voltage; AF (20%);may be normal

• Echocardiogram: LV dilatation, ↓EF, regional or global LV HK ±RV HK, ± mural thrombi

• Cardiac MRI: up to 76% Se, 96%Sp for myocarditis or

infiltrative dis. ( JACC2005;45:1815); extent ofmidwall fibrosis correlated w/mortality in NICMP ( JAMA2013;309:896)

• Laboratory evaluation: TFTs,iron studies, HIV, SPEP, ANA;others per clinical suspicion;viral serologies notrecommended ( JACC2012;59:779)

• Family hx (20–35% w/ familialdis.), genetic counseling ±genetic testing ( JAMA2009;302:2471)

• Stress test: useful to r/o ischemia(low false rate), high false

rate, even w/ imaging• Coronary angiography to r/o

CAD if risk factors, h/oangina, Qw MI on ECG,equivocal ETT; consider CTangiography (JACC2007;49:2044)

• ? Endomyocardial biopsy (JACC2007;50:1914): yield 10% (ofthese, 75% myocarditis, 25%systemic disease); 40% false rate (patchy dis.) & false (necrosis → inflammation)noproven Rx for myocarditis; ∴biopsy if: acute & hemodyncompromise (r/o GCM,ANEM); arrhythmia or RCMP

features (r/o infiltrative); orsuspect toxic, allergic, tumor

Treatment (see “Heart Failure”for standard HF Rx)• Implantation of devices may be

tempered by possibility ofreversibility of CMP

• Immunosuppression: for giantcell myocarditis (prednisone +AZA), collagen vasculardisease, peripartum (? IVIg), &eosinophilic; no proven benefitfor viral myocarditis

• Prognosis differs by etiology(NEJM 2000;342:1077):postpartum (best),

ischemic/GCM (worst)

HYPERTROPHICCARDIOMYOPATHY (HCMP)

Definition and epidemiology• LV (usually ≥15 mm) and/or RV

hypertrophy disproportionateto hemodynamic load

• Prevalence: 1/500; 50% sporadic,50% familial, mostasymptomatic

• Ddx: LVH 2° to HTN, AS, eliteathletes (wall usually <13 mm& symmetric and nl/↑ rates oftissue Doppler diastolicrelaxation; Circ2011;123:2723), Fabry dis. (↑Cr, skin findings)

Pathology• Autosomal dominant mutations

in cardiac sarcomere genes(eg, b-myosin heavy chain)

• Myocardial fiber disarray withhypertrophy, which createsarrhythmogenic substrate

• Morphologic hypertrophyvariants: asymmetric septal;concentric; midcavity; apical

Pathophysiology• Subaortic outflow obstruction:

narrowed tract 2°hypertrophied septum +systolic anterior motion (SAM)of ant. MV leaflet (may be

fixed, variable or nonexistent)and papillary muscledisplacement. Gradient (∇)worse w/ ↑ contractility(digoxin, b- agonists, exercise,PVCs), ↓ preload or ↓afterload.

• Mitral regurgitation: due to SAM(mid-to-late, post.-directedregurg. jet) and/or abnlmitral leaflets and papillary

muscles (pansystolic, ant.-directed regurg. jet)

• Diastolic dysfunction: ↑ chamberstiffness + impairedrelaxation

• Ischemia: small vessel dis.,

perforating artery compression(bridging), ↓ coronaryperfusion

• Syncope: Δs in load-dependentCO, arrhythmias

Clinical manifestations (70% areasymptomatic at dx)• Dyspnea (90%): due to ↑ LVEDP,

MR, and diastolic dysfunction• Angina (25%) even w/o

epicardial CAD; microvasc.dysfxn (NEJM 2003;349:1027)

• Arrhythmias (AF in 20–25%;VT/VF) → palpitations,syncope, sudden cardiac death

Physical exam

• Sustained PMI, S2 paradoxicallysplit if severe outflowobstruction, S4 (occ.palpable)

• Systolic murmur: crescendo-decrescendo; LLSB; ↑ w/Valsalva & standing (↓preload)

• ± mid-to-late or holosystolicmurmur of MR at apex

• Bifid carotid pulse (brisk rise,decline, then 2nd rise); JVP w/prominent a wave

• Contrast to AS, which hasmurmur that ↓ w/ Valsalvaand ↓ carotid pulses

Diagnostic studies• CXR: cardiomegaly (LV and LA)• ECG: LVH, anterolateral and

inferior pseudo-Qw, ± apicalgiant TWI (apical variant)

• Echo: no absolute cutoffs fordegree of LVH butseptum/post. wall ≥1.3suggestive,as is septum >15 mm; other

findings include dynamicoutflow obstruction, SAM,MR

• MRI: hypertrophy + patchydelayed enhancement (usefulfor dx & prog) ( JACC CV Imag2012;2:370)

• Cardiac cath: subaortic pressure∇; Brockenbrough sign = ↓pulse pressure post-PVC (incontrast to AS, in which pulsepressure ↑ post-PVC)

• ? Genotyping for familyscreening, but pathogenicmutation ID’d in <½ (Circ2011;124:2761)

Treatment (Circ 2011;124:e783 &2012;125:1432; Lancet2013;381:242)• Heart failure

inotropes/chronotropes: b-blockers, CCB (verapamil),disopyramide

Careful use of diuretics, as mayfurther ↓ preload.Vasodilators only if systolicdysfxn. Avoid digoxin.

If sx refractory to drug Rx +obstructive physiology (∇>50 mmHg):

(a) Surgical myectomy: long-term ↓ symptoms in 90%(Circ 2005;112:482)

(b) Alcohol septal ablation(Circ CV Interv 2011;4;256;JACC 2011;58:2322):gradient ↓ by ~80%, only 5–20% remain w/ NYHA III–IVsx; 14% require repeatablation or myectomy. Good

alternative for older Pts,multiple comorbidities.Complic: transient (& occ.delayed) 3° AVB w/ 10–20%req. PPM; VT due to scarformation.

No clear benefit of dual-chamber pacing ( JACC1997;29:435; Circ1999;99:2927)

If refractory to drug therapyand there is nonobstructivepathophysiology: transplant

• Acute HF: can be precip. bydehydration or tachycardia; Rxw/ fluids, bB, phenylephrine

• AF: rate control with bB,

maintain SR withdisopyramide, amiodarone

• SCD: ICD ( JACC 2003;42:1687).Risk factors: h/o VT/VF, FHxSCD, unexplained syncope,NSVT, ↓ SBP or rel HoTN (↑SBP <20 mmHg) w/ exercise,LV wall ≥30 mm, extensiveMRI delayed enhancement.EPS not useful. Risk 4%/y ifhigh-risk (JAMA2007;298:405).

• Counsel to avoid dehydration,extreme exertion

• Endocarditis prophylaxis notrecommended (Circ2007;16:1736)

• First-degree relatives: periodicscreening w/ echo, ECG (astiming of HCMP onsetvariable). Genetic testing ifknown mutation.

RESTRICTIVE CARDIOMYOPATHY(RCMP)

Definition (Circ 2006;113:1807)• Impaired ventricular filling with

↓ complicance innonhypertrophied, nondilatedventricles; normal or ↓diastolic volumes, normal ornear-normal EF; must r/opericardial disease

Etiology ( JACC 2010;55:1769)• Myocardial processes

Autoimmune (scleroderma,polymyositis-dermatomyositis)

Infiltrative diseases (see

primary entries forextracardiac manifestations,Dx, Rx)Amyloidosis (CIrc

2011;124:1079): age atpresentation ~60 y; := 3:2 AL (MM, light-chain, MGUS, WM);familial (transthyretin,TTR); AA/senile (TTR,ANP) ECG: ↓ QRSamplitude (50%),pseudoinfarction pattern(Qw), AVB (10–20%), hemiblock (20%), BBB (5–20%)Echo: biventricular wall

thickening (yet w/ lowvoltage on ECG),granular sparklingtexture (30%), biatrialenlargement (40%),thickened atrial septum,valve thickening (65%),diastolic dysfxn, smalleffusions

Normal voltage & normalseptal thickness has NPV~90%

MRI: distinct lategadoliniumenhancement pattern( JACC 2008;51:1022)

Sarcoidosis: age at present.

~30 y; more common inblacks, N. Europeans,women5% of those w/ sarcoid

have overt cardiacinvolvement; cardiacw/o systemic in 10%

ECG: AVB (75%), RBBB(20–60%), VT; PET: ↑FDG uptake in affectedarea

Echo: regional WMA(particularly basalseptum) with thinningor mild hypertrophy

Nuclear imaging: galliumuptake in areas of

sestaMIBI perfusiondefects; cardiac MR

Hemochromatosis: inmiddle-aged men (esp. N.European); 15% p/wcardiac sx

Storage diseases: Gaucher’s,Fabry, Hurler’s, glycogenstorage diseases

Diabetes mellitus• Endomyocardial processes

Chronic eosinophilic: Löffler’sendocarditis (temperateclimates; ↑ eos; muralthrombi that embolize);endomyocardial fibrosis(tropical climates; var. eos;

mural thrombi)Toxins: radiation (also p/w

constrictive pericarditis,valvular dis, ostial CAD),anthracyclines

Serotonin: carcinoid, serotoninagonists, ergot alkaloids

Metastatic cancer

Pathology & pathophysiology• Path: normal or ↑ wall thickness

± infiltration or abnormaldeposition

• ↓ myocardial compliance → nlEDV but ↑ EDP → ↑ systemic &pulm. venous pressures

• ↓ ventricular cavity size → ↓ SV

and ↓ CO

Clinical manifestations (Circ2000;101:2490)• Right-sided > left-sided heart

failure with peripheral edema> pulmonary edema

• Diuretic “refractoriness”• Thromboembolic events• Poorly tolerated

tachyarrhythmias; VT →syncope/sudden cardiac death

Physical exam• ↑ JVP, ± Kussmaul’s sign ( JVP ↑

w/ inspiration, classically seenin constrictive pericarditis)

• Cardiac: ± S3 and S4, ±

murmurs of MR and TR• Congestive hepatomegaly, ±

ascites and jaundice,peripheral edema

Diagnostic studies• CXR: normal ventricular chamber

size, enlarged atria, ±pulmonary congestion

• ECG: low voltage,pseudoinfarction pattern(Qw), ± arrhythmias

• Echo: symmetric wall thickening,biatrial enlarge., ± muralthrombi, ± cavity oblit. w/diast dysfxn: ↑ early diast (E)and ↓ late atrial (A) filling, ↑

E/A ratio, ↓ decel. time• Cardiac MRI/PET: may reveal

inflammation or evidence ofinfiltration (but nonspecific)

• Cardiac catheterizationAtria: M’s or W’s (prominent x

and y descents)Ventricles: dip & plateau

(rapid ↓ pressure at onset ofdiastole, rapid ↑ to earlyplateau)

Concordance of LV and RVpressure peaks duringrespiratory cycle (vs.discordance in constrictivepericarditis; Circ1996;93:2007)

• Endomyocardial biopsy if suspectinfiltrative process

• Restrictive cardiomyopathy vs.constrictive pericarditis: see“Pericardial Disease”

Treatment (in addition to Rx’ingunderlying disease)• Gentle diuresis. May not tolerate

CCB or other vasodilators.• Control HR (but can ↓ CO);

maintain SR (helps filling).Digoxin ↑ arrhythmias inamyloid.

• Anticoagulation (particularlywith AF or low CO)

• Transplantation for refractory

VALVULAR HEART DISEASE

AORTIC STENOSIS (AS)

Etiology• Calcific: predominant cause in

Pts >70 y; risk factors includeHTN, ↑ chol., ESRD

• Congenital (ie, bicuspid AoV w/premature calcification): causein 50% of Pts <70 y

• Rheumatic heart disease (ASusually accompanied by AI andMV disease)

• AS mimickers: subvalvular(HCMP, subAo membrane) orsupravalvular stenosis

Clinical manifestations (usuallyindicates AVA <1 cm2 orconcomitant CAD)• Angina: ↑ O2 demand

(hypertrophy) + ↓ O2 supply(↓ cor perfusion pressure) ±CAD

• Syncope (exertional): peripheralvasodil. w/ fixed CO → ↓ MAP→ ↓ cerebral perfusion

• Heart failure: outflow obstruct+ diastolic dysfxn → pulm.edema; esp. if ↑ HR/AF (↓ LVfill.)

• Acquired vWF disease (~20% ofsev. AS): destruction of vWF;

GI angiodysplasia• Natural hx: usually slowly

progressive (AVA ↓ ~0.1cm2/y, but varies; Circ1997;95:2262), until sxdevelop; mean survival basedon sx: angina = 5 y; syncope= 3 y; CHF = 2 y

Physical exam• Midsystolic crescendo-

decrescendo murmur atRUSB, harsh, high-pitched,radiates to carotids, apex(holo-systolic = Gallavardineffect), ↑ w/ passive leg raise,↓ w/ standing & Valsalva. In

contrast, dynamic outflowobstruction (HCMP) ↓ w/ legraise, ↑ w/ standing, Valsalva.

• Ejection click after S1 sometimesheard with bicuspid AoV

• Signs of severity: late-peakingmurmur, paradoxically split S2

or inaudible A2, small anddelayed carotid pulse (“pulsusparvus et tardus”), LV heave, S4 (occasionally palpable)

Diagnostic studies• ECG: may see LVH, LAE, LBBB,

AF (in late disease)

• CXR: cardiomegaly, AoVcalcification, poststenoticdilation of ascending Ao,pulmonary congestion

• Echo: valve morphology, estimpressure gradient & calculateAVA, EF

• Cardiac cath: usually to r/o CAD(in ~½ of calcific AS); forhemodyn. if disparity betweenexam & echo: ✓ pressuregradient (∇) across AoV, calcAVA (underestim. if mod/sevAI)

• Dobutamine challenge duringecho or cath if low EF and ∇<30 to differentiate: afterload

mismatch: 20% ↑ SV & ∇, no ΔAVA (implies contractilereserve & ↑ EF post-AVR)pseudostenosis: 20% ↑ SV, no Δ

in ∇, ↑ AVA (implies lowAVA artifact of LV dysfxn)

limited contractile reserve: no ΔSV, ∇ or AVA (implies EFprob. will not improve w/AVR)

Treatment (Circ 2008;118:e523;Lancet 2009;373:956; EHJ2012;33:2451)• Management decisions are based

on symptoms: once theydevelop AVR is needed.If asx, HTN can be cautiously

Rx’d; statins have not beenproven to ↓ progression.

• AVR: indicated in sx AS (almostinvariably severe; if not, lookfor another cause of sx) & asxsevere AS + EF < 50%. Mayconsider if asx but either sxor ↓ BP w/ exercise (cancarefully exercise asx AS touncover sx, do not exercise sx

AS) or extremely severe (AVA<0.6 cm2, mean ∇ >60mmHg, aortic jet >5 m/s).Reasonable if asx mod-severeAS and undergoing CV surgery.

• Medical (if not AVR candidate orto temporize): careful diuresisprn, control HTN, maintainSR; digoxin if ↓ EF & HF or ifAF; avoid venodilators(nitrates) & inotropes(bB/CCB) if severe; avoidvigorous physical exertiononce AS mod–severe;? nitroprusside if p/w CHF w/

sev. AS, EF <35%, CI <2.2,& nl BP (NEJM

2003;348:1756)• IABP: stabilization, bridge to

surgery• Balloon AoV valvotomy (BAV):

50% ↑ AVA & ↓ peak ∇, but50% restenosis by 6–12 mo &↑ risk of peri-PAV stroke/AI

(NEJM 1988;319:125), ∴bridge to AVR or palliation

• Transcatheter AoVreplacement (TAVR): sx,hemodyn, & mortality tosurgical AVR, but ↑ (mostlyearly) risk of vasc complic andstroke/ TIA; paravalvularleaks in ~7% (NEJM2012;366:1686); in

nonoperative Pts, 44% ↓mortality vs. standard Rx(NEJM 2012;366:1696)

AORTIC INSUFFICIENCY (AI)

Etiology (Circ 2006;114:422)• Valve disease (43%)

rheumatic heart disease(usually mixed AS/AI andconcomitant MV disease)bicuspid AoV: natural hx:1⁄3→ normal, 1⁄3 → AS, 1⁄6 →AI, 1⁄6 → endocarditis → AIinfective endocarditisvalvulitis: RA, SLE; anorectics

(fen/phen) & otherserotoninergics (NEJM2007;356:29,39), XRT

• Root disease (57%)HTN

aortic aneurysm or dissection,annuloaortic ectasia, Marfansyndrome

aortic inflammation: giant cell,Takayasu’s, ankylosingspond., reactive arthritis,syphilis

Clinical manifestations• Acute: sudden ↓ forward SV and ↑

LVEDP (noncompliantventricle) → pulmonary edema± hypotension andcardiogenic shock

• Chronic: clinically silent while LVdilates (to ↑ compliance tokeep LVEDP low) more than it

hypertrophies → chronicvolume overload → LVdecompensation → CHF

• Natural hx: variable progression(unlike AS, can be fast orslow); once decompensationbegins, prognosis poor w/oAVR (mortality ~10%/y)

Physical exam• Early diastolic decrescendo

murmur at LUSB (RUSB ifdilated Ao root); ↑ w/ sittingforward, expir, handgrip;severity of AI ∝ duration ofmurmur (except inacute and severe late); Austin

Flint murmur: mid-to-latediastolic

rumble at apex (AI jetinterfering w/ mitral inflow)

• Wide pulse pressure due to ↑stroke volume, hyper- dynamicpulse → many of classic signs(see table); pulse pressurenarrows in late AI with ↓ LVfxn; bisferiens (twice-beating)arterial pulse

• PMI diffuse and laterallydisplaced; soft S1 (early closureof MV); ± S3 (≠ ↓ EF butrather just volume overload inAI)

Diagnostic studies• ECG: can see LVH, LAD, abnl

repol; CXR: cardiomegaly ±ascending Ao dilatation

• Echo: severity of AI (severe =width of regurgitant jet >65%LVOT, vena contracta >0.6cm, regurg fraction ≥50%,regurg orifice ≥0.3 cm2, flowreversal in descending Ao); LV

size & fxn

Treatment (Circ 2008;118:e523;EHJ 2012;33:2451)• Acute decompensation (consider

ischemia and endocarditis aspossible precipitants):surgery usually urgently

needed for acute severe AIwhich is poorly tolerated byLV

IV afterload reduction(nitroprusside) and inotropicsupport (dobutamine)

± chronotropic support (↑ HR→ ↓ diastole → ↓ time forregurgitation)

pure vasoconstrictors and IABPcontraindicated

• In chronic AI, managementdecisions based on LV size andfxn (and before sx occur)

• Surgery (AVR, replacement orrepair if possible)sx (if equivocal, consider stress

test) severe AI (if notsevere, unlikely to be causeof sx)

asx severe AI and EF ≤ 50%or LV dilation (end syst.diam. >50–55 mm or enddiast. diam. >70–75 mm,esp. if progression) orundergoing cardiac surgery

• Transcatheter AoV replacement(TAVR) being explored ( JACC2013;61:1577)

• Medical therapy: vasodilators(nifedipine, ACEI/ARB,hydralazine) if severe AI w/ sxor LV dysfxn & Pt notoperative candidate or toimprove hemodynamics beforeAVR; no clear benefit onclinical outcomes or LV fxnwhen used to try to prolongcompensation in asx severe AIw/ mild LV dilation & nl LVfxn (NEJM 2005;353:1342)

MITRAL REGURGITATION (MR)

Etiology (Lancet 2009;373:1382;NEJM 2010;363:156)• Leaflet abnormalities:

myxomatous degeneration(MVP), endocarditis, calcificRHD, valvulitis (collagen-

vascular disease),congenital, anorectic drugs,XRT

• Functional: inferoapicalpapillary muscledisplacement due toischemic LV remodeling orother causes of DCMP; LVannular dilation due to LV

dilation• Ruptured chordae tendinae:

myxomatous, endocarditis,spontaneous, trauma

• Acute papillary muscle dysfxn b/cof ischemia or rupture duringMI [usu. posteromedialpapillary m. (supplied by PDAonly) vs. anterolateral (suppl.by diags & OMs)]

• HCMP: (see “Cardiomyopathy”)

Clinical manifestations• Acute: pulmonary edema,

hypotension, cardiogenic shock(NEJM 2004;351:1627)

• Chronic: typically asx for yrs,

then as LV fails → progressiveDOE, fatigue, AF, PHT

• Prognosis: 5-y survival w/medical therapy is 80% if asx,but only 45% if sx

Physical exam• High-pitched, blowing,

holosystolic murmur atapex; radiates to axilla; ±thrill; ↑ w/ handgrip (Se 68%,Sp 92%),↓ w/ Valsalva (Se 93%) (NEJM

1988;318:1572)ant. leaflet abnl → post. jet

heard at spinepost. leaflet abnl → ant. jet

heard at sternum• ± diastolic rumble b/c ↑ flow

across valve• Lat. displ. hyperdynamic PMI,

obscured S1, widely split S2 (A2

early b/c ↓ LV afterload, P2

late if PHT); ± S3

• Carotid upstroke brisk (vs.diminished and delayed in AS)

Diagnostic studies (NEJM2005;352:875)• ECG: may see LAE, LVH, ± atrial

fibrillation• CXR: dilated LA, dilated LV, ±

pulmonary congestion• Echo: MV anatomy (ie, etiol);

MR severity: jet area (canunderestimate eccentric jets),jet width at origin (venacontracta) or effectiveregurgitant orifice (ERO;predicts survival); LV fxn (EFshould be supranormal ifcompensated, ∴ EF <60% w/sev. MR = LV dysfxn); TEE ifTTE inconclusive orpre/intraop to guide repair vs.replace

• Cardiac cath: prominent PCWP

c-v waves (not spec. for MR),LVgram for MR severity & EF

Treatment (Circ 2008;118:e523;NEJM 2009;361:2261; EHJ2012;33:2451)• Acute decompensation (consider

ischemia and endocarditis asprecipitants)IV afterload reduction

(nitroprusside), ± inotropes(dobuta), IABP, avoid

vasoconstrictorssurgery usually needed for

acute severe MR asprognosis is poor w/o MVR

• Surgery (repair [preferred iffeasible] vs. replacement w/preservation of mitralapparatus)sx severe MR, asx severe MR

and EF 30–60% or LV sys.diam. >40 mm

consider MV repair for asxsevere MR w/ preserved EF,esp. if new AF or PHT

if AF, maze procedure or pulmvein isolation may → NSRand prevent future stroke

• In Pts undergoing CABG w/mod–sev fxnal MR, considerannuloplasty ring

• Percutaneous MV repair: edge-to-edge clip less effective thansurgery, but ? consider forelderly, fxnal MR or low EF(NEJM 2011;364:1395);percutaneous valve understudy

• Medical: � clinical benefit in asxPts; bB preserve LV fxn ( JACC2012;60:833); if sx but notoperative candidate ↓ preload(↓ HF and MR by ↓ MVorifice): diuretics, nitrates(esp. if ischemic/fxnal MR); if

LV dysfxn: ACEI, bB, ± BiVpacing; maintain SR

MITRAL STENOSIS (MS)

Etiology (Lancet 2012;379:953)• Rheumatic heart disease

(RHD): fusion of commissures →“fish mouth” valvefrom autoimmune rxn to b

strep infxn; seen largely indeveloping world today

• Mitral annular calcification(MAC): encroachment uponleaflets → functional MS

• Congenital, infectiousendocarditis w/ large lesion,myxoma near MV, thrombus

• Valvulitis (eg, SLE, amyloid,carcinoid) or infiltration (eg,

mucopolysaccharidoses)

Clinical manifestations (Lancet2009;374:1271)• Dyspnea and pulmonary

edema (if due to RHD, sxusually begin in 30s)precipitants: exercise, fever,

anemia, volume overload(incl. pregnancy),tachycardia, AF

• Atrial fibrillation: onset oftenprecipitates heart failure in Ptsw/ MS

• Embolic events: commonlycerebral, esp. in AF orendocarditis

• Pulmonary: hemoptysis, frequentbronchitis (due to congestion),PHT, RV failure

• Ortner’s syndrome: hoarsenessfrom LA compression ofrecurrent laryngeal nerve

Physical exam• Low-pitched mid-diastolic

rumble at apex w/ presystolicaccentuation (if not in AF);best heard in L lat decubitusposition during expiration, ↑w/ exercise; severityproportional to duration (notintensity) of murmur

• Opening snap (high-pitched

early diastolic sound at apex)from fused leaflet tips;MVA proportional to S2–OS

interval (tightervalve → ↑ LA pressure →

shorter interval)• Loud S1 (unless MV calcified)

Diagnostic studies• ECG: LAE (“P mitrale”), ± AF, ±

RVH• CXR: dilated LA (straightening

of left heart border, doubledensity on right, left mainstembronchus elevation)

• Echo: estimate pressure gradient(∇), RVSP, valve area, valveecho score (0–16, based onleaflet mobility & thick.,subvalvular thick., Ca++);exer. TTE (to assess ∆ RVSPand ∇) if sx & severity of MSat rest discrepant; TEE toassess for LA thrombus beforePMV

• Cardiac cath: ∇ fromsimultaneous PCWP & LVpressures, calculated MVA; LApressure tall a wave and

blunted y descent; ↑ PApressures

Treatment (NEJM 1994;331:961;Circ 2002;105:1465 &2008;118:e523; EHJ2012;33:2451)• Medical: Na restriction, cautious

diuresis, bB, sx-limited physicalstress

• Antibiotic Ppx recommended ifh/o RHD w/ valvular disease

for 10 y or until age 40• Anticoag if: AF, prior embolism,

LA thrombus; ? LA >55 mm orlg LA w/ spont contrast

• Mechanical intervention if: heartfailure sx w/ MVA ≤1.5, orheart failure sx w/ MVA >1.5

but ↑ PASP, PCWP, or MV ∇w/ exercise, or

asx Pts w/ MVA ≤1.5 and PHT(PASP >50 or >60 mmHgw/ exercise) or new-onsetAF

• Percutaneous mitralvalvotomy (PMV): preferredRx if RHD; MVA doubles, ∇↓by 50%; MVR if valve score

<8, ≤ mild MR, � AF or LAclot

• Surgical (MV repair if possible,o/w replacement): consider insx Pts w/ MVA ≤1.5if PMV

unavailable/contraindicated(mod. MR, LA clot), or valvemorphology unsuitable

• Pregnancy: if NYHA class III/IV→ PMV, o/w medical Rx w/low-dose diuretic & bB

MITRAL VALVE PROLAPSE (MVP)

Definition and Etiology• Billowing of MV leaflet ≥2 mm

above mitral annulus inparasternal long axis echoview

• Leaflet redundancy frommyxomatous proliferation ofspongiosa of MV apparatus

• Idiopathic, familial and a/wconnective tissue diseases (eg,Marfan’s, Ehlers-Danlos)

• Prevalence 1–2.5% of gen.population, > (NEJM1999;341:1), most commoncause of MR

Clinical manifestations (usuallyasymptomatic)• MR (from leaflet prolapse or

ruptured chordae); infectiveendocarditis; embolic events

• Arrhythmias, rarely suddencardiac death

Physical exam• High-pitched, midsystolic click ±

mid-to-late systolic murmur• ↓ LV volume (standing) → click

earlier; ↑ LV volume orafterload → click later, softer

Treatment• Endocarditis prophylaxis no

longer recommended (Circ

2007:116:1736)• Aspirin or anticoagulation if

prior neurologic event or atrialfibrillation

TRICUSPID REGURGITATION• Primary etiol: rheumatic, CTD,

radiation, IE, Ebstein’sanomaly, carcinoid, tumors

• Fxnal etiol: RV and/or pulm HTN(may be 2° to L-sided dis.), RVdilation and/or infarct

• Consider repair, annuoplasty orreplacement for sx and severeTR (eg, ERO ≥0.40 cm2)

PROSTHETIC HEART VALVES

Mechanical (60%)• Bileaflet (eg, St. Jude Medical);

tilting disk; caged-ball• Very durable (20–30 y), but

thrombogenic and ∴ requireanticoagulationconsider if age <~65 y or if

anticoagulation alreadyindicated ( JACC2010;55:2413)

Bioprosthetic (40%)• Bovine pericardial or porcine

heterograft (eg, Carpentier-Edwards), homograft

• Less durable, but min.

thrombogenic; consider if>~65 y, lifespan <20 y or �anticoag

Physical exam• Normal: crisp sounds, ± soft

murmur during forward flow(normal to have small ∇)

• Abnormal: regurgitant murmurs,absent mechanical valveclosure sounds

Anticoagulation & antiplatelettherapy (Circ 2008;118:e523;JAMA 2012;308:2118)• Assess for high-risk features: prior

thromboembolism, AF,EF<30–35%, hypercoagulable

• Warfarin: low-risk mech AVR:INR 2–3 (consider 2.5–3.5 for1st 3 mo)mech MVR or high-risk mech

AVR: INR 2.5–3.5high-risk bioprosthetic: INR 2–

3 (and consider in low-riskfor 1st 3 or even ? 6 mo)

• ASA (75–100 mg) for allprosthetic valves; avoid addingto warfarin if h/o GIB,uncontrolled HTN, erratic INRor >80 y; ASA + clopidogrel(or warfarin) × 3–6 mo afterTAVR

• If thrombosis, ↑ intensity (eg,INR 2–3 → 2.5–3.5; 2.5–3.5 →

3.5–4.5; add ASA if not on)

Correction ofoveranticoagulation (Circ2008;118:e626)• Risk from major bleeding must be

weighed against risk of valvethrombosis

• Not bleeding: withhold warfarin,give vit K 1–2.5 mg PO only ifINR 5–10, ✓ serial INRs

• Bleeding or INR >10: FFP ±low-dose (1 mg) vit K IV

Endocarditis prophylaxis: for allprosthetic valves (see“Endocarditis”)

Complications• Structural failure (r/o

endocarditis); mechanicalvalves: rare except for Bjork-Shiley; bioprosthetic valves: upto 30% fail rate w/in 10–15 y,mitral > aortic

• Paravalvular leak (r/oendocarditis); small central jetof regurg is normal in mech.valves

• Obstruction from thrombosis orpannus ingrowth: ✓ TTE, TEE

and/or fluoroscopy if ? clotsignificantly sx pannusingrowth: remove w/ surgerythrombosis: surgery if L-sided

valve & either severe sx or lg(? >1 cm) clot burden; lyticoften ineffective for L-sidedthrombosis & 12–15% risk ofstroke; consider UFH ± lytic(? low-dose tPA via slowinfusion, JACC CV Imaging2013;6:206) if mild sx &small clot burden or poorsurg candidate; lyticreasonable for R-sided

• Infective endocarditis ± valvularabscess and conduction system

dis. (see “Endocarditis”)• Embolization (r/o endocarditis);

risk ~1%/y w/ warfarin (vs.2% w/ ASA, or 4% w/o meds)mech MVR 2 × risk of embolic

events vs. mech AVR (Circ1994;89:635)

• Bleeding (from anticoag),hemolysis (esp. w/ caged-ballvalves or paravalvular leak)

HEART VALVES (superior view,JAMA 1976;235:1603)

PERICARDIAL DISEASE

GENERAL PRINCIPLES

Anatomy• 2-layered (parietal & visceral)

tissue sac surrounding heart &proximal great vessels

Disease states• Inflammation (w/ or w/o fluid

accumulation) → pericarditis• Fluid accumulation → effusion ±

tamponade• Decrease in compliance (sequela

of inflammation) →constrictive pericarditis

• Tamponade and constriction

characterized by increasedventricular interdependence

PERICARDITIS ANDPERICARDIAL EFFUSION

Clinical manifestations (NEJM2004;351:2195)• Pericarditis: retrosternal chest

pain that is pleuritic,positional (↓ by sitting

forward), radiates to trapezius;may be absent in tuberculous,neoplastic, post-XRT anduremic pericarditis; ± fever;± s/s of systemic etiologies

• Effusion: ranges from asx totamponade (see below)

Physical exam• Pericarditis: multiphasic

friction rub best heard atLLSB w/ diaphragm ofstethoscope. Notoriouslyvariable and evanescentleathery sound w/ up to 3components: atrialcontraction, ventricular

contraction, ventricularrelaxation (NEJM2012;367:e20).

• Effusion: distant heart sounds,dullness over left posteriorlung field due to compressiveatelectasis from pericardialeffusion (Ewart’s sign)

Diagnostic studies (EHJ2004;25:587; Circ 2006;113:1622& 2010;121:916)• ECG: may show diffuse STE

(concave up) & PR depression(except in aVR: ST ↓ & PR ↑),TWI; classically and incontrast to STEMI, TWI do not

occur until STs normalizeStages: (I) STE & PR ↓; (II) ST

& PR normalize; (III) diffuseTWI; (IV) Tw normalize

ECG may show evidence oflarge effusion w/ lowvoltage & electricalalternans (beat-to- beat Δ inQRS amplitude and/or axisdue to swinging heart)

• CXR: if large effusion (>250 mLof fluid) → ↑ cardiac silhouettew/ “water-bottle” heart andepicardial halo

• Echocardiogram: presence, size,& location of effusion; presenceof tamponade physiology;

pericarditis itself w/o spec.abnl (∴ echo can be nl),although can see pericardialstranding (fibrin or tumor);can also detect LV/RV dysfxn(myocarditis ?)

• CT will reveal pericardialeffusions, often appearinglarger than onechocardiography

• CK-MB or troponin ( in ~30%,JACC 2003;42:2144) ifmyopericarditis. ConsiderCRP/ESR.

Workup for effusion• r/o infxn: usually apparent from

Hx & CXR; ? value of ✓ acuteand convalescent serologies

• r/o noninfectious etiologies:BUN, Cr, ANA, RF, HIV, screenfor common malignancies

• Pericardiocentesis if suspect infxnor malignancy or largeeffusion (>2 cm) or recurrent✓ cell counts, TP, LDH, glc,

Gram stain & Cx, AFB,cytology

ADA, PCR for MTb, andspecific tumor markers asindicated by clinicalsuspicion

“exudate” criteria: TP >3g/dL, TPeff/TPserum >0.5,

LDHeff/LDHserum >0.6 or glc<60 mg/dL high Se (~90%)but very low Sp (~20%);overall low utility (Chest1997;111:1213)

• Pericardial bx if suspicionremains for malignancy ortuberculosis

Treatment of pericarditis (EHJ2004;25:587; Circ2006;113:1622)• NSAIDs (eg, ibuprofen 600–800

mg tid × 7–14 d then taper)± colchicine 1–2 mg × 1 →0.5–1 mg bid × 3 mo (Circ2005;112:2012; Heart

2012;98:1078); sx usuallysubside in 1–3 d

• Steroids (usually systemic; occ.intrapericardial) only forsystemic rheum or autoimmunedisorder, uremic, preg.,contraindication to NSAID, orrefractory idiopathic dis.Systemic steroids appear to ↑

rate of pericarditisrecurrence (Circ2008;118:667).

• Avoid anticoagulants• Infectious effusion → pericardial

drainage (preferablysurgically) + systemicantibiotics

• Acute idiopathic effusion self-limited in 70–90% of cases

• Recurrent pericarditis (Circ2007;115:2739)risk factors: subacute, lg

effusion/tamponade, T>38°C, lack of NSAIDresponse after 7 d treatment:add colchicine 0.5–1 mg bid× 6 mo (Annals2011;155:409)

• Recurrent effusion: considerpericardial window(percutaneous vs. surgical)

PERICARDIAL TAMPONADE

Etiology• Any cause of pericarditis but esp.

malignancy, uremia,idiopathic, proximal aorticdissection with rupture,myocardial rupture

• Rapidly accumulating effusionsmost likely to causetamponade as no time forpericardium to stretch (eg, to ↑compliance) and accommodate↑ intrapericardial fluid volume

Pathophysiology (NEJM2003;349:684)• ↑ intrapericardial pressure,

compression of heartchambers, ↓ venous return → ↓CO

• Diastolic pressures ↑ & equalizein all cardiac chambers →minimal flow of blood from RAto RV when TV opens →blunted y descent

• ↑ ventricular interdependence →pulsus paradoxus (pathologicexaggeration of nl physio)Inspiration → ↓

intrapericardial & RApressures → ↑ venous return→ ↑ RV size → septal shift toleft. Also, ↑ pulmonaryvascular compliance → ↓

pulm venous return. Resultis ↓ LV filling → ↓ LV strokevolume & blood pressure.

Clinical manifestations• Cardiogenic shock

(hypotension, fatigue)without pulmonary edema

• Dyspnea (seen in ~85%) may bedue to ↑ respiratory drive toaugment venous return

Physical exam ( JAMA2007;297:1810)• Beck’s triad (present in minority

of cases): distant heartsounds, ↑ JVP, hypotension

• ↑ JVP (76%) w/ blunted y

descent• Reflex tachycardia (77%),

hypotension (26%;occasionally hypertensive),cool extremities

• Pulsus paradoxus (Se 82%, Sp70%) = ↓ SBP ≥10 mmHgduring inspiration

LR 3.3 (5.9 if pulsus >12), LR 0.03

Ddx = PE, hypovolemia,severe COPD, constriction(~1⁄3), RV infarct

Can be absent if pre-existing ↑LVEDP, arrhythmia, severeAI, ASD, regional

tamponade• Distant heart sounds (28%), ±

pericardial friction rub (30%)• Tachypnea but clear lungs

Diagnostic studies• ECG: ↓ voltage (seen in 42%),

electrical alternans (20%), ±signs of pericarditis

• CXR: ↑ cardiac silhouette (89%)• Echocardiogram: effusion,

IVC plethora, septal shift withinspirationdiastolic collapse of RA (Se

85%, Sp 80%) and/or RV (Se<80%, Sp 90%)

respirophasic Δ’s in

transvalvular velocities (↑across TV & ↓ across MV w/inspir.)

postsurgical tamponade maybe localized and not easilyvisible

• Cardiac cath (right heart andpericardial): elevation (15–30mmHg) and equalization ofintrapericardial and diastolic

pressures (RA, RV, PCWP),blunted y descent in RA

↑ in stroke volumepostpericardiocentesis =ultimate proof of tamponade

if RA pressure remainselevated after drainage, may

have effusive-constrictivedisease (NEJM2004;350:469) ormyocardial dysfxn (eg, fromconcomitant myocarditis)

Treatment• Volume (but be careful as

overfilling can worsentamponade) and inotropes(avoid bB)

• Avoid vasoconstrictors as will ↓stroke volume & potentially ↓HR

• Pericardiocentesis (except ifdue to aortic or myocardialrupture, in which case

consider removing just enoughfluid to reverse PEA en routeto emergent surgery)

CONSTRICTIVE PERICARDITIS

Etiology (Circ 2011;124:1270)• Any cause of pericarditis (~1–2%

incidence overall after acutepericarditis)

• Highest risk w/ TB, bacterial,neoplastic, connective tissue,postcardiac surgery

• Viral/idiopathic, as mostcommon cause of pericarditis,also account for signifproportion

Pathophysiology• Adhesion of visceral and parietal

pericardial layers → rigidpericardium that limits

diastolic filling of ventricles →↑ systemic venous pressures

• Venous return is limited onlyafter early rapid filling phase;∴ rapid ↓ in RA pressure withatrial relaxation and openingof tricuspid valve andprominent x and y descents

• Kussmaul sign: JVP does notdecrease with inspiration (↑venous return with inspirationbut negative intrathoracicpressure not transmitted toheart because of rigidpericardium)

Clinical manifestations (NEJM

2011;364:1350)• Right-sided > left-sided heart

failure (systemic congestion >pulmonary congestion)

Physical exam• ↑ JVP with prominent y

descent, Kussmaul sign(Ddx: tricuspid stenosis, acutecor pulmonale, RV failure andRV infarct, RCMP)

• Hepatosplenomegaly, ascites,peripheral edema. Consider onDdx of idiopathic cirrhosis.

• PMI usually not palpable,pericardial knock, usually nopulsus paradoxus

Diagnostic studies• ECG: nonspecific, AF common

(up to 33%) in advanced cases• CXR: calcification (MTb most

common), esp. in lateral view(although not specific)

• Echocardiogram: ± thickenedpericardium, “septal bounce”= abrupt displacement ofseptum during rapid filling inearly diastole

• Cardiac catheterizationatria: Ms or Ws (prominent x

and y descents)ventricles: dip-and-plateau or

square-root sign (rapid ↓pressure at onset of diastole,

rapid ↑ to early plateau)discordance between LV & RV

pressure peaks duringrespiratory cycle (Circ1996;93:2007)

• CT or MRI: thickenedpericardium (>4 mm; Se~80%), w/ tethering (Circ2011;123:e418)

Treatment• Diuresis for intravascular volume

overload; surgicalpericardiectomy in advancedcases

• ? MRI able to predict reversibilitywith anti-inflammatory agents

(Circ 2011;124:1830)

HYPERTENSION

BP should be determined bymaking ≥2 measurementsseparated by >2 min. Confirmstage 1 w/in 2 mo; can Rx stage2 immediately.

Epidemiology ( JAMA2003;290:199 & 2010;303:2043)• Prevalence 30% in U.S. adults;

>68 million affected (29% inwhites, 33.5% in blacks)

• Only 50% of patients with dx ofHTN have adequate BP control

Etiologies• Essential (95%): onset 25–55 y;

FHx. Unclear mechanism but? additive microvascrenal injury over time w/

contribution of hyperactivesympathetics (NEJM2002;346:913).

↑ Age → ↓ arterial compliance→ syst HTN. Genetics alsoinvolved (Nature2011;478:103).

• Secondary: Consider if Pt <20or >50 y or if sudden onset,severe, refractory HTN

Standard workup• Goals: (1) identify CV risk factors

or other diseases that would

modify prognosis or Rx;(2) reveal 2° causes of

hypertension; (3) assess fortarget-organ damage

• History: CAD, HF, TIA/CVA,PAD, DM, renal insufficiency,sleep apnea, preeclampsia; FHx for HTN; diet, Na intake,smoking, alcohol, prescriptionand OTC meds, OCP

• Physical exam: ✓ BP in botharms; funduscopic exam,cardiac (LVH, murmurs),vascular (bruits, radial-femoraldelay), abdominal (masses orbruits), neuro exam

• Testing: K, BUN, Cr, Ca, glc, Hct,

U/A, lipids, TSH, urinaryalbumin:creatinine (if ↑ Cr,DM, peripheral edema), ?renin, ECG (for LVH), CXR,TTE (eval for valve abnl, LVH)

Complications of HTN• Each ↑ 20 mmHg SBP or 10 mmHg

DBP → 2× ↑ CV complications(Lancet 2002;360:1903)

• Neurologic: TIA/CVA, rupturedaneurysms, vascular dementia

• Retinopathy: stage I = arteriolarnarrowing; II = copper-wiring, AV nicking; III =hemorrhages and exudates; IV= papilledema

• Cardiac: CAD, LVH, HF, AF• Vascular: aortic dissection, aortic

aneurysm (HTN = key riskfactor for aneurysms)

• Renal: proteinuria, renal failure

Treatment (Lancet 2012;380:591)• Goal: <140/90 mmHg; if DM or

CKD goal is <130/80 mmHg(nb, in DM, target of <120does not ↓ CV risk & ↑ adverseevents; NEJM 2010;362:1575)

• Treatment results in 50% ↓ HF,40% ↓ stroke, 20–25% ↓ MI(Lancet 2000;356:1955);benefits of Rx’ing stage II HTNextend to Pts >80 y, goal BP

<150/80 (NEJM2008;358:1887)

• Lifestyle modifications (each ↓SBP ~5 mmHg)weight loss: goal BMI 18.5–

24.9; aerobic exercise: ≥30min exercise/d, ≥5 d/wk

diet: rich in fruits &vegetables, low in saturated& total fat (DASH, NEJM2001;344:3)

sodium restriction: ≤2.4 g/dand ideally ≤1.5 g/d (NEJM2010;362:2102)

limit alcohol consumption: ≤2drinks/d in men; ≤1drink/d in women & lighter-

wt Pts• Pharmacologic options (if HTN

or pre-HTN + diabetes orrenal disease)Pre-HTN: ARB prevents onset

of HTN, no ↓ in clinicalevents (NEJM2006;354:1685)

HTN: choice of therapycontroversial, concomitantdisease and stage may helpguide Rx

uncomplicated: thiazide iflikely salt sensitive (eg,elderly, black, obese), o/wstart w/ ACEI or CCB (NEJM2009;361:2153). bB not first

line (Lancet 2005;366:1545).+high-risk CAD: ACEI or ARB

(NEJM 2008;358:1547);ACEI + CCB superior toACEI + thiazide (NEJM2008;359:2417) or bB +diuretic (Lancet2005;366:895)

+angina: bB, CCB, nitrates+post-MI: ACEI, bB ±

aldosterone antagonist (see“ACS”)

+HF: ACEI/ARB, bB, diuretics,aldosterone antagonist (see“Heart Failure”)

+2° stroke prevention:ACEI (Lancet

2001;358:1033); ? ARB(NEJM 2008;359:1225)+diabetes mellitus:ACEI or ARB; can alsoconsider diuretic, bB orCCB

+chronic kidney disease:ACEI/ARB (NEJM1993;329:1456 &2001;345:851 & 861)

• Tailoring therapyif stage 1, start w/ monoRx; if

not at goal, Δ to differentclass rather than adding 2ndagent

if stage 2, consider starting w/combo (eg, ACEI + CCB;

NEJM 2008;359:2417) asmost will require ≥2 drugs;low–mod doses of 2 drugsgenerally preferred overmax dose of 1 drug (b/c ofdose-related AEs)

if resistant [= HTN despite≥3 drugs (incl diuretic) atopt doses], considernoncompliance, volumeoverload, secondary causes;? renal artery denervation(Lancet 2010;376:1903)

• Secondary causesRenovascular: control BP w/

diuretic + ACEI/ARB (watchfor ↑ Cr w/ bilat. RAS) or

CCB Atherosclerosis risk-factor modification: quitsmoking, ↓ chol. If refractoryHTN, recurrent flash pulmedema, worse CKD, considerrevascFor atherosclerosis: stenting

↓ restenosis vs. PTA alone,but no clear improvementin BP or renal function vs.med Rx (NEJM2009;361:1953; Annals2009;150:840)

For FMD (usually moredistal lesions): PTA ±bailout stenting

Renal parenchymal disease:

salt and fluid restriction, ±diuretics

Endocrine etiologies: see“Adrenal Disorders”

• Pregnancy: methyldopa,labetalol, nifedipine,hydralazine; avoid diuretics; �ACEI/ARB

HYPERTENSIVE CRISES• Hypertensive emergency: ↑ BP

→ acute target-organ ischemiaand damageneurologic damage:

encephalopathy,hemorrhagic or ischemicstroke, papilledema

cardiac damage: ACS,HF/pulmonary edema,aortic dissection

renal damage: proteinuria,hematuria, acute renalfailure; scleroderma renalcrisis

microangiopathic hemolytic

anemia; preeclampsia-eclampsia

• Hypertensive urgency: SBP>180 or DBP >120 (?110) w/min. or no target-organdamage

Precipitants• Progression of essential HTN ±

medical noncompliance (esp.clonidine) or Δ in diet

• Progression of renovasculardisease; acuteglomerulonephritis;scleroderma; preeclampsia

• Endocrine: pheochromocytoma,Cushing’s

• Sympathomimetics: cocaine,amphetamines, MAO inhibitors+ foods rich in tyramine

• Cerebral injury (do not treat HTNin acute ischemic stroke unlessPt getting lysed, extremeBP (>220/120), Ao dissection,

active ischemia or HF (Stroke2003;34:1056)

Treatment (Chest2007;131:1949)• Tailor goals to clinical context

(eg, more rapid lowering forAo dissection)

• Emergency: ↓ MAP by ~25% inmins to 2 h w/ IV agents (may

need arterial line formonitoring); goal DBP <110w/in 2–6 h, as tolerated

• Urgency: ↓ BP in hours using POagents; goal normal BP in ~1–2 d

• Watch UOP, Cr, mental status:may indicate a lower BP is nottolerated

AORTIC ANEURYSMS

Definitions• True aneurysm (dilation of all 3

layers of aorta) vs. false(rupture contained byadventitia)

• Location: root (annuloaorticectasia), thoracic aorticaneurysm (TAA),thoracoabdominal aorticaneurysm (TAAA), abdominalaortic aneurysm (AAA)

• Type: fusiform (circumferentialdilation) vs. saccular (localizeddilation of aortic wall)

Epidemiology (Circ

2010;121:e266; Nat Rev Cardiol2011;8:92)• In U.S., ~15,000 deaths/y from

aortic ruptures; overall~50,000 deaths/y from Aodisease

• TAA: : ~1.7:1; ~60%root/ascending Ao; 40%descending Ao; arch & TAAArarerRisk factors: HTN;

atherosclerosis; congenital(bicuspid AoV, Turner’s);connective tissue diseases(Marfan, Ehlers-Danlos typeIV, Loeys-Dietz); aortitis(Takayasu’s, GCA,

spondyloarthritis, IgG4,syphilis); familialsyndromes; chronic AoD;trauma

• AAA: ~4–8% prev. in those >65y; 5–10× more common in vs. ; mostly infrarenalRisk factors = similar to

atherosclerosis: smoking,HTN, hyperlipidemia, age,FHx

Pathophysiology (NEJM2009;361:1114; Nat Med2009;15:649)• LaPlace’s law: tension across a

cylinder ∝ [(ΔP × r) / (wall

thickness)]• TAA: medial degeneration =

muscle apoptosis, elastin fiberweakening, mucoid infiltration

• AAA: atherosclerosis &inflammation → matrixdegeneration → medialweakening

• Inflammatory and infectious(“mycotic”) aneurysmsrelatively rare

Screening (Annals 2005;142:203;JAMA 2009;302:2015; Circ2010;121:e266)• TAA: no consensus guidelines; ?

screen if bicuspid AoV or first-

degree relative• AAA: ✓ for pulsatile abd mass;

U/S >60 y w/ FHx of AAA & 65–75 y w/ prior tobacco

Diagnostic studies (Circ2005;111:816 & 2010;121:e266)• Contrast CT: quick, noninvasive,

high Se & Sp for all aorticaneurysms

• TTE/TEE: TTE most useful forroot and proximal Ao; TEE canvisualize other sites of TAA

• MRI: preferred over CT for aorticroot imaging for TAA; alsouseful in AAA but time-consuming; noncontrast “black

blood” MR to assess aortic wall• Abdominal U/S: screening and

surveillance test of choice forinfrarenal AAA

Treatment (Circ 2006;113:e463;2008;177:1883; 2010;121:1544 &e266)• Risk factor modification:

smoking cessation, statin toachieve LDL-C <70 mg/dL

• BP control: bB (↓ dP/dt) ↓aneurysm growth (NEJM1994;330:1335); ACEI a/w ↓risk of rupture (Lancet2006;368:659), ARB may ↓rate of aortic root growth in

Marfan (NEJM2008;358:2787); no burstactivity/exercise requiringValsalva maneuvers (eg, heavylifting)

• Indications for surgery:individualize based on FHx,body size, genderTAA: sx; asc Ao ≥5.5 cm (?

5.0 cm Marfan, bicuspidAoV; 4.2–4.4 cm Loeys-Dietz); descending >6 cm; ↑>0.5 cm/y; aneurysm ≥4.5cm and planned AoV surgery

AAA: infrarenal ≥5.5 cm(NEJM 2002;346:1437) butconsider ≥5.0 cm in ; sx; ↑

>0.5 cm/y; inflam/infxn• Endovascular aneurysm repair

(EVAR) (NEJM 2008;358:494;Circ 2011;124:2020)↓ short-term mort., bleeding,

LOS; but long-term graftcomplic. (3–4%/y; endoleak,need for reintervention,rupture) necessitate periodicsurveillance, with no provenΔ in overall mortality,except ? in those <70 y(NEJM 2010;362:1863, 1881& 2012;367:1988)

Guidelines support open repairor EVAR for infrarenal AAAin good surg candidates

In Pts unfit for surgery or highperi-op risks: ↓ aneurysm-related mortality but no Δ inoverall mortality overmedical Rx (NEJM2010;362:1872). EVARnoninferior (? superior) toopen repair in ruptured AAAw/ favorable anatomy (AnnSurg 2009;250:818).

TEVAR (thoracic EVAR) fordescending TAA ≥5.5 cmmay ↓ peri-op morbidity, noproven mortality benefit(Circ 2010;121:2780; JACC2010;55:986; J Thorac CVSurg 2010;140:1001)

Complications (Circ2010;121:e266; Nat Rev Cardiol2011;8:92)• Pain: gnawing chest, back or

abdominal pain; new or worsepain may signal rupture

• Rupture: risk ↑ w/ diameter, ,current smoking, HTNTAA: ~2.5%/y if <6 cm vs.

7%/y if >6 cm; AAA:~1%/y if <5 cm vs. 6.5%/yif 5–5.9 cm

rupture p/w severe constantpain and hemorrhagic shock;~80% mortality at 24 h

• Acute aortic syndromes (qv)

• Thromboembolic ischemicevents (eg, to CNS, viscera,extremities)

• Compression of adjacentstructures (eg, SVC, trachea,esophagus, laryngeal nerve)

Follow-up (Circ 2010;121:e266;Nat Rev Cardiol 2011;8:92; JAMA2013;309:806)• Expansion rate ~0.1 cm/y for

TAA, ~0.3–0.4 cm/y for AAA• AAA: q3y if 3–3.9 cm; q6–12 mo

if 4.0–5.4 cm (? q2y if 4–4.4)• TAA: 6 mo after dx to ensure

stable, then annually.• Screen for CAD, PAD and

aneurysms elsewhere, esp.popliteal. About 25% of Pts w/TAA will also have AAA, and

25% of AAA Pts will have aTAA: consider pan-Aoimaging.

ACUTE AORTIC SYNDROMES

Definitions (Circ 2003;108:628 &2010;121:e266; Eur Heart J2012;33:26)• Aortic dissection: intimal tear

→ blood extravasates into Aomedia (creates false lumen)

• Intramural hematoma (IMH):vasa vasorum rupture →medial hemorrhage that doesnot communicate with aorticlumen; 6% of aorticsyndromes; clinically identicalto AoD

• Penetrating ulcer:atherosclerotic plaque

penetrates elastic lamina →medial hemorrhage

Classification (proximal twice ascommon as distal)• Proximal: involves ascending

Ao, regardless of origin (=Stanford A, DeBakey I & II)

• Distal: involves descending Aoonly, distal to L subclavian art.(= Stanford B, DeBakey III)

Risk factors• Hypertension (h/o HTN in

>70% of dissections); malesex (~70% ); cocaine

• Connective tissue disease:Marfan (fibrillin-1):

arachnodactyly, joint disloc.,pectus, ectopia lentis, MVP;Ehlers-Danlos type IV (type IIIprocollagen): translucent skin;bowel or uterine rupture;Loeys-Dietz (TGFbR);annuloaortic ectasia, familialAoD; PCKD

• Congenital aortic anomaly:bicuspid AoV, coarctation (eg,in Turner’s syndrome)

• Aortitis (eg, Takayasu’s, GCA,Behçet’s, syphilis, now rare);pregnancy (typ. 3rd trim.)

• Trauma: blunt, decelerationinjury; IABP, cardiac or aorticsurgery, cardiac

catheterization

Diagnostic studies (Circ2005;112:3802; & 2010;121:e266;Annals 2006;166:1350)• Check bilateral BP and radial

pulses for symmetry• CXR: abnl in 60–90% (↑

mediastinum, left pl effusion),

but cannot be used to r/odissection

• CT: quick, noninvasive, readilyavailable, Se ≥93% & Sp 98%;however, if & high clin.suspicion → additional studies(2⁄3 w/ AoD have ≥2 studies;AJC 2002;89:1235)

• TEE: Se >95% prox, 80% fordistal; can assesscors/peric/AI; “blind spot”behind trachea

• MRI: Se & Sp >98%, but time-consuming test & not readilyavailable

• Aortography: Se ~90%, time-

consuming, cannot detect IMH;can assess branch vessels

• D-dimer: Se/NPV ~97%; ? <500ng/mL to r/o dissec (Circ2009;119:2702); does not r/oIMH

Treatment (Lancet 2008;372:55;Circ 2010;121:1544; JACC2013;61:1661)• Initial Medical: ↓ dP/dt

targeting HR ~60 & central BP100–120 (or lowest thatpreserves perfusion; r/opseudohypotension, eg, armBP ↓ due to subclaviandissection)

first with IV bB (eg,propranolol, esmolol,labetalol) to blunt reflex ↑HR & inotropy that wouldoccur in response tovasodilators; verap/dilt if bBcontraindic.

then ↓ SBP with IVvasodilators (eg,nitroprusside)

control pain with MSO4 prn toblunt sympathetic response

• Proximal: surgery (rootreplacement); all acute;chronic if c/b progression, AIor aneurysm

• Distal: med Rx unless c/bprogression, branch arteryinvolvement → malperfusion/ischemia, refractory HTN,refractory pain, rapid ↑aneurysm size, rapid ↑ falselumen size. Repeat imaging:routinely (eg, 7 d, 3 wk, then qyr) & with any clinical orsignificant lab Δ. If complic.,endovascular repair (coveredstent graft to seal off entry,fenestrate flap, open occludedbranch) preferred over surgerydue to possible ↓ mort. ( JACC2013;61:1661).

Complications

• Rupture: pericardial sac →tamponade (avoidpericardiocentesis unless PEA);blood in pleural space,mediast., retroperitoneum; ↑ inhematoma on imagingportends rupture.

• Malperfusion (obstruction ofbranch artery)can be static

(avulsed/thrombosed) ordynamic (Δs in pressure intrue vs. false lumen)

coronary → MI (usually RCA→ IMI, since dissection oftenalong outer Ao curvature)

innominate/carotid → CVA,

Horner; intercostal/lumbar→ spinal cordischemia/paraplegia

innominate/subclavian →upper extremity ischemia;iliac → lower extremityischemia

celiac/mesenteric → bowelischemia; renal → acuterenal failure, refractory HTN

• AI: due to annular dilatation ordisruption or displacement ofleaflet by false lumen

• Mortality: 1–2%/h × 48 h foracute proximal; 10% at 30 dfor acute distal

ARRHYTHMIAS

BRADYCARDIAS, AV BLOCK ANDAV DISSOCIATION

Sinus bradycardia (SB) (NEJM2000;342:703)• Etiologies: meds (incl bB, CCB,

amio, Li, dig), ↑ vagal tone(incl. athletes, sleep, IMI),metabolic (hypoxia, sepsis,myxedema, hypothermia, ↓glc), OSA, ↑ ICP

• Treatment: usually nonerequired; atropine, b1 agonistsor temp. pacing ifsymptomatic

• Most common cause of sinuspause is blocked prematureatrial beat

Sick sinus syndrome (SSS)• Features may include: periods of

unprovoked SB, SA arrest,paroxysms of SB and atrialtachyarrhythmias (“tachy-

brady” syndrome),chronotropic incompetencew/ ETT

• Treatment: meds alone usuallyfail (adeq. control tachy →unacceptable brady); usuallyneed combination of meds(bB, CCB, dig) for tachy &

PPM for brady

AV dissociation• Default: slowing of SA node

allows subsidiary pacemaker(eg, AV junction) to take over

• Usurpation: acceleration of

subsidiary pacemaker (eg, AVjunctional tach, VT)

• 3° AV block: atrial pacemakerunable to capture ventricles,subsidiary pacemaker emergesdistinguish from isorhythmicdissociation (A V rate, some Pwaves nonconducting)

Temporary pacing wires• Consider w/ bradycardia with

hemodyn instability orunstable escape rhythm whenperm pacer not readilyavailable. Risks: RV perf, VT,PTX, CHB if existing LBBB, etc.

• Consider instead of PPM for sx

bradycardia due to reversiblecause (bB/CCB O/D, Lyme,myocarditis, SBE, s/p cardiacsurgery/trauma), TdP, acuteMI (sx brady, high grade AVB)

SUPRAVENTRICULARTACHYCARDIAS (SVTS)

Arise above the ventricles, ∴ narrowQRS unless aberrant conduction or

pre-excitation.

Figure 1-4 Approach to SVT(adapted from NEJM2012;367:1438)

• Catheter ablation: high overall

success rate (AFL/AVNRT~95%, AVRT ~90%, AF~80%)Complications: stroke, MI,

bleeding, perforation,conduction block (JAMA2007;290:2768)

ACCESSORY PATHWAYS (WOLFF-PARKINSON-WHITE)

Definitions• Accessory pathway (bypass

tract) of conductingmyocardium connecting atria& ventricles, allowing impulsesto bypass normal AVN delay

• Preexcitation (WPW) pattern: ↓PR interval, ↑ QRS width w/ Δwave (slurred onset, can besubtle), ST & Tw abnl (canmimic old IMI); only seen w/pathways that conduct antegrade(if pathway only conductsretrograde then

ECG will be normal duringSR; “concealed” bypasstract)

PAC can exaggeratepreexcitation if AV nodeconduction slowed

• WPW syndrome: accessorypathway + paroxysmaltachycardia

Classic tachycardias of WPW• Orthodromic AVRT: narrow-

complex SVT (typically),conducting ↓ AVN & ↑accessory pathway; requiresretrograde conduction and ∴can occur w/ concealed bypasstracts

• Antidromic AVRT (rare): wide-complex SVT, conducting ↓accessory pathway & ↑ AVN;requires antegrade conduction

and ∴ should see WPWpattern during SR

• AF w/ rapid conduction downaccessory pathway; ∴ wide-complex irregular SVT;requires antegrade conduction;∴ should see WPW pattern in

SR. Rarely can degenerate intoVF.

Treatment• AVRT: vagal, bB, ? CCB; caution

w/ adenosine (can precip. AF);have defibrillator ready

• AF/AFL w/ conduction downaccessory pathway: need to Rxarrhythmia and ↑ pathwayrefractoriness; use

procainamide, ibutilide,amio, flecainide or DCCV;avoid CCB & bB(ineffective), dig/adenosine(can ↓ refractoriness ofpathway → ↑ vent. rate →

VF)• Long term: Rx sx tachycardias

w/ RFA, antiarrhythmics (IA,IC) if not candidate for RFA;consider RFA if asx but AVRT

or AF inducible on EPS(NEJM 2003;349:1803) of ifrapid conduction possible (✓w/ EPS if preexcitationpersists despite exercisetesting)

risk of SCD related to howshort RR interval is in AFand if SVT inducible w/exercise

WIDE-COMPLEX TACHYCARDIAS(WCTS)

Etiologies (Lancet2012;380:1520)• Ventricular tachycardia (VT)• SVT conducted with aberrancy:

either fixed BBB, rate-dependent BBB (usuallyRBBB), conduction via anaccessory pathway or atriallytriggered ventricular pacing

Monomorphic ventriculartachycardia (MMVT)• All beats look similar;

predominantly upward in V1

= RBBB-type vs. downward =

LBBB-type

• In structurally abnormal heart:prior MI (scar); CMP;myocarditis;arrhythmogenic RV CMP

(ARVC): incomplete RBBB,ε wave (terminal notch in

QRS) & TWI in V1–V3 onresting ECG, LBBB-type VT,dx w/ MRI (Lancet2009;373:1289)

• In structurally normal heart (w/normal resting ECG):RVOT VT: LBBB-type VT w/

inferior axis; typically ablateidiopathic LV VT: RBBB-type

VT w/ superior axis;responds to verapamil

Polymorphic ventriculartachycardia (PMVT)• QRS morphology changes from

beat to beat• Etiologies: ischemia; CMP;

catecholaminergic;torsades de pointes (TdP =

“twisting of the points,”PMVT + ↑ QT): ↑ QT

acquired (meds, lytes,stroke, see "ECG") w/ risk ↑w/ ↓ HR, freq PVCs (pausedependent) or congenital(K/Na channelopathies) w/resting Tw abnl & TdPtriggered by sympatheticstimulation (eg, exercise,emotion, sudden loud noises)(Lancet 2008;372:750).

Brugada syndrome (Nachannelopathy): > ;pseudo-RBBB w/ STE in V1–V3 (provoked w/ class IA orIC) on resting ECG

Diagnostic clues that favor VT(assume until proven o/w)• Prior MI, CHF or LV

dysfunction best predictorsthat WCT is VT (Am J Med1998;84:53)

• Hemodynamics and rate do notreliably distinguish VT fromSVT

• MMVT is regular, but initially itmay be slightly irregular,mimicking AF w/ aberrancy;grossly irregularly irregular

rhythm suggests AF w/aberrancy

• ECG features that favor VT (Circ1991;83:1649)AV dissociation (independent P

waves, capture or fusionbeats) proves VT

very wide QRS (>140 ms inRBBB-type or >160 in LBBB-type); extreme axis deviation

QRS morphology atypical for BBBRBBB-type: absence of tall R′(or presence of monophasicR) in V1, r/S ratio <1 in V6

LBBB-type: onset to nadir>60–100 ms in V1, q wave

in V6

concordance (QRS in allprecordial leads w/ samepattern/direction)

Long-term management ( JACC2006;48:1064)• Workup: echo to ✓ LV fxn, cath

or stress test to r/o ischemia,? MRI and/or RV bx tolook for infiltrative CMP or

ARVC, ? EP study to assessinducibility

• ICD: 2° prevention afterdocumented VT/VF arrest(unless due to reversible cause)1° prev. if high risk, eg, EF

<30–35%, ARVC, Brugada,certain LQTS, severe HCMP.See “Intracardiac Devices.” ?Wearable vest if revers.etiol. waiting for ICD (Circ2013;127:854).

Antitachycardia pacing (ATP= burst pacing faster thanVT) can terminate VT w/oshock

• Meds: bB, antiarrhythmics (eg,amio, mexiletine) to suppressVT which could trigger shock

• If med a/w TdP → QT >500 ±VPBs: d/c med, replete K, giveMg, ± pacing (JACC2010;55:934)

• Radiofrequency ablation ifisolated VT focus or ifrecurrent VT triggering ICDfiring; ablation before ICDimplantation ↓ discharge rateby 40% (Lancet 2010;375:31)

ATRIAL FIBRILLATION

Classification (Circ2006;114:e257 & 2011;123:104)• Paroxysmal (self-terminating,

usually <48 h) vs. persistent(sustained >7 d or terminatedafter Rx) vs. permanent(typically >1 y and whencardioversion has failed or isforegone)

• Valvular (rheumatic MV disease,prosthetic valve or valverepair) vs. nonvalvular

• Lone AF = age <60 y and w/oclinical or echo evidence ofcardiac disease (including

HTN)

Epidemiology and etiologies(Annals 2008;149:ITC5-2)• 1–2% of pop. has AF (8% of

elderly); lifetime risk 25%;mean age at presentation ~75y

• Acute (up to 50% w/oidentifiable cause)Cardiac: HF, myo/pericarditis,

ischemia/MI, hypertensivecrisis, cardiac surgery

Pulmonary: acute pulmonarydisease or hypoxia (eg,COPD flare, PNA), PE, OSA

Metabolic: high

catecholamine states (stress,infection, postop, pheo),thyrotoxicosis

Drugs: alcohol (“holidayheart”), cocaine,amphetamines, theophylline,caffeine

Neurogenic: subarachnoidhemorrhage, ischemic stroke

• Chronic: ↑ age, HTN, ischemia,valve dis. (MV, TV, AoV),CMP, hyperthyroidism, obesity

Evaluation• H&P, ECG, CXR, TTE (LA size,

thrombus, valves, LV fxn,pericardium), K, Mg, FOBT

before anticoag, TFTs; r/o MInot necessary unless otherischemic sx

Figure 1-5 Approach to acuteAF

(Adapted from NEJM2004;351:2408; JACC2006;48:e149)

Strategies for recurrent AF (Circ2011;123:104; Lancet2012;379:648)• Rate control: goal HR <110 at

rest if EF >40% and asx(NEJM 2010;362:1363)AV node ablation + PPM as a

last resort (NEJM2001;344:1043;2002;346:2062)

• Rhythm control: no clearsurvival benefit vs. rate cntl(NEJM 2002;347:1825 &2008;358:2667)Consider if sx w/ rate cntl,

difficult to cntl rate, ?unable to anticoag, ? benefitin CRT

Cardioversion• Consider pharm or electrical

cardioversion w/ 1st AFepisode or if sx;if AF >48 h, 2–5% risk stroke

w/ cardioversion(pharmacologic or electric) ∴either TEE to r/o thrombus orensure therapeuticanticoagulation for ≥3 wkprior

• Likelihood of success ∝ AFduration & atrial size; controlprecip. (eg, vol status, thyroid)

• Consider pre-Rx w/antiarrhythmic drugs (esp. if1st cardioversion attempt fails)

• For pharmacologic cardioversion,class III and IC drugs have bestproven efficacy

• If SR returns (spont. or w/ Rx),atria may be mech. stunned;

also, high risk of recurrent AFover next 3 mo. ∴ Anticoagpostcardioversion ≥4–12 wk(? unless <48 h and low risk).

Nonpharmacologic therapy• Radiofrequency ablation

(circumferential pulm. veinisolation; Lancet2012;380:1509): ~80%success; reasonable alternativeto AAD in sx persistent orparoxysmal AF w/o ↑↑ LA or ↓EF (NEJM 2012;367:1587;RAAFT 2, HRS 2012)

• Surgical “maze” procedure (70–95% success rate) option if

undergoing cardiac surgery• LA appendage closure/resection:

reasonable if anotherindication for cardiac surgerypercutaneous closure

noninferior to warfarin, ↓risk of ICH, but w/procedural complic;additional studies &approaches underway(Lancet 2009;374:534;PREVAIL, ACC 2013)

Oral anticoagulation (Chest2012;141:e531S; EHJ2012;33:2719; Circ2013;127:1916)

• All valvular AF as stroke risk veryhigh

• Nonvalvular AF: stroke risk~4.5%/y; anticoag → 68% ↓stroke; use a risk score to guideRx:CHADS2: CHF (1 point), HTN

(1), Age ≥75 y (1), DM (1),prior Stroke/TIA (2)

CHA2DS2-VASc: adds 65–74 y(1), >75 y (2); vasc dis. (1);

sex (1)score >2 → anticoag; score

1 → consider anticoag orASA (? latter reasonable ifrisk factor 65–74 y, vasc dis.

or ); antithrombotic Rxeven if rhythm cntl

• Rx options: factor Xa or directthrombin inhib (non-valvonly; no monitoring required)or warfarin (INR 2–3; w/ UFHbridge if high risk of stroke); ifPt refuses anticoag, considerASA + clopi or, even less

effective, ASA alone (NEJM2009;360:2066)

SYNCOPE

Definition• Symptom of sudden transient loss

of consciousness due to globalcerebral hypoperfusion

• If CPR or cardioversion required,then SCD and not syncope(different prognosis)

Etiologies (NEJM 2002;347:878;JACC 2006;47:473; Eur Heart J2009;30:2631)• Neurocardiogenic (a.k.a.

vasovagal, ~20%; NEJM2005;352:1004): ↑ sympathetictone → vigorous contraction ofLV → mechanoreceptors in LV

trigger ↑ vagal tone(hyperactive Bezold-Jarischreflex) → ↓ HR(cardioinhibitory) and/or ↓ BP(vasodepressor)cough, deglutition, defecation,& micturition → ↑ vagal toneand thus can be precipitantsrelated disorder: carotid sinushypersensitivity (exagg vagalresp to carotid massage)

• Orthostatic hypotension (10%)hypovolemia/diuretics,deconditioning; vasodilat.(esp. if combined w/ chronotropes)autonomic neuropathy [1° =

Parkinson’s, Shy-Drager,Lewy body dementia, POTS(dysautonomia in theyoung); 2° = DM, EtOH,amyloidosis, CKD] (NEJM2008;358:615)

• CardiovascularArrhythmia (15%)

Bradyarrhythmias: SSS, high-grade AV block, chronotropes, PPMmalfunction

Tachyarrhythmias: VT, SVT(syncope rare unlessstructural heart disease orWPW)

Mechanical (5%)

Endocardial/Valvular: AS,MS, PS, prosthetic valvethrombosis, myxoma

Myocardial: pump dysfxnfrom MI or outflowobstruction from HCMP(but usually VT)

Pericardial: tamponadeVascular: PE, PHT, aortic

dissection, ruptured AAA,subclavian steal

• Neurologic (10%): seizure(technically not syncope),TIA/CVA, vertebrobasilarinsufficiency, dissection of

cerebral arteries, migraine,narcolepsy

• Misc. causes of LOC (but notsyncope): hypoglycemia,hypoxia, anemia, psychogenic

Workup (etiology cannot bedetermined in ~40% of cases)• H&P incl. orthostatic VS have

highest yield and most costeffective (Archives2009;169:1299)

• History (from Pt and witnesses ifavailable)activity and posture before the

incidentprecipitating factors: exertion

(AS, HCMP, PHT), positionalΔ (orthostatic hypotension),

stressors such as sight ofblood, pain, emotionaldistress, fatigue, prolongedstanding, warmenvironment, N/V,cough/micturition/defecation/swallowing(neurocardiogenic), headturning or shaving (carotidsinus hypersens.); armexercise (subclavian steal)

prodrome (eg, diaphoresis,nausea, blurry vision):cardiac <~5 sec, vasovagal>~5 sec

associated sx: chest pain,palp., neurologic, postictal,bowel or bladder

incontinence (convulsiveactivity for <10 sec mayoccur w/ transient cerebralHoTN & mimic seizure)

• PMH: prior syncope, previouscardiac or neurologic dis.; noCV disease at baseline → 5%cardiac, 25% vasovagal; CVdisease → 20% cardiac, 10%vasovagal (NEJM2002;347:878)

• Medications that may act asprecipitantsvasodilators: a-blockers,

nitrates, ACEI/ARB, CCB,hydralazine, phenothiazines,antidep.

diuretics; chronotropes (eg,bB and CCB)

proarrhythmic or QTprolonging: class IA, IC orIII antiarrhythmics (see“ECG”)

psychoactive drugs:antipsychotics, TCA,barbiturates,benzodiazepines, EtOH

• Family history: CMP, SCD,syncope (vasovagal may havegenetic component)

• Physical examVS including orthostatics (

if supine → standing resultsin >20 mmHg ↓ SBP, >10

mmHg ↓ DBP, or >10–20bpm ↑ HR), BP in both arms

cardiac: HF (↑ JVP, displ. PMI,S3), murmurs, LVH (S4, LVheave), PHT (RV heave, ↑P2)

vascular: ✓ for asymmetricpulses,carotid/vertebral/subclavianbruits; carotid sinus massageto assess for carotidhypersensitivity (if nobruits)

neurologic exam: focalfindings, evidence of tonguebiting; FOBT

• ECG (abnormal in ~50%, butonly definitively identifiescause of syncope in ~10%)Conduction: SB, sinus

pauses/sinus arrhythmia,AVB, BBB/IVCD

Arrhythmia: ectopy, ↓ QT,preexcitation (WPW),Brugada, e wave (ARVC),SVT/VT

Ischemic changes (new or old):atrial or ventricularhypertrophy

Other diagnostic studies(consider based on results ofH&P and ECG)

• Ambulatory ECG monitoring: ifsuspect arrhythmogenicsyncopeHolter monitoring (continuous

ECG 24–48 h): useful iffrequent events arrhythmia+ sx (4%); asx but signif.arrhythmia (13%); sx but noarrhythmia (17%)

Event recorder (activated by Ptto record rhythm strip):limited role as only useful ifestablished prodrome(because must be Ptactivated)

Loop recorders (continuouslysaves rhythm, ∴ can be

activated after an event):useful for episodes(including w/o prodrome)likely to occur w/in month.

Implantable loop recorders(inserted SC; can record upto 3 y): useful for infrequentepisodes (<1/mo);recommended for recurrentsyncope w/o prodrome

• Echo: consider to r/o structuralheart disease (eg, CMP [inclHCMP & ARVC], valvulardisease [incl AS, MS, MVP],myxoma, amyloid, PHT, ±anomalous coronaries)

• ETT: esp. w/ exertional syncope;

r/o ischemia- orcatecholamine-inducedarrhythmias

• Cardiac catheterization: considerif noninvasive tests suggestischemia

• Electrophysiologic studies (EPS):consider in high-risk Pts inwhom tachy or brady etiologyis strongly suspected, butcannot be confirmed;50% abnl (inducible VT,

conduction abnormalities) ifheart disease, but ?significance

3–20% abnl if abnl ECG; <1%abnl if normal heart and

normal ECG (Annals1997;127:76)

• ? Tilt table testing: utility isdebated due to poorSe/Sp/reproducibility; consideronly if vasovagal dx suspectedbut can’t be confirmed by hx

• Cardiac MRI: helpful to dx ARVCif suggestive ECG, echo (RVdysfxn) or FHx of SCD

• Neurologic studies(cerebrovascular studies, CT,MRI, EEG): if H&P suggestive;low yield

Figure 1-6 Approach to syncope

High-risk features (usually admitw/ telemetry & testing; J EmergMed 2012;42:345)• Age >60 y, h/o CAD, HF/CMP,

valvular or congenital heart

dis., arrhythmias, FHx SCD• Syncope c/w cardiac cause (lack

of prodrome, exertional,resultant trauma) or recurrent

• Complaint of chest pain ordyspnea; abnl VS or cardiacexam

• ECG suggesting tachy or brady-induced syncope; Pt w/PPM/ICD

Treatment• Arrhythmia, cardiac mechanical

or neurologic syncope: treatunderlying disorder

• Vasovagal syncope: no provenbenefit for midodrine,

fludrocortisone, disopyramide,SSRI ? 16 oz of H2O before at-risk situations (Circ2003;108:2660)no proven benefit w/ bB (Circ

2006;113:1164)? benefit w/ PPM if ≥3

episodes/2y & loop recorderw/ asystole >3 sec (Circ2012;125:2566)

• Orthostatic syncope: volumereplete (eg, 500 mL PO qa.m.); if chronic → rise fromsupine to standing slowly,compressive stockings,midodrine, fludrocortisone,high Na diet

Prognosis (Ann Emerg Med1997;29:459; NEJM2002;347:878)• 22% overall recurrence rate if

idiopathic, else 3% recurrence• Cardiac syncope: 2-fold ↑ in

mort., 20–40% 1-y SCD rate,median survival ~6 y

• Unexplained syncope w/ 1.3-fold↑ in mort., but noncardiac orunexplained syncope w/ nlECG, no h/o VT, no HF, age

<45 → low recurrence rateand <5% 1-y SCD rate

• Vasovagal syncope: Pts not atincreased risk for death, MI orstroke

• ✓ state driving laws and MDreporting requirements.Consider appropriateness of Ptinvolvement in exercise/sport,operating machinery, high-riskoccupation (eg, pilot).

INTRACARDIAC DEVICES

Cardiac resynch therapy(CRT)/Biventricular (BiV) pacing(Circ 2012;126:1784)• 3-lead pacemaker (RA, RV,

coronary sinus to LV); R>S inV1 suggests approp LV capture

• Synchronize & enhance LV fxn (↑CO, ↓ adverse remodeling)

• Indic: LVEF ≤35% + NYHA II–IV despite med Rx + SR +

LBBB ≥150 ms (alsoreasonable if either LBBB ≥120ms or no LBBB but QRS ≥150ms + NYHA III–IV); considerin AF, but rate cntl → ~100%vent capture; ? NYHA I w/LVEF ≤30% + LBBB ≥150ms; ? EF ≤50% w/ AVB +indic for PPM (NEJM2013;368:1585)

• Benefits: ↓ HF sx, ↓ HF hosp., ↑survival (NEJM2005;352:1539;2010;363:2385)

Implantable cardiac defibrillator(ICD) (NEJM 2003;349:1836;JACC 2009;54:747)

• RV lead: defib & pacing (±antitachycardia pacing [ATP]= burst pacing > VT rate tostop VT); ± RA lead for dualchamber PPM. Wearable vest& SC ICD exist (Circ2013;127:854).

• Pt selection (NEJM2004;350:2151 & 351:2481;2005;352:225; 2009;361:1427;Circ 2012;126:1784)2° prevention: survivors of VF

arrest, unstable VT w/oreversible cause (NEJM1997;337:1576); structuralheart disease & spontaneoussustained VT (even if asx)

1° prevention: LVEF ≤30% &post-MI or LVEF ≤35% &NYHA II-III (wait: ≥40 d ifpost-MI, ? until stabilized onmeds for NICMP, or ifpresumed reversible) orLVEF ≤40% & inducibleVT/VF; life expectancy mustbe >1 y; consider for HCM,ARVC, Brugada, sarcoid,LQTS, Chagas or congenitalheart disease if risk factorsfor SCD

• Benefits: ↓ mortality from SCDc/w antiarrhythmics orplacebo

• Risks: inapprop shock in ~15–

20% at 3 y (most commonlyd/t misclassified SVT); infxn

• ICD discharge: ✓ device to see ifapprop; r/o ischemia; 6-modriving ban (✓ state law); ifrecurrent VT, ? drug Rx (eg,amio + bB, JAMA2006;295:165) or VT ablation(NEJM 2007;357:2657);ablation at time of ICD ↓ riskof VT by 40% (Lancet2010;375:31)

Device infection (Circ2010;121:458; JAMA2012;307:1727; NEJM2012;367:842)

• Presents as pocket infection(warmth, erythema,tenderness) and/or sepsis w/bacteremia

• Incidence ~2% over 5 y; if S.aureus bacteremia, infxn in≥35%

• TTE/TEE used to help visualizecomplic. (eg, vegetation), buteven TEE does not r/o

• Treatment: abx and removal ofsystem; Ppx: no rec for routineabx prior to invasive proc.

CARDIAC RISK ASSESSMENTFOR NONCARDIAC SURGERY

Preoperative evaluation

Figure 1-7 ACC/AHA approachto preoperative cardiovascularevaluation for noncardiacsurgery

Preoperative testing andassessment• ECG if ≥1 risk factor and

planned vascular surgery or ifknown vascular disease andintermediate risk surgery. ?prior to any vascular surgery.

• TTE if dyspnea of unknownorigin or if HF w/ ↑ dyspneaand no TTE in past 12 mo

• Stress test if active cardiac issues(see above) or vascular surgeryw/ ≥3 risk factors & it will Δmgmt. Overall low PPV topredict periop CV events.

• ? consider CXR and ECG in preopevaluation of severely obesePts (Circ 2009;120:86)

• Comorbidity indices (eg,Charlson index) may predict

mortality (Am J Med Qual2011;26:461)

Pre- & perioperativemanagement• Coronary revascularization

should be based on standardindications (eg, ACS,refractory sx, lg territory atrisk). Has not been shown to Δrisk of death or postop MIwhen done prior to electivevasc. surgery based onperceived cardiac risk (NEJM2004;351:2795) or documentedextensive ischemia (AJC2009;103:897), but systematicangio ↓ 2–5 y mortality in a

vascular surgery trial ( JACC2009;54:989).

• Continue ASA: ↓ MACE in Pts w/cardiac risk factors (Br JAnaesth 2010;104:305)

• Given need for dual antiplateletRx after stenting, wait 4–6 wkafter BMS and ideally >12 moafter DES before discontinuingADP receptor blockade

• If possible, wait >4–6 wk afterMI (even if ETT or ETT &revascularized). If norevasc, wait 6 mo before

elective surgery.• Preop statins: ↓ ischemia & CV

events in Pts undergoing

vascular surg (NEJM2009;361:980); may reduce AF,MI, LOS in statin-naïve Pts(Arch Surg 2012;147:181)

Perioperative β-blocker (Circ2009;120:2123; JAMA2010;303:551; Am J Med2012;125:953)• Conflicting evidence: some

studies show ↓ death & MI(NEJM 1996;335:1713 &1999;341:1789), anothershowed ↓ MI, but ↑ death &stroke and ↑bradycardia/HoTN (Lancet2008;371;1839)

• ? consider if CAD, stress test,or ≥2 cardiac risk factor, esp.if vascular surgery

• Ideally initiate weeks prior tosurgery and titrate slowly andcarefully to achieve desiredindividual HR and BP goal (?HR ~55–65). Avoidbradycardia and hypotension.Do not discontinue bB abruptlypostop, as may causesympathetic activation fromwithdrawal.

Postoperative monitoring• ✓ Postop ECG if known CAD or

high-risk surgery. Consider if

>1 risk factor for CAD.• ✓ Postop troponin only if new

ECG Δs or chest painsuggestive of ACS

PERIPHERAL ARTERY DISEASE(PAD)

Clinical features• Prev. ↑ w/ age: <1% if <40 y,

~15% if ≥70 y; risk factorsincl. smoking, DM, HTN, chol

• Claudication (dull ache, often incalves) precip by walking andrelieved by stopping (vs.spinal stenosis, qv); Lerichesynd = claudication, ↓ or �femoral pulses, & erectiledysfxn

• Critical limb ischemia (CLI):rest pain (↑ w/ elevation b/c↓ perfusion), ulcer (typically

at pressure foci, often dry; incontrast, venous ulcers aremore often at medialmalleolus, wet, and withhemosiderin deposition) organgrene, due to PAD, and>2-wk duration (implieschronicity vs. acute limbischemia, see below)

Diagnosis• ↓ peripheral pulses; other signs of

chronic PAD: hair loss, skinatrophy, nail hypertrophy

• Ankle:brachial index (ABI): nl 1–1.4; borderline 0.91–0.99; abnl≤0.90; if >1.4, non-dx

possibly due to calcifiednoncompressible vessel → ✓PVR. If ABI abnl → segmentalABI w/ PVR to localize disease.If sx but nl ABI, ✓ for ↓lower extrem BP after exercise.

• Duplex arterial U/S; CTA w/distal run-off; MRA or angio

Treatment (JACC 2013;61:1555;JAMA 2013;309:453)• Risk factor modification.

Supervised exercise Rx. Screenfor CAD.

• Cilostazol (if no HF) & ? ACEI to↓ sx. ASA or clopi to ↓D/MI/stroke if claud. or ABI

<0.9.• Revasc if CLI or

limiting/refractoryclaudication

Acute limb ischemia (ALI)• Sudden decrement in limb

perfusion that threatensviability; viable (no immedthreat of tissue loss): audibleart. Doppler signals, sensory &motor OK threatened (salvagerequires prompt Rx): loss ofarterial Doppler signal,sensory or motor

• Etiologies: embolism > acutethrombosis (eg, athero, APLA,

HITT), trauma to artery• Clinical manifestations (6 Ps):

pain (distal to proximal, ↑ inseverity), poikilothermia,pallor, pulselessness,paresthesias, paralysis

• Testing: thorough pulse & neuroexam; arterial Doppler;angiography, either CT w/bilateral run-off through feetor arteriography

• Urgent consultation w/ vascularmedicine and/or vascularsurgery

• Treatment: immediateanticoagulation ±intraarterial lytic; angioplasty

or surgery

DYSPNEA

Evaluation• History: quality of sensation,

tempo, positional dependence,exac./allev. factors, exertion

• Cardiopulmonary exam, SaO2,CXR (see Appendix &

Radiology inserts), ECGpredictors of CHF: h/o CHF,PND, S3, CXR w/ venouscongestion, AF ( JAMA2005;294:1944) dyspnea w/ nlCXR → CAD, asthma, PE, PHT,early ILD, anemia, acidosis,NM disease

• Based on results of initialevaluation: PFT, chest CT,TTE, cardiopulmonary testing

• BNP & NT-proBNP ↑ in CHF(also ↑ in AF, RV strain fromPE, COPD flare, PHT, ARDS)BNP <100 pg/mL to r/o CHF(90% Se), >400 to r/i (NEJM2002;347:161)

NT-proBNP <300 pg/mL tor/o CHF (99% Se); age-related cut points to r/i:>450 pg/mL (<50 y),>900 (50–75 y), >1800(>75 y) (EHJ 2006;27:330)

↑ in chronic heart failure, ∴need to compare to known“dry BNP”

PULMONARY FUNCTION TESTS(PFTs)

• Spirometry: evaluate forobstructive diseaseFlow-volume loops: diagnose

and/or localize obstructionBronchodilator: indicated if

obstruction at baseline orasthma clinically suspected

Methacholine challenge: helpsdx asthma if spirometry nl,>20% ↓ FEV1 → asthma

• Lung volumes: evaluate forhyperinflation or restrictivedisease including NM causes

• DLCO: evaluates functional

surface area for gas exchange;helps differentiate causes ofobstructive and restrictivediseases and screens forvascular disease & early ILD

Figure 2-1 Approach toabnormal PFTs

ASTHMA

Definition and epidemiology• Chronic inflam. disorder w/

airway hyperresponsiveness+ variable airflowobstruction

• Affects ~5% population; ~85%of cases by age 40 y

Clinical manifestations (NEJM2001;344:350)• Classic triad = wheezing,

cough and dyspnea; othersinclude chest tightness,sputum; symptoms typicallychronic with episodicexacerbation

• Precipitants (triggers)respiratory irritants (smoke,

perfume, etc.) & allergens(pets, dust mites, pollen,etc.)

infections (URI, bronchitis,sinusitis)

drugs (eg, ASA & NSAIDs vialeukotrienes, bB viabronchospasm, MSO4 viahistamine) emotional stress,cold air, exercise (increase inventilation dries outairways)

Physical examination• Wheezing and prolonged

expiratory phase• Presence of nasal polyps, rhinitis,

rash → allergic component• Exacerbation → ↑ RR, ↑ HR,

accessory muscle use,diaphoresis, pulsus paradoxus

Diagnostic studies• Peak exp flow (PEF): ≥60

L/min ↑ after bronchodil or≥20% diurnal variation c/wasthma. <80% personal bestc/w poor control, <50% c/wsevere exacerbation.

• Spirometry: ↓ FEV1, ↓ FEV1/FVC,coved flow-volume loop; lungvolumes: ± ↑ RV & TLC

bronchodilator response (↑FEV1 ≥12% & ≥200 mL)strongly suggestive ofasthma methacholinechallenge (↓ FEV1 ≥20%) ifPFTs nl: Se >90% (AJRCCM2000;161:309)

• Sputum: eos >3% has 86% Se,88% Sp; can also seeCurschmann’s spirals (mucuscasts of distal airways) andCharcot-Leyden crystals(eosinophil lysophospholipase)

• Allergy suspected → consider ✓serum IgE, eos, skintesting/RAST

Ddx (“all that wheezes is notasthma … ”)• Hyperventilation & panic attacks• Upper airway obstruction or inh

foreign body; laryngeal/vocalcord dysfxn (eg, 2° to GERD)

• CHF (“cardiac asthma”); COPD,bronchiectasis; ILD (includingsarcoidosis); vasculitis; PE

“Asthma plus” syndromes(Lancet 2002;360:1313)• Atopy = asthma + allergic

rhinitis + atopic dermatitis• ASA-sensitive asthma (Samter’s

syndrome) = asthma + ASAsensitivity + nasal polyps

• ABPA = asthma + pulmonaryinfiltrates + allergic rxn toAspergillus

• Churg-Strauss = asthma +eosinophilia + granulomatousvasculitis

“Reliever” medications (used prnto quickly relieve sx)• Short-acting inh β2-agonists

(SABA): albuterol Rx of choice• Short-acting inh anticholinergics

(ipratropium) ↑ β2-agonistdelivery → ↑ bronchodilation

“Controller” meds (taken daily tokeep control) (NEJM

2009;360:1002)• Inh corticosteroids (ICS): Rx of

choice ( JAMA2001;285:2583). PRN ? as goodas daily for mild asthma(NEJM 2005;352:1519 &2007;356:2040). PO steroidsmay be needed for severelyuncontrolled asthma, but avoidif possible b/c systemic sideeffects.

• Long-acting inh β2-agonists(LABA; eg, salmeterol): ↑ PEFwhen added to ICS (Lancet2009;374:1754). Except forexercise-induced asthma,should not be used w/o ICS

(may ↑ mortality, esp. inAfrican Americans) (Chest2006;129:15; Annals2006;144:904). Clinicalrelevance of β2-receptorpharmacogenetic interactionnot validated (Lancet2009;374:1754).

• Long-act inh anticholinergics(LAA; eg, tiotropium): add-onif sx despite ICS (superior to ↑ICS, to adding LABA; NEJM2010;363:1715) or if sx despiteICS+LABA (NEJM2012;367:1198)

• Nedocromil/cromolyn: limiteduse in adults. Useful in young

Pts, exercise-inducedbronchospasm; ineffectiveunless used before trigger orexercise exposure.

• Theophylline: useful if hard tocontrol sx; PO convenient, buthigh side-effect profile

• Leukotriene antagonists (LTA):some Pts very responsive, esp.ASA-sens (AJRCCM2002;165:9) and exercise-induced (Annals 2000;132:97).May be noninf to ICS initial Rxand LABA add-on Rx (NEJM2011;364:1695).

• Anti-IgE: for uncontrolled mod-to-severe allergic asthma (↑

IgE) on ICS ± LABA (NEJM2006;354:2689; Annals2011;154:573); not cost-effective for most Pts ( JACI2007;120:1146)

Other• Behavior modification: identify

and avoid triggers; PPI w/obenefit (NEJM 2009;360:1487)

• Immunotherapy (eg,desensitization): may be usefulif significant allergiccomponent

• TNF antagonists may be helpfulin Pts w/ refractory asthma(NEJM 2006;354:697)

• Anti-IL5 (mepolizumab) ↓ exac.w/ sev asthma (Lancet2012;380:651), not yet FDAapproved

• Anti-IL13 (lebrikizumab) ↑ FEV1

(NEJM 2011;365:1088), not yetFDA approved

• Bronchial thermoplasty (exp’tal):radiofrequency destruction ofairway smooth muscle no Δ inFEV1, but ↓ in sx and # ofexacerbations (NEJM2007;356:1327)

Principles of treatment• Education and avoidance of

environmental triggers for all

Pts; yearly flu shot• Use quick-relief rescue

medication as needed for allPts

• Goal to achieve completecontrol = daily sx ≤2/wk, Ønocturnal sx or limitation ofactivity, reliever med ≤2/wk,nl PEF or FEV1; partlycontrolled = 1–2 of the abovepresent in a wk; uncontrolled= ≥3 of the above present ina wk

• Step up treatment as needed togain control, step down astolerated

• If PEF ↓ 15% × 2 d or ↓ 30%,4× ICS dose ↓ need for POsteroids (AJRCCM2009;180:598)

• Variants in glucocorticoid-induced transcript 1 gene a/wresp to ICS (NEJM2011;365:1173)

EXACERBATION

Evaluation• History: baseline PEF, steroid

requirement, ED visits,hospital admissions, priorintubation Currentexacerbation: duration,severity, potentialprecipitants, meds usedRisk factors for life-threatening:

prior intubation, h/o near-fatal asthma, ED visit/hospfor asthma w/in 1 y,current/recent PO steroids,not using ICS,overdependent on SABA, Ψ,

h/o noncompl• Physical exam: VS, pulm,

accessory muscle use, pulsusparadoxus, abdominal paradoxAssess for barotrauma:

asymmetric breath sounds,tracheal deviation,subcutaneous air →pneumothorax, precordial(Hamman’s) crunch →pneumomediastinum

• Diagnostic studies: PEF (used tofollow clinical course); SaO2;CXR to r/o PNA or PTX ABG ifsevere: low PaCO2 initially; nlor high PaCO2 may signify

tiring

Initial treatment (NEJM2010;363;755)• Oxygen to keep SaO2 ≥90%• Inhaled SABA (eg, albuterol) by

MDI (4–8 puffs) or nebulizer

(2.5–5 mg) q20min• Corticosteroids: prednisone 0.5–

1 mg/kg PO; IV if impendingresp arrest

• Ipratropium MDI (4–6 puffs) ornebulizer (0.5 mg) q20min ifsevere (Chest 2002;121:1977)

• Epinephrine (0.3–0.5 mL SC of1:1000 dilution) no advantageover inh SABA

• Montelukast IV ↑ FEV1 but didnot Δ rate of hosp ( J AllergyClin Immunol 2010;125:374)

• Reassess after 60–90 min of RxMild-mod exacerbation: cont

SABA q1h

Severe exacerbation: SABA &ipratropium q1h orcontinuously; ± Mg 2 g IVover 20 min (Lancet2003;361:2114); ± heliox(60–80%)

• Decide disposition within 4 h ofpresentation and after 1–3 h ofRx

Figure 2-2 Disposition ofpatients after initial treatment ofasthma exacerbation

ICU-level care• High-dose steroids:

methylprednisolone 125 mg IVq6h (Archives 1983;143:1324)

• Invasive ventilation:large ET tube, Pplat <30 cm

H2O (predicts barotraumabetter than PIP), max exp

timePEEP individualized to Pt

physiologyparalysis, inhalational

anesthetics, bronchoalveolarlavage w/ mucolytic, heliox(60–80% helium) and ECMOhave been used with success

• NPPV likely improves obstruction(Chest 2003;123:1018), butcontroversial and rarely used

ANAPHYLAXIS

Definition and pathophysiology(Ann Emerg Med 2006;47:373)• Severe, rapid-onset (mins to hrs),

potentially life-threateningsystemic allergic response

• IgE-mediated mast celldegranulation with release ofhistamine, tryptase and TNF

• Precipitates systemic reactions(bronchospasm, tissueswelling, fluid shifts,vasodilation)

• Common triggers: penicillins,cephalosporins, shellfish, nuts,insect stings, IV contrast (not

truly an IgE-mediatedmechanism, but clinicallysimilar)

Diagnosis: any of the threefollowing criteria1) Acute illness with skin ±

mucosal involvement (rash,flushing, hives), AND at leastone of:• Respiratory compromise

(wheeze, stridor, dyspnea,hypoxemia)

• Hypotension orhypoperfusion (syncope,incontinence)

2) Two or more of the following

after exposure to a likelyallergen: skin/mucosalinvolvement, respiratorycompromise, ↓ BP orhypoperfusion, GI symptoms

3) Hypotension after exposure toknown allergen for that Pt

Treatment• Epinephrine: IM or SC 0.3–0.5

mL of 1:1000 dilution (1mg/mL) q5–20min; if HoTN orcardiac arrest, IV (or via ETT)2.5–10 mL of 1:10,000 dilutionq5min ± gtt

• Airway management: suppl O2

± intubation (or

cricothyroidotomy if laryngealedema) β2-agonists (stacked orcontinuous nebulizers) forrefractory bronchospasm

• Fluid resuscitation w/ lg volumeof crystalloid (may extravasateup to 35% of blood volume)

• Antihistamines relieve hives &itching, no effect on airway orhemodynamics H1RA(diphenhydramine 50 mgIV/IM) ± H2RA (eg, ranitidine50 mg IV)

• Corticosteroids have noimmediate effect but may helpprevent relapse:methylprednisolone 125 mg IV

q6h if severe or prednisone 50mg PO

• Glucagon (1–5 mg IV over 5 min)if inotropic or chronotropicsupport needed in Pt taking bB

• Avoid unopposed a-adrenergicvasopressors

Disposition• Mild rxn limited to urticaria or

mild bronchospasm can beobserved for ≥6 h; admit allothers

• Watch for biphasic reaction;occurs in 23%, typically w/in8–10 h but up to 72 h

• At time of d/c: education re:

allergen avoidance, instructionand Rx for EpiPen, allergistf/u

CHRONIC OBSTRUCTIVEPULMONARY DISEASE

Definition and epidemiology(NEJM 2004;350:26)• Progressive airflow limitation

caused by airway andparenchymal inflammation

Pathogenesis (Lancet

2003;362:1053)• Cigarette smoke (centrilobular

emphysema, affects 15–20% ofsmokers)

• Recurrent airway infections• ɑ1-antitrypsin defic.: early-onset

panacinar emphysema, 1–3%of COPD cases. Suspect if age<45, lower lungs affected,extrathoracic manifestations(liver disease [not if MZsubtype], FMD, pancreatitis).✓ serum AAT level (nb, acutephase reactant).

Clinical manifestations• Chronic cough, sputum

production, dyspnea; laterstages → freq exac., a.m. HA,wt loss

• Exacerbation triggers: infxn,other cardiopulmonarydisease, incl. PE (Annals2006;144:390)Infxn: overt

tracheobronchitis/pneumoniafrom viruses, S. pneumoniae,H. influenzae, M. catarrhalisor triggered by changes instrain of colonizers (NEJM2008;359:2355)

• Physical exam: ↑ AP diameter ofchest (“barrel-chest”),hyperresonance, ↓

diaphragmatic excursion, ↓breath sounds, ↑ expiratoryphase, rhonchi, wheezes duringexacerbation: tachypnea,accessory muscle use, pulsusparadoxus, cyanosis

Diagnostic studies• CXR (see Radiology inserts):

hyperinflation, flatdiaphragms, ± interstitialmarkings & bullae

• PFTs: Obstruction: ↓↓ FEV1, ↓FVC, FEV1/FVC <0.7 (no sigΔ post bronchodilator),expiratory scooping of flow-volume loop; Hyperinflation:

↑↑ RV, ↑ TLC, ↑ RV/TLC;Abnormal gas exchange: ↓

DLCO (in emphysema)• ABG: ↓ PaO2, ± ↑ PaCO2 (in

chronic bronchitis, usually onlyif FEV1 <1.5 L) and ↓ pH

• ECG: PRWP, S1S2S3, R-sidedstrain, RVH, ↑ P waves in leadII (“P pulmonale”)

Chronic treatment (NEJM2010;362:1407; Lancet2012;379:1341)• Bronchodilators (first-line

therapy): anticholinergics, β2-agonists (BA), theophylline

Long-acting (LA)anticholinergic (LAA,tiotropium): ↓ exac., ↓admit, ↓ resp failure (NEJM2008;359:1543), better thanipratropium or LABA asmono Rx (NEJM2011;364:1093)

LABA: ~15% ↓ inexacerbations, ↓ FEV1

decline, trend toward ↓mort. (NEJM 2007;356:775)

LABA + inh steroid: ? ↓ mort.(NEJM 2007;356:775;AJRCCM 2008;177:19)

LAA + LABA + inh steroid: ↑

FEV1, ↓ COPD admits(Annals 2007;146:545)

• Corticosteroids (inhaled, ICS):~20% ↓ in exacerb if FEV1

<2.0 L (Chest 2009;136:1029)may slow ↓ FEV1, but more soin combo with LABA (NEJM2007;356:775); ↑ in PNA (notseen w/ budesonide; Lancet2009;374:712); no Δ in mort.w/ ICS alone (NEJM2007;356:775)

• Antibiotics: daily azithro ↓exacerb, but not yet routine(NEJM 2011;365:689 &2012;367:340)

• Mucolytics: no Δ FEV1, but ? ↓exacerbation rate (Lancet2008;371:2013)

• Oxygen: if PaO2 ≤55 mmHg orSaO2 ≤89% (during rest,exercise or sleep) to preventcor pulmonale; only Rx provento ↓ mortality (Annals1980;93:391; Lancet1981;i:681)

• Prevention: Flu/Pneumovax;smoking cessation (eg,varenicline, bupropion) →50% ↓ in lung function decline(AJRCCM 2002;166:675) and ↓long-term mortality (Annals

2005;142:223)• Rehabilitation: ↓ dyspnea and

fatigue, ↑ exercise tolerance, ↓QoL (NEJM 2009;360:1329)

• ExperimentalLung volume reduction

surgery: ↑ exer. capacity, ↓mort. if FEV1 >20%, upper-lobe, low exer. capacity(NEJM 2003;348:2059);bronchoscopic w/endobronchial valves w/mixed benefits: ↑ lung fxnbut ↑ PNA, exacerb,hemoptysis (NEJM2010;363:1233)

Roflumilast (PDE-4 inhibitor):↑ FEV1 when added tostandard Rx (Lancet2009;374:685&695)

Nocturnal BiPAP: may improvesurvival, ? decrease QoL(Thorax 2009;64:561)

• Lung transplant: ↑ QoL and ↓ sx(Lancet 1998;351:24), ?survival benefit (Am JTransplant 2009;9:1640)

Staging and prognosis• FEV1: 50–80% predicted → 3-y

mort. ~11%; 30–50% →~15%; <30% → ~24%

• BODE 10-pt scale (Lancet

2009;374:704); HR 1.62 forresp mort., 1.34 mort. for each1-pt ↑ BMI: ≤21 (+1)Obstruction (FEV1): 50–64%

(+1), 36–49% (+2), ≤35%(+3)

Dyspnea (MMRC scale):walking level (+1), after100 yd (+2), with ADL (+3)

Exs capacity (6-min walk):250–349 m (+1), 150–249(+2), ≤149 (+3)

superior to FEV1 (NEJM2004;350:1005); can predictsurvival from LVRS (Chest2006;129:873)

• mMRC score: ≥2 defined aswalking slowly b/cbreathlessness or having tostop to catch breath walkinglevel

• Ratio of diam PA/aorta >1associated with ~3× ↑ risk ofexacerbations (NEJM2012;367:913)

EXACERBATION

HEMOPTYSIS

Definition and pathophysiology• Expectoration of blood or blood-

streaked sputum• Massive hemoptysis: ~>600

mL/24–48 h; gas exchangemore important than bloodloss

• Massive hemoptysis usually fromtortuous or invaded bronchialarteries

Diagnostic workup• Localize bleeding site

Rule out GI or ENT source byexam, history; may requireendoscopy

Pulmonary source: determinewhether unilateral orbilateral, localized ordiffuse, parenchymal orairway by CXR or chest CT,

bronchoscopy if necessary• PT, PTT, CBC to rule out

coagulopathy• Sputum culture/stain for

bacteria, fungi and AFB;cytology to r/o malignancy

• ANCA, anti-GBM, urinalysis to ✓for vasculitis or pulmonary-renal syndrome

Treatment• Mechanism of death is

asphyxiation notexsanguination; maintain gasexchange, reverse coagulationand treat underlyingcondition; cough supp. may ↑

risk of asphyxiation• Massive hemoptysis: put bleeding

side dependent; selectivelyintubate nl lung if neededAngiography: Dx & Rx (vascularocclusion balloons or selectiveembol of bronchial art) Rigidbronchoscopy: allows moreinterventional options(electrocautery, laser) thanflex. Surgical resection

BRONCHIECTASIS

Definition and epidemiology(NEJM 2002;346:1383)• Obstructive airways disease of

bronchi and bronchioles,chronic transmural inflammw/ airway dilatation andthickening, collapsibility,mucus plugging w/ impairedclearance

• Frequency: > ; in the U.S.more frequent in AsianAmericans (Chest2012;142:432)

Initial workup• H&P: cough, dyspnea, copious

sputum production, ±hemoptysis, inspiratory“squeaks”

• CXR: scattered or focal; rings ofbronchial cuffing; “tram track”of dilated, thick airways

• PFTs: obstructive pattern• Chest CT: dilation and thickening

of airways; ± cystic changes,infiltrates, adenopathy

Treatment• Treat underlying condition;

mucolytics & bronchodilators• Antibiotics: CF Pts often have

multiple drug-resistantorganisms (Pseudomonas,Burkholderia cepacia, S. aureus)and require IV antibioticsduring exacerbations. Azithroshown to ↓ exacerb. in non-CFbronchiectasis (Lancet2012;380:660; JAMA2013;309:1251).

• Emerging data on gene-basedtargeted therapies in CF (NEJM2011;365:1663)

SOLITARY PULMONARYNODULE

Principles• Definition: single, <3 cm,

surrounded by normal lung, noLAN or pleural effusion

• Often “incidentalomas,” esp with↑ CT use, but may still beearly, curable malignancy

Initial evaluation

• History: h/o cancer, smoking,age (<30 y = 2% malignant,+15% each decade >30)

• CT: size/shape, Ca2+, LAN,effusions, bony destruction,compare w/ old studiesØ Ca → ↑ likelihood

malignant; laminated →granuloma; “popcorn” →hamartoma

• High-risk features formalignancy: ≥2.3 cmdiameter, spiculated, >60 yo,>1 ppd current smoker, noprior smoking cessation (NEJM2003;348:2535)

Diagnostic studies• PET: detects metab. activity of

tumors, 97% Se & 78% Sp formalig. (esp. if >8 mm) alsouseful for surgical staging b/cmay detect unsuspected mets(JAMA 2001;285:914) useful indeciding which lesions to bxvs. follow w/ serial CT ( JThor Oncol 2006;1:71)

• Transthoracic needle biopsy(TTNB): if tech. feasible, 97%will obtain definitive tissue dx(AJR 2005;185:1294); ifnoninformative or malignant→ resect

• Video-assisted thoracoscopic

surgery (VATS): forpercutaneously inaccessiblelesions; highly sensitive andallows resection; has replacedthoracotomy

• Transbronchial bx (TBB): mostlesions too small to reliablysample w/o endobronchial U/S(Chest 2003;123:604); bronchw/ brushings low-yield unlessinvading bronchus;navigational bronchoscopy w/70% yield, ↑ sens w/ largernodules (Chest 2012;142:385)

• PPD, fungal serologies, ANCA

Management (for solid SPN >8

mm; if ≤8 mm, serial CT) (Chest2013;143:840)• Low risk (<5%, see ref): serial

CT (freq depending on risk);shared decision w/ Pt re: bx

• Intermediate risk (5–60%):PET, if → follow low-riskprotocol; if → high-riskprotocol

• High risk (and surgicalcandidate): TBB, TTNB, orVATS → lobectomy ifmalignant

• Ground-glass nodules: longerf/u b/c even if malignant canbe slow-growing and PET

OBSTRUCTIVE SLEEP APNEA(OSA)

Definition and pathophysiology• Repetitive pharyngeal collapse

during sleep causing apnea(≥10 s) or hypopnea (airflowreduction) ± desaturation,arousals from sleep → daytimesleepiness

• Apnea-hypopnea index = avg #apneas and hypopneas per hrof sleep

• Sleep-induced loss of activity ofpharyngeal dilator muscles →pharyngeal collapse → arousal→ activation of sympathetic

nervous system; phenotypesvary across OSA Pts

• Apnea → negative intrathoracicpressure → ↑ preload, ↑afterload → HTN, CV sequelae

• Risk factors: obesity (present in70%), male, age, alcohol,smoking, black race

Clinical manifestations (Lancet2002;360:237; Lancet Resp Med2013;1:61)• Snoring, witnessed

apneas/gasping, daytimesleepiness

• Cardiovascular: HTN ( JAMA2012;307:2169); a/w ↑ risk of

stroke and death (NEJM2005;353:2034) & possiblyCAD & endothelial dysfxn(AJRCCM 2001;163:19; Circ2008;117:2270)

• Neurocognitive: ↓ cognitiveperformance, ↓ QoL, ↑ motorvehicle and work accidents(NEJM 1999;340:847; AJRCCM2001;164:2031)

Diagnosis and treatment• Polysomnography (sleep study);

can do home-testing. If , trialof CPAP.

• CPAP: ↓↓ apnea/hypopnea, ↓ BP(Lancet 2002;359:204), ↓

sleepiness, ↑ performance(AJRCCM 2012;186:677), ↑ EFin Pts with CHF (NEJM2003;348:1233), ↓ metabsyndrome (NEJM2011;365:2277), ↓ mortalityafter stroke (AJRCCM2009;180:36)

• Oral appliances can preventretroglossal collapse. Offer ifrefusing CPAP.

• Avoid alcohol and sedatives• Surgery (eg,

uvulopalatopharyngoplasty,UPPP) of limited benefit (Chest1997;111:265)

INTERSTITIAL LUNG DISEASE

WORKUP OF ILD

Rule out mimickers of ILD• Congestive heart failure (✓

BNP, trial of diuresis)• Infection: viral, atypical

bacterial, fungal,mycobacterial, parasitic

• Malignancy: lymphangiticcarcinomatosis,bronchoalveolar, leukemia,lymphoma

History and physical exam• Occupational, travel, exposure

(including tobacco), meds,

FHx, precipitating event• Tempo (acute → infxn, CHF,

hypersens pneumonitis, eosPNA, AIP, COP, drug-induced)

• Extrapulmonary s/s (skin Ds,arthralgias/arthritis, clubbing,neuropathies, etc.)

Diagnostic studies (see Appendix& Radiology inserts)• CXR and high-resolution chest

CT: reticular, nodular orground glass pattern upper →coal, silicon, hypersens,sarcoid, TB, RA; lower → IPF,asbestos, sclerodermaadenopathy → sarcoidosis,

berylliosis, silicosis,malignancy, fungal infectionspleural disease → collagen-vascular diseases, asbestosis,infections, XRT

• PFTs: ↓ DLCO (early sign),restrictive pattern (↓ volumes),↓ PaO2 (esp. w/ exercise); ifalso obstructive, considersarcoid, LAM, silicosis

• Serologies: ✓ ACE, ANA, RF,ANCA, anti-GBM, HIV

• Bronchoalveolar lavage: dxinfxn, hemorrhage,eosinophilic syndromes, PAP

• Biopsy (transbronch, CT-guided,

VATS, open) if no clearprecipitant and w/uunrevealing

ETIOLOGIES OF ILD

Sarcoidosis (NEJM2007;357:2153; JAMA2011;305:391)• Prevalence: African Americans,

northern Europeans andfemales; onset in 3rd–4thdecade

• Pathophysiology: depression ofcellular immune systemperipherally, activationcentrally

• Löfgren’s syndrome: erythemanodosum + hilar adenopathy+ arthritis (good prognosis)

• Diagnostic studies: LN bx →noncaseating granulomas +multinucleated giant cells18FDG PET can be used to

identify extent and potentiallytargets for dx bx ↑ ACE (Se60%, 90% w/ active dis., Sp80%, false in granulomatousdiseases)

• To assess extent: CXR, PFTs, fullophtho exam, ECG, CBC(lymphopenia, ↑ eos), Ca, 24-hurine for Ca, LFTs; ± Holter,echo, cardiac MRI, brain MRI,etc., based on s/s

• Rx: steroids (eg, prednisone 20–40 mg/d) if sx or extrathoracicorgan dysfxn (improves sx, butdoesn’t Δ long-term course);hydroxychloroquine forextensive skin disease; anti-

TNF, MTX, AZA,mycophenolate orcyclophosphamide forchronic/refractory disease

• Prognosis: ~2/3 spontaneouslyremit w/in 10 y (60–80% ofstage I, 50–60% stage II, 30%stage III), w/ relapsesuncommon; ~1/3 haveprogressive disease

Iatrogenic• Amiodarone (~10%; dose &

duration depend.): chronicinterstitial pneumonia ↔ARDS; bx → vacuolized Mf w/lamellar inclusions on EM; Rx:

d/c amio, give steroids• Other drugs: nitrofurantoin,

sulfonamides, thiazides, INH,hydralazine, gold

• Chemo: bleomycin (triggered byhyperoxia), busulfan,cyclophosphamide, MTX, etc.

• XRT: COP/BOOP w/ sharplylinear, nonanatomicboundaries; DAH

Idiopathic interstitialpneumonias (IIPs) (AJRCCM2005;172:268)• Definition: ILD of unknown

cause; dx by radiographic,histologic and clinical features

UIP, usual interstitial PNA (IP);IPF, idiopathic pulm fibrosis(Lancet 2011;378:1949); NSIP,nonspecific IP; COP, cryptogenicorganizing PNA; BOOP,bronchiolitis obliterans w/organizing PNA; AIP, acute IP(Hamman-Rich syndrome); DIP,desquamative IP; RB-ILD, resp

bronchiolitis-assoc ILD.

• Rx for UIP/IPF: ?? NAC (NEJM2005;353:2229); pred + AZAharmful (NEJM 2012;366:1968)Experimental: tyrosine kinase

inhib (NEJM2011;365:1079); pirfenidone(Lancet 2011;377:1760; notavail in U.S.); ? sildenafil(NEJM 2010;363:621);thalidomide for cough(Annals 2012;157:398)

• Steroids for other IIPs: NSIP (esp.cellular type) and COP(AJRCCM 2000;162:571); ?benefit for AIP and DIP/RB-

ILD (for which Pts should stopsmoking)

Environmental & occupationalexposures (NEJM 2000;342:406;Lancet 2012;379:2008)• Pneumoconioses (inorganic

dusts)Coal worker’s: upper lobe coal

macules; may progress tomassive fibrosis

Silicosis: upper lobe opacities± eggshell calcification oflymph nodes; ↑ risk of TB

Asbestosis: lower lobe fibrosis,calcified pleural plaques,DOE, dry cough, rales on

exam. Asbestos exposurealso → pleural plaques,benign pleural effusion,diffuse pleural thickening,rounded atelectasis,mesothelioma, lung Ca (esp.in smokers).

Berylliosis: multisystemicgranulomatous disease thatmimics sarcoidosis

• Hypersensitivitypneumonitides (organicdusts): loose, noncaseatinggranulomasAntigens: farmer’s lung (spores

of thermophilicactinomyces); pigeon

fancier’s lung (proteins fromfeathers and excreta ofbirds); humidifier lung(thermophilic bacteria)

Collagen vascular diseases(NEJM 2006;355:2655)• Rheumatologic disease

Scleroderma: fibrosis in ~67%;PHT seen in ~10% of CRESTPts

PM-DM: ILD & weakness ofrespiratory muscles; MCTD:PHT & fibrosis

SLE & RA: pleuritis and pleuraleffusions more often thanILD; SLE can cause DAH

• Vasculitis (can p/w DAH)Wegener’s granulomatosis (

c-ANCA) w/ necrotizinggranulomas

Churg-Strauss syndrome ( c-or p-ANCA) w/ eosinophilia& necrotizing granulomas

Microscopic polyangiitis ( p-ANCA) w/o granulomas

• Goodpasture’s syndrome =DAH + RPGN; typically insmokers; anti-GBM in 90%

• Lymphangioleiomyomatosis(LAM): cystic, ↑ in , Rx w/sirolimus (NEJM2011;364:1595)

Pulmonary infiltrates w/eosinophilia (PIE) = eos on BAL± periph. blood• Allergic bronchopulmonary

aspergillosis (ABPA): allergicreaction to AspergillusCriteria: asthma, pulm

infiltrates (transient orfixed), skin rxn & serumprecipitins to Aspergillus, ↑IgE to Aspergillus & total(>1000), ↑ eos, centralbronchiectasis

Rx: steroids ± itraconazole forrefractory cases (NEJM2000;342:756)

• Löffler’s syndrome:

parasites/drugs → transientpulm infilt + cough, fever,dyspnea, eos

• Acute eosinophilic PNA (AEP):acute hypox febrile illness; Rx:steroids, tobacco cessation

• Chronic eosinophilic pneumonia(CEP): “photonegative” ofCHF, typically in women

• Other: Churg-Strauss syndrome;hypereosinophilic syndrome

Miscellaneous• Pulm alveolar proteinosis (PAP):

accum of surfactant-likephospholipids; smokers;white & gummy sputum; BAL

milky fluid (NEJM2003;349:2527); Rx w/ lunglavage & GMCSF

• Langerhans cell granulomatosis(LCG): young smokers;apical cysts; PTX (25%)

• Lymphocytic interstitial PNA:polyclonal B-cell infiltration (?lymphoma); Rx: steroids

PLEURAL EFFUSION

Pathophysiology• Systemic factors (eg, ↑ PCWP, ↓

oncotic pressure) →transudative effusion

• Local factors (ie, Δ pleuralsurface permeability) →exudative effusion

Transudates• Congestive heart failure

(40%): 80% bilateral, ±cardiomegaly on CXRoccasionally exudative (esp.after aggressive diuresis or ifchronic), but ~75% ofexudative effusions in CHF Pts

found to have non-CHF cause(Chest 2002;122:1518)

• Constrictive pericarditis (knockon exam, calcification orthickening on imaging)

• Cirrhosis (“hepatichydrothorax”): diaphragmaticdefect w/ passage of asciticfluid often right-sided (2/3) &massive (even w/o markedascites)

• Nephrotic syndrome: usuallysmall, bilateral, asymptomatic(r/o PE b/c hypercoag)

• Other: PE (usually exudate),malignancy (lymphatic

obstruction), myxedema, CAPD

Exudates• Lung parenchymal infection

(25%)bacterial (parapneumonic):

can evolve along spectrumof exudative (but sterile) →fibropurulent (infected fluid)→ organization (fibrosis &formation of rigid pleuralpeel). Common causes: Streppneumo, Staph aureus, Strepmilleri, Klebsiella,Pseudomonas, Haemophilus,Bacteroides,Peptostreptococcus, mixed

flora in aspirationpneumonia.

mycobacterial: >50% lymphs80% of the time, ADA >40,pleural bx ~70% Se

fungal, viral (usually small),parasitic (eg, amebiasis,echinococcosis,paragonimiasis)

• Malignancy (15%): primarylung cancer most common,metastases (esp. breast,lymphoma, etc.),mesothelioma (✓ serumosteopontin levels; NEJM2005;353:15)

• Pulmonary embolism (10%):

effusions in ~40% of PEs;exudate (75%) > transudate(25%); hemorrhagic—musthave high suspicion b/cpresentation highly variable

• Collagen vascular disease: RA(large), SLE (small),Wegener’s, Churg-Strauss

• Gastrointestinal diseases:pancreatitis, esophagealrupture, abdominal abscess

• Hemothorax (Hcteff/Hctblood

>50%): trauma, PE,malignancy, coagulopathy,leaking aortic aneurysm, aorticdissection, pulmonary vascularmalformation

• Chylothorax (triglycerides>110): thoracic duct damagedue to trauma, malignancy,LAM

• Other:post-CABG: left-sided; initially

bloody, clears after severalwks

Dressler’s syndrome(pericarditis & pleuritis post-MI), uremia, postradiationtherapy

Asbestos exposure: benign; eosinophils

Drug-induced (eg,nitrofurantoin,methysergide,

bromocriptine, amiodarone): eos

Uremia; post-XRT; sarcoidosisMeigs’ syndrome = benign

ovarian tumor → ascites &pleural effusion

Yellow-nail syndrome: yellownails, lymphedema, pleuraleffusion, bronchiectasis

Diagnostic studies• Thoracentesis (NEJM

2006;355:e16)Indications: all effusions >1

cm in decubitus view ifsuspect due to CHF, candiurese and see if effusions

resolve (75% do so in 48 h)asymmetry, fever, chest painor failure to resolve →thoracentesisparapneumonics should betapped ASAP (cannotexclude infxn clinically)

Diagnostic studies: ✓ totalprotein, LDH, glucose, cellcount w/ differential, Gramstain & culture, pH;remaining fluid foradditional studies as dictatedby clinical scenario

Complications: PTX (5–10%),hemothorax (~1%), re-expansion pulm edema (if

>1.5 L removed),spleen/liver lac.; post-tapCXR not routinely needed(Annals 1996;124:816)

↓ PTX w/ U/S and experiencedsupervisor (Chest2009;135:1315; Archives2010;170:332)

• Transudate vs. exudate (Annals1972;77:507)Light’s criteria: exudate =

TPeff/TPserum >0.5 orLDHeff/LDHserum >0.6 orLDHeff >2/3 ULN ofLDHserum; 98% Se, 83% Sp;best Se of all methods (Chest

1995;107:1604); however,will misidentify 25% oftransudates as exudates; ∴if clinically suspecttransudate but meetscriterion for exudate,confirm w/ test w/ higher Sp

exudative criteria w/ better Sp:serum-effusion alb gradient≤1.2, Se 87%, Sp 92%;serum-effusion TP gradient≤3.1, Se 84%, Sp 91%;choleff >45 mg/dL andLDHeff >200, 90% Se, 98%Sp (no serum required)

CHF effusions: TP may ↑ with

diuresis or chronicity →“pseudoexudate”; albgradient ≤1.2, choleff >60mg/dL (Se 54%, Sp 92%) orclin judgment to distinguish(Chest 2002;122:1524)

• Complicated vs. uncomplicatedparapneumonic (Chest1995;108:299)complicated = Gram stain

or culture or pH <7.2 orglucose <60

complicated parapneumoniceffusions usually requiredrainage to achieveresolution

empyema = frank pus, alsoneeds drainage to achieveresolution

• Additional pleural fluid studies(NEJM 2002;346:1971)NT-proBNP ≥1,500 pg/mL has

91% Se & 93% Sp for CHF(Am J Med 2004;116:417)

WBC & diff.: exudates tend tohave ↑ WBC vs. transudatesbut nonspecific neutrophils→ parapneumonic, PE,pancreatitis lymphocytes(>50%) → cancer, TB,rheumatologic eos (>10%)→ blood, air, drug rxn,asbestos, paragonimiasis,

Churg-Strauss, PERBC: Hcteff 1–20% → cancer,

PE, trauma; Hcteff/Hctblood

>50% → hemothoraxAFB: yield in TB 0–10% w/

stain, 11–50% w/ culture,~70% w/ pleural bx

adenosine deaminase (ADA):seen w/ granulomas, >70suggests TB, <40 excludesTB

cytology: ideally ≥150 mL andat least 60 mL should beobtained (Chest2010;137:68)

glucose: <60 mg/dL →

malignancy, infection, RAamylase: seen in pancreatic

disease and esophagealrupture (salivary amylase)

rheumatoid factor, CH50, ANA:limited utility in dx collagenvascular disease

triglycerides: >110 →chylothorax, 50–110 → ✓lipoprotein analysis forchylomicrons

cholesterol: >60; seen inchronic effusions (eg, CHF,RA, old TB)

creatinine: effusion/serumratio >1 → urinothorax

fibulin-3: ↑ plasma and/oreffusion levels →mesothelioma (NEJM2012;367:1417)

• Chest CT; pleural biopsy; VATS• Undiagnosed persistent pleural

effusions (Clin Chest Med2006;27:309)Transudative: most commonly

CHF or hepatic hydrothorax.✓ s/s CHF or cirrhosis, NT-proBNPeff; considerintraperitoneal injection oftechnetium-99m sulfurcolloid

Exudative (ensure using Sp test

listed above): mostcommonly malig, empyema,TB, PE. ✓ s/s malig, chestCT (I+), ADA or IFN-grelease assay; considerthoracoscopy.

Treatment• Symptomatic effusion:

therapeutic thoracentesis, treatunderlying disease process

• Parapneumonic effusion (Chest

2000;118:1158)uncomplicated → antibiotics

for pneumonia>1/2 hemithorax or

complicated or empyema→ tube thoracostomy(otherwise risk oforganization and subsequentneed for surgicaldecortication)

loculated→ tube thoracostomyor VATS; intrapleural t-PA +DNase ↓ need for surgicalreferral (NEJM2011;365:518)

• Malignant effusion: serial

thoracenteses vs. tubethoracostomy + pleurodesis(success rate ~80–90%) vs.indwelling pleural catheter ( JAMA 2012;307:2383); choiceof pleurodesis agent (talc,bleo, doxy) controversial;systemic steroids & pH <7.2a/w ↑ pleurodesis failure rate

• TB effusions: effusion will oftenresolve spontaneously;however, treat Pt for active TB

• Hepatic hydrothoraxRx: Δ pressure gradient (ie, ↓

ascitic fluid volume, NIPPV)avoid chest tubes; prn

thoracenteses, pleurodesis,

TIPS or VATS closure ofdiaphragmatic defects ifmedical Rx fails; NIPPV foracute short-termmanagement

spontaneous bacterialempyema (SBEM) can occur(even w/o SBP beingpresent), ∴ thoracentesis ifsuspect infection

transplant is definitivetreatment and workupshould begin immediately

VENOUS THROMBOEMBOLISM(VTE)

Definitions• Proximal deep venous thrombosis

(DVT): thrombosis of popliteal,femoral or iliac veins(nb, “superficial” femoral vein

part of deep venous system)• Pulmonary embolism (PE):

thrombosis originating invenous system and embolizingto pulmonary arterialcirculation; 1 case/1000person y; 250,000/y (Archives2003;163:1711)

Risk factors

• Virchow’s triad forthrombogenesisstasis: bed rest, inactivity,

CHF, CVA w/in 3 mo, airtravel >6 h (NEJM2001;345:779)

injury to endothelium:trauma, surgery, prior DVT,inflammation

thrombophilia: APCresistance, protein C or Sdeficiency, APS,prothrombin genemutation,↑ factor VIII,hyperhomocysteinemia, HIT,OCP, HRT, tamoxifen,raloxifene

• Malignancy (12% of “idiopathic”DVT/PE)

• History of thrombosis (greaterrisk of recurrent VTE thangenetic thrombophilia)

• Statin therapy ↓ risk (NEJM2009;360:1851)

Clinical manifestations—DVT• Calf pain, swelling (>3 cm c/w

unaffected side), venousdistention, erythema, warmth,tenderness, palpable cord, Homan’s sign (calf pain ondorsiflexion, seen in <5% ofPts), phlegmasia cerulea dolens:stagnant blood → edema,cyanosis, pain

• 50% of Pts with sx DVT have asxPE

Diagnostic studies—DVT• D-dimer: <500 helps r/o; ? use

1000 as threshold if low risk(Annals 2013;158:93)

• Compression U/S >95% Se & Spfor sx DVT (lower for asxDVT); survey whole leg ratherthan just proximal if ≥mod

prob ( JAMA 2010;303:438);venography rarely used

Figure 2-3 Approach tosuspected DVT (Chest2012;141:e351S)

Clinical manifestations—PE• Dyspnea (73%), pleuritic chest

pain (66%), cough (37%),hemoptysis (13%)

• ↑ RR (>70%), crackles (51%), ↑HR (30%), fever, cyanosis,

pleural friction rub, loud P2

• Massive: syncope, HoTN, PEA; ↑JVP, R-sided S3, Graham Steell(PR) murmur

Diagnostic studies—PE (NEJM2010;363:266)• CXR (limited Se & Sp): 12% nl,

atelectasis, effusion, ↑hemidiaphragm, Hamptonhump (wedge-shaped density

abutting pleura); Westermarksign (avascularity distal to PE)

• ECG (limited Se & Sp): sinustachycardia, AF; signs of RVstrain → RAD, P pulmonale,RBBB, SIQIIITIII & TWI V1–V4

(McGinn-White pattern, Chest1997;111:537)

• ABG: hypoxemia, hypocapnia,respiratory alkalosis, ↑ A-agradient (Chest 1996;109:78)18% w/ room air PaO2 85–105mmHg, 6% w/ nl A-a gradient(Chest 1991;100:598)

• D-dimer: high Se, poor Sp(~25%); ELISA has >99%

NPV and can be used to r/o PEin Pts w/ “unlikely” pretestprob. ( JAMA 2006;295:172)

• Echocardiography: useful for riskstratification (RV dysfxn), butnot dx (Se <50%)

• V/Q scan: high Se (~98%), lowSp (~10%). Sp improves to97% for high prob VQ. Use ifpretest prob of PE high and CTnot available orcontraindicated. Can alsoexclude PE if low pretest prob,low prob VQ, but 4% false ( JAMA 1990;263:2753).

• CT angiography (CTA; seeRadiology inserts): Se ~90% &

Sp ~95% w/ MDCT (NEJM2006;354:2317); PPV & NPV>95% if imaging concordantw/ clinical suspicion, ≤80% ifdiscordant (∴ need to considerboth); CT may also provideother dx

• Lower extremity compressionU/S shows DVT in ~9%,sparing CTA, but when addedto CTA, does not Δ outcomes(Lancet 2008;371:1343)

• Pulmonary angio: ? goldstandard (morbidity 5%,mortality <0.5%),infrequently performed

• MR angiography: Se 84%

(segmental) to 100% (lobar)(Lancet 2002;359:1643); if addMR venography, Se 92%, Sp96% (Annals 2010;152:434)

Figure 2-4 Approach tosuspected PE using CTA

Workup for idiopathic VTE• Thrombophilia workup: ✓ if

FH, consider if age <50 y or

on OCP/HRT. Send panel 2 wkafter completeanticoagulation, as thrombus,heparin and warfarin Δresults. Nb, does not changemanagement after 1stidiopathic DVT if plan forlong- term anticoagulation ( JAMA 2005;293:2352; Blood2008;112:4432; Am J Med2008;121:458).

• Malignancy workup: 12% Ptsw/ “idiopathic” DVT/PE willhave malignancy; age-appropriate screeningadequate; avoid extensive w/u(NEJM 1998;338:1169)

Risk stratification for Pts withPE• Clinical: hypotension and/or

tachycardia (~30% mortality),hypoxemia

• CTA: RV / LV dimension ratio>0.9 (Circ 2004;110:3276)

• Biomarkers: ↑ troponin (Circ2002;106:1263), ↑ BNP (Circ2003;107:1576) a/w ↑mortality

• Echocardiogram: RV dysfxn(controversial in absence ofhypotension)

• Simplified PE Severity Index: 0RFs → 1.1% mort.; ≥1 →8.9% mort (Archives

2010;170:1383) RFs: age >80y; h/o cancer; h/o HF or lungdisease; HR ≥110; SBP <100;SaO2 <90%

Treatment of VTE (Lancet2012;379;1835; Chest2012;141:e419S)• LE DVT: proximal →

anticoagulate; distal:anticoagulate if severe sx orrisk for extension, o/w mayconsider serial imaging(although if bleeding risk low,many would anticoagulate)

• UE DVT: anticoagulate (sameguidelines as LE; NEJM

2011;364:861). If catheter-associated, need not remove ifcatheter functional andongoing need for catheter.

• Superficial venous thrombosis:anticoagulate (esp. if extensiveclot) as 10% experiencethromboembolic event w/in 3mo (Annals 2010;152:218)

• Acute anticoagulation options(initiate immediately if highclinical suspicion!)LMWH (eg, enoxaparin 1

mg/kg SC bid or dalteparin200 IU/kg SC qd)

Preferred over UFHexcept: renal failure

(CrCl <25), ? extremeobesity, hemodynamicinstability or bleed risk(Cochrane2004;CD001100)

No need to monitor anti-factor Xa unless concernre: dosing (eg, renalinsuffic.)

Attractive option as outPtbridge to long-term oralanticoagulation

Fondaparinux: 5–10 mg SC qd(NEJM 2003;349:1695); useif HIT ; avoid if renalfailure

IV UFH: 80 U/kg bolus → 18

U/kg/h → titrate to PTT1.5–2.3 × cntl (eg, 60–85sec)

Rivaroxaban: 15 mg bid (for1st 3 wk) LMWH followedby warfarin (NEJM2010;363:2499 &2012;366:1287); effect wearsoff w/in 24 h, but not easilyimmediately reversed

Direct thrombin inhibitors (eg,argatroban, lepirudin) usedin HIT Pts

• Early ambulation• DVT & low-risk PE can be treated

completely as outPt (Lancet2011;378:41)

• Thrombolysis (eg, TPA 100 mgover 2 h or wt-adjusted TNKbolus)Use if PE a/w hemodynamic

compromise (“massive PE”)Consider if PE w/o

hemodynamic compromise,but high-risk (“submassivePE,” eg, marked dyspnea,severe hypoxemia, RVdysfxn on echo, RVenlargement on CTA) andlow bleed risk. Risk of ICH~1% and no provenmortality benefit (NEJM2002;347:1143; Cochrane2006:CD004437).

Consider if extensive (eg,iliofemoral) acute DVT andcatheter-directed Rx notavailable

• Catheter-directed therapy(fibrinolytic & thrombusfragmentation/aspiration)Consider if extensive vs. in all

acute DVT as ↓postthrombotic synd (Lancet2012;379:31)

Consider if PE w/hemodynamic compromiseor high risk and notcandidate for systemicfibrinolytic therapy orsurgical thrombectomy (Circ

2011;124:2139)• Thrombectomy: if large,

proximal PE + hemodynamiccompromise + contra. to lysis;consider in experienced ctr if

large prox. PE + RV dysfxn( J Thorac CV Surg2005;129:1018)

• IVC filter: if anticoagulationcontraindication, failure orbleed, or ? ↓ CP reserve; temp.filter if risk time limited;adding filter toanticoagulation → PE ↓ 1/2,DVT ↑ 2×, no mort. diff.(NEJM 1998;338:409; Circ

2005;112:416)• Long-term anticoagulation

optionsWarfarin (goal INR 2–3): start

same day as heparin unlessinstability and ? need forlytic, catheter-based Rx orsurgery; overlap ≥5 d w/heparin & until INR ≥2 ×≥24 h

Rivaroxaban (after 15 mg bidfor 1st 3 wk, then 20 mg qd)

warfarin (see refs above)Dabigatran (NEJM

2009;361:2342) andidrabiotaparinux (weekly SCFXa inhib; Lancet 2012;

379:123) both appear warfarin, but neither FDAapproved

VTE a/w cancer: LMWH × 3–6 mo, then LMWH/warfarinindefinitely or until cancercured (NEJM 2003;349:146);✓ head CT for brain mets ifmelanoma, renal cell,thyroid, chorioCA

• Duration of anticoagulation:Superficial venous thrombosis:

4 wk1st prox DVT or PE 2°

reversible/time-limited riskfactor or distal DVT: 3 mo

1st unprovoked prox DVT or

PE: ≥3 mo, then reassess; iflow bleed risk → indefiniteRx w/ warfarin; extended Rxw/ newer agents understudy: c/w placebo apixaban(either 2.5 or 5 mg) ↓↓ VTEw/o ↑ major bleeding (NEJM2013;368:699); rivaroxaban(20 mg qd) or dabigatran(150 mg bid) also ↓↓ VTE but↑ major bleeding (NEJM2010;363:2499 &2013;368:709)

2nd VTE event: indefinitewarfarin (NEJM1997;336:393 &2003;348:1425)

Can be guided by D-dimertesting at 1 & 3 mo (NEJM2006;355:1780; Blood2010;115:481)

After 6–18 mo of anticoag forunprovoked VTE, if decide tostop anticoag (eg, b/c ofbleeding) ASA ↓ risk ofrecurrent VTE by 32%(NEJM 2012;366:1959 &367:1979)

Complications & prognosis• Postthrombotic syndrome (25%):

pain, swelling; ↓ withcompression stockings × 3 mo

• Recurrent VTE: 1%/y (after 1st

VTE) to 5%/y (after recurrentVTE)after only 6 mo of Rx: 5%/y &

>10%/y, respectivelypredictors: abnl D-dimer 1

month after d/c anticoag(NEJM 2006;355:1780); U/S after 3 mo of anticoag(Annals 2002;137:955);thrombin generation >400nM ( JAMA 2006;296:397)

• Chronic thromboembolic PHTafter acute PE ~3.8% (NEJM2004;350:2257), considerthromboendarterectomy

• Mortality: ~10% for DVT and~10–15% for PE at 3–6 mo

(Circ 2008;117:1711)

PULMONARY HYPERTENSION(PHT)

PA mean pressure >25 mmHg at rest

Pathobiology (NEJM2004;35:1655)• Smooth muscle & endothelial cell

proliferation; mutations inbone morphogenic proteinreceptor 2 (BMPR2) in ~50%familial & ~26% sporadiccases of IPAH (NEJM2001;345:319)

• Imbalance betweenvasoconstrictors andvasodilators↑ vasoconstrictors:

thromboxane A2 (TXA2),serotonin (5-HT),endothelin-1 (ET-1)

↓ vasodilators: prostacyclin(PGI2), nitric oxide (NO),vasoactive peptide (VIP)

• In situ thrombosis: ↑ TXA2, 5-HT,PAI-1; ↓ PGI2, NO, VIP, tissueplasminogen activator

Clinical manifestations• Dyspnea, exertional syncope

(hypoxia, ↓ CO), exertionalchest pain (RV ischemia)

• Symptoms of R-sided CHF (eg,peripheral edema, RUQfullness, abdominal distention)

• WHO class: I=asx w/ ordinaryactivity; II=sx w/ ord. activ.;III=sx w/ min activ.; IV=sx atrest

Physical exam• PHT: prominent P2, R-sided S4,

RV heave, PA tap & flowmurmur, PR (Graham Steell),TR

• ± RV failure: ↑ JVP,hepatomegaly, peripheraledema

Diagnostic studies & workup

(Circ 2009;119:2250)• IPAH yearly incidence 1–2 per

million, ∴ r/o 2° causes• CXR and high-resolution chest

CT: dilatation & pruning ofpulmonary arteries,enlargement of RA and RV; r/oparenchymal lung disease

• ECG: RAD, RBBB, RAE (“Ppulmonale”), RVH (Se 55%, Sp70%)

• PFTs: ↓ DLco, mild restrictivepattern; r/o obstructive andrestrictive lung disease

• ABG & polysomnography: ↓ PaO2

and SaO2 (esp. w/ exertion), ↓

PaCO2, ↑ A-a gradient; r/ohypoventilation and OSA

• TTE: ↑ RVSP (but over or underby ≥10 mmHg in 1/2 of PHTPts; Chest 2011;139:988),flattened (“D”) septum, TR,PR; r/o LV dysfxn, MV diseaseand congenital heart disease

• RHC: ↑ RA, RV, & PA pressures,nl PCWP (unless due to L-sidedheart disease), ↑ transpulmgradient (PAP-PCWP >12–15,but can be nl if due to LV orvalvular dis.), ↑ PVR, ↓ CO; r/o↑ L-sided pressures shunt

• CTA (large/med vessel), V/Q

scan (small vessel to r/oCTEPH), ± pulmonaryangiogram: r/o PE and chronicthromboembolic disease

• Vasculitis labs: ANA (~40% inPAH), RF, anti-Scl-70,anticentromere, ESR

• LFTs & HIV: r/o portopulmonaryand HIV-associated PAH

• 6-min walk test (6MWT) orcardiopulmonary exercisetesting to establish fxnlcapacity

Treatment (NEJM2004;351:1425; JIM2005;258:199; Circ

2009;119:2250)• Principles 1) prevent and reverse

vasoactive substanceimbalance and vascularremodeling

2) prevent RV failure: ↓ wallstress (↓ PVR, PAP, RV diam);ensure adeq. systemic DBP

• SupportiveOxygen: maintain SaO2 >90–

92% (reducesvasoconstriction)

Diuretics: ↓ RV wall stress andrelieve RHF sx; gentle b/c RVis preload dependent

Digoxin: control AF, ?counteract neg. inotropiceffects CCB

Dobutamine and inhaled NOfor decompensated PHT

Anticoagulation: ↓ VTE risk ofRHF; ? prevention of in situmicrothrombi; ? mort.benefit even if in NSR (Circ1984;70:580; Chest2006;130:545)

• Vasodilators (right heartcatheterization prior toinitiation) acute vasoreactivitytest: use inhaled NO, adenosineor prostacyclin to identify Ptslikely to have a long-term

response to oral CCB (vasoreactive response definedas ↓ PAP ≥10 mmHg to a level<40 mmHg with ↑ or stableCO); ~10% Pts are acuteresponders; no response → stillcandidates for othervasodilators (NEJM2004;351:1425)

• Treat underlying causes of 2°PHT; can use vasodilators,although little evidence

• Refractory PHT:balloon atrial septostomy:

R→L shunt causes ↑ CO, ↓SaO2, net ↑ tissue O2 delivery

lung transplant (single orbilateral); heart-lung neededif Eisenmenger physiology

Figure 2-5 Treatment of PAH(modi ed from JACC2009;54:S78)

Management of ICU patient

• Avoid overly aggressive volumeresuscitation

• Caution with vasodilators if anyL-sided dysfunction

• May benefit frominotropes/chronotropes

• Consider fibrinolysis if acute,refractory decompensation(eg, TPA 100 mg over 2 h)

Prognosis• Median survival after dx ~2.8 y;

PAH (all etiologies): 2-y 66%,5-y 48% (Chest 2004;126:78-S)

• Poor prognostic factors: clinicalevidence of RV failure, rapidlyprogressive sx, WHO (modified

NYHA) class IV, 6MWT <300m, peak VO2 <10.4mL/kg/min, ↑ RA or RV or RVdysfxn, RA >20 or CI <2.0, ↑BNP (Chest 2006;129:1313)

• Lung transplant: 1-y survival 66–75%; 5-y survival 45–55%(Chest 2004;126:63-S)

RESPIRATORY FAILURE

• A-a gradient = PAO2 – PaO2:normal (on room air) = “4 +age/4” or “2.5 + (0.2 × age)”hypoxemia + normal A-agradient → problem is excessPaCO2 (ie, hypoventilation)

• V/Q mismatch and shuntrepresent spectrum w/ bothcoexisting in alveolar disease100% O2 can overcome V/Q

mismatch but not large

shunt b/c sigmoidal Hg-O2

curve

Figure 2-6 Workup of acutehypoxemia

• Cyanosis: seen when >4 g/dL ofreduced Hb in blood vessels ofskin/mucous membranes

central: ↓ SaO2 (pulm disease,shunt); abnl Hb [metHb,sulfHb, COHb (not truecyanosis)] peripheral: ↓ bloodflow → ↑ O2 extraction (eg, ↓CO, cold, arterial or venousobstruction)

CO binds to Hb more avidly thandoes O2. Pulse oximeter (Ox)misreads COHb as HbO2 →

falsely nl sat. Oxidizing drugs ΔHb (ferrous) to MetHb (ferric),which cannot carry O2. Pulse oxmisreads MetHb as HbO2.Cyanide inhibits mitochondrialO2 use → cellular hypoxia butpink skin and ↑ venous O2 sat.

MECHANICAL VENTILATION

Indications• Improve gas exchange

↑ oxygenation↑ alveolar ventilation and/or

reverse acute respiratoryacidosis

• Relieve respiratory distress↓ work of breathing (can

account for up to 50% oftotal oxygen consumption)

↓ respiratory muscle fatigue• Apnea, airway protection,

pulmonary toilet

Choosing settings (NEJM2001;344:1986)

1. Choose method (includingpotentially noninvasiveventilation, see later)2. Pick ventilator mode, and (ifappropriate) volume targeted orpressure targeted3. Set or ✓ remaining variables(eg, FiO2, PEEP, I:E time, ow,airway pressures)

Tailoring the ventilator settings• To improve oxygenation: options

include ↑ FiO2, ↑ PEEPFirst, ↑ FiO2. If >0.6 and

oxygenation remainssuboptimal, then try ↑ PEEP:

If ↑ PaO2/FiO2 and Pplat stable,suggests recruitable lung (ie,atelectasis). Continue to ↑PEEP until either can ↓ FiO2

to <0.6 or Pplat ≥30 cmH2O. If PEEP 20 & FiO2 1.0and oxygenation remainssuboptimal, considerrescue/expt strategies (see“ARDS”).

If ↑ PEEP yields no Δ or ↓PaO2/FiO2 or ↑ PaCO2,suggests additional lung not

recruitable and insteadoverdistending lung → ↑shunt & dead space; ∴ ↓PEEP

• To improve ventilation: ↑ VT orinspiratory pressure, ↑ RR(may need to ↓ I time). Nb,tolerate ↑ PaCO2 (permissivehypercapnia) in ALI/ARDS(qv) as long as pH >7.15.

Acute ventilatory deterioration(usually ↑ PIP)• Response to ↑ PIP: disconnect Pt

from vent., bag, auscultate,suction, ✓ CXR & ABG

Figure 2-7 Approach to acuteventilatory deterioration

Weaning from the ventilator(NEJM 2012;367:2233)• Perform daily assessment of

readiness for spontaneousbreathing trial (SBT)

• Clinical screening criteria: VSstable, minimal secretions,

adequate cough, cause ofrespiratory failure orpreviously failed SBT reversed

• Vent parameters: PaO2/FiO2

>200, PEEP ≤5, f/VT <105,VE <12 L/min, VC >10mL/kg rapid shallow breathingindex (f/VT) >105 predictsfailure; NPV 0.95 (NEJM1991;324:1445)

• Daily awakening trial (d/c allsedation; Lancet2008;371:126): open eyes &w/o: agitation, RR >35, SaO2

<88%, resp distress or

arrhythmias (if fail, restartsedation at 1/2 prior dose).

• SBT = CPAP or T piece × 30–120 minfailure if: deteriorating ABGs, ↑

RR, ↑ or ↓ HR, ↑ or ↓ BP,diaphoresis, anxiety

• Tolerate SBT → extubation. FailSBT → ? cause → work tocorrect → retry SBT qd

Complications• Oxygen toxicity (theoretical);

proportional to duration +degree of ↑ oxygen (FiO2

>0.6)• Ventilator-associated pneumonia

(~1%/day, mortality rate~30%)typical pathogens: MRSA,

Pseudomonas, Acinetobacterand Enterobacter species

preventive strategies (AJRCCM2005;171:388): wash hands,HOB elevated, non-nasalintub., enteral nutritionrather than TPN, routinesuction of subglotticsecretions, avoidunnecessary abx &transfusions, routine oralantiseptic, stress-ulcerprophylaxis w/ ? sucralfate(↓ VAP, ↑ GIB) vs.

H2RA/PPI, ? silver-coatedtubes ( JAMA 2008;300:805)

• Laryngealedema: for Pts vent >36 h; ?

predicted by cuff leak test.Methylprednisolone 20 mgIV q4h starting 12 h pre-extub. → ↓↓ edema and 50%↓ in reintubation (Lancet2007;369:1003)

ulceration: considertracheostomy for patients inwhom expect >14 d of mechvent → ↓ duration mechvent, ↓ # ICU days (BMJ2005;330:1243); no benefit

to performing at ~1 wk vs.waiting until ~2 wk ( JAMA2010;303:1483)

• Malnutrition (for all critically illPts): enteral nutrition initiatedearly is safe but not necessary( JAMA 2012;307:795), butbolus may ↑ risk of VAP & Cdiff. ( JPEN 2002;26:174); noclear benefit to ✓ing gastricresiduals ( JAMA2013;309:249); parenteralnutrition should be delayeduntil after day 8 to ↓ risk ofinfections, cholestasis, RRT,ventilator days (NEJM2011;365:506)

• Oversedation/delirium: BDZs andpolypharmacy are risk factorspropofol: HoTN in ~25%;

propofol infusion syndrome(PRIS) ? esp. w/ high (>5mg/kg/h) & prolonged(>48 h) infusions & concomvasopressors → ↑ AG,cardiac dysfxn,rhabdomyolysis, ↑triglycerides, & renal failure(Crit Care 2009;13:R169)

dexmedetomidine: ↑ vent-freedays, but brady & HoTN c/wBDZ ( JAMA 2012;307:1151)

ACUTE RESPIRATORY DISTRESSSYNDROME

New “Berlin” definition ( JAMA2012;307:2526)• Acute onset within 1 wk of

clinical insult or worseningrespiratory status

• Bilateral infiltrates withoutalternative explanation (eg,effusion, atelectasis, nodules)

• Edema not fully explained byfluid overload or congestiveheart failure

• Hypoxemia: PaO2/FiO2

determined with 5 cm H2O ofPEEP

PaO2/FiO2 200–300 = mildARDS (may be on NIPPV),100–200 = mod, <100 =severe

• Chest CT: heterogeneous lungwith densities greater independent areas

• Lung bx: diffuse alveolar damage(DAD); Ø req, may give usefuldx info (Chest 2004;125:197)

Pathophysiology• ↑ intrapulmonary shunt →

hypoxemia (∴ Rx w/ PEEP toprevent derecruitment)

• ↑ increased dead space fraction(see Appendix), predicts ↑

mort. (NEJM 2002;346:1281)• ↓ compliance: VT/(Pplat – PEEP)

<50 mL/cm H2O

Treatment (primarily supportive)(Lancet 2007;369:1553; NEJM2007;357:1113)• Goal is to maintain gas

exchange, sustain life, & avoidventilator-induced lung injury(VILI)

• Fluid balance: target CVP 4–6cm H2O (if nonoliguric &normotensive) → ↑ vent/ICU-free days, but no Δ mortality(NEJM 2006;354:2564); PAcatheter unproven (NEJM2006;354:2213); using BNP>200 to trigger diuresis (UOP

goal 4.5–9 mL/kg/h × 3 h) ↓time to extubation (AJRCCM2012;186:1256)

• Steroids: debate continues.Adverse effects includeneuromuscular weakness, poorglc control, ? infection. Benefitmay vary by time since ARDSonset:<72 h: older studies w/o

benefit (NEJM1987;317:1565); ? ↓mortality, ↑ vent/ICU-freedays in more recent,controversial study (Chest2007;131:954)

7–13 d: ? benefit → ↑

vent/ICU-free days, nomortality difference (NEJM2006;354:1671)

≥14 d: ↑ mortality (NEJM2006;354:1671)

• Paralysis: if PaO2/FiO2 <150,cisatracurium × 48 h ↓mortality (NEJM2010;363:1107)

• Experimental ( JAMA2010;304:2521)Inhaled NO or prostacyclins: ↑

PaO2/FiO2, no ↓ mort. orvent-free days (BMJ2007;334:779)

Prone: ↑ PaO2, but ↑

complications and no ↓mortality ( JAMA2009;302:1977); ? ↓mortality if PaO2/FiO2 <100(Intens Care Med2010;36:585)

High-freq oscillatory vent: nobenefit and possible harm(NEJM 2013;368:795, 806, &863)

Lung recruitment: apply CPAP40–45 cm H2O × 2 min torecruit lung and then ↑ PEEPto maintain; sicker Pts had ↑recruitable lung (NEJM2006;354:1775, 1839)

ECMO: may be useful inrefractory ARDS, but nogood trial data (NEJM2011;365:1905)

Esoph manometry: adjust PEEPaccording to esoph pressure( pleural pressure) tomaintain positive transpulmpressure → ↑ PaO2/FiO2, ↑compliance and possibleoutcome benefit (NEJM2008;359:2095); helpful inobese Pts or w/ ↑ abdominalpressure

Prognosis• Mortality ~40% overall in

clinical trials; 9–15% resp.causes, 85–91% extrapulm(MODS)

• ↑ BNP & troponin a/w ↑mortality (Chest 2007;131:964;PLoS One 2012;7:e40515)

• Survivors: PFTs ~normal, ↓DLCO, muscle wasting,weakness persists (NEJM2003;348:683), ↓ exercisetolerance, ↓ QoL, ↑ psychmorbidity (NEJM2011;364:1293)

SEPSIS

Fluids & vasoactive drugs• Early goal-directed therapy

(“Rivers Protocol,” NEJM2001;345:1368), confirm. trialspendingInsert arterial & central venous

lines (NEJM 2007;356:e21;PAC not needed) and ✓

MAP, CVP & ScvO2 (centralvenous O2 sat, nl 60–80%)which measures O2

consumption vs. delivery(less invasive than mixedvenous) w/ low SCVO2 → ↓O2 delivery (↓ SaO2, nl SaO2

but ↓ CO or anemia) orexcessive O2 consumption

Target MAP ≥65 mmHg, CVP8–12 mmHg, & UOP ≥0.5mL/kg/h using fluid (eg, 500mL NS q30min) andvasopressors as needed

Target ScvO2 ≥70% using

PRBCs & inotropes(dobutamine, ↑ dose asneeded q15min)

When done w/in first 6 h forsevere sepsis & septic shock,42% ↓ mortality

• Lactate clearance (≥20% / 2 h)as effective as ScvO2 to guideresuscitation ( JAMA2010;303:739)

• Crystalloid better than colloid forresuscitation (NEJM2004;350:2247 &2012;367:124 & 1901)

• Norepi ↓ arrhyth. & mort. c/wdopamine (NEJM

2010;362:779; Crit Care Med2012;40:725)

• Vasopressin added to low-dosenorepinephrine not superior tohigh-dose norepinephrine(NEJM 2008;358:877); considerif HoTN refractory tocatecholamine vasopressors

• Use PRBC w/ caution, may ↑mortality/morbidity, ↑ risk ofARDS (Crit Care Med2005;33:1191); ∴ goal Hb 7unless active cardiac ischemia(NEJM 1999;340:409)

• After early resuscitation, ifALI/ARDS, target CVP 4–6mmHg as additional fluids may

be harmful → ↑ ventilator/ICUdays (NEJM 2006;354:2564;Chest 2008;133:252)

• Pulse pressure variation >13%with respiration → likelyvolume-responsive (Chest2008;133:252); only validatedin passive, intubated Pts andstudied in higher tidal volumes

Antibiotics• Start empiric IV abx w/in 1 h of

recognition of severe sepsis orseptic shock; every hour delayin abx admin a/w 8% ↑ inmortality (Crit Care Med2006;34:1589)

• If possible, obtain 2 sets of BCxbefore urgently starting abx(but do not delay abx)

• Typically want broad gram-positive and gram-negativecoverage, including MRSA andhighly resistant gram-negativebacilli ± anaerobes

Steroids (NEJM 2003;348:727;JAMA 2009;301:2362)• Cortisol secretion helps predict

mortality, but treatment ofadrenal insufficiency isunproven ( JAMA2000;283:1038; NEJM2008;358:111)

• Earlier study showed possiblemortality benefit w/in 8 h ofsevere septic shock (SBP <90for >1 h despite fluids &pressors) if post ACTH stimcortisol Δ ≤ 9 µg/dL ( JAMA2002;288:862)

• No mortality benefit to early(<72 h) empiriccorticosteroids in all Pts w/septic shock, regardless ofACTH stim; faster resolution ofshock, more superinfection(NEJM 2008;358:111)

• ? hydrocortisone 50–100 q6–8h± fludrocortisone 50 µg dailyin septic shock refractory to

fluids & pressors, regardless ofACTH stim (Crit Care Med2008;36:296)

Activated protein C• No longer FDA approved, no

improvement in mortality(NEJM 2012;366:2055)

Intensive glycemic control(NEJM 2010;363:2540)• No evidence of improved

outcomes in MICU populationw/ intensive glycemic control

• Intensive glycemic control togoal 80–110 mg/dL in surgicalICU population → mortalitybenefit, greatest if >3-d ICU

stay (NEJM 2001;345:1359)• Repeat studies suggest intensive

glycemic control → either no Δor ↑ increased mortality, anddefinite ↑ hypoglyc. ( JAMA2008;300:933; NEJM2006;354:449; 2008;358:125;2009;360:1283)

• Hypoglycemia associated withmortality (NEJM2012;367:1108)

• Reasonable to keep glc <150mg/dL in severe sepsis, usingvalidated protocol (Crit CareMed 2008;36:296)

ESOPHAGEAL AND GASTRICDISORDERS

DYSPHAGIA

Definitions• Oropharyngeal: inability to

propel food from mouththrough UES into esophagus

• Esophageal: difficulty swallowing& passing food from esophagusinto stomach

Figure 3-1 Etiologies of andapproach to dysphagia (NCPGastrohep 2008;5:393;Neurogastro 2012;24:57)

Achalasia• Etiologies: idiopathic (most

common), pseudoachalasia(due to GE jxn tumor), Chagas

• Sx: dysphagia (solid & liquid),chest pain (1/3 of Pts),regurgitation

• Dx: barium swallow → dilatedesophagus w/ distal “bird’sbeak” narrowing; manometry→ simultaneous, lowamplitude contractions ofesophageal body, incompleterelaxation of lower esophagealsphincter (± LEShypertension); EGD → r/opseudoachalasia (retroflex)

• Rx: expert pneumatic dilation(≤4% eso perf) lap Hellermyotomy (NEJM2011;364:1868)

Other esophageal disorders• Webs (upper/mid esoph;

congenital, GVHD, Fe-deficanemia); Rings (lower; ? dueto GERD); Zenker’sdiverticulum (pharyngoesophjxn); dx w/ barium swallow;Rx: endo/surg

• Infxn esophagitis: odynophagia> dysphagia; oftenimmunosupp w/ Candida, HSV,CMV

• Pill esophagitis: odynophagia >dysphagia; NSAID, KCl,bisphosp., doxy & tetracycline

• Eosinophilic esophagitis (ClinGastro & Hep 2012;10:1066):seen in young or middle-aged,predom . Dx req >15 eos/hpf

on bx & exclude GERD (eg,empiric PPI trial). Rx: 3Ds:Diet (elim milk, soy, eggs,wheat, nuts, fish); Drugs(swallow inh steroids),Dilation

GASTROESOPHAGEAL REFLUXDISEASE (GERD)

Pathophysiology• Excessive transient relaxations of

lower esophageal sphincter(LES) or incompetent LES

• Mucosal damage (esophagitis)due to prolonged contact w/acid can evolve to stricture

• Risk factors: hiatal hernia,obesity, gastric hypersecretorystates, delayed emptying

• Precipitants: supine position,fatty foods, caffeine, alcohol,cigarettes, CCB, pregnancy

Clinical manifestations

• Esophageal: heartburn, atypicalchest pain, regurgitation,water brash, dysphagia

• Extraesophageal: cough, asthma(often poorly controlled),laryngitis, dental erosions

Diagnosis (Gastro 2008;135:1383;Am J Gastro 2010;105:747; Annals2012;157:808)• Based on hx & empiric trial of

PPI (Se & Sp: 78% & 54%)(Annals 2004;140:518)

• EGD if: (1) failure to respond tobid PPI; (2) alarm features:dysphagia, vomiting, wt loss,evid of blood loss; or ? (3)

>50 y w/ sx ≥5 y +nocturnal sx, hiatal hernia,obesity, cigs

• If dx uncertain & EGD nl → highres manometry w/ 24-h esophpH monitoring ± impedance

Treatment (NEJM 2008;359:1700)• Lifestyle: avoid precipitants, lose

weight, avoid large & latemeals, elevate head of bed

• Medical: PPI achieve relief in 80–90% (titrate to lowest dosethat achieves sx control) surgery among Pts whoinitially respond to acidsuppression (JAMA

2011;305:1969)• Refractory: confirm w/ pH

testing: if acidic or sx correlatew/ reflux episodes → surgicalfundoplication (implantationof magnetic esophagealsphincter device being studied;NEJM 2013;368:719); if nl pHor no sx correlation → TCA,SSRI or baclofen (Gastro2010;139:7.e3)

Complications (NEJM2009;361:2548; Gastro2011;140:1084 & e18)• Barrett’s esophagus: dx by bx of

intestinal metaplasia above GE

jxn. Screen for BE if ≥2 of thefollowing risk factors: >50 y,male, white, chronic GERD,hiatal hernia, high BMI.

• Esophageal adenocarcinoma: risk~0.12%/y if Barrett’s,~2.3%/y if low-gradedysplasia, ~6%/y if high-grade dysplasia; ~40% of Ptsw/ esoph adenoca report no hxof GERD sx

• Management: Barrett’s w/odysplasia: surveillance EGDq3–5 y; low-grade dysplasia: q6– 12 mo. 4 quadrant bx q 2cm. Chemopreventive benefitof ASA under study.

High-grade dysplasia: U/S tor/o invasive cancer;endoscopic mucosalresection of any visiblemucosal irregularity +ablation of dysplasia(radiofrequency orphotodynamic).

DYSPEPSIA (“INDIGESTION”)

Definition• Upper abdominal sx: discomfort,

pain, fullness, early satiety,bloating, burning

Etiologies• Functional (“nonulcer

dyspepsia” or NUD ~60%):some combination of visceralafferent hypersensitivity &abnormal gastric motility(Rome III criteria in Gastro2006;130:1377)

• Organic (~40%): GERD, PUD,rarely gastric cancer, other(meds, diabetic gastroparesis,

lactose intolerance, biliarypain, chronic pancreatitis,mesenteric ischemia)

• Alarm features that suggestorganic cause & warrant EGD:see list above under GERD

Treatment of functionaldyspepsia (Gastro 2005;129:1756;Alim Pharm Ther 2012;36:3)• H. pylori eradication → empiric

Rx if serology, NNT = 14(Cochrane 2006(2) CD002096)

• PPI effective in some (? misdxGERD), others: TCA,prokinetics, buspirone

PEPTIC ULCER DISEASE (PUD)

Epidemiology & etiologies(Lancet 2009;374:1449)• Lifetime prevalence ~10%, but

incidence ↓ (H. pylori andpotent acid suppression Rx).However, hosp for complicunD’d in general and ↑ inelderly, likely 2° to ↑ NSAIDuse.

• H. pylori infection: 80% ofduodenal ulcers (DU) and 60%of gastric ulcers (GU) ~50% ofpopulation colonized w/ H.pylori, but only 5–10% willdevelop PUD

• ASA & NSAIDs: 45% erosions,15–30% GU, 0.1–4% UGIB

• Hypersecretory states (oftenmult. recurrent ulcers):gastrinoma (Zollinger-Ellisonsyndrome, also p/w diarrhea,<1% of PUD), carcinoid,mastocytosis

• Malignancy: 5–10% of GU• Other: smoking, stress ulcers,

XRT, chemo, CMV/HSV(immunosupp),bisphosphonates; steroidsalone generally not a riskfactor, but may exacerbateNSAID-induced ulceration

Clinical manifestations• Epigastric abdominal pain:

relieved with food (DU) orworsened by food (GU)

• Complications: UGIB, perforation& penetration, gastric outletobstruction

Diagnostic studies• Test for H. pylori

Stool antigen or EGD + rapidurease test now dx tests ofchoice & to confirm erad (4–6 wk post txment); false ifon abx, bismuth, PPI, so stopprior to testing if possible

Serology: ↓ utility, useful only

to exclude infection in lowprevalence areas (most ofU.S.)

• EGD req to def make dx; considerif fail empiric Rx or alarmfeatures; bx GU to r/o malig;relook in 6–12 wk ifapparently benign ulcer >2.5cm, complicated or sx persist

Treatment (NEJM 2010;362:1597,Gut 2012;61:646)• If H. pylori , eradicate:

Triple Rx: clarith+[amox,MNZ or levoflox]+PPI bid× 10–14 d (if clarith resistrate <20%)

Quadruple Rx: MNZ + TCN +bismuth + PPI (if clarithresist rate >15% or amoxallergy) erad vs. triple 93 vs.70%, clarith sens 95 vs.85%, resist 91 vs. 8% (Lancet2011;377:905)

Sequential Rx: PPI + amox ×7 d → PPI + clarith + MNZ× 7 d (Lancet 2013;381:205)

Besides PUD, test & Rx if:gastric MALT lymphoma,atrophic gastritis, FHxgastric ca

• If H. pylori : gastric acidsuppression w/ PPI

• Discontinue ASA and NSAIDs; add

PPI• Lifestyle changes: d/c smoking

and probably EtOH; diet doesnot seem to play a role

• Surgery: if refractory to med Rx(1st r/o NSAID use) or forcomplications (see above)

Prophylaxis if ASA/NSAIDrequired (JACC 2008;52:1502)• PPI if (a) h/o PUD/UGIB; (b)

also on clopidogrel (although ?↓ antiplt effect); (c) ≥2 of thefollowing: age >60, steroidsor dyspepsia; prior to start test& Rx H. pylori

• Consider misoprostol; consider

H2RA if ASA monotherapy(Lancet 2009;374:119)

• Consider Δ to COX-2 inhibit (↓PUD & UGIB but ↑ CV events)if low CV risk & not on ASA

• Stress ulcer: risk factors = ICU &coagulopathic, mech vent, h/oGIB, steroid use; Rx w/ PPI

GASTROINTESTINAL BLEEDING

Definition• Intraluminal blood loss anywhere

from the oropharynx to theanus

• Classification: upper = abovethe ligament of Treitz; lower= below the ligament of Treitz

• Signs: hematemesis = blood invomitus (UGIB);hematochezia = bloodystools (LGIB or rapid UGIB);melena = black, tarry stoolsfrom digested blood (usuallyUGIB, but can be anywhereabove and including the right

colon)

Etiologies of upper GI bleed(UGIB)• Peptic ulcer disease (50%): H.

pylori, NSAIDs, gastrichypersecretory states

• Varices (10–30%): esophageal ±gastric, 2° to portal HTN. Ifisolated gastric → r/o splenicvein thrombosis.

• Gastropathy/gastritis/duodenitis(15%): NSAIDs, ASA, alcohol,stress, portal hypertensive

• Erosive esophagitis/ulcer(10%): GERD, XRT, infectious(CMV, HSV or Candida if

immunosuppressed), pillesophagitis (bisphosphonate,NSAIDs; ± odynophagia)

• Mallory-Weiss tear (10%): GEjunction tear due to retchingagainst closed glottis

• Vascular lesions (5%)Dieulafoy’s lesion: superficial

ectatic artery usually incardia → sudden, massiveUGIB

AVMs, angioectasias, hered.hemor. telangiectasia:submucosal, anywhere in GItract

Gastric antral vascular ectasia(GAVE): “watermelon

stomach,” tortuous, dilatedvessels; a/w cirrhosis,atrophic gastritis, CRESTsyndrome

Aortoenteric fistula: AAA oraortic graft erodes into 3rdportion of duodenum; p/w“herald bleed”; if suspected,diagnose by endoscopy orCT

• Neoplastic disease: esophageal orgastric carcinoma, GIST

• Oropharyngeal bleeding andepistaxis → swallowed blood

Etiologies of lower GI bleed(LGIB)

• Diverticular hemorrhage (33%):60% of diverticular bleedinglocalized to right colon

• Neoplastic disease (19%): usuallyoccult bleeding, rarely severe

• Colitis (18%): infectious,ischemic, radiation,inflammatory bowel disease(UC >> CD)

• Angiodysplasia (8%): mostcommonly located inascending colon and cecum

• Anorectal (4%): hemorrhoids,anal fissure, rectal ulcer

• Other: postpolypectomy,vasculitis

Clinical manifestations• UGIB > LGIB: N/V,

hematemesis, coffee-groundemesis, epigastric pain,vasovagal, melena

• LGIB > UGIB: diarrhea,tenesmus, BRBPR,hematochezia (11% UGIB;Gastro 1988;95:1569)

Initial management• Assess severity: tachycardia

(can be masked by bB use)suggests 10% volume loss,orthostatic hypotension 20%loss, shock >30% loss

• Resuscitation: placement of 2

large-bore (18-gauge or larger)intravenous lines Volumereplacement: NS or LR toachieve normal VS, UOP, &mental status

• Transfuse: blood bank samplefor type & cross; use O-neg ifemerg; transfuse as needed; forUGIB (esp. w/ portal HTN) usemore restrictive Hb goal (eg, 7g/dL) (NEJM 2013;368:11)

• Reverse coagulopathy: FFP &vit K to normalize PT; plts tokeep count >50,000

• Triage: consider ICU if unstableVS or poor end organperfusion

Intubation for emergent EGD,if ongoing hematemesis,shock, poor resp status, ΔMS

? OutPt management if SBP≥110, HR <100, Hb ≥13 (

) or ≥12 ( ), BUN <18, �melena, syncope, heartfailure, liver disease (Lancet2009;373;42)

Workup• History: where (anatomic

location) & why (etiology)acute or chronic, prior GIB, #

of episodes, other GI dxhematemesis, vomiting prior to

hematemesis (Mallory-Weiss), melena,hematochezia

abdominal pain, wt loss,anorexia, Δ in stool caliber

gastric irritants (ASA/NSAIDs),antiplatelet drugs,anticoagulants, knowncoagulopathy

alcohol (gastropathy, varices),cirrhosis, known liverdisease, risk factors for liverdisease

abdominal/rectal radiation,history of cancer, prior GI oraortic surgery

• Physical exam: VS most

important, orthostatic Ds, JVPlocalizable abd tenderness,

peritoneal signs, masses,LAN, signs of prior surgery

signs of liver disease(hepatosplenomegaly,ascites, etc.)

rectal exam: masses,hemorrhoids, anal fissures,stool appearance, color,occult blood

pallor, jaundice,telangiectasias (alcoholicliver disease or hered.hemor. telangiectasia)

• Lab studies: Hct (may be normalin first 24 h of acute GIB

before equilibration)↓ 2–3% → 500 mL blood loss;

low MCV → Fe deficient andchronic blood loss; plt, PT,

PTT; BUN/Cr (ratio >36 inUGIB b/c GI resorption ofblood ± prerenal azotemia);LFTs

Diagnostic studies• Nasogastric tube can aid

localization: fresh blood →active UGIB; coffee grounds →recent UGIB; nonbloody bile →? lower source, but does notexclude active UGIB (~15%missed); occult blood testing

of no value• UGIB: EGD w/in 24 h for dx and

poss Rx; ↓ LOS & need forsurgery, consider erythro 250mg IV 30 min prior → emptystomach of blood → ↑ Dx/Rxyield (Am J Gastro2006;101:1211)

• LGIB: first r/o UGIB beforeattempting to localizepresumed LGIB (10–15%actually UGIB, 3–5% smallbowel), then colonoscopy(identifies cause in >70%);consider rapid purge w/ PEGsolution 4 L over 2 h; no clearbenefit of colonoscopy w/in 12

vs. 36–60 h (AJG2010;105;2636); CT angiopromising (Radiology2010;262:109)

• Unstable or recurrent UGIB &LGIB:tagged RBC scan: can localizebleeding rates ≥0.1 mL/minfor surg but unreliablearteriography: can localize ifbleeding rates ≥0.5 mL/minand can Rx (coil, vaso, glue)emergent exploratorylaparotomy (last resort)

Obscure GIB (Gastro2007;133:1694; GIE 2010;72:471)• Definition: continued bleeding

(melena, hematochezia)despite EGD & colo; 5% ofGIB

• Etiologies: Dieulafoy’s lesion,small bowel angiodysplasia,ulcer or cancer, Crohn’sdisease, aortoenteric fistula,Meckel’s diverticulum (2% ofpop., remnant of vitelline ductw/ ectopic gastric mucosa),hemobilia

• Diagnosis: repeat EGD w/ pushenteroscopy/colonoscopywhen bleeding is active

If , video capsule to evaluatesmall intestine (Gastro2009;137:1197)

If still , consider 99mTc-pertechnetate scan(“Meckel’s scan”),enteroscopy (single-balloon,double-balloon or spiral),tagged RBC scan andarteriography

DIARRHEA, CONSTIPATION ANDILEUS

ACUTE DIARRHEA (<4 wk)

Evaluation (NEJM 2009;361:1560;Gastro 2009;136:1874)• Hx: stool freq, bloody, abd pain,

duration of sxs [~1 wk forviral & bacterial (except C.diff), >1 wk for parasitic],travel, food, recent abx

• PEx: vol depletion (VS, UOP,axillae, skin turgor, MS), fever,abd tenderness, ileus, rash

• Further evaluation if warningsigns: fever, signific abd pain,blood or pus in stools, >6stools/d, severe dehydration,immunosupp, elderly, duration>7 d, hosp-acquired

• Etiology established in only ~3%of community-acquireddiarrhea

• Laboratory: fecal WBC (highfalse & ; ✓ fecalcalprotectin or lactoferrinSe/Sp >90%), stool cx, BCx,lytes, C. diff (if recent hosp orabx), stool O&P (if >10 d,travel to endemic area,exposure to unpurified H2O,community outbreak, daycare,HIV or MSM)± stool ELISAs (viruses,

Crypto, Giardia), serologies(E. histolytica), special stool

cx• Imaging/endoscopy: CT/KUB if

? toxic megacolon; sig/colo ifimmunosupp or cx

• Ddx: infxn vs. preformed toxinvs. med-induced vs. initialpresentation of chronicdiarrhea

Treatment• If none of the above warning

signs and Pt able to take POs→ supportive Rx only: oralhydration, loperamide,bismuth subsalicylate (avoidanticholinergics)

• If moderate dehydration: 50–200

mL/kg/d of oral solution (1/2

tsp salt, 1 tsp baking soda, 8tsp sugar, & 8 oz OJ diluted to1 L w/ H2O) or Gatorade, etc.If severe, LR IV.

• For traveler’s diarrhea, bismuthor rifaximin useful forprophylaxis & empiric Rx

• Empiric abx for non–hospital-acquired inflammatory diarrheareasonable: FQ × 5–7 dabx rec for Shigella, cholera,

Giardia, amebiasis,Salmonella if Pt >50 y orimmunosupp or hospitalized,? Campylobacter (if w/in 4 d

of sx onset)avoid abx if suspect E. coli

O157:H7 as may ↑ risk ofHUS

CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA (CDAD)

Pathogenesis• Ingestion of C. difficile spores →

colonization when colonicflora Dd by abx or chemo →release of toxin A/B → colonicmucosal necrosis &inflammation →pseudomembranes

• ↑ toxigenic strain (NAP 1/027) ↑mort. & length of hosp (esp. inelderly) (NEJM 2008;359:1932)

• Additional risk factors: elderly,nursing home residents, IBD,PPI (CID 2011;53:1173)

Clinical manifestations (aspectrum of disease)• Asx colonization: <3% healthy

adults; ~20% in hospitalizedpatients on antibiotics

• Acute watery diarrhea (occbloody) ± mucus, often w/lower abd pain, fever, ↑↑↑WBC

• Pseudomembranous colitis: abovesx + pseudomembranes +bowel wall thickening

• Fulminant colitis (2–3%): toxicmegacolon (colon dilatation≥6 cm on KUB, colonicatony, systemic toxicity)

and/or bowel perforation

Diagnosis• Only test if symptomatic; test

liquid stool (unless concern forileus)

• Stool EIA: detects toxin B and/orA (1–2% strains make A); fast(2–6 h); most often used

• PCR: quick, becoming test ofchoice (Mayo 2012;87:643)

• Alternative is 2-step method: ✓glutamate dehydrogenase(GDH) EIA (high Se, even ifno toxin production), then if , ✓ cytotoxin assay ortoxigenic cx

• Consider flex sig if dx uncertainand/or evidence of no

improvement w/ standard Rx

Treatment (Infect Control HospEpidemiol 2010;31:431)• Start contact precautions; if

possible d/c abx ASAP; stopantimotility agents

• Mild-Moderate (WBC <15k, Cr<1.5 × baseline, age <65 yand no peritoneal sx): MNZ500 mg PO tid × 10–14 d

• Severe (WBC >15k or Cr>1.5× baseline or age ≥65y): vanco 125 mg PO qid ×10–14 d

• Complicated (ileus,malabsorption, shock,

megacolon, peritonitis): vanco500 mg PO q6h and MNZ 500mg IV q8h; PR vanco if ileus,but avoid if evidence of toxicmegacolon; abd CT & urgentsurg consult re: colectomy; ?IVIG fidaxomicin 200 mg bidnoninferior to vanco PO & ↓rate of recurrence (NEJM2011;364:422)

• If Pt needs to stay on originalabx, continue C. diff. Rx for≥7 d post-abx cessation

• Stool carriage may persist 3–6wk postcessation of sx andshould not trigger further Rx

• Recurrent infection: 15–30%

risk after d/c of abx, mostw/in 2 wk of stopping abx1st relapse: if mild; repeat 14-

d course of MNZ or vanco2nd relapse: PO vanco taper

for 6 wk>2 relapses: vanco taper &

adjunctive Rx such as S.boulardii, probiotics,rifaximin, nitazoxanide,fidaxomicin orcholestyramine (binds vancoso cannot take concurrently)

Fecal transplant in refractorydisease appears safe andeffective (Clin Gas Hep2011;9:1044; NEJM

2013;368:407)• Probiotics may prevent CDAD by

66% in non-immunosuppressedPts (Annals 2012;157:878)

CHRONIC DIARRHEA (>4 wk;Gastro 2004;127:287)

Medications (cause ↑ secretion, ↑motility, Δ flora, ↑ cell death orinflammation)• PPI, colchicine, abx, H2RA,

SSRIs, ARBs, NSAIDs, chemo,caffeine

Osmotic (↓ diarrhea with fasting, fecal fat, ↑ osmotic gap)

• Lactose intolerance: seen in75% nonwhites & in 25%whites; can be acquired aftergastroenteritis, med illness, GIsurgery. Clinical: bloating,flatulence, discomfort,

diarrhea. Dx: hydrogen breathtest or empiric lactose-freediet. Rx: lactose- free diet, useof lactose-free dairy productsand lactase enzyme tablets.

• Other: lactulose, laxatives,antacids, sorbitol, fructose

Malabsorption (↓ diarrhea withfasting, ↑ fecal fat, ↑ osmotic gap)• Celiac disease (NEJM

2012;367:2419)Immune rxn in genetically

predisposed Pts (~1% pop)to gliadin, a component ofgluten (wheat protein) →small bowel inflammatory

infiltrate → crypthyperplasia, villus atrophy→ impaired intestinalabsorption

Other s/s: Fe/folate deficanemia; osteoporosis;dermatitis herpetiformis(pruritic papulovesicular); ↑AST/ALT

Dx: IgA tissuetransglutaminase orendomysial Abs ~90% Se &>98% Sp (JAMA2010;303:1738). Small bowelbx and clinical/serologicresponse to gluten-free dietdefinitive.

Rx: gluten-free diet; 7–30% donot respond to diet → ?wrong dx or noncompliant

Complic: ~5% refractory (sxdespite strict dietaryadherence), risk of T-celllym- phoma and small boweladenocarcinoma

• Whipple’s disease: infxn w/ T.whipplei (NEJM 2007;365:55)Other s/s: fever, LAN, edema,

arthritis, CNS Ds, gray-brown skin pigmentation, AI& MS, oculomasticatorymyorhythmia (eyeoscillations + masticationmuscle contract)

Rx: (PCN + streptomycin) or3rd-gen ceph × 10–14 d →Bactrim for ≥1 y

• Small Intestinal bacterialovergrowth (SIBO; Inf Dis Clin2010;24:943): ↑ SI bacteriafrom incompetent/absentileocecal valve, s/p RYGB,scleroderma, diabetes, s/pvagotomy → fat & CHOmalabsorption. Dx: 14C-xylose & H+ breath tests; Rx:cycled abx (eg, MNZ, FQ,rifaximin)

• Pancreatic insufficiency: mostcommonly from chronicpancreatitis or pancreatic

cancer• ↓ bile acids due to ↓ synthesis

(cirrhosis) or cholestasis (PBC)→ malabsorption

• Other: s/p short bowel resection(short bowel syndrome),Crohn’s disease, chronicmesenteric ischemia,eosinophilic gastroenteritis,intestinal lymphoma, tropicalsprue

Inflammatory ( FOB, fever, abdpain, fecal WBC or lactoferrin orcalprotectin)• Infections: particularly parasitic

(incl above pathogens &

Strongyloides), CMV, TB• Inflammatory bowel disease• Radiation enteritis, ischemic

colitis, neoplasia (coloncancer, lymphoma)

Secretory (nocturnal diarrhea freqdescribed, no Δ diarrhea after NPO,normal osmotic gap)• Hormonal: VIP (VIPoma,

Verner-Morrison), serotonin(carcinoid), thyroxine,calcitonin (medullary cancer ofthe thyroid), gastrin(Zollinger-Ellison), glucagon,substance P

• Laxative abuse

• Neoplasm: carcinoma,lymphoma, villous adenoma

• ↓ bile acids absorption (s/p ilealresection, Crohn’s) → colonicexposure & ↑ secretion

• Lymphocytic colitis, collagenouscolitis (may be a/w meds,including NSAIDs)

Motility (normal osmotic gap)• Irritable bowel syndrome (10–

15% of adults; BMJ2012;345:e5836; NEJM2012;367:1626)Due to altered intestinal

motility/secretion inresponse to luminal or

environmental stimuli w/enhanced pain perceptionand dysregulation of thebrain–gut axis

Rome III criteria: recurrent abdpain ≥3 d/mo over last 3mo plus ≥2 of following: (i)improvement w/ defecation,(ii) onset w/ Δ freq of stool,(iii) onset w/ Δ in form ofstool

Rx sx-guided (AJG2009;104:51)Pain: antispasmodics, TCA,SSRIBloating: rifaximin (NEJM2011;364:22), probiotics

Diarrhea: loperamide,alosetron (5-HT3 antagonist)for women (↑ risk ofischemic colitis), rifaximin

Constipation: ↑ fiber 25g/d, lubiprostone (Cl–channel activator)

• Scleroderma; diabetic autonomicneuropathy; hyperthyroidism;amyloidosis; s/p vagotomy

Figure 3-2 Workup of chronicdiarrhea

CONSTIPATION & ADYNAMICILEUS

Constipation (Gastro2013;144:211 & 218)• Definition (Rome III): ≥2 of the

following during last 3 mo atleast 25% of time: straining,lumpy/hard stools, incompleteevacuation, sensation ofanorectal obstruction, manualmaneuvers to facilitatedefecation, stool frequency <3per wk

• EtiologyFunctional: normal transit,

slow transit, pelvic floor

dysfunction, constipation-predom IBS

Meds: opioids, anticholinergics(TCAs & antipsychotics), Fe,CCB, diuretics, NSAIDs

Obstruction: cancer, stricture,rectocele, anal stenosis,extrinsic compression

Metabolic/endo: DM,hypothyroid, uremia, preg,panhypopit, porphyria, ↑Ca, ↓ K, ↓ Mg

Neuro: Parkinson’s,Hirschsprung’s, amyloid, MS,spinal injury, autonomicneuropathy

• Diagnosis: H&P w/ DRE. Labs:

consider CBC, electrolytes w/Ca, TSHColonoscopy if alarm sx: wt

loss, FOBT, fever, FHx ofIBD or colon cancer.Sigmoidoscopy if no alarmsx & <50 y

For functional constipation:Sitzmark study, anorectalmanometry, defecography

• Treatment: Bulk laxatives (fiber~20 g/d) → osmotic laxative→ stimulant laxativeBulk laxatives (psyllium,

methylcellulose,polycarbophil): ↑ colonicresidue, ↑ peristalsis

Osmotic laxatives (Mg, sodiumphosphate [avoid if CKD],lactulose): ↑ water in colon

Stimulant laxatives (senna,castor oil, bisacodyl,docusate sodium): ↑ motility& secretion

Enema/suppository(phosphate, mineral oil, tapwater, soapsuds, bisacodyl)

Lubiprostone (see “IBS”).Methylnaltrexone andalvimopan for opioid-induced (AJG 2011;106:835)

Linaclotide ↑ stool freq, ↓straining/bloating (NEJM2011;365;6:527)

Acute pseudo-obstruction(adynamic ileus)• Definition: loss of intestinal

peristalsis in absence ofmechanical obstructionOgilvie’s = acute colonic

adynamic ileus in presenceof competent ileocecal valve

• Precipitants: intra-abd process(surgery, pancreatitis,peritonitis); severe medicalillness(eg, PNA, sepsis); intestinal

ischemia; meds (opiates,anticholinergics); electrolyteabnl

• Clinical manifestations: abd

discomfort, N/V, hiccups, abddistention, ↓ or absent bowelsounds, no peritoneal signs

(unless perforation); cecum≥10–12 cm → ↑ risk ofrupture

• Dx: supine & upright KUB vs.CT→ gas-filled loops of small& large intestine. Must excludemechanical obstruction(absence of gas in rectum).

• Treatment: NPO, mobilize (walk,roll), d/c Rxs that ↓ intestinalmotility, enemas;decompression (NGT, rectaltube, colonoscope);neostigmine (for colonic),

methylnaltrexone (for smallbowel, ? colonic)

NUTRITION IN HOSPITALIZEDPATIENTS

Pathophysiology• When acutely ill, catabolism >

anabolism, carbohydratespreferred due to ↓ fat metab

• When recovering, anabolism >catabolism, so body restoresprotein and muscle loss

Critical illness (see “MechVentilation” for recs in thatsetting) (JPEN 2009;33:277)• Goals not well validated but 18–

30 kcal/kg/d & 1.2–1.5g/kg/dprotein

• Enteral: start w/in 24–48 hrs of

admission, trend toward ↓infxns and mortality in early(<48 h) feeding in critically illPts who are adequatelynourished at presentationContraindic: inadequatevolume resusc, intestinalobstruction, major GIB, severevomiting, ischemic bowel

• Parenteral: start if unable totolerate enteral w/in 7 d orevidence of protein/calmalnutrition on admission;may be beneficial in thosebelow calorie goal w/ enteral(Lancet 2013;381:385)Contraindic: hyperosmolality,

severe electrolyte disturbances,severe hyperglycemia; sepsis isrelative contraindication

End-stage liver disease (ClinGastro & Hep 2012;10:117)• Nutrition status predicts

morbidity/mortality;malnutrition in 50–90% ofcirrhotics

• Protein requirement higher thanhealthy adults (1–1.5 g/kg/dvs. 0.8 g/kg/d); proteinrestrict only if acute hepaticencephalopathy Supplementvitamins ADEK, zinc, selenium;do not carbohydrate restrict

Refeeding syndrome (BMJ2008;336;1495)• Fluid/electrolyte shifts in

malnourished Pts receivingartificial nutrition;hypophosphatemia ishallmark, but also ↓ K & Mg,hyperglycemia, ↓ thiamine,hypervolemia

• Prevention: (1) thiamine 300 mgPO qd, vit B complex tid, MVI;(2) start feeding at ~10kcal/kg/d (or 25% of estimgoal) & ↑ over 3–5 d; advanceonly when electrolytes arew/in nl range; (3) followelectrolytes and volume status,

rehydrating and repleting

DIVERTICULAR DISEASE

DIVERTICULOSIS

Definition & pathobiology(Lancet 2004;363:631)• Acquired herniations of colonic

mucosa and submucosathrough the colonic wall

• Existing dogma is low-fiber diet→ ↑ stool transit time and ↓stool volume → ↑ intraluminalpressure → herniation wherevasa recta penetrate, but now?’d (Gastro 2012;142:266)

Epidemiology• Prevalence higher w/ ↑ age (10%

if <40 y; 50–66% if >80 y);“Westernized” societies

• Left side (90%, mostly sigmoid)> right side of colon (exceptin Asia, where R > L)

Clinical manifestations• Usually asx, but 5–15% develop

diverticular hemorrhage and<5% diverticulitis

• Nuts, etc. intake in asxdiverticulosis does not ↑ risk ofdiverticulitis (JAMA2008;300:907)

DIVERTICULITIS

Pathophysiology (NEJM2007;357:2057)• Retention of undigested food and

bacteria in diverticulum →fecalith formation →obstruction → compromise ofdiverticulum’s blood supply,infection, perforation

• Uncomplicated:microperforation → localizedinfection

• Complicated (25%):macroperforation → abscess,peritonitis, fistula (65% w/bladder), obstruction, stricture

Clinical manifestations• LLQ abdominal pain, fever,

nausea, vomiting, constipation• PEx ranges from LLQ tenderness

± palpable mass to peritonealsigns & septic shock

• Ddx includes IBD, infectiouscolitis, PID, tubal pregnancy,cystitis, colorectal cancer

Diagnostic studies• Plain abdominal radiographs to

r/o free air, ileus orobstruction

• Abdominal CT (I+O+): >95%Se & Sp; assess complicateddisease (abscess, fistula)

• Colonoscopy contraindicatedacutely ↑ risk of perforation;do 6 wk after to r/o neoplasm

Treatment (Am J Gastro2008;103:1550)• Mild: outPt Rx indicated if Pt has

few comorbidities and cantolerate POsPO abx: (MNZ + FQ) or

amox/clav for 7–10 d; liquiddiet until clinicalimprovement, though recentevidence suggest abx may beunnecessary (Br J Surg2012;99:532)

• Severe: inPt Rx if cannot take

POs, narcotics needed for pain,or complicationsNPO, IV fluids, NGT (if ileus)IV abx (GNR & anaerobic

coverage): amp/gent/MNZor piperacillin-tazobactam

• Abscesses >4 cm should bedrained percutaneously orsurgically

• Surgery: if progression despitemed Rx, undrainable abscess,free perforation or possiblyrecurrent disease (≥2 severeepisodes)

• Colonic stricture: latecomplication of diverticulitis;Rx w/ endoscopic dilation vs.

resection; colonoscopy after 6wk to exclude neoplasm

Prevention• Low-fiber diet immediately after

acute episode; high-fiber dietwhen >6 wk w/o sx

• Consider mesalamine ±rifaximin if multiple episodes

• Risk of recurrence 10–30% w/in10 y of 1st episode; more likely2nd episode complicated

DIVERTICULAR HEMORRHAGE(ALSO SEE “GASTROINTESTINAL

BLEEDING”)

Pathophysiology• Intimal thickening and medial

thinning of vasa recta as theycourse over dome of diver-ticulum → weakening ofvascular wall → arterialrupture

• Diverticula more common in leftcolon; but bleeding diverticulamore often in right colon

Clinical manifestations• Painless hematochezia/BRBPR;

can have abdominal cramping

• Usually stops spontaneously(~75%) but resolution mayoccur over hrs–days; ~20%recur

Diagnostic studies• Colonoscopy: rapid prep w/ PEG-

based solution via NGT (4–6 Lover 2–4 h)

• Arteriography ± tagged RBCscan if severe bleeding

Treatment• Colonoscopy: epinephrine

injection ± electrocautery(NEJM 2000;342:78),hemoclip, banding

• Arteriography: intra-arterial

vasopressin infusion orembolization

• Surgery: if above modalities fail& bleeding is persistent &hemodynamically significant

INFLAMMATORY BOWELDISEASE

Definition• Ulcerative colitis (UC):

idiopathic inflammation of thecolonic mucosa

• Crohn’s disease (CD): idiopathictransmural inflammation of theGI tract, skip areas

• Indeterminate colitis: in 5–10%of chronic colitis, cannotdistinguish UC vs. CD even w/bx

Epidemiology & pathophysiology(NEJM 2009;361:2066; Gastro2011;140:1785)

• 1.4 million people in U.S.; prev1:1000 UC & 1:3000 CD; ↑incidence in Caucasians, Jews

• Age of onset 15–30 y in UC andCD; CD is bimodal and hassecond peak at 50–70 y

• Smokers at ↑ risk for CD, whereasnonsmokers & former smokersat ↑ risk for UC

• Genetic predisposition +disruption of intestinal barrier(epithelial or ↓ defenses) ± Δin gut microbiota → acuteinflam w/o immunedownregulation or tolerance→ chronic inflam

ULCERATIVE COLITIS (NEJM2011;365:1713; Lancet

2012;380:1606)

Clinical manifestations• Grossly bloody diarrhea, lower

abdominal cramps, urgency,tenesmus

• Severe colitis (15%): progressesrapidly over 1–2 wk with ↓Hct, ↑ ESR, fever, hypotension,>6 bloody BMs per day,distended abdomen withabsent bowel sounds

• Extracolonic (>25%): erythemanodosum, pyodermagangrenosum, aphthous ulcers,

uveitis, episcleritis,thromboembolic events (esp.during a flare; Lancet2010;375:657), AIHA, seronegarthritis, chronic hepatitis,cirrhosis, PSC (↑ risk cholangioCA, CRC)

Diagnosis• Colonoscopy: involves rectum

(95%) & extends proximallyand contiguously within colon

• Classify by location: proctitis(25–55%), left-sided colitis(50–70%) and pancolitis(20%)

• Appearance: granular, friable

mucosa with diffuse ulceration;pseudopolyps

• Microscopy: superficial chronicinflammation; crypt abscesses& architectural distortion

Complications• Toxic megacolon (5%): colon

dilatation (≥6 cm on KUB),colonic atony, systemictoxicity, & ↑ risk of perf. Rx w/IV steroids & broad-spectrumabx; surgery if fail to improvew/in 48–72 h

• Stricture (5%): occurs inrectosigmoid after repeatedepisodes of inflammation

Prognosis• 50% of Pts in remission at any

given time; intermittentexacerbations in 90%;continual active disease in~18%. Rate of colectomy at 10y is 24%.

• Mortality rate of severe UC flareis <2%, & overall lifeexpectancy in UC = non-UCPts

CROHN’S DISEASE (Lancet2012;380:1590)

Clinical manifestations• Abdominal pain, fever, malaise,

wt loss• Mucus-containing, nongrossly

bloody diarrhea; N/V,bloating, obstipation

• ↓ albumin, ↑ ESR/CRP, ↓ Hct(due to Fe, B12, folatedeficiency; chronicinflammation)

• Extracolonic as in UC

Diagnosis• EGD/colonoscopy + small

bowel imaging (eg, video

capsule endoscopy [if nostricture] or CT/MR-enterography); CD can affectany portion of GI tract withskip lesions

• Classify by location: small bowel(47%), ileocolonic (21%),colonic (28%); upper tract rare

• Appearance: nonfriablemucosa, cobblestoning,aphthous ulcers, deep &long fissures

• Microscopy: transmuralinflammation withmononuclear cell infiltrate,noncaseating granulomas(seen in <25% of mucosal

biopsies), fibrosis, ulcers,fissures

Complications• Perianal disease: fissures,

fistulas, perirectal abscesses(up to 30% of Pts)

• Stricture: small bowel,postprandial abd pain; canlead to complete SBO

• Fistulas: perianal, enteroenteric,rectovaginal, enterovesicular,enterocutaneous

• Abscess: fever, tender abd mass,↑ WBC; steroids mask sx, ∴need high-level suspicion

• Malabsorption: ileal

disease/resection: ↓ bile acidsabs → gallstones; ↓ fatty acidabs → Ca oxalate kidneystones; ↓ fat soluble vitaminabs → vit Δ deficiency →osteopenia

Prognosis• Variable at 1 y: ~50% in

remission, ~20% flared, ~20%low activity, ~10% chronicactive

• At 20 y, majority will haverequired some surgery; overalllife expectancy is slightly ↓

MANAGEMENT (Gastro2011;140:1827)

Initial evaluation• H&P (✓ for intestinal &

extraintestinal manifestations)and endoscopy as above

• Laboratory: ESR, CRP, CBC,LFTs, Fe, B12, folate, vit D.Fecal calprotectin appearsuseful for Ddx IBD vs. IBS &may predict IBD flare (InflBowel Dis 2012;18:2218).

• Exclude other etiologies:infectious/ischemic colitis, medadverse effect, intestinallymphoma/carcinoma, colon

cancer, IBS, vasculitis,Behçet’s, celiac disease, SIBO

• Rule out infection beforetreating withimmunosuppressants andbiologics

Goals of treatment• Avoid NSAIDs (both UC and CD)• Induce remission of acute flare →

maintain remission; mucosalhealing 1° goal

• Convention has been step up Rx(least → most toxic). Recentshift to early and/or combinedimmunomodulation to improvedisease outcome (Lancet

2008;371:660; NEJM2010;362:1383).

Complications of therapy (ClinGastro Hep 2009;7:874)• Anti-TNFα: reactivation TB;

must doc PPD prior to Rx.Exclude viral hepatitis. Small↑’d risk of NHL. Other: infusionrxn; lupus-like rxn, psoriasis,MS, CHF.

• 6MP/AZA: BM suppression,lymphoma, pancreatitis,hepatitis; ✓ TPMT genotype

prior to dosing to ↓ risk ofgeneration of toxic metabolites

• 5-ASA: diarrhea, abd pain,pancreatitis. If sx, consider 3-dholiday.

Cancer screening (Gastro2010;138:738)• Colon cancer: risk in UC ~2%

at 10 y, ~8% at 20 y, ~18% at30 y. Similar for colonic CD,plus risk of small bowel canceras well. Dysplasia best markerfor risk. Other risk factorsinclude: PSC, FHx, greaterextent of disease, stricture, &pseudopolyps.

• Surveillance: colonoscopy w/random bx 8 y after dx to evalfor dysplasia, q1–3y thereafterbased on risk factors. If high-grade dysplasia or dysplasiaassoc. lesion/mass →colectomy. Chemoprophylaxis:5-ASA & ursodeoxycholic acid(if PSC) ? beneficial (AJG2011;106:731; AlimentPharmacol Ther 2012;35:451).

INTESTINAL ISCHEMIA

ACUTE MESENTERIC ISCHEMIA(25%)

Etiologies• SMA embolism (50%): from LA

(AF), LV (↓ EF) or valves; SMAmost prone to embolism

• Nonocclusive mesentericischemia (25%): transientintestinal hypoperfusion due to↓ CO, atherosclerosis, sepsis,drugs that ↓ gut perfusion(pressors, cocaine, dig,diuretics)

• SMA thrombosis (10%): usuallyat site of atherosclerosis, often

at origin of artery• Venous thrombosis (10%):

hypercoagulable states, portalhypertension, IBD,malignancy, inflammation(pancreatitis, peritonitis),pregnancy, trauma, surgery

• Focal segmental ischemia ofthe small bowel (<5%):vascular occlusion to smallsegments of the small bowel(vasculitis, atheromatousemboli, strangulated hernias,XRT)

Clinical manifestations• Occlusive: sudden abd pain out

of proportion to abdominaltenderness on exam atleastinitially (2–4 h) untilsevere ischemia → frankinfarction w/ peritoneal signs

• Nonocclusive: abd distention &pain, though up to 25% maybe pain-free, N/V; often insetting of CHF ± h/o chronicmesenteric ischemia sx

• Hematochezia due to mucosalsloughing (right colon suppliedby SMA)

• “Intestinal angina”: postprandialabd pain, early satiety, & ↓ wtfrom gastric vascular “steal”;may occur wks to mos before

onset of acute pain in Pts w/chronic mesenteric ischemia

Physical exam• May be unremarkable, or may

only show abdominaldistention; FOBT ~75% ofPts

• Bowel infarction suggested byperitoneal signs (diffusetenderness, rebound, guarding)

Diagnostic studies• Dx relies on high level of

suspicion; rapid dx essential toavoid infarction (occurs w/inh)

• Laboratory: often nl; ~75% ↑

WBC; ↑ amylase, LDH,phosphate, D-dimer; ~50%acidosis w/ ↑ lactate (late)

• KUB: nl early before infarct;“thumbprinting,” ileus,pneumatosis in later stages

• CT angiography (arterial phaseimaging): noninvasive test ofchoice; can detect thrombi inmesenteric vessels, colonicdilatation, bowel wallthickening, pneumatosis/portal venous gas; venousphase imaging for dx ofmesenteric vein thrombosis

• Angiography: gold standard;potentially therapeutic;

indicated if vasc occlusionsuspected

Treatment• Fluid resuscitation, optimize

hemodynamics (minimizepressors); broad-spectrum abx

• Emergent surgery for promptresection of necrotic bowel ifevidence of peritonitis

• Anticoagulation for arterial &venous thrombosis and embolicdisease

• Papaverine (vasodilator)catheter-directed infusion intoSMA, typically in nonocclu-sive ischemia when spasm is

considered the primary causeof the ischemia

• SMA embolism: considerfibrinolytic; if no quickimprovement → surgicalembolectomy if possible, o/waortomesenteric bypass

• SMA thrombosis: percutaneousor surgical revascularization (JVasc Surg 2009;50:341)

• Nonocclusive: correctunderlying cause (esp. cardiac)

• Consider angioplasty/stent vs.surg revasc in cases of chronicmesenteric ischemia if: ≥2vessels or occl SMA, supportiveclinical hx, & other etiologies

for abd pain excluded

Prognosis• Mortality 20 to >70% if bowel

infarcted; dx prior toinfarction strongest predictorof survival

ISCHEMIC COLITIS (75%)

Definition & pathophysiology• Nonocclusive disease 2° to Ds in

systemic circulation oranatomic/fxnal Ds in localmesenteric vasculature; oftenunderlying etiology unknown,frequently seen in elderly

• “Watershed” areas (splenicflexure & rectosigmoid) mostsusceptible, 25% involve R side

Clinical manifestations,diagnosis, & treatment• Disease spectrum: reversible

colopathy (35%), transientcolitis (15%), chronic

ulcerating colitis (20%),resulting stricture (10%),gangrene (15%), fulminantcolitis (<5%)

• Usually p/w cramping LLQ painw/ overtly bloody stool; feverand peritoneal signs shouldraise clinical suspicion forinfarction

• Dx: r/o infectious colitis;consider flexsig/colonoscopy if sx persistand no alternative etiologyidentified (only if peritonitisnot present, o/w avoidoverdistention of colon)

• Treatment: bowel rest, IV

fluids, broad-spectrum abx,serial abd exams; surgery forinfarction, fulminant colitis,hemorrhage, failure of med Rx,recurrent sepsis, stricture

• Resolution w/in 48 h w/conservative measures occursin >50% of cases

PANCREATITIS

Pathogenesis• Acinar injury via direct or

indirect toxicity → release orimpaired secretion (ie, ductobstruction) of enzymes →autodigestion → fat necrosis

• Profound acute inflammatoryresponse

Etiologies• Gallstones (40%): > ,

usually small stones (<5 mm)or microlithiasis

• Alcohol (30%): > , usuallychronic, w/ acute flares

• Drugs (via hypersens, toxicmetab or direct toxicity):furosemide, thiazides, sulfa,ddI, ? DPP- 4 inhib,asparaginase, estrogen, 6-MP/AZA, ACEI, dapsone, 5-ASA, valproic acid

• Obstructive: panc/ampullarytumors, mets (breast, lung),annular pancreas, divisum w/concurrent minor papillastenosis and ascaris

• Metabolic: hypertriglyceridemia(TG >1000 and usually~4500; seen w/ types I, IV, &V familial hyperlipidemia),hypercalcemia

• Infections: coxsackie, mumps,EBV, CMV, HAV, HBV,mycoplasma, TB,candida/toxo/crypto

• Autoimmune: can p/w chronicdisease or panc mass; ↑ IgG4,

ANA, duct abnl• Ischemia: vasculitis, cholesterol

emboli, hypovolemic shock,cardiopulmonary bypass

• Post ERCP: ~5% w/ clinical,overt pancreatitis; 35–70%with asx ↑ amylase; preventw/ indomethacin 100 mg PRimmediately after ERCP (NEJM2012;366:1414)

• Post trauma: blunt abd trauma,

pancreatic/biliary surgery• Familial: autosomal dominant w/

variable penetrance (PRSS1,CFTR, SPINK1 genes)

• Scorpion sting (in Trinidad):mechanism believed to behyperstimulation of pancreas

Clinical manifestations• Epigastric abdominal pain,

radiating to back, constant,some relief w/ leaning forward

• Nausea and vomiting• Ddx: acute cholecystitis,

perforated viscus such as DU,intestinal obstruction, mesen-teric ischemia, IMI, AAA leak,

distal aortic dissection,ruptured ectopic pregnancy

Physical exam• Abdominal tenderness and

guarding, ↓ bowel sounds(adynamic ileus) ± palpableabdominal mass; ± jaundice ifbiliary obstruction

• Signs of retroperitonealhemorrhage (Cullen’s =periumbilical; Grey Turner’s =flank) rare

• Fever, tachycardia, hypotension± shock

Diagnostic studies (Gastro2007;132:2022)

• Laboratory↑ amylase: levels >3× ULN

suggestive of pancreatitis;level ≠ severity

false : acute on chronic(eg, alcoholic);hypertriglyceridemia (↓amylase activity)

false : other abd orsalivary gland process,acidemia, renal failure,macroamylasemia (amylase binds to otherproteins in serum, cannot befiltered by kidneys)

↑ lipase: more specific thanamylase

false : renal failure, otherabd process, diabeticketoacidosis, HIV,macrolipasemia

ALT >3 × ULN suggestsgallstone pancreatitis (Am JGastro 1994;89:1863); AΦ,bili not helpful

Other labs (see “Prognosis”): ↑WBC, ↑ or ↓ Hct, ↑ BUN, ↓Ca, ↑ glc, ↑ CRP

• Imaging studiesKUB/CXR: can see “sentinel

loop” air in small bowel inLUQ, atelectasis, effusion

Abd CT: not required for dx,but test of choice to make

dx. Helps exclude other dx,stage severity, & r/ocomplications. CT w/ IVcontrast on day 3 ofpresentation in severecases to evaluate forpancreatic necrosis (avoidon presentation b/ctheoretical concern of ↑necrosis w/ IV contrast;defer if concomitant AKI).

Abd U/S: typically not usefulto visualize pancreas(obscured by bowel gas), buthelpful to investigate biliaryetiology (ie, gallstones andBD dilatation); can see

pseudocystMRI/MRCP: can detect

necrosis; also used to assessfor stones & ductaldisruption

Endoscopic U/S (EUS): limitedrole acutely; useful for occultbiliary disease(microlithiasis)

Treatment (Lancet 2008;371:143;AJG 2012;107:1146)• Supportive therapy: in mild

cases, bowel rest is usuallysufficientFluid resuscitation LR may

be superior to NS (↓ SIRS,

CRP at 24 h; contraindicatedif ↑ Ca); at least 250 mL/h,may need up to 10 L/d ifsevere; titrate to UOP ≥0.5mL/kg/h

Nutrition: if mild, initiate oralnutrition when pain, nauseaallow.

If severe and NPO >7 dexpected, early (w/in 48 h)enteral nutrition indicatedand preferred over TPN; ↓infectious complications &disease severity, & trendtoward ↓ mortality (BMJ2004;328:1407). Ideally NJtube, but NG okay.

Analgesia: IV meperidine,morphine, hydromorphone(theoretical risk of sphincterof Oddi spasm by opiates,but has not been shown toadversely affect outcome)

• Prophylactic systemic abx (eg,imipenem) to ↓ mortality &prevent conversion of sterile toinfected necrosis controversial(Am J Surg 2009;197:806;Gastro 2007;132:2022); ?reserve for severe pancreatitisw/ >30% necrosis by CT, &no >14 d

• Debridement: infected necrosisusually requires percut,

endoscopic or surgicaldebridement. Improvedoutcomes by delaying surgery≥2 wk if possible to alloworganization of necrosis. CCYif gallstones (w/in 48 h ifmild, o/w w/in 14 d; Surg2009;145:260; Ann Surg2010;251:615)

• ERCP + sphincterotomy: inacute setting, reserved forsevere cholangitis/sepsis and Tbili >5 (ie, presumptiveobstructive BD stone).Otherwise, early ERCP doesnot reduce risk of local orsystemic pancreatitis

complications (Ann Surg2007;245:10).

Complications• Systemic: shock, ARDS, renal

failure, GI hemorrhage, DIC• Metabolic: hypocalcemia,

hyperglycemia,hypertriglyceridemia

• Acute fluid collection (30–50%): seen early, no capsule,no Rx required

• Pseudocyst (10–20%): fluidcollection, persists for 4–6 wk,encapsulated suggested bypersistent pain & elevation ofamylase or lipase, or mass on

exam most resolve spont.; if>6 cm or persists >6 wk +pain → endo/perc/surgdrainage

• Sterile pancreatic necrosis(20%): area of nonviablepancreatic tissue ?prophylactic abx (see above);supportive measures, surgery ifPt unstable

• Infection (5% of all cases, 30%of severe): usually 2° entericGNRinfected pancreatic necrosis:

new SIRS after 7 d typical;perc drainage followed bymin invasive surg

debridement or endoscopicnecrosectomy superior toopen necrosectomy; FNA nolonger routinelyrecommended (Pancreas2012;41:1176)

pancreatic abscess:circumscribed collection ofpus (usually w/o pancreatictissue) treat with abx +drainage (CT-guided ifpossible), usually seen ≥4wk into course

• Ascites or pleural effusion:occurs due to disruptedpancreatic duct; consider earlyERCP w/ stent across duct; can

also occur from drainingpseudocyst

Prognosis (Gastro 2007;132:2022)• Severe pancreatitis (20%) =

organ failure or localcomplications (necrosis,pseudocyst)

• Scoring systems: HAPS, BISAP,APACHE II, Ranson’s criteria,CT Severity IndexHAPS: no abd tenderness or

rebound on exam plus nl Hctand Cr on admission predictsnon-severe course w/ 98%accuracy (Clin Gas Hep2009;6:702)

BISAP: 5-point scoring systemon admission (BUN >25,GCS <15, SIRS, age >60,and pleural effusion)identifies Pts at risk for ↑’dmortality (Am J Gastro2009;104:966)

APACHE II(www.mdcalc.com/apache-ii-score-for-icu-mortality): severe ifscore ≥8

http://www.mdcalc.com/apache-ii-score-for-icu-mortality

Chronic pancreatitis (Lancet2011;377:1184)• 70–80% due to EtOH, also

consider autoimmunepancreatitis. Smoking majorrisk factor.

• Often, but not always, recurrentacute attacks → inflammatoryinfiltrate → fibrosis →exocrine then endocrineinsufficiency (eg, diabetes)

• Sxs include epigastric pain, N/V;over time will be painless andp/w steatorrhea and wt loss

• Amylase/lipase ↑ early, but maybe nl later. fecal fat, ↓’dstool elastase & chymotrypsin,

Ca2+ in pancreas on KUB/CT.• ERCP/MRCP/EUS high Se for dx:

stricture, dilated ducts,honeycombing of parenchyma

• Treatment is low-fat diet andenzyme replacement. AvoidEtOH & tobacco. Analgesia w/NSAID ± mild opioid (eg,tramadol). Surgery in selectedcases.

ABNORMAL LIVER TESTS

Tests of hepatocellular injury orcholestasis• Aminotransferases (AST, ALT):

intracellular enzymes released2° necrosis/inflammationALT more specific for liver

than is AST (heart, skeletalmuscle, kidney, brain,RBC/WBC)

ALT > AST → viral hepatitisor fatty liver/nonalcoholicsteatohepatitis (precirrhotic)

AST: ALT >2:1 → alcoholichepatitis, cirrhosis;nonhepatic source

ALT/AST >15× ULN →etiologies of acute liverfailure (↑↑↑ LDH →ischemia/toxic)

• Alkaline phosphatase (AΦ):enzyme bound in hepaticcanicular membranebesides liver, also found in

bone, intestines, kidney andplacenta

confirm liver origin with: ↑ 5′-NT, ↑ GGT or AΦ heatfractionation

↑ levels seen with biliaryobstruction or intrahepaticcholestasis (eg, hepaticinfiltration)

Tests of hepatic function• Albumin: marker for liver

protein synthesis, ↓ slowly inliver failure (t1/2 ~20 d)

• Prothrombin time (PT):depends on synthesis of coagfactors by liver (except FVIII);b/c t1/2 of some factors (eg, V,VII) is short, ↑ PT can occurw/in hrs of liver dysfxn

• Bilirubin: product of hememetab (unconjugated,“indirect”) carried by alb toliver where taken up forconjugation (“direct”) to makesoluble, then excreted into bile;

most sensitive test to detectparenchymal disease; in thosew/ normal LFTs, high nl Tbili(? marker of ↑ hemeoxygenase) a/w ↓ resp disease& death (JAMA 2011;305:691)

Patterns of liver injury• Hepatocellular: ↑↑

aminotransferases, ± ↑bilirubin or AΦ↑↑↑ ALT & AST (>1000):

severe viral hepatitis, drugs,ischemia, Wilson’s, AIH

• Cholestasis: ↑↑ AΦ and bilirubin,± ↑ aminotransferases

• Isolated hyperbilirubinemia:

↑↑ bilirubin (direct or indirect),nl AΦ and aminotransferases

• Infiltrative: ↑ AΦ, ± ↑ bilirubinor aminotransferases

• Jaundice is a clinical sign seenwhen bilirubin >2.5 mg/dL(esp. in sclera or undertongue); if hyperbilirubinemia

conjugated → ↑ urinebilirubin

Figure 3-3 Approach toabnormal liver tests withhepatocellular pattern

• Acute workup: toxins (EtOH,acetaminophen); vascular abnl(U/S w/ Doppler); viral tests:IgM anti-HAV, HBsAg, IgManti-HBc, HBV DNA, HCV RNA,anti-HEV, ± EBV, CMV, HSV,VZV; autoimmune (ANA, ASMA,ALKM); ceruloplasmin

• Chronic workup: HBsAg, anti-HCV; Fe, TIBC; glc, HbA1c, TG;

ANA, ASMA, ALKM; anti-tissuetransglutaminase;ceruloplasmin & ɑ1-AT; TSH;vascular abnl (U/S w/Doppler)

Figure 3-4 Approach toabnormal liver tests withcholestatic pattern

Figure 3-5 Approach toabnormal liver tests with isolatedhyperbilirubinemia

Figure 3-6 Approach toabnormal liver tests withinfiltrative pattern

Abnormal liver tests inasymptomatic patients (Clin LiverDis 2009;13:167)• Careful review of history (meds,

EtOH/drug use, exposures, riskfactors for liver disease) andphysical exam. Evaluate forany clues to etiology 1st (eg,d/c med and repeat LFTs).

• Confirm hepatic source: ifprimarily ↑ AΦ (✓ GGT) or

AST > ALT (✓ CK, aldolase,TFT)

• HepatocellularEvaluate for most common

causes: hepatitis A/B/C,hemochromatosis; screen forevidence of chronic liverdisease (platelets, PT/INR,albumin)

If evaluation → lifestylemodification (wt loss, DMcontrol) + repeat test 6 mo

If evidence of chronic liverdisease or persistent lababnl, screen for less commoncauses: AIH, Wilson’s, celiac,ɑ1-AT; ✓ U/S & consider

liver bxIf still → liver bx if ALT or

AST >2× ULN for >6 mo;o/w observe

• Cholestatic: ✓ RUQ U/S, AMAif biliary dilatation or

obstruction → MRCPif AMA and U/S , or AMA

and U/S w/ abnlparenchyma → liver bx

if AMA & U/S : AΦ >1.5×ULN → consider bx; AΦ<1.5× ULN → observe

• Isolated hyperbilirubinemia: ✓conjugated vs. unconjugatedconjugated → perform

abdominal U/S → MRCP ifdilatation or obstruction; ifnl ultrasound ✓ AMA andconsider MRCP or liver bx

unconjugated → ✓ Hct, reticcount, smear, LDH,haptoglobin

Common medications that causeabnormal liver tests(http://livertox.nlm.nih.gov)

http://livertox.nlm.nih.gov

HEPATITIS

VIRAL

Hepatitis A (ssRNA; 30–45% ofacute viral hepatitis in U.S.)• Transmission: fecal–oral route;

contaminated food, water,shellfish; daycare ctr outbreaks

• Incubation: 2–6 wk; no chroniccarrier state

• Sx: ↓ appetite, malaise, fever,N/V, RUQ pain, ± jaundice;rarely fulminant

• Diagnosis: acute hepatitis = IgM anti-HAV; past exposure= IgG anti-HAV ( IgM)

• Treatment for acute HAVsupportive. Prevention:vaccinate children & Pts w/chronic HBV, HCV (? if cost-effective) or other chronic liverdisease (2 doses at 0, 6–12 mo)

• Postexposure ppx: age 1–40 y →vaccine; age <1 or >40 y orimmunosupp → Ig

Hepatitis B (dsDNA; ~45% ofacute viral hepatitis in U.S.; Lancet2009;373:582)• Transmission: blood (IVDU,

transfusion), sexual, perinatal• Incubation: 6 wk–6 mo (mean

12–14 wk)

• Acute infxn: 70% subclinical,30% jaundice, <1% fulminanthepatitis (up to 60% mortality)

• Chronic infxn: <5% (adult-acquired; higher ifimmunosupp), >90%(perinatally acquired); ~40%chronic carriers → cirrhosis; ↑risk of cirrhosis if HCV, HDV orHIV coinfection

• Hepatocellular carcinoma (w/ orw/o concurrent cirrhosis); ↑risk w/ perinatal transmission& ↑’d HBV DNA. Screen chroniccarriers w/ AFP & U/S vs. MRIq6mo.

• Extrahepatic syndromes: PAN

(<1%), MPGN, arthritis,dermatitis, PMR

• Serologic and virologic testsHBsAg: appears before sx; used

to screen blood donors;persists >6 mo = chronicHBV

HBeAg: evidence of viralreplication and ↑ infectivity

IgM anti-HBc: first Ab toappear; indicates acuteinfection window period =HBsAg become , anti-HBsnot yet , anti-HBc only clueto infection

IgG anti-HBc: indicatesprevious (HBsAg ) or

ongoing (HBsAg ) HBVinfection

anti-HBe: indicates waningviral replication, ↓infectivity

anti-HBs: indicates resolutionof acute disease & immunity(sole marker after vac)

HBV DNA: presence in serumcorrelates w/ active viralreplication in liver

Figure 3-7 Serologic course ofacute HBV infection withresolution

• Treatment for acute HBV:

supportive; hospitalize for ΔMS or ↑ INR (liver transplantctr)

• Treatment for chronic HBV if: (1)HBeAg w/ DNA >20,000IU/mL & elevated ALT; (2)HBeAg w/ DNA >2000IU/mL & elevated ALT or liverbx demonstrates stage ≥2fibrosis (NEJM 2008;359:1486;Hep 2009;50:661; Clin Gas Hep2011;9:285)

• 1st line is nucleo(s/t)ideanalogues: entecavir ortenofovir; well tolerated &low resistance (1% forentecavir at 5 y in Rx-naïve

Pts); at 5 y HBeAgseroconversion is 30–40% &loss of HBsAg is 5–10% (Gastro2012;142:1360; Lancet2013;381:468)

• PEG IFNɑ-2a: best rate of HBeAgseroconversion at 1 y (27%),low tolerability limits use

• Goal: if HBeAg → HBeAg ,anti-HBe ; if HBeAg or �seroconversion or Asian Pt →indefinite tx or until HBsAgclears (if ever)

• If undergo liver transplant: HBIG+ nucleo(s/t)ide analogueeffective in preventingreinfection

• HIV/HBV coinfection: Rx w/ 2drugs active against both HBV& HIV (NEJM 2007;356:1445)

• If inactive carrier scheduled toreceiveimmunosuppression/chemotherapy→ Rx

• Prevention: vaccinate all infants& children and at-risk adults (3doses 0, 1 & 6–12 mo)

• Postexposure (risk infxn ~30%)ppx: HBIG → vaccine (if unvacor known nonresponder)

Hepatitis C (ssRNA; ~10% ofacute viral hepatitis in U.S.; NEJM2011;364:2429)

• Transmission: blood (IVDU,transfusion) >> sexual; 20–30% w/o clear precipitant

• Incubation: 1–5 mo; mean 6–7wk

• Natural hxacute infxn: 80% subclinical;

10–20% sx hepatitis w/jaundice; fulminant hepatitisvery rare; prob of spontclearance a/w IL28B & HLAclass II genotypes (Annals2013;158:235)

chronic: up to 85% → chronichepatitis, 20–30% of whomdevelop cirrhosis (after ~20y) ↑ risk of cirrhosis in men,

EtOH, HIV; HCC in 2–5% ofcirrhotics/y

• Extrahepatic syndromes:cryoglobulinemia, porphyriacutanea tarda (blistering rashin sun-exposed areas), MPGN,MGUS, IPF, NHL and DM

• Serologic, virologic, & genetictestsanti-HCV (ELISA): in 6 wk,

does not = recovery orimmunity; can be afterrecovery

HCV RNA: w/in 2 wk,marker of active infection

HCV RIBA: used to confirm

anti-HCV ELISA in Pts w/undetectable HCV RNA

HCV genotype (1–6): guidesduration & predicts responseto Rx

• Dx: acute hepatitis = HCVRNA, ± anti-HCV; resolved =

HCV RNA, ± anti-HCV;chronic = HCV RNA, anti-HCV

• Treatment indications (Hep2009;49:1335 & 2011;54:1433;NEJM 2013;368:1907)Acute: if no spont. clearance at

8–12 wk, consider PEG-IFNɑ-2a/b ± RBV × 12–24 wk

Chronic: RNA , plus bx w/either chronic hepatitis &fibrosis stage >1 orcompensated liver disease(in genotype 2 or 3, mayproceed to Rx w/o bx b/chigh response rate)

• Triple therapy (genotype 1):PEG-IFN ɑ-2a/b, RBV, &protease inhibitor (PI), eitherboceprevir (BOC) or telaprevir(TVR) (NEJM 2011;364:1195 &2405). Rx 24–48 wk; SVR rate30–80% based on variablessuch as advanced fibrosis,IL28B genotype, prior responseto IFN and rapid virologic resp

(� RNA at wk 4 [TVR] or wk 8[BOC]) (Gastro 2012;142:1314)

• Dual therapy (genotypes 2 & 3):PEG-IFNɑ-2a/b + RBV; Rx 24wk; SVR rate ~80%

• Goal is sustained virologic response(SVR) = � viremia 24 wkafter completion of Rx

• IFN-free regimens incl. replic.complex, polymerase, &microRNA-122 inhibs. & otherdirect acting antivirals understudy (NEJM 2012;366:216;2013;368:34, 45, 1685, 1867 &1878)

• Risks of Rx: flu-like sx, psych sx(if depressed can give SSRI),

thyroid dysfxn, marrowsuppression (can give EPO &G-CSF), hemolysis (RBV),sexual dysfxn; PIs w/ sig drug-drug interactions, worsenanemia, & TVR a/wrash/pruritus in 6%,DRESS/SJS in <1%

• Contraindic.: decompensatedcirrhosis, preg, severe psychillness, active substance abuse,severe cardiac/pulm disease,uncontrolled DM, seizure d/o,autoimmune disease

• CDC rec screening for HCV inanyone born 1945–1965(Annals 2012;156:263)

• Vaccinate all chronic HCVpatients against HBV and HAVif not immune

• Postexposure (needlestick risk~3%) ppx: none; if HCV RNA→ , consider Rx w/in 3 mo

Hepatitis D (RNA)• Transmission: blood or sexual;

endemic in Africa & E. Europe• Pathogenesis: requires HBV to

cause either simultaneous orsuperimposed infection

• Natural hx: in HBV ↑ severity ofinfxn and ↑ progression tocirrhosis and HCC in chroniccarriers; clears w/ HBV

• Serologic/virologic tests: anti-HDV; follow HDV RNA duringRx (high relapse rate)

Hepatitis E (ssRNA; NEJM2012;367:1237; Lancet2012;379:2477)• In endemic areas most common

cause of acute viral hepatitis• Transmission: fecal–oral;

travelers to central & SE Asia,Africa and Mexico, exp. toswine

• Natural hx: acute hepatitis w/ ↑mort. (10–20%) if pregnant;rare chronic in transplant Pts

• Dx: IgM anti-HEV (through CDC)

• Extrahepatic sx: arthritis,pancreatitis, neuro (GBS,inflam polyradic.,meningoenceph.)

Other viruses (HGV, CMV, EBV,HSV, VZV)

AUTOIMMUNE HEPATITIS (AIH)

Classification (J Hep 2011;55:171;Hep 2010;51:1)• Type 1: antismooth muscle Ab

(ASMA), ANA; antisoluble liverantigen (anti-SLA), a/w moresevere disease and relapsingdisease

• Type 2: anti–liver/kidneymicrosome 1 (anti-LKM1) orliver/cytosol (LC1); kids (2–14y)

• Overlap syndrome: AIH + PBCor PSC; Rx-induced:minocycline, nitrofurantoin,infliximab

Diagnosis and treatment• 70% female; 40% present acutely

(occ. fulminant); 34% asx; ALTcan be >1000

• Extrahepatic syndromes:thyroiditis, arthritis, UC,Sjögren’s, Coombs’ hemolytic anemia

• Dx: scoring system combiningserologies, ↑ IgG, � viralhepatitis, & characteristic liverbx (lymphoplasmacyticinfiltrate & interface hepatitis)has high Sp & mod Se (Hep2008;48:169)

• Rx: if LFTs 10× ULN, or if 5×ULN w/ IgG 2× ULN, or

bridging/multiacinar necrosison bx

• Prednisone + azathioprine →65% remission w/in 3 y; 50%relapse on withdrawal of medsat 6 mo; up to 90% by 3 y; ∴most will require long-term Rx;consider substitutingbudesonide for pred innoncirrhrotics w/ Rx-naiveAIH (Gastro 2010;139:1198)

• Liver transplant for ESLD; recursin ~30% of Pts, but generallyeasily treated

OTHER CAUSES OF HEPATITISOR HEPATOTOXICITY

Alcoholic hepatitis (NEJM2009;360:2758; Clin Liv Dis2012;16:371)• Sxs: can range from asx

hepatomegaly todecompensation w/ ascites,encephalopathy and death.AST & ALT usually <300–500w/ AST:ALT > 2:1, in part b/cconcomitant B6 defic (ALT canbe normal); ↓ plt, ↑ iron sat,↑’d Tbili & INR indicate severehepatitis.

• Rx: if discriminant fxn (= 4.6 ×

[PT-control] + Tb in mg/dL)>32 or encephalopathymethylprednisolone 32 mg/d

× 4 wk → 4–6 wk taper; ↓death (NEJM 1992;326:507)contraindications: GIB,chronic HBV, severeinfections such as sepsis

pentoxifylline 400 mg tid ↓mortality due to reduction inHRS (Coch2009;4:CD007339)

NAC + steroids ↓ 30-d but not6-mo mortality (NEJM2011;365:1781)

• Lille model predicts nonresponseto corticosteroids & mortality,

powered by Δ Tb from day 1→ 7; nonresponders have 6-mosurvival of 25%(www.lillemodel.com; Hep2007;45:1348)

Acetaminophen hepatotoxicity(NEJM 2008;359:285; BMJ2011;342:d2218)• Normal metabolism via

glucuronidation and sulfation→ nontoxic metabolites

• Overdose (usually >10 g):CYP2E1 hydroxylation →reactive electrophilic species(NAPQI) that are scavenged byglutathione until reserves

http://www.lillemodel.com

exhausted → hepatotoxicity• CYP2E1 induced by fasting and

alcohol allowing for“therapeutic misadventure” inmalnourished alcoholics takingeven low doses (2–6 g) ofacetaminophen

• Liver dysfunction may not beapparent for 2–6 d

• Rx: NG lavage, activatedcharcoal if w/in 4 h. Considerearly transfer to transplant ctr.N-acetylcysteine: administer

up to 72 h after ingestion, iftime of ingestion unknownor if chronic ingestion >4g/d

Rumack-Matthew nomogram(www.tylenolprofessional.com/assets/Nomogram.pdfpredicts risk ofhepatotoxicity from serumlevel of acetaminophenwhen time of ingestion isknown

Low threshold to start NACeven w/ low or undetectableserum acetaminophen levels

PO NAC (preferred): 140mg/kg loading dose → 70mg/kg q4h × 17 additionaldoses

IV NAC: 150 mg/kg over 1 h →50 mg/kg over 4 h → 100mg/kg over 16 h; risk of

http://www.tylenolprofessional.com/assets/Nomogram.pdf

anaphylaxis; use if unable totolerate POs, GIB, preg,fulminant hepatic failure

Ischemic hepatitis• “Shock liver” w/ AST & ALT

>1000 + ↑↑ LDH; delayed ↑↑Tbili

• Seen in HoTN & CHF; oftenrequires ↑ venous + ↓portal/arterial pressure +hypoxia

Nonalcoholic fatty liver disease(NAFLD, a spectrum of disease; Hep2012;55:2005)• Definition: fatty infiltration of

liver and absence of EtOH or

other cause of steatosis (TPN,rapid wt loss or Rxs such asHAART, tamoxifen,amiodarone, MTX)NAFL = steatosis, �

inflammation; NASH =steatosis + inflammation ±fibrosis on liver bx

• NAFLD: 10–30% of U.S. pop. &over 60% in T2DM & obesity

• NASH: 2–5% of NAFLD & risk ofcirrhosis in NASH w/ fibrosison bx is 30% at 10 y

• Pathophys: hepatic lipotoxicityw/ oxidant stress &inflammatory response;PNPLA3 high-risk SNP confers ↑

risk of hepatic fat content,NASH, & fibrosis (Hep2011;53:1883)

• Clinical: 80% asx, ↑ ALT > AST,but nl ALT/AST does notexclude poss. of NASH on bx

• Dx: based on clinical variables &imaging. Liver bx remains goldstandard. NAFLD fibrosis score(www.nafldscore.com) =clinical variables to predictNASH w/ advanced fibrosis.

• Rx: wt loss, exercise, DM/lipidcontrol (statins; Lancet2010;376:1916); pioglitazone+ vit E ↓ steatosis & inflam,not fibrosis (NEJM

http://www.nafldscore.com

2010;362:1675). Pentoxifyllineunder study (Hep2011;54:1610).

ACUTE LIVER FAILURE

Definition• Acute hepatic disease +

coagulopathy +encephalopathy; w/o knownpre-existing liver dis.

• Fulminant = develops w/in 8wk; subfulminant = developsbetween 8 wk and 6 mo

Etiology (Lancet 2010;376:190)• Viral (12% of cases)

HAV, HBV, HCV (rare), HDV+ HBV, HEV (esp. ifpregnant)

HSV (immunosupp Pt), EBV,CMV, adenovirus,

paramyxovirus, parvovirusB19

• Drugs/toxins (nearly 80% ofcases; Hep 2010;52:2065)Drugs: acetaminophen (most

common cause; >40% of allcases), phenytoin, INH,rifampin, sulfonamides,tetracycline, telithromycin,amiodarone, PTU, valproate

Toxins: fluorinatedhydrocarbons, CCl4, Amanitaphalloides

• Vascular: ischemic hepatitis,Budd-Chiari syndrome, hepaticSOS, malignant infiltration

• Autoimmune hepatitis (initialpresentation)

• Misc.: Wilson’s, acute fatty liverof pregnancy (HELLP, Reye’s),idiopathic (up to 20%)

Clinical manifestations• Initial presentation usually

nonspecific, w/ nausea,vomiting, malaise, followed byjaundice

• Neurologicencephalopathy: stage I =

DMS; stage II = lethargy,confusion; stage III =stupor; stage IV = coma

asterixis in stage I/II/III

encephalopathy;hyperreflexia, clonus,rigidity in stage III/IV

cerebral edema → ↑ ICP, ↓CPP → cerebral hypoxia,uncal herniation, Cushing’sreflex (hypertension +bradycardia), pupillarydilatation, decerebrateposturing, apnea

• Cardiovascular: hypotensionwith low SVR

• Pulmonary: respiratoryalkalosis, impaired peripheralO2 uptake, pulm edema, ARDS

• Gastrointestinal: GIB (↓ clotting

factors, ↓ plt, DIC),pancreatitis (? due toischemia)

• Renal: ATN, hepatorenalsyndrome, hyponatremia,hypokalemia,hypophosphatemia

• Hematology: coagulopathy(due to ↓ synthesis of clottingfactors ± DIC)

• Infection (~90% of Pts): esp.with Staph, Strep, GNRs andfungi (↓ immune fxn, invasiveprocedures); SBP in 32% ofPts; fever and ↑ WBC may beabsent

• Endocrine: hypoglycemia (↓ glc

synthesis), metabolic acidosis(↑ lactate), adrenal insuf.

Workup (Hep 2012;55:965)• Viral serologies (see “Acute

Hepatitis Workup”)• AIH serologies, ceruloplasmin &

serum/urine copper,pregnancy test, arterial NH3

• Toxicology screen(acetaminophen levels q1–2huntil peak determined)

• Imaging studies (RUQ U/S or abdCT, Doppler studies of portaland hepatic veins)

• Liver biopsy (unless precluded bycoagulopathy → in which case

consider transjugular)

Treatment (Hep 2012;55:965)• ICU care at liver transplant ctr

for hemodynamic &ventilatory support; CVVH forARF

• IV N-acetylcysteine (same doseas for acetaminophen): all Ptsw/ hepatic failure and grade1–2 enceph: ↑ cerebral bloodflow and ↑ transplant-freesurvival (Gastro 2009;137:856)

• Cerebral edema: rare w/ NH3

<75 mM/L, invariable if>200 mM/L; consider ICPmonitoring if stage III/IV

enceph; if ↑ ICP → mannitol0.5–1.0 mg/kg; prophylactic3% saline for goal Na 145–155mEq/L if NH3 >150 mM/L,grade 3/4 enceph, ARF or onvasopressors; barbiturates &hypothermia if ↑ ICPrefractory to osmotic agents

• Encephalopathy: intubate forgrade III or IV; lactulose(avoid diarrhea &overdistension)

• Coagulopathy: vit K;FFP/plts/cryo if activebleeding; ? recomb. factorVIIa; PPI prophylaxis

• Infection: low threshold for abx

(broad spectrum, eg,vancomycin & 3rd-gen ceph.),albeit no proven mortalitybenefit to empiric abx

• Treatment of specific causes:nucleo(s/t)ides for HBV;steroids for AIH; considerplasma exchange for Wilson’s;IV acyclovir for HSV; gastriclavage & PCN-G for Amanitaphalloides; delivery of child forpregnancy related; TIPS andanticoag for Budd-Chiari

• Liver transplantation if poorprognosis w/ grade II or IIIencephalopathy (see below)

Prognosis• Non-acetaminophen ALF

mortality ~80%,acetaminophen-induced ALFmortality ~30%

• Predictors of poor outcomeAcetaminophen-induced: pH

<7.3 after fluids or INR>6.5, Cr >3.4, or gradeIII/IV enceph.

Non-acetamin.-induced: INR>6.5 or 3 of the following:non-A/B viral hep; otherdrug toxicity; time fromjaundice to enceph. >7 d;age <10 or >40 y; INR>3.5; Tbili >17.4

• ALFED model: NH3, Tbili, INR, &≥2 enceph (Gut 2012;61:1068)& ALFSG index: coma grade,INR, Tbili, PO4, & serum CK18(Gastro 2012;143:1237) arenew indices for predictingneed for liver Tx and mortality

• ~25–30% of Pts w/ ALF undergoliver transplantation w/ 5-ysurvival rate of 70%

CIRRHOSIS

Definition (Hep 2011;54:1864 &2012;56:1983; J Hep 2012;56:S13)• Definition: fibrosis and

regenerative nodulesresulting from hepatocellularinjury

• Decompensated = jaundice,variceal bleed,encephalopathy, ascites; worseprognosis

Etiologies• Alcohol (~60–70%): Laennec’s

cirrhosis; micronodular• Viral hepatitis (~10%): chronic

HBV, HCV, HDV infection

• Autoimmune hepatitis: female,↑ IgG, ANA, antismoothmuscle Ab

• Metabolic diseases (~5%):hemochromatosis, Wilson’sdisease, ɑ1-AT deficiency

• Biliary tract diseases (~5%):primary biliary cirrhosis,secondary biliary cirrhosis(calculus, neoplasm, stricture,biliary atresia), primarysclerosing cholangitis

• Vascular diseases: Budd-Chiarisyndrome, R-sided CHF,constrictive pericarditis,sinusoidal obstruction

syndrome• Nonalcoholic fatty liver dis.

(NAFLD, 10–15%) cause ofmost “cryptogenic cirrhosis”

Clinical manifestations• Subclinical or may p/w liver

dysfunction (jaundice,coagulopathy,encephalopathy) and/or portalHTN (ascites, varices); 35%p/w fever (SBP, acute EtOH);25% p/w hematemesis

Physical exam• Liver: initially enlarged, palpable

(L lobe predom), firm;eventually shrunken and

nodular• Signs of liver failure: jaundice

(bili >2), spider angiomata &palmar erythema (↑ estra-diol), Dupuytren’scontractures, white nail lines(Muehrcke’s lines) & proximalnail beds (Terry’s nails), ↑parotid & lacrimal glands,gynecomastia, testicularatrophy, asterixis,encephalopathy, fetorhepaticus, clubbing,hypertrophic osteoarthropathy

• Signs of portal hypertension:splenomegaly, ascites, dilatedsuperficial abdominal veins

(caput medusae), epigastricCruveilhier-Baumgartenvenous hum

Laboratory studies• ↑ bilirubin, ↑ PT (poor

correlation w/ bleeding; factorVIII nl as not synthesized byliver), ↓ alb, ± ↑aminotransferases (AST > ALTif late) and ↑ AΦ (variable), ↓Na, ↑ γ-glob

• Anemia (marrow suppression,hypersplenism, Fe and/orfolate defic.), neutropenia(hypersplenism),thrombocytopenia

(hypersplenism, ↓ Tpoproduction by liver, EtOH tox)

Workup• Abdominal U/S w/ Doppler:

liver size (↑ L & caudate lobe),r/o HCC, ascites, ✓ patency ofportal, splenic and hepaticveins

• Assess fibrosis: biomarkers (eg,FibroSURE = panel of 6markers validated in HCV, ↑score predictive of fibrosis);U/S or acoustic radiation forceimpulse or MR elastography

• Determine etiology: hepatitisserologies (HBsAg, anti-HBs,

anti-HCV), autoimmunehepatitis studies (IgG, ANA,anti–smooth muscle Ab), Feand Cu studies, ɑ1-AT, AMA

• ± Liver bx: percutaneous ortransjugular (consider if ascitesor coagulopathy) used to dxetiology and presence ofcirrhosis

Ascites (see “Ascites” for details ondx eval; Hep 2009;29:2087)• Due to portal HTN (defined as

hepatic venous pressuregradient [HVPG] >5 mmHg)

• Develops in 60% w/in 10 y;~50% mortality at 5 y

• Treatment (Am J Gastro2009;104:1802): ↓ Na intake(1–2 g/d); free H2O restrict ifNa <125Diuretics: goal 1 L/d; urine

Na/K >1 implies effectivealdo block; spironolactone± furosemide in 5:2 ratio(eg, 100 & 40 mg daily); ↑doses in proportion

� NSAID as interferes w/diuretic action (commoncause of refractory ascites)

• Refractory ascites (Clin Gas Hep2011;9:931): seen in 5–10% ofPts; 2-y survival is 25%

Diuretic resistant on 2g Na dietor diuretic-induced complic(Cr >2, Na <125, ↑ or ↓ K,enceph)

Large-volume paracentesis(LVP); if >5 L, replace w/8–10 g/L of alb → ↓ risk ofparacentesis-induced circ.dysfxn (AKI & lyte abnl) & ?↓ mortality (Hep2012;55:1172)

Beware LVP if SBP as ↑risk of ARF → considerdx tap to r/o SBP first

Transjugular intrahepaticportosystemic shunt (TIPS)(Clin Gas Hep 2011;9:936)

↓ ascites in 75%, ↑ CrCl, ↑enceph, survival benefitover LVP remainscontroversial

Contraindic: grade IIenceph, CHF or pulmHTN, active infxn orbiliary obstruction

Complications includetechnical: bleeding,fistula; related to stent:thrombosis w/in 24 hrare, 1 y patency w/coated stents ~80%,infxn (endotipsitis);shunting: new or ↑enceph in 20–30%,

hemolysis (Hep2010;51:306)

• Hepatic hydrothorax: 2°diaphragmatic defect; oftenunilateral, R > L, ± ascitesTreatment: � chest tube due to

↑ complications; Rx same asascites

Spont empyema can occur(even w/o SBP) → dxthoracentesis; Rx same as forSBP

Spontaneous bacterialperitonitis (SBP; see “Ascites” fordetails; J Hep 2010;53:397)• Develops in ~20%; 20%

mortality; risk factors: AFTP<1 g/dL, hx of SBP, currentGIB

• Can p/w encephalopathy, abdpain, fever, but often (25%)asx; consider paracentesis inall hospitalized cirrhotics w/ascites

• Micro: 70% GNR (E. coli, Klebs),30% GPC (Enterococcus, S.pneumo), nosocomial (fungi,Pseud); ~40% culture

• Rx: 3rd gen. ceph (eg, cefotaxime4g/d total dose) or amox/clav× 5 d, if � enceph/AKI canuse FQ (cipro/oflox) but avoidif already on for ppx or in ↑

FQ resist. areas IV albumin 1.5g/kg at time of dx & 1 g/kg onday 3 → ↑ survival (NEJM1999;341:403) If notimproving, repeat paracentesisat 48 h: ~25% ↓ PMN count =Rx success

• Ppx: if h/o SBP or AFTP <1.5 +Na <130, Cr >1.2 or Child-Pugh B (Am J Gastro2009;4:993) norfloxacin 400mg PO qd or Bactrim DS qd

Gastroesophageal varices ±UGIB (see also “GIB”; NEJM2010;362:823)• Present in 60% of

decompensated cirrhotics;incidence of bleeding is 24%by 2 y; bleeding risk if HVPG>12 mmHg; screen allcirrhotics at time of dx

• 1° prevention of UGIB: med-to-large varices or “red wale”marks or Child-Pugh B or Cnonselective b-blockers:

~50% ↓ risk of bleeding ± ↓mortality; typically nadololor propranolol (considercarvedilol if systemic HTN asɑ1 blockade ↓ intrahepaticvasc resist.; Hep2010;54:2214); titrate to25% ↓ HR; EGD � req. to

document improvementendoscopic variceal ligation

(EVL): ↓ bleeding & death bB (Ann Hep 2012;11:369)q1–2wk until gone → surveyEGD at 3 mo → q6–12mo;adding bB only ↑ side effects

bB vs. EBL: choice based onPt/physician preference, bBoften 1st (Hep2008;47:1764)

• 2° prevention: for all Pts after 1stbleed b/c ~50% rebleed &~30% mortality bB + EBL >either alone (Annals2008;149:109); TIPS ifrefractory or consider in Child-

Pugh B or C w/in 72 h ofadmission for esoph varicealbleed (↑ 1-y survival; NEJM2010;362:2370)

Portosystemic (hepatic)encephalopathy (PSE) (Clin GasHep 2012;10:1208)• Pathogenesis: failure of liver to

detoxify NH3 + othersubstances (eg, ADMA; J Hep2013;58:38) that causecerebral edema, ↓ O2

consumption, ↑ ROS → braindysfxn

• Precipitants: ↑ dietary protein,constip., GIB, med

nonadherence, infxn,azotemia, ↓ K, Δvolume/water, hypoxia, HCC,portosystemic shunt, meds,PVT

• Stages: (1) confusion; (2)drowsiness; (3) stupor; (4)coma

• Dx: asterixis can be seen; NH3

poor Se for dx & monitoringRx; remains a clinical dx

• Treatment: identify/correctprecipitants, restrict dietaryprotein acutely (60–80 g/d),lactulose (acidification ofcolon: NH3 → NH4+) w/ goal

2–4 stools/d ± rifaximin 550mg bid (↓ gut bacteria → ↓NH3 prod); correct zincdeficiency

• 2° prevention: lactulose ±rifaximin 550 bid (Gastro2009;137:885; NEJM2010;362:1071)

Hepatorenal syndrome (HRS)(NEJM 2009;361:1279; Crit Care2012;16:R23(1))• Pathophys: renal

vasoconstriction w/ ↓ renalblood flow; kidneyhistologically nl

• Criteria: (1) cirrhosis w/ ascites;

(2) Cr >1.5 mg/dL; (3) �improvement in Cr (to ≤1.5)after d/c diuretic & volumeexpansion (1 g/kg/d ofalbumin × 2 d); (4) � shock(prerenal azotemia/ATN); (5)� nephrotoxic meds; (6) �organic kidney dis (eg, GN) orobstructionType I: Cr >2.5 or 1.5×

baseline in <2 wk; usuallyoccurs in severe liver failure,often following precipitatingevent (see later); mediansurvival 2 wk

Type II: more indolent course,median survival 6 mo; liver

failure present < in type I• Precipitants: GIB, overdiuresis,

infection, paracentesis, drugs(aminoglycosides, NSAIDs)

• Rx: Type 1: octreotide (100–200mcg SC tid) + midodrine (7.5–12.5 mg PO tid, titrate to ↑MAP 15 mmHg) + 20–40 g/dalbumin or terlipressin +albumin (Hep 2010;51:576);definitive Rx = liver tx. Type2 w/ refractory ascites → TIPS.

Hepatocellular carcinoma (HCC)(Hep 2011;53:1020; Lancet2012;379:1245)• Epi: worldwide, 6th most

prevalent cancer, 3rd mostfrequent cancer-related death,80% of cases due to HCV/HBVcirrhosis, in which annual riskof HCC is ~3–8% (Gastro2012;142:1264). ↑’d risk w/cirrhosis of any type but esp.w/ viral, HFE, PBC, ?ɑ1-AT.

• Clinical: asx vs. hepaticdecompensation (eg, ascites,PSE), PVT w/ tumor thrombus

• Dx: screen cirrhotics q6mo w/U/S ± AFP, though manycenters choose dual phaseCT/MRI (if arterial enhancing& venous phase or delayedwashout, no bx req for dx)

• Rx: radiofrequency ablation (RFA)for HCCs <3 cm in size;consider resection if singlelesion <2 cm and Child-PughA w/o portal HTN; transarterialchemoembolization (TACE)preferred for large cancers(not curative) or if notamenable to RFA (nearIVC/lung); consider livertransplant if up to 3 HCCs ≤3cm or 1 HCC ≤5 cm

• Complications of Rx in 2–11%,procedure mortality ~0.5%.RFA → PVT, colon perforation,abscess, skin burn, PTX,subcapsular hematoma, AKI,

diaphragm injury. TACE →postembolization syndrome(PES) = nausea, RUQ pain,ileus, fever, ↑ ALT/AST; self-limited, resolves w/in 1 wk.Other: hepatic ischemia,abscess (2%), biliary treeinjury, cholecystitis,gastroduodenal ulceration(~5%), kidney injury (2%).

Other complications• Coagulopathy (NEJM

2011;365:147): complexbalance of pro- & anti-hemostatic drivers ↑ bleeding:↓ plts (sequestration & ↓ Tpo)& ↓ clotting factors, renal

dysfxn ↑ clotting: ↑ vWF &factor VIII, ↓ protein C, S,ATIII

• Hepatopulmonary syndrome(HPS) (NEJM 2008;358:2378)Definition/etiology: abnl pulm

gas exchange (A-a gradient≥15 or PaO2 <80) +intrapulm vascular shuntingw/o intrinsic pulm disease; ?due to ↑ pulmonary NO

S/S: platypnea-orthodeoxia,clubbing, cyanosis

Dx w/ contrast echo showingpulm A-V shunt (opac. in LA3–6 cycles after RA)

Rx: O2; potential embolizationif large vessel on CT, ? TIPS,liver tx only definitive Rx

• Portopulmonary hypertension(POPH) ( J Clin Gastr2011;45:703): ↑ PAP (MPAP>25 mmHg), PVR >240dyns/cm5 and PAOP <15mmHg. Due to pulmvasoconstriction from ↑endothelin in ESLD. If PASP≥40 mmHg by TTE → RHC.

• Cirrhotic cardiomyopathy: ↓inotropic & chronotropicresponse, ↓ systolic anddiastolic fxn, prolonged QT,hyperkinetic circulation; ↑

troponin, BNP (JACC2010;56:539)

• Infxn: Kupffer cell (hepatic mΦ)dysfxn, ↓ opsonic activity;vaccinate for HAV & HBV,influenza yearly,pneumococcal vaccine, avoidPPIs? (Alim Pharm Ther2012;36:866)

• Endocrine: diabetes (15–30%)due to altered glc & insulinmetabolism; ↑ frequency ofadrenal insufficiency in ESLD(Hep 2012;55:1282)

Prognosis

• MELD (Model for End-Stage LiverDisease): used to stratify Ptson liver tx list & to predict 3-mo survival in Pts w/ cirrhosisand some acute forms of liverdisease. Based on Cr, INR, &total bili. Calculator:www.mayoclinic.org/meld/mayomodel6.html(Gastro 2011;14:1952). If

http://www.mayoclinic.org/meld/mayomodel6.html

MELD <21 additionalpredictors of mortality includeNa <130 (NEJM2008;359:1018; Clin Gastro Hep2009;7:1236), refractoryascites, ↑ HVPG and low QoL.

Liver transplantation• Undertake evaluation when

MELD ≥15• Indic: recurrent/severe enceph,

refractory ascites, SBP,recurrent variceal bleeding,HRS, HPS, HCC (if no singlelesion is >5 cm or ≤3 lesionswith largest ≤3 cm), acuteliver failure

• Contraindic: inadequate socialsupport, active substanceabuse (EtOH w/in 6 mo),sepsis, significant comorbidity(eg, PoPH w/ MPAP ≥45mmHg refractory to Rx),extrahepatic cancer, persistentnoncompliance

• Survival: 1-y up to 90%, 5-y upto 80%, though lower withHCV; autoimmune liverdisease, such as AIH/PBC/PSCmay recur in 10–30% ofallografts

OTHER ETIOLOGIES OFCIRRHOSIS

Hemochromatosis (Hep2011;54:328; BMJ 2011;342:218)• Recessive disorder of iron

sensing or transport leadingto tissue iron deposition

• HFE mutations (85% of cases),typically C282Y homozygotes(~0.5% of N. EuropeanCaucasians), rarelyC282Y/H63D compoundheterozygotes; C282Yhomozygotes: 28% of develop sx (88% lab abnl), and1% of develop sx (due to

menses ↓ Fe load → laterpresentation). C282Y/H63D:only 1.5% manifest dis.

• Non-HFE mutations:hemojuvelin, hepcidin,transferrin receptor 2, &ferroportin

• 2° Fe overload: thalassemia,PRBC transfusion, MDS, EtOH,NASH (NEJM 2012;366:348)

• Sx: fatigue & arthralgias. Inadvanced disease (rare): bronzeskin (melanin + iron),hypogonadism (esp. injuvenile onset), DM,arthropathy (MCP), CHF,infxns (Vibrio, Listeria,

Yersinia), cirrhosis (↑ risk ifEtOH/fatty liver disease; 15%risk of HCC). Disease also a/wALS (H63D homozygotes) &porphyria.

• Dx: fasting iron sat >45%(iron/TIBC × 100%); ↑ ferritin(acute phase reactant, so poorSp; often nl in young Pts). If ↑iron sat. → ✓ HFE to confirmdx, imaging by MRI (blackliver) If HFE & ferritin>1000 ng/mL or ↑ LFTs →liver bx for quant Fe index &to stage fibrosis

• Treatment: phlebotomy (250 mL= 1 unit, ~250 mg of Fe) qwk

until Fe sat <50% & ferritin50–100 μg/L, then q3–4mo;avoid vit C, PPI (↓ intestinaliron transport); deferoxamineor deferasirox if phleb.contraindic.; geneticcounseling

Wilson’s disease (J Hep2012;56:671)• Recessive disorder of copper

transport (mutation in ATP7B)→ copper overload; primarilyaffects liver, but also othertissues (brain, eye)

• Epidemiology: 1 in 40,000,majority present b/t 5 & 35

y/o, only 3% of Pts present>40 y/o

• Extrahepatic s/s: neuro ψdisease, parkinsonism &movement disorder(hepatolenticular disease),Kayser-Fleischer rings ( in99% w/ neuro ψ but in <50%w/ hepatic disease), Coombs hemolytic anemia, renaldisease

• Dx: ↑ 24-h urine Cu, ↓ serumceruloplasmin (Se 90%), rarelypenicillamine challenge w/ ↑urine Cu excretion, liver bx w/hepatic Cu content. In acuteliver failure, AΦ/bili <4 +

AST/ALT >2.2 better Se & Spthan urine Cu or ceruloplasmin(Hepatology 2008;4:1167).

• Treatment: chelation w/penicillamine + pyridoxine;2nd line trientine (↓ toxicityw/ similar efficacy). Zinc: ↓intestinal Cu transport and canhelp delay disease; best used ifasx or in conjunction w/chelation (must give 4–5 hapart from chelators).

ɑ1-antitrypsin deficiency (ɑ1-AT)(NEJM 2009;360:2749; Clin GasHep 2012;10:575)• Abnl ɑ1-AT → polymerization in

liver (cirrhosis) & uninhibitedprotease activity in lung(emphysema). Affects 1/3000of European ancestry. Variedpresentations: neonatalhepatitis in infants; cholestaticjaundice in kids; ↑ AST/ALT orcirrhosis in kids/adults.

• Extrahepatic disease:emphysema, necrotizingpanniculitis, ANCA vasculitis(Wegener)

• Dx: serum ɑ1-AT level (acutephase reactant), level <50%of nl typically diagnostic;gold standard = phenotyping

of protease inhibitor (Pi); Z

is high-risk allele (ZZ =liver dis); S is “slow” allele(SZ = liver or lung dz); M isnl (MZ ? ↑ risk of dis);null/null → no ɑ1-ATprotein, ∴ only emphysemaand not liver dis (nopolymerization)

liver bx shows characteristicPAS cytoplasmic inclusionbodies

• Treatment: standard Rx forcirrhosis/chronic liver dis.; ɑ1-AT replacement foremphysema

Primary biliary cirrhosis (PBC)

(Hepatology 2009;50:291; Lancet2011;377:1600)• Autoimmune destruction of

intrahepatic bile ducts; may betriggered by certain infxns ortoxins; a/w X monosomy,variants in IL12ɑ & IL12receptor genes (NEJM2009;360:2544)

• Epi: 40–60 y/o; a/w Sjögren’s,Raynaud’s, scleroderma, celiac& thyroid disease

• Sx (late): fatigue, pruritus,jaundice, steatorrhea,xanthelasma, autonomic & cogdysfxn

• Ddx: PSC, autoimmune hepatitis

(overlap syndrome), sarcoid,meds, idiopathic adultductopenia, biliarystricture/cancer

• Dx: ↑ AΦ, ↑ bili, ↑ IgM, ↑ chol, antimitochondrial Ab (AMA) in95%. If AMA, liver bx notneeded due to high Se & Sp.0.5% gen pop AMA & nlLFTs → 10% develop PBC at 6y. If AMA , liver bx (Pts often

ANA, smooth muscle Ab;same prognosis as AMA).

• Rx: ursodeoxycholic acid (13–15 mg/kg/d) regardless ofstage~25% complete response, ↑

survival & ↓ histologicchange & complications (eg,varices) (Gastro2005;128:297). Trials ofcolchicine, MTX, budesonideif refractory to urso.

Pruritus: cholestyramine (give2–4 h after UDCA); ifrefractory sx: naltrexone,rifampin

Fat-soluble vitamins;screen/Rx osteoporosis (riskindependent of vit Δdeficiency)

If ESLD: liver tx: ~20% recurbut no impact on long-termsurvival

Primary sclerosing cholangitis(PSC) (Liver Transpl 2008;14:735)• Diffuse inflammation of

intrahepatic and extrahepaticbile ducts leading to fibrosis &stricturing of biliary system.A/w HLA-B8 and -DR3 or -DR4, frequent autoantibodies but poorresponse to immunomodulatorRx suggesting nonautoimmunepathogenesis.

• Epi: > (20–50 y). ~70% of Ptsw/ PSC have IBD (usually UC);only 1–4% w/ UC get PSC.

• Clinical sx: fatigue, pruritus,jaundice, fevers, RUQ pain,

cholangioca., ↑ Tb, ↑ AΦ• Ddx: extrahepatic obstruction,

PBC, may also have overlapw/ AIH and similarpresentation to IgG4autoimmune cholangitis(steroid responsive) (Gastro2008;134:706)

• Dx: MRCP ± ERCP → multifocalbeaded bile duct strictures, butmay miss dx if confined tosmall intrahepatic ducts (~2%“small duct PSC”: betterprognosis,? different disease).Liver bx may show “onion-skin” fibrosis around bileducts, but not necessary for dx,

plays role in excludingautoimmune sclerosingcholangitis.

• Treatment: supportive care, fat-soluble vitamins; no meds haveimproved survivalUrsodeoxycholic acid may ↓colon CA risk in Pts w/ UC &improve LFTs in Pts w/o UCDominant stricture: endoscopicdilation, short-term stenting orsurgical resectionCholangiocarcinoma (20%): ?biannual surveillance w/MRCP/RUQ U/S and CA19-9Liver transplantation: ~30%recurrence, though if UC,

colectomy may ↓ recurrence

HEPATIC VASCULAR DISEASE

Portal vein thrombosis (PVT) (AlPhar Ther 2009;30:881; J Hepatol2012;56:S1)• Definition: thrombosis,

constriction or invasion ofportal vein → portal HTN →varices. Isolated splenic veinthrombosis (eg, 2° topancreatitis) → isolated gastricvarices.

• Etiologies: cirrhosis, neoplasm(pancreas, HCC), abdominalinfxn → pylephlebitis (infectedthrombosis of PVT), hypercoagstate (incl MPS), pancreatitis,

IBD, surgery, trauma• Clinical manifestations

acute PVT: can p/w pain;often asx and dx asincidental finding on U/S orCT if mesenteric veininvolved may p/w intestinalinfarct; if fever considerpylephlebitis

chronic PVT: asx/incidentalfinding; may p/w s/s ofportal HTN → hematemesis2° variceal bleeding,splenomegaly, mild enceph;ascites uncommon unlesscirrhosis

• Diagnostic studies: LFTs usually

normal; U/S w/ Doppler,MRA, CT (I+), angiography;“portal cavernoma” network

of hepatopedal collaterals inchronic PVT—can rarelycause biliary obstruction andcholestatic LFTs = portalcholangiopathy (may requiresurgery)

• Treatment: eval for underlyingcause (cirrhosis, MDS,hypercoag); if cirrhotic, Rx lessclearacute: LMWH → warfarin × 6

mo, or indefinitely ifirreversible cause (exceptcirrhosis),

chronic: anticoag ifnoncirrhotic or hypercoagstate; unclear if benefit >bleed risk

ppx: LMWH may prevent PVT& liver decomp in advancedcirrhosis (Gastro2012;143:1253)

Varices: screen at dx; noevidence for 1° ppx of bleed;if bleed endoscopic Rx andbB. If refractory bleedconsider TIPS, shunt.Isolated gastric varices 2°splenic vein thrombosis:splenectomy is curative.

Budd-Chiari syndrome (J Hepatol2012;56:S1)• Occlusion of hepatic vein(s) or

IVC → sinusoidal congestionand portal HTN

• Etiol: ~50% due tomyeloproliferative disordera/w JAK2 mutations (esp. P.vera), other hypercoag state,tumor invasion (HCC, renal,adrenal), IVC webs, trauma,1/4 idiopathic

• Symptoms: hepatomegaly, RUQpain, ascites, dilated venouscollaterals

• Dx: ± ↑ aminotransferases & AΦ;

Doppler U/S of hepatic veins(85% Se & Sp); CT (I+) orMRI/MRV → vein occlusion or↑ caudate lobe (separatevenous drainage); “spider-web” pattern on hepaticvenography; liver bx showingcongestion (r/o right-sidedCHF)

• Treatment: anticoag (LMWH →warfarin); considerthrombolysis acutely; if shortstenosis stent may be possible;consider TIPS (↑ occlusion riskc/w side-to-side portocavalshunt); liver transplant ifhepatic failure or failed shunt

(J Gastro Surg 2012;16:286)

Sinusoidal obstruction syndrome(SOS) (J Hepatol 2012;56:S1)• Occlusion of hepatic venules

and sinusoids (formerlyveno-occlusive disease)

• Etiologies: HSCT, chemo (esp.cyclopho), XRT, Jamaicanbush tea

• Clinical manifestations:hepatomegaly, RUQ pain,ascites, weight gain, ↑ bilirubin

• Dx: U/S w/ reversal of portalflow, but often not helpful; dxmade clinically (↑ bili, wtgain/ascites and RUQ pain)

or, if necessary, by liver bx orHVPG (>10 mmHg)

• Treatment (20% mortality):supportive; ? defibrotide(adenosine agonist ↑ TPAlevels)

• Ppx: defibrotide; ursodeoxycholicacid for high-risk HSCT pop; ?use of low-dose heparin

Figure 3-8 Hepatic vasculature

ASCITES

Pathophysiology• Portal hypertension → systemic

vasodilatation (? due torelease of NO) → ↓ effectivearterial volume → renal Naretention

• ↓ serum oncotic pressure fromhypoalbuminemia; ↑ hepaticlymph production

Symptoms• ↑ abd girth, wt gain, new abd

hernia, abd pain, dyspnea,nausea, early satiety

Evaluation (JAMA 2008;299:1166;Hepatology 2009;29:2087)• Physical exam: flank dullness

(NPV ~90%; >1500 mLneeded), shifting dullness (Se~83%)

• Radiologic: U/S detects >100mL; MRI/CT (also help withDdx)

• Paracentesis (NEJM2006;355:e21; Dig Dis Sci2007;52:3307): perform in all

Pts w/ new ascites andconsider in all hospitalizedcirrhotics w/ ascites; complic.<1% (bleeding, but risk notrelated to PT or plt count;Hepatology 2004;40:484); U/S↑ success but does not ↓complic.

• Serum-ascites albumingradient (SAAG): ~95% acc.for portal HTN (Annals1992;117:215)≥1.1 g/dL → portal

hypertension related; <1.1g/dL → non–portalhypertension related

if portal HTN + another cause

(seen in ~5% of cases)SAAG still ≥1.1

if known cirrhosis and SAAG<1.1 but no other readilyidentifiable cause, likely justcirrhosis (Am J Gastro2009;104:1401)

• Ascites fluid total protein (AFTP):useful when SAAG ≥1.1 todistinguish cirrhosis (AFTP<2.5 g/dL) from cardiacascites (AFTP ≥ 2.5 g/dL)

• Rule out infection: cell countw/ diff + Gram stain/cxdefine bacterial peritonitis (seelater); bedside inoculation ofcx bottles ↑ yield to 90%

(Gastro 1988;95:1351) fungalcx if prolonged hosp, abx use;AFB cx + adenosinedeaminase to r/o TB

• Other tests: amylase(pancreatitis, gut perforation);triglycerides (chylous ascites);cytology (peritonealcarcinomatosis, ~95% Se w/ 3samples); LDH, glc, CEA, AΦ(perforation)

Treatment• If 2° to portal HTN (see

“Cirrhosis” for details): ↓ Naintake + diuretics(spironolactone +

furosemide); if refractory →large-volume paracentesis orTIPS

• If non–portal HTN related:depends on underlying cause(TB, malignancy, etc.)

• Vaptans ↑ Na, mobilize ascites,but no morb/mort benefit (AlPharm & Ther 2012;36:619)

Bacterial peritonitis (Gut2012;61:297)

• SBP/CNNA: seen in cirrhosis (qv)b/c ascites have ↓ opsonins;rare in other causes

• NNBA: often resolves w/o Rx;follow closely → Rx only if sxor persistently culture

• Secondary intra-abdominalabscess or perforation so oftenpolymicrobial ascitic fluid TP>1 g/dL, glc <50 mg/dL,LDH >225 U, CEA >5, AΦ>240 Rx: 3rd-gen. ceph +metronidazole; urgentabdominal imaging ± ex lap

• Peritoneal dialysis-associated:cloudy fluid, abd pain, fever,nausea pathogens: 70% GPC,

30% GNR; Rx: vanc + gent (IVload, then administer in PD)

BILIARY TRACT DISEASE

CHOLELITHIASIS (GALLSTONES)

Epidemiology & pathogenesis (JHep 2008;48:S124)• >10% adults in the U.S. have

gallstones; a/w ↑ overallmortality (Gastro2011;140:508)

• Bile = bile salts, phospholipids,cholesterol; ↑ cholesterolsaturation in bile +accelerated nucleation +gallbladder hypomotility →gallstones

• Risk factors: ; South, Central,

Native American; ↑ age (>40y), obesity, pregnancy, TPN,rapid ↓ wt; drugs (OCPs,estrogen, clofibrate, octreotide,ceftriaxone); ileal disease

• ? statin use >1 y ↓ risk of sxgallstones & cholecystectomy(JAMA 2009;302:2001)

Types of gallstones• Cholesterol (90%): 2 subtypes

mixed: contain >50%cholesterol; typicallysmaller, multiple stones

pure: 100% cholesterol; larger,yellow, white appearance

• Pigment (10%)

Black: unconjugated bilirubin(chronic hemolysis, cirrhosis)and calcium

Brown: stasis & infection in bileducts → bacteriadeconjugate bilirubin →precipitates w/ calcium;seen w/ duodenaldiverticula, biliary strictures,parasites

Clinical manifestations• May be asx; biliary pain in

~2%/y; once sx, rate ofcomplications ~2%/y

• Biliary pain (“colic”) =episodic RUQ or epigastric

abd pain that begins abruptly,is continuous, resolves slowlyand lasts for 30 min–3 h; ±radiation to scapula; nausea

• May be precipitated by fattyfoods

• Physical exam: afebrile, ± RUQtenderness or epigastric pain

Diagnostic studies• RUQ U/S: Se & Sp >95% for

stones >5 mm; can showcomplications (cholecystitis);should be performed only afterfasting ≥8 h to ensuredistended, bile-filledgallbladder

Treatment• Cholecystectomy (CCY), usually

laparoscopic, if symptomatic• CCY in asx Pts w/: GB

calcification (~7% risk of ca)(Surgery 2001;129:699), GBpolyps >10 mm, NativeAmerican, stones >3 cm orbariatric surgery or cardiactransplant candidates

• Ursodeoxycholic acid (rare) forcholesterol stones w/uncomplicated biliary pain orif poor surgical candidate; alsoreduces risk of gallstoneformation with rapid wt loss

• Biliary pain: NSAIDs (eg,

diclofenac 50 mg IM) drug ofchoice, efficacy opiates & ↓complications (AlimentPharmacol Ther 2012;35:1370)

Complications• Cholecystitis: 20% of sx biliary

pain → cholecystitis w/in 2 y• Choledocholithiasis → cholangitis

or gallstone pancreatitis• Mirizzi’s syndrome: common

hepatic duct compression bycystic duct stone → jaundice,biliary obstruction

• Cholecystenteric fistula: stoneerodes through gallbladderinto bowel

• Gallstone ileus: SBO (usually atterm ileum) due to stone inintestine that passed thrufistula

• Gallbladder carcinoma (~1% inU.S.)

CHOLECYSTITIS (NEJM2008;358:2804)

Pathogenesis• Acute cholecystitis: stone

impaction in cystic duct →inflammation behindobstruction → GB swelling ±secondary infection (50%) ofbiliary fluid

• Acalculous cholecystitis:gallbladder stasis and ischemia→ inflammatory response;occurs mainly in critically ill,hosp. Pts (postop majorsurgery, TPN, sepsis, trauma,burns, opiates,

immunosuppression, infxn [eg,CMV, Crypto, Campylobacter,typhoid fever])

Clinical manifestations• History: RUQ/epigastric pain ±

radiation to R shoulder/back,nausea, vomiting, fever

• Physical exam: RUQtenderness, Murphy’s sign =↑ RUQ pain and inspiratoryarrest with deep breath duringpalpation of R subcostalregion, ± palpable gallbladder

• Laboratory evaluation: ↑ WBC,± mild ↑ bilirubin, AΦ,ALT/AST and amylase;

AST/ALT >500 U/L, bili >4mg/dL or amylase >1000 U/L→ choledocholithiasis

Diagnostic studies• RUQ U/S: high Se & Sp for

stones, but need specific signs ofcholecystitis: GB wallthickening >4 mm,pericholecystic fluid and asonographic Murphy’s sign

• HIDA scan: most Se test (80–90%) for acute cholecystitis. IVinj of HIDA (selectivelysecreted into biliary tree). Inacute cholecystitis, HIDAenters BD but not GB. 10–20%

false (cystic duct obstructedfrom chronic cholecystitis,lengthy fasting, liver disease).

Treatment• NPO, IV fluids, nasogastric tube

if intractable vomiting,analgesia

• Antibiotics (E. coli, Klebsiellaand Enterobacter sp. are usualpathogens) ([2nd- or 3rd-generation cephalosporin orFQ] + MNZ) or piperacillin-tazobactam

• Early CCY (usually w/in 72 h).Delaying surgery 2–3 mo ↓operative time w/o Δ rate of

complications or conversion toopen procedure (Am J Surg2008;194:40).

• If unstable for surgery, EUS-guided transmural or ERCP-guided transcystic ductdrainage is equivalent tocholecystostomy (Gastro2012;142:805)

• Intraoperative cholangiogram orERCP to r/ocholedocholithiasis in Pts w/jaundice, cholangitis or stonein BD on U/S

Complications• Gangrenous cholecystitis:

necrosis w/ risk of empyemaand perforation

• Emphysematous cholecystitis:infection by gas-formingorganisms (air in GB wall)

• Post CCY: bile duct leak, BDinjury or retained stones,cystic duct remnant, sphincterof Oddi dysfxn

CHOLEDOCHOLITHIASIS

Definition• Gallstone lodged in bile duct

(BD)

Epidemiology• Occurs in 15% of Pts w/

gallbladder stones; can formde novo in BD

Clinical manifestations• Asymptomatic (50%)• RUQ/epigastric pain due to

obstruction of bile flow → ↑BD pressure, jaundice,pruritus, nausea

Diagnostic studies

• Labs: ↑ bilirubin, AΦ; transientspike in ALT or amylasesuggests passage of stone

• RUQ U/S: BD stones seen ~50%of cases; usually inferred fromdilated BD (>6 mm)

• ERCP preferred dx modalitywhen likelihood high;cholangiogram (percutaneous,operative) when ERCPunavailable or unsuccessful;EUS/MRCP to exclude BDstones when suspicion low

Treatment• ERCP & papillotomy w/ stone

extraction (± lithotripsy)

• CCY typically w/in 6 wk unlesscontraindication (>15% Ptswill develop indication forCCY if left unRx’d)

Complications• Cholangitis, cholecystitis,

pancreatitis, stricture

CHOLANGITIS

Definition & etiologies• BD obstruction → infection

proximal to the obstruction• Etiologies: BD stone (~85%)

Malignant (biliary, pancreatic)or benign stricture

Infection w/ fluke (Clonorchissinensis, Opisthorchis viverrini)

Clinical manifestations• Charcot’s triad: RUQ pain,

jaundice, fever/chills; presentin ~70% of Pts

• Reynolds’ pentad: Charcot’s triad+ shock and Δ MS; present in~15% of Pts

Diagnostic studies• RUQ U/S• Labs: ↑ WBC, bilirubin, AΦ,

amylase; BCx• ERCP; percutaneous transhepatic

cholangiogram (if ERCPunsuccessful)

Treatment• Antibiotics (broad spectrum) to

cover common bile pathogens(see above) ampicillin +gentamicin (or levofloxacin)± MNZ (if severe);carbapenems; pip/tazo

• ~80% respond to conservativeRx and abx → biliary drainage

on elective basis• ~20% require urgent biliary

decompression via ERCP(papillotomy, stone extractionand/or stent insertion). Ifsphincterotomy cannot beperformed (larger stones),decompression by biliary stentor nasobiliary catheter can bedone; otherwise percutaneoustranshepatic biliary drainageor surgery.

ACID-BASE DISTURBANCES

GENERALDefinitions• Acidemia → pH <7.36,

alkalemia → pH >7.44• Acidosis → process that

increases [H+]; alkalosis →process that decreases [H+]

• Primary disorders: metabolicacidosis or alkalosis,respiratory acidosis oralkalosis

• Compensationrespiratory: hyper- or

hypoventilation alters PaCO2

to counteract 1° metabolicprocess renal:excretion/retention ofH+/HCO3 to counteract 1°respiratory processrespiratory compensationoccurs in minutes; renalcompensation takes hours todays compensation never fullycorrects pH; if pH normal,consider mixed disorder

Workup• Determine primary disorder: ✓

pH, PaCO2, HCO3

• Determine if degree ofcompensation is appropriate

Mixed disorders (more than oneprimary disorder at the same time)• If compensation less or greater

than predicted, may be 2disorders:PaCO2 too low → concomitant

1° resp. alk.PaCO2 too high → concomitant

1° resp. acid.HCO3 too low → concomitant

1° met. acid.HCO3 too high → concomitant

1° met. alk.• Normal pH but …

↑ PaCO2 + ↑ HCO3 → resp.acid. + met. alk.

↓ PaCO2 + ↓ HCO3 → resp.alk. + met. acid.

normal PaCO2 & HCO3, but ↑AG → AG met. acid. + met.alk.

normal PaCO2, HCO3, & AG →no disturbance or non-AG

met. acid. + met. alk.• Cannot have resp. acid.

(hypoventilation) and resp.alk. (hyperventilation)simultaneously

Figure 4-1 Acid-basenomogram

• ABG vs. VBG: concordant for pH(~0.04), HCO3 (~2 mEq) butnot PaCO2 (~8±17 mmHg)

VBG can be used to screen forhypercarbia w/ PaCO2 cutoff≥45 mmHg (100% Se), butdoes not accurately assessdegree of hypercarbia (Am JEmerg Med 2012;30:896)

METABOLIC ACIDOSIS

Initial workup (Nat Rev Nephol2010;6:274)• ✓ anion gap (AG) = Na+ – (Cl-

+ HCO3-) = unmeasuredanions - unmeasured cationsif ↑ glc, use measured not

corrected Naexpected AG is [albumin] ×

2.5 (ie, 10 if albumin is 4g/dL, 7.5 if albumin is 3g/dL)

↑ AG → ↑ unmeasured anionssuch as organic acids,phosphates, sulfates

↓ AG → ↓ alb or ↑ unmeasured

cations (Ca, Mg, K, Li,bromine, immunoglobulin)

• If ↑ AG, ✓ delta-delta (ΔΔ =DAG/DHCO3) to assess if thereis an additional metabolicacid-base disturbance; DAG =(calculated AG – expected AG),DHCO3 = (24 – HCO3)ΔΔ = 1–2 → pure AG

metabolic acidosisΔΔ < 1 → AG metabolic

acidosis and simultaneousnon-AG acidosis

ΔΔ > 2 → AG metabolicacidosis and simultaneousmetabolic alkalosis

Workup for AG metabolicacidosis• ✓ for ketonuria (dipstick

acetoacetate) or plasma b-hydroxybutyrate (bOHB) nb,urine acetoacetate often notpresent in early ketoacidosisdue to shunting to bOHB; ∴

acetoacetate may later turn ,but does not signify worseningdisease

• If ketones, ✓ renal function,lactate, toxin screen, andosmolal gap

• Osmolal gap (OG) = measuredosmoles – calculated osmolescalculated osmoles = (2 ×

Na) + (glucose / 18) +(BUN / 2.8) (can +[EtOH/4.6] if have EtOHlevel and want to test ifother ingestions)

OG >10 → suggests ingestion(see below)

for methanol/ethylene

glycol: early on, OGprecedes AG; later OGmay be nl with AG

Workup for non-AG metabolicacidosis (CJASN 2012;7:671)• Evaluate history for causes (see

above)• ✓ urine anion gap (UAG) =

(UNa + UK) – UCl

UAG = unmeasured anions –unmeasured cations; asNH4+ is primaryunmeasured cation, UAG isindirect assay for renalNH4+ excretion (NEJM1988;318:594)

• UAG → ↑ renal NH4+excretion → appropriate renalresponse to acidemia Ddx: GI

causes, proximal RTA,ingestions or dilutional

• UAG → failure of kidneys tosecrete NH4+ Ddx: distal orhypoaldo RTA, early renalfailurenb, plasma K usually ↓ in

distal and ↑ in hypoaldo RTA• UAG evaluation assumes Pt

volume replete (UNa >25) &no AG met. acid. (which causes

UAG due to excretion oforganic anions)

Renal tubular acidoses (RTAs)(JASN 2002;13:2160; Int J Clin Pract2011;65:350)

• Proximal (Type II): ↓ proximalreabsorption of HCO3

1° (Fanconi’s syndrome = ↓proximal reabsorption ofHCO3, PO4, glc, aminoacids), paraprotein (multiplemyeloma, amyloidosis),meds (acetazolamide, heavymetals, ifosfamide), renaltransplant, ↓ Vit D, NRTIs

• Distal (Type I): defective distalH+ secretion1°, autoimmune (Sjögren’s,

RA), nephrocalcinosis, meds(ampho, Li, ifosfamide);normally a/w ↓ K; if with ↑

K → sickle cell, obstruction,SLE, renal transplant

• Hypoaldo (Type IV): ↑ K → ↓NH3 synthesis/delivery → ↓urine acid carrying capacity↓ renin: diabetic nephropathy,

NSAIDs, chronic interstitialnephritis, HIV

normal renin, ↓ aldo synthesis:1° adrenal disorders, ACEI,ARBs, heparin

↓ response to aldosterone meds: K-sparing diuretics,

TMP-SMX, pentamidine,calcineurin inhibitors

tubulointerstitial disease:

sickle cell, SLE, amyloid,diabetes

• Combined (Type III): rarelydiscussed or clinically relevant,also called juvenile RTA, hasdistal & proximal features, canbe due to carbonic anhydraseII deficiency

Figure 4-2 Approach tometabolic acidosis

Treatment of severe metabolicacidoses (pH <7.2) (Nat RevNephol 2012;8:589)• DKA: insulin & IVF; AKA:

dextrose, IVF, replete K, Mg,PO4 as needed

• Lactic acidosis: treat underlyingcondition, avoidvasoconstrictors

• Renal failure: hemodialysis• Methanol & ethylene glycol:

early fomepizole, vit. B6

(ethylene glycol), folate(methanol), hemodialysis (esp.if late presentation) (NEJM2009;360:2216)

• Alkali therapy: NaHCO3 (eg,three 50-mmol amps in 1 LD5W) to get serum HCO3 >8and pH >7.2 (estimate mmolof HCO3 needed as 8-[HCO3]serum × wt × 0.5) side

effects: ↑ volume, ↑ Na, ↓ ICa,↑ PaCO2 (& ∴ intracellularacidosis), overshootNo proven benefit in lactic

acidosis or DKA (Annals1986;105:836 &1990;112:492)

• THAM (proton acceptor) in Ptsw/ ↑ PaCO2

METABOLIC ALKALOSIS

Pathophysiology• Saline-responsive etiologies

require initiating event andmaintenance phase

• Initiating event: gain of HCO3 orloss of acidloss of H+ from GI tract or

kidneysexogenous alkali: iatrogenic

HCO3 administration, milkalkali syndrome

contraction alkalosis:diuresis → excretion ofHCO3-poor fluid →

extracellular fluid“contracts” around fixedamount of HCO3 → ↑ HCO3

concentrationposthypercapnia: respiratory

acidosis → renalcompensation with HCO3

retention; rapid correctionof respiratory disorder (eg,with intubation) → transientexcess HCO3

• Maintenance phasevolume depletion → ↑

proximal reabsorption ofNaHCO3 and ↑ aldosterone(see next)

hyperaldosteronism (either1° or 2°) → distal Nareabsorption in exchange forK+ and H+ excretion (andconsequent HCO3 retention)

hypokalemia → transcellularK+/H+ exchange;intracellular acidosis inrenal proximal tubular cellspromotes bicarbonatereabsorption andammoniagenesis

Workup• Check volume status and UCl

UCl <20 mEq/L → saline-responsive

UCl >20 mEq/L → saline-resistant (unless currentlyreceiving diuretics)

(UNa unreliable determinant ofvolume status as alkalemia

→ ↑ HCO3 excretion → ↑ Naexcretion; negativelycharged HCO3 “drags” Na+along)

If UCl >20 and volume replete,✓ blood pressure

Figure 4-3 Approach tometabolic alkalosis

Treatment of severe metabolicalkalosis (pH >7.6)• If volume depletion: d/c diuretics

and correct volume deficit withisotonic saline Ifcardiopulmonary diseaseprecludes hydration, can useKCl, acetazolamide, HCl

• If NGT drainage that cannot bestopped: PPI

• Hyperaldosteronism: treatunderlying condition

RESPIRATORY ACIDOSIS

Etiologies• CNS depression: sedatives, CNS

trauma, O2 in chronichypercapnia (↓ hypoxemicdrive), central sleep apnea

• Neuromuscular disorders:myasthenia gravis, Guillain-Barré, poliomyelitis, ALS,muscular dystrophy, severehypophosphatemia, highspinal cord injury, drugs(paralytics)

• Upper airway abnormalities:acute airway obstruction,laryngospasm, obstructive

sleep apnea, esophagealintubation

• Lower airway abnormalities:asthma, COPD

• Lung parenchyma abnormalities(often cause hypoxia → ↑ RR→ resp. alk., but eventualmuscle fatigue → resp. acid.):pneumonia, pulmonaryedema, restrictive lung disease

• Thoracic cage abnormalities:pneumothorax, flail chest,kyphoscoliosis

• Post infusion of bicarbonate inacidemic Pt w/ limited abilityto ↑ minute ventilation

RESPIRATORY ALKALOSIS

Etiologies (NEJM 2002;347:43)• Hypoxia → hyperventilation:

pneumonia, pulm. edema, PE,restrictive lung disease

• Primary hyperventilationCNS stimulation, pain, anxiety,

fever, trauma, stroke,voluntary

drugs: salicylates,progesterone,methylxanthines, nicotinepregnancy, sepsis, hepaticfailure

• Pseudorespiratory alkalosis: ↓perfusion w/ preserved

ventilation (eg, CPR, severeHoTN) → ↓ delivery of CO2 tolungs for excretion; low PaCO2

but ↑ tissue CO2

SODIUM AND WATERHOMEOSTASIS

OVERVIEW

General• Disorders of serum sodium are

generally due to Ds in totalbody water, not sodium

• Hyper- or hypo-osmolality →rapid water shifts → Ds inbrain cell volume → Δ MS,seizures

Key hormones• Antidiuretic hormone (ADH):

primary hormone thatregulates sodium concentration

stimuli for secretion:hyperosmolality, ↓↓ effectivearterial volume (EAV),angiotensin II action: insertionof aquaporin-2 channels incollecting ducts → passivewater reabsorption urineosmolalityis an indirectfunctional assay of the ADH-renal axis Uosm range: 60mOsm/L (no ADH) to 1200mOsm/L (maximal ADH)

• Aldosterone: primary hormonethat regulates total body sodium(and ∴ volume) stimuli forsecretion: hypovolemia (viarenin and angiotensin II),

hyperkalemia action: iso-osmotic reabsorption ofsodium in exchange forpotassium or H+

HYPONATREMIA

Pathophysiology• Excess of water relative to

sodium; almost always due to↑ ADH

• ↑ ADH may be appropriate (eg,hypovolemia or hypervolemiawith ↓ EAV)

• ↑ ADH may be inappropriate(SIADH)

• Rarely, ↓ ADH (appropriatelysuppressed), but kidneysunable to maintain nl[Na]serum

1° polydipsia: ingestion ofmassive quantities (usually

>12 L/d) of free H2Ooverwhelms diluting abilityof kidney (normal dietarysolute load ~750 mOsm/d,minimum Uosm = 60mOsm/L → excrete in ~12L; if H2O ingestion exceedsthis amount → H2Oretention)

“tea & toast” and “beerpotomania”: ↓↓ daily soluteload, ↑ free H2O →insufficient solute to excreteH2O intake (eg, if only 250mOsm/d, minimum Uosm =

60 mOsm/L → excrete in ~4L; if H2O ingestion exceedsthis amount → H2Oretention)

Workup (NEJM 2000;342:1581;JASN 2012;23:1140)• History: (1) acute vs. chronic

(>48 h); (2) sx severity; (3)risk for neuro complications(alcoholism, malnourished,cirrhosis, older females onthiazides, hypoxia, hypoK)

• Measure plasma osmolalityHypotonic hyponatremia most

common scenario; trueexcess of free H2O relative to

Na Hypertonic hyponatremia:excess of another effectiveosmole (eg, glc, mannitol)that draws H2Ointravascularly; each 100mg/dL ↑ glc >100 mg/dL →↓ [Na] by 2.4 mEq/L Isotonichyponatremia: rare labartifact from hyperlipidemiaor hyperproteinemia

• For hypotonic hyponatremia, ✓volume status (vital signs,orthostatics, JVP, skin turgor,mucous membranes, peripheraledema, BUN, Cr, uric acid)

• Uosm diagnostically useful in

limited circumstances, becausealmost always >300exceptions: Uosm <100 in 1°polydipsia & ↓ solute intakemoreover, Uosm >300 ≠SIADH; must determine if ↑ADH appropriate orinappropriate however, Uosm

important when deciding ontreatment (see below)

• If euvolemic and ↑ Uosm, evaluatefor glucocorticoid insufficiencyand hypothyroidism

Figure 4-4 Approach to

hyponatremia

Hypovolemic hypotonichyponatremia (ie, ↓↓ total bodyNa, ↓ TBW)• Renal losses (UNa >20 mEq/L,

FENa >1%): diuretics (esp.thiazides, as loop diuretics↓ tonicity of medullary

interstitium and impair

urine concentrating ability),salt- wasting nephropathy,cerebral salt wasting,mineralocorticoid deficiency

• Extrarenal losses (UNa <10mEq/L, FENa <1%): GI losses(eg, diarrhea), third-spacing(eg, pancreatitis), inadequateintake, insensible losses

Euvolemic hypotonichyponatremia (ie, ↑ TBW relativeto total body Na)• SIADH (eu- or mild

hypervolemia, inapprop ↑UOsm, normal UNa, ↓ BUN &UA)

malignancy: lung, brain, GI,GU, lymphoma, leukemia,thymoma, mesothelioma

pulmonary: pneumonia, TB,aspergillosis, asthma, COPD,PTX, pressure ventilation

intracranial: trauma, stroke,hemorrhage, infxn,hydrocephalus, Guillan-Barrésyndrome

drugs: antipsychotics,antidepressants (esp. SSRIs),chemotherapy, AVP, MDMA

miscellaneous: pain, nausea,postoperative state

• Endocrinopathies: ↑ ADHactivity seen in glucocorticoid

deficiency (co-secretion of ADH& CRH) and severehypothyroidism/myxedema coma(↓ CO & ↓ GFR)

• Psychogenic polydipsia (Uosm

<100, ↓ uric acid): usuallyrequires intake >12 L/d

• Low solute (↓ UNa, ↓ Uosm) “tea& toast”; “beer potomania”

• Reset osmostat: chronicmalnutrition (↓ intracellularosmoles) or pregnancy(hormonal effects) → ADHphysiology reset to regulate alower [Na]serum

Hypervolemic hypotonic

hyponatremia (ie, ↑ total bodyNa, ↑ ↑ TBW)• CHF (↓ CO → ↓ EAV; UNa <10

mEq/L, FENa <1%)• Cirrhosis (splanchnic arterial

vasodilation + ascites → ↓EAV; UNa <10 mEq/L, FENa

<1%)• Nephrotic syndrome

(hypoalbuminemia → edema→ ↓ EAV; UNa <10 mEq/L,FENa <1%)

• Advanced renal failure(diminished ability to excretefree H2O; UNa >20 mEq/L)

Treatment (Curr Opin NephrolHypertens 2010;19:493)• Approach: depends on volume

status, acuity of hypoNa, and ifsymptomaticAsx or chronic symptomatic:

correct [Na]serum at rate of≤0.5 mEq/L/h

Acute sx: initial rapidcorrection of Na (2 mEq/L/hfor the first 2–3 h) until sxresolve

Rate of ↑ Na should not exceed6 (chronic) to 8 (acute)mEq/L/d to avoid centralpontine

myelinolysis/osmoticdemyelination syn.(CPM/ODS: paraplegia,dysarthria, dysphagia)

• Frequent lab draws and IVFrate adjustments arecornerstones of treatment

• Overly rapid correction: canlead to CPM/ODS. Should beemergently reversed w/dDAVP ± D5W; partialneurologic recovery possible(CJASN 2008;3:331)

• Effect of IV fluids(http://www.medcalc.com/sodium.html

http://www.medcalc.com/sodium.html

however, above assumes entireinfusate retained without anyoutput of Na or H2O if Pteuvolemic, as in SIADH,infused Na will be excreted eg,1 L NS (154 mEq of Na or 308mOsm of solute in 1 L freeH2O) given to Pt with SIADHwith Uosm = 616 → 308 mOsmsolute excreted in 0.5 L H2O →

net gain 0.5 L H2O → ↓[Na]serum ∴ normal saline canworsen hyponatremia 2° SIADHif Uosm > infusateosm

• Hypovolemic hyponatremia:volume repletion with normalsaline at a slow rate. Oncevolume replete → stimulus forADH removed → kidneysexcrete free H2O → serum Nawill correct very rapidly (D5W± ddAVP if overcorrection) (KI2009;76:587).

• SIADH (NEJM 2007;356:2064):free water restrict + treat

underlying causehypertonic saline (± loop

diuretic) if sx or Na fails to ↑w/ free H2O restriction 1 Lhypertonic saline (3% NaCl)will raise [Na]serum by ~10mEq (see above) ~50 mL/hwill ↑ [Na] by ~0.5mEq/L/h; 100–200 mL/hwill ↑ [Na] by ~1–2mEq/L/h formula onlyprovides estimate; ∴recheck serum Na frequently(at least q2h)

salt tabs: particularly ifchronic and no CHF

aquaresis: conivaptan (IV V1a& V2 vasopressin receptorantag) or tolvaptan (oral V2antag; NEJM2006;355:2099); used forsymptomatic SIADHresistant to above Rx butrate of correction can berapid (AJKD 2010;56:325)

demeclocycline: causesnephrogenic DI, ↓ Uosm

• Hypervolemic hyponatremia:free water restrictmobilize excess Na & H2O (use

loop diuretics; avoidthiazides) & ↑ EAV

(vasodilators to ↑ CO inCHF, colloid infusion incirrhosis)

aquaresis: tolvaptan effectiveand safe, however noproven mortality benefit,hypoNa recurs afterstopping drug, expensiveand must monitor forovercorrection (JASN2010;21:705; J Hepatol2012;56:571)

HYPERNATREMIA

Pathophysiology (NEJM2000;342:1493)• Deficit of water relative to

sodium; by definition, allhypernatremic Pts arehypertonic

• Usually loss of hypotonic fluid(ie “dehydration”);occasionally infusion ofhypertonic fluid

• And impaired access to freewater (eg, intubation, Δ MS,elderly): hypernatremia is apowerful thirst stimulus, ∴usually only develops in Pts

w/o access to H2O

Workup• ✓ Uosm, UNa, volume status (vital

signs, orthostatics, JVP, skinturgor, BUN, Cr)

Figure 4-5 Approach tohypernatremia

Extrarenal H2 O loss (Uosm

>700–800)• GI H2O loss: vomiting, NGT

drainage, osmotic diarrhea,fistula

• Insensible loss: fever, exercise,ventilation

Renal H2O loss (Uosm <700–800)• Diuresis: osmotic (glc, mannitol,

urea), loop diuretics• Diabetes insipidus (J Clin

Endocrinol Metab2012;97:3426)ADH deficiency (central) or

resistance (nephrogenic)

Central: hypothalamic orposterior pituitary disease(congenital, trauma/surgery,tumors, infiltrative/IgG4);also idiopathic, hypoxicencephalopathy, anorexia,EtOH

Nephrogenic (Annals2006;144:186)

congenital (ADH receptor V2mutation, aquaporin-2mutation; Pediatr Nephrol2012;27:2183)

drugs: lithium, amphotericin,demeclocycline, foscarnet,cidofovir metabolic:hypercalcemia, severe

hypokalemia, proteinmalnutrition, congenital tubulointerstitial:postobstruction, recoveryphase of ATN, PKD, sicklecell, Sjögren’s, amyloid,pregnancy (placentalvasopressinase)

DI usually presents as severepolyuria and mildhypernatremia

Other (Uosm >700–800)• Na overload: hypertonic saline

(eg, resuscitation w/ NaHCO3),mineralocorticoid excess

• Seizures, ≠ exercise: ↑

intracellular osmoles → H2Oshifts → transient ↑ [Na]serum

Treatment• Restore access to H2O or supply

daily requirement of H2O (≥1L/d)

• Replace free H2O deficit (alsoreplace concurrent volumedeficit if appropriate):

eg, 1 L D5W given to 70-kg

man w/ [Na] = 160 mEq/Lwill ↓ [Na]serum by 3.7 mEq

• Rate of Ø of Na should notexceed 0.5 mEq/L/h to avoidcerebral edema shortcut: in 70-kg man, 125 mL/h of free H2Owill ↓ [Na] by ~0.5 mEq/L/h

• 1/2 NS (77 mEq/L) or 1/4 NS (38mEq/L) provides both volume& free H2O (500 or 750 mL offree H2O per L, respectively);can give free H2O viaNGT/OGT

• Formulas provide only estimates;∴ recheck serum Na

frequently• DI and osmotic diuresis: see

“Polyuria” section below• Na overload: D5W + diuretic

POLYURIA

Definition and pathophysiology• Polyuria defined as >3 L UOP

per day• Due to an osmotic or a water

diuresis; almost always due toosmotic diuresis in inpatients

Workup• Perform a timed urine collection

(6 h sufficient) and measureUosm

• 24-h osmole excretion rate = 24-h UOP (actual or estimate) ×Uosm

>1000 mOsm/d → osmotic

diuresis<800 mOsm/d → water

diuresis

Osmotic diuresis• Etiologies

Glucose (uncontrolled diabetesmellitus)

MannitolUrea: recovering ARF, ↑

protein feeds,hypercatabolism (burns,steroids), GI bleed

NaCl administrationPropylene glycol

Water diuresis• Etiologies: diabetes insipidus

(DI) (Naserum >140) or 1°polydipsia (Naserum <140) see“Hypernatremia” above for listof causes of central andnephrogenic DI

• Workup of DI: Uosm <300(complete) or 300–600(partial)water deprivation test (start

in a.m., ✓ Naserum, Posm,Uosm, UOP q1–2h)

Deprive until Posm >295, then✓ Uosm. If Uosm <300, thenadminister vasopressin (5 USC) or dDAVP (10 µg

intranasal), then check Uosm

in 1–2 h: Uosm ↑ by >50% =central DI Uosm unchanged= nephrogenic DI

✓ ADH level before and afterwater deprivation toevaluate proper response

Figure 4-6 Approach topolyuria

Treatment• 1º polydipsia: treat psychiatric

illness, check meds, restrictaccess to free H2O

• Osmotic diuresis: addressunderlying cause, replace freeH2O deficit (see“Hypernatremia” for formulato calculate) and ongoinglosses

• DI:central DI: desmopressin

(dDAVP)nephrogenic DI: treat

underlying cause if possible;

Na restriction + thiazide(mild volume depletion → ↓delivery of filtrate todysfxnal diluting segment ofkidney), consider amiloridefor lithium-induced DI (KidInt 2009;76:44)

pregnancy-induced DI: due tovasopressinase fromplacenta, ∴ Rx w/ dDAVP

POTASSIUM HOMEOSTASIS

Overview (Annals 2009;150:619)• Renal: potassium excretion

regulated at distal nephron(collecting tubule) distal Nadelivery & urine flow: Naabsorption → lumenelectronegative → K secretionmetabolic alkalemia andaldosterone: increase Naabsorption and K secretion

• Transcellular shifts: mostcommon cause of acute changein serum potassium Acid-basedisturbance: K+/H+exchange across cell

membranes Insulin →stimulates Na-K ATPase →hypokalemia (mitigatespostprandial ↑ K)Catecholamines → stimulateNa-K ATPase → hypokalemia;reversed by b-blockers Digoxin→ blocks Na-K ATPase →hyperkalemia Massive necrosis(eg, tumor lysis, rhabdo,ischemic bowel) → release ofintracellular K Hypo- orhyperkalemic periodicparalysis: rare disorders due tochannel mutations

• Diet: alone rarely causes ↑ or ↓ K(total body store ~3500 mEq,

daily intake ~100 mEq)

HYPOKALEMIA

Transcellular shifts• Alkalemia, insulin,

catecholamines,hypokalemic/thyrotoxicperiodic paralysis, acute ↑ inhematopoiesis (megaloblasticanemia Rx w/ B12, AML crisis),hypothermia, chloroquine,barium/cesium intoxication,antipsychotic overdose(risperidone, quetiapine)

GI potassium losses (UK<25mEq/d or <5 mEq/L or TTKG <3)• GI losses plus metabolic acidosis:

diarrhea, laxative abuse,villous adenoma

• Vomiting & NGT drainage usuallymanifest as renal losses due to2° hyperaldo & met. alk.

Renal potassium losses (UK>30mEq/d or >15 mEq/L or TTKG>7)• Hypotensive or normotensive

acidosis: DKA, RTA [proximalRTA (type II) and some distalRTAs (type I)] alkalosis:diuretics, vomiting/NGTdrainage (via 2°hyperaldosteronism) Bartter’ssyndrome (loop of Henle

dysfxn → furosemide-likeeffect; NEJM 1999;340:1177)Gitelman’s syndrome (distal

convoluted tubule dysfxn →thiazide-like effect)

↓ Mg: ? release Mg-mediatedinhib. of ROMK channel ∴ ↑K secretion (JASN2007;18:2649)

• Hypertensive: mineralocorticoidexcess1° hyperaldosteronism (eg,

Conn’s syndrome,glucocorticoid-remediablealdosteronism)

2° hyperaldosteronism (eg,renovascular disease, renin-

secreting tumor)nonaldosterone

mineralocorticoid (eg,Cushing’s, Liddle’s,exogenous mineralocort.,licorice, congenital adrenalhyperplasia)

Clinical manifestations• Nausea, vomiting, ileus,

weakness, muscle cramps,rhabdomyolysis, polyuria

• ECG: U waves, ± ↑ QT interval,ventricular ectopy (PVCs, VT,VF)

Workup (NEJM 1998;339:451)• Rule-out transcellular shifts

• ✓ 24-h UK and transtubularpotassium gradient (TTKG)= (UK/PK) / (Uosm/Posm)UK >30 mEq/d or >15 mEq/L

or TTKG >7 → renal lossUK <25 mEq/d or <15 mEq/L

or TTKG <3 → extrarenalloss

• If renal losses, ✓ BP, acid-base,UCl (UNa unreliable for volumestatus w/ alkalemia)

Figure 4-7 Approach tohypokalemia

Treatment• If true potassium deficit:

potassium repletion (↓ 1mEq/L 200 mEq total bodyloss) KCl 40 mEq PO q4–6h ifnonurgent, KCl 10 mEq/h IV ifurgent, recheck K freq

• Beware of excessive potassium

repletion if transcellular shiftcause of hypokalemia

• Treat underlying cause (ifhydration needed, avoiddextrose-containing solutionsas dextrose → ↑ insulin →intracellular potassium shifts)

• Replete low Mg: IV Mg-SO4 1–2 gq2h (oral Mg-oxide poorlytolerated b/c diarrhea) Causesof low Mg: GI loss (diarrhea,bypass, pancreatitis,malnutrition, PPI); renal loss(diuretics, nephrotoxic drugs,EtOH, ↑ Ca, 1° wastingsyndromes, volume expansion)

HYPERKALEMIA

Transcellular shifts (BMJ2009;339:1019)• Acidemia, insulin defic. (DM), b-

blockers, dig intox., massivecellular necrosis (tumorlysis,rhabdo, ischem. bowel,hemolysis), hyperkalemicperiodic paralysis,succinylcholine

Decreased GFR• Any cause of oliguric or anuric

AKI or any cause of end stagerenal disease

Normal GFR but with Ø renal Kexcretion

• Normal aldosterone function↓ EAV (K excretion limited by ↓

distal Na delivery & urineflow): CHF, cirrhosisexcessive K intake: inconjunction withimpairment in K excretion ortranscellular shiftureterojejunostomy(absorption of urinary K injejunum)

• Hypoaldosteronism: same asetiologies of hypoaldo RTA(type IV)↓ renin: diabetic nephropathy,

NSAIDs, chronic interstitialnephritis, HIV normal renin,

↓ aldo synthesis: 1° adrenaldisorders, ACEI, ARBs,heparin

↓ response to aldosteronemeds: K-sparing diuretics,TMP-SMX, pentamidine,calcineurin inhibitorstubulointerstitial disease:sickle cell, SLE, amyloid,diabetes

Clinical manifestations• Weakness, nausea, paresthesias,

palpitations• ECG: peaked T waves, ↑ PR

interval, ↑ QRS width, loss of Pwave, sine wave pattern,

PEA/VF (ECG: low sensitivity,cardiac arrest can be firstelectrical manifestation!)

Workup (Crit Care Med2008;36:3246)• Rule out pseudohyperkalemia

(IVF with K, hemolysis duringvenipuncture, ↑ plt or WBC)

• Rule out transcellular shift• Assess GFR, if normal: Consider

↓ distal Na delivery and urineflow✓ transtubular K gradient

(TTKG) =(UK/PK)/(Uosm/Posm) <6c/w hypoaldo (JASN

2008;19:424)

• Rate of onset important to notewhen establishing a treatmentplan

• Calcium helps prevent/treatcardiac complications; ∴should be initial Rx, esp. if

ECG Ds• Insulin, bicarbonate (esp. if

acidemic), and b2 agonistsshould follow to ↓ plasma K

• Treatments that eliminate totalbody K essential as other Rxswill wear off with time;Kayexalate ± diuretics may beeffective in many cases, butemergent hemodialysis shouldbe considered in life-threatening situations

• Patient information for dieteducation:http://www.kidney.org/atoz/content/potassium.cfm

http://www.kidney.org/atoz/content/potassium.cfm

RENAL FAILURE

ACUTE KIDNEY INJURY (AKI)

Definition (CJASN 2008;3:844; KISuppl 2012;2:19)• AKI: abrupt (<48 h) ↑ Cr ≥0.3

mg/dL, ↑ Cr ≥50%, or UOP<0.5 mL/kg/h for ≥6 hadditional gradations based onfurther ↑ Cr & ↓ UOP, but notused clinically

• Cannot estimate GFR using Cr insetting of AKI or D’ing Cr(requires steady state)

Workup (Lancet 2012;380:756)• H&P: recent procedures & meds;

thirst; VS & vol status; s/s ofobstruction, vasc or systemicdis.; ischemia (prerenal &ATN) accounts for >50% of in-hospital AKI

• Urine evaluation: output,urinalysis, sediment,electrolytes, and osmolality

• Fractional excretion of sodium(FENa) = (UNa/PNa)/(UCr/PCr)<1% → prerenal, contrast,

HRS or glomerulonephritis;>2% → ATN In setting ofdiuretics, ✓ FEUN =(UUN/PUN)/(UCr/PCr); <35%→ prerenal

• Renal U/S or CT: r/o obstruction& eval kidney size to estimatechronicity of kidney disease

• Serologies (if indicated): see“Glomerular Disease”

• Renal bx: may be necessary ifcause remains unclear (esp ifhematuria and/or proteinuria)

Contrast-induced acute kidneyinjury (CIAKI)• Risk factors: CKD, DM, CHF, age,

hypotension, ↑ contrastvolume (JACC 2004;44:1393)

• Clinical: Cr ↑ 25% or 0.5 mg/dLw/in 48 h, peaks in 3–5 d,resolves in 7–10 d

• Prevention (NEJM 2006;354:379;JAMA 2006;295:2765; KI Suppl2012;2:69)Isotonic IV fluids (unless

contraindic, eg, CHF): 3mL/kg/h × 1 h before, 1mL/kg/h × 6 h after (JAMA2004;291:2328); NaHCO3 ?more effective than NaCl(Annals 2009;151:631)

Hold ACEI/ARB (AJKD

2012;60:576), NSAIDs,diuretics

N-acetylcysteine 1200 mg PObid on day prior to & day ofcontrast; safe & ∴reasonable in high-risk Pts,but benefit remains unclear(JACC CV Interv2009;2:1116; Circ2011;124:1250) Minimizecontrast volume andconsider iso-osmolar contrast(JACC 2006;48:692) ? high-dose statin (Circ2012;126:3008) No provenbenefit to Ppx RRT inaddition to above, may be

harmful (Am J Med2012;125:66)

• Gadolinium: can cause AKI instage IV CKD (Neph Dial Trans2006;21:697), no effective PpxNephrogenic systemic fibrosis:fibrosis of skin, joints, eyes,and internal organs ~2–4 wkpost exposure in Pts w/ mod-severe CKD (JACC2009;53:1621). ? role ofpostgado HD (Radiat Med2006;24:445). Rx is ↑ renalfunction, physical therapy.Can be irreversible.

Treatment

• Treat underlying disorder (seerelevant sections); ? steroids ifAIN (KI 2008;73:940)

• Prerenal: Isotonic IVF alb(NEJM 2004;350:22), HES(starch) nephrotoxic (NEJM2012;367:124)

• Avoid nephrotoxic insults; reviewdosing of renally cleared drugs

• Optimize hemodynamics (bothMAP & CO); may take 1–2 wkto recover from ATN

• Watch for and correct volumeoverload, electrolyte (↑ K, ↑PO4), & acid/base status

• If obstruction is diagnosed and

relieved, watch for:Hypotonic diuresis (2° buildup

of BUN, tubular damage); Rxw/ IVF (eg, 1/2 NS)

Hemorrhagic cystitis (rapid Δin size of bladder vessels);avoid by decompressingslowly

• Indications for urgent dialysis(when condition refractory toconventional therapy)Acid-base disturbance:

acidemiaElectrolyte disorder: generally

hyperkalemia; occasionallyhypercalcemia, tumor lysis

Intoxication: methanol,ethylene glycol, lithium,salicylates (Kid Int2009;75:1349)

Overload of volume (CHF)Uremia: pericarditis,

encephalopathy, bleeding• No benefit to dopamine (Annals

2005;142:510), diuretics(JAMA 2002;288:2547), ormannitol

CHRONIC KIDNEY DISEASE (CKD)

Definition and etiologies (Lancet2012;379:165)• ≥3 mo of reduced GFR (<60)

and/or kidney damage (path,markers, imaging)

• Prevalence 13% in U.S.; Cr poorestimate of GFR; ∴ useprediction equation, eg, MDRDor CKD-EPI:www.kidney.org/professionals/KDOQI/gfr_calculator.cfmnb, equation mayunderestimate GFR in Pts w/normal renal fxn, esp MDRD

• Etiologies: DM (45%), HTN/RAS(27%), glomerular (10%),

http://www.kidney.org/professionals/KDOQI/gfr_calculator.cfm

interstitial (5%), PKD (2%)(NEJM 2008;359:1477),congenital, drugs, myeloma,progression of AKI (JAMA2009;302:1179)

• Presence and degree ofalbuminuria a/w worseoutcomes independent of GFR

• Rates of all-cause mortality andCV events increase with eachstage of CKD and aresignificantly higher than therate of progression to kidneyfailure (NEJM 2004;351:1296)

Treatment (Annals 2009;150:ITC2-1; NEJM 2010;362:57)• General: nephrology referral

when GFR <30 and access

planning (avoid subclavianlines; preserve an arm foraccess by avoiding blooddraws, BP measurements, IVs);Rx CV risk factors (eg,smoking, LDL-C; Lancet2011;377:2181), vaccines (flu,PNA, HBV)

• Dietary restrictions: Na (ifHTN), K (if oliguric orhyperkalemic), PO4, ?moderate protein restriction,strict glc control in DM

• BP Control: goal <130/80, startwith ACEI (or ARB), effectivein DM & nondiabetic CKD(NEJM 2004;351:1952); likely

no benefit of ACEI + ARB(BMJ 2013;346:f360). ForoutPts, ✓ Cr & K in 1–2 wk,d/c if Cr ↑ 30% or K >5.4(after dietary Δ & loopdiuretic).

• Metabolic acidosis: sodiumbicarbonate or sodium citrateif low HCO3 (JASN2009;20:2075)

• Anemia: goal Hb ~10 g/dL,worse outcomes if higher(NEJM 2006;355:2085 &2009;361:2019) epoetin (start80–120 U/kg SC, divided3×/wk) or darbepoetin (0.45µg/kg q wk) iron

supplementation to keeptransferrin sat >20% (oftengiven IV in HD Pts)

• Uremic bleeding: desmopressin(dDAVP) 0.3 µg/kg IV or 3µg/kg intranasally

• 2° Hyperparathyroidism: ↑ PO4,↓ Ca, ↓ calcitriol → ↑ PTH →renal osteodystrophy

phosphorus binders (take withmeals!) (NEJM 2010;362:1312)if ↑ PO4 and ↓ Ca → calcium

acetate (PhosLo) or calciumcarbonateif refractory ↑ PO4 or insetting of ↑ Ca → sevelamer(Renagel), lanthanum(Fosrenol)if severe ↑ PO4 → aluminumhydroxide (Amphojel), short-term use only

vit. Δ or analogue (paricalcitol)if 25-(OH)D <30, stop if ↑ Ca(AJKD 2009;53:408) calcitriolor paricalcitol if Ca-PO4

product <55 (? ↑ survival inHD Pts, NEJM 2003;349:446)cinacalcet (parathyroid

calcium-sensing receptoragonist) if PTH remainselevated despite phosphorusbinders ± vit. Δ analogue(NEJM 2004;350:1516; NDT2011;26:1327)parathyroidectomy

• Consider transplantevaluation

DIURESIS

General considerations• Increases Na excretion for

treatment of HTN or edema inCHF, renal failure, andcirrhosis

• Daily wt most effective methodof documenting successfuldiuresis

Loop diuretics (NEJM1998;339:387)• Drugs: furosemide (Lasix),

torsemide, bumetanide(Bumex), ethacrynic acid

• Mechanism: inhibit Na-K-2Cltransporter in thick ascending

limb (ThAL) Transient,immediate venodilation mayaid in pulmonary congestion(NEJM 1973;288:1087)Response is fxn of amt of drugexcreted; ∴ ↑ dose needed inrenal insufficiency, CHFSigmoidal dose response curve;∴ ↑ dose until induce diuresis,↑↑ dose beyond that pointyields diminishing returnscompared with ↑ frequency ofdosing

• Dosing: PO bioavailability offurosemide ~50%, ∴ IV dose~2× as potent as PO dosetorsemide & bumetanide ~90%

bioavailability; use ethacrynicacid if sulfa allergy 40 mgfurosemide PO 20 mgfurosemide IV 20 mgtorsemide PO 1 mgbumetanide dose furosemidebid-qid; qd dosing can lead toinitial diuresis →antinatriuresis Continuous vs.bolus IV: similar results inacute CHF (NEJM2011;364:797)? ↑ diuresis w/ co-

administration of albumin if↓ serum albumin (Crit CareMed 2005;33:1681)

Thiazide diuretics (NEJM

2009;361:2153)• Drugs: hydrochlorothiazide

(HCTZ), chlorothiazide(Diuril), metolazone(Zaroxolyn)

• Mechanism: inhibit Na-Clcotransporter in the distalconvoluted tubule (DCT)synergistic with loop

diuretic, esp. if chronic loopuse

↓ effect when GFR <30, exceptmetolazone which is stilleffective in renalinsufficiency

• Dosing: give prior to loopdiuretic, typically ~30 min

before

K-sparing diuretics• Drugs: spironolactone

(Aldactone), amiloride,triamterene, eplerenone

• Mechanism: ↓ Na reabsorptionin collecting duct(amiloride/triamterene inhibitprincipal cell Na channel[ENaC];spironolactone/eplerenoneinhibit mineralocorticoidreceptor). Relatively weaknatriuretic activity, useful incombination with thiazide orin cirrhosis.

Disease state specific regimens• Renal insufficiency: loop diuretic

(↑ dose to achieve effectivedelivery to ThAL) ± thiazide

• CHF: loop diuretic (↑ frequencyover ↑ dose) + thiazide (watchK & Mg)

• Nephrotic syndrome: urinaryalbumin binds secreted loopdiuretic, use 2–3 × normaldose

• Cirrhosis: spironolactone (blocks2° hyperaldosteronism) + lasixin 2.5:1 ratio

• Severe metabolic alkalosis:acetazolamide & treatunderlying cause

Adverse effects• Loop: ± ↑ Na, ↓ K, ↓ Mg, ↓ Ca,

hyperuricemia, ototoxicity,hypersensitivity (sulfa)

• Thiazide: ↓ Na, ↓ K, ↓ Mg, ↑ Ca,hyperlipidemia, pancreatitis, ↑glucose

• K-sparing: ↑ K (esp. w/ ACEI),metabolic acidosis,gynecomastia (spironolactone)

RENAL REPLACEMENT ANDDIALYSIS

General• Substitutes for renal solute and

fluid removal; Acute: CVVH vs.HD; Chronic: PD vs. HD

Hemodialysis (HD) (NEJM2010;363:1833)• Physiology: blood flows along

one side of semipermeablemembrane, dialysate alongotherFluid removal (ie, Na + H2O)

via transmembrane pressure(TMP) gradient

Solute removal via

transmembraneconcentration gradient andinversely proportional tosize (∴ effective removal ofK, urea, and Cr, but notPO4)

• Typical orders: duration, volumeremoval goals, K and Ca indialysate bath, anticoagulation

• 6× vs. 3×/wk improved HTN,LV mass, QoL, but ↑ vasc issues(NEJM 2010;363:2287); w/3×/wk HD, ↑ adverseoutcomes after 2 d interval(NEJM 2011;365:1099)

• Complications: HoTN,arrhythmia, access issues (clot,

stenosis, infxn, recirculation),disequilibrium syndrome (sx ofcerebral edema due to H2Oshifts after removal of plasmaurea during dialysis, esp. innew HD Pts w/ ↑ ↑ BUN), highoutput HF

• Fever w/ catheter: empiric abx(vanc + AG qHD). GPC >GNR > mixed/fungal.

Catheter removal,replacement, or “lock” abx.Consider metastatic infxn w/u(AJKD 2004;44:779).

Continuous veno-venoushemofiltration (CVVH) (NEJM2012;367:26)• Physiology: hemofiltration rather

than dialysis. Blood underpressure passes down one sideof highly permeable membraneallowing H2O and solutes topass across membrane viaTMP gradient (convectiveclearance). Filtrate discarded.Replacement fluid infused

(solute concentrations similarto plasma, except no K, urea,Cr, PO4). Fluid balanceprecisely controlled byadjusting filtrate/replacementfluid.

• Access: double-lumen centralvenous catheter

• Typical orders: volume goals,replacement fluid buffer: HCO3

(requires heparin to preventmachine from clotting) vs.citrate (hepaticallymetabolized to HCO3; providesanticoagulation w/ in machinevia Ca chelation; ∴ requires

Ca infusion)• Complications: hypotension, ↓

PO4, access complications; ↓ICa (citrate toxicity in Pts withhepatic dysfunction → look for↓ ICa but normal/ ↑ serum Caand AG met acidosis)

• Potential advantages over HD:less hypotension, bettervolume control, removal ofinflammatory mediators;however, no survivaladvantage (Lancet2006;368:379)

• No advantage for high intensityCVVH over standard intensity(NEJM 2008;359:7)

Peritoneal dialysis (PD) (Perit DialInt 2001;21:25)• Physiology: peritoneum acts as

membrane. Fluid balancecontrolled by choosingdialysate [glc] (higherconcentrations pull more fluidinto peritoneum); longer dwelltimes pull less fluid as glcequilibrates across peritoneum

• Access: permanent catheterinserted in OR

• Typical orders for CAPD(continuous ambulatoryperitoneal dialysis):PD fluid = dextrose (1.5%,

2.5%, or 4.25%), buffer

(lactate), Na+, Ca2+,Mg2+

infuse 10 min, dwell 90 min–5.5 h, drain 20 min

• Can use overnight cycler devicethat infuses & drains morerapidly, with shorter dwells,while Pt sleeps. Calledautomated or continuouscycling peritoneal dialysis(APD, CCPD).

• Complications:hypoalbuminemia; right-sidedpleural effusion Peritonitis:abd pain, tenderness, cloudydrainage (WBC >100 and>50% PMNs) spectrum: 60–

70% GPC, 15–20% GNR,remainder no bacteria orfungal Rx: abx IV or in PD,catheter removal for certainpathogens (eg, yeast,Pseudomonas) Hyperglycemia:exacerbated by inflammation,long dwell times, and higher[glc]

Kidney transplantation (NEJM1994;331:365)• Rx of choice for ESRD;

contraindic: active malig,infxn, ischemia, noncompl,subst abuse

• Immunosuppression: calcineurin

inhib (tacrolimus, CsA),antimetabolite (AZA, MMF),prednisone, ± mTOR inhibitor(sirolimus) (NEJM2004;351:2715)

• Late renal dysfxn: usual AKIcauses + calcineurin tox,rejection, BK virus, recurrenceof 1° disease; usual w/u +immunosupp levels, BK virusload, U/S, then bx if no othercause

• ↑ risk of infxn (incl opportunisticsuch CMV, JC, BK viruses) &malignancy (incl PTLD)

• ↑ CVD risk due to HTN(calcineurin inhib, RAS), DM &

dyslipidemia (immunosuppmeds)

GLOMERULAR DISEASE

GLOMERULONEPHRITIS (GN)

Definition (NEJM 1998;339:888;Lancet 2005;365:1797)• Pathologically: intraglomerular

inflammation (ranging fromfocal proliferative [<50% ofglomeruli] to diffuseproliferative to crescentic)(Lancet 2006;368:404)

• Clinically: hematuria w/dysmorphic RBCs or RBC casts,± subnephrotic proteinuriaoften w/ renal failure, HTN,

edema

• Progression: acute GN days;rapidly progressive GN (RPGN)

wks; chronic GN mos; cansimply have asx hematuria

• Crescentic GN (pathologicdescription) RPGN (clinicaldescription)

Workup (Archives 2001;161:25)• Acute GN/RPGN ± lung

hemorrhage is an emergency →requires early Dx and Rx

• ANCA (Lancet 2006;368:404),anti-GBM, complement levels

• Depending on clinical hx: ANA,ASLO, BCx, cryocrit, hepatitisserologies, skin bx

• Consider GN mimicsthrombotic microangiopathy: ↓

Hct & Plts, schistocytes onsmear, ↑ LDH cholesterolemboli (Lancet2010;375:1650): purple toes,livedo, ↓ C3/C4, eos, priorcath AIN: rash, new drugexposure, urine WBCs (incleos) ± WBC casts (and UCx) myeloma: anemia,hypercalcemia, lytic bonelesions, SPEP/serum freelight chains

• Renal biopsy withimmunofluorescence (IF) ±electron microscopy (EM)

Figure 4-8 Approach toglomerulonephritis

Treatment (Kid Int Sup2012;2:143)• If acute GN/RPGN suspected,

give 1 g methylprednisolone IVqd x 3 d ASAP while awaitingbx results, further Rx based onunderlying disease (AJKD1988;11:449)

• SLE nephritis: steroids +cyclophosphamide (CYC) orMMF (JASN 2009;20:1103)

• ANCA or anti-GBM: pulsesteroids + CYC (or rituximab)± plasmapheresis (JASN2007;18:2180; NEJM2010;363:221)

• See “Vasculitis” for furtherdisease specific treatmentdetails

ASYMPTOMATIC GLOMERULARHEMATURIA

Definition and etiologies• Hematuria ± proteinuria of

glomerular origin w/o renalinsufficiency or systemicdisease (nonglomerularhematuria more common; see“Hematuria”)

• Ddx: any cause of GN (esp. IgA);also consider Alport’s (X-linked, deafness, renal failure),thin basement membranenephropathy (autosomaldominant, benign; JASN2006;17:813)

IgA nephropathy (NEJM2002;347:738; JASN 2005;16:2088)• Most common cause of GN; male

predominance w/ peakincidence 20–30s

• Wide range of clinicalpresentations: asx hematuria(30–40%), gross hematuria~1–3 d after URI (30–40%),chronic GN (10%), nephroticsyndrome (5%), RPGN (<5%)

• Though clinical presentation canbe highly suggestive, definitivedx only w/ bx

• Prognosis: 25–30% will reachESRD w/in 20–25 y ofpresentation

• Treatment: ACEI/ARB, ± fishoils (JASN 1999;10:1772);steroids (JASN 2012;23:1108);± cytotoxic therapy forcrescentic GN and nephroticsx, consider for progressivechronic GN

NEPHROTIC SYNDROME

Definition (NEJM 1998;338:1202)• Proteinuria >3.5 g/d, albumin

<3.5 mg/dL, edema, ↑cholesterol

Primary glomerular diseases(grouped by pathology)• Focal segmental

glomerulosclerosis (40%;NEJM 2011;365:2398;): 1º (? ↑soluble urokinase receptor; NatMed 2011:17;952), HIV(collapsing variant), NSAIDs,lymphomas, pamidronate,heroin, congenital, ↑ filtrationfrom prior nephron loss,

obesity, vesicoureteral reflux,anabolic steroids, genetic(trypanolytic ApoL1 mutationin AA; Science 2010;329:841)

• Membranous nephropathy(30%; JASN 2012;23:1617)idiopathic (phospholipase A2

receptor Abs; NEJM2009;361:11), infxn (esp. HBV,also HCV, syphilis),autoimmune (esp. SLE),carcinomas, drugs (NSAIDs,penicillamine)

• Minimal change disease (20%,more common in children; NDT2003;18:vi52) idiopathic,NSAIDs, Hodgkin’s disease, &

other lymphoproliferativedisorders

• Membranoproliferative GN(5%, mixednephrotic/nephritic features;NEJM 2012;366:1119) Immunecomplex-mediated: infection(esp. HCV ± cryos, IE, HBV,“shunt” nephritis, otherchronic infxns), SLE, cryos,Sjögren’s, lymphomas,dysproteinemia, idiopathicComplement-med (rare); abnlC3 convertase activity, densedeposit dis, C3GN

• Fibrillary-immunotactoidglomerulopathy (1%; Kid Int

2003;63:1450)• Mesangial proliferative GN (?

atypical forms of MCD/FSGS,5%) IgM, C1q nephropathy

Systemic diseases• Diabetes mellitus: nodular

glomerulosclerosis(Kimmelstiel-Wilson lesion);large kidneys hyperfiltration→ microalbuminuria →dipstick → nephrotic range(10–15 y) concomitantproliferative retinopathy seenin 90% of type 1 and 60% oftype 2

• Amyloidosis: AL or light chain

amyloid or AA amyloidsecondary to inflammation

• SLE: typically with membranousnephropathy (WHO class V)

• Cryoglobulinemia: typicallywith membranoproliferativeGN

Workup (Archives 2001;161:25;BMJ 2008;336:1185)• Urine sediment: usually benign;

± oval fat bodies (“Maltesecrosses”; NEJM 2007;357:806)

• Measure proteinuria: 24-h urinecollection or urine prot/Crratio (not accurate in AKI)

• r/o 2° causes: ↑ HbA1C + retinop.

→ presumpt. dx of diab.nephrop.; ✓ ANA, anti-dsDNA,C3/C4, SPEP/free light chains,fat pad bx, cryocrit, HBV/HCV,HIV, RPR, PLA2 recept. Ab

• Renal biopsy

Treatment (Kid Int Sup2012;2:143; NEJM 2013;368:10)• General: protein suppl.; diuretics

for edema; treathyperlipidemia, Na restriction(<2 g/d)

• ACEI/ARB: decrease proteinuria→ slow nonimmunologicprogression of renal disease

• 1° glomerular dis: steroids ±

cytotoxic therapy; cancerscreening if membranousneph.

• Secondary causes: treatunderlying disease

• Watch for malnutrition (proteinloss), thrombosis (in ~25%,esp. renal vein, b/c loss ofATIII & other endogenousanticoags), infxn (esp. encaps.organisms b/c loss of Ig)

URINALYSIS

PROTEINURIA

• Urine dipstick1+ 30 mg/dL, 2+ 100

mg/dL, 3+ 300 mg/dL,4+ >2 g/dL; interpretationdepends on SG; eg, 3+ invery concentrated urinemight not indicate heavyproteinuria

Insensitive formicroalbuminuria andmyeloma light chains

• Spot urine: protein(mg/dL)/creatinine (mg/dL) g/d of proteinuria (NEJM1983;309:1543) unlike urinedipstick, will accuratelymeasure myeloma light chainsreliable surrogate for 24-hrurine, esp. 1st morning void(JASN 2009;20:436);inaccurate if AKI depends onCr production, ∴underestimates if muscular,overestimates if cachectic

• Microalbuminuria (30–300

mg/24h or mg/L or mg/mg ofCr): early sign of glomerularvascular disease; marker for ↑risk of CV adverse outcomes(JAMA 2001;286:421)

• Orthostatic proteinuria: typicallyin adolescents; ~90% of young

with isolated proteinuriahave orthostatic proteinuria;typically resolvesspontaneously

HEMATURIA

• Wide, overlapping ages forvarious etiologies, but generalguide for common causes:<20 y: GN, UTI, congenital;

20–60 y: UTI,nephrolithiasis, cancer

>60 y : prostatitis, cancer,UTI; >60 y : UTI, cancer

Workup (J Urol 2012;188(6suppl):2473)• Urine dipstick: if ≥3 RBCs;

dipstick and sediment →myo- or hemoglobinuria

• Urine sediment: dysmorphicRBCs or RBC casts → GN →consider renal bx

• If no evidence ofglomerulonephritis:r/o UTI and non-GU causes (GI

or vaginal bleed)Urine cytology (Se ~70%, Sp

~95%), not adequatesubstitute for cystoscopy

Renal imaging: helical CT ±

contrast (r/o nephrolithiasisand neoplasia of uppertract), cystoscopy (r/obladder neoplasia, esp. ≥35y), ± MRI, retrogradepyelogram, U/S

NEPHROLITHIASIS

Types of stones and risk factors(J Clin Endocrinol Metabol2012;97:1847)• Calcium (Ca oxalate > Ca

phosphate): 70–90% ofkidney stonesUrine findings: ↑ Ca, ↑ oxalate

(Ca-ox only), ↑ pH (Ca-phosonly), ↓ citrate, ↓ volume

2° hypercalciuria: 1°hyperparathyroidism, distalRTA, sarcoid

2° hyperoxaluria: Crohn’s, ilealdisease w/ intact colon,gastric bypass

Diet: ↑ animal protein, ↑sucrose, ↑ Na, ↓ K, ↓ fluid, ↓fruits/vegetables, ↑ vit. C, ↓Ca

• Uric acid: 5–10% of kidneystones, radiolucent on plainfilmUrine findings: ↑ uric acid, ↓

pH (eg, from chronicdiarrhea)

• Magnesium ammoniumphosphate (“struvite” or“triple phosphate”)Chronic upper UTI w/ urea-

splitting organisms (eg,Proteus, Klebs) → ↑ urineNH3, pH >7

• Cystine: inherited defects oftubular amino acidreabsorption

Clinical manifestations• Hematuria (absence does not

exclude diagnosis), flank pain,N/V, dysuria, frequency

• Ureteral obstruction (stones >5mm unlikely to pass spont.) →AKI if solitary kidney

• UTI: ↑ risk of infection proximalto stone; urinalysis of distalurine may be normal

Workup• Noncontrast helical CT scan

(ureteral dilation w/o stone

suggests recent passage) 97%sens. 96% spec. (AJR2008;191:396)

• Strain urine for stone to analyze;U/A & UCx; electrolytes,BUN/Cr, Ca, PO4, PTH

• 24-h urine × 2 (>6 wk afteracute setting) for Ca, PO4,oxalate, citrate, Na, Cr, pH, K,vol.

Acute treatment (NEJM2004;350:684)• Analgesia (narcotics ± NSAIDs;

combination superior, AnnEmerg Med 2006;48:173),ensure adequate fluid

repletion, antibiotics if UTI• Consider alpha blocker > CCB to

promote ureteral relaxation(Lancet 2006;368:1171)

• Indications for immediateurologic eval and/or hosp:obstruction (esp. solitary ortransplant kidney), urosepsis,intractable pain or vomiting,significant AKI

• Urologic Rx: lithotripsy (NEJM2012:367:50), stent, percnephrostomy, ureteroscopicremoval

Chronic treatment (J ClinEndocrinol Metabol 2012;97:1847)

• Increase fluid intake (>2 L/d)for goal UOP 2 L/d

• Calcium stones: 24-h urineidentifies specific urinaryrisk factors to treat↓ Na and meat intake (NEJM

2002;346:77), thiazides:decrease urine Ca

Depending on 24-h urine: K-citrate, dietary oxalaterestriction, allopurinol

High dietary Ca is likelybeneficial by ↓ oxalateabsorp., unclear role of Casupplements

• Uric acid: urine alkalinization (K-citrate), allopurinol

• Magnesium ammoniumphosphate: antibiotics to treatUTI, urologic intervention,acetohydroxamic acid: ureaseinhibitor, reserve forexperienced clinician, poorlytolerated

• Cystine: urine alkalinization (K-citrate), D-penicillamine,tiopronin

ANEMIA

↓ in RBC mass: Hct <41% or Hb<13.5 g/dL (men); Hct <36% orHb <12 g/dL (women)

Clinical manifestations• Symptoms: ↓ O2 delivery →

fatigue, exertional dyspnea,angina (if CAD)

• Signs: pallor (mucousmembranes, palmar creases),tachycardia, orthostatichypotension

• Other findings: jaundice(hemolysis), splenomegaly(thalassemia, neoplasm,chronic hemolysis),

petechiae/purpura (bleedingdisorder), glossitis (iron,folate, vitamin B12 defic.),koilonychia (iron defic.),neurologic abnormalities(B12 defic.)

Diagnostic evaluation• History: bleeding, systemic

illness, drugs, exposures,alcohol, diet (including pica),FHx

• CBC w/ diff.; RBC params incl.retics, MCV (nb, mixeddisorder can → nl MCV), RDW

• Reticulocyte index (RI) =[reticulocyte count × (Pt’s

Hct/nl Hct)]/maturation factormaturation factors for a givenHct: 45% = 1, 35% = 1.5,25% = 2, 20% = 2.5RI >2% → adequate marrowresponse; RI <2% →hypoproliferation

• Peripheral smear: select areawhere RBCs evenly spaced andvery few touch each other; ✓RBC size, shape, inclusions(see Appendix & PeripheralSmear inserts), WBCmorphology, plt count

• Additional labs as indicated:hemolysis labs (if RI >2%),iron/TIBC, ferritin, folate, B12,

LFTs, BUN and Cr, TFTs, Hbelectrophoresis, enzymeanalyses, gene mutationscreens

• Bone marrow (BM) aspirateand biopsy (bx) withcytogenetics as indicated

Figure 5-1 Approach toanemia

MICROCYTIC ANEMIAS

Figure 5-2 Approach tomicrocytic anemias

Iron deficiency (NEJM1999;341:1986; Gut 2011;60:1309)• ↓ marrow iron & depleted body

iron stores → ↓ heme synthesis→ microcytosis → anemia

• Special clinical manifestations:

angular cheilosis, atrophicglossitis, pica (consumption ofnonnutritive substances suchas ice, clay), koilonychia (nailspooning) Plummer-Vinsonsyndrome (iron deficiencyanemia, esophageal web &atrophic glossitis)

• Etiologies: chronic bleeding (GI—incl. cancer, menstrual,parasites, etc.), ↓ supply(malnutrition; ↓ absorp. due toceliac sprue, Crohn’s, ↑ gastricpH, subtotal gastrectomy), ↑demand (preg., Epo). Rare Ferefractory genetic disorder dueto hepcidin dysregulation (Nat

Genet 2008;40:569).• Diagnosis: ↓ Fe, ↑ TIBC, ↓

ferritin (esp. <15), ↓transferrin sat (Fe/TIBC; esp.<15%), ↑ soluble transferrinreceptor; ↑ plt; unless hx c/wother etiology, initiate workupfor GIB; incl. H. pylori serology,? celiac sprue labs (anti-TTG,antigliadin, antiendomysialAb)

• Treatment (Fe supplementation):oral Fe tid (~6 wk to correctanemia; ~6 mo to replete Festores); in cases ofexcessive/persistent GI lossesor for dialysis or cancer Pts

prior to Epo Rx, IV iron (Fe-sucrose, -gluconate, -dextran)should be considered

Thalassemias (Lancet2013;379:373)• ↓ synthesis of ɑ- or β-globin

chains of Hb → ≠ subunits →destruction of RBCs anderythroid precursors; ∴anemia from hemolysis andineffective erythropoiesis

• ɑ-thalassemia: deletions in ɑ-globin gene complex on chr.16 (nl 4 ɑ genes)3 ɑ → ɑ-thal-2 trait = silentcarrier; 2 ɑ → ɑ-thal-1 trait or

ɑ-thal minor = mild anemia1 ɑ → HbH (β4) disease =severe anemia, hemolysis andsplenomegaly0 ɑ genes → Hb Barts (γ4) =intrauterine hypoxia andhydrops fetalis

• β-thalassemia: mutations in β-globin gene on chr. 11 →absent or ↓ gene product1 mutated β gene → thalminor (or trait) = mildanemia (no transfusions)2 mutated β genes → thalintermedia (occasionaltransfusions) or thal major ( =

Cooley’s anemia; transfusiondependent) depending onseverity of mutations

• Special clinical manifestations(in severe cases): chipmunkfacies, pathologic fractures,hepatosplenomegaly (due toextramedullaryhematopoiesis), high-outputCHF, bilirubin gallstones, ironoverload syndromes (fromchronic transfusions)

• Diagnosis: MCV <70, normalFe, MCV/RBC count<13[Mentzer Index, 60% Se, 98%Sp; (Ann Hem 2007;86:486)],± ↑ retics, basophilic

stippling; Hb electrophoresis:↑ HbA2 (ɑ2δ2) in β-thal; normalpattern in ɑ-thal trait

• Treatment: folate; transfusions +deferoxamine, deferasirox(oral iron chelator); splen-ectomy if ≥50% ↑transfusions; consider allo-HSCT in children w/ severe β-thal major

Anemia of chronic inflammation(see below)

Sideroblastic anemia• Defective heme biosynthesis

within RBC precursors• Etiologies: hereditary/X-linked

(ALAS2 mutations),idiopathic, MDS-RARS,reversible (alcohol, lead,isoniazid, chloramphenicol,copper deficiency,hypothermia)

• Special clinical manifestations:hepatosplenomegaly, ironoverload syndromes

• Dx: review social, work & TB hx;can be microcytic, normocyticor macrocytic; variable pop ofhypochromic RBCs; ↑ Fe, nlTIBC, ↑ ferritin, basophilicstippling, RBC Pappenheimerbodies (Fe-containinginclusions), ring sideroblasts

(w/ iron-laden mitochondria)in BM

• Treatment: treat reversiblecauses; trial of pyridoxine,supportive transfusions forsevere anemia; high-dosepyridoxine for some hereditarycases

NORMOCYTIC ANEMIAS

Pancytopenia (see below)Anemia of chronic inflammation(ACI; NEJM 2005;352:1011;2009;361:1904)• ↓ RBC production due to

impaired iron utilization andfunctional iron deficiency from↑ hepcidin; cytokines (IL-6,TNF-a) cause ↓ Eporesponsiveness/production

• Etiologies: autoimmunedisorders, chronic infection,inflammation, HIV,malignancy

• Dx: ↓ Fe, ↓ TIBC (usually

normal or low transferrinsat), ± ↑ ferritin; usuallynormochromic, normocytic(~70% of cases) but can bemicrocytic if prolonged

• Coexisting iron deficiencycommon. Dx clues include ↓serum ferritin levels, absenceof iron staining on BM bx, response to a trial of oral ironand/or ↑ soluble transferrinreceptor/ferritin index (Blood1997;89:1052).

• Treatment: treat underlyingdisease ± iron and/orerythropoiesis-stimulatingagent (ESA, eg, Epo). Iron if

ferritin <100 or Fe/TIBC<20%. Consider ESA if Epo<500. Avoid ESA in cancer iftreatment goal is cure (LeukRes 2012;36:939). Unclear ifone should treat highly sx Ptsw/ goal Hb 10–12 g/dL; weighrisk of thrombosis.

Anemias of chronic disorders• Anemia of chronic inflammation

(see above)• Anemia of chronic kidney

disease: ↓ Epo; treat w/ Epo(see “Chronic Kidney Disease”)

• Endocrine deficiencies:hypometabolism and ↓ O2

demand with thyroid,pituitary, adrenal, orparathyroid disease → ↓ Epo;can be normocytic ormacrocytic

Sideroblastic anemia (see above)Pure red cell aplasia• Destructive antibodies or

lymphocytes → ineffectiveerythropoiesis

• Associated with thymoma, CLLand parvovirus infection

• Diagnostic studies: lack oferythroid precursors on BMbx, other lines normal

• Treatment: thymectomy if

thymus enlarged; IVIg ifparvovirus infection;immunosuppression if CLL oridiopathic; supportive carewith PRBC transfusions; ?erythropoietin receptor agonistif due to antierythropoietin Ab(NEJM 2009;361:1848)

MACROCYTIC ANEMIASincludes megaloblastic andnonmegaloblastic causes

Megaloblastic anemia• Impaired DNA synthesis →

cytoplasm matures faster thannucleus → ineffectiveerythropoiesis andmacrocytosis; due to folate orB12 deficiency; MDS

• ✓folate and vitamin B12; ↑LDH & indirect bilirubin (dueto ineffective erythropoiesis)

• Smear: neutrophilhypersegmentation, macro-ovalocytes, anisocytosis,

poikilocytosis

Folate deficiency• Folate present in leafy green

vegetables and fruit; totalbody stores sufficient for 2–3mo

• Etiologies: malnutrition(alcoholics, anorectics,elderly), ↓ absorption (sprue),impaired metabolism(methotrexate, pyrimethamine,trimethoprim), ↑ requirement(chronic hemolytic anemia,pregnancy, malignancy,dialysis)

• Diagnosis: ↓ folate; ↓ RBC folate,

↑ homocyst. but nlmethylmalonic acid (unlike B12

defic.)• Treatment: folate 1–5 mg PO qd

for 1–4 mo or until completehematologic recovery; criticalto r/o B12 deficiency first (seebelow)

Vitamin B12 deficiency (NEJM2013;368:149)• B12 present only in foods of

animal origin; total bodystores sufficient for 2–3 y

• Binds to intrinsic factor (IF)secreted by gastric parietal

cells; absorbed in terminalileum

• Etiologies: malnutrition(alcoholics, vegans),pernicious anemia (PA,autoimmune disease againstgastric parietal cells, a/wpolyglandular endocrineinsufficiency and ↑ risk ofgastric carcinoma), othercauses of ↓ absorption(gastrectomy, sprue, Crohn’sdisease), ↑ competition(intestinal bacterialovergrowth, fish tapeworm)

• Clinical manifestations:neurologic changes (subacute

combined degeneration)affecting peripheral nerves,posterior and lateral columnsof the spinal cord and cortex→ numbness, paresthesias, ↓vibratory and positional sense,ataxia, dementia

• Dx: ↓ B12; ↑ homocysteine andmethylmalonic acid; anti-IFAb; Schilling test; ↑ gastrin inPA

• Treatment: 1 mg B12 IM qd × 7 d→ q wk × 4–8 wk → q monthfor life neurologicabnormalities are reversible iftreated w/in 6 mo folate can

reverse hematologicabnormalities of B12 deficiencybut not neurologic changes(and can lead to “steal” of B12

stores → worsening of neurocomplications) oralsupplementation (2 mg qd)appears feasible as well (Blood1998;92:1191) even w/o IF

Nonmegaloblastic macrocyticanemias• Liver disease: often macrocytic,

may see target cells• Alcoholism: BM suppression &

macrocytosis independent offolate/B12 defic. or cirrhosis

• Reticulocytosis• Other causes: hypothyroidism;

MDS; meds that impair DNAsynthesis (zidovudine, 5-FU,hydroxyurea, Ara-C);hereditary orotic aciduria;Lesch-Nyhan syndrome.

PANCYTOPENIA

Etiologies• Hypocellular bone marrow (nl

cellularity ~100 – age):aplastic anemia, hypoplasticMDS

• Cellular bone marrow: MDS,aleukemic leukemia, PNH,severe megaloblastic anemia

• Marrow replacement(myelophthisis):myelofibrosis, metastaticsolid tumors, granulomas

• Systemic diseases: hypersplenism,sepsis, alcohol, toxins


• Anemia → fatigue• Neutropenia → recurrent

infections• Thrombocytopenia → mucosal

bleeding & easy bruisability

Aplastic anemia = stem cellfailure (Lancet 2005;365:1647;Blood 2012;120:1185)• Epidemiology: 2–5 cases/106/y;

biphasic (major peak inadolescents, 2nd peak inelderly)

• Diagnosis: pancytopenia w/ ↓retics, BM bx w/ cytogeneticsshowing hypocellularity

• Etiologies: idiopathic (1/2 –1/3

of cases)stem cell destruction:

radiation, chemotherapy,chemicals (eg, benzene)idiosyncratic med rxn (eg,chloramphenicol, NSAIDs,sulfa drugs, gold,carbamazepine, antithyroid)

viruses (HHV-6, HIV, EBV,parvovirus B19); also post-hepatitis (non A, B or C)

immune disorders (SLE,GVHD post-HSCT, thymoma)

PNH (see below); Fanconi’sanemia (congenital disorderw/ pancytopenia,macrocytic anemia, ↑ risk of

MDS, AML, & SCC of head &neck, and multiple physicalanomalies);

shortened telomeres: seen w/telomerase (TERT, TERC)mut (10% of aplasticanemia), dyskeratosiscongenita/DKC1 mut; a/wIPF, cirrhosis (NEJM2009;361:2353)

• Treatment and prognosisallogeneic HSCT: for young

Pts → ~80% long-termsurvival and significantly ↓risk of malignant evolution,but has risk of transplant-related morbidity &

mortality; if possible avoidtransfusions (andalloimmunization)pretransplant

immunosuppression(CsA/tacrolimus, ATG): 70–80% respond, with 80–90%5-y survival in responders(96% vs. 76% w/ horse vs.rabbit ATG; NEJM2011;365:430); 15–20% 10-yincidence of clonal disorders(mostly MDS, AML, PNH)

TPO mimetics (eg,eltrombopag) may be optionin refractory disease (NEJM2012;367:11)

supportive care: transfusions,antibiotics, possible utility ofG-CSF and Epo

Myelodysplastic syndromes(MDS) (qv)

Paroxysmal nocturnalhemoglobinuria (PNH) (Blood2009;113:6522)• Acquired clonal stem cell disorder

= inactivating somaticmutation of PIG-A gene →deficiency of GPI-anchor forCD55 & CD59 (inhib ofcomplement) → complement-mediated RBC lysis, pltaggreg., & hypercoagulability

• Clinical: intravascular hemolyticanemia, hypercoagulability(venous > arterial; esp.intraabdominal, cerebral),smooth muscle dystonias,deficient hematopoiesis(cytopenias); a/w aplasticanemia, MDS and evolution toAML

• Dx: flow cytometry (↓ CD55 &CD59) on RBCs andgranulocytes; urinehemosiderosis

• Treatment: supportive care (iron,folate, transfusions); consideranti-coagulation allogeneicHSCT for hypoplasia or severe

thrombosis eculizumab (Abinactivates terminalcomplement C5s): ↓ hemolysis,improves QoL & stabilizes Hblevels (NEJM 2004;350:552 &2006;355:1233; Lancet2009;373:759); must havemeningococcal vaccination

Myelophthisic anemia (see also“Primary Myelofibrosis”)• Infiltration of bone marrow by

cancer, leukemia, infection,fibrosis (primary myelofi-brosis), granulomas, lysosomalstorage disorders

HEMOLYTIC ANEMIAS

Diagnostic evaluation• ↑ reticulocyte count (RI >2%), ↑

LDH, ↓ haptoglobin (83% Se,96% Sp), ↑ indirect bili

• Autoimmune hemolysis: Coombs’test = direct antiglobulin test(DAT) → if agglutinationoccurs when antisera against

Ig or C3 are applied to patientRBCs

• Intravascular: ↑↑ LDH, ↓↓haptoglobin; hemoglobinemia,hemoglobinuria,hemosiderinuria

• Extravascular: splenomegaly• Family h/o anemia; personal or

family h/o cholelithiasis

Glucose-6-phosphatedehydrogenase (G6PD)deficiency (Lancet 2008;371:64)• X-linked defect of metabolism

(G6PD mutations) w/ ↑susceptibility to oxidativedamage

• Most common in of African orMediterranean descent(malaria-endemic areas)

• Hemolysis precipitated by drugs(sulfonamides, dapsone,primaquine, doxorubicin,methylene blue), infection,DKA or foods (fava beans inchildren)

• Diagnosis: smear may show RBCHeinz bodies (oxidized Hb)that result in bite cells onceremoved by spleen; ↓ G6PDlevels (may be normal afteracute hemolysis as older RBCshave already lysed and youngRBCs may still have near

normal levels)

Sickle cell anemia (Lancet2010;376:2018)• Recessive β-globin mutation →

structurally abnl hemoglobin(HbS). ~8% African Americansheterozygotes (“sickle trait”;usually w/o sx); ~1/400homozygotes (sickle celldisease).

• ↓ O2 → HbS polymerizes → RBCsickles, ↓ RBC deformability →hemolysis & microvascularocclusion

• Anemia: chronic hemolysis ±acute aplastic (parvo. B19) or

splenic sequestration crises• Vaso-occlusion and infarction:

painful crises, acute chestsyndrome, CVA, splenicsequestration, hand-footsyndrome, renal papillarynecrosis, aseptic necrosis,priapism

• Infection: splenic infarction →overwhelming infection byencapsulated organisms;infarcted bone →osteomyelitis (Salmonella,Staph. aureus)

• Diagnosis: sickle-shaped RBCsand Howell-Jolly bodies onsmear; Hb electrophoresis

• Treatment: hydroxyurea causes↑ HbF → ↓ painful crises, acutechest episodes and may ↓mortality (NEJM2008;358:1362); allogeneicHSCT may have a role inyoung Pts w/ severe disease(Blood 2000;95:1918) andadults (NEJM 2009;361:2309)

• Supportive care: folic acid qd;pneumococcal, meningococcal,H. flu & HBV vaccination; paincrises treated with hydration,oxygen and analgesia; simpleor exchange transfusion forTIA or stroke, severe acutechest syndrome, or preop (goal

Hb 10 g/dL)

Hereditary spherocytosis (HS)(Br J Hematol 2004;126:455)• Defect in a cytoskeletal protein

of RBC membrane →membrane loss mutations inankyrin, a- and β-spectrin,band 3 and pallidin have beenidentified

• Most common in N. Europeanpopulations (1/5000 births); FHx (75% of Pts)

• Anemia, jaundice (mostlyneonates), splenomegaly,pigmented gallstones

• Diagnosis: spherocytes on smear,

osmotic fragility test (~80%Se), ↓ eosin-5-maleimide(EMA) binding (92% Se; 99%Sp)

• Treatment: folate, transfusions,splenectomy for moderate andsevere HS (balance w/ ↑ risk offuture thrombosis andinfection (J Thromb Haemost2008;6:1289)

Paroxysmal nocturnalhemoglobinuria (see above)

Autoimmune hemolytic anemia(AIHA)• Acquired, antibody-mediated RBC

destruction

• Warm AIHA: IgG Abs opsonizeRBCs at body temp → removalby spleen Etiologies:idiopathic, lymphoproliferative(CLL, NHL), autoimmune(SLE), drugs

• Cold AIHA: IgM Ab binds toRBCs at temp <37°C →complement fixation →intravascular hemolysis andacrocyanosis on exposure tocoldEtiologies: idiopathic,

lymphoprolif. disorders (eg,Waldenström’s;monoclonal), Mycoplasmapneumoniae infxn and

infectious mononucleosis(polyclonal)

• Diagnosis: spherocytes on smear, Coombs’; ✓ cold agglutinin

titer, splenomegaly• Treatment: treat underlying

diseasewarm AIHA: corticosteroids ±

splenectomy, IVIg, cytotoxicagents, rituximab

cold AIHA: avoid cold; steroidsineffective; rituximab (Blood2004;103:2925)

Drug-induced hemolytic anemia• Acquired, antibody-mediated,

RBC destruction precipitated

by a medication:abx: cephalosporins, sulfa

drugs, rifampin, ribavirinCV: methyldopa,

procainamide, quinidine,thiazides

TCAs, phenothiazines, NSAIDs,sulfonylureas, MTX, 5-FU,rasburicase (G6PD defic.)

• Diagnosis: Coombs’ usuallynegative, ↑ LDH

• Treatment: discontinue offendingagent

Microangiopathic hemolyticanemia (MAHA)• Intra-arteriolar fibrin damages

RBCs → acquired intravascularhemolysis

• Etiologies: hemolytic-uremicsyndrome (HUS), thromboticthrombocytopenic purpura(TTP), disseminatedintravascular coagulation(DIC), malignancy, malignantHTN, eclampsia/HELLP, mech.cardiac valves, infectedvascular prostheses

• Diagnosis: schistocytes ±thrombocytopenia ±abnormalities a/w specificdisorders (eg, ↑ PT in DIC, ↑ Crin HUS, ↑ LFTs in HELLP)

• Treatment: treat underlying

abnormality; urgent plasmaexchange for TTP

Hypersplenism• Stasis/trapping in spleen → mf

attack & remodeling of RBC →spherocytosis → hemolysis

DISORDERS OF HEMOSTASIS

Figure 5-3 Approach toabnormal hemostasis

Figure 5-4 Coagulation Cascade

Purpura (nonblanching purple/redlesions due to extravasation ofRBCs into dermis)• Nonpalpable (macular; ≤3 mm

in diameter = petechiae; >3mm = ecchymoses)platelet disorder:

thrombocytopenia, defect inplatelet fxn

thromboemboli: DIC, TTP,cholesterol or fat emboli

trauma or vascular fragility:amyloidosis, Ehlers-Danlos,scurvy

• Palpable (papular); vasculitis:leukocytoclastic, HSP, PAN,RMSF;infectious emboli:

meningococcemia, bacterialendocarditis

• Purpura fulminans (aka retiformpurpura): purpura +hypotension + DIC; typicallydue to infxn/sepsis, protein C

or S deficiency or APS (seesection on DIC)

PLATELET DISORDERS

THROMBOCYTOPENIA (PLTCOUNT <150,000/µL)

Etiologies• ↓ production

hypocellular bone marrow:aplastic anemia (qv), rarelyMDS, drugs (eg, thiazides,antibiotics), alcohol,cirrhosis

hypercellular bone marrow:MDS, leukemia, severemegaloblastic anemia

marrow replacement:myelofibrosis, hematologicand solid malignancies,granulomas

• ↑ destructionimmune-mediated

(distinguish primary fromsecondary; Blood2009;113:2386) Primary(idiopathic): immunethrombocytopenic purpura(ITP, see below)

Secondary: infxn (HIV, HCV,HSV), collagen vascular

diseases (SLE), APS,lymphoproliferative(CLL, lymphoma), drugs(many, includingheparin, abciximab,quinidine, sulfonamides,vancomycin),alloimmune(posttransfusion)

non–immune-mediated:MAHA (DIC, HUS, TTP),ticlopidine/clopidogrel,vasculitis,preeclampsia/HELLP,cardiopulm bypass, CVVH,IABP, cavernoushemangioma

• Abnormal distribution orpooling: splenic sequestration,dilutional, hypothermia

• Unknown:ehrlichiosis/anaplasmosis,babesiosis, RMSF

Diagnostic evaluation• H&P: meds, infxns, underlying

conditions, splenomegaly,lymph nodes, bleeding hx

• CBC with differential: isolatedthrombocytopenia vs.multilineage involvement

• Peripheral smear↑ destruction → look for large

plts, schistocytes (see

“Peripheral Smear” inserts)↓ production → rarely limited

to platelets → look forblasts, hypersegmentedPMNs, leukoerythroblasticDs; can see inclusion bodies(anaplasma), parasites(babesia)

r/o pseudothrombocytopeniadue to platelet clumping (✓platelet count in non–EDTA-containing tube, eg, citrate-containing yellow top tube)

Figure 5-5 Approach tothrombocytopenia

• Additional laboratory evaluationsas indicated (eg, viral titers,flow cytometry, ANA, APLA)if anemia: ✓ reticulocyte

count, LDH, haptoglobin,bilirubin to detect hemolysis

if hemolytic anemia: ✓ PT,PTT, fibrinogen, D-dimer,Coombs, ANA

BM bx for unexplained

thrombocytopenia, esp. ifassociated withsplenomegaly

Primary immunethrombocytopenic purpura (ITP)(Blood 2010;115:168)• Primary ITP: isolated

thrombocytopenia due toimmune plt destruction & ↓production (auto-Ab tomegakaryocytes); (2° ITP a/wdisease/drug exposure; Rxunderlying disorder)

• Primary ITP is diagnosis ofexclusion; no robust clinical orlab parameters, but typically:

CBC: isolated ↓ plt(<100,000/µL); 10% haveITP + AIHA = Evanssyndrome

Peripheral smear: largeplatelets

BM bx: ↑ megakaryocytes;perform in adults >60 y tor/o myelodysplasia

R/o other etiologies: viralserologies (HIV, HCV, HBV,EBV), H. pylori Ab, ANA,pregnancy test, APLA, TSH,parvovirus, & CMV PCR.Anti-plt Ab tests not useful.

• Clinical manifestations: insidiousonset of mucocutaneous

bleeding; : = 3:1• Treatment: goals based on

individual Pt rarely indicatedif plt >50,000/µL unlessbleeding, trauma/surgery,anticoag, comorbiditiessteroids, IVIg, & splenectomymainstay of initial Rx;romiplostim/eltrombopag ifrefractory

• Pathophysiology (type II): Abbinds heparin-PF4 → immunecomplex binds to plt → pltactivation, further PF4release → plt aggregatesremoved from circulation →thrombocytopenia;procoagulants released by pltsand tissue factor released by

endothelial cells damaged byHIT Abs → prothromboticstate

• Diagnosis (need clinical +pathologic)Clinical: plt <100k or ↓ 50%

from baseline; or venous(DVT/PE) or arterial (limbischemia, CVA, MI)thrombosis (4:1 ratio); skinnecrosis; ? ↑ heparinresistance

Pathologic: HIT Ab usingPF4-heparin ELISA (≥90%Se, IgG-specific ELISA Sp94%), may confirm w/functional plt aggregation

(serotonin-release) assay(>90% Sp)

Pretest prob w/ “4T’s” criteria(Blood 2012;120:4160): ≤3points → 99% NPV,investigate other causes; 4–5points 22% PPV & 6–8points 64% PPV, ✓ lab testand replace UFH

• Treatment of HIT (type II) (Chest

2012;141:e495S; Blood2012;119:2209; NEJM2013;368:737)Discontinue heparin

(including flushes, LMWHprophylaxis, heparin-impregnated lines)

Avoid plt transfusions if notactively bleeding(anecdotally linked w/thrombotic events)

Nonheparin anticoag(argatroban, bivalirudin;NEJM 2013;368:737)regardless of thrombosis; startwarfarin when plt >150k,overlap ≥5 d (✓

chromogenic Xa to titrate) thrombosis (HITT):anticoagulate for ≥ 3–6 mo thrombosis (HIT): screen forDVT; unclear duration ofsubsequent anticoag (untilplt count recovers, often~2–3 mo if no clot); 25–50%thrombosis rate w/in 30 d

• Heparin use if h/o HIT: if PF4 Ab (typically >100 d after dx)

→ re-exposure to UFHreasonable (eg, for surgery);HIT recurrence low

Hemolytic-uremic syndrome(HUS) & thrombotic

thrombocytopenic purpura (TTP)• Definition: vascular occlusive

disorders w/ systemic (TTP) orintrarenal (HUS) plt aggreg.→ thrombocytopenia &

mechanical injury to RBCs(MAHA) (NEJM2002;347:589)

HUS triad =thrombocytopenia + MAHA+ renal failure

TTP pentad (all 5 in only~5%) = thrombocytopenia+ MAHA (100%) ± Δ MS(65%) ± renal failure (50%)± fever (25%)

• Pathophysiology: mechanism in

most HUS cases is distinct fromTTP (NEJM 1998;339:1578)HUS: Shiga toxin binds &

activates renal endothelialcells & plts → intrarenalthrombi

TTP: ↓ ADAMTS13 proteaseactivity or inhibitor→persistence of large vWFmultimers on endothelialsurface → adhesion andaggregation of passingplatelets → thrombosis

• Clinical manifestations andassociationsHUS: usually in children;

prodrome of bloody diarrhea

due to enterohemorrhagic E.coli

TTP: usually in adults;idiopathic, drugs (CsA,tacrolimus, gemcitabine,mitomycin-C, ticlopidine,clopidogrel, quinine), HIV,pregnancy, HSCT,autoimmune disease,familial

• Dx: unexplainedthrombocytopenia (typically<20k) + MAHA → sufficientfor dx schistocytes (>2–3/hpf), Coombs, normalPT/PTT & fibrinogen, ↓↓ADAMTS13 ↑↑ LDH (tissue

ischemia + hemolysis), ↑indirect bili., ↓↓ haptoglobin, ↑Cr (esp. in HUS)Biopsy: arterioles filled with

platelet hyaline thrombiDdx: DIC, vasculitis, malignant

hypertension,preeclampsia/HELLPsyndrome

• Treatment: urgent plasmaexchange ± glucocorticoids ifsuspected; FFP if delay toplasma exchange (Blood2010;116:4060); ? eculizumabin HUS (NEJM 2011;364:2561);plt transfusions contraindicated→ ↑ microvascular thrombosis

(NEJM 2006;354:1927)

Disseminated intravascularcoagulation (DIC): see“Coagulopathies”

DISORDERS OF PLATELETFUNCTION

Tests of platelet function• Bleeding time: global screen of

platelet function; not reliableand rarely used

• Platelet aggregation tests:measure aggregation inresponse to agonists (eg, ADP)

von Willebrand’s disease (vWD)

(NEJM 2004;351:683 &2012;367:1954)• von Willebrand’s factor (vWF)

function = platelet glue &plasma carrier of factor VIII

• vWD most common inherited(usually auto dom) bleedingdisorder; ~85% (type 1) havepartial quantitative defic ofvWF, ~15% (type 2) havequalitative defic in vWF

• Acquired vWD: a/w manydisorders (malig, MPN w/ ↑ pltcount; autoimmune; hypo-thyroidism; drugs) and causedby different mechanisms (anti-vWF Abs, ↑ clearance, ↓

synthesis); Heyde’s syndrome= vWF destruction by severeAS, a/w GI AVMs/bleed

• Diagnosis: ↓ vWF:Ag, ↓ vWFactivity (measured byristocetin cofactor assay), ↓factor VIII, ± ↑ PTT, ± ↓platelets; confirm with vWFmultimer analysis

• Clinical condition, factor VIIIlevels and ristocetin cofactorassay useful to guide Rxdecision

• Rx: desmopressin (dDAVP,IV/IN) → ↑ endothelial cellrelease of vWF; efficacydepends on type (avoid in

Type 2), ∴ ✓ response beforeuse w/ subseq. bleeding orprocedures;vWF replacement:

cryoprecipitate, factor VIIIconcentrates rich in vWF,recomb. vWF

Uremic bleeding• Uremia → platelet dysfunction

including ↓ aggregation,impaired adhesiveness

• Treatment: dDAVP,cryoprecipitate, correctanemia (improves pltaggregation andadhesion by increasing plt

interactions withendothelium), considerholding anti-plt agents

COAGULOPATHIES

Further coagulation tests• Mixing study: useful if ↑ PT or

PTT; mix Pt’s plasma 1:1 w/normal plasma and retestPT/PTT normalizes → factordeficiency; PT/PTT remainselevated → factor inhibitor

• Coagulation factor levels: usefulif mixing study suggests factordeficiencyDIC → all factors consumed; ∴

↓ factors V and VIII liverdisease → ↓ all factorsexcept VIII; ∴↓ factor V,normal factor VIII vitamin Kdeficiency → ↓ factors II,VII, IX, X (and protein C, S);∴ normal V and VIII

• DIC screen: fibrinogen(consumed), fibrin degradationproducts (FDPs, due tointense fibrinolysis), D-dimer(more specific FDP test thatdetects degradation of X-linkedfibrin)

Hemophilias (NEJM2001;344:1773)

• X-linked recessive factor VIII(hemophilia A) or factor IX(hemophilia B) deficiency

• Classification: mild (5–25%normal factor activity),moderate (1–5%) or severe(<1%)

• Clinical manifestations:hematomas, hemarthroses,bruising, bleeding (mucosal,GI, GU)

• Diagnosis: ↑ PTT (normalizesw/mixing study), normal PT &vWF, ↓ factor VIII or IX

• Treatment: purified/recomb.factor VIII or IX concentrate,desmopressin (mild disease),

aminocaproic acid; recomb.factor VIIa if factor inhib.,cryo (only has factor VIII)

Coagulation factor inhibitors• Etiologies: hemophilia (treated

with factor replacement);postpartum;lymphoproliferative disordersand other malignancies;autoimmune diseases; mostcommonly anti–factor VIII

• Diagnosis: ↑ PTT (does notnormalize w/mixing study);Bethesda assay quantitatestiter

• Treatment: high titer → recomb.

factor VIIa, porcine factorconcentrates, activatedprothrombin complex; others→ high-purity human factor,plasmapheresis, immunosupp.w/ steroids, cyclophosphamideand/or rituximab (Curr OpinHematol 2008;15:451)

Disseminated intravascularcoagulation (DIC) (NEJM1999;341:586)• Etiologies: trauma, shock,

infection, malignancy (esp.APL), obstetric complications

• Pathogenesis: massive activationof coagulation that

overwhelms controlmechanisms thrombosis inmicrovasculature → ischemia+ microangiopathic hemolyticanemia acute consumption ofcoagulation factors andplatelets → bleeding chronicDIC → able to replete factorsand platelets → thrombosis

• Diagnosis: ↑ PT, ↑ PTT, ↓fibrinogen (may be nl b/cacute phase), FDP/D-dimer,↓ plts, schistos, ↑ LDH, ↓hapto; chronic DIC: FDP/D-dimer, variable plts, other labsnl

• Treatment: treat underlying

process; support with FFP,cryoprecipitate (goalfibrinogen>100 mg/dL) and platelets;

no role for activated proteinC in sepsis (NEJM2012;366:2055)

Vitamin K deficiency• Etiologies: malnutrition, ↓

absorption (antibioticsuppression of vitamin K-producing intestinal flora ormalabsorption), liver disease(↓ stores), warfarin

HYPERCOAGULABLE STATES

Suspect in Pts with venous or arterialthrombosis at young age or unusuallocations, recurrent thromboses or

pregnancy loss or FHx

Diagnostic evaluation (notroutinely required for initial VTE)• APC resistance screen;

prothrombin PCR test;functional assays for proteinsC and S, ATIII; homocysteinelevel; factor VIII levels;anticardiolipin and lupusanticoagulant Ab. Alsoconsider nephrotic syndrome,

PNH (esp. if mesentericthrombus).

• Consider JAK2 mutation testing ifsuspect MPN or splanchnicthrombosis.

• Proteins C & S and ATIII levelsare affected by acutethrombosis andanticoagulation ∴ levels bestassessed ≥2 wk aftercompleting anticoagulationcourse

• Age-appropriate malignancyscreening ( in 7–10% in“idiopathic” DVT; Annals2008;149:323)

Treatment• Asx w/ inherited risk factor:

consider prophylacticanticoag. if develops acquiredrisk factor

• Thrombosis w/ inherited riskfactor: see “VenousThromboembolism”

Antiphospholipid syndrome(APS) ( J Thromb Haemost2006;4:295; NEJM 2013;368:1033)• Definition: dx requires ≥1

clinical & ≥1 laboratorycriteriaClinical: thrombosis (any) or

complication of pregnancy

(≥3 spont. abortions before10 wk or ≥1 fetal loss after10 wk or premature birthbefore 34 wk)

Laboratory: moderate–hightiter anticardiolipin (ACL),

lupus anticoagulant (LA)or β2-glycoprotein-I (β2-GP-I) Ab on ≥2 occasions atleast 12 wk apart

• Clinical: DVT/PE/CVA,recurrent fetal loss,thrombocytopenia, hemolyticanemia, livedo reticularis;“catastrophic APS” = ≥3organ systems in <1 wk w/

APLA & tissue microthrombi(Lupus 2003;12:530) → 44%mortality (Arth Rheum2006;54:2568)

• Antiphospholipid antibodies(APLA) ✓ if: SLE, age <40 y &arterial thromb, recurrent venousthromb, spontaneous abortionACL: Ab against cardiolipin, a

mitochondrial phospholipid;IgG more specific than IgM

LA: Ab that prolongsphospholipid-dependentcoagulation reactions; ∴ ↑PTT that does not correctwith mixing study but doescorrect with excess

phospholipids or platelets;PT not affected b/c thereaction contains much morephospholipid

β2-GP-I: Ab against β2-glycoprotein-I, IgG or IgM

False VDRL: nontreponemaltest for syphilis in whichcardiolipin is part of Agcomplex

Clinical significance ofdifferent Abs in pathogenesisuncertain

Risk of thromboembolicphenomena may increasewith titer of APLs

• Etiologies: primary (idiopathic)or secondary due toautoimmune syndromes (eg,SLE), malignancy, infections,drug reactions

• Treatment: UFH/LMWH →warfarin after thromboembolicevent (lifelong for most Pts)Intensity of anticoagulation

controversial (ArthritisRheum 2007;57:1487)

Initial venous thrombosis: INR2–3 (NEJM 2003;349:1133; J Thromb Haemost2005;3:848)

Initial arterial thrombosis:typically INR 2–3 + ASA 81,

although some treat to INR3–4

Recurrent thrombosis onwarfarin: INR 3–4 vs.LMWH (Arth Rheum2007;57:1487)

Consider ASA prophylaxis forhigh-risk asx Pt (eg, SLE)

DISORDERS OF LEUKOCYTES

TRANSFUSION THERAPY

Transfusion reactions• For all reactions (except minor

allergic): stop transfusion;send remaining blood productand fresh blood sample toblood bank

• Acute hemolytic: fever,hypotension, flank pain, renalfailure <24 h after transfusionDue to ABO incompatibility →

preformed Abs against donor

RBCsTreatment: vigorous IVF,

maintain UOP withdiuretics, mannitol ordopamine

• Delayed hemolytic: generallyless severe than acutehemolytic; 5–7 d aftertransfusionDue to undetected allo-Abs

against minor antigens →anamnestic response

Treatment: usually no specifictherapy required; dx isimportant for futuretransfusion

• Febrile nonhemolytic: fever

and rigors 0–6 h aftertransfusionDue to Abs against donor

WBCs and cytokines releasedfrom cells in blood product

Treatment: acetaminophen ±meperidine; r/o infectionand hemolysis

• Allergic: urticaria; rarely,anaphylaxis: bronchospasm,laryngeal edema, hypotensionReaction to transfusedproteins; anaphylaxis seen inIgA-deficient Pts w/ anti-IgAAbsTreatment: urticaria →

diphenhydramine;

anaphylaxis → epinephrine± glucocorticoids

• Transfusion-related acute lunginjury (TRALI):noncardiogenic pulmonaryedema Due to donor Abs thatbind recipient WBCs, whichthen aggregate in pulmonaryvasculature and releasemediators causing ↑ capillarypermeability Treatment: see“ARDS”

MYELODYSPLASTICSYNDROMES (MDS)

Myeloid neoplasm overview(Blood 2009;114:937)• 5 categories based on BM

morphology, clinicalcharacteristics and genetics

Myelodysplastic syndromes(MDS) overview (NEJM2009;361:1872)

• Acquired clonal stem cell disorder→ ineffective hematopoiesis →cytopenias, dysmorphicblood cells and precursors,variable risk of leukemictransformation

• Epidemiology: >10,000 cases/y;median age ~65 y; malepredominance (1.8×)

• Idiopathic or 2° to chemo w/alkylating agents; ↑ risk w/radiation, benzene

• Clinical manifestations: anemia(85%), neutropenia (50%),thrombocytopenia (40–65%)

• Diagnosis: dysplasia (usuallymultilineage) in peripheral

smear (ovalomacrocytes,pseudo-Pelger-Huëtanomaly) and bone marrow(≥10% dysplasia with blasts± RS)

• Both cytogenetic [eg, del(5q),mono 7, del(7q), trisomy 8,del(20q)] and molec abnl (eg,TP53, EZH2, ETV6, RUNX1,ASXL1, SF3B1) have prognosticsignif (NEJM 2011;364:2496)

• Prior to dx MDS: exclude AML(≥20% blasts) and CMML(monocyte count >1 ×109/L); r/o 2° BM Ds due todefic. of B12, folate, copper;viral infections (eg, HIV);

chemotherapy; alcohol abuse;lead or arsenic toxicity

• Rx (Am J Hematol 2012;87:692):intensity based on IPSS-R (qv),age, performance status (PS)Poor PS, any risk → supportive

care = transfusions, G-CSF,

Epo, abx if neededLow/intermediate risk → Epo

(esp. if Epo level <500);lenalidomide (esp. for 5qsyndrome; NEJM2005;352:549); DNAhypomethylating agents(azacitidine or decitabine)

Intermediate/high risk → DNAhypomethylating agents(survival advantage w/azacytidine; Lancet Oncol2009;10:223), combinationchemo (akin to AML Rx) orallogeneic HSCT if age<55 (consider reduced-intensity transplant for ages

55–75)Hypoplastic MDS (rare) → can

considerimmunosuppression (CsA,ATG, prednisone)

• Prognosis: IPSS correlates withsurvival and progression toAML

MYELOPROLIFERATIVENEOPLASMS (MPN)

General (NEJM 2006;355:2452;Nat Rev Clin Oncol 2009;6:627; AmJ Hematol 2012;87:285)• Results from clonal expansion of

multipotent hematopoieticstem cell

• A type of myeloid neoplasm (seeMDS for classification)

• Different from MDS in that thecells are not dysplastic (ie,normally developed)

• 8 categories of MPN:polycythemia vera (PV);essential thrombocythemia

(ET); primary myelofibrosis(PM); chronic myelogenousleukemia (CML), BCR-ABL1 ;chronic neutrophilic leukemia;chronic eosinophilic leukemia,not otherwise specified; masto-cytosis; myeloproliferativeneoplasms, unclassifiable

• Gain of fxn mutations in JAK2V617F ( Janus kinase) presentin many cases (PV ~95%, ET~50%, PMF ~50%; NEJM2005;352:1779) and BCR-ABLfusion in all cases of CML; KITmutations in virtually allsystemic mastocytosis; MPLand TET2 mutations w/ lower

frequency; genetic lesions areuseful as a clonal marker anddx tool

POLYCYTHEMIA VERA (PV)

Definition• ↑ in RBC mass ± ↑ granulocytes

and platelets in the absence ofphysiologic stimulus

Etiologies of erythrocytosis• Relative ↑ RBC (↓ plasma):

dehydration; “stress”erythrocytosis (Gaisböck’ssyndrome)

• Absolute ↑ RBC: 1° (PV, otherMPD) or 2° due to hypoxia;carboxyhemoglobinemia;inappropriateerythropoietin (renal,hepatic, cerebellar tumors);

Cushing’s syndrome

Clinical manifestations (commonbetween PV and ET)• Symptoms → often termed

“vasomotor symptoms”hyperviscosity

(erythrocytosis): headache,dizziness, tinnitus, blurredvision

thrombosis (hyperviscosity,thrombocytosis): transientvisual disturbances(amaurosis, ocularmigraine); Budd-Chiarisyndrome; erythromelalgia= intense burning, pain and

erythema of extremities dueto microvascular thrombi; ↑risk of DVT, MI, stroke. Riskof thrombosis highlycorrelated with ↑ WBC in PVand ET (see below).

bleeding (abnormal plateletfunction): easy bruising,epistaxis, GI bleeding

↑ histamine from basophils →pruritus, peptic ulcers; ↑uric acid (cell turnover) →gout

• Signs: plethora, splenomegaly,hypertension, engorged retinalveins

Diagnostic evaluation• Hb >18.5 g/dL (men), >16.5

g/dL (women)• ✓ Epo to rule out secondary

causes of erythrocytosis; if Epo↓, PV likely If Epo ↑, then ✓SaO2 or PaO2,carboxyhemoglobin, BM exam

• JAK2 V617F mutation screen onperipheral blood is positive in~95% of PV and JAK2 exon 12mutations are present in theremainder of Pts

• ± ↑ WBC, platelets, basophils; ↑uric acid, leukocyte alkalinephosphatase, vit B12

• Peripheral smear → nomorphologic abnormalities

• BM bx → hypercellular,megakaryocytic hyperplasia, ↓iron, absence of Phchromosome

Treatment• Phlebotomy to moderate degree

of Fe defic., goal Hct <45%(NEJM 2013;368:22), consider<42% in

• Low-dose ASA in all Pts (NEJM2004;350:114)

• Hydroxyurea if high risk ofthrombosis (age ≥60, priorthrombosis) or sx throm-

bocytosis (plt >1.5 × 106/µL)• PEG IFNa-2a yields high response

rate w/ limited toxicity (Blood2008;112:3065)

• Supportive: allopurinol (gout),H2-blockers/antihistamines(pruritus)

Prognosis• Median survival w/ Rx 9–12 y. ↑

age, WBC predict ↓ survival(Br J Haematol 2013;160:251)

• Post-PV myelofibrosis (spentphase) occurs in 10–20% ofcases, usually after 10 y

• Risk of transformation into acuteleukemia (2-5%; higher if

previous cytoreductive chemo)

ESSENTIAL THROMBOCYTHEMIA(ET)

Definition• Sustained ↑ in platelets

(>450,000/µL) ± ↑ RBC andgranulocytes

Etiologies of thrombocytosis• 1° = ET or other MPN;

myelodysplastic syndromes(5q-syndrome)

• 2° = reactive thrombocytosis:inflammation (RA, IBD,vasculitis), infection, acutebleeding, iron deficiency,postsplenectomy, neoplasms(particularly Hodgkin

lymphoma)• Of patients with plt >106/µL,

<1 in 6 will have ET

Clinical manifestations (see“Polycythemia Vera”)• Thrombosis with erythromelalgia

(risk of thrombosis highest inPts with WBC >8700),bleeding, pruritus; mildsplenomegaly; migraine, TIA;early fetal loss

Diagnostic evaluation• Peripheral smear: large

hypogranular platelets• BM bx: megakaryocytic

hyperplasia; absence of

Philadelphia chromosome andlack of collagen fibrosis;normal iron stores

• JAK2 V617F present in ~50% ofET

• Patients should not meet WHOcriteria for diagnosis of CML,PV, PMF or MDS

Prognosis

• Low-risk Pts have overallsurvival control population.Risk of transformation intoacute leukemia ~2–3%.

PRIMARY MYELOFIBROSIS (PMF)

Definition• Clonal myeloproliferation with

reactive marrow fibrosis &extramedullary hematopoiesis

• Formerly known as agnogenicmyeloid metaplasia withmyelofibrosis

Etiologies of myelofibrosis• Myeloproliferative neoplasm =

primary myelofibrosis; post-PV/ET myelofibrosis

• Other hematologic: eg, CML,AML, ALL, MDS

• Metastatic malignancies: eg,breast, prostate

• Autoimmune: eg, SLE and othercollagen vascular disorders

• Other: toxins (eg, benzene);radiation; granulomas frominfection (eg, TB, fungal) orsarcoid; deposition diseases(eg, Gaucher’s disease)

Clinical manifestations (NEJM2000;342:1255; BJH 2012;158:453)• Ineffective erythropoiesis →

anemia; extramedullaryhematopoiesis → massivesplenomegaly (abdominalpain, early satiety) ±hepatomegaly

• Tumor bulk and ↑ cell turnover

→ fatigue, weight loss, fever,sweats

Diagnostic evaluation (NEJM2006;355:2452; JAMA2010;303:2513)• Anemia with variable WBC and

platelet counts• Peripheral smear →

“leukoerythroblastic”(teardrop cells, nucleatedRBCs, immature WBCs); largeabnormal platelets

• BM aspirate → “dry” tap; BM bx→ severe fibrosis,replacement by reticulin &collagen

• JAK2 V617F present in ~50% ofPMF; MPL mutations in ~11%of JAK2 Pts

• No BCR-ABL translocation; alsodoes not meet criteria for PVor MDS

Treatment (Blood 2011;117:3494)• In absence of adverse prognostic

factors (eg, anemia or sx) →no treatment

• Allogeneic HSCT only potentialcure → consider in young Ptswith poor prognosis

• Supportive care: transfusions;inconsistent benefit fromandrogens or Epo;

splenectomy for blood countsrefractory to transfusion orpainful splenomegaly

• Hydroxyurea for significantleukocytosis or thrombocytosis

• Ruxolitinib (JAK1/JAK2inhibitor) ↓ sx, ↓splenomegaly, ↑ survival(NEJM 2012;366:787 & 799)

• Thalidomide and lenalidomide(improve red cell count)

Complications and prognosis• Median survival ~5 y;

transformation into AMLoccurs at a rate of ~8%/y

• International Working Group

(IWG) poor prognostic factors:age >65, WBC >25k, Hgb<10, blasts >1%, symptoms (Blood2009;113:2895). Stratificationbased on IWG factors allowsprognostication at any pointduring clinical course (Blood2010;115:1703).

LEUKEMIA

ACUTE LEUKEMIA

Definition• Clonal proliferation of

hematopoietic progenitor with↓ ability to differentiate intomature elements → ↑ blasts inbone marrow and periphery →↓ RBCs, platelets andneutrophils

Epidemiology and risk factors• Acute myelogenous leukemia

(AML): ~14,000 cases/y;median age 66 y; >80% ofadult acute leukemia cases

• Acute lymphocytic leukemia(ALL): ~6000 cases/y; medianage 14 y; bimodal with 2ndpeak in adults

• Risk factors: radiation, chemo(alkylating agents, topo IIinhib), benzene, smoking

• Acquired hematopoietic diseases:MDS, MPN (esp. CML),aplastic anemia, PNH

• Inherited: Down’s & Klinefelter’s,Fanconi’s anemia, Bloomsyndrome, ataxiatelangiectasia

Clinical manifestations• Cytopenias → fatigue (anemia),

infection (neutropenia),bleeding (thrombocytopenia)

• More common in AML (esp.monocytic leukemias):leukostasis (when blast count

>50,000/µL): occludedmicrocirculation → localhypoxemia and hemorrhage→ dyspnea, hypoxia,headache, blurred vision,TIA/CVA; look forhyperviscosity retinopathy(vascular engorgement,exudates, hemorrhage)

DIC (esp. with APL)leukemic infiltration of skin,

gingiva (esp. with monocytic

subtypes)chloroma: extramedullary

tumor of leukemic cells,virtually any location

• More common in ALL:bone pain, lymphadenopathy,

hepatosplenomegaly (alsoseen in monocytic AML)

CNS involvement (up to10%):cranial neuropathies, N/V,headache anteriormediastinal mass (esp. in T-cell); tumor lysis syndrome(qv)

Diagnostic evaluation (Blood2009;114:937)

• Peripheral smear: anemia,thrombocytopenia, variableWBC (50% p/w ↑ WBC) +circulating blasts (seen in>95%; Auer Rods in AML)

• Bone marrow: hypercellularwith >20% blasts;cytogenetics, flow cytometry

• Presence of certain cytogeneticanomalies, eg, t(15;17),t(8;21), inv(16) or t(16;16),are sufficient for dx of AMLregardless of the blast count

• ✓ for tumor lysis syndrome(rapid cell turnover): ↑ UA, ↑LDH, ↑ K, ↑ PO4, ↓ Ca

• Coagulation studies to r/o DIC:PT, PTT, fibrinogen, D-dimer,haptoglobin, bilirubin

• LP (w/ co-admin of intrathecalchemotherapy to avoidseeding CSF w/ circulatingblasts) for Pts w/ ALL (CNS issanctuary site) and for Pts w/AML w/ CNS sx

• TTE if prior cardiac history orbefore use of anthracyclines

• HLA typing of Pt, siblings andparents for potentialallogeneic HSCT candidates

ACUTE MYELOGENOUSLEUKEMIA (AML)

Classification (FAB no longer usedclinically; Blood 2009;114:937)• Features used to confirm myeloid

lineage and subclassify AML toguide treatment: morphology:blasts, granules, ± Auerrods (eosinophilic needle-likeinclusions) cytochemistry: myeloperoxidase and/ornonspecific esterase

• Immunophenotype: myeloidantigens → CD13, CD33,CD117; monocytic antigens →CD11b, CD64, CD14, CD15

• Cytogenetics: important forprognosis. Intermed. risk = nofavorable/unfavorablefeatures.

Treatment (Blood 2010;115:453;JNCCN 2012;10:984; Lancet

2013;381:484)• Induction chemo followed by

consolidation Rx• Induction chemo: “7 + 3” =

cytarabine × 7 d +ida/daunorubicin × 3 d.Cytarabine dose: continuousintermed. high dose (NEJM2011;364:1027). Daunorubicindose: age <60 → high (90mg/m2); age >60 → standard(60 or 45 mg/m2) (NEJM2009;361:1249). Gemtuzumabozogamicin (ɑ-CD33) ? benefitin fav/int risk AML (Lancet2012;379:1508)

• ✓ for complete remission (CR) =

normal peripheral counts,<5% BM blasts CR ≠ cure; ∴must always f/u induction withconsolidation Rx

• If CR: consolidation Rx basedon risk stratification (age,genetics, PS): chemo (eg, highdose cytarabine) if favorablerisk; otherwise → allo-HSCT( JAMA 2009;301:2349)

• If CR: reinduction with similarchemotherapy (“5 + 2”) oralternative regimen

• If relapse after CR: salvagechemo → allogeneic HSCT (↓intensity conditioning if >60y)

• Supportive care: hydration +allopurinol or rasburicase fortumor lysis prophylaxis;transfusions; antibiotics forfever and neutropenia;antifungals for prolongedfever & neutropenia;hydroxyurea ± leukophoresisfor leukostasis

Prognosis• CR achieved in 70–80% of Pts

<60 y and in 40–50% for Pts>60 y

• Overall survival depends onprognostic factors: ranges from~50% for Pts <60 y w/

favorable prognostic factors to<10% for Pts >60 y w/ poorprognostic factors

• Poor prognostic factors: age>60, unfavorable cytogenetics(see above), FLT3-ITD , poorperformance score, antecedentMDS/MPN, therapy-relatedAML; genetic profiling (NEJM2012;366:1079)

Acute promyelocytic leukemia(APL) (Blood 2009;113:1875)• Rare disease w/ only ~1000

cases/y in the U.S. butbiologically and clinically distinct

• Atypical promyelocytes (large,

granular cells; bilobed nuclei)in blood and bone marrow

• Defined by translocation ofretinoic acid receptor:t(15;17); PML-RARɑ (>95%of cases)

• Medical emergency with DICand bleeding common;supportive care measurescrucial

• Remarkable responses toall-trans-retinoic acid(ATRA), which inducesdifferentiation, and arsenictrioxide (ATO); earlyinitiation of ATRA is critical assoon as APL suspected; ATO

highly active as first-linetherapy or in treatment ofrefractory disease.

• Induction regimen: anthracycline+ ATRA ± cytarabine → CRin ~90%; or ATRA + ATOalone (ASH 2012; JCO2009;27:504)

• Differentiation (ATRA)syndrome: ~25% of Pts; fever,pulm infiltrates, SOB, edema,HoTN, AKI; tx w/dexamethasone 10 mg bid,supportive care (eg, diuresis)(Blood 2008;113:775)

• Consolidation Rx: eg, ATO →anthracycline + ATRA (Blood

2010;116:3751)• Role of maintenance Rx (eg,

ATRA + 6MP + MTX)currently controversial

• Best prognosis of all AMLs:>90% cure; WBC >10,000/µL= ↓ prognosis (Blood2000;96:1247)

ACUTE LYMPHOBLASTICLEUKEMIA (ALL)

Classification• Lymphoblastic neoplasms may

present as acute leukemia(ALL) with >20% BM blastsor as lymphoblastic lymphoma(LBL) w/ mass lesion & <20%BM blasts. ALL and LBL areconsidered the same diseasewith different clinicalpresentations.

• Morphology: no granules(granules seen in myeloidlineage)

• Cytochemistry: terminal

deoxynucleotidyl transferase(TdT) in 95% of ALL

• Cytogenetics (Blood2010;115:206): t(9;22) =Philadelphia chrom (Ph) ~25%of adults w/ ALL

• Immunohistochemistry: 3 majorphenotypes (Burkitt’s usuallytreated differently)

Treatment (NEJM 2006;354:166;JCO 2011;29:532)

• Induction chemo: multipleacceptable regimens includingcombination of anthracycline,vincristine, steroids,cyclophosphamide, ±asparaginase

• CNS prophylaxis: intrathecalMTX/cytarabine ± cranialirradiation or systemic MTX

• Postremission therapy options:consolidation/intensification

chemo (~7 mo) followed bymaintenance chemo (~2–3y) high-dose chemo w/ alloHSCT considered for all Ptsin CR1 w/ available donorpediatric regimens in young

adults (<30 y); consider alloSCT for all Pts <50(controversial)

• If relapse → salvage chemofollowed by allogeneic HSCT ifable

• Ph t(9;22) → add imatinib ordasatinib, followed byallogeneic HSCT

• MLL-AF4 t(4;11) or hypodiploidy(<44 chromosomes) →consider for allogeneic HSCT

• Infusion of chimeric antigenreceptor–modified T cellspromising (NEJM2013;368:1509)

Prognosis• CR achieved in >80% of adults• Cure achieved in 50–60% if good

prog. factors vs. 10–30% w/poor prog. factors

• Good prognostic factors: youngerage, WBC <30,000/µL, T-cellimmunophenotype, absence ofPh chromosome or t(4;11),early attainment of CR

• Gene expression patterns may beuseful in predicting chemoresistance (NEJM2004;351:533)

CHRONIC MYELOGENOUSLEUKEMIA (CML)

Definition (Blood 2009;114:937)• Myeloproliferative neoplasm

with clonal overproduction ofhematopoietic myeloid stemcells that can differentiate

• Philadelphia chromosome (Ph)= t(9;22) → BCR-ABL fusion→ ↑ Abl kinase activityBCR-ABL required for Dx of

CML• “Atypical CML” (BCR-ABL )

now considered a separatedisease and reclassified asMDS/MPN (see

“Myelodysplastic Syndromes”)

Epidemiology and risk factors• ~5400 new cases/y in U.S.;

median age ~64 atpresentation; ~15% of adultleukemias

• ↑ risk with irradiation; no clearrelation to cytotoxic drugs

Clinical manifestations• Triphasic clinical course; 85%

present in the chronic phase• Chronic phase: often

asymptomatic but commonfeatures are fatigue, malaise,weight loss, night sweats,abdominal fullness

(splenomegaly 50%)• Accelerated phase: refractory

leukocytosis,thrombocytopenia andworsening sx → fever, wt loss,↑ splenomegaly, bone pain,bleeding, infections, pruritus(basophilia)

• Blastic phase acute leukemia→ severe constitutionalsymptoms, infection, bleedingand possible leukostasis (see“Acute Leukemia”)

Diagnostic evaluation• Peripheral smear: leukocytosis

(often >100,000/µL), left-

shifted with all stages ofmyeloid maturation; anemia,thrombocytosis, basophilia

• Bone marrow: hypercellular, ↑myeloid to erythroid ratio, ↓leuk alkaline phosphatase

• Chronic: <10% blasts(peripheral or BM)

• Accelerated: 10–20% blasts,>20% basos, plts <100k, ↑spleen size, karyotypic prog.

• Blastic: >20% blasts (2⁄3

myeloid, 1⁄3 lymphoid), maysee extramedullary leukemia

Treatment (NEJM 2010;362:2260;Blood 2011;118:1208 &

2012;120:1390)• Tyrosine kinase inhibitor

(TKI): imatinib, dasatinib,nilotinib, bosutinib, ponatinibare selective inhibitors of BCR-ABL (JCO 2010;28:428; Blood2012;120:1390).Imatinib, nilotinib, & dasatinib

approved as initial Rx.Resistance = recurrent dis. on

TKI, often result of BCR-ABLmutation or amplification.

Nilotinib, dasatinib, bosutinib,& ponatinib approved forresistant disease, w/ onlyponatinib effective on T315Iresistance mutation (NEJM

2012;367:2075).Side effects include nausea,

diarrhea, muscle cramps,cytopenias, ↓ PO4, ↑ QT,rarely CHF; dasatinib alsoa/w pericardial & pleuraleffusions, nilotinib w/ ↑ bili& lipase.

• Chronic phase: TKI; continuedindefinitely in responders(Blood 2012;120:1390)

• Accelerated phase: TKI upfront,consider allogeneic HSCT

• Blastic phase: TKI + HSCT vs.ALL or AML induction (basedon cell type) + HSCT

• Allogeneic HSCT: consider forPts w/ available donor whopresent in accelerated orblastic phase; reasonableoption for Pts withrelapsed/refractory disease toTKIs

Prognosis• Chronic phase CML Rx’d w/

imatinib: 89% overall survival,95% survival free of CML-

related deaths, 7% progressionto blast phase at 5 y (NEJM2006;355:2408)

• Accelerated phase CML Rx’d w/imatinib: ~50% overallsurvival at 4 y (Cancer2005;103:2099)

• Poor prognostic factors: ↑ age, ↑platelet count, ↑ spleen size, ↑percentage of blasts

CHRONIC LYMPHOCYTICLEUKEMIA (CLL)

Definition (NEJM 2005;352:804;Blood 2008;111:5446)• Monoclonal accumulation of

functionally incompetentmature B lymphocytes

• CLL (>5000/µL malignant cells)& small lymphocyticlymphoma (SLL; <5000/µLmalignant cells, but + LAN ±splenomegaly) now classifiedas same disease

• Monoclonal B lymphocytosis(<5000/µL, nodes <1.5 cm,nl RBC and Plt counts):

observe

Epidemiology and risk factors• ~16,000 new cases/y; median

age at dx is 72 y; mostcommon adult leukemia

• ↑ incidence in 1st-degreerelatives; no knownassociation with radiation,chemicals, drugs

Clinical manifestations• Symptoms: often asx &

identified when CBC revealslymphocytosis; 10–20% p/wfatigue, malaise, night sweats,weight loss (ie, lymphoma “B”sx)

• Signs: lymphadenopathy (80%)and hepatosplenomegaly(50%)

• Autoimmune hemolyticanemia (AIHA) (~7%) orthrombocytopenia (ITP)(~1–2%)

• Hypogammaglobulinemia ±neutropenia → ↑ susceptibilityto infections

• Bone marrow failure in ~13%;monoclonal gammopathy in~5%

• Aggressive transformation: ~5%develop Richter’s syndrome= transformation into high-grade lymphoma (usually

DLBCL) and sudden clinicaldeterioration

Diagnostic evaluation (see“Lymphoma” for generalapproach)• Peripheral smear:

lymphocytosis (>5000/µL,mature-appearing small cells)“smudge” cells from damageto abnl lymphs from shearstress of making blood smear

• Flow cytometry: clonality withdim surface Ig (sIg); CD5+,CD19+, CD20(dim), CD23+.CD38+ or ZAP70+ a/wunmutated Ig variable heavy

chain region & worseprognosis.

• Bone marrow: normo- orhypercellular; infiltrated w/small B-cell lymphocytes(≥30%)

• Lymph nodes: infiltrated w/small lymphocytic or diffusesmall cleaved cells = SLL

• Genetics: del 11q22-23 & 17p13unfavorable; trisomy 12neutral; del 13q14 and mutIgVH favorable. Ninesignificantly mutated genes,including TP53, NOTCH1,MYD88 and SF3B1. Key rolefor spliceosome mutations

(NEJM 2011;365:2497; JCI2012;122:3432).

Treatment• Treatment is primarily palliative

→ early stage disease can befollowed w/o Rx

• Indications for treatment: Raistages III/IV, Binet stage C,disease-related sx, progressivedisease, AIHA or ITP

refractory to steroids,recurrent infections

• Options:purine analogues:

fludarabine (“F”),pentostatin (“P”)

alkylating agents:cyclophosphamide (“C”),bendamustine (“B”), CVP,CHOP; ? chlorambucil forelderly (lower response vs.F, but survival; NEJM2000;343:1750)

± monoclonal Ab againstCD20 (rituximab, “R”) orCD52 (alemtuzumab, esp.w/ 17p-) combination

regimens (eg, FR, FCR, BR)superior to monoRx (Lancet2007;370:230)

• Novel Rx refractory dis.:ofatumumab (ɑ-CD20),ibrutinib (BTK inhib), CAL101(PI3K inhib)

• Consider allo-HSCT in p53 mut orrefractory CLL (BBMT2009;15:53; BJH2012;158:174)

• Supportive care: PCP, HSV, VZVprophylaxis; CMV monitoringfor Pts receiving anti-CD52;AIHA/ITP → steroids;recurrent infections → IVIg

Prognosis (NEJM 2004;351:893;JCO 2006;24:4634 &2010;28:4473; Blood 2008;111:865)• Survival varies substantially.

Median overall survival ~10 y(Am J Hematol 2011;12:985)

• Favorable prognosis: 13q14deletion (~50% of CLL cases)

• Factors a/w worse prognosisinclude:unfavorable cytogenetics (eg,

17p-/TP53 mutation)unmutated (<2% c/w

germline) IgVH gene (<8–10y vs. >20–25 y if mutated)

high (>20–30%) Zap-70expression (part of T cell

receptor; correlated w/unmutated IgVH)

CD38 >30% or CD49d <30%(correlated with unmutatedIgVH)

higher β2-microglobulin levels(correlate with disease stageand tumor burden)

LYMPHOMA

Definition• Malignant disorder of lymphoid

cells that reside predominantlyin lymphoid tissues

• Hodgkin lymphoma (HL) isdistinguished from non-Hodgkin lymphoma (NHL) bythe presence of Reed-

Sternberg (RS) cells

Clinical manifestations• Lymphadenopathy (nontender)

HL: superficial (usuallycervical/supraclavicular)± mediastinallymphadenopathy; nodal

disease with orderly,anatomic spread toadjacent nodes

NHL: diffuse; nodal andextranodal disease withnoncontiguous spread;symptoms reflect involvedsites (abdominal fullness,bone pain)

• Constitutional (“B”) symptoms:fever (>38°), drenchingsweats, ↓ weight (>10% in 6mo)HL: periodic, recurrent “Pel-

Ebstein” fever; 10–15% havepruritus; ~35% “B”symptoms

NHL: “B” symptoms varybetween types, ~15–50%

Diagnostic and stagingevaluation• Physical exam: lymph nodes,

liver/spleen size, Waldeyer’sring, testes (~1% of NHL),skin

• Pathology: excisional lymphnode bx (not FNA b/c needsurrounding architecture) withimmunophenotyping andcytogenetics; BM bx (except inHL clinical stage IA/IIA withfavorable features or CLLclone by flow); LP if CNS

involvement clinicallysuspected

• Lab tests: CBC, BUN/Cr, LFTs,ESR, LDH, UA, Ca, alb; ✓ HBV& HCV (and must ✓ HBsAg &anti-HBc if planning rituximabRx as can lead to HBVreactivation); consider HIV,HTLV, & EBV serologies andconnective tissue diseasesautoAbs

• Imaging: chest/abd/pelvic CT,but doesn’t reliably detectspleen/liver involvementconsider PET-CT scans (esp. in

HL, DLBCL). PET responseto Rx can be prognostic

(Blood 2006;107:52; JCO2007;25:3746); has role toassess PR/CR aftertreatment.

Head CT/MRI only ifneurologic symptoms.

HODGKIN LYMPHOMA (HL)(NEJM 2010;363:653)

Epidemiology and risk factors• ~9,000 cases/y; bimodal

distribution (15–35 & >50 y);↑ ; role of EBV in subsets ofHL, esp. immunocompromisedpatients

Pathology• Affected nodes show RS cells

(<1%) in background of non-neoplastic inflammatory cells

• Classic RS cells: bilobed nucleus& prominent nucleoli withsurrounding clear space(“owl’s eyes”). RS cells are

clonal B-cells: CD15+,CD30+, CD20– (rarely +).

• Nonclassical (5%): nodularlymphocyte predominant(NLP); involves peripheral LN80% present in stages I–II and

Rx can be RT alone orcombination chemo + RTw/ 80% 10-y progression-free survival, 93% overall

survival ( JCO1997;15:3060)

Consider rituximab as mostNLP RS cells are CD20+

Stages III–IV treated withcombination chemo (seebelow)

Treatment (Lancet 2012;380:836)• Stages I–II: ABVD (doxorubicin,

bleomycin, vinblastine,dacarbazine) ± RTLower intensity regimens

comparable efficacy iffavorable prognosis (NEJM2010;363:640)

• Stages III–IV: ABVD × 6 cycles

or escalated BEACOPP(bleomycin, etoposide,doxorubicin,cyclophosphamide, vincristine,procarbazine and prednisone)

• Refractory/relapsed disease:salvage chemo + auto HSCT,± RT

• Late effects include ↑ risk for:second cancers: breast (if RT),

∴ annual screening at age40 or 8–10 y post RT; lung, ?role of screening CXR or CT(controversial); acuteleukemia/MDS; NHL

cardiac disease (if RT oranthracycline), ? role of

echo/stress at 10 y(controversial)

pulmonary toxicity (ifbleomycin)

hypothyroidism (if RT), ∴annual TSH (if neck RT)

NON-HODGKIN LYMPHOMA(NHL)

Epidemiology and risk factors• ~70,000 new cases/y; median

age at dx ~65 y; predominance; 85% B-cellorigin

• Associated conditions:immunodeficiency (eg, HIV,posttransplant); autoimmunedisorders (eg, Sjögren’s, RA,SLE); infection (eg, EBV,HTLV-I, H. pylori)

• Burkitt’s lymphoma: (1) endemicor African (jaw mass, 80–90%EBV-related); (2) sporadic or

American (20% EBV-related);(3) HIV-related

Treatment (Lancet 2012;380:848)• Treatment and prognosis

determined by histopathologicclassification rather than stage

• Rituximab (antibody to CD20;

NEJM 2012;366:2008) ifCD20+; no role if tumor isCD20–

• Indolent: goal is sx management(bulky dis., cytopenias, “B”sx); not curable w/o allo HSCTOptions include radiation for

localized disease, rituximab± chemo (bendamustine,CVP, fludarabine)

For MALT → treat H pylori if Rituximab maintenance ↑

survival in relapsed disease(JNCI 2009:101:248);growing role for rituximabmaintenance in indolent andaggressive disease (Lancet

2011;377:42)• Aggressive (DLBCL, 30–40% of

NHL): goal is cure (JCO2005;23:6387)R-CHOP (rituximab,

cyclophosphamide,doxorubicin =hydroxydaunorubicin,vincristine = Oncovin,prednisone) (NEJM2002;346:235 &2008;359:613) 10-yprogression-free survival =45%; overall survival =55% (Blood 2010;116:2040)

? R-ACVBP (ritux, doxorubicin= Adriamycin, cyclophosph,

vindesine, bleo, prednisone)↑ 3-y OS vs. R-CHOP, but ↑adverse events (Lancet2011;378:1858)

+ Radiation for localized orbulky disease

Consider CNS prophylaxis w/intrathecal or systemic high-dose methotrexate ifparanasal sinus, testicular,breast, periorbital,paravertebral or bonemarrow involved; ≥2extranodal site + ↑ LDHmay also warrant

Refractory/relapsed disease:salvage chemo; high-dose

chemo + auto-HSCT (NEJM1995;333:1540); allo-HSCT ifbeyond 2nd relapse

• Highly aggressiveBurkitt’s: intensive short-course

chemotherapy (Blood2004;104:3009)

Low risk defined as nl LDH &single focus of disease <10cm; all others high risk

Low risk Rx = CODOX-M(cyclophosphamide,vincristine, doxorubicin,high-dose methotrexate ±rituximab) (Leuk Lymph2004;45:761)

High risk Rx = CODOX-

M/IVAC (above w/ifosfamide, etoposide, high-dose cytarabine), hyper-CVAD (cyclophosphamide,vincristine, doxorubicin,dexamethasone)

All Pts receive CNS prophylaxis& tumor lysis syndromeprophylaxis

Lymphoblastic lymphoma (Bor T cell): treated like ALL(see “Acute Leukemia”)

Prognosis• Indolent: typically incurable, but

long median survival

• Aggressive: ↑ chance of cure, butoverall worse prognosis

HIV-associated NHL (Blood2006;107:13)• HIV imparts 60–100× relative

risk• NHL is an AIDS-defining

malignancy along withKaposi’s, cervical CA, anal CA

• Concurrent HAART &chemotherapy likely providesurvival benefit

• DLBCL & immunoblasticlymphoma (67%): CD4 <100,EBV-associated Treat asimmunocompetent (CHOP-R),but avoid rituximab if CD4<100 Alternative regimensinclude R-EPOCH (etop, pred,

vincristine, cyclophos,doxorubicin)

• Burkitt’s (20%): can occur withCD4 >200 Treat asimmunocompetent; prognosisis not significantly worse

• Primary CNS lymphoma (16%):CD4 <50, EBV-associated(also seen in Pts w/o HIV)Treat with high-dosemethotrexate + steroids ± RT

• Primary effusion lymphoma(<5%): HHV8 driven; also canbe seen in other immuno-supp. Pts such as s/p solidorgan transplant or w/ chronicHBV. Treat with standard

CHOP (often CD20–), but poorprognosis.

PLASMA CELL DYSCRASIAS

MULTIPLE MYELOMA (MM)

Definition and epidemiology(NEJM 2011;364:1046)• Malignant neoplasm of plasma

cells producing a monoclonalIg = “M protein”

• ~21,700 new cases and ~10,710deaths/y in U.S. (2012);median age at diagnosis 69 y

• African American:Caucasian ratio2:1

Clinical manifestations (CRABcriteria)• HyperCalcemia due to ↑

osteoclast activity• Renal disease: multiple

mechanisms include toxiceffect of filtered light chains →renal failure (cast nephropathy)or type II RTA; amyloidosis orlight chain deposition disease→ nephrotic syndrome;hypercalcemia, uratenephropathy, type Icryoglobulinemia

• Anemia (normocytic) due to bonemarrow involvement andautoimmune Ab

• Bone pain due to ↑ osteoclastactivity → lytic lesions,pathologic fx

• Recurrent infxns due to relativehypogammaglob. (clonalplasma cells suppress nl Ig)

• Neurologic: cord compression;POEMS (polyneuropathy,organomegaly,endocrinopathy, M protein,skin changes) syndrome

• Hyperviscosity: usually whenIgM >4 g/dL, IgG >5 g/dL,or IgA >7 g/dL

• Coagulopathy: inhibition of or Abagainst clotting factor; Ab-coated platelets

• Amyloidosis (see “Amyloidosis”)

Diagnostic and staging

evaluation• Symptomatic MM criteria (all 3

must be met)1) M protein in serum or urine

(no specific level required)2) bone marrow clonal

plasmacytosis (≥10%) orpresence of a plasmacytoma

3) myeloma-related organ ortissue impairment (ROTI) =lytic bone lesions, Ca >11.5g/dL, Cr >2 mg/dL, or Hb<10

• Variantssmoldering MM: M protein >3

g/dL and/or plasmacytosis>10%, but asx & no ROTI

risk of prog.: M proteinconcen., subtype & free lightchain ratio (NEJM2007;356:2582)

solitary bone plasmacytoma: 1lytic lesion w/o M protein,plasmacytosis, or other ROTI

extramedullary (nonosseous)plasmacytoma: usuallyupper respiratory tract

plasma cell leukemia: plasmacell count >2000/µL inperipheral blood

nonsecretory MM (~2% ofMM Pts): no M protein, butmarrow plasmacytosis &ROTI

• Ddx of M component: MM,MGUS (see below), CLL,lymphoma, cirrhosis,sarcoidosis, RA

• Peripheral smear → rouleaux(see insert); ✓ Ca, alb, Cr; ↓anion gap, ↑ globulin, ↑ ESR

• Protein electrophoresis andimmunofixationserum protein

electrophoresis (SPEP):quantitates M component; in ~80% of Pts

urine protein electrophoresis(UPEP): detects the ~20% ofPts who secrete only lightchains ( = Bence Jones

proteins), which are filteredrapidly from the blood

immunofixation: showscomponent is monoclonaland identifies Ig type → IgG(50%), IgA (20%), IgD (2%),IgM (0.5%), light chain only(20%), nonsecretors (<5%)

serum-free light chain assay:important test for dx andfollow-up of response to Rx

• β2-microglobulin and LDH levelsreflect tumor burden

• BM bx cytogenetics: normalkaryotype better than abnl.Standard risk =

hyperdiploidy or t(11;14);high risk = hypodiploidy,del. 17p13 (~10% of Pts),t(4;14) & t(4;16)

• Gene mutations include TP53,NRAS, KRAS, BRAF & NK-kBpathway (Nature2011;471:467)

• Skeletal survey (plainradiographs) to identify lyticbone lesions and areas at riskfor pathologic fracture; bonescan is not useful for detectinglytic lesions

Treatment (NEJM 2011;364:1046;Am J Hematol 2012;87:79)• Not indicated for smoldering MM

or asx stage I disease• Decisions generally dictated by

risk stratification and transplanteligibility

• Active agents include: bortezomib(V), dexamethasone (D),

prednisone (P), lenalidomide(R), thalidomide (T),melphalan (M),cyclophosphamide (C),doxorubicin, carfilzomib (Cz)

• Induction Rx regimens w/ bestresponse rate incl. those w/proteasome inhib (V, Cz) &immunomod (R), but many 2-or 3-drug options used basedon comorbidities and risk.Proteasome inhib containingregimens incl. MPV, RVD, VCD& CzRD.

• If not transplant eligible:induction chemo ↑ survival,not curative; consider maint

chemo• If transplant eligible: induction

chemo (eg, RVD, VCD, RD,VTD; Lancet 2010;376:2075)then high-dose chemo +auto-HSCT. Not curative, but ↑survival c/w chemo (NEJM2009;360: 2645). Timing ofHSCT (upfront vs. relapse)under study. Offer if <70 y w/good perf. status & noprohibitive comorbidities.Maint Rx w/ R or V untilprogression or intolerance.Role of tandem auto-HSCT &allo-HSCT remainscontroversial (NEJM

2003;349:2495).• Local radiation for solitary or

extramedullary plasmacytoma• Adjunctive Rx

bone: bisphosphonates (JCO2007;25:2464); XRT for sxbony lesions

renal: avoid NSAIDs & IVcontrast; considerplasmapheresis for acuterenal failure

hyperviscosity syndrome:plasmapheresis; infxns:consider IVIg for recurrentinfections

• Common toxicities of Rx:melphalan →

myelosuppression;lenalidomide → low plts &thromboembolism; bortezomib→ periph. neuropathy; steroids→ hyperglycemia, infxn

MONOCLONAL GAMMOPATHYOF UNCERTAIN SIGNIFICANCE

(MGUS)

Definition and epidemiology(NEJM 2006;355:2765)• M protein <3 g/dL, no urinary

Bence Jones proteins, marrowplasmacytosis <10%, no ROTI

• Prevalence ~3% in population>50 y of age, ~5% inpopulation >70 y of age, and7.5% in population >85 y of

age (NEJM 2006;354:1362)

Management• ✓ CBC, Ca, Cr, SPEP, serum free

light chains, UPEP w/

immunofixation (to excludeMM)

• Close observation: repeat SPEPin 6 mo, then yearly thereafterif stable

Prognosis (NEJM 2002:346:564)• ~1%/y or ~25% lifetime risk →

MM, WM, amyloidosis, ormalign. lymphoproliferativedis.

• Abnormal serum-free light chainratio: ↑ risk of progression toMM (Blood 2005;105:812)

WALDENSTRÖM’SMACROGLOBULINEMIA (WM)

Definition (Blood 2009;114:2375)• B-cell neoplasm

(lymphoplasmacyticlymphoma) that secretesmonoclonal IgM

• MYD88 (NF-кB pathway) L265Psomatic mutation found in91% of Pts w/ WM and couldbe used to distinguish WMfrom MM (NEJM2012;367:826)

• No evidence of bone lesions (IgMM component + lytic bonelesions = “IgM myeloma”)

Clinical manifestations• Fatigue from anemia is most

common sx• Tumor infiltration: BM

(cytopenias), hepatomegaly,splenomegaly,lymphadenopathy

• Circulating monoclonal IgMhyperviscosity syndrome

(~15%)neurologic: blurred vision

(“sausage” retinal veins onfunduscopy), HA, dizziness,Δ MS

cardiopulmonary: congestiveheart failure, pulmonaryinfiltrates

type I cryoglobulinemia →Raynaud’s phenomenon

platelet dysfxn → mucosalbleeding

• IgM deposition (skin, intestine,kidney); amyloidosis andglomerulopathy

• Autoantibody activity of IgMchronic AIHA (prominent

rouleaux; 10% Coombs’ = AIHA)

peripheral neuropathy: maybe due to IgM againstmyelin-associatedglycoprotein

Diagnostic evaluation

• SPEP + immunofixation withIgM >3 g/dL; 24-h urine forUPEP (only 20% have UPEP)

• Bone marrow biopsy: ↑plasmacytoid lymphocytes; β2-microglobulin for prognosticeval

• Relative serum viscosity:defined as ratio of viscosity ofserum to H2O (nl ratio 1.8)hyperviscosity syndrome whenrelative serum viscosity >5–6

Treatment• Hyperviscosity: plasmapheresis• Symptoms (eg, progressive

anemia): rituximab ±chemotherapy (eg,cyclophosphamide,chlorambucil, fludarabine,cladribine, bendamustine) orbortezomib

• Thalidomide, alemtuzumab,everolimus, ibrutinib & auto-HSCT are investigational Rx

HEMATOPOIETIC STEM CELLTRANSPLANTATION (HSCT)

Transplantation of donor pluripotentcells that can reconstitute all recipient

blood lineages

• Types of Allo HSCT: based ondonor/recipient matching ofmajor HLA antigens on Chr. 6 (4principal genes for serotyping:HLA-A, -B, -C, & -DR; each w/ 2

alleles ∴ 8 major Ag)Matched related (sibling

matched at 8/8 major Ag):lowest risk of GVHD;preferred donor

Mismatched related (eg, 1/8 Agmismatch) or haploidentical(mismatch at 4/8 Ag):easiest to find, but ↑ risk ofGVHD, rejection; ∴ needadditionalimmunosuppression

Matched unrelated: ↑ risk ofGVHD; ∴ matching of 10HLA alleles (DQ also) to ↓risk; chance of matchcorrelates w/ ethnicity

Umbilical cord blood: HSCprocessed at birth & stored; ↓risk of GVHD; toleratemismatch but much slowerimmune reconstitution(Blood 2010;116:4693)

• Graft-vs.-host disease (GVHD):undesirable side effect of alloHSCT allogeneic T cells viewhost cells as foreign; ↑ incid.w/ mismatch or unrelateddonors

• Graft-vs.-tumor (GVT) effect:desired in allo-SCT; graft Tcells attack host tumor cells

Indications (NEJM 2006;354:1813;

BMT 2010;45:1259)• Malignant disease:

Auto HSCT allows higherablative chemo doses andthen rescues thehematopoietic system (usedmostly for lymphoma,multiple myeloma, testicularcancer)

Allo HSCT produces graft-versus-tumor (GVT) effect,in addition to hematopoieticrescue (used for AML, ALL,CML, CLL, MDS, lymphoma)

• Nonmalignant disease: alloHSCT replaces abnllymphohematopoietic system

w/ one from nl donor (eg,immunodef., aplastic anemia,hemoglobinopathies, ?autoimmune dis.)

Transplantation procedure• Preparative regimen:

chemotherapy and/orimmunosuppression prior totransplantationmyeloablative (traditional):

chemotherapy and/or totalbody irradiation. Goal iseradication of underlyingdisease for which transplantis being performed.

reduced intensity conditioning

(RIC or “mini”): lower doseconditioning → ↓ toxicity toallow Pts w/ comorbiditiesor ↑ age to tolerate HSCT.Goal to proceed w/transplant when in diseaseremission. Depends mostlyon GVT; ↓ mortality w/ RIC,but ↑ relapse.

• Sources of stem cells:bone marrow (BM): original

source of HSCT, now lesscommonly used than PBSC

peripheral blood stem cells(PBSC): easier collection,most commonly used source

BM vs. PBSC survival; BM ↓

chronic GVHD, PBSC ↓ graftfailure (NEJM2012;367:1487)

umbilical cord blood (UCB):less stringent HLA-matchingrequirements, but fewer cellsavailable from single donor(∴ 2 donors combined inadults); slower engraftment

haploidentical: mostavailable; newer regimensstarting to make safer/morecommon

• Engraftment: absoluteneutrophil count (ANC)recovers to 500/µL w/in ~2wk w/ PBSC, ~3 wk w/ BM,

~4 wk w/ UCB. G-CSFaccelerates recovery by 3–5 din all scenarios.Engraftment syndrome: fever,

rash, noncardiogenic pulmedema, abnl LFTs, AKI, wtgain. Dx of exclusion: r/oinfection, GVHD; Rx w/ IVsteroids.

Complications• Either direct

chemoradiotoxicitiesassociated with preparativeregimen or consequences ofinteraction between donorand recipient immune

systems• Sinusoidal obstruction

syndrome (SOS): incidence~10%, mortality ~30%Previously known as veno-

occlusive disease (VOD)Mechanism: direct cytotoxic

injury to hepatic venules →in situ thrombosis

Symptoms: tenderhepatomegaly, ascites,jaundice, fluid retentionwith severe disease → liverfailure, encephalopathy,hepatorenal syndrome

Diagnosis: ↑ ALT/AST, ↑bilirubin; ↑ PT with severe

disease; Doppler U/S mayshow reversal of portal veinflow; ↑ hepatic wedgepressure; abnl liver bx

Treatment: supportive;prophylaxis with ursodiol;defibrotide

• Idiopathic pneumoniasyndrome (IPS): up to 70%mortality (Curr Opin Oncol2008;20:227)Mech: alveolar injury due to

direct toxicity → fever,hypoxia, diffuse pulmonaryinfiltrates

Diffuse alveolar hemorrhage(DAH): subset of IPS

Diagnosis: bronchoscopy toexclude infection; ↑ bloodylavage fluid seen with DAH

Treatment: high-dosecorticosteroids, etanercept(Blood 2008;112:3073)

• Acute GVHD (usually within 6mo of transplant; Lancet2009;373:1550)Clinical grades I–IV based on

scores for skin (severity ofmaculopapular rash), liver(bilirubin level) and GI(volume of diarrhea); bxsupports diagnosis

Prevention:immunosuppression (MTX

+ CsA or tacrolimus) or T-cell depletion of graft

Treatment: grade I → none;grades II–IV → associatedwith ↓ survival and ∴treated withimmunosuppressants(corticosteroids, CsA,tacrolimus, rapamycin,MMF)

• Chronic GVHD (developing orpersisting beyond 3 moposttransplant)Clinical: malar rash, sicca

syndrome, arthritis,obliterative bronchiolitis,bile duct degeneration,

cholestasis and many others.More common w/ PBSC thanBM.

Treatment:immunosuppressants;rituximab; photopheresis

• Graft failurePrimary = persistent

neutropenia withoutevidence of engraftment

Secondary = delayedpancytopenia after initialengraftment; either immunemediated viaimmunocompetent host cells(graft rejection) or non–immune mediated (eg, CMV)

• Infectious complicationsdue to regimen-induced

pancytopenia andimmunosuppression

auto HSCT recipients: noimmunosuppression ∴ at ↑risk only pre-/postengraftment

both primary infectionsand reactivation eventsoccur (eg, CMV, HSV,VZV)

LUNG CANCER

(NEJM 2008;359:1367; JCO2012;30:863; J Thorac Oncol2 0 1 2 ; 7 : 9 2 4 ; Nature2 0 1 1 ; 4 8 9 : 5 1 9 ; Cell2012;150:1107)

Epidemiology and risk factors• Most common cause of cancer-

related death for both men andwomen in the U.S.

• Cigarette smoking: 85% of lungcancers occur in smokers; risk∝ total pack-yrs, ↓ risk afterquitting/reducing, but not tobaseline (Int J Cancer2012;131:1210) squamous &small cell almost exclusively insmokers adenocarcinoma mostcommon type in nonsmokersbronchioalveolar carcinomaassociated with women,nonsmokers, EGFR mutations

• Asbestos: when combined withsmoking, synergistic ↑ in riskof lung cancer

• Radon: risk to generalpopulation unclear

Clinical manifestations• ~10% are asx at presentation

and are detected incidentallyby imaging

• Endobronchial growth of 1°tumor: cough, hemoptysis,dyspnea, wheezing, post–obstructive pneumonia; morecommon with squamous orsmall cell (central location)

• Regional spreadpleural effusion, pericardial

effusion, hoarseness(recurrent laryngeal nerve

palsy), dysphagia(esophageal compression),stridor (tracheal obstruction)

Pancoast’s syndrome: apicaltumor → brachial plexusinvolvement (C8, T1, T2) →Horner’s syndrome, shoulderpain, rib destruction,atrophy of hand muscles

SVC syndrome (NEJM2007;356:1862): centraltumor → SVC compression→ face or arm swelling(>80%), venous distentionof neck & chest wall(~60%), dyspnea/cough(~50%), HA (~10%); Rx =

steroids & diuretics, RT ±chemo after tissue dx, SVCstent for severe sx,fibrinolytic + anticoag ifthrombus

• Extrathoracic metastases:brain, bone, liver, adrenal

• Paraneoplastic syndromesEndocrine:ACTH (SCLC) → Cushing’s

syndrome; ADH (SCLC) →SIADH

PTH-rP (squamous cell) →hypercalcemia

Skeletal: digital clubbing (non–small cell), hypertrophicpulmonary

osteoarthropathy(adenocarcinoma) =symmetric polyarthritis andproliferative periostitis oflong bones

Neurologic (SCLC): Eaton-Lambert, peripheralneuropathy, cerebellardegeneration, limbicencephalitis

Cutaneous: acanthosisnigricans, dermatomyositis

Hematologic: hypercoagulablestate (adenocarcinoma),DIC, marantic endocarditis

Screening (JAMA 2011;306:1865;

NEJM 2011;365:395)• No benefit to CXR or sputum

cytology, even in high-risk Pts• Low-dose chest CT in >30 pack-y

smokers age 55–74 y → 20% ↓in lung cancer–relatedmortality vs. CXR; numberneeded to screen = 320; highfalse rate

Diagnostic and stagingevaluation (NCCN Guidelinesv.3.2012)• Initial imaging: chest CT

(include liver and adrenalglands) w/ contrast if possible

• Tissue

bronchoscopy (for centrallesions) or CT-guidedneedle bx (for peripherallesions or accessible sites ofsuspected metastasis)

mediastinoscopy (lymph nodebx), VATS (eval. of pleuraperipheral lesions),thoracentesis (cell block forcytology) or sputumcytology (for central lesions)

• StagingIntrathoracic: mediastinoscopy

(± preceded by U/S-guidedtransesoph. or transbronch.needle aspiration; JAMA2010;304:2245) or VATS;

thoracentesis if pleuraleffusion

Extrathoracic: PET-CT more Sethan CT alone for detectingmediastinal and distant metsas well as bone mets (NEJM2009;361:32); brain MRI forall Pts (except IA)

• Genetic testing for EGFRmutations and ALK rearrang.for stage IV nonsquam NSCLC

• PFTs w/ quantitative V/Q ifplanned treatment includessurgical resection; need tohave 30% of normal, predictedlung fxn after resection

NSCLC treatment (NCCNGuidelines v.3.2012)• Stages I & II: surgical resection

+ adjuvant chemo (surgeryalone for stage IA) (NEJM2004;350:351 &2005;352:2589)

• Stage III: chemoradiation ismain treatment modality

IIIA viewed as potentiallyresectable (Lancet2009;374:379) and IIIB asunresectable neoadjuvantchemoradiation may convertunresectable → resectable

• Stage IV: chemotherapy ↑survival vs. best supportivecarebackbone of therapy is

platinum-based doublet;cisplatin/pemetrexed betterfor adenocarcinoma;cisplatin/gemcitabine betterfor squamous (JCO2008;26:3543)

bevacizumab (anti-VEGF mAb)

+ chemo ↑ median survivalby 2 mo; ↑ risk of bleeding,∴ do not use if untreated orhemorrhagic brain mets(JCO 2009;27:5255) orsquamous cell (hemoptysis)(NEJM 2006;355:2542)

if EGFR mutation (a/wimproved prognosis): EGFRtyrosine kinase inhibitor(TKI, eg, erlotinib) first-lineRx (Lancet 2008;372:1809;NEJM 2010;362:2380 &2011;364:947)

if ALK rearrangement: ALKTKI (eg, crizotinib) first-lineRx (Lancet Oncol

2011;12:1004)TKI toxicities: rash & diarrhea

(common); lung & liverinjury (rare but potentiallyserious) palliative radiationused to control local sxcaused by tumor ormetastasis solitary brainmetastasis: surgical resection+ brain radiation may ↑survival

SCLC treatment (NCCN Guidelinesv.2.2013)• SCLC usually disseminated at

presentation, but can be veryresponsive to chemoradiation

• Chemotherapy (platinum +etoposide) is primarytreatment modality

• Thoracic radiation added tochemotherapy improvessurvival in limited stagedisease

• Prophylactic cranialirradiation (PCI) improvessurvival for limited stagedisease in complete remission(NEJM 1999;341:476)

BREAST CANCER

Epidemiology and genetics (riskassessment tool:www.cancer.gov/bcrisktool/)• In U.S., most common cancer in

women; 2nd leading cause ofcancer death in women

• Age: incidence rates ↑ with age,with possible ↓ in slope aftermenopause

• Genetics (Nature 2012;490:61):Mutations in TP53, PIK3CA andGATA3; HER2 amplified. 15–20% have FHx → 2× ↑ risk;~45% of familial cases a/wknown germline mutation

http://www.cancer.gov/bcrisktool/

BRCA1/2: 35–85% lifetimerisk of breast cancer & ↑ riskof ovarian cancer; ? ↑colon & prostate cancer;prog not worse than innoncarriers w/ breast ca(NEJM 2007;357:115);BRCA2: a/w ↑ male breastcancer & pancreatic cancer.Rare mutations in CHEK2,HRAS, TP53 a/w ↑ risk infamilial breast cancer (BreastCancer Treat Res2011;127:309)

• Estrogen: ↑ risk with earlymenarche, late menopause,late parity or nulliparity

(NEJM 2006;354:270); ↑ riskwith prolonged HRT (RR =1.24 after 5.6 y, JAMA2003;289:3243);no ↑ risk shown with OCP use

(NEJM 2002;346:2025)• Benign breast conditions: ↑ risk

w/ atypia (atypical ductal orlobular hyperplasia) &proliferative (ductalhyperplasia, papilloma, radialscar or sclerosing adenosis)features; no ↑ risk w/ cysts,fibroadenoma or columnarchanges (NEJM 2005;352:229)

• ↑ risk with h/o ionizing radiationto chest for treatment of

Hodgkin lymphoma

Clinical manifestations• Breast mass (hard, irregular,

fixed, nontender), nippledischarge (higher risk ifunilateral, limited to one duct,bloody, associated with mass)

• Special types: Paget’s disease →unilateral nipple eczema +nipple discharge;inflammatory breast cancer→ skin erythema and edema(peau d’orange)

• Metastases: lymph nodes, bone,liver, lung, brain

Screening (NEJM 2011;365:1025)

• Self breast exam (SBE): noproven mortality benefit (JNCI2002;94:1445); notrecommended

• Clinical breast exam (CBE):benefit independent ofmammography not established

• Mammography: ~20–30% ↓ inbreast cancer mortality(smaller abs. benefit in women<50 y) (Lancet 2006;368:2053;Annals 2009;151:727); 75% ofall abnl findings benign;suspicious: clusteredmicrocalcifications,spiculated, enlarging addingU/S ↑ Se, but ↓ PPV (JAMA

2008;299:3151)• ACS/NCI recommend annual

mammo + CBE beginning atage 40; USPSTF recommendsbeginning at 50 and biennially(Annals 2009;151:716),controversial (NEJM2009;361:2499)

• ↑ risk: screen earlier w/ CBE andmammo (age 25 in BRCA1/2carrier, 5–10 y before earliestFHx case, 8–10 y after thoracicRT, upon dx of ↑ risk benigndisease)

• MRI: superior to mammo in high-risk Pts; consider annually if>20% lifetime risk (eg,

FHx, BRCA1/2, prior chest RT)(Lancet 2011;378:1804)

• Genetic testing should beconsidered in women withstrong FHx

Diagnostic evaluation• Palpable breast mass: age <30

y → observe for resolutionover 1–2 menstrual cycles;age <30 y, unchanging mass

→ U/S → aspiration if massnot simple cyst;

age >30 y or solid mass onU/S or bloody aspirate orrecurrence after aspiration→ mammo (detect other

lesions) and either fine-needle asp. or core-needlebx clearly cancerous onexam or indeterminate reador atypia on bx →excisional bx

• Suspicious mammogram withnormal exam: stereotacticallyguided bx

• MRI: detects contralateral cancerin 3% of women w/ recentlydx breast cancer & negativecontralateral mammogram(but PPV only 21%) (NEJM2007;356:1295); whether touse routinely remains unclear

Staging• Anatomic: tumor size, chest wall

invasion, axillary LN mets(strongest prognostic factor)

• Histopathologic: type (littleprognostic relevance) & grade;lymphatic/vascular invasionIn situ carcinoma: no invasion

of surrounding stromaDuctal (DCIS): ↑ risk of

invasive cancer in ipsilateralbreast (~30%/10 y)

Lobular (LCIS): marker of ↑risk of invasive cancer ineither breast (~1%/y)

Invasive carcinoma:infiltrating ductal (70–80%);

invasive lobular (5–10%);tubular, medullary andmucinous (10%, betterprognosis); papillary (1–2%); other (1–2%)

Inflammatory breast cancer(see above): not a histologictype but a clinical reflectionof tumor invasion of dermallymphatics; very poorprognosis

Paget disease: ductal cancerinvading nipple epidermis± associated mass

• Biomarkers: determine estrogen,progesterone receptor (ER/PR)and HER2/neu status for all

invasive breast cancers• Oncotype DX 21-gene risk

recurrence score has predictiveand prognostic value in ER ,node or Pts (JCO2007;25:5287 & 2010;28:1829;Lancet 2011;378:1812)

• Circulating tumor DNA may serveas biomarker of met tumorburden (NEJM 2013;368:1199)

Treatment• Local control: surgery and

radiation therapy (RT)Breast-conserving =

lumpectomy + breast RT +axillary node dissection(ALND) is equivalent tomastectomy + ALND (NEJM2002;347:1227);contraindications:multicentric disease, diffusemicrocalcifications, prior RT,pregnancy, ? tumor >5 cm

Sentinel lymph node dissection(SLND) prior to ALNDpreferred if w/o palpaxillary LNs; T1-2 w/

SLND & Rx w/lumpect./RT/chemo may notneed ALND (JAMA2011;305:569)

Radiation therapy (RT) aftermastectomy for ≥4 LN,tumor >5 cm or surgicalmargins → ↓ locoregionalrecurrence and ↑ survival(Lancet 2011;378:1707)

• Systemic therapy: for stage I-IIIexcept tumors <1 cm(complex risk assessmentneeded).http://www.adjuvantonline.com/index.jspcan guide use of chemo and/orhormonal Rx.

http://www.adjuvantonline.com/index.jsp

Chemotherapy (Lancet2008;371:29): inneoadjuvant setting usuallyanthracycline-based (eg,adriamycin +cyclophosphamide).Sequential Rx w/ taxane(eg, paclitaxel) → small ↑survival (NEJM2007;357:1496;2010;362:2053 &2010;363:2200).

Anti-HER2 therapy (growing listof agents) in HER2 tumors(NEJM 2012;366:176)

trastuzumab (Herceptin;anti-HER2 mAb) ↑ survival

(NEJM 2001;344:783); giveafter anthracycline or w/taxane to avoid cardiotox(JCO 2002;20:125 & NEJM2011;365:1273) lapatinib(tyrosine kinase inhib. ofHER2 & EGFR) +trastuzumab ↑ survival afterfailing trastuzumab (JCO2012;30:2585); dual inhib.initial Rx ↑ response (Lancet2012;379:633) pertuzumab(anti-HER2 mAb, preventsdimerization) ↑ progression-free survival when added totrastuzumab as first-line Rxfor metastatic dis. (NEJM

2012;366:109) trastuzumabemtansine (T-DM1, HER2mAb conjugated tomicrotubule inhibitor)↑ survival compared tosecond-line lapatinib +capecitabine (NEJM2012;367:1783)

Bevacizumab (anti-VEGF): ? inneoadjuvant Rx if HER2 (NEJM 2012;366:299 & 310)

Hormonal (in ER/PR orunknown status)

tamoxifen: 39% ↓ recurrenceand 30% ↓ breast cancermortality in pre- and post-menopausal patients; 10 y of

Rx superior to 5 y (Lancet2011;378:771 &2013;381:805)

aromatase inhibitors (AI)(anastrozole, letrozole,exemestane): ~18% ↓recurrence vs. tamoxifen inpostmenopausal Pts (Lancet2005;365:60; NEJM2005;353:2747)

everolimus ↑ progression-freesurvival if postmenopausal& failed AI (NEJM2012;366:520)

2nd-line: ovarian ablation withLHRH agonists (goserelin) oroophorectomy if

premenopausal; pureantiestrogens (fulvestrant) ifpostmenopausal

Prevention (with selectiveestrogen receptor modulator[SERM] or AI)• Tamoxifen: ↓ risk contralat.

breast CA as adjuvant Rx.

Approved for 1° prevent. if ↑risk: ↓ invasive breast ca, but ↑DVT & uterine CA; ? ↑ inmortality (Lancet2002;360:817 ).

• Raloxifene: ↓ risk of invasivebreast cancer & vertebral fx, ↑risk of stroke & DVT/PE (NEJM2006;355:125); tamoxifen inprevention of breast cancer w/↓ risk of DVT/PE & cataracts,trend toward ↓ uterine cancer( JAMA 2006;295:2727 )

• Exemestane in high-riskpostmenopausal ↓ invasivebreast ca by 65% (NEJM2011;364:2381)

• BRCA1/2 : intensifiedsurveillance as describedabove. Prophylactic bilat.mastectomy → ~90% ↓ risk;bilat. salpingo-oophorectomy ↓risk of ovarian and breastcancer.

PROSTATE CANCER

Epidemiology and risk factors(NEJM 2003;349:366)• Most common cancer in U.S.

men; 2nd most common causeof cancer death in men

• Lifetime risk of prostate cancerdx ~16%; lifetime risk ofdying of prostate cancer ~3%

• More common with ↑ age (rare if<45 y), in African Americansand if FHx

• ↑ risk w/ BRCA2 (4.7) and BRCA1(1.8) (JNCI 1999;91:1310 &2002;94:1358)

Clinical manifestations (usually

asymptomatic at presentation)• Obstructive sx (more common

with BPH): hesitancy, ↓stream, retention, nocturia

• Irritative sx (also seen withprostatitis): frequency,dysuria, urgency

• Periprostatic spread: hematuria,hematospermia, new-onseterectile dysfunction

• Metastatic disease: bone pain,spinal cord compression,cytopenias

Screening (NEJM 2012;367:e11)• Digital rectal exam (DRE): size,

consistency, lesions

• PSA: 4 ng/mL cut point neitherSe nor Sp; can ↑ with BPH,prostatitis, acute retention,after bx or TURP, andejaculation (no significant ↑after DRE, cystoscopy); 15% ofmen >62 y w/ PSA <4 & nlDRE have bx-proven T1 cancer(NEJM 2004;350:2239)

• Per American Cancer Soc. men≥50 y (or ≥ 45 y if African-Am or FHx) should discussPSA screening w/ their MD;USPSTF rec. against screeningin asx males (no reduction inprostate cancer-relatedmortality) (NEJM

2009;360:1310; Annals2012;157:120)

Diagnostic and stagingevaluation• Transrectal ultrasound (TRUS)

guided biopsy, with 6–12 corespecimens

• Histology: Gleason grade (2–10; low grade ≤6) = sum ofthe differentiation score (1 =best, 5 = worst) of the 2 mostprevalent patterns in the bx;correlates with prognosis

• Imaging: to evaluateextraprostatic spread bonescan: for PSA >10 ng/mL,

high Gleason grade orclinically advanced tumorabdomen-pelvis CT: inaccuratefor detecting extracapsularspread and lymph node metsendorectal coil MRI: improvesassessment of extracapsularspread

Prognosis• PSA level, Gleason grade and age

are predictors of metastaticdisease

• In surgically treated Pts, 5-y

relapse-free survival >90% ifdisease confined to organ,~75% if extension throughcapsule, and ~40% if seminalvesicle invasion

• PSA doubling time, Gleason, &time to biochemical recurrencepredict mortality followingrecurrence. For localrecurrence following RP,salvage RT may be beneficialif low PSA.

• Metastatic disease: mediansurvival ~24–30 mo; allbecome castrate resistant (in15–20% discontinuation ofantiandrogens results in

paradoxical ↓ in PSA)• Long-term consequences of

antiandrogen therapy includeosteoporosis

Prevention• Finasteride and dutasteride ↓

total prostate cancers detectedby bx, but ↑ number of highGleason grade tumors (NEJM2003;349:215 &2010;362:1192)

COLORECTAL CANCER (CRC)

Epidemiology and risk factors(Lancet 2010;375:1030; CA Cancer JClin 2011;61:212)• 4th most common cancer in U.S.

men & women; 2nd leadingcause of all cancer death

• Rare before age 40, w/ 90% ofcases occurring after age 50.~75% are sporadic.

• Family history: up to 25% of Ptshave FHx. Risk depends on# of 1st-degree relatives (w/CRC or polyp) and their age atdx; ~5% have an identifiablegermline mutation

Familial adenomatouspolyposis (FAP): mutationin APC gene → 1000s ofpolyps at young age →~100% lifetime risk; ↑ riskof thyroid, stomach, smallbowel cancers

Hereditary nonpolyposiscolorectal cancer(HNPCC): most commonhereditary CRC (~3% of allCRC; NEJM 2003;348:919);mutations in DNA mismatchrepair genes (eg, MSH2,MLH1) → microsatelliteinstability (MSI) → ↑ tumorprogression → ~80%

lifetime risk; predom. right-sided tumors; ↑ risk ofendometrial, ovarian,stomach, urothelial, smallbowel and pancreaticcancers.

Amsterdam criteria: ≥3 familymembers w/ HNPCC-relatedcancer, one of which is dxbefore age 50, affecting 2successive generations.

• Inflammatory bowel disease: ↑risk with ↑ extent and durationof disease

• Other factors a/w ↑ risk of CRC:diet rich in animal fat, ?smoking, ? diabetes/obesity

• COX-2: ↓ risk of adenomas w/ASA & NSAIDs. ASA assoc. w/ ↓CRC incidence, mets andmortality (Lancet:2010;376:1741; 2012;379:1591& 1602). ↓ COX-2-expressingCRC after prolonged ASA(NEJM 2007;356:2131). ASAeffect limited to PIK3CA-mutCRC (NEJM 2012;367:1596).COX-2 inhib. effective but ↑bleeding & CV events (NEJM2006;355:873 & 885).

Pathology and genetics (NEJM2009;361:2449; Nature2012;487:330)• Adenoma → carcinoma

sequence reflectsaccumulation of multiplegenetic mutations. ↑ risk ofmalig. w/ large (>2.5 cm),villous, sessile adenomatouspolyps. Adenomas typicallyobserved ~10 y prior to onsetof cancer (both sporadic &familial).

• Genetic profile in sporadic CRC:APC (~80%), KRAS (~40%),TP53 (50–70%), DCC orSMAD4, or BRAF (~15%);chrom instability (majority) ormismatch repair defic (10–15%)

• Upfront genotyping may guide

Rx; eg, benefit of anti-EGFR Abcetuximab greater in KRASwild-type than KRAS mutant(NEJM 2008;359:1757). BRAFmutation may guide clinicaltrials.

Clinical manifestations• Distal colon: Δ bowel habits,

obstruction, colickyabdominal pain,hematochezia

• Proximal colon: iron defic.anemia, dull vague abd pain;obstruction atypical due tolarger lumen, liquid stool andpolypoid tumors (vs. annular

distal tumors)• Metastases: nodes, liver, lung,

peritoneum → RUQtenderness, ascites,supraclavicular LN

• Associated with Streptococcusbovis bacteremia andClostridium septicum sepsis

Screening (NEJM 2009;361:1179)• Average risk: colonoscopy

starting at age 50 & repeatq10y strongly preferredmethod

• ↑ risk: earlier and/or morefrequent screening. FHx: age40 or 10 y before index dx,

then q5y. IBD: 8–10 y after dx,then q1–2y. Known orsuspected familial syndrome:genetic counseling & veryearly screening (eg, age 20–25y), then q1–2y.

• ImagingColonoscopy: test of choice as

examines entire colon; 90%Se for lesions >1 cm. Flexsig less Se vs. colo and CTC(Gut 2009;58:241). If polypfound, re ✓ in 3–5 y.Removal of adenomatouspolyps associated with lowerCRC mortality (NEJM2012;366:687).

Sigmoidoscopy: 21% ↓incidence in CRC & 26% ↓mortality in distal CRC(NEJM 2012;366:2345).Benefit may also be seen w/1-time flex-sig (Lancet2010;375:9726).

CT colonography (CTC): c/wcolonoscopy, ~90% Se forlesions ≥1 cm butconsiderably less for smallerlesions (NEJM2008;359:1207). In high-riskPts, Se only 85% foradvanced neoplasia ≥6 mm(JAMA 2009;301:2453). Atpopulation level, ↑

participation w/ CTC, but ↓yield vs. colonoscopy; ∴similar screening overall(Lancet 2012;13:55).

• Biochemical fecal testingOccult blood (FOBT): ↓

mortality (NEJM1993;328:1365 &2000;343:1603); 3 cardhome testing more Se (24%vs. 5%) than DRE/FOBT(Annals 2005;142:81).Repeat q1y.

Immunohisto for Hb: Se~35% & ~80% for advneoplasia & CRC (AJG2012;107:1570)

DNA: ↑ Se, Sp c/w FOBT, butless Se than colonoscopy(NEJM 2004;351:2704)

Staging (AJCC Cancer StagingManual, 7th ed, 2010)• TNM staging: Size/depth of

primary (T), locoregionalnodes (N), distant metastases(M). Staging is complex andbased on pathologiccorrelation with observedsurvival data.

• Colonoscopy +biopsy/polypectomy +intraoperative andpathologic staging essential

for evaluating extracolonicspread

• CT scans of chest andabdomen/pelvis (inaccuratefor depth of invasion &malignant LN)

• Baseline CEA in Pt with knownCRC has prognosticsignificance and is useful tofollow response to therapyand detect recurrence; not ascreening tool

• ChemotherapyFOLFOX (5-FU + leucovorin

+ oxaliplatin), FOLFIRI orCapeOx (NEJM2004;350:2343)

± Bevacizumab (anti-VEGFAmAb, NEJM 2004;350:2335)or cetuximab (anti-EGFRmAb, NEJM 2004:351:337;benefit limited to Pts w/oKRAS mutation; NEJM2008;359:1757)

Regorafenib (multikinaseinhib.) ↑ survival in Pts w/progressive metastatic CRC(Lancet 2013;381:303).

CHEMOTHERAPY SIDE EFFECTS

PANCREATIC TUMORS

Pathology and genetics (AnnuRev Pathol 2008;3:157; Nature2012;491:399)• Histologic types:

adenocarcinoma, acinar cellcarcinoma, endocrine tumors,cystic neoplasms (eg, IPMN,see below); rarely, mets topancreas (eg, lung, breast,renal cell)

• Pancreatic adenocarcinomaaccounts for majority ofpancreatic cancer (~85%)

• Location: ~60% in head, 15% inbody, 5% in tail; in 20%

diffuse infiltration of pancreas• Mutations in adenoca.: KRAS

(>90%), p16 (80–95%), p53(50–75%), SMAD4 (~55%)

Epidemiology and risk factors(Lancet 2011;378:607)• Pancreatic adenocarcinoma 4th

leading cause of cancer deathin U.S. men and women

• 80% of pancreaticadenocarcinomas occur in Pts60–80 y

• Acquired risk factors: smoking(RR ~1.5; 20% Pts), obesity,chronic pancreatitis, ? diabetes

• Hereditary risk factors: genetic

susceptibility may play a rolein 5–10% of casesHereditary chronic

pancreatitis: mutation incationic trypsinogen gene(PRSS1)

Familial cancer syndromes andgene mutations with ↑ risk:familial atypical multiplemole melanoma(CDKN2A/p16), familialbreast and ovarian cancer(BRCA2), Peutz-Jeghers(LKB1), ataxia-telangiectasia(ATM), ? hereditarycolorectal cancer (HNPCCand FAP)

Clinical manifestations• Painless jaundice (w/

pancreatic head mass), painradiating to back, ↓ appetite& wt

• New-onset atypical diabetesmellitus (25%); unexplainedmalabsorption or pancreatitis

• Migratory thrombophlebitis(Trousseau’s sign), not specificto panc cancer (JCO1986;4:509)

• Exam: abd mass; nontender,palpable gallbladder(Courvoisier’s sign, but moreoften seen w/ biliary tractcancers); hepatomegaly;

ascites; left supraclavicular(Virchow’s) node & palpablerectal shelf (both nonspecificsigns of carcinomatosis)

• Laboratory tests may show ↑bilirubin, ↑ alk phos, anemia

Diagnostic and stagingevaluation (NCCN Guidelinesv.2.2012)• Pancreatic protocol CT scan

(I+ w/ arterial & venous phaseimaging) or MRI

• If no lesion seen → EUS, ERCP,MRI/MRCP may reveal massor malignant ductal strictures

• Biopsy pancreatic lesion via EUS-

guided FNA (preferred inpotential surgical candidates)or CT-guided (potential risk ofseeding) or biopsy of possiblemetastasis

• ↑ CA19-9 (nb, also ↑ in benignliver/biliary disease); may beuseful to follow dis. postop

Treatment of pancreaticadenocarcinoma (NEJM

2010;362:1605; Lancet2011;378:607)• Resectable: surgery ± adjuvant

(neoadjuvant orpostoperative) therapypancreaticoduodenectomy =

Whipple procedure =resection of pancreatic head,duodenum, CBD andgallbladder ± partialgastrectomy

adjuvant therapy: ↑ survivalbut choice of regimencontroversial (chemo vs.chemo/RT and gemcitabinevs. 5-FU (J Surg Oncol2013;107:78)

• Locally advanced: optimalstrategy controversial.Gemcitabine alone vs.gemcitabine + RT ( JCO2008;26:214s; Ann Oncol2008;19:1592; JCO2011;29:4105).

• Metastatic: FOLFIRINOX (5-FU+ leucovorin, irinotecan,oxaliplatin) if good perform.status (NEJM 2011;364:1817);gemcitabine combination (eg,w/ nab-paclitaxel; JCO2011;29:4548) ormonotherapy if poorperformance status (JCO1997;15:2403). Offer clinical

trials.• Palliative and supportive care:

obstructive jaundice or gastricoutlet obstruction:endoscopic stenting orsurgical bypass pain:opiates, celiac plexusneurolysis, radiation therapyweight loss: pancreaticenzyme replacement,nutrition consult, end-of-lifediscussions

Cystic lesions of the pancreas(NEJM 2004;351:1218; Oncologist2009;14:125)• <10% of pancreatic neoplasms.

Dx w/ CT, ERCP, MRCP orEUS.

• Serous cystadenoma: usuallybenign; central scar orhoneycomb appearance onimaging

• Mucinous cystic neoplasm(MCN): predominantly youngfemales; multiloculated tumorsin body or tail w/ ovarian-typestroma and mucin-rich fluid w/↑ CEA levels; precancerous

• Intraductal papillary mucinousneoplasm (IPMN): neoplasmarising in main pancreatic ductor a branch; a/w ductaldilation w/ extrusion of

mucinous material. Uncertainprogression to cancer (? 5–20y). Surgery based on age, size,location, dysplasia.

ONCOLOGIC EMERGENCIES

FEVER AND NEUTROPENIA (FN)

Definition• Fever: single oral temp ≥38.3°C

(101°F) or ≥38°C (100.4°F) for≥1 h

• Neutropenia: ANC <500cells/µL or <1000 cells/µLwith predicted nadir <500cells/µL

Pathophysiology andmicrobiology• Predisposing factors: catheters,

skin breakdown, GI mucositis,obstruction (lymphatics,

biliary tract, GI, urinary tract),immune defect a/wmalignancy

• Most episodes thought to resultfrom seeding of bloodstreamby GI flora

• Neutropenic enterocolitis(typhlitis): RLQ pain,watery/bloody diarrhea, cecalwall thickening

• GNRs (esp. P. aeruginosa) werehistorically most common

• Gram infections have recentlybecome more common (60–70% of identified organisms)

• Fungal superinfection oftenresults from prolonged

neutropenia & antibiotic use• Infection with atypical organisms

and bacterial meningitis is rare

Prevention• Levofloxacin (500 mg qd) ↓

febrile episodes & bacterialinfections in chemo-relatedhigh-risk neutropenic patients;no difference in mortality(NEJM 2005;353:977 & 988)

Diagnostic evaluation• Exam: skin, oropharynx, lung,

perirectal area, surgical &catheter sites; avoid DRE

• Labs: CBC with differential,electrolytes, BUN/Cr, LFTs,

U/A• Micro: blood (peripheral &

through each indwellingcatheter port), urine, & sputumcx; for localizing s/s → ✓ stool(C. difficile, cx), peritonealfluid, CSF (rare source)

• Imaging: CXR; for localizing s/s→ CNS, sinus, chest orabdomen/pelvis imaging

• Caveats: neutropenia →impaired inflammatoryresponse → exam andradiographic findings may besubtle; absence of neutrophilsby Gram stain does not r/oinfection

Risk stratification (factors thatpredict lower risk)• History: age <60 y, no

symptoms, no majorcomorbidities, cancer inremission, solid tumor, no h/ofungal infection or recentantifungal Rx

• Exam: temp <39°C, notachypnea, no hypotension, noΔ MS, no dehydration

• Studies: ANC >100 cells/µL,anticipated duration ofneutropenia <10 d, normalCXR

Initial antibiotic therapy (Clin

Infect Dis 2011;52:e56)• Empiric regimens including drug

w/ antipseudomonalactivity; consider VREcoverage if colonized; OR 3.8for VRE if VRE (BBMT2010;16:1576)

• PO abx may be used in low-riskPts (<10 d neutropenia, nlhep/renal fxn, no N/V/D, noactive infxn, stable exam):cipro + amoxicillin-clavulanate (NEJM1999;341:305)

• IV antibiotics: no clearly superiorregimen; monotherapy or 2-drug regimens can be used

Monotherapy: ceftazidime,cefepime, imipenem ormeropenem

2-drug therapy:aminoglycoside +antipseudomonal β-lactam

PCN-allergic: levofloxacin +aztreonam oraminoglycoside

• Vancomycin added in selectcases (hypotension, indwellingcatheter, severe mucositis,MRSA colonization, h/oquinolone prophylaxis),discontinue when cultures ×48 h

Modification to initial antibioticregimen• Low-risk Pts who become afebrile

w/in 3–5 d can be switched toPO antibiotics

• Empiric antibiotics changed forfever >3–5 d or progressivedisease (eg, add vancomycin)

• Antifungal therapy is added forneutropenic fever >5 dliposomal amphotericin B,

caspofungin, micafungin,anidulafungin, voriconazole,posaconazole all options(NEJM 2002;346:225;2007;356:348)

Duration of therapy• Known source: complete

standard course (eg, 14 d forbacteremia)

• Unknown source: continueantibiotics until afebrile andANC >500 cells/µL

• Less clear when to d/c abx whenPt is afebrile but prolongedneutropenia

Role of hematopoietic growthfactors (NEJM 2013;368:1131)• Granulocyte (G-CSF) and

granulocyte-macrophage (GM-CSF) colony-stimulating factorscan be used as 1° prophylaxis

when expected FN incidence>20% or as 2° prophylaxisafter FN has occurred in aprevious cycle (to maintaindose-intensity for curabletumors). CSFs ↓ rate of FN buthave not been shown toimpact mortality.

• Colony-stimulating factors can beconsidered as adjuvant therapyin high-risk FN Pts

SPINAL CORD COMPRESSION

Clinical manifestations (LancetNeuro 2008;7:459)• Metastases located in vertebral

body extend and causeepidural spinal cordcompression

• Prostate, breast and lungcancers are the most commoncauses, followed by renal cellcarcinoma, NHL and myeloma

• Site of involvement: thoracic(60%), lumbar (25%), cervical(15%)

• Signs and symptoms: pain(>95%, precedes neuro Ds),

weakness, autonomicdysfunction (urinaryretention, ↓ anal sphinctertone), sensory loss

Diagnostic evaluation• Always take back pain in Pts

with solid tumors veryseriously

• Do not wait for neurologic signsto develop before initiatingevaluation b/c duration &severity of neurologicdysfunction before Rx are bestpredictors of neurologicoutcome

• Urgent whole-spine MRI (Se

93%, Sp 97%); CT myelogramif unable to get MRI

Treatment• Dexamethasone (10 mg IV × 1

stat, then 4 mg IV or PO q6h)initiate immediately while

awaiting imaging if backpain + neurologic deficits

• Emergent RT or surgicaldecompression if confirmedcompression/neuro deficits

• Surgery + RT superior to RTalone for neuro recovery insolid tumors (Lancet2005;366:643)

• If pathologic fracture causing

compression → surgery; if notsurgical candidate → RT

TUMOR LYSIS SYNDROME

Clinical manifestations (NEJM2011;364:1844; BJH 2010;149:578)• Large tumor burden or a rapidly

proliferating tumor →spontaneous or chemotherapy-induced release of intracellularelectrolytes and nucleic acids

• Most common w/ Rx of high-grade lymphomas (Burkitt’s)and leukemias (ALL, AML,CML in blast crisis); rare withsolid tumors; rarely due tospontaneous necrosis

• Electrolyte abnormalities: ↑ K, ↑uric acid, ↑ PO4 → ↓ Ca

• Renal failure (uratenephropathy)

Prophylaxis• Allopurinol 300 mg qd to bid PO

or 200–400 mg/m2 IV(adjusted for renal fxn) &aggressive hydration prior tobeginning chemotherapy or RT

• Rasburicase (recombinant urateoxidase) 0.15 mg/kg or 6 mgfixed dose (except in obese Pts)& aggressive hydration prior tobeginning chemotherapy or RT(see below)

Treatment• Avoid IV contrast and NSAIDs

• Allopurinol + aggressive IVhydration ± diuretics to ↑UOP

• Consider alkalinization of urinew/ isotonic NaHCO3 to ↑ UAsolubility & ↓ risk of uratenephropathy (controversial:may cause metabolic alkalosisor Ca3(PO4)2 precipitation)

• Rasburicase (0.1–0.2 mg/kg × 1,repeat as indicated) for ↑↑ UA,esp. in aggressive malig; UAlevel must be drawn on ice toquench ex vivo enzyme activity(JCO 2003;21:4402; ActaHaematol 2006;115:35). Avoid

in G6PD deficiency as resultsin hemolytic anemia.

• Treat hyperkalemia,hyperphosphatemia andsymptomatic hypocalcemia

• Hemodialysis may be necessary;early renal consultation for Ptsw/ renal insuffic. or ARF

CANCER OF UNKNOWNPRIMARY SITE

• Bony mets: common primarytumors include breast, lung,thyroid, kidney, prostate

PNEUMONIA

Clinical manifestations• “Typical”: acute onset of fever,

cough w/ purulent sputum,dyspnea, consolidation on CXR

• “Atypical” (originally describedas cx ): insidious onset of drycough, extrapulm sx (N/V,diarrhea, headache, myalgias,sore throat), patchy interstitialpattern on CXR

• S/s & imaging do not reliablydistinguish between “typical”(S. pneumo, H. flu) and“atypical” (Mycoplasma,Chlamydia, Legionella, viral); ↑aminotransferases & ↓ Na w/Legionella

Diagnostic studies• Sputum Gram stain: utility

debated. Good sample (ie,

sputum not spit) has <10squamous cells/lpf. Purulentsample has >25 PMNs/lpf.

• Sputum bacterial culture:transport to lab w/in 1–2 h ofcollection

• Blood cultures (beforeantibiotics!): in ~10% ofinPts, depending on pathogen

• CXR (PA & lateral; see Radiologyinserts) → tap effusions if >5cm or severe PNA

• Other: SaO2 or PaO2, arterial pH(if severe), CBC w/ diff, Chem-20; HIV test (if unknown)

• Other micro based on clinical

suspicion (paired serologiesavailable for most atypicals):Mycoplasma: PCR of throat or

sputum/BAL before first doseabx

Legionella urinary Ag (detectsL. pneumophila L1 serotype,60–70% of clinical disease)

S. pneumoniae urinary Ag (Se50–80%, Sp >90%)

MTb: induced sputum for AFBstain and mycobacterial cx(empiric respiratory isolationwhile pending); avoidquinolones if suspect TB;request rapid DNA probe ifstain

Induced sputum for PCP if HIV or known ↓ cell-mediated

immunity• Viral testing (DFA or PCR) on

nasopharyngeal swab orsputum; rarely viral cx

• Bronchoscopy: consider ifimmunosupp., critically ill,failing to respond, or chronicpneumonia. Also if suspectedTB or PCP, but inadequate or

sputum cx. Some pathogensneed specific cx (eg, Legionellaon BCYE); collaborate withlab.

• Reasons for failure to improve oninitial Rx:

Insufficient time: may take≥72 h to see clinicalimprovementInsufficient drug levels: eg,

vanco trough <15–20µg/mL (needed for lungpenetration)

Resistant organisms (orsuperinfxn): eg, MRSA,Pseudomonas; considerbronchoscopy

Wrong dx: fungal/viral,chemical pneumonitis, PE,CHF, ARDS, DAH, ILD;consider CT

Parapneumoniceffusion/empyema/abscess:

esp. seen w/ strep; if CXR ,consider CT (dx tap ± chesttube if effusion present, esp.if loculated)

Metastatic infection (eg,endocarditis, meningitis,arthritis)

Prognosis• Pneumonia and influenza are the

8th leading cause of death inthe U.S.

• For low-risk Pts, can dischargeimmediately after switching toPO abx (CID 2007;44:S27)

• CXR resolves in most by 6 wk;consider f/u to r/o underlying

malignancy (esp. if age >50 yor smoker, Archives2011;171:1192) or other dx

• Severe CAP (generally requiringICU) defined as: septic shock,resp failure, or ≥3 of: RR≥30, PaO2/FiO2 ≤250, <36°C,HoTN, DMS, multilobar, WBC<4k, plt <100, BUN ≥19.9,metabolic acidosis, ↑ lactate(ATS/IDSA criteria, CID2007;44:S27)

• SMART-COP risk score: SBP <90(2 points), Multilobarinfiltrates, Alb <3.5 g/dL, RR≥30, Tachycardia (HR >125),Confusion, O2 sat <90% (2

points), arterial pH <7.35 (2points) score ≥3 points has Se~60–90% & Sp 45–75% forneed for ICU care (CID2008;47:375)

Prevention• Pneumococcal vaccine (PPSV23):

all persons >65 y of age. Ifhigh-risk comorbidity, give atyounger age and consideradditional vaccination withPCV13.

• VAP precautions: HOB >30°,chlorhexidine rinse; aspirationprecautions in high-risk Pts

• Tdap booster: 1 time dose inadults with uncertainvaccination history (MMWR2012; 61:468)

VIRAL RESPIRATORYINFECTIONS

URI, bronchitis, bronchiolitis,pneumonia (Lancet 2011;377:1264)

Microbiology & epidemiology• Typical pathogens: short, mild =

rhinovirus, coronavirus;longer, more severe orcomplicated = influenza,parainfluenza, respiratorysyncytial virus (RSV),adenovirus, metapneumovirus.Can be esp. severe inimmunosupp.

• Seasonal flu: 365,000 hosp,51,000 deaths per y in U.S.;

most >65 y (NEJM2008;359:2579)

• Pandemic 2009 H1N1 (swine):more severe in younger andobese Pts (JAMA2009;302:1896)

• Sporadic 2011 H3N2: adultsexposed to swine (also human-to-human) (MMWR2011;60:1615)

• H5N1 influenza (avian): ongoingsmall outbreaks globally.

• For weekly influenza updates:http://www.cdc.gov/flu/weekly

Diagnosis• Primarily clinical: cough, fever,

http://www.cdc.gov/flu/weekly

myalgias, arthralgias,rhinorrhea, pharyngitis (incontrast, viral bronchitis p/wcough ± low-grade temp;usually benign & self-limited)

• Respiratory viral panel on nasalwashing or sputum/BAL

• Rapid influenza test on nasalswab: Se ~50–70% (? lowerfor pandemic flu), Sp >95%

• DFA (Se ∼85%), RT-PCR (goldstandard) avail. for influenza(PCR distinguishes type)

Treatment (NEJM2008;359:2579)• Seasonal influenza: treat with

neuraminidase inhib.(oseltamivir, zanamivir),which are effective vs. A & B,but resistance emerging. M2inhib. (amantadine,rimantadine) notrecommended due towidespread resistance (MMWR2011;60:1).

• Pandemic H1N1: nearly 100%sens. to oseltamivir. H5N1:Uncertain resistance pattern.H7N9: newly emerging in Asia

(NEJM 2013;368:1888)• Oseltamivir dosed 75 mg PO bid

× 5 d. Must start w/in 48h ofsx for low-risk; for critically ill

or immunosupp., start ASAPeven if >48 h.

• Consider inhaled ribavirin forRSV in immunosupp. (eg,BMT, lung tx); limited adultdata

Prevention• Inactivated influenza vaccine:

incl. H1N1. Rec for all >6 moof age and esp. if pregnant,>50 y, immunosupp., or HCW(MMWR 2012;61:613)

• Isolation, droplet precautions forinPts strongly recommended

• Prophylaxis for high-risk contactsof confirmed influenza:

oseltamivir 75 mg PO daily ×10 d

FUNGAL INFECTIONS

Candida species• Microbiology: normal GI flora;

C. albicans & nonalbicans spp.(consider azole resistance ifh/o Rx or nonalbicans; C.parapsilosis ↑ echinocandinresistant). Sensi testingavailable.

• Risk factors: neutropenia,immunosupp., broad-spectrumabx, intravascular catheters(esp. if TPN), IVDU, abdsurgery, DM, renal failure, age>65

• Clinical manifestations

Mucocutaneous: cutaneous (eg,red, macerated lesions inintertriginous zones); oralthrush (exudative,erythematous or atrophic; ifunexplained, r/o HIV);esophageal (odynophagia;± oral thrush);vulvovaginal, balanitis

Candiduria: typicallycolonization due to broad-spectrum abx and/orindwelling catheter

Candidemia (#4 cause ofhealth care assoc.bloodstream infxn): r/oretinal involvement (req ↑

Rx); endocarditis rare butserious (esp. w/ nonalbicans& prosthetic valve)

Hepatosplenic: intestinalseeding of portal & venouscirculation; esp. in acuteleukemia

Hematogenous dissemination:lung, brain, meninges, etc.

Cryptococcus (CID 2010;50:291)

• Epidemiology: immunosupp.(esp. AIDS) most susceptible;can occur in healthy host, esp.elderly, EtOH, DM. If fromPacific NW, consider C. gatti (↑mortality in healthy host).

• Clinical manifestationsCNS (meningitis): HA, fever,

meningismus, ↑ ICP, CNabnl, ± stupor, oftensubacute. Dx: CSF CrAg,India ink stain, fungal cx.Cell counts vary; serum CrAg>1:8 Se/Sp in AIDS.

Other sites: pulm, GU,cutaneous, CNScryptococcoma. With any

crypto dx, LP all Pts.• Treatment

CNS: If ↑ ICP, repeat large-volume LPs or temp. lumbardrain; few require VP shunt

In HIV or immunosupp.Pts, CNS Rx hasinduction (ampho ±flucytosine),consolidation andmaintenance(fluconazole) phases(NEJM 2013;368:1291).If r/o CNS disease, thenfluconazole. Dosing andduration vary by host.

Non-CNS disease in healthy

Pts: fluconazole vs.observation, based onclinical setting

Histoplasmosis (CID2007;45;807)• Endemic: central & SE U.S. (esp.

in areas w/ bird & batdroppings), river bankselsewhere

• Clinical manifestationsAcute: often subclinical, but

may see mild to severe PNA± cavitary & hilar LAN

Chronic pulm: ↑ productivecough, wt loss, night sweats,apical infiltrates, cavitation

Disseminated (typically inimmunosupp.): fever, wtloss, HSM, LAN, oral ulcers,skin lesion, fibrosingmediastinitis, reactivearthritis, pericarditis

• Treatment: itraconazole(monitor levels); ampho ±steroids if severe orimmunosupp.

Coccidioidomycosis (CID2005;41:1217)• Endemic: SW U.S. (San Joaquin

or “Valley” fever)• Clinical manifestations

Acute: 50–67% subclinical;

PNA w/ cough, chest pain,fever, arthralgias, fatigue

Chronic pulm: nodule(s),cavity or progressivefibrocavitary PNA (can beasx or sx)

Disseminated (typically inimmunosupp.): fever,malaise, diffuse pulmonaryprocess, bone, skin, &meningeal involvement

• Treatment: monitor mild diseaseclosely q3–6mo; for severedisease: fluconazole,itraconazole or amphotericin

Blastomycosis (CID

2008;46:1801)• Endemic: south central, SE and

midwest U.S.• Clinical manifestations

Acute: 50% subclinical; cough,multilobar PNA; canprogress to ARDS

Chronic pulm: cough, wt loss,malaise, CT w/ masses &fibronodular infiltrates

Disseminated: (25–40% of allbut >> in immunosupp.):verrucous & ulcerated skinlesions, bone, & GUinvolvement; CNS rareunless immunosupp.

• Treatment: itraconazole

(monitor levels); ampho B ifsevere, disseminated orimmunosupp.

Aspergillosis (CID 2008;46:327;NEJM 2009;360:1870)• ABPA; hypersensitivity

pneumonitis: see “InterstitialLung Disease”

• Aspergilloma: usually in pre-existing cavity (from TB, etc.);most asx, but can lead tohemoptysis; sputum cx in<50%; CT → mobileintracavitary mass with aircrescentRx: antifungals w/o benefit;

embolization or surgery forpersistent hemoptysis

• Necrotizing tracheitis: whitenecrotic pseudomembranes inPts w/ AIDS or lung Tx

• Chronic necrotizing: seen inCOPD, mild immunosupp.;subacute sputum, fever, wtloss; CT: infiltrate ± nodule ±thick pleura; lung bx →invasion

• Invasive/disseminated: seen ifimmunosupp. (neutropenia,s/p transplant, steroid Rx,AIDS esp. w/ steroids orneutropenia); s/s PNA w/ chestpain & hemoptysis; CT: nodules,

halo sign, air crescent sign;BAL + galactomannan; lungbx if dx inconclusive

• Rx (necrotizing/invasive):voriconazole PO preferred toampho; monitor serum levels

Zygomycetes (eg, Mucor,Rhizopus)• Epidemiology: diabetes

mellitus (70%), hememalignancy, s/p transplant,chronic steroids, deferoxamineor iron overload, trauma, h/ovoriconazole Rx or Ppx

• Clinical manifestations:rhinocerebral =

periorbital/forehead pain(more extensive than orbitalcellulitis), ± fever (mayappear nontoxic at first),exophthalmos, ↓ EOM, CNs (V> VII); nasal turbinates ±black eschar but exam can bequite nl. Also, pulmonary(PNA w/ infarct & necrosis);cutaneous (indurated painfulcellulitis ± eschar); GI(necrotic ulcers).

• Treatment: Serial debridement+ ampho (? + posaconazole).High mortality despite Rx.

Fungal diagnostics

• Culture: Candida grows inblood/urine Cx, but ↓ Se ofBCx if deep tissue infection;others (eg, Crypto, Histo) ↓↓ Seof BCx; if suspect Coccidio alertlab (biohazard)

• Antibody detection: Histo,Blasto, Coccidio, Aspergillus. Sevariable (best for Coccidio).

• Antigen detectionHisto urine/serum Ag: Se of

urine Ag 90% (serum 80%)if dissem; Sp limited by X-react

Crypto Ag (serum, CSF):serum Ag >90% Se & Sp ininvasive infxn, less for pulm

only1,3-b-D-glucan: Se for many

fungal infxns (Candida,Aspergillus, Histo, Coccidio,Fusarium, Pneumocystis,Sporothrix; but not Crypto,Blasto, Mucor, Rhizopus); notSp

Galactomannan: morespecific for Aspergillus, but Se<50%. ↑ Se on BAL.

• Biopsy (ie, histopathology): nb,no grinding of tissue ifZygomycetes suspected

INFXNS INIMMUNOSUPPRESSED HOSTS

Overview• Many immunophenotypes, meds

or systemic diseases predisposeto infection

• Many Pts have ≥1 risk (eg, DM,ESRD, transplant, extremes ofage); duration of risk varies

• The following is not anexhaustive list, but adelineation of common orclassic etiologies

URINARY TRACT INFECTIONS

Definitions• Anatomic

lower: urethritis, cystitis(superficial infection ofbladder)

upper: pyelonephritis (inflamof renal parenchyma),renal/perinephric abscess,prostatitis

• Clinicaluncomplicated: cystitis in

immunocompetentnonpregnant women w/ounderlying structural orneurologic disease

complicated: upper tractinfection in women or anyUTI in men or pregnantwomen or UTI withunderlying structural diseaseor immunosuppression

Microbiology• Uncomplicated UTI: E. coli

(80%), Proteus, Klebsiella, S.saprophyticus (CID 2004;39:75).In healthy, nonpregnantwomen, lactobacilli,enterococci, Group B strep andcoag-neg staph (except S.saprophyticus) usuallycontaminants (Annals2012;156:ITC3).

• Complicated UTI: E. coli (30%),enterococci (20%), PsA (20%),S. epi (15%), other GNR

• Catheter-associated UTI: yeast(30%), E. coli (25%), otherGNR, enterococci, S. epi

• Urethritis: Chlamydia trachomatis,Neisseria gonorrhoeae,Ureaplasma urealyticum,Trichomonas vaginalis,Mycoplasma genitalium, HSV

• S. aureus: uncommon primaryurinary pathogen in absence ofcatheter or recentinstrumentation; ∴ considerbacteremia w/ hematogenousseeding

Clinical manifestations• Cystitis: dysuria, urgency,

frequency, hematuria, Δ inurine color/odor, suprapubicpain; fever usually absent. R/ovaginitis with symptoms ofcystitis and urethritis.

• Urethritis: similar to cystitisexcept urethral discharge can bepresent

• Prostatitischronic: similar to cystitis

except symptoms ofobstruction (hesitancy, weakstream)

acute: perineal pain, fever,tenderness on prostate exam

• Pyelonephritis: fever, chills,flank or back pain, nausea,vomiting, diarrhea

• Renal abscess (intrarenal,perinephric): identical topyelonephritis w/ persistentfever despite appropriateantibiotics

Diagnostic studies• Urinalysis: pyuria +

bacteriuria ± hematuria ±nitrites

• Urine Cx (from clean-catchmidstream or straight-cathspecimen): obtain cx only if sxSignificant bacterial counts:

typically ≥105 CFU/mL inwomen, ≥103 CFU/mL inmen or catheterized Pts.Counts may vary dependingon dilution & stage of infxn;interpret in context ofsymptoms and host.

Pyuria & UCx = sterilepyuria → urethritis,nephritis, renal tuberculosis,foreign body

• Blood cultures: obtain in febrilePts; consider in complicatedUTIs

• DNA detection/cx for C.trachomatis/N. gonorrhoeae inhigh-risk Pts or sterile pyuria

• If ? prostatitis: 1st void,midstream, prostaticexpressage & postprostaticmassage UCx

• Abdominal CT: r/o abscess in Ptswith pyelo who fail todefervesce after 72 h

• Urologic w/u (renal U/S w/ PVR,abd CT, voiding cystography)if recurrent UTIs in men

SOFT TISSUE AND BONEINFECTIONS

CELLULITISInfection of superficial and deep

dermis and subcutaneous fat

Microbiology & clinical (NEJM2004;350:904; CID 2005;41:1373)• Primarily strep and staph,

including MRSA; may includeGNRs indiabetics/immunosupp.

• Community-acquired MRSA(CA-MRSA) (NEJM2005;352:1485 &2006;355:666)

Up to 75% of purulentskin/soft tissue infxns,depending on local epi(rapidly increasing)

Clinically indistinguishablefrom MSSA, often assoc. w/purulent drainage orexudate

High-risk groups: athletes,military, prison, MSM,communities w/ highprevalence

Often TMP-SMX sensitive;variably clindamycinsensitive (may falselyappear susceptible on labtesting, requires

confirmation w/ D-test;NEJM 2007;357:380)

• Erythema, edema, warmth, pain(rubor, tumor, calor, dolor)

• Lymphangitis (proximal redstreaking) and regionallymphadenopathy

• Toxic shock syndrome canoccur w/ staph or strep infxn.Fever, HA, N/V, diarrhea,myalgias, pharyngitis, diffuserash w/ desquamation, HoTN,shock. BCx may be .

• Bites: skin and oral flora (inclanaerobes) + specialexposures:

Diagnosis• Largely clinical diagnosis; BCx

low yield (Se <5% in simplecellulitis) but useful if

• Aspirate of bulla or pus fromfuruncle or pustule mayprovide microbiologic dx

Treatment

• Limb elevation; erythema mayworsen after starting abx b/cbacterial killing → inflam.

• I&D if abscess is present inaddition to cellulitis

• Worse outcomes if vasc. insuff.,edema, immunosupp., resistantorgs. or deeper infxn

• In obese Pts, adequate drugdosing important to avoidtreatment failure (J Infect2012;2:128)

OTHER CUTANEOUS INFECTIONS

“DIABETIC FOOT” = INFECTEDNEUROPATHIC FOOT ULCER

Leading cause of DM-related hosp.days & nontrauma amputations

Microbiology• Mild (superficial, no bone or

joint involvement): usually S.aureus or aerobic streptococci

• Limb- or life-threatening =deep, bone/joint involvement,systemic tox., limb ischemia

• Mono- or polymicrobial withaerobes + anaerobesaerobes = S. aureus, strep,

enterococci and GNR(including Pseudomonas)

anaerobes = anaerobicstreptococci, Bacteroides,Clostridium (rare)

Clinical manifestations• Clinical dx: ≥2 classic s/s of

inflammation (erythema,warmth, tenderness [may beabsent in neuropathy], pain orinduration) or purulentsecretions ± crepitus(indicating gas and ∴ mixedinfection w/ GNR & anaerobesor Clostridium)

• Complications: osteomyelitis,systemic toxicity (fever, chills,leukocytosis, hyperglycemia)

Diagnostic studies• Avoid superficial swabs (only

helpful if for S. aureus andsuspect infxn); wound cx (eg,deep tissue sample orcurettage at ulcer base afterdébridement) has ↑ Se

• Blood cx should be obtained in allPts, in 10–15%

• Osteomyelitis should alwaysbe ruled out: probe to bonetest for all open wounds in adiabetic foot (high Sp but lowSe); imaging (see below);bone biopsy best

Treatment (CID 2012;54:e132)

• Elevation, non–weight-bearingstatus, wound care, glycemiccontrol, antibiotics

• Evaluation and treatment forvenous insufficiency andarterial ischemia

• Many require surgery: early,aggressive and repeateddébridement; revascularizationor amputation may benecessary

• Management bymultidisciplinary teamimproves outcomes (Circulation2006;113:e463)

NECROTIZING FASCIITIS

Definition• Infection and necrosis of

superficial fascia,subcutaneous fat and deepfascia (necrosis of arteries andnerves in subcutaneous fat →gangrene)

• Fournier’s gangrene: necrotizingfasciitis of the male genitaliaor female perineum

Epidemiology• Affects healthy individuals but ↑

risk: DM, PVD, EtOH abuse,IDU, immunosupp., cirrhosis

Microbiology

• Type I (after abd/perinealsurgery or trauma; in DM,PVD): polymicrobial (w/anaerobes)

• Type II (usually extremities):Strep pyogenes ± CA-MRSA,often healthy w/o obviousportal of entry; up to 1/2 havetoxic shock syndrome (TSS)

Clinical manifestations• Need high degree of clinical

suspicion because ofnonspecific physical exam

• Most common sites: extremities,abdominal wall and perineum,but can occur anywhere

• Cellulitic skin Ds with poorlydefined margins + rapidspread + systemic toxicity

• Pain out of proportion toapparent cellulitis; skinhyperesthetic and lateranesthetic

• Bullae, darkening of skin tobluish-gray ± crepitus orradiographically visible gas

Diagnostic signs• Clinical dx sufficient to initiate

urgent surgical exploration• Aspiration of necrotic center;

BCx; Gram stain; ✓ CK fortissue necrosis

• Imaging: non-contrast CT, butdo not delay therapy (ArchSurg 2010;145:452)

• Microbiologic dx from Gram stainand culture of surgicalspecimens

Treatment• Definitive treatment is surgical

débridement of necrotic tissueand fasciotomy

• Type I: breadth of GNR coveragedetermined by host, prev hosp,prev Rx and initialGram stain; eg, carbapenem or

(3rd-gen ceph + amp +[clinda or metronidazole])

• Type II: PCN + clinda. If ↑ riskof CA-MRSA, + vanco. Ifconcern for strep, IVIG.

Prognosis• Generally fatal if untreated;

reported mortality 20–50%

CLOSTRIDIAL MYONECROSIS(GAS GANGRENE)

Definition• Life-threatening, fulminant

clostridial infection of skeletalmuscle

• Wound contamination w/clostridial spores after trauma(penetrating or crush injury)

• Most commonly C. perfringens; C.septicum assoc w/ cancer (GI,heme), even w/o trauma

Clinical manifestations• Incubation period 6 h to 2–3 d• Sense of heaviness/pain, often at

site of trauma; rapid

worsening; marked systemictoxicity

• Bronze skin discoloration, tensebullae, serosanguineous ordark fluid and necrotic areas

• Crepitus present but notprominent (gas is in muscle),may be obscured by edema

Diagnostic studies• Gram stain: lg, Gram bacilli

w/ blunt ends (can be Gram-variable), few polys

• Bacteremia in ~15%• Plain radiographs: gas dissecting

into muscle

Treatment

• Surgical exploration withdébridement, fasciotomiesand amputation if necessary

• Antibiotics: high-dose penicillinG 24 MU IV divided q2–3h +clinda 900 mg IV q8h

OSTEOMYELITISInfection of bone due to

hematogenous seeding or directspread from contiguous focus

Microbiology (NEJM1997;336:999; Lancet2004;364:369)• Hematogenous: S. aureus;

mycobacterial infection ofvertebral body = Pott’sdisease

• Contiguous focus (may be acuteor chronic)open fracture, orthopedic

surgery, etc.: S. aureus andS. epi

skin breakdown + vasc.insuffic. (eg, diabetic foot):polymicrobial (aerobic +anaerobic GPC & GNR)

Clinical manifestations• Surrounding soft-tissue

compromise ± fistula tosuperficial skin

• ± Fever, malaise and nightsweats (more common inhematogenous thancontiguous)

• Vertebral osteomyelitis (seen inPts >50 y): unremitting, focalback pain, usually fever (NEJM2010;362:1022)

Diagnostic studies (JAMA2008;299:806)• Identification of the causative

organism is key• Culture from tissue (surgical

sampling/needle bx), notswabs of ulcers or fistulaedrainage

• High suspicion in diabetic foot(see above) if can probe ulcerto bone or ulcer >2 cm2

• Blood cultures (more often with acute hematogenousosteomyelitis)

• ESR >70 greatly increaseslikelihood of osteo (JAMA2008;299:806)

• ImagingPlain radiographs: normal

early in disease; lytic lesionsseen after 2–6 wk

MRI: can detect very earlychanges (overall Se 90%, Sp82%; Archives 2007;167:125)

CT: can demonstrate periostealreaction and cortical andmedullary destruction

CT & MRI very Se but ↓ Sp;false if contig focus w/periosteal reaction, CharcotDs

Radionuclide imaging: very Sebut non-Sp (false if softtissue inflammation)

Treatment• Antibiotics (based on cx data)

× 4–8 wk• Surgery should be considered for

any of the following: acuteosteo that fails to respond tomedical Rx, chronic osteo,complications of pyogenicvertebral osteo (eg, early signsof cord compression, spinalinstability, epidural abscess) orinfected prosthesis

EPIDURAL ABSCESS

Etiology• Hematogenous spread (2/3): skin

infection, soft tissue (dentalabscess) or endocarditis

• Direct extension (1/3): vertebralosteo, sacral ulcer, spinalanesthesia or surgery, LP

• Risk factors: diabetes, renalfailure, alcoholism, IVDU,immunosupp.

• S. aureus most commonpathogen, increasing incidenceof MRSA


• Back pain (unremittingincluding midline) + oftenfever ± nerve root or cordsigns

Diagnostic studies• MRI• Aspiration of abscess fluid for

Gram stain & cx or operativeGram stain & cx

• Blood cx (frequently )

Treatment• Antibiotics ± surgery

(decompressive laminectomyand débridement) for failure toimprove on medical Rx orearly s/s of cord compression

(w/ vertebral osteo andepidural abscess, may seeparaplegia 48–72 h after firstsigns)

INFECTIONS OF THE NERVOUSSYSTEM

ACUTE BACTERIAL MENINGITIS

Definition• Bacterial infection of the

subarachnoid space

Clinical manifestations (NEJM2006;354:44; Lancet2012;380:1684)• Fever (77%), headache (87%),

stiff neck (31%),

photosensitivity, Δ MS (69%)(defined as GCS <14),seizures (5%); 2 of 4 (fever,HA, stiff neck, Δ MS) presentin 95%

• Presentation may be atypical (eg,lethargy w/o fever) in elderlyand immunosupp.

Physical exam• Nuchal rigidity (Se 31%),

Kernig’s sign (Pt supine, hipflexed at 90°, knee flexed at90°; if passive extension ofknee results in resistance),Brudzinski’s sign (Pt supineand limbs supine; if passive

neck flexion → involuntary hipand/or knee flexion)nb, Kernig’s or Brudzinski’s

signs in only ~10% of Pts(Lancet 2012;380:1684)

• ± Focal neuro findings (~30%;hemiparesis, aphasia, visualfield cuts, CN palsies)

• ± Funduscopic findings:papilledema, absent venouspulsations

• ± Rash: maculopapular,petechial or purpuric

Diagnostic studies (Lancet2012;380:1684)• Blood cultures ¥ 2 before abx

• WBC count: >10,000 in >90%of bacterial meningitis inhealthy hosts

• Consider head CT to r/o masseffect before LP if presence ofhigh-risk feature (age>60 y, immunosupp., h/o CNS

disease, new-onset seizure, ΔMS, focal neuro

findings, papilledema);absence of all these has NPV97%; however, in Pts w/mass effect, herniation mayoccur w/o LP and may notoccur even w/ LP (NEJM2001;345:1727)

• Lumbar puncture (NEJM

2006;355:e12)CSF Gram stain has 30–90%

Se; cx 80–90% Se if LP doneprior to abx role of CSF PCRfor common bacterial causes(? ~90% Se if w/in 2 h) tobe defined repeat LP only ifno clinical response after 48h of appropriate abx or CSFshunt

Opening pressure typically ↑in bact meningitis; mustmeasure w/ Pt’s legsextended

Rule of 2s: CSF WBC >2k, glc<20, & TP >200 has >98%Sp for bacterial meningitis

Recurrent meningitis• Bacterial: consider CSF leak,

dermal sinus or othercongenital/acquired anatomicdefects

• Viral: HSV-2 (causes majority ofMollaret’s meningitis)

• Aseptic (see below): leak fromcyst/tumor/lesion withdermoid/epidermoid elements,autoimmune (eg, SLE,Behçet’s), medications

• Additional CSF studies based onclinical suspicion: AFB smear &cx, India ink prep,cryptococcal Ag, fungal cx,VDRL, PCR (eg, of HSV, VZV,enteroviral), cytology

Prognosis• For community-acquired S.

pneumo mort. 19–37%; 30%have long-term neuro sequelae

ASEPTIC MENINGITIS

Definition• Negative bacterial micro data,

CSF pleocytosis with appropriate blood & CSFcultures (aseptic meningitiscan be neutrophilic, thoughless common)

• Aseptic = less likely to bebacterial, but can be infectiousor noninfectious

Etiologies (Neurology2006;66:75)• Viral: enteroviruses (most

common), HIV, HSV (type 2 >1), VZV, mumps, lymphocytic

choriomeningitis virus,encephalitis viruses,adenovirus, polio, CMV, EBV

• Parameningeal focus ofinfection (eg, brain abscess,epidural abscess, septicthrombophlebitis of duralvenous sinuses or subduralempyema)

•Partially treated bacterialmeningitis

• TB, fungal, spirochetal (Lyme,syphilis, leptospirosis),rickettsial, Coxiella, Ehrlichia

• Medications: TMP/SMX,NSAIDs, IV Ig andantilymphocyte Ig, PCN, INH,

lamotrigine• Systemic illness: SLE,

sarcoidosis, Behçet’s, Sjögren’ssyndrome, RA

• Neoplasm: intracranial tumors(or cysts), lymphomatous orcarcinomatous meningitis (CSFcytology or flow may bereactive and dx may requiremeningeal bx)

Empiric treatment• No abx if suspect viral (cell count

<500 w/ >50% lymphs, TP<80–100 mg/dL, normal glc,

Gram stain, notelderly/immunosupp.); o/w

start empiric abx, wait for cxdata

• If suspect MTb:antimycobacterial Rx +dexamethasone (NEJM2004;351:1741)

• If suspect fungal: ampho lipidformulation, ± 5-fluorouracil

ENCEPHALITIS

Definition• Infection of brain parenchyma

with evidence of neurologicdysfunction

Etiologies (specific etiology foundin <20% of cases; Neurology2006;66:75; CID 2008;47:303)• HSV-1 (~9%): all ages/seasons;

MRI: temporal lobelesions/edema; EEG: temporalfocus

• VZV (~9%): 1° or reactivation;± vesicular rash; all ages(favors elderly), all seasons

• Arboviruses (~9%):

Eastern/Western equine, St.Louis, Japanese, Powassan, W.Nile (NEJM 2005;353:287):mosquito vector, birdreservoir; fever, HA, flaccidparalysis, rash. Risk factorsfor severe dis: renal dis.,cancer, EtOH, DM, HTN (Am JTrop Med Hyg 2012;87:179).

• Enteroviruses (coxsackie, echo):viral syndrome; peaks in latesummer/early fall

• Others: CMV, EBV, HIV, JC virus(PML), measles, mumps,rubella, rabies, flu, adenovirus

• Nonviral mimics: bacterialendocarditis, brain abscess,

toxoplasmosis, TB, toxins, vas-culitis, hematologicmalignancies, Whipple’sdisease, subdural hematoma,encephalomyelitis (eg, ADEM),paraneoplastic syndromes,seizure, mitochondrialdisorders, autoimmune anti N-methyl-D-aspartate receptor(esp. if <30 y, CID2012;54:899)

Clinical manifestations• Fever, HA, Δ MS, ± seizures and

focal neuro findings (latteratypical for viral meningitis)

Diagnostic studies (etiologic dx

made in only about 25% of cases)• Vaccine hx, dilated retinal exam,

ELISA or DFA nasal/respswabs for viruses, serologies

• Lumbar puncture: lymphocyticpleocytosis; PCR for HSV (95%Se & Sp at 2–3 d), VZV, CMV,EBV, HIV, JC,adeno/enterovirus, W. Nile(<60% Se); W. Nile CSF IgM80% Se

• MRI (CT if MRI unavailable); W.Nile w/ thalamichyperintensity

• EEG to r/o seizure; findings inencephalitis are nonspecific

Treatment• HSV, VZV: acyclovir 10 mg/kg IV

q8h (often empiric Rx givenfrequency of HSV/VZV)

• CMV: ganciclovir ± foscarnet;supportive care for most otheretiologies

BELL’S PALSY

Definition & etiology• Acute idiopathic unilat. facial

nerve palsy (CN VII), oftenpresumed HSV-1 reactivation

Clinical manifestations• Unilateral facial muscle

weakness, hyperacusis, ↓taste/lacrimation/salivation

Diagnosis• Dx of exclusion: r/o brainstem

lesion, Lyme, zoster (incl sineherpete), HIV/AIDS, sarcoid

Treatment (NEJM2007;357:1598; JAMA

2009;302:985)• ~80% recover spontaneously by

9 mo (much lower rate in DM)• Corticosteroids (prednisolone 25

mg PO bid × 10 d) startedw/in 72 h of sx onset improveodds of recovery (note: noconclusive data for use in DM,immunosupp.)

• No conclusive data to support theuse of acyclovir orvalacyclovir, though oftenprescribed

ZOSTER

Definition & etiology• Zoster = herpes zoster =

shingles: acute, unilat.,painful dermatomal skineruption

• VZV reactivation in peripheralnerve distribution from latencyin dorsal root ganglion

Clinical manifestations• Neuritic pain in a dermatomal

distribution, then acutedermatomal eruption ofclustered rash (vesicles >papules/pustules > macules)in varying stages of evolution

• Consecutive dermatomes may beseen in all Pts; morewidespread in immunosupp.

• Lesions in V1 distribution offacial nerve require urgentophthalmologic evaluation

• Post-herpetic neuralgia (PHN) =severe pain lasting >90 dafter episode; may last mos toy, more frequent w/ ↑ age anddelay of antiviral Rx

Diagnosis• Appearance of rash; DFA is most

Se from scrape of newlyunroofed vesicle. Tzanck doesnot distinguish HSV or VZV, cx

insensitive for VZV (unlikeHSV).

Treatment• Rx if can initiate w/in 72 h of

skin lesions in healthy Pt orat any time in immunosupp.

• Valacyclovir or famciclovir × 7–14 d, or until lesions fullycrusted; acyclovir 10 mg/kg IVq8h if dissem. or high-risk Pt(medically ill, immunosupp.,V1 zoster w/ ophthalmic s/s,etc.)

• Prevention: vaccine approved forPts >50 y (↓ lifetime risk from20% to 10%, also ↓ PHN)

BACTERIAL ENDOCARDITIS

Definition• Infection of endothelium of heart

(including but not limited tothe valves)

• Acute (ABE): infxn of normalvalves w/ virulent organism(eg, S. aureus, group A or otherβ-hemolytic strep, Streppneumo)

• Subacute (SBE): indolent infxnw/ less virulent organism (eg,S. viridans); often abnl valves

Predisposing conditions• Abnormal valve

High risk: prior endocarditis,

rheumatic valvular disease,AoV disease (incl. bicuspid),complex cyanotic lesions,prosthesis (annual risk 0.3–1%)

Medium risk: MV disease(including MVP w/ MR orleaflet thickening), HCMP

• Abnormal risk of bacteremia:IDU, indwelling venouscatheters, poor dentition,hemodialysis, DM, intracardiacdevices (eg, pacemaker, ICD)

Clinical manifestations (Archives2009;169:463)• Persistent bacteremia: fever

(80–90%), chills, night sweats,anorexia, wt loss, fatigue

• Valvular or perivalvularinfection: CHF, conductionabnormalities

• Septic emboli: systemic emboli(eg, to periphery, CNS,kidneys, spleen or joints),stroke,PE (if right-sided), mycotic

aneurysm, MI (coronaryartery embolism)

• Immune complex phenomena:arthritis, glomerulonephritis,

RF, ↑ ESR• SBE: can p/w fatigue,

nonspecific sx in Pts w/o riskfactors; ∴ need high index ofsuspicion

Physical exam• HEENT: Roth spots (retinal

hemorrhage + pale center),petechiae (conjunctivae,palate)

• Cardiac: murmur (85%), newvalve regurgitation (40–85%) ± thrill (fenestratedvalve or ruptured chordae),muffled sounds (PV). Frequentexams for Δ murmurs, s/s CHF.

• Abdomen: tender splenomegaly;musculoskeletal: arthritis,vertebral tenderness

• Extremities (typically seen in SBE,not ABE)Janeway lesions (septic

emboli → nontender,hemorrhagic macules onpalms or soles)

Osler’s nodes (immunecomplexes → tender noduleson pads of digits)

proximal nail bed splinterhemorrhages (8–15%);petechiae (33%); clubbing

• Neuro: Δ MS or focal deficits• Devices: erythema, tenderness or

drainage at catheter site,PM/ICD pocket tenderness

Diagnostic studies• Blood cultures (before abx): at

least 3 sets (aerobic &anaerobic bottles) fromdifferent sites, ideally spaced≥1 h apart. ✓ BCx (at least 2sets) after appropriate abxhave been initiated todocument clearance; repeatq24–48h until .

• CBC w/ diff (↑ WBC common inABE; anemia in 90% SBE),ESR, RF, BUN/Cr, U/A, & UCx

• ECG (on admission and at

regular intervals) to assess fornew conduction abnormalities

• Echocardiogram: obtain TTE iflow clinical suspicion, expectgood image quality; TEE if (i)mod-to-high suspicion, (ii)high-risk Pt (prosthetic valve,prior IE, congenital heart dis),(iii) TTE nondx, (iv) TTE buthigh-risk endocarditis, or (v)suspect progressive or invasiveinfection (eg, persistentbacteremia or fever, newconduction abnl, etc.) (Circ2005;111:e394)

• Cx endocarditis: may be dueto abx prior to BCx. PCR,bacterial 16S ribosomal RNA,serologies may be helpful.Detailed hx: animal exposure,travel, unpasteurized dairy,etc. Seek ID eval (Med2005;84:162; NEJM2007;356:715).

Treatment (NEJM2013;368:1425)• Obtain culture data first

ABE → abx should startpromptly after cx dataobtained

SBE → if Pt hemodynamicallystable, may delay abx toproperly obtain adequateBCx data, esp. if prior abxused

• Suggested empiric therapy(Circ 2005;111:e394)native valve ABE: vanco (±

gent; no longer routinelyrecommended)

native valve SBE:ceftriaxone (or amp if ?enterococcus; eg, older orob/gyn) ± gent

PVE: early (≤60 d): vanco +cefepime + gent;intermediate (60–365 d):vanco + gent; late (>1 y):vanco + CTX + gent

native or prosthetic cx :depends on host & epi,seek ID consultation

• Adjust abx regimen & durationbased on valve (NVE vs. PVE);if possible, de-escalate abx toorganism-directed Rx guidedby in vitro sensi's or localpatterns of Rx-resist. Addrifampin for PVE due to staphspp. (usually after BCx to ↓risk resistance develops).

• Repeat BCx qd until Ptdefervesces and BCx ; usually2–3 d

• Fever may persist even >1 wkafter appropriate abx or due tometastatic sites

• Systemic anticoagulationrelatively contraindicated givenrisk of hemorrhage in cerebralembolic strokes; w/o stroke,can continue short-actinganticoag for pre-existingindication

• Monitor for complications ofendocarditis (CHF, conductionblock, new emboli, etc., whichcan occur even on abx) and of

abx Rx (interstitial nephritis,ARF, neutropenia, etc.)

• Duration of Rx: usually 4–6 wk.With NVE & sx <3 mo → 4 wkof abx; sx >3 mo → ≥6 wk.Uncomplicated right-sided NVEor PCN-S strep spp → 2 wkmay be comparable.

• Posthospitalization outPt IV abxmonitoring; future endocarditisPpx

Indications for surgery (EHJ2009;30:2369; Circ2010;121:1005 & 1141)• Several days of abx (if possible)

to ↓ recurrence of infection

and improve structuralintegrity of tissue to receiveprosthesis

• Severe valvular dysfunction →refractory CHF: emergent ifrefractory cardiogenic shock(ie, despite ICU-level Rx);urgent (w/in days) if persistentrefractory heart failure;elective (w/in wks) if asxsevere AI or MR

• Uncontrolled infxn (urgentsurgery w/in days):periannular abscess (10–40%NVE, 60– 100% PVE), fistula,worsening conduction, PVE w/dehiscence, ↑ veg. size or

persistent sepsis (eg, BCx [?or fever] after ~1 wk ofappropriate IV abx and nodrainable metastatic focus orother identifiable cause)

• Organism: consider surgery forS. aureus, fungal or multiRxresistant organisms

• Systemic embolism (20–50%):risk 4.8/1000 Pt days in 1stwk, 1.7/1000 thereafterurgent surgery if L-sided w/

>10 mm veg & severeAI/MR (NEJM2012;366:2466) or ifrecurrent emboli, embolism& >10 mm veg, or >15 mm

veg despite approp. abxcerebral emboli no longer

considered contraindic tosurgery unless hemorrhage(then ideally wait 1 mo) orsevere stroke (Stroke2006;37:2094)

• PVE: esp. w/ valve dysfxn ordehiscence or S. aureus or GNRinfection. Seek ID eval.

Prognosis• NVE: non-IVDU S. aureus → 30–

45% mortality; IVDU S. aureus(typically right-sided) → 10–15% mortality; SBE → 10–15%mortality

• PVE → 23% mortality• Aortic valve worse prognosis

than mitral valve

BACTEREMIA

Etiologies• 1° infxn due to direct inoculation

of the blood, frequently assocw/ intravascular catheters.Catheter-related bloodstreaminfection = same org fromperipheral cx and cath tip cx orcx drawn from catheter (CID2009;49:1).

• 2° infxn due to infection inanother site (eg, UTI, lung,biliary tree, skin) spreading toblood

Microbiology• 1° infxn/indwelling catheters

(ICHE 2008;29:996): coag-negstaph (incl S. epi and others)34%, S. aureus 10%,enterococci 16%, Candida spp.12%, Klebsiella spp. 5%

• 2° infxn: dependent on source

Risk factors for true bacteremia(JAMA 2012;308:502)• Pt: fever, shaking chills, IVDU,

comorbidities, immunosupp,indwelling catheter, SIRS

• Organismmore likely pathogenic: S.

aureus, b-hemolytic strep,enterococci, GNR, S. pneumo,Neisseria less likely

pathogenic: coag-neg staph(~10%), diphtheroids,Propionibacterium (~0%)

• Time to growth: <24 h →higher risk, >72 h → lowerrisk (except for slow-growingorganisms such as HACEKgroup)

• Factors increasing thelikelihood of endocarditis:high-grade bacteremia w/osource, persisting after lineremoval or drainage of focalsource, in hosts at risk forendocarditis or w/ organismsknown to cause IE (Dukecriteria); emboli

Diagnosis• Blood Cx: prior to 1st abx dose if

possible; 10 cc in each Cxbottle; add’l Cx if high risk

Treatment• 1° infxn: antibiotics based on

Gram stain/culture results;tailor abx to sensitivitiesempiric therapy for GPC:vanco to cover coag-neg staphand MRSA while awaitingsensi

• 2° infxn: assess for primarysource of infection and treat.Source control essential forcure and to preventrecurrence.

• Persistently BCx: d/cindwelling catheters, considermetastatic infxn, infected

thrombosis or infectedprosthetic material (joint,abscess, vascular graft,pacemaker, etc.)

TUBERCULOSIS

Epidemiology• U.S.: 10–15 million infected

(10× ↑ risk if foreign-born orminority); worldwide: ~2billion

• After resurgence in U.S. 1984–1992, rates declined, thoughslower than CDC goals

• Multidrug resistant (MDR) TB:resistant to isoniazid (INH)and rifampin (RIF). Can occuras new (not previouslytreated) infxn if exposed informer Soviet Republics,Russia, China

• Extensively drug resistant (XDR)TB resistant to INH, RIF, FQand injectables

• Pts more likely to develop TBdisease (NEJM2011;364:1441)High-prevalence populations

(more likely to be exposed to& infected): immigrant fromhigh-prevalence area,homeless, IDU or medicallyunderserved, resident orworker in jail or long-termfacility, HCW at facility w/TB, close contact to Pt w/active TB

High-risk populations (infected &

likely to progress to activedisease): HIV ,immunosupp. incl. biologics,uncontrolled DM & smoking,close contact w/ active TBPt, underweight, CKD, organTx, IVU, EtOH,malnourished, cancer,gastrectomy

Microbiology & natural history• Transmission of Mycobacterium

tuberculosis via small-particleaerosols (droplet nuclei)

• 90% of infected normal hosts willnever develop clinicallyevident disease

• Localized disease: healing &calcification or progressive 1°TB (at site of infection)

• Hematogenous spread: latentinfection ± reactivation TB orprogressive dissem. TB

Screening for prior infection• Whom to screen: high-

prevalence and high-riskpopulations (HIV Pts shouldhave PPD testing as part ofinitial evaluation and annuallythereafter)

• How to screen: Mantouxtuberculin test (ie, purifiedprotein derivative or PPD)

inject 5-TU (0.1 mL) intermed.strength PPD intradermally →wheal; examine 48–72 h

• How to interpret PPD:determine max. diameter ofinduration by palpation

• IFN-γ release assays (IGRA):(Ag-stimulated IFN-g release

from Pt’s T-cells): can be usedfor screening where you woulduse PPD (MMWR 2010;59:1); ↑Sp, esp. in BCG Rx’d Pts(Annals 2008;149:177). Doesnot distinguish active vs.latent, or recent vs. remoteinfxn. Relies on host immunefxn; Se limited in immunosupp.Lack of gold standard forlatent TB infxn compromisesSe/Sp estimates (J Clin Epi2010;63:257; CID2011;52:1031).

Clinical manifestations• Primary TB pneumonia: middle

or lower lobe consolidation,

± effusion, ± cavitation• TB pleurisy: can occur w/

primary or reactivation. Dueto breakdown of granulomaw/ spilling of contents intopleural cavity and localinflammation. Pulmonaryeffusion ± pericardial andperitoneal effusions(tuberculous polyserositis).

• Reactivation TB pulmonarydisease: apical infiltrate ±volume loss ± cavitation

• Miliary TB: acute or insidious;due to widespreadhematogenous dissemination;usually in immunosupp, DM,

EtOH, elderly or malnourished.Constitutional sx (fever,night sweats, weight loss)usually prominent. Pulmdisease w/ small millet seed-like lesions (2– 4 mm) on CXRor chest CT (latter more Se)present in 60–80% of those w/miliary TB.

• Extrapulmonary TB:lymphadenitis, pericarditis,peritonitis, meningitis,nephritis ± sterile pyuria,osteomyelitis (vertebral =Pott’s disease), hepatitis,splenitis, cutaneous, arthritis

• TB and HIV: HIV at ↑ risk

infxn, progressive 1° infxn andreactivation. Risk ofprogression from infxn todisease >8–10%/y, higher riskwith ↓ CD4. Reinfection (alsow/ MDR) significant, esp. inhyperendemic areas.

Diagnostic studies for active TB(high index of suspicion is key!)• AFB smear (rapid dx) and

culture (↑ Se & allowssensitivity testing) of sputum,BAL, pleura, etc.; avoid FQ ifconsidering TB (cancompromise dx yield)

• PCR: 94–97% Se c/w smear; 40–

77% Se c/w culture (JAMA2009;301:1014)

• CXR: classically fibrocavitaryapical disease in reactivationvs. middle & lower lobeconsolidation in 1° TB, butdistinction imperfect. HIV assoc. w/ non-apical diseaseregardless of timing (JAMA2005;293:2740).

• Adenosine deaminase testing:useful in extrapulmonary sites,best validated for ascites

Preventive therapy (Annals2009;150:ITC6-1; NEJM2010;362:707)

• Prophylaxis reduces incidence ofsubsequent disease by 65–75%

• Treat Pts who are based onguidelines listed above or anyexposed HIV orimmunocompromised Pt

• R/o active disease in any Pt w/suggestive s/s before startingINH. If HIV , routinely ask ifcough, fever or night sweats; ifyes → ✓ sputum smear, CXR,CD4

• ✓ LFTs monthly (risk ↑ w/ age;Chest 2005;128:116): if 5×ULN or sx → stop TB meds &reeval

Treatment of active tuberculosis(Annals 2009;150:ITC6-1; NEJM2013;368:745)• Isolate Pt per infection control if

hospitalized, modified isolationper Dept of Health if outPt

• Use multiple drugs (see below) towhich organism susceptible;consult ID before empiric Rx ifpossible MDR-TB (suspect ifprior TB Rx, from or travel toarea w/ ↑ rates of MDR,

exposure to person w/ likelyMDR-TB, poor Rx adherence)or if INH resistance incommunity ≥4% (includesmost of U.S.), extrapulm. TB orHIV (NEJM 2008;359:636)

• Screen for HIV in Pts starting TBRx; if HIV , consult ID re:timing of concurrent HIV Rx

• Promote adherence to Rx; directlyobserved Rx cost-effective ifhigh risk for nonadherence

• Obtain monthly smears/cx ontreatment until 2 consecutiveare for TB

• Monthly clinical evaluation tomonitor for Rx response and

adverse drug rxns• “Paradoxical worsening” of sx can

occur after starting Rx. Morecommon w/ extrapulm. TB(eg, tuberculoma, LAN) likelydue to hypersensitivityresponse to killing of bacilli.More frequent/severe w/concurrent immunereconstitution (eg, HIV Ptsstarted on ARVs, Pts taken offimmunosuppress, etc.). Mustr/o tx failure (repeat Cx,imaging, etc.).

HIV/AIDS

Definition• AIDS: HIV + CD4 <200/mm3 or

AIDS-defining opportunisticinfection (OI) or malignancy

Epidemiology• ~1 million Americans living w/

HIV; ~34 million individualsworldwide

• 20% in U.S. are unaware ofinfection; 6th leading cause ofdeath in 25–44-y age group

• Routes: sexual (risk is 0.3% formale-to-male, 0.2% for male-to-female, 0.1% for female-to-male transmission), IVDU,

transfusions, needle sticks(0.3%), vertical (15–40% w/oARV)

• Postexposure (risk infxn ~0.3%)Ppx: 2 NRTIs (+ PI or NNRTIif high-risk) × 4 wk

Acute retroviral syndrome (ARS)• Occurs in ~40–90% of Pts ~2–6

wk after infxn; ± ELISA, viral load (2 wk after infxn);early ART in ARS may bebeneficial (NEJM 2013;368:207& 218)

• Mono-like syndrome (↑ mucocut.& neuro manifestationscompared to EBV or CMV)

Diagnostic studies• ELISA for HIV-1 Ab/Ag: 1–12

wk after acute infxn; >99%Se; 1° screening test

• Western blot: if ≥2 bandsfrom HIV genome; >99% Sp;confirmatory after ELISA

• Rapid preliminary tests: 4 Abtests; use saliva, plasma, bloodor serum; 99% Se & 96–99% Sp(Annals 2008;149:153); PPV inlow prev populations as low as50%

• PCR (viral load): detects HIV-1RNA in plasma; assay range is48–10 million copies/mL ~2%false , but usually low #

copies; in contrast, should bevery high (>750 k) in 1° infxn

• At least 1 time HIV screeningrecommended for all adultPts (MMWR 2006;55:1)

• CD4 count: not a dx test, b/c canbe HIV w/ normal CD4 or beHIV w/ low CD4

Approach to newly diagnosedHIV Pt• Document HIV infection;

counseling re: treatmentoptions, adherence &disclosure

• H&P (including focus on h/o OIs,STDs); review all current

meds• Lab evaluation: CD4 count, PCR,

HIV genotype, CBC w/ diff.,Cr, lytes, LFTs, A1c & fastinglipids; PPD or IGRA, syphilis &toxo screen & CMV IgG; HAV,HBV, & HCV serologies;Chlamydia & gonorrhea screen;baseline CXR; Pap smear/analpap in /

• ARVs should be given inconsultation w/ HIV specialist(JAMA 2010;304:321)

• Counseling re: strict adherenceto ARVs is essential; genotype

prior to ART-initiation• All HIV Pts should be

considered for ARVs; stronglyrecommended initiate Rx for:AIDS-defining illness,

pregnancy, HIV-assoc.nephropathy, HCV/HBV co-infxn

CD4 £500/mm3 (NEJM2009;360:1815 &2011;365:193; DHHS 2012;http://aidsinfo.nih.gov)

Consider if CD4 >500;depends on Rx toxicity,adherence, potential fortransmission

• Regimens for treatment-naïve Pts

http://aidsinfo.nih.gov

(DHHS guidelines Mar 29,2012; http://aidsinfo.nih.gov)[NNRTI + 2 NRTI] or [PI (±

low-dose ritonavir) + 2NRTI] or [II + 2 NRTI]

• Initiation of ARVs may transientlyworsen existing OIs for severalwks due to immunereconstitution inflammatorysyndrome (IRIS)

Approach to previouslyestablished HIV Pt• H&P (mucocutaneous,

neurocognitive, OIs,malignancies, STDs); meds

• Review ARVs (past and current);

http://aidsinfo.nih.gov

if any must be interrupted, stopall to ↓ risk of resistance

• Failing regimen = unable toachieve undetectable viralload, ↑ viral load, ↓ CD4 countor clinical deterioration (withdetectable viral load considergenotypic or phenotypicassay)

COMPLICATIONS OF HIV/AIDS

Fever• Etiologies (Infect Dis Clin North

Am 2007;21:1013)infxn (82–90%): MAC, TB,

CMV, early PCP, Histo,Crypto, Coccidio, Toxo,endocarditis

noninfectious: lymphoma,drug reaction. Non 1° HIV

itself rarely (<5%) cause offever.

• Workup: guided by CD4 count,s/s, epi, & exposuresCBC, chem, LFTs, BCx, CXR,

UA, mycobact. & fungal cx,✓ meds, ? ✓ chest & abd CT

CD4 <100–200 → serumcrypto Ag, LP, urinary HistoAg, CMV PCR orantigenemia

pulmonary s/s → CXR; ABG;sputum for bacterial cx, PCP,AFB; bronchoscopy

diarrhea → stool for fecalleuks, culture, O&P, AFB;endoscopy

abnormal LFTs → abd CT,liver bx (for pathology andculture)

cytopenias → BM bx (includeaspirate for culture)

Cutaneous• Seborrheic dermatitis;

eosinophilic folliculitis; warts(HPV); HSV & VZV; MRSA skin& soft tissue infxns; scabies;candidiasis; eczema; prurigonodularis; psoriasis; drugeruptions

• Dermatophyte infx: proxsubungual onychomycosis (atnail bed); pathognomonic for

HIV• Molluscum contagiosum

(poxvirus): 2–5 mm pearlypapules w/ centralumbilication

• Kaposi’s sarcoma (KSHV orHHV8): red-purplenonblanching nodular lesions

• Bacillary angiomatosis(disseminated Bartonella):friable violaceous vascularpapules

Ophthalmologic• CMV retinitis (CD4 usu <50);

Rx: gan- or valganciclovir,ganciclovir implant or

cidofovir• HZV, VZV, syphilis (at any CD4

count) or Toxo: CD4 usually<100

Oral• Aphthous ulcers; KS; thrush

(oral candidiasis): curd-likepatches typically w/ burningor pain; oral hairyleukoplakia: painlessproliferation of papillae w/adherent white coating usuallyon lateral tongue, caused byEBV but not precancerous

Endocrine/metabolic• Hypogonadism; adrenal

insufficiency (CMV, MAC, TB,HIV or med-related); wastingosteopenia/porosis (at all CD4counts); fragility fractures

• Lipodystrophy: central obesity,peripheral lipoatrophy,dyslipidemia, hyperglycemia

• Lactic acidosis: N/V, abd pain; ?mitochondrial toxicity of AZT,d4T, ddI, other NRTI

Cardiac (JACC 2013;61:511)• Dilated CMP (10–20%); PHT;

CVD (NEJM 2003;348:702);pericarditis/effusion, VTE

Pulmonary

• Pneumocystis jiroveci (PCP)pneumonia (CD4 <200)(NEJM 1990;323:1444)constitutional sx, fever, night

sweats, dyspnea on exertion,nonproductive cough

CXR w/ interstitial pattern, ↓PaO2, ↑ A-a ∇, ↑ LDH, PCP sputum stain, β-glucan

Rx if PaO2 >70: TMP-SMX 15–

20 mg of TMP/kg dividedtid, avg dose = DS 2 tabsPO tid

Rx if PaO2 <70 or A-a gradient>35: prednisone beforeabx (40 mg PO bid; ↓ after 5d) Alternative Rx if sulfa-allergy or renal insufficiency

Gastrointestinal & hepatobiliary• Esophagitis: Candida, CMV,

HSV, aphthous ulcers, pills;EGD if no thrush orunresponsive to empiricantifungals

• Enterocolitis: bacterial (esp ifacute: shigella, salmonella, C.

diff); protozoal (esp. if chronic:Giardia, Entamoeba, etc.); viral(CMV, adeno); fungal (histo);MAC; AIDS enteropathy

• GI bleeding: CMV, KS,lymphoma, histo; proctitis:HSV, CMV, LGV, N.gonorrhoeae

• Hepatitis: HBV, HCV, CMV,MAC, TB, histo, drug-induced

• AIDS cholangiopathy: oftena/w CMV or Cryptosporidium orMicrosporidium (at ↓ CD4)

Renal• HIV-associated nephropathy

(collapsing FSGS); nephrotoxic

drugs (incl TDF)

Hematologic/oncologic (Lancet2007;370:59; CID 2007;45:103)• Anemia: ACD, BM infiltration by

infxn or tumor, drug toxicity,hemolysis

• Leukopenia; thrombocytopenia(bone marrow involvement,ITP); ↑ globulin

• Non-Hodgkin lymphoma: ↑frequency with any CD4 count,but incidence ↑ with ↓ CD4

• CNS lymphoma: CD4 count<50, EBV-associated

• Kaposi’s sarcoma (HHV-8): atany CD4 count, incidence ↑ as

CD4 ↓, usu. MSMMucocutaneous (red-purple

nodular lesions); pulmonary(nodules, infiltrates,effusions, LAN); GI(bleeding, obstruction,obstructive jaundice)

• Cervical/anal CA (HPV); ↑ ratesof liver (a/w HBV/HCV),gastric & lung CA

Neurologic• Meningitis: Crypto (p/w HA, Δ

MS, CN palsy ± meningeals/s; dx w/ CSF; serum CrAg90% Se), bact (inc. Listeria),viral (HSV, CMV, 1° HIV), TB,

histo, Coccidio, lymphoma• Neurosyphilis: meningitis,

cranial nerve palsies,dementia, otic or ophtho s/s

• Space-occupying lesions: maypresent as HA, focal deficits orΔ MS. Workup: MRI, brain bxif suspect non-Toxo etiology(Toxo sero ) or no responseto 2 wk of empiric anti-ToxoRx (if Toxo, 50% respond byd3, 91% by d14; NEJM1993;329:995)

• AIDS dementia complex:memory loss, gait disorder,spasticity (usually at CD4 ↓)

• Myelopathy: infxn (CMV, HSV),cord compression (epiduralabscess, lymphoma)

• Peripheral neuropathy: meds,HIV, CMV, demyelinating

Disseminated Mycobacteriumavium complex (DMAC)• Fever, night sweats, wt loss,

HSM, diarrhea, pancytopenia.Enteritis and mesentericlymphadenitis if CD4 <150,bacillemia if <50. Rx:clarithromycin + ethambutol± rifabutin.

Cytomegalovirus (CMV)• Usually reactivation with ↓ CD4.

Retinitis, esophagitis, colitis,hepatitis, neuropathies,encephalitis. Rx: ganciclovir,valganciclovir, foscarnet orcidofovir.

TICK-BORNE DISEASES

LYME DISEASE

Microbiology• Infection with spirochete

Borrelia burgdorferi (considercoinfection w/ Ehrlichia,Babesia)

• Transmitted by ticks (Ixodes,deer tick); infxn usuallyrequires tick attached >36–48h

Epidemiology• Most common vector-borne

illness in U.S.; peak incidencein summer (May–Aug)

• Majority of cases in MN, WI,New England, northern mid-

Atlantic, northern CA• Humans contact ticks usually in

fields with low brush nearwooded areas

Diagnostic studies• Often a clinical dx esp. in early

disease; dx w/o EM requiresconfirmation testing (perIDSA)

• Serology (in right clinicalsetting): screen w/ ELISA, butfalse from other spirochetaldisease, SLE, RA, EBV, HIV,etc.; false due to early abxor w/in 6 wk of infxn.Confirm ELISA results w/

Western blot (↑ Sp)• ✓ CSF if suspected neuro disease:

intrathecal Ab if(IgGCSF/IgGserum)/(albCSF/albserum

>1

Treatment (NEJM

2006;354:2794)• Prophylaxis (best prevention is

tick avoidance): protectiveclothing, tick ✓ q24h, DEETChemoprophylaxis w/

doxycycline 200 mg PO × 1only if all of the following:

1. Ixodes scapularis tickattached ≥36 h

2. Local Lyme carriage inticks ≥20% (peakseason in New England,mid-Atl, MN, WI)

3. Abx can be given w/in≤72 h

4. No contraindication todoxy (eg, preg, allergy,

age <8 y)If all the above met, NNT still

40–150 to prevent 1 case ofLyme (NEJM 2001;345:79)

Regardless of Ppx, monitor forfever, flu-like sx, rash(erythema migrans) × 30 d

• Antibiotics: if clin. manifestationsand serology (? and h/o tickbite if nonendemic area)local or early dissem. w/o

neuro or cardiacinvolvement: doxycycline100 mg PO bid × 2 wk(range: 10–21 d); alternative(eg, pregnancy, doxyallergy): amox 500 mg PO

tid or cefuroxime 500 mg PObid × 14–21 d neuro (otherthan isolated CN VII palsy),cardiac, chronic arthritis:CTX 2 g IV qd × 2–4 wk; alt(eg, severe b-lactamallergy): doxy 100–200 mgPO bid × 2–4 wk.

• Consider coinfection ifsevere/refractory sx, persistentfever, cytopenias

ROCKY MOUNTAIN SPOTTEDFEVER (RMSF)

Microbiology & epidemiology• Infection with Rickettsia rickettsii

(Gram obligate intracellularbacterium)

• Transmitted by Dermacentorvariabilis, D. andersoni (dogtick); peak in spring/earlysummer

• Occurs in mid-Atl, SE, Midwest,New Engl, NW, Canada,Mexico, Central & S. America

• Consider other rickettsial spp.: R.akari (Rickettsial pox), R.conorii (Mediterranean spotted

fever), R. africae (African tickbite fever), R. felis (Flearickettsiosis)

Clinical manifestations (typicallyw/in 1 wk of tick exposure)• Nonspecific: fever, HA, DMS,

myalgias, N/V, occasionallyabdominal pain

• Rash (2–5 d after onset) =centripetal: starts on ankles andwrists → trunk, palms & soles;progresses from macular tomaculopapular to petechial

• Severe cases → vasculitis,hypoperfusion/shock, end-organ damage; more likely in

elderly• Up to 75% mortality if untreated,

5–10% even w/ Rx (esp. ifdelayed) (NEJM 2005;353:551)

Diagnosis• Usually a clinical dx; requires

early clinical suspicion givenrisks of delayed Rx

• Acute illness dx by skin bx forrickettsiae (Se ~70%); 7–10 dafter sx onset, serology

Treatment• Doxycycline 100 mg PO bid (give

empirically if clinical suspicion)

EHRLICHIOSIS/ANAPLASMOSIS

Microbiology• Gram obligate intracellular

bacterium; human monocyticehrlichiosis (E. chaffeensis,HME); human granulocyticanaplasmosis (A.phagocytophilum, HGA)

• Transmission: HME byAmblyomma americanum,Dermacentor variabilis; HGA byIxodes

Epidemiology• HGA cases typically in RI, MN,

CT, NY, MD; HME in SE, southcentral and mid-Atlantic

• Peak incidence spring and earlysummer; can be transmitted byblood transfusion

Clinical manifestations (typicallyw/in 3 wk of tick exposure)• Asx or nonspecific: fever,

myalgias, malaise, HA, cough,dyspnea; onset often acute

• Laboratory: leukopenia,thrombocytopenia, ↑aminotransferases, LDH, Af,renal insuff

• More severe disease can occurwith bacterial superinfectionin HGA

Diagnosis

• Acute: intraleukocytic morulaeon peripheral blood smear(rare); PCR; later: serology

Treatment• Start Rx based on clinical

suspicion; definitive dxrequires PCR (may not detectall spp.)

• Doxycycline 100 mg PO bid(often × 10 d); shoulddefervesce in ≤48 h, elsereconsider dx

BABESIOSIS

Microbiology & epidemiology• Infxn w/ parasite Babesia microti

(U.S.), transmitted by Ixodesticks; also a/w transfusion

• Europe & U.S. (more commonlyMN, WI, coastal areas &islands of MA, NY, NJ, RI,CT)

• Peak incidence June–August(MMWR 2012;61:505)

Clinical manifestations (typically1–4 wk after tick exposure; <9wk if transfusion)• Range from asx to fevers, sweats,

myalgias, & HA to severe

hemolytic anemia,hemoglobinuria, & death(degree of parasitemiacorrelates roughly withseverity)

• Risk factors for severe disease:asplenia, ↓ cellular immunity,TNF inhib, ↑ age, pregnancy

Diagnosis (NEJM 2012;366:2397)• Clinical syndrome + blood

smear w/ intraerythrocyticparasites

• Repeat smears (q12–24h) if sxpersist despite negative initialsmear

• PCR serum if smear and high

clinical suspicion, serum IgGcan help but some false

Treatment (NEJM2002;343:1454)• Atovaquone & azithro for

mild/mod illness; clinda &quinine if severe (more toxic)

• Duration depends on host;immunosupp Pts often needlonger Rx

• Exchange transfusion ifparasitemia >10%, severehemolysis or SIRS

TULAREMIA

Microbiology• Infxn w/ Francisella tularensis via

contact w/ animal tissue,aerosol, tick/insect bite

Clinical manifestations (typicallyw/in 2–10 d of exposure)• Acute onset of fever, HA, nausea;

ulcer w/ black eschar at site ofentry; LAN; PNA

Diagnosis & treatment• Hazardous and difficult to Cx,

alert lab. Serology by wk 2.PCR by research lab.

• Streptomycin or gentamicin × 7–

14 d; empiric Rx may beneeded given challenges in dx

FEVER SYNDROMES

Temperature >101°F or >38.3°C

Diagnostic approach• Thorough history including ROS,

PMH/PSH, immunizations,including from childhood

• Fever curve (consider holdingantipyretics); less likely tomount fever if: chronic renalor liver dis., extremes of age,protein calorie malnutrition,immunosupp., steroid use

• Exposures: travel, occupation orhobbies, animals and insects,sexual contacts, TB; considerage, geography, season and

incubation time in relation toexposures

• Physical exam: complete examw/ focus on mucuousmembranes & conjunctiva;cardiac murmurs; liver andspleen size; skin, genitals,lymph nodes, & joints;complete neuro exam inclcranial nerves and meningealsigns

• If rash: location, duration,progression/∆ in appearance,was prodrome present

FEVER OF UNKNOWN ORIGIN(FUO)

Definition & etiologies• Fever (as per above def) on >1

occasion during ≥3 wk & nodx despite 1 wk of evaluation

• More likely to be subtlemanifestation of common diseasethan an uncommon disease

• In Pts with HIV: >75% causesare infectious, but rarely due toHIV itself

• Frequent reassessment neededto identify focal signs andprogression of disease

Workup• Focus by H&P, incl: CBC w/ diff,

lytes, BUN, Cr, LFTs, ESR,CRP, ANA, RF, cryoglobulin,LDH, CK, SPEP, 3 sets BCx (offabx), U/A, UCx, PPD or IGRA,

HIV Ab ± PCR, heterophile Ab(EBV serologies if ), CMVantigen, Hep serologies if LFTsabnl

• Stop unnecessary meds (only20% with a med cause haveeos or rash), reassess 1–3 wk

• Imaging: CXR, chest & abd CT,consider tagged WBC, galliumscan, PET, TTE, LENI

• Duke’s criteria for endocarditis(qv) have good Se & Sp in Ptswith FUO

• Consider temporal artery bx if ↑ESR and age >60, particularlyif other s/s

• ? Bone marrow aspirate & bx

(esp. if signs of marrowinfiltration) or liver bx (esp. if↑ Af): even w/o localizing s/s,yield may be up to 24% (pathand culture) (Archives2009;169:2018)

• Pursue abnormalities raised byabove w/u (eg, bx, MRI, etc.,for dx, not screening)

Treatment• Empiric abx not indicated (unless

Pt neutropenic)• Empiric glucocorticoids not

indicated unless strongsuspicion for specificrheumatologic dx

• Up to 30% of cases remainundiagnosed, mostspontaneously defervesce (wksto mos)

FEVER AND RASH

Approach to diagnostic workup• Meningococcemia, IE, RMSF,

sepsis, toxic shock requireimmediate dx & Rx

• Workup: CBC w/ diff, lytes,BUN/Cr, LFTs, LDH, CK, U/A,HIV Ab ± PCR, BCx (off abx)

• To narrow Ddx: characterize timecourse of rash, progression &morphology (ie, vesicular,maculopapular, pustular,purpuric, ulcerative)

• Erythema multiforme:symmetric “target” lesionsoften of palms, soles, &

mucous membInfxn etiol: HSV 1/2,

Mycoplasma, syphilis, tickborne diseases, etc.

Non-infxn etiol: meds (eg,NSAIDs, sulfa), malignancy,autoimmune & rheumdisease

• Erythema nodosum: tendererythematous or violaceousnodules usually symmetric onLEInfxn etiol: Strep, TB, EBV,

Bartonella, HBV, psittacosis,fungal, L. venereum, etc.

Non-infxn etiol: sarcoidosis,IBD, Behçet’s, other rheum,

pregnancy/OCP use• Pursue specific dx based on

exposure hx & exam, includingserologies, viral swab PCR,antigen tests and possibly skinbiopsy ± exam of vesicular orbullae fluid if present

• Etiologies more broad inimmunosupp. Pts, and dxapproach usually moreextensive; higher risk ofcritical illness due todisseminated or rapidlyprogressive infxns

Treatment• Empiric abx are not indicated

(unless Pt neutropenic orcritically ill)

FEVER IN A RETURNEDTRAVELER

Definition & etiologies• Febrile illness after recent travel

outside of U.S./Canada; Ddx isextensive:

• Pts visiting friends and relativesabroad are most likely to

contract illness during travel• Emerging pathogens: Influenza

occurs year round in thetropics. Chikungunya anddengue w/ ↑ areas oftransmission, hemorrhagicfevers primarily in CentralAfrica.

• Consider domestic infxns, STIs, &non-infxn causes. Entericparasites rarely cause fever.

Select clinical manifestations• Malaria: nonspecific symptoms

including diarrhea, myalgias,cough, altered mental status

• Dengue: nonspecific symptoms

including headache, severemyalgias, rash/petechiae

• Typhoid: constipation,abdominal pain, possible rash,relative bradycardia

• Rickettsial disease: headache,myalgias, lymphadenopathy,possible rash/eschar

Workup• Routine testing: CBC w/ diff,

lytes, LFTs, BCx, UA, rapidmalaria test

• Fever in a traveler from amalaria zone is malariauntil proven otherwise;consider hospitalization and

empiric Rx. One smear doesnot r/o malaria.

• Other tests based on s/s, labs,exposure, incubation period,geography and seasonality.O&P exam, CXR, blood smearsfor filaria/Babesiosis/Borrelia,serologies, STI & HIV, PPD orIGRA, bone marrow aspirate,bx of lymph nodes or skinlesions, CSF studies.

PITUITARY DISORDERS

HYPOPITUITARY SYNDROMES

Panhypopituitarism• Etiologies

Primary: surgery, radiation,tumors (primary ormetastatic), infection,infiltration (sarcoid,hemochromatosis),autoimmune, ischemia(including Sheehan’ssyndrome caused bypituitary infarctionintrapartum), carotidaneurysms, cavernous sinusthrombosis, trauma

Secondary (hypothalamicdysfunction or stalkinterruption): tumors(includingcraniopharyngioma),infection, infiltration,radiation, surgery, trauma

• Clinical manifestationsHormonal: acute → weakness,

easy fatigability,hypotension, polyuria andpolydipsia; chronic →bradycardia, sexual dysfxn,loss of axillary & pubic hair,wt loss, amenorrhea

Mass effect: headache, visualfield Δs, cranial nerve

palsies, galactorrheaApoplexy (pituitary

hemorrhage or infarction,usually w/ underlyingpituitary adenoma): suddenheadache, N/V, visual fieldΔs, cranial nerve palsies,meningismus, Δ MS,hypoglycemia, hypotension

• Diagnostic studiesHormonal studies

chronic: ↓ target glandhormone + ↓ or normaltrophic pituitary hormoneacute: target gland hormonalstudies may be normal partialhypopituitarism is more

common thanpanhypopituitarism

Pituitary MRI• Treatment

Replace deficient target glandhormones

Most important deficiencies torecognize and treat in inPtsare adrenal insufficiency andhypothyroidism; if bothpresent, treat withglucocorticoids first, thenreplace thyroid hormone soas not to precipitate adrenalcrisis

↓ ACTH

• Adrenal insufficiency similar to1° (see “Adrenal Disorders”)except:no salt cravings or

hypokalemia (b/c aldopreserved)

no hyperpigmentation (b/cACTH/MSH is not ↑)

↓ TSH• Central hypothyroidism similar

to 1° (see “Thyroid Disorders”)except absence of goiter

• Dx with free T4 in addition toTSH, as TSH may be low orinappropriately normal

↓ PRL

• Inability to lactate

↓ GH• ↑ chronic risk for osteoporosis,

fatigue, weight gain• Dx with failure to ↑ GH w/

appropriate stimulus (eg,insulin tolerance test, glucagonstimulation)

• GH replacement in adultscontroversial (Annals2003;35:419)

↓ FSH & LH• Clinical manifestations: ↓ libido,

impotence, oligomenorrhea oramenorrhea, infertility

• Physical exam: ↓ testicular size;

loss of axillary, pubic and bodyhair

• Dx with: ↓ a.m. testosterone orestradiol (also assess SHBG,esp. in obese) and ↓ or normalFSH/LH (all levels ↓ in acuteillness, ∴ do not measure inhospitalized Pts)

• Treatment: testosterone orestrogen replacement vs.correction of the underlyingcause

↓ ADH (hypothalamic or stalkdisease): diabetes insipidus• Typically from mass lesion

extrinsic to sella; pituitary

tumor doesn’t typically presentw/ DI

• Clinical manifestations: severepolyuria, mild hypernatremia(severe if ↓ access to H2O)

• Diagnostic studies: see “Sodiumand Water Homeostasis”

HYPERPITUITARY SYNDROMES

Pituitary tumors• Pathophysiology: adenoma →

excess of trophic hormone (iftumor fxnal, but 30–40% not)and potentially deficiencies inother trophic hormones due tocompression; cosecretion ofPRL and growth hormone in10% of prolactinomas

• Clinical manifestations:syndromes due tooversecretion of hormones (seebelow)± mass effect: headache,

visual Ds, diplopia, cranial

neuropathies• Workup: MRI, hormone levels, ±

visual field testing, considerMEN1 (see below)if <10 mm, � mass effect, no

hormonal effects, can f/upq3–6mo

Hyperprolactinemia (NEJM2010;362:1219)• Etiology

prolactinoma (50% ofpituitary adenomas)

stalk compression due tononprolactinoma → ↓inhibitory dopamine → ↑PRL (mild)

• Physiology: PRL induces lactationand inhibits GnRH → ↓ FSH &LH

• Clinical manifestations:amenorrhea, galactorrhea,infertility, ↓ libido, impotence

• Diagnostic studies: ↑ PRL (✓fasting levels), but elevated inmany situations, ∴ r/opregnancy or exogenousestrogens, hypothyroidism,dopamine agonists (psychmeds, antiemetics), renalfailure (↓ clearance), cirrhosis,stress, ↑ carb diet. MRI toevaluate for tumor; visual fieldtesting if MRI shows

compression of optic chiasm.• Treatment

If asx (no HA, galactorrhea,hypogonadal sx) &microadenoma (<10 mm),follow w/ MRI

If sx or macroadenoma (≥10mm) options include:

medical with dopamine agonistsuch as cabergoline (70–100% success rate) orbromocriptine (not as welltol); side effects include N/V,orthostasis, nasalcongestion, tricuspid valveregurgitation (✓ echo before& q1–2y during Rx) (JCEM

2010:95:1025)surgical: transsphenoidal

surgery (main indications:failed or cannot toleratemedical Rx, GH cosecretionor neurologic sx notimproving); 10–20%recurrence rate

radiation: if medical or surgicaltherapy have failed or arenot tolerated

Acromegaly (↑ GH; 10% ofadenomas; NEJM 2006;355:2558)• Physiology: stimulates secretion

of insulin-like growth factor 1(IGF-1)

• Clinical manifestations: ↑ softtissue, arthralgias, jawenlargement, headache, carpaltunnel syndrome,macroglossia, hoarseness,sleep apnea, amenorrhea,impotence, diabetes mellitus,acanthosis/skin tags, ↑sweating, HTN/CMP, colonicpolyps

• Diagnostic studies: no utility inchecking random GH levelsbecause of pulsatile secretion≠ IGF-1 (somatomedin C); ±

↑ PRL; OGTT → GH notsuppressed to <1 (<0.3 ifnewer assay) ng/mL;

pituitary MRI to evaluate fortumor

• Treatment: surgery, octreotide(long- and short-actingpreparations), dopamineagonists (if PRL co-secretion),pegvisomant (GH receptorantagonist), radiation

• Prognosis: w/o Rx 2–3× ↑mortality, risk of pituitaryinsufficiency, colon cancer

Cushing’s disease (↑ ACTH): 10–15% of adenomas; see“Adrenal Disorders”

Central hyperthyroidism (↑ TSH,↑ ɑ-subunit): extremely rare;see “Thyroid Disorders”

↑ FSH & LH: usually non-fxn,presents as hypopituitarism b/cof compression effects

THYROID DISORDERS

Figure 7-1 Approach to thyroiddisorders

HYPOTHYROIDISM

Etiologies• Primary (>90% of cases of

hypothyroidism; ↓ free T4, ↑TSH)Goitrous: Hashimoto’s

thyroiditis, afterhyperthyroid phase ofthyroiditis, iodine defic, Li,amiodarone

Nongoitrous: surgicaldestruction, s/p radioactiveiodine or XRT, amiodarone

• Central (↓ free T4, low/nl orslightly high TSH):hypothalamic or pituitary

failure (TSH levels ↓ or“normal,” can be slightly ↑although functionally inactivedue to abnormal glycosylation)

Hashimoto’s thyroiditis• Autoimmune destruction with

patchy lymphocytic infiltration• Associated with other

autoimmune disease and maybe part of PGA syndrome typeII

• antithyroid peroxidase (anti-TPO) and antithyroglobulin(anti-Tg) Abs in >90%

Clinical manifestations (Annals2009;151:ITC61)

• Early: weakness, fatigue,arthralgias, myalgias,headache, depression, coldintolerance, weight gain,constipation, menorrhagia, dryskin, coarse brittle hair, brittlenails, carpal tunnel syndrome,delayed DTRs (“hung up”reflexes), diastolic HTN,hyperlipidemia

• Late: slow speech, hoarseness,loss of outer third of eyebrows,myxedema (nonpitting skinthickening due to↑glycosaminoglycans),periorbital puffiness,bradycardia, pleural,

pericardial, & peritonealeffusions, atherosclerosis

• Myxedema crisis: hypothermia,hypotension, hypoventilation,Δ MS (including coma)hyponatremia, hypoglycemia;often precipitated by infectionor major cardiopulmonary orneurologic illness (Med ClinNorth Am 2012;96:385)

Diagnostic studies• ↓ FT4; ↑ TSH in primary

hypothyroidism; antithyroidAb in Hashimoto’s thyroiditis

• May see hyponatremia,hypoglycemia, anemia, ↑ LDL,

↓ HDL and ↑ CK• Screening recommended for

pregnant women

Treatment of overthypothyroidism• Levothyroxine (1.5–1.7 µg/kg/d),

re ✓ TSH q5–6wk and titrateuntil euthyroid;sx can take mos to resolve;

lower starting dose (0.3–0.5µg/kg/d) if at risk forischemic heart disease orelderly; advise Pt to keepsame formulation oflevothyroxine

↑ dose typically needed if:

pregnancy (~30% ↑ by wk8), initiation of estrogenreplacement, on meds thataccelerate T4 catabolism (eg,phenytoin, phenobarbital),poor GI absorption(concomitant Fe or Ca suppl,PPI, sucralfate,cholestyramine, celiacdisease, IBD)

• Myxedema coma: load 5–8 µg/kgT4 IV, then 50–100 µg IV qd;b/c peripheral conversionimpaired, may also give 5–10µg T3 IV q8h if unstable w/bradycardia and/or

hypothermia (T3 morearrhythmogenic); must giveempiric adrenal replacementtherapy first as ↓ adrenalreserves in myxedema coma

Subclinical hypothyroidism(Lancet 2012;379:1142)• Mild ↑ TSH and normal free T4

with only subtle or no sx• If TSH <7 or anti-TPO Ab,

~1⁄2 euthyroid after 2 y (JCEM2012;97:1962) if ↑ titers ofantithyroid Abs, progression toovert hypothyroidism is~4%/y

• Rx controversial: followexpectantly or treat toimprove mild sx ordyslipidemia most initiate Rx ifTSH >10 mU/L, goiter,pregnancy or infertility if TSH5–10 mU/L Rx if ≤60 y(usually don’t Rx if ≥60 b/c ↑risk CV complications)

HYPERTHYROIDISM

Etiologies (Lancet 2012;379:1155)• Graves’ disease (60–80% of

thyrotoxicosis)• Thyroiditis: thyrotoxic phase of

subacute (granulomatous) orpainless (lymphocytic)

• Toxic adenomas (single ormultinodular goiter)

• TSH-secreting pituitary tumor orpituitary resistance to thyroidhormone (↑ TSH, ↑ free T4)

• Misc: amiodarone, iodine-induced, thyrotoxicosis factitia,struma ovarii (3% of ovariandermoid tumors and

teratomas), hCG-secretingtumors (eg, choriocarcinoma),large deposits of metastaticfollicular thyroid cancer

Clinical manifestations ofhyperthyroidism• Restlessness, sweating, tremor,

moist warm skin, fine hair,tachycardia, AF, weight loss, ↑frequency of stools, menstrualirregularities, hyperreflexia,osteoporosis, stare and lid lag(due sympathetic overactivity)

• Apathetic thyrotoxicosis: seenin elderly who can presentwith lethargy as only sx

• Thyroid storm (extremely rare):delirium, fever, tachycardia,systolic hypertension but widepulse pressure and ↓ MAP, GIsymptoms; 20–50% mortality

Laboratory testing• ↑ FT4 and FT3; ↓ TSH (except in

TSH-secreting tumors)• RAIU scan is very useful study to

differentiate causes (see tableon page 7-3); cannot do ifrecent IV contrast or amio loadb/c iodine blocks uptake so ✓autoantibodies instead

• Rarely need to ✓ forautoantibodies except in

pregnancy (to assess risk offetal Graves’)

• May see hypercalciuria ±hypercalcemia, ↑ AΦ, anemia

Graves’ disease (NEJM2008;358:2594)• : ratio is 5–10:1, most Pts

between 40–60 y at dx• thyroid antibodies: TSI or

TBII ( in 80%), anti-TPO,antithyroglobulin; ANA

• Clinical manifestations inaddition to those ofhyperthyroidism (see above):goiter: diffuse, nontender, w/

thyroid bruit

ophthalmopathy (NEJM2009;360:994): Seen in 50%;up to 90% if formally tested.Periorbital edema, lidretraction, proptosis,conjunctivitis, diplopia(EOM infiltration);associated w/ smoking.Stare and lid lag seen in anytype of hyperthyroidism.

pretibial myxedema (3%):infiltrative dermopathy

Thyroiditis (NEJM 2003;348:2646;Med Clin North Am 2012;96:223)• Acute: bacterial infection (very

rare in U.S. except

postsurgical)• Subacute: transient

thyrotoxicosis → transienthypothyroidism → normalthyroid fxnpainful (viral, granulomatous

or de Quervain’s): fever, ↑ESR; Rx = NSAIDs, ASA,steroids

silent (postpartum,autoimmune includingHashimoto’s, orlymphocytic): painless, TPO Abs; if postpartum, canrecur with subsequentpregnancies

other: amiodarone, palpation

thyroiditis, after radiation

Treatment• β-blockers: control tachycardia

(propranolol also ↓ T4 → T3

conversion)• Graves’ disease: either

antithyroid drugs orradioactive iodine (NEJM2005;352:905)methimazole: 70% chance of

recurrence after 1 y; sideeffects include pruritus, rash,arthralgia, fever, N/V andagranulocytosis in 0.5%. PTU:2nd line (risk ofhepatocellular necrosis; TID

dosing; slower effect). Forboth, need to ✓ LFTs, WBC,TSH at baseline and infollow-up.

radioactive iodine (RAI)(NEJM 2011;364:542):typically done as outPt;preRx selected Pts w/ CVdisease or elderly w/antithyroid drugs to prevent↑ thyrotoxicosis, stop 3 dbefore to allow RAI uptake;>75% of treated Pts becomehypothyroid

surgery: less commonlychosen for Graves’, usuallyfor Pts w/ obstructive goiter

or ophthalmopathy• Toxic adenoma or toxic

multinodular goiter: RAI orsurgery (methimazole preRxfor surgery, in selectedpatients before RAI)

• Thyroid storm: β-blocker, PTU ormethimazole, iopanoic acid oriodide (for Wolff-Chaikoffeffect) >1 h after PTU, ±steroids (↓ T4 → T3)

• Ophthalmopathy: can worsenafter RAI, prevented byprophylactic Rx w/ prednisonein high-risk Pts; can be Rx’d w/radiation and/or surgicaldecompression of orbits

Subclinical hyperthyroidism(Lancet 2012;379:1142)• Mild ↓ TSH and normal free T4

with only subtle or no sx• ~15% → overt hyperthyroidism

in 2 y; ↑ risk of AF, CHD(Archives 2012;172:799),osteoporosis

• Rx controversial: consider if TSH<0.1 mU/L and ↑ risk for CVdisease or osteopenic

NONTHYROIDAL ILLNESS (SICKEUTHYROID SYNDROME)

• TFT abnormalities in Pts w/severe nonthyroidal illness (∴in acute illness, ✓ TFTs only if↑ concern for thyroid disease);may have acquired transientcentral hypothyroidism

• If thyroid dysfxn suspected incritically ill Pt, TSH alone notreliable; must measure totalT4, FT4, & T3 (J Endocrinol2010;205:1)

• Mild illness: ↓ T4 → T3

conversion, ↑ rT3 ⇒ ↓ T3; insevere illness: ↓ TBG &

albumin, ↑↑ rT3 ⇒ ↓↓ T3, ↑degradation of T4, central ↓TSH ⇒ ↓↓ T3, ↓↓T4, ↓FT4, ↓TSH

• Recovery phase: ↑ TSH followedby recovery of T4 and then T3

• Replacement thyroxine nothelpful or recommended forcritically ill Pts w/ ↓ T3 and T4

unless other s/s ofhypothyroidism

AMIODARONE AND THYROIDDISEASE

6 mg iodine per 200 mg tablet; riskof thyroid dysfunction lower withlower doses✓ TSH prior to therapy, at 4-mointervals on amio, and for 1 y afterif amio d/c’d

Hypothyroidism (occurs in ~10%;more common in iodine-repleteareas)• Pathophysiology

(1) Wolff-Chaikoff effect: iodineload ↓ I– uptake,organification and release ofT4 & T3

(2) inhibits T4 → T3 conversiondirect/immune-mediatedthyroid destruction

• Normal individuals: ↓ T4; thenescape Wolff-Chaikoff effectand have ↑ T4, ↓ T3, ↑ TSH;then TSH normalizes (after 1–3mo)

• Susceptible individuals (eg,subclinical Hashimoto’s, ∴ ✓anti-TPO) do not escape effects

• Treatment: thyroxine tonormalize TSH; may needlarger than usual dose

Hyperthyroidism (3% of Pts onamio; ∼10–20% of Pts in iodine-

deficient areas)• Type 1 = underlying

multinodular goiter orautonomous thyroid tissueJod-Basedow effect: iodine

load → ↑ synthesis of T4

and T3 in autonomous tissue• Type 2 = destructive thyroiditis

↑ release of preformed T4 & T3

→ hyperthyroidism →hypothyroidism → recovery

• Doppler U/S: type 1 w/ ↑ thyroidblood flow; type 2 w/ ↓ flow

• Treatment: not absolutelynecessary to d/c amio b/camio ↓ T4 → T3 conversion

methimazole for type 1;steroids for type 2 oftendifficult to distinguish so Rx forboth typically initiated ( JCEM2001;86:3) considerthyroidectomy in severely illpatient

THYROID NODULES• Prevalence 5–10% (50–60% if

screen with U/S), ~5%malignant

• Features associated w/ ↑ risk ofmalignancy: age <20 or >70y, , h/o neck XRT, hard andimmobile mass, cold nodule onRAIU, large size, worrisomeU/S findings (hypoechoic,solid, irregular borders,microcalcifications, centralblood flow), cervical LAN

• Features associated w/ benigndx: FHx of autoimmune thyroiddisease or goiter, presence of

hypothyroidism orhyperthyroidism, noduletenderness

• Screening U/S recommended forthose with FHx of MEN2 ormedullary thyroid cancer,personal h/o neck XRT,palpable nodules ormultinodular goiter

• Any evidence of trachealdeviation or compression → ✓PFTs & refer to surgery

• FNA for nodules >10 mm (>8mm if irregular borders),microcalcifications or centralvasculature; FNA any nodulesin Pts with h/o neck XRT or

FHx of MEN2 or MTC• Indeterminate pattern in 15–30%

of FNA; gene expressionpattern has Se 92% & Sp 52%for malignancy (NEJM2012;367:705)

• Suppressive Rx w/ high doses oflevothyroxine less successful iniodine-sufficient regions

• After complete surgical resectionof thyroid cancer, RAI isadministered (in Pts w/ low-risk thyroid cancer, thispractice is controversial)(Lancet 2013;381:1046 & 1058)

Figure 7-2 Approach to thyroidnodules (Thyroid 2009;19:1167;

Am J Clin Pathol 2009;132:658)

ADRENAL DISORDERS

CUSHING’S SYNDROME(HYPERCORTISOLISM)

Definitions• Cushing’s syndrome = cortisol

excess• Cushing’s disease = Cushing’s

syndrome 2° to pituitary ACTHhypersecretion

Etiologies of hypercortisolism• Most common is iatrogenic

Cushing’s syndrome caused byexogenous glucocorticoids

• Cushing’s disease (60–70%):pituitary adenoma (usually

microadenoma) or hyperplasia• Adrenal tumor (15–25%):

adenoma or (rarely)carcinoma

• Ectopic ACTH (5–10%): SCLC,carcinoid, islet cell tumors,medullary thyroid cancer, pheo

Clinical manifestations• Nonspecific: glucose intolerance

or DM, HTN, obesity, oligo- oramenorrhea, osteoporosis

• More specific: central obesity w/extremity wasting,dorsocervical fat pads,rounded facies

• Most specific: spontaneous

bruising, proximal myopathy,wide striae, hypokalemia

• Other: depression, insomnia,psychosis, impaired cognition,facial plethora, acne,hirsutism, hyperpigmentation(if ↑ ACTH), fungal skininfxns, nephrolithiasis,polyuria

Figure 7-3 Approach tosuspected Cushing’s syndrome(nb, very di cult to diagnose asan inpatient)

CRH, corticotropin-releasinghormone; DST, dexamethasonesuppression test; UFC, urinaryfree cortisol

Overnight 1 mg DST = give 1 mgat 11 p.m.; ✓ 8 a.m. serumcortisol (suppression if <1.8µg/dL); 1–2% false (primarilyused to evaluate subclinicalCushing’s in adrenal“incidentalomas”) (JCEM2008;93:1526)

11 pm salivary cortisol = abnl iflevel ↑; 24-h UFC = abnl if level↑, > 4× ULN virtuallydiagnostic

48-h LD DST + CRH = 0.5 mg q6h× 2 d, then IV CRH 2 h later; ✓serum cortisol 15 min later ( =>1.4 µg/dL)

48-h LD DST = 0.5 mg q6h × 2 d;

✓ 24-h UFC at base. & duringlast 24 h of dex (suppress if<10% of base)

48-h HD DST = 2 mg q6h × 2 d; ✓24-h UFC as per LD DST

O/N HD DST = 8 mg at 11 p.m.; ✓9 a.m. serum cortisol(suppression if <32% ofbaseline)

CRH test = 1 µg/kg IV; ✓ cortisoland ACTH ( stim if > 35% ↑ inACTH or >20% ↑ in cortisolabove baseline)

BIPSS, bilat. inferior petrosal sinusvein sampling; ✓petrosal:peripheral ACTH ratio (

= 2 basal, >3 after CRH)

(J Clin Endocrinol Metab2008;93:1526)

Treatment of Cushing’ssyndrome• Surgical resection of pituitary

adenoma, adrenal tumor orectopic ACTH-secreting tumor

• If transsphenoidal surgery (TSS)not successful → pituitaryXRT, medical adrenalectomyw/ mitotane, or bilat surgicaladrenalectomy; ketoconazole(± metyrapone) to ↓ cortisol

• Glucocorticoid replacementtherapy × 6–36 mo after TSS(lifelong glucocorticoid +

mineralocorticoid replacementif medical or surgicaladrenalectomy)

HYPERALDOSTERONISM

Etiologies• Primary (adrenal disorders,

renin independent increase inaldosterone) adrenalhyperplasia (60%), adenoma(Conn’s syndrome, 35%),carcinoma (5%) glucocorticoid-remediable aldosteronism(GRA; ACTH-dep. rearrangedpromoter)

• Secondary (extra-adrenaldisorders, ↑ aldosterone isrenin dependent)Primary reninism: renin-

secreting tumor (rare)

Secondary reninism renovascular disease: RAS,

malignant hypertension edematous states w/ ↓ effective

arterial volume: CHF, cirrhosis,nephrotic syndrome

hypovolemia, diuretics, T2D,Bartter’s (defective Na/K/2Cltransporter receiving loop diuretic), Gitelman’s (defectiverenal Na/Cl transporter receiving thiazide diuretic)

• Nonaldosteronemineralocorticoid excessmimics hyperaldosteronism11β-HSD deficiency (→ lack of

inactivation of cortisol,

which binds to nonselectivemineralocorticoid receptor)

Black licorice (glycyrrhizinicacid inhibits 11β-HSD),extreme hypercortisolism(overwhelming 11β-HSD),exogenousmineralocorticoids

Liddle’s syndrome(constitutivelyactivated/overexpresseddistal tubular renal Nachannel)

Clinical manifestations• Mild to moderate HTN (11% of

Pts w/ HTN refractory to 3

drugs; Lancet 2008;371:1921),headache, muscle weakness,polyuria, polydipsia; noperipheral edema because of“escape” from Na retention;malignant HTN is rare

• Classically hypokalemia (butoften normal), metabolicalkalosis, mild hypernatremia

Diagnostic studies• 5–10% of Pts w/ HTN; ∴ screen

if HTN + hypokalemia,adrenal mass or refractoryHTN

• Screening: aldo (>15–20 ng/dL)and plasma aldo:renin ratio

(>20 if 1°) obtain 8 a.m.paired values (offspironolactone & eplerenonefor 6 wk); Se & Sp >85%

• ACEI/ARB, diuretics, CCB can ↑renin activity → ↓ PAC/PRAratio and βBs may ↑ PAC/PRAratio;∴ avoid. ɑ-blockersgenerally best to control HTNduring dx testing.

• Confirm with sodiumsuppression test (fail tosuppress aldo after sodiumload) oral salt load (+ KCl) ×3 d, ✓ 24-h urine ( if aldo>12 µg/d while Na >200mEq/d) or 2L NS over 4 h,

measure aldo at end ofinfusion ( if aldo >5 ng/dL)

Figure 7-4 Approach tosuspected hyperaldosteronism

Treatment• Adenoma → adrenalectomy vs.

medical Rx w/ spironolactoneor eplerenone

• Carcinoma → adrenalectomy• Hyperplasia → spironolactone or

eplerenone; GRA →glucocorticoids ±spironolactone

ADRENAL INSUFFICIENCY

Etiologies• Primary = adrenocortical

disease = Addison’s diseaseautoimmune: isolated or in

assoc w/ PGA syndromes(see table on page 7-2)

infection: TB, CMV,histoplasmosis

vascular: hemorrhage (usuallyin setting of sepsis),thrombosis, HIT and trauma

metastatic disease: (90% ofadrenals must be destroyedto cause insufficiency)

deposition diseases:

hemochromatosis,amyloidosis, sarcoidosis

drugs: ketoconazole,etomidate (even after singledose), rifampin,anticonvulsants

• Secondary = pituitary failure ofACTH secretion (butaldosterone intact b/c RAAaxis) any cause of primary orsecondary hypopituitarism (see“Pituitary Disorders”)glucocorticoid therapy (can

occur after ≥2 wk of“suppressive doses”; doseeffect variable; <10 mgprednisone daily chronically

can be suppressive)megestrol (a progestin with

some glucocorticoid activity)

Clinical manifestations (NEJM1996;335:1206)• Primary or secondary:

weakness and fatigability(99%), anorexia (99%),orthostatic hypotension(90%), nausea (86%),vomiting (75%), hyponatremia(88%)

• Primary only (extra s/s due tolack of aldosterone and ↑ACTH): marked orthostatichypotension (because volume-

depleted), salt craving,hyperpigmentation (seen increases, mucous membranes,pressure areas, nipples),hyperkalemia

• Secondary only: ± othermanifestations ofhypopituitarism (see “PituitaryDisorders”)

Diagnostic studies (Annals2003;139:194)• Early a.m. serum cortisol: <3

µg/dL virtually diagnostic;≥18 µg/dL rules it out (exceptin severe septic shock—seebelow)

• Standard (250 µg) cosyntropinstimulation test (testingability of ACTH → ↑ cortisol)normal = 60-min post-ACTH

cortisol ≥18 µg/dLabnormal in primary b/c

adrenal gland diseased andunable to give adequateoutput

abnormal in chronic secondaryb/c adrenals atrophied andunable to respond

(very rarely, may be normal inacute secondary b/c adrenalsstill able to respond; earlya.m. cortisol can be usedrather than post-stim value

in these cases)• Other tests to evaluate HPA axis

(w/ guidance byendocrinologist): insulin-inducedhypoglycemia (measure serum

cortisol response);metyrapone (blocks cortisolsynthesis

and therefore stimulatesACTH, measure plasma 11-deoxycortisol and urinary

17-hydroxycorticosteroidlevels)

• Other lab abnormalities:hypoglycemia, eosinophilia,lymphocytosis, ± neutropenia

• ACTH: ↑ in 1°, ↓ or low-normal in2°

• Imaging studies to considerpituitary MRI to detect

anatomical abnormalitiesadrenal CT: small, noncalcified

adrenals in autoimmune,enlarged in metastaticdisease, hemorrhage,infection or deposition(although they may benormal-appearing)

Adrenal insufficiency & criticalillness (NEJM 2003;348:727; JAMA 2009;301:2362)• ↑ circulating cortisol despite ↓

ACTH due to ↓ clearance andpossibly stimulation bycytokines; ∴ dx of adrenalinsufficiency problematic(NEJM 2013;368:1477)

• Nonetheless, reasonable toperform ACTH stim ASAP inhypotensive Pt suspected tohave absolute adrenal insuffic.

• Initiate corticosteroids early: usedexamethasone 2–4 mg IV q6h+ fludrocortisone 50 µg dailyprior to ACTH stim; change tohydrocortisone 50–100 mg IVq6–8h once test completed.

• Rx of relative adrenal insufficiencycontroversial (see “Sepsis”)

Treatment• Acute insufficiency: volume

resuscitation w/ normal saline+ hydrocortisone IV asabove

• Chronic insufficiencyHydrocortisone: 20–30 mg PO

qd (2⁄3 a.m. 1⁄3 early p.m.)or prednisone ~5 mg POqam

Fludrocortisone (not needed in2° adrenal insufficiency):0.05–0.1 mg PO qam

backup dexamethasone 4-mgIM prefilled syringe given toPt for emergency situations

PHEOCHROMOCYTOMA

Clinical manifestations (five Ps)• Pressure (hypertension,

paroxysmal in 50%, severe &resistant to Rx, occ orthostatic)

• Pain (headache, chest pain)• Palpitations (tachycardia,

tremor, wt loss, fever)• Perspiration (profuse)• Pallor (vasoconstrictive spell)• “Rule of 10”: 10% extra-adrenal

(known as paraganglioma),10% in children,10% multiple or bilateral, 10%

recur (↑ in paraganglioma),10% malignant (↑ in

paraganglioma), 10% familial,10% incidentaloma

• Emotional stress does not triggerparoxysms, but abdominalmanipulation can triggercatecholamine release; some

reports of IV contrastcausing paroxysms

• Associated with MEN2A/2B, vonHippel Lindau,neurofibromatosis type 1,familialparaganglioma (mutations in

succinate dehydrogenasegene B, C and D)

Diagnostic studies

• 24° urinary fractionatedmetanephrines & catechols:90% Se, 98% Sp (JCEM2003;88:553). Screening test ofchoice if low-risk (as false with severe illness, renalfailure, OSA, labetalol due toassay interference, TCAs,medications containingsympathomimetics).

• Plasma free metanephrines: 99%Se, 89% Sp (JAMA2002;287:1427). Screening testof choice if high risk, but ↑ rateof false in low-preval.population.

• Adrenal CT or MRI; consider

MIBG scintigraphy if CT/MRI , PET can be used to

localize nonadrenal mass, butusually easy to find

• Consider genetic testing inappropriate circumstances(bilateral, young Pt, FHx,extra-adrenal)

Treatment• ɑ-blockade first (usually

phenoxybenzamine) ± β-blockade (often propranolol)→ surgery

• Preoperative volume expansionis critical due to possiblehypotension after tumor

excision

ADRENAL INCIDENTALOMAS

Epidemiology• 4% of Pts undergoing abdominal

CT scan have incidentallydiscovered adrenal mass;prevalence ↑ with age

Differential diagnosis• Nonfunctioning mass:

adenoma, cysts, abscesses,granuloma, hemorrhage,lipoma,myelolipoma, primary or

metastatic malignancy• Functioning mass:

pheochromocytoma, adenoma(cortisol, aldosterone, sex

hormones), nonclassical CAH,other endocrine tumor,carcinoma

• Nonadrenal mass: renal,pancreatic, gastric, artifact

Workup (NEJM 2007;356:601;JCEM 2010;95:4106)• Rule out subclinical Cushing’s

syndrome in all Pts using 1 mgovernight DST (Sp 91%).Abnormal results requireconfirmatory testing.

• Rule out hyperaldosteronism ifhypertensive w/ plasma aldo &renin (see above)

• Rule out pheochromocytoma in

ALL Pts (b/c of morbidityunRx’d pheo) using 24-h urinefractionated metanephrinesand catecholamines or plasmafree metanephrines

• Rule out metastatic cancer andinfection by history or CT-guided biopsy if suspicious (inPts w/ h/o cancer, ~50% ofadrenal incidentalomas aremalignant)

• CT and MRI characteristics maysuggest adenoma vs.carcinomaBenign features: size <4 cm;

smooth margins,homogenous and hypodense

appearance; unenhanced CT<10 Hounsfield units or CTcontrast-medium washout>50% at 10 min. Canfollow such incidentalomasw/ periodic scans.

Suspicious features: size >4 cmor ↑ size on repeat scan;irregular margins,heterogeneous, dense orvascular appearance; h/omalignancy or young age(incidentaloma lesscommon). Suchincidentalomas warrantresection or repeat scan atshort interval.

CALCIUM DISORDERS

Pitfalls in measuring calcium• Physiologically active Ca is free

or ionized (ICa). Serum Careflects total calcium (bound+ unbound) and ∴ influencedby albumin (main Ca-bindingprotein).

• Corrected Ca (mg/dL) =measured Ca (mg/dL) + {0.8

× [4 − albumin (g/dL)]}• Alkalosis will cause more Ca to

be bound to albumin (∴ totalCa may be normal but ↓ ICa)

• Best to measure ionized Cadirectly (but accuracy is labdependent)

HYPERCALCEMIA

Clinical manifestations (“bones,stones, abdominal groans andpsychic moans”)• Hypercalcemic crisis (usually

when Ca >13–15): polyuria,

dehydration, ΔMSCa toxic to renal tubules →

blocks ADH activity, causesvasoconstriction and ↓ GFR→ polyuria but Careabsorption → ↑ serum Ca→ ↑ nephrotoxicity and CNSsx

• Osteopenia, fractures and osteitisfibrosa cystica (latter seen insevere hyperpara. only →↑ osteoclast activity → cysts,

fibrous nodules, salt &pepper appearance on X-ray)

• Nephrolithiasis, nephrocalcinosis,nephrogenic DI

• Abdominal pain, anorexia,nausea, vomiting,constipation, pancreatitis,PUD

• Fatigue, weakness, depression,confusion, coma, ↓ DTRs, shortQT interval

• 1° HPT: 80% asx, 20%nephrolithiasis, osteoporosis,etc.

• Calciphylaxis (calcific uremicarteriopathy): calcification ofmedia of small- to med-sizedblood vessels of dermis & SCfat → ischemia and skinnecrosis (NEJM2007;356:1049).

Associated w/ uremia, ↑ PTH,↑ Ca, ↑ PO4 and ↑ (Ca ×PO4) product. Dx by biopsy.

Rx: aggressive wound care,keep Ca & PO4 nl (goal<55), avoid vitamin Δ & Casuppl. IV Na thiosulfate,cinacalcet, &parathyroidectomycontroversial.

Overall portends a poorprognosis

Diagnostic studies• Hyperparathyroidism and

malignancy account for 90%

of cases of hypercalcemiahyperparathyroidism more

likely if asx or chronichypercalcemia

malignancy more likely ifacute or sx; malignancyusually overt or becomes soin mos

• Ca, alb, ICa, PTH (may beinappropriately normal in 1°HPT & FHH), PO4;↑ or high nl PTH: 24-h UCa

>200 mg → HPT; 24-h UCa

<100 mg & FECa <0.01 →FHH

↓ PTH: ✓ PTHrP, AΦ, & searchfor malig (eg, CT,mammogram, SPEP/UPEP)and ✓ vit D: ↑ 25-(OH)D →meds; ↑ 1,25-(OH)2D →granuloma (✓ CXR, ACE,r/o lymph)

Treatment of asymptomatic 1°HPT (JCEM 2009;94:335)

• Surgery if: age <50 y; serum Ca>1 mg/dL >ULN; CrCl <60mL/min, DEXA T score <-2.5

• If surgery declined/deferred, canRx with bisphosphonates (↑BMD but do not ↓ Ca & PTH)or cinacalcet (↓ Ca & PTH butmay not ↑ BMD)

• If not yet candidate for surgery:✓ serum Ca & Cr annually andBMD q1–2y

HYPOCALCEMIA

Clinical manifestations• Neuromuscular irritability:

perioral paresthesias, cramps, Chvostek’s (tapping facial

nerve → contraction of facialmuscles), Trousseau’s

(inflation of BP cuff → carpalspasm), laryngospasm;irritability, depression,psychosis, ↑ ICP, seizures, ↑ QT

• Rickets and/or osteomalacia:chronic ↓ vit Δ → ↓ Ca, ↓ PO4

→ ↓ bone/cartilagemineralization, growth failure,bone pain, muscle weakness

• Renal osteodystrophy (↓ vit Δ &↑ PTH in renal failure):osteomalacia [↓ mineralizationof bone due to ↓ Ca and 1,25-(OH)2D] & osteitis fibrosacystica (due to ↑ PTH)

Diagnostic studies

• Ca, alb, ICa, PTH, 25-(OH)D,1,25-(OH)2D (if renal failure orrickets), Cr, Mg, PO4, Af, UCa

Treatment (also treat concomitantvitamin Δ deficiency)• Symptomatic: Ca gluconate (1–2

g IV over 20 mins) + calcitriol(most effective in acutehypocalcemia, but takes hrs towork) ± Mg (50–100 mEq/d)

• Asymptomatic and/or chronic:oral Ca (1–3 g/d; Ca citratebetter absorbed then Cacarbonate, esp. if on PPI) &vitamin Δ (eg, ergocalciferol50,000 IU PO q wk × 8–10

wk). In chronic hypopara.,calcitriol is needed, consideralso thiazide.

• Chronic renal failure: phosphatebinder(s), oral Ca, calcitriol oranalogue (calcimimetic may beneeded later to preventhypercalcemia)

DIABETES MELLITUS

Definition (Diabetes Care2010;33:S62; NEJM 2012;367:542)• HbA1c ≥6.5 or fasting glc ≥126

mg/dL × 2 or random glc≥200 mg/dL × 2 (× 1 ifsevere hyperglycemia andacute metabolic decomp);routine OGTT notrecommended (except duringpregnancy)

• Blood glc higher than normal, butnot frank DM (“prediabetics,”~40% U.S. population)HbA1c 5.7–6.4% or impaired

fasting glc (IFG): 100–125

mg/dLPreventing progression to DM:

diet & exercise (58% ↓),metformin (31% ↓; NEJM2002;346:393), TZD (60% ↓;Lancet 2006;368:1096)

Categories• Type 1: islet cell destruction;

absolute insulin deficiency;ketosis in absence of insulin;prevalence 0.4%; usual onsetin childhood but can occurthroughout adulthood; ↑ risk if

FHx; HLA associations; anti-GAD, anti-islet cell & anti-insulin autoAb

• Type 2: insulin resistance +relative insulin ↓; prevalence8%; onset generally later inlife; no HLA associations; riskfactors: age, FHx, obesity,sedentary lifestyle

• Type 2 DM p/w DKA (“ketosis-prone type 2 diabetes” or“Flatbush diabetes”): mostoften seen in nonwhite, ±anti-GAD Ab, eventually maynot require insulin (Endo Rev2008;29:292)

• Mature-Onset Diabetes of theYoung (MODY): autosomaldom. forms of DM due todefects in insulin secretion

genes; genetically andclinically heterogeneous (NEJM2001;345:971)

• Secondary causes of diabetes:exogenous glucocorticoids,glucagonoma (3 Ds = DM,DVT, diarrhea), pancreatic(pancreatitis,hemochromatosis, CF,resection), endocrinopathies(Cushing’s disease,acromegaly), gestational,drugs (protease inhibitors,atypical antipsychotics)

Clinical manifestations• Polyuria, polydipsia, polyphagia

with unexplained weight loss;can also be asymptomatic

Complications• Retinopathy

nonproliferative: “dot & blot”and retinal hemorrhages,cotton-wool/proteinexudates

proliferative:neovascularization, vitreoushemorrhage, retinaldetachment, blindness

treatment: photocoagulation,surgery, intravitrealbevacizumab injections

• Nephropathy: microalbuminuria→ proteinuria ± nephrotic

syndrome → renal failurediffuse glomerular basement

membranethickening/nodular pattern(Kimmelstiel-Wilson)

usually accompanied byretinopathy; lack ofretinopathy suggests anothercause

treatment: strict BP controlusing ACE inhibitors (NEJM1993;329:1456 & 351:1941;Lancet 1997;349:1787) orARBs (NEJM 2001;345:851 &861), low-protein diet,dialysis or transplant

• Neuropathy: peripheral:

symmetric distal sensory loss,paresthesias, ± motor lossautonomic: gastroparesis,

constipation, neurogenicbladder, erectile dysfxn,orthostasis

mononeuropathy: sudden-onsetperipheral or CN deficit(footdrop, CN III > VI >IV)

• Accelerated atherosclerosis:coronary, cerebral andperipheral arterial beds

• Infections: UTI, osteomyelitis offoot, candidiasis,mucormycosis, necrotizingexternal otitis

• Dermatologic: necrobiosislipoidica diabeticorum,lipodystrophy, acanthosisnigricans

Outpatient screening andtreatment goals (Diabetes Care2012;35:1364)• ✓ HbA1C q3–6mo, goal <7% for

most Pts. Can use goal HbA1C

≥7.5–8% if h/o severehypoglycemia or othercomorbidities. Microvascular &macrovascular complications ↓by strict glycemic control inT1D (NEJM 1993;329:997 &2005;353:2643) & T2D (Lancet

2009;373:1765; Annals2009;151:394).

• Microalbuminuria screeningyearly with spotmicroalbumin/Cr ratio, goal<30 mg/g

• BP≤130/80 (? ≤140/85,Archives 2012;172:1296),benefit of ACE-I; LDL < 100,TG <150, HDL >40; benefitof statins even w/o overt CAD(Lancet 2003;361:2005 &2004;364:685); ASA if age>50 ( ) or 60 ( ) or othercardiac risk factors (Circ2010;121:2694)

• Dilated retinal exam yearly;

comprehensive foot exam qy

Management of hyperglycemiain inpatients (for ICU Pts: see“Sepsis”)• Identify reversible

causes/exacerbaters (dextroseIVF, glucocorticoids, postop, ↑carb diet)

• Dx studies: BG fingersticks(fasting, qAC, qHS; or q6h ifNPO), HbA1C

• Treatment goals: avoidhypoglycemia, extremehyperglycemia (>180 mg/dL)

• Modification of outPt treatmentregimen: In T1D, do not stop

basal insulin (can → DKA).In T2D: stopping oral DM

meds generally preferred toavoid hypoglycemia or medinteraction (except if shortstay, excellent outPt cntl, noplan for IV contrast, nl diet)

• InPt insulin: can use outPtregimen as guide; if insulinnaïve:total daily insulin = wt (kg)

÷ 2, to start; adjust asneeded

give 1/2 of total daily insulinas basal insulin in long-acting form to target fasting

glcgive other 1/2 as short-acting

boluses (standing premeal &sliding scale correctiveinsulin)

• Discharge regimen: similar toadmission regimen unless pooroutPt cntl or strong reason forΔ. Arrange early insulin andglucometer teaching, promptoutPt follow-up.

DIABETIC KETOACIDOSIS (DKA)

Precipitants (the I’s)• Insulin defic. (ie, failure to take

enough insulin); Iatrogenesis(glucocorticoids)

• Infection (pneumonia, UTI) orInflammation (pancreatitis,cholecystitis)

• Ischemia or Infarction(myocardial, cerebral, gut);Intoxication (alcohol, drugs)

Pathophysiology• Occurs in T1D (and in ketosis-

prone T2D); ↑ glucagon and ↓insulin

• Hyperglycemia due to: ↑

gluconeogenesis, ↑glycogenolysis, ↓ glucoseuptake into cells

• Ketosis due to: insulin deficiency→ mobilization and oxidationof fatty acids,↑ substrate for ketogenesis, ↑

ketogenic state of the liver, ↓ketone clearance

Clinical manifestations (DiabetesCare 2003;26:S109)• Polyuria, polydipsia, &

dehydration → ↑ HR, HoTN,dry mucous membranes, ↓ skinturgor

• N/V, abdominal pain (either due

to intra-abdominal process orDKA), ileus

• Kussmaul’s respirations (deep) tocompensate for metabolicacidosis with odor of acetone

• Δ MS → somnolence, stupor,coma; mortality ~1% even attertiary care centers

Diagnostic studies• ↑ Anion gap metabolic

acidosis: can later developnonanion gap acidosis due tourinary loss of ketones (HCO3

equivalents) and fluidresuscitation with chloride

• Ketosis: urine and serum

ketones (predominant ketoneis β-OH-butyrate, butacetoacetate measured byassay; urine ketones may be in fasting normal Pts)

• ↑ Serum glc; ↑ BUN & Cr(dehydration ± artifact due toketones interfering w/ someassays)

• Hyponatremia: corrected Na =measured Na + [2.4 ×(measured glc −100)/100]

• ↓ or ↑ K (but even if serum K iselevated, usually total body Kdepleted); ↓ total body phos

• Leukocytosis, ↑ amylase (even ifno pancreatitis)

HYPEROSMOLARHYPERGLYCEMIC STATE

Definition, precipitants,pathophysiology (Diabetes Care2003;26:S33)• Extreme hyperglycemia (w/o

ketoacidosis) + hyperosm. +Δ MS in T2D (typically elderly)

• Precip same as for DKA, but alsoinclude dehydration and renalfailure

• Hyperglycemia → osmoticdiuresis → vol depletion →prerenal azotemia → ↑ glc, etc.

Clinical manifestations & dxstudies (Diabetes Care

2006;29[12]:2739)• Volume depletion and Δ MS• ↑ serum glc (usually >600

mg/dL) and ↑ meas. serumosmolality (>320 mOsm/L)effective Osm = 2 × Na(mEq/L) + glc (mg/dL)/18

• No ketoacidosis; usually ↑ BUN &Cr; [Na] depends onhyperglycemia & dehydration

Treatment (r/o possibleprecipitants; ~15% mortality dueto precipitating factors)• Aggressive hydration: initially

NS, then 1/2 NS, average fluidloss up to 8–10 L

• Insulin (eg, 10 U IV followed by0.05–0.1 U/kg/h)

HYPOGLYCEMIA

Clinical manifestations (glucose<~55 mg/dL)• CNS: headache, visual Δs, Δ MS,

weakness, seizure, LOC(neuroglycopenic sx)

• Autonomic: diaphoresis,palpitations, tremor(adrenergic sx)

Etiologies in diabetics• Excess insulin, oral

hypoglycemics, missed meals,renal failure (↓ insulin & SUclearance)

• β-blockers can mask adrenergicsymptoms of hypoglycemia

Etiologies in nondiabetics• ↑ insulin: exogenous insulin,

sulfonylureas, insulinoma,anti-insulin antibodies

• ↓ glucose production:hypopituitarism, adrenalinsufficiency, glucagondeficiency, hepatic failure,renal failure, CHF, alcoholism,sepsis, severe malnutrition

• ↑ IGF-II: non-islet tumor• Postprandial, esp.

postgastrectomy or gastricbypass: excessive response toglc load

• Low glc w/o sx can be normal

Evaluation in nondiabetics (JClin Endocrinol Metab 2009;94:709)• If clinically ill: take measures to

avoid recurrent hypoglycemia;✓ BUN, Cr, LFTs, TFTs,prealbumin; IGF-I/IGF-II ratiowhen appropriate

• If otherwise healthy: 72-h fast w/monitored blood glc; stop forneuroglycopenic sx

• At time of hypoglycemia: insulin, Cpeptide (↑ w/ insulinoma andsulfonylureas, ↓ w/ exogenousinsulin), β-OH-butyrate,sulfonylurea levels

• At end of fast, give 1 mgglucagon IV and measure

response of plasma glc beforefeeding

Treatment• Glucose tablets, paste, fruit juice

are first-line Rx for Pts whocan take POs

• If IV access available, give 25–50g of D50 (50% dextrose)

• If no IV, can give glucagon 0.5–1mg IM or SC (side effect: N/V)

LIPID DISORDERS

Measurements• Lipoproteins = lipids

(cholesteryl esters &triglycerides) + phospholipids+ proteinsinclude: chylomicrons, VLDL,

IDL, LDL, HDL, Lp(a)• Measure after 12-h fast; LDL is

calculated = TC – HDL –(TG/5) (if TG >400, orderdirect LDL measurement as

calc. LDL inaccurate). Lipidlevels stable up to 24 h

after ACS and other acuteillnesses, then ↓ and may

take 6 wk to return to nl.• Metabolic syndrome (≥3 of

following): waist ≥40” ( ) or≥35” ( ); TG ≥150; HDL <40mg/dL ( ) or <50 mg/dL ( );BP ≥130/85 mmHg; fastingglc ≥100 mg/dL (Circ2009;120:1640)

Primary dyslipidemias

• Familial hypercholesterolemia(FH, 1:500): defective LDLreceptor; ↑↑ chol, nl TG; ↑ CAD

• Familial defective apoB100 (FDB,1:1000): similar to FH

• Familial combinedhyperlipidemia (FCH, 1:200):polygenic; ↑ chol, ↑ TG, ↓ HDL;↑ CAD

• Familial dysbetalipoproteinemia(FDBL, 1:10,000): apoE ε2/ε2+ DM, obesity, renal disease,etc.;↑ chol and TG;tuberoeruptive and palmarstriated xanthomas; ↑ CAD

• Familial hypertriglyceridemia(FHTG, 1:500): ↑ TG, ± ↑ chol,

↓ HDL, pancreatitisPhysical exam findings• Tendon xanthomas: seen on

Achilles, elbows and hands;imply LDL >300 mg/dL

• Eruptive xanthomas: pimple-likelesions on extensor surfaces;imply TG >1000 mg/dL

• Xanthelasma: yellowish streakson eyelids seen in variousdyslipidemias

• Corneal arcus: common in olderadults, imply hyperlipidemiain young Pts

Treatment• Every 1 mmol (39 mg/dL) ↓ LDL

→ 22% ↓ major vascular

events (CV death, MI, stroke,revasc) in individuals w/ &w/o CAD (Lancet2010;376:1670); in healthyindividuals w/ LDL <130mg/dL & hs-CRP >2,rosuvastatin → 47% ↓CVD/MI/stroke (NEJM2008;359:2195)

• Fewer clinical data, but TG <400and HDL >40 are additionalreasonable targets

ARTHRITIS—OVERVIEW

Approach to patient with jointpain• Articular vs. periarticular

(bursitis, tendinitis) pain:typically active ROM morepainful in periarticular processthan passive ROM

• Inflammatory vs.noninflammatory pain:features of inflammatory paininclude swelling, warmth orredness in specific joint,persistence over days toweeks, prolonged morningstiffness (>30 min),improvement of pain/stiffness

w/ motion/exercise• Physical exam (see table):

localize complaint and identifyobjective signs ofinflammation

• The physical exam is only 50–70%sensitive for detectinginflammatory arthritis

aMay initially present as arthralgiaw/o signs of overt arthritis. bRangeof motion (ROM) of joint or jointassociated with bursa or tendon.

Approach to arthritisFigure 8-1 Approach to arthritis

Radiologic features• OA

plain films: osteophyes, asymjoint space narrowing (JSN),subchondral sclerosis/cystsMRI may show early diseasenot seen on plain films; U/S MRI for structural damage

• RAplain films:early=periarticularosteopenia; late=erosions,symmetric JSN MRI & U/S ableto detect early and subclinicaldisease; MRI U/S forerosions

• Gout

plain films: early=nonspecswelling; late=tophus, jointerosions w/ overhanging edgesU/S > MRI for detection ofmicrotophi (double contoursign); MRI U/S for erosions

• Spondyloarthritis (sacroiliacjoint)plain films: pseudo-wideningof joint space (early), sclerosis,erosions, ankylosis MRI mostsensitive for early Δ in SIJ;U/S MRI for early detectionof peripheral enthesitis

INFLAMMATORY MARKER &AUTOANTIBODY TESTING

Inflammatory markers (ModRheumatol 2009;19:469)• ESR: indirect measure of

inflammation (↑ RBCaggregation due to acute-phaseproteins); slow to rise; ↑ w/age, pregnancy, anemia,obesity

• CRP: direct measure ofinflammation (proteinproduced by liver, part ofinnate immune system);typically rises and falls beforethe ESR w/

treatment/resolution ofprocess

Autoantibody testing• ANA: screening test for Ab

directed against extractablenuclear antigens (ENAs) foundin autoimmune conditions,most useful in testing forconnective tissue diseases

• ENAs: proteins precipitated fromspleen extracts; targets aregenerally of nuclear origin

• Order ANA only when clinicalsuspicion for disease b/cnonspecific: 1:40 (low , 25–30% of healthy people); 1:80

(low , 10–15% of healthypeople); ≥1:160 ( , 5% ofhealthy). May be in Pts priorto clin manifest (NEJM2003;349:1526; Arthritis ResTher 2011;13:1).

• Does not correlate well w/disease activity, ∴ no clinicalvalue in serial testing

• dsDNA and ENA antibodies(Ro/La/Smith/RNP) are highlyspecific for various CTD andcan be used to further w/u ANA in setting of clinicalsuspicion

• RF and anti-CCP can be seen inCTD but are not specific

RHEUMATOID ARTHRITIS (RA)

Definition & epidemiology(Lancet 2010;376:1094; NEJM2011;365:2205)• Chronic, symmetric, debilitating

and destructive inflammatorypolyarthritis characterized byproliferative synovial tissue(pannus) formation in affectedjoints

• Genetic (~50% of risk) &environmental factors (eg,smoking, silica dust exposure)

• ↑ risk w/ shared epitope & smokeb/c gene–environmentinteraction (Ann Rheum Dis

2010;69:70)• Prevalence=1% adults; 5% of

>70 y; to ratio=3:1; peakincidence 50–75 y

Clinical manifestations(Medicine 2010;38:167)• Usually insidious onset pain,

swelling and impairedfunction of joints (typicallyPIPs, MCPs, wrists, knees,ankles, MTPs and cervicalspine) with morning stiffnessfor ≥1 h

• Typically polyarticular (60%small joints, 30% large joints,10% both), may be

monoarticular (knee, shoulder,wrist) early in course; nb,rheumatoid joints can becomeinfected

• Joint deformities: ulnardeviation, swan neck (MCPflexion, PIP hyperextension,DIP flexion), boutonnière(PIP flexion, DIPhyperextension), cock-updeformities (toes)

• C1–C2 instability →myelopathy, ∴✓ C-spineflex/ext films prior to electiveintubation

• Constitutional symptoms: low-grade fever, weight loss,

malaise• Extra-articular manifestations

(18–41% of Pts) can occur atany time; ↑ frequency inseropositive (RF or anti-CCP)(Autoimmun Rev 2011;11:123)

Laboratory & radiologic studies• RF (IgM/IgA/IgG anti-IgGAb) in

~70% of Pts; also seen inother rheumatic diseases (SLE,Sjögren’s), infection (SBE,hepatitis, TB), types II & IIIcryo, 5% of healthy population

• Anti-CCP (Ab to cycliccitrullinated peptide): in~80% of Pts, similar Se(~70%), more Sp (>90%)than RF particularly for earlyRA (Arth Rheum2009;61:1472); a/w increasedjoint damage and lowremission rates

• ~20% are seronegative (RF and

anti-CCP negative)• ↑ ESR/CRP but nl in ~30%;

ANA in ~15%; ↑ globulinduring periods of activedisease

• Radiographs of hands and wrists:periarticular osteopenia, boneerosions, joint subluxation

ACR/EULAR classificationcriteria (Arth Rheum2010;62:2569)• Use for Pts with ≥1 joint with

synovitis not better explainedby another disease

• Summed score of ≥6 c/w RA

Management (Lancet2009;373:659; Ann Rheum Dis2010;69:631)• Early dx and Rx (esp. DMARD)

w/ frequent follow-up andescalation of Rx as needed toachieve clinical remission or lowdisease activity

• ↓ time to remission ↑ length ofsustained remission (Arthritis

Res Ther 2010;12:R97)• Sero- disease (eg, RF or anti-

CCP) a/w aggressive jointdisease & EAM

• Start both rapid acting agent (toacutely ↓ inflammation) andDisease-Modifying Anti-Rheumatic Drug (DMARD)(typically take 1–3 mo to havemax effect) at dx

• Rapid-acting drugs: NSAIDs orCOX-2 inhibitors (↑ CV adverseevents);glucocorticoids [low-dose

(<20 mg/d oral) or jointinjection]; or

NSAIDs + glucocorticoids: ↑ GI

adverse events, minimizelong-term concurrent use

• DMARDsMTX (1st line unless CKD,

hepatitis, EtOH or lungdisease), SAS or leflunomide;consider HCQ ifseronegative and milddisease;

if inadequate response after 3mo (despite DMARD doseescalation): combinationRx w/ other traditionalDMARDs (ie, MTX, SAS andHCQ) or biologic (anti-TNFtypically 1st line unlesscontraindication)

• Given ↑ r/o early CVmorbidity/mortality, ↓ risk w/lifestyle mgmt, lipid & DMscreening

ADULT ONSET STILL’S DISEASE& RELAPSING

POLYCHONDRITIS

Adult onset Still’s disease (Drugs2008;68:319)• Rare autoinflammatory synd;

= w/ typical onset 16–35 y;sx evolve over wks to mos

• Dx if 5 criteria are present & ≥2major; exclude infxn, malig,other rheumatic, drug rxnmajor: fever ≥39°C for ≥1

wk (usually daily or twicedaily high-spiking fever);arthralgias/arthritis ≥2 wk;Still’s rash (qv); ↑ WBC w/

80% PMNminor: sore throat; LAN; HSM;

↑ AST/ALT/LDH; negativeANA & RF

• Still’s rash (>85%): nonpruriticmacular or maculopapularsalmon-colored rash; usuallytrunk or extremities; may beprecipitated by trauma(Koebner phenomenon), warmwater

• Plain films: soft tissue swelling(early) → cartilage loss,erosions, carpal ankylosis(late)

• Treatment: NSAIDs, steroids;steroid-sparing: MTX,

anakinra, anti-TNF,tocilizumab

• Variable clinical course: 20% w/long-term remission; 30%remit-relapse; ~50% chronic(esp. arthritis); ↑ risk ofmacrophage activationsyndrome (life-threatening)

Relapsing polychondritis(Autoimmun Rev 2010;9:540)• Inflammatory destruction of

cartilaginous structures; onsetusually age 40–60 y, =

• Subacute onset of red, painfuland swollen cartilage;ultimately atrophic &

deformed• Common clinical features:

bilateral auricular chondritis;nonerosive inflammatoryarthritis; nasal chondritis;ocular inflammation; laryngealor tracheal chondritis; cochlearand/or vestibular dysfxn

• 40% of cases a/w immunologicdisorder (eg, RA, SLE, vasc.,Sjögren’s), cancer or MDS

• Clinical diagnosis based on examwith multiple sites ofcartilaginous inflammation

• Labs: ↑ ESR & CRP, leukocytosis,eosinophilia, anemia ofchronic inflammation

• Bx (not req for dx): proteoglycandepletion, perichondrialinflammation and replacementwith granulation tissue andfibrosis; immunofluorescencewith Ig and C3 deposits

• Screen for pulm (PFTs, CXR/CT,± bronch) and cardiac (ECG,TTE) involvement

• Therapy guided by diseaseactivity and severity: steroids1st line; NSAIDs, dapsone forsx control of arthralgias andmild disease; MTX or AZA forsteroid-sparing;cyclophosphamide for organ-threatening disease

CRYSTAL DEPOSITIONARTHRITIDES

GOUT

Definition & epidemiology(Lancet 2010;375:318; NEJM2011;364:443)• Humans lack enzyme to

metabolize urate (end-productof purine metabolism)

• Monosodium urate (MSU) crystaldeposition in joints promotesinflammation

• > (9:1); peak incidence 5thdecade; most common cause ofinflammatory arthritis in

over 30 y; rare inpremenopausal (estrogenspromote renal urate excretion)

(Lancet 2004;363:1277; NEJM2004;350:1093; Ann Rheum Dis2012;71:1448)

Clinical manifestations• 4 stages: asx ↑ UA → acute gouty

arthritis → intercritical (in

between acute flares, usuallyasx) → chronic goutyarthropathy/tophaceous gout

• Asx hyperuricemia: majoritynever develop gout

• Acute arthritis: sudden onset(freq. nocturnal) of painfulmonoarticular arthritisMTP of great toe (podagra);

LE > UE; occasionallypolyarticular (esp. in subseqflares)

precipitants: rapid Δ UA; ↑dietary purine; surgery;infection; dehydration, meds(diuretics, urate loweringagents); ∴ frequent in

hospitalized Ptsself-limited in 3–10 d; can

involve bursa (eg, olecranonor patella); can mimiccellulitis

• Intercritical period: may beyears but progressively shorteras freq of attacks ↑

• Chronic tophaceous gout: solidMSU crystal deposition intissue & joints; commonly injoints (fingers, wrists, knees),pinna, Achilles tendon andpressure areas;chronic gouty arthropathy:

deforming arthritis fromtophus → pain, joint erosion

• Renal: uric acid stones; uratenephropathy (interstitialdeposits)

Diagnostic studies• ↑ UA does not make dx: 25% of

measurements nl during flare;± ↑ WBC & ESR

• Arthrocentesis: polarizedmicroscopy → needle-shaped,negatively birefringentcrystals (yellow parallel toaxis marked on polarizer),intracellular or extracellular(less specific)WBC 20,000–100,000/mm3,

>50% polys

infxn can coexist with acuteattacks, ∴ always ✓ Gramstain & Cx (J Rheum2012;39:157)

• Radiology: erosions withoverhanging edge (late), usefulto exclude chondrocalcinosis

Acute treatment (Arthritis Care Res2012;64:1447)• No superior option; start w/in 24

h of sx onset; continue untilacute flare resolves; for severecases, consider combinationtherapy; rest and ice

Chronic treatment (Lancet2011;377:165)• Approach: if ≥2 attacks/y, ≥1

tophus, joint erosions orurolithiasis → start uratelowering Rx & pharmacologicprophylaxis to ↓ risk of acuteattacks

• Urate lowering Rx: goal UA <6mg/dL; do NOT discontinue

during acute attack• Pharmacologic prophylaxis:

continue for at least 6 mo orlonger if frequent attacks:low-dose colchicine (~50% ↓

risk of acute flare; J Rheum2004;31:2429), NSAIDs (lessevidence; Ann Rheum Dis2006;65:1312), low-dose(<10 mg/d) steroids (minevidence)

• Lifestyle Δs: ↓ intake of meat,EtOH & seafood; ↑ low-fatdairy products; wt loss; avoiddehydration andhyperuricemia-promotingdrugs (eg, diuretics)

• Allopurinol hypersensitivitysyndrome: 10–25% mortality;↓ risk by starting w/ dose100 mg/d if eGFR >40 or 50mg/d if eGFR <40; titrate upby 100 mg/d (if eGFR >40) or50 mg/d (if eGFR <40) q2–5wk until goal UA (<6mg/dL) reached (dose can be

>300 mg/d even in CKD)(Arthritis Rheum2012;64:2529; Arthritis CareRes 2012;64:1431)

CALCIUM PYROPHOSPHATEDIHYDRATE (CPPD) DEPOSITION

DISEASE

Definition• Deposition of CPPD crystals w/in

tendons, ligaments, articularcapsules, synovium, cartilage;frequently asymptomatic

Etiologies (Rheumatology2012;51:2070)• Most cases idiopathic; consider

further metabolic eval inyoung (<50 y) and floridforms

• Metabolic (3 H’s):hemochromatosis;

hyperparathyroidism;hypomagnesemia (esp. inGitelman’s or Bartter’ssyndromes)

• Joint trauma (incl. previoussurgery); intra-articularhyaluronate can precipitateattacks

• Familial chondrocalcinosis(autosomal dominantdisorder); early-onset,polyarticular dis.

Clinical manifestations(Rheumatology 2009;48:711)• Chondrocalcinosis: calcification

of cartilage, resulting from

CPPD deposition in articularcartilage, fibrocartilage ormenisci.↑ incidence w/ age; 20% >60

y have kneechondrocalcinosis in autopsystudies

• Pseudogout: acute CPPD crystal-induced mono- or asymmetricoligoarticular arthritis,indistinguishable from goutexcept through synovial fluidexam for crystalslocation: knees, wrists and

MCP jointsprecipitants: surgery, trauma

or severe illness

• “Pseudo-RA”: chronicpolyarticular arthritis withmorning stiffness

• Pyrophosphate arthropathy:resembles OA and difficult todistinguish; may involve axialskeleton

Diagnostic studies• Arthrocentesis

polarized microscopy →rhomboid-shaped, weaklypositively birefringentcrystals (yellowperpendicular and blueparallel to axis marked onpolarizer)

WBC 2000–100,000/mm3,>50% polys

infection can coexist withacute attacks, ∴ always ✓Gram stain & Cx

• Screen for associated disease ifyoung or severe: ✓ Ca, Mg, Fe,ferritin, TIBC, UA, PTH

• Radiographs: chondrocalcinosisappears as punctate and lineardensities in articular cartilage,menisci, triangularfibrocartilage of wrist, smalljoints of fingers and symphysispubis; may be asx (15% in Pts>60 y, 30–60% in Pts >80 y)not a prerequisite for the

diagnosis of CPPD disease

Treatment (Ann Rheum Dis2011;70:571)• Asymptomatic chondrocalcinosis

requires no treatment• Acute therapy for pseudogout: no

RCTs, extrapolated frompractice in gout; ∴same as forgout, though colchicine not aseffective

• If associated metabolic disease,Rx of underlying disorder mayimprove arthritis sx

• Low-dose daily colchicine orNSAID may be effective forprophylaxis or chronic

arthropathy

SERONEGATIVESPONDYLOARTHRITIS

Classification system (Curr OpinRheumatol 2010;22:375)• 5 subtypes: ankylosing

spondylitis (most common),reactive arthritis, psoriaticarthritis, IBD-associatedarthritis and undifferentiated

• All subtypes share commonclinical manifestations:inflammatory spine disease,peripheral arthritis, enthesitisand extra-articularmanifestations (primarilyocular and skin disease)

Epidemiology & pathogenesis(Semin Arthritis Rheum 2008;38:83)• ↑ prevalence of HLA-B27; HLA-

B27 accounts for ~30% ofattributable genetic risk

• Environmental factors likelycritical for disease, esp.reactive arthritis (eg,infection)

• Prevalence of 0.5–2% ofpopulation, worldwide

Major clinical manifestations(Lancet 2011;377:2127)• Inflammatory back pain: SI

joints (sacroiliitis),apophyseal joints of spinecharacterized by IPAIN

(Insidious onset, Pain atnight, Age of onset <40 y,Improves w/ exercise/hot

water, No improvement w/rest), a.m. stiffness,responsive to NSAIDs

• Peripheral arthritis: typicallyasymmetric, oligoarticular,large joints, lower > upperlimb; however, can besymmetric & polyarticular(thus, mimic RA), esp. inpsoriatic arthritis

• Enthesitis: inflammation at siteof tendon/ligament insertioninto bone, esp. Achilles, pre-patellar, elbow epicondyles,plantar fasciitis. Rigidity ofspine (bamboo spine by X-ray,ankylosis due to progressive

growth of bony spurs whichbridge intervertebral disc).

• Dactylitis (“sausage digit”):inflammation of entire digit(joint + tenosynovialinflamm)

• Uveitis: anterior uveitis mostcommon extra-articularmanifestation; p/w pain, redeye, blurry vision,photophobia, usuallyunilateral

Descriptions of skinmanifestations• Psoriasis: erythematous plaques

with sharply defined marginsoften w/ thick silvery scale

• Circinate balanitis: shallow,painless ulcers of glans penisand urethral meatus

• Keratoderma blennorrhagica:hyperkeratotic lesions on solesof feet, scrotum, palms, trunk,scalp

• Erythema nodosum: red tendernodules due to panniculitis,typically on shins; Ddx incl.idiopathic, infxn, sarcoid,drugs, vasculitis, IBD,lymphoma

• Pyoderma gangrenosum:neutrophilic dermatosis →painful ulcers w/ violaceousborder; Ddx incl. idiopathic,

IBD, RA, myelogenousleukemia

Psoriatic arthritis subtypes(Lancet 2011;377:2127)• Monoarticular/oligoarticular

(eg, large joint, DIP joint,dactylitic digit): most commoninitial manifestation

• Polyarthritis (small joints of thehands/feet, wrists, ankles,knees, elbows):indistinguishable from RA, butoften asymmetric

• Arthritis mutilans: severedestructive arthritis with boneresorption, esp. hands

• Axial disease: similar toankylosing spondylitis ±peripheral arthritis

• DIP-Limited: good correlationwith nail pitting andonycholysis

Clinical assessment (Nat RevRheumatol 2012;8:253)• Axial disease assessment

Severity of lumbar flexiondeformity assessed bymodified Schober’s test ( if<5 cm ↑ in distancebetween a point 5 cm belowthe lumbosacral jxn andanother point 10 cm above,

when going from standing tomaximum forward flexion)

T-spine mobility (extension)and kyphosis severitymeasured by occiput-to-walldistance

• Seronegative: notable forabsence of rheumatoid factoror autoantibodies; ± ↑ ESR

• HLA-B27: nonspecific, ascommon in general population(6–8%); most useful when highclinical suspicion but nlimaging; 90% of Pts w/ AS,but only 20–80% in other SpA

• RadiologyMRI preferred for early

detection of inflammation(sacroiliitis)

Plain films detect latestructural changes (SIerosions/sclerosis)

calcification of spinalligaments w/ bridgingsymm syndesmophytes(“bamboo spine”)

squaring and generalizeddemineralization ofvertebral bodies (“shinycorners”)

• Infectious evaluation forreactive arthritis ( studiesdo not r/o)U/A, PCR of urine and/or

genital swab for Chlamydia;urethritis usually due toChlamydia infxn precedingarthritis, but also can seesterile urethritis postdysentery

stool Cx, C. diff toxinconsider HIV in workup of

reactive or psoriatic arthritis

Treatment approach (Lancet2011;377:2127; Rheumatology2012;51:1378)• Untreated disease may lead to

irreversible structural damageand associated ↓ function

• Early physiotherapy beneficial

• NSAIDs: 1st line; rapidly ↓stiffness and pain; prolonged,continuous administration maymodify disease course butassociated w/ GI and CVtoxicity

• Intra-articular corticosteroidsin mono- or oligoarthritis;limited role for systemicsteroids, esp. for axial disease

• Conventional DMARDs (eg,MTX and SAS): no efficacy foraxial disease or enthesitis; mayhave role in peripheralarthritis, uveitis and otherextra-articular manifestations

• Anti-TNFs: effective for both

axial and peripheralmanifestations; improvesfunction (Ann Rheum Dis2006;65:423) and may slowprogression of structuralchanges (Curr Rheumatol Rep2012;14:422); unclear role ofother biologics

• OtherAbx in reactive arthritis if

evidence of active infxn;consider prolonged abx forrefractory Chlamydia ReA(Arthritis Rheum2010;62:1298)

Involve ophthalmologist forany evidence of

inflammatory eye disease(may benefit from steroideye drops or intravitrealsteroid injections)

Treat underlying IBD whenappropriate

INFECTIOUS ARTHRITIS &BURSITIS

ETIOLOGIES & DIAGNOSIS OFINFECTIOUS ARTHRITIS

Etiologies• Bacterial (nongonococcal): early

diagnosis required• Gonococcal (N. gonorrhea):

consider in sexually activeyoung adults

• Viral: parvovirus, HCV, HBV,acute HIV; typicallypolyarticular, may mimic RA

• Mycobacterial: monoarticular oraxial (Pott’s disease)

• Fungal: Candida (esp. prostheticjoints), coccidiomycosis (valleyfever), histoplasmosis

• Other: Lyme, mycoplasma

Diagnosis (JAMA 2007;297:1478)• H&P w/ poor sensitivity and

specificity for septic arthritis;∴ arthrocentesis should beperformed as soon assuspected

• Take care not to tap through aninfected area thus introducinginfxn into joint space

• ✓ Synovial fluid cell count, Gramstain, bacterial culture, crystalsWBC >50k w/ poly predom

suspicious for bact. infxn;crystals do not r/o septicarthritis!

BACTERIAL (NONGONOCOCCAL)ARTHRITIS

Epidemiology & risk factors• Immunocompromised host:

diabetics, HIV, elderly, SLE,etc.

• Damaged joints: RA, OA, gout,trauma, priorsurgery/prosthetic, priorarthrocentesis (rare)

• Bacterial seeding: bacteremiasecondary to IVDU,endocarditis or skin infectiondirect inoculation or spread

from contiguous focus (eg,cellulitis, septic bursitis,

osteo)

Clinical manifestations (JAMA2007;297:1478; Lancet2010;375:846)• Acute onset monoarticular

arthritis (>80%) w/ pain (Se85%), swelling (Se 78%),warmth

• Location: knee (most common),hip, wrist, shoulder, ankle. InIVDU, tends to involve otherareas (eg, sacroiliac joint,symphysis pubis,sternoclavicular and manubrialjoints).

• Constit. sx: fevers (Se 57%),

rigors (Se 19%), sweats (Se27%), malaise, myalgias, pain

• Infection can track from initialsite to form fistulae, abscessesor osteomyelitis

• Septic bursitis must bedifferentiated from septicintra-articular effusion

Additional diagnostic studies(JAMA 2007;297:1478)• Synovial fluid: WBC usually

>50k (Se 62%, Sp 92%) butcan be <10k, >90% polys;Gram stain in ~75% ofStaph, ~50% of GNR; Cx in>90%.

Synovial bx for Cx most sens.• Leukocytosis (Se 90%, Sp 36%)• Blood cultures in >50% of

cases, ~80% when more than1 joint involved

• Conventional radiographsusually normal until after ~2wk of infection when bonyerosions, joint spacenarrowing, osteomyelitis,periostitis can be seen

• CT & MRI useful esp. forsuspected hip infection orepidural abscess

Treatment (for native joints)• Prompt empiric antibiotics guided

by Gram stain after surgicaldrainage. If Gram stain ,empiric Rx w/ vancomycin;add anti-pseudomonal agent ifelderly, immunosupp.

• Tailor antibiotics based on Gramstain, culture results, & clinicalcourse

• IV antibiotics × ≥2 wkfollowed by oral antibiotics;varies by clinical course &microbiology

• Joint must be drained, oftenserially; surgical drainage(usually arthroscopic), esp. forlarger joints and as initialtreatment, but may also beaccomplished byarthrocentesis.Serial synovial fluid analyses

should demonstrate ↓ inWBC and sterility.

• Prognosis: 10–50% mortalitydepending on virulence oforganism, time to Rx, host

Prosthetic joint infections (InfectDis Clin North Am 2012;26:29; CID2013;66:e1)• ↑ risk in first 2 y s/p procedure;

rate generally low (0.5–2.4%);risk factors include obesity,RA, immunocompromisedstate, steroids, & superficialsurgical site infxn

• Staphylococci (coag negative & S.aureus) in >50%;polymicrobial in 10–20%

• Early (<3 mo s/p surgery) ordelayed (3–24 mo) onsettypically acquired duringimplantation; early w/virulent organisms (eg, MRSA)

and delayed w/ less virulentorganisms (eg, P. acnes, coagnegative Staph) & moreindolent presentation

• Late (>24 mo) onset typicallyrelated to secondaryhematogenous seeding

• Diagnosis requires arthrocentesisby orthopedics; ESR & CRP canbe helpful

• Treatment typically requiresprolonged abx & two-stagejoint replacement (jointretention a/w ~40% failurerate; CID 2013;56:182) or life-long suppressive abx. ID andorthopedics consultation

required.

DISSEMINATED GONOCOCCALINFECTION (DGI)

Epidemiology (Infect Dis ClinNorth Am 2005;19:853)• N. gonorrhea; most frequent type

of infectious arthritis insexually active young adults

• Normal host as well as Pts w/deficiencies of terminalcomponents of complement

• : =4:1; ↑ incidence duringmenses, pregnancy, &postpartum period; ↑ incidencein homosexual males; rareafter age 40 y


• Preceded by mucosal infection(eg, endocervix, urethra orpharynx) that is often asx

• Two distinct syndromes:Joint localized: purulent

arthritis (40%), usually 1–2joints (knees > wrists >ankles)

DGI: triad of polyarthralgias,tenosynovitis, skinlesions; purulent arthritisrare

acute onset of tenosynovitis(60%) in wrists, fingers,ankles, toes rash (>50%):gunmetal gray pustules witherythematous base on

extremities & trunk• Rare complications: Fitz-Hugh-

Curtis syndrome(perihepatitis), pericarditis,meningitis, myocarditis,osteomyelitis from directextension of joint-localizedinfection

Additional diagnostic studies• Synovial fluid: WBC >50k (but

can be <10k), polypredominantGram stain in ~25%; culture

in up to 50% if done w/Thayer-Martin media

• Blood culture: more likely in

DGI; rarely in joint localizeddisease

• Gram stain and culture of skinlesions occasionally

• Cervical, urethral, pharyngeal,rectal PCR or cx on Thayer-Martin media; ✓ Chlamydia

Treatment• Ceftriaxone or cefotaxime ¥ 7

Δ w/ empiric doxycycline forChlamydia (fluoroquinolonesno longer recommended due toresistance)

• Joint arthroscopy/lavage may berequired if purulent arthritis;rarely >1 time

OLECRANON & PREPATELLARBURSITIS

Epidemiology & risk factors(Infect Dis North Am 2005;19:991)• >150 bursae in the body; 2 most

commonly infected areolecranon and prepatellar

• Most commonly (esp. superficialbursae) due to direct trauma,percutaneous inoculation orcontiguous spread fromadjacent infection (eg,cellulitis)

• Other risk factors: recurrentnoninfectious inflammation(eg, gout, RA, CPPD), diabetes

• S. aureus (80%) most common,followed by streptococci

Diagnosis• Physical exam: discrete bursal

swelling, erythema, maximaltenderness at center of bursawith preserved joint range ofmotion

• Aspirate bursa if concern forinfxn, ✓ cell count, Gramstain, bacterial cx, crystalsWBC >20k w/ poly

predominance suspiciousfor bacterial infection, butlower counts common(crystals do not rule out

septic bursitis!)• Assess for adjacent joint effusion,

which can also be septic• Take care not to tap through

infected skin thus introducinginfxn into bursa

Initial therapy• Prompt empiric coverage for

staphylococci and streptococci:PO abx acceptable for mildpresentation; vancomycin ifill-appearing; broadenspectrum based on risk factors

• Modify antibiotics based onGram stain, culture results, &clinical course

• Duration of therapy is 1–4 wk• Serial aspirations every 1–3 Δ

until sterile or noreaccumulation of fluid

• Surgery if unable to drain bursathrough aspiration, evidence offoreign body or necrosis,recurrent/refractory bursitisw/ concern for infxn ofadjacent structures

CONNECTIVE TISSUE DISEASES

• Autoantibody testing is directedby clinical findings, asautoantibodies themselves donot define a particularconnective tissue disease

• Overlap syndromes encompassingmore than one connectivetissue disorder may bereflected serologically by thepresence of multipleautoantibodies

see “Systemic Lupus Erythematosus”and “Rheumatoid Arthritis” for those

diseases

SYSTEMIC SCLEROSIS ANDSCLERODERMA DISORDERS

Definition & epidemiology (BestPract Res Clin Rheumatol2010;24:857)• Scleroderma refers to the

presence of tight, thickenedskin

• Localized scleroderma:morphea (plaques of fibroticskin), linear (fibrotic bands),“en coup de saber” (linearscleroderma on one side ofscalp and forehead saberscar)

• Systemic sclerosis

(SSc)=scleroderma + internalorgan involvement. Subgroups:SSc w/ limited cutaneous

diseaseSSc w/ diffuse cutaneous

disease: rapidly progressivedisorder affecting skin

SSc sine scleroderma (visceraldisease without skininvolvement, rare)

• Peak onset of SSc between ages30–50; > (7:1); AfricanAmerican > white

• 1–2/100,000 annual incidence ofsystemic disease in the U.S.

• Pathogenesis: immune damage to

endothelial cells and reactiveO2 species production →persistent oxidative stress →perivascular inflammation →fibroblast activation andfibrosis. Cytokines, growthfactors, genetics,environmental factors andautoantibodies (against PDGFreceptor, endothelial cells andfibroblasts) all contribute(NEJM 2009;360:1989).

Classification criteria (1 major or2 minor; 97% Se, 98% Sp; ArthRheum 1980;23:581)• Major: skin findings extend

proximal to MCP or MTPjoints

• Minor: sclerodactyly (skinfindings limited to the fingers)digital pitting scars from loss

of substance on the fingerpad

bibasilar pulmonary fibrosis• Other causes of thickened skin:

diabetes (scleredema ≠scleroderma), hypothyroidism,nephrogenic systemic fibrosis,eosinophilic fasciitis,amyloidosis, GVHD, drug ortoxin

Diagnostic studies & monitoring

• Autoantibodies anti-Scl-70(antitopoisomerase 1): 40%of diffuse, 15% of limited; ↑risk pulm fibrosis anticentromere: 60–80% oflimited, <5% of diffuse, ↑risk of severe digit ischemia ANA (>90%), RF (30%),

anti-RNP a/w overlapsyndrome

• At baseline: ✓ BUN/Cr & UA forproteinuria, PFTs (spirometry,lung volumes, DLCO), high-reschest CT (if diffuse disease),TTE (RVSP for PHT), RHC if ↑

RVSP or suspect PHT• Annual PFTs; TTE q1–2y• Skin bx not routine, but helpful

to assess other possible causesfor skin thickening

• ↑ r/o malignancy at affected sites

Treatment (Ann Rheum Dis2009;68:620)• Pulmonary Fibrosis:

cyclophosphamide (NEJM2006;354:2655), steroidsPAH: pulmonary vasodilators

(see “Pulm Hypertension”),

early Rx a/w betteroutcomes

• Renal: monitor BP monthly,intervene early to avoid HTNcrisis; dipstick for proteinScleroderma renal crisis: ACE

inhibitors (not ARB); ACEinot indicated for prophylaxis

• GI: PPI and/or H2-blockers forGERD; antibiotics formalabsorptionhypomotility: metoclopramide

or erythromycin;nonoperative Rx of pseudo-obstruction

• Cardiac: NSAIDs or steroids forpericarditis

• Arthritis: acetaminophen,NSAIDs, hydroxychloroquine,PT

• Myositis: MTX, AZA, steroids• Skin: PUVA for morphea. For

pruritus: emollients, topical ororal steroids (↓ dose).Immunosuppressives offer onlyminimal to modest benefit forskin fibrosis.

INFLAMMATORY MYOPATHIES

Definition & epidemiology(JAMA 2013;305:183)• Polymyositis (PM): T cell–

mediated muscle injury →skeletal muscle inflam &weakness

• Dermatomyositis (DM): immunecomplex deposition in bloodvessels with complementactivation → skeletal muscle

inflam. & weakness + skinmanifestations

• Inclusion body myositis (IBM):T cell–mediated muscle injury,vacuole formation with

amyloid deposition → skeletalmuscle inflam & weakness

• 10% of PM and 24% of DM a/wmalignancy (typicallyadenocarcinomas, a/w moresevere disease) (CurrRheumatol Rep 2011;13:208)

• PM/DM: onset typically 40s and50s; > ; DM also occurs inchildhood

• IBM: onset after age 50; > ;often misdiagnosed aspolymyositis

Clinical manifestations (RheumDis Clin N Am 2011;37:143)• Muscle weakness: gradual (wks

→ mos), progressive andpainlessDM/PM: proximal and

symmetric; difficultyclimbing stairs, arising fromchairs, brushing hair; ±tenderness of affected areas;fine motor skills (eg,buttoning, writing) lost late

IBM: may be asymmetric anddistal

• Dermatologic: may precedemyositis by mos to yrs(uncommon for converse)erythematous rash on sun-

exposed skin: neck &shoulders (shawl sign), face,

chestheliotrope rash (purplish

discoloration) over uppereyelids ± periorbital edema

Gottron’s papules (in >80%& pathognomonic):violaceous often scaly areassymmetrically over dorsumof PIP and MCP joints,elbows, patellae, medialmalleoli

subungual erythema,“mechanic’s hands” (skincracks on digits), pruritus

dermatologic features w/omyositis=DM sine myositis(amyopathic DM) in 10–20%

• Polyarthralgias or polyarthritis:usually early; nonerosive;small joints > large joints

• Raynaud’s (30%, DM andoverlap CTD) w/ dilatation &dropout of nailbed capillaries

• Visceral involvement (JRheumatol 2009;36:2711)pulmonary: acute alveolitis;

ILD; respiratory muscleweakness; aspiration

cardiac (33%): often asx;conduction abnl;myo/pericarditis; HFuncommon; ↑ CK-MB/Tn

GI: dysphagia, aspiration• Antisynthetase syndrome (PM

> DM): fever, ILD, Raynaud’s,mechanics hands, arthritis

• Ddx: drug-induced myopathy(statins, cocaine, steroids,colchicine); infxn (HIV, EBV,CMV); metabolic (hypothyroid,hypo-K, hypo-Ca);neuromuscular dis. (eg,myasthenia gravis); glycogenstorage disease; mitochondrialcytopathy; muscular dystrophy

Diagnostic studies• ↑ CK (rarely >100,000 U/L),

aldolase, SGOT and LDH; ±↑ESR & CRP

• Autoantibodies: ANA (>75%),

RF (33%) anti-Jo-1 (25%): mostcommon specific Ab; a/wantisynthetase syndrome

myositis antibody panel mayassist in prognosis (anti-Mi-2better, anti-SRP worse)

• EMG: ↑ spontaneous activity, ↓amplitude, polyphasicpotentials with contraction

• Muscle biopsy: all withinterstitial mononuclearinfiltrates, muscle fibernecrosis, degeneration &regeneration (required fordefinitive diagnosis)PM: endomysial inflam. (CD8

T cells) surrounds non-necrotic fibers, ↑ MHC class I

DM: perimysial, perivascularinflam (B & CD4 T cells),complement in vessels

IBM: same as PM witheosinophilic inclusions andrimmed vacuoles (EM)

Treatment (PM & DM, no effectivetreatment for IBM) (AutoimmunRev 2011;11:6)• Steroids (prednisone 1 mg/kg);

MTX or AZA early ifmod/severe or taper fails (2–3mo)

• For resistant (30–40%) or severe

disease: AZA/MTX combo, IVIg(DM ± PM), rituximab, MMF,cyclophosphamide (esp. if ILDor vasculitis)

• IVIg w/ pulse steroids acutely forlife-threatening esoph or respmuscle involvement

• ✓ for occult malignancy (esp. ifDM); monitor respiratorymuscle strength withspirometry

SJÖGREN’S SYNDROME

Definition & epidemiology• Chronic dysfxn of exocrine

glands (eg, salivary/lacrimal)due to lymphoplasmacyticinfiltration. Extraglandularmanifestations common inprimary form.

• Can be primary or secondary(a/w RA, scleroderma, SLE,PM, hypothyroidism, HIV)

• More prevalent in than ;typically presents between 40& 60 y of age

Clinical manifestations• Dry eyes (keratoconjunctivitis

sicca): ↓ tear production;burning, scratchy sensation

• Dry mouth (xerostomia):difficultyspeaking/swallowing; dentalcaries; xerotrachea; thrush

• Parotid gland enlargement:intermittent, painless,typically bilateral

• Vaginal dryness anddyspareunia

• Recurrent nonallergicrhinitis/sinusitis due toupper airway glandinvolvement

• Extraglandularmanifestations: arthritis;

interstitial nephritis (40%);type I RTA (20%); cutaneousvasculitis (25%); neuropathies(10%); PNS or CNS disease;ILD; PBC

• ↑ risk of lymphoproliferativedisorders (~50× ↑ risk oflymphoma and WM in 1°Sjögren’s)

Diagnostic studies• Autoantibodies: ANA (95%),

RF (75%)Primary Sjögren’s: anti-Ro

(anti-SS-A, 56%) and/or anti-La (anti-SS-B, 30%)

• Schirmer test: filter paper in

palpebral fissures to assesstear production

• Rose-Bengal staining: dye thatreveals devitalized epitheliumof cornea/conjunctiva

• Ocular staining score:substitute for Rose-Bengalstaining to determine degreeof keratoconjunctivitis siccausing fluorescein and lissaminegreen

• Biopsy (minor salivary, labial,lacrimal or parotid gland):lymphoplasmacytic infiltration

Classification criteria (2 of 3have 93% Se & 95% Sp; Arthritis

Care Res 2012;64:475)1. anti-Ro or anti-La or RF +

ANA>1:3202. Labial salivary gland bx w/

lymphocytic sialadenitis andscore >1 focus/4 mm2

3. Keratoconjunctivitis sicca w/ocular staining score ≥3

Treatment• Ocular: artificial tears,

cyclosporine eyedrops• Oral: sugar-free gum, lemon

drops, saliva substitute,hydration, pilocarpine,cevimeline

• Systemic: NSAIDs, steroids,

DMARDs, rituximab

MIXED CONNECTIVE TISSUEDISEASE (MCTD)

Definition (Best Pract Res ClinRheumatol 2012;26:61)• Features of SLE, systemic

sclerosis and/or polymyositisthat appear gradually andoften evolve to a dominantphenotype of SLE or systemicsclerosis

• Different from undifferentiatedCTD (UCTD): fail to meetcriteria for any CTD; 30% goon to develop CTD over 3–5 y(usually SLE)

Clinical manifestations (variable

clinical course)• Raynaud’s phenomenon typical

presenting symptom (75–90%)• Hand edema (“puffy hands”),

sclerodactyly, RA-like arthritisw/o erosions, polyarthralgias

• Pulmonary involvement (85%)with pulmonaryhypertension, fibrosis

• Pericarditis most frequentcardiovascular manifestation;GI: dysmotility (70%)

• Membranous & mesangial GNcommon (25%); low risk forrenal HTN crisis or severe GN(if either, reconsider diagnosisof MCTD)

Diagnostic studies• ANA (>95%); RF (50%);

anti-U1-RNP in all, but notspecific (seen in ~50% SLE)

Treatment• As per specific rheumatic diseases

detailed above

RAYNAUD’S PHENOMENON

Clinical manifestations (NEJM2002;347:1001 & 2013;368:1344;BMJ 2012;344:e289)• Episodic, reversible digital

ischemia, triggered by temp Δ(cold) or stress, classically:blanching (white, ischemia)→ cyanosis (blue, hypoxia) →rubor (red, reperfusion); colorΔ usually well demarcated;affects fingers, toes, ears, noseassociated sx include cold,numbness, & paresthesias →throbbing & pain

• Key to diagnosis and Rx is

distinguishing betweenprimary and secondaryRaynaud’s

Primary (80–90%=Raynaud’sdisease; excluded all secondarycauses)• Onset 20–40 y, > (5:1);

thought due to functionalabnl of vessel wall

• Clinical: mild, symmetric episodicattacks; no evidence of periphvascular disease; no tissueinjury; nl nail-fold capillaryexam; no systemic sx; ANA;nl ESR

Secondary (10–20%)

• Typically >35 y of age; due tostructural abnl of vessel wall

• Tissue ischemia & injury (eg,digital ulcers), which is notseen in primary Raynaud’s

• Etiologies: CTD (abnl nail-foldexam): SSc, SLE, PM-DM,MCTD, Sjögren’s, RAArterial disease: periph

atherosclerosis,thromboangiitis obliterans(abnormal pulses)

Hematologic:cryoglobulinemia,Waldenström’s,antiphospholipid syndrome

Trauma (vibration or

repetitive motion injury) &drugs (ergot alkaloids,estrogens, cocaine)

Treatment (Curr Opin Rheumatol2011;23:555; BMJ 2012;344:e289)• All: avoid cold, maintain warmth

of digits & body; avoidcigarettes, drugs and trauma

• Mild–mod: long-acting CCB,topical nitrates, SSRI, ARB, ɑ-blockers, ASA/clopidogrel

• Severe: PDE inhibitors, anti-ET-1receptor (if ulcers esp. w/PHT), digital sympathectomy

• Digit-threatening: IVprostaglandins, digital

sympathectomy, ±anticoagulation

• Others: fish oil (1° RP only; Am JMed 1989;86:158), abx forinfected ulceration

SYSTEMIC LUPUSERYTHEMATOSUS (SLE)

Multisystem inflammatoryautoimmune disease with a broad

spectrum of clinical manifestationsin association with antinuclear

antibody (ANA) production

Epidemiology (NEJM2011;365:2110)• Prevalence 15–50/100,000;

predominantly affects women2nd to 4th decade

• : ratio=8:1; AfricanAmerican:Caucasian ratio=4:1

• Complex genetics; some HLA

assoc.; rare C1q & C2 defic.

Workup• Autoantibodies: ANA, if → ✓

anti-ds-DNA, anti-Sm, anti-Ro,anti-La, anti-U1-RNP

• Lytes, BUN, Cr, U/A, urine sed,spot microalb:Cr ratio or 24-hurine for CrCl and protein

• CBC, PTT, APLA ( in 20–40%;

ACL IgG/IgM, B2GP1, lupusanticoagulant), C3, C4

• If ↓ GFR, active sediment,hematuria or proteinuria →renal bx to guide Rx

Prognosis• 5-y survival rate >90%, 10-y

survival rate >80%• Leading causes of morbidity and

mortality: infection, renalfailure, neurologic andcardiovascular events;thrombotic complications(Medicine 2003;82:299)

Drug-induced lupus (DLE) (DrugSaf 2011;34:357; Curr OpinRheumatol 2012;24:182)• Many drugs: procainamide,

hydralazine, penicillamine,minocycline, INH, methyldopa,quinidine, chlorpromazine,diltiazem, anti-TNF (esp.infliximab), interferons

• Idiosyncratic onset; generallymild disease with arthritis,serositis, skin disease

• Anti-histone (95%) (may be in anti-TNF); anti-ds-DNA(may be in anti-TNF) & anti-Sm; normal complement levels

• Usually reversible w/in 4–6 wk

after stopping medication

VASCULITIS

OVERVIEW• Inflammation w/in blood vessel

walls causing end-organdamage often a/w systemic sx;may be primary or secondary(eg, infection, malignancy) inetiology

• Classified by size of predominantvessel affected (ArthritisRheum 2013;65:1); overlap ofvessel size affected is common

• Clinical manifestations based onsize of vessels involved;constitutional sx (low-gradefever, fatigue, weight loss,

myalgias, anorexia) commonto all

LARGE-VESSEL VASCULITIS

Takayasu’s arteritis (“pulselessdisease”)• Arteritis of aorta and its

branches →stenosis/aneurysm →claudication; onset <50 y

• Pattern of involvement: aortaand branches; most oftensubclavian and innominatearteries (>90%), as well ascarotid, coronary, renal,pulmonary (~50%)

• Epidemiology: Most common inAsia; : ~9:1; age <50 y

• Clinical manifestations and

physical findingsSystemic inflamm with fever,

arthralgias, wt lossVessel inflamm w/ pain &

tenderness, ↓ & unequalpulses/BPs in extremities,bruits, limb claudication,renovascular HTN (>50%),neurogenic syncope; Aoaneurysm ± AI

“Burnt out” or fibrotic period(eg, vascular stenosis)

• Dx studies: ↑ ESR (75%), CRP;arteriography → occlusion,stenosis, irregularity andaneurysms; carotid U/SDoppler studies; PET-CT; MRA;

pathology → focalpanarteritis, cellular infiltratewith granulomas and giantcells (bx not required for dx)

• Treatment: steroids ± MTX orAZA; anti-TNF (2nd line,Autoimmun Rev 2012;11:678),ASA, surgical/endovascularrevasc (Circ 2008;69:70)

• Monitoring: MRA or PET-CT(Arth Rheum 2012;64:866);ESR/CRP (Ann Rheum Dis2009;68:318)

Giant cell arteritis (GCA) (CurrRheumatol Rep 2010;12:436)• Granulomatous arteritis of

aorta/branches w/predilection for temporalartery, a/w PMR, onset >50 y

• Pattern of involvement:extracranial branches ofcarotid artery, esp. temporalartery (thus also calledtemporal arteritis); aortaand/or its branches in 10–80%

• Epidemiology: 90% of Pts >60 y,extremely rare <50 y; :=3:1

• Clinical manifestations (JAMA2002;287:92)constitutional sx: fevers,

fatigue, wt loss, PMR sx(see below)

temporal artery (TA) →headache, tender TAs andscalp; absent TA pulse

ophthalmic artery (20%) →optic neuritis, diplopia,amaurosis fugax, blindness

facial arteries → jawclaudication

large vessel vasculitis →intermittent claudication ofextremities; thoracic Aoaneurysm

• Dx studies: ↑ ESR (ESR <40 in~5%), ↑ CRP, anemia(ESR related to fibrinogen & Ig

in blood; Ddx for >100:malignancy esp. multiple

myeloma, lymphoma; GCAor other vasculitis; ESRD;endocarditis, TB,osteomyelitis)

temporal artery bx wheneverGCA suspected (Se ≤85%);1–2 cm ± bilat to ↑ yield (3–7% discordance) (AnnRheum Dis 2009;68:318) →vasculitis & granulomas

if suspect aortitis or lg vesselinvolvement (BP Δ or bruits)→ MRI/MRA or PET-CT

• Polymyalgia rheumatica(Lancet 2013;381:63)seen in 50% of GCA Pts; 15%

of Pts w/ PMR develop GCA

age ≥50 y; ESR >40 mm/h(and/or ↑ CRP); bilateralpain & morning stiffness(>30 min × ≥1 mo),involving 2 of 3 areas: neckor torso, shoulders or prox.arms, hips or prox. thighs;nighttime pain; excludeother causes of sx (eg, RA);nl CK

• Rx: steroids (do not awaitbx/path results to beginsteroids, have at least 2 wk tobx)GCA: 40–60 mg/d w/ slow

taper, ASA daily; consider IVpulse if vision threatened

PMR:10–20 mg/d (SeminArthritis Rheum 2007;37:13)

• Monitoring: follow clinical status& ESR/CRP (Ann Rheum Dis2009;68:318)

MEDIUM-VESSEL VASCULITIS

Polyarteritis nodosa (“classic”PAN) (Arth Rheum 2010;62:616)• Necrotizing

nongranulomatousvasculitis of medium andsmall arteries (w/ muscularmedia) w/o glomerulonephritisor capillary involvement (ie,DAH), not a/w ANCA

• Epidemiology: > ; average ageof onset ~50 y; primary orHBV-associated (~10%)

• Clinical manifestationsconstitutional sx (80%): wt

loss, fever, fatigue

neuro (79%): mononeuritismultiplex, peripheralneuropathies, stroke

musculoskeletal (64%):extremity pain, myalgias,arthralgias, arthritis

renal (51%): HTN, hematuria,proteinuria, renal failure,glomerulonephritis unusual

GI (38%): abd pain,GIB/infarction, cholecystitis;GU (25%): ovarian ortesticular pain

skin (50%): livedoreticularis, purpura,nodules, ulcers, Raynaud’s

ophthalmic (9%): retinal

vasculitis, retinal exudates,conjunctivitis, uveitis

cardiac (22%): coronaryarteritis, cardiomyopathy,pericarditis

if lung involvement, suspectother vasculitis

• Dx studies: ↑ ESR/CRP, ANCA;✓ HBs Ag; ↓ C3/C4 if HBV-associatedangiogram (mesenteric or

renal vessels) →microaneurysms & focalvessel narrowing

CTA may be adequate to makedx, but conventionalangiogram is most sensitive

biopsy (sural nerve, skin oraffected organ) → vasculitisof small and medium vesselarteries with fibrinoidnecrosis without granulomas

• Treatment: steroids ± CYC (ifsevere or failure to induceremission); antivirals if a/wHBV

ANCA-ASSOCIATED SMALL-VESSEL VASCULITIS

Microvascular vasculitis (eg,capillaries, postcapillary venules, &

arterioles)

Differential diagnosis of ANCA• anti-PR3 (c-ANCA):

granulomatosis w/polyangiitis, eosinophilic

granulomatosis andpolyangiitis, microscopicpolyangiitis (rarely)

• anti-MPO (p-ANCA): microscopicpolyangiitis, eosinophilicgranulomatosis andpolyangiitis, granulomatosis

w/ polyangiitis, drug-induced vasculitis,nonvasculitic

rheumatic diseases• Atypical ANCA patterns: drug-

induced vasculitis,nonvasculitic rheumaticdiseases,ulcerative colitis, primary

sclerosing cholangitis,

endocarditis, cystic fibrosis

Granulomatosis withpolyangiitis (GPA, formerlyWegener’s granulomatosis)• Necrotizing granulomatous

systemic vasculitis frequentlyaffecting nose, sinuses and/orupper respiratory tract inaddition to kidneys, lungs, etc.

• Epidemiology: any age, but ↑incidence in young andmiddle-aged adults; =

• Clinical manifestationsrespiratory (90%)

upper: sinusitis, rhinitis,oral/nasal ulcers,

saddle-nose deformity,otitis, hearing loss,subglottic stenosis

lower: pulmonaryinfiltrates, nodules,pulmonary hemorrhage,hemoptysis, pleurisy

renal (80%): RPGN (pauci-immune), RBC casts,dysmorphic RBCs, hematuria

ocular (50%): episcleritis,scleritis, uveitis, orbitalgranulomas → proptosis,corneal ulcer

neurologic: cranial andperipheral neuropathies,mononeuritis multiplex

skin (50%): palpable purpura,livedo reticularis

hematologic: ↑ incidenceDVT/PE (20×) when diseaseactive (Ann Intern Med2005;142:620)

• Dx studies: 90% ANCA (80%PR3, 20% MPO), less Se inlimited upper airway diseaseCXR or CT → nodules,

infiltrates, cavities; sinus CT→ sinusitis ± bone erosions

↑ BUN & Cr, proteinuria,hematuria; sediment w/ RBCcasts, dysmorphic RBCs

Biopsy → necrotizinggranulomatous

inflammation of arterioles,capillaries, veins

• Treatment (Annals 2009;150:670;NEJM 2010;363:211 & 221)Induction: RTX (375

mg/m2/wk × 4 wk) +steroids (1 g IV × 3 Δ → 1–2 mg/kg/d) or CYC (2mg/kg/d × 3–6 mo or pulse15 mg/kg q2–3wk) +steroids

RPGN: ± plasmaexchange to ? ↓ risk ofESRD (Am J Kidney Dis2011;57:566)

if mild (nonorgan- or life-threatening): MTX +

prednisone may beadequate for induction(Arth Rheum2012;64:3472)

Maintenance: MTX or AZA for≥2 y after CYC induction(NEJM 2008;359:2790);after RTX induction repeatRTX q6mo (Arth Rheum2012;64:3760) vs. watchfulwaiting

Relapse: if severe, reinduce w/steroids + RTX or CYC;steroids ± MTX or AZA ifmild;

↑ ANCA w/o clinical evidenceof flare should not prompt Δ

Rx (Annals 2007;147:611)

Microscopic polyangiitis (MPA)(Rheum Dis Clin North Am2010;36:545)• Similar to GPA, but w/o

ENT/airway involvement &nongranulomatous

• Epidemiology: > ; avg onset50–60 y

• Clinical manifestations: similarto GPA w/o upper respiratoryinvolvement; renal (80–100%): glomerulonephritispulmonary (25–50%):pulmonary capillary alveolitis,pulmonary fibrosis

constitutional and neuro sxsimilar to GPA; skin lesions(eg, palpable purpura) in 30–60%

• Dx studies: 70% ANCA (almostall anti-MPO)biopsy → necrotizing,

nongranulomatousinflammation of smallvessels, pauci-immune(minimal deposition ofcomplement or Ig; contrastw/ HSP, cryoglobulinemia,etc.)

urine sediment and CXRfindings similar to thoseseen in GPA

• Treatment: as for GPA; ↓ relapserate compared to GPA

Eosinophilic granulomatosiswith polyangiitis (EGPA, formerlyChurg-Strauss)• Similar to GPA w/ more frequent

cardiac involvement, a/wasthma and eosinophilia

• Epidemiology: rare; can presentat any age (typically 30–40 y);a/w HLA-DRB4

• Clinical manifestations (CurrRheumatol Rep 2011;13:489)initial sx: asthma, sinusitis,

allergic rhinitis (new asthmain adult raises suspicion)

eosinophilic infiltrativedisease: shifting or transientpulmonary infiltrates,gastroenteritis or esophagitis

systemic small-vesselvasculitis: neuropathy(mononeuritis multiplex),renal (glomerulonephritis),skin (palpable purpura,petechial, nodules)

cardiac: coronary arteritis,myocarditis, CHF, valvularinsufficiency (Medicine2009;88:236)

• Dx studies: 50% ANCA (MPO> PR3), eosinophilia (5–10k/µL, 80–100%),

biopsy → microgranulomas,fibrinoid necrosis andthrombosis of small arteriesand

veins with eosinophilicinfiltrates

• Treatment: high-dosecorticosteroids +cyclophosphamide if severe

Renal-limited vasculitis• Small vessel pauci-immune

vasculitis causing RPGN w/oother organ involvement

• Dx studies: 80% ANCA (MPO> PR3); biopsy with pauci-immune GN ± granulomas

• Treatment identical to that forGPA/MPA

IMMUNE COMPLEX–ASSOCIATEDSMALL-VESSEL VASCULITIS

Henoch-Schönlein purpura (HSP)• IgA-mediated vasculitis w/

predilection for skin, GI tractand kidneys

• Epidemiology: > , children >adults, onset in winter >summer

• May develop after upperrespiratory tract infection(esp. strep) or drug exposure

• Clinical manifestationspalpable purpura on extensor

surfaces (lower extremityfirst) & buttocks

polyarthralgias(nondeforming) esp.involving hips, knees, &ankles

colicky abdominal pain ±GIB or intussusception

nephritis ranging frommicroscopic hematuria &proteinuria to ESRD

• Dx studies: skin bx w/immunofluorescence →leukocytoclastic vasculitisw/ IgAand C3 deposition in vessel

wall; renal bx → mesangialIgA deposition

• Treatment: often self-limiting

over 4 wk; steroids ±DMARDs for renal or severedisease

Cryoglobulinemic vasculitis (see“Cryoglobulinemia”)

Connective tissue disease–associated vasculitis• Small vessel vasculitis a/w RA,

SLE or Sjögren’s syndrome• Clinical manifestations

distal arteritis: digitalischemia, livedo reticularis,palpable purpura, cutaneousulceration

visceral arteritis: pericarditisand mesenteric ischemia

peripheral neuropathy• Dx studies: skin/sural nerve bx,

angiography, EMG; ↓ C′ inSLE; RF or anti-CCP in RA

• Treatment: steroids,cyclophosphamide, MTX (otherDMARDs)

Cutaneous leukocytoclasticangiitis• Heterogeneous group of clinical

syndromes due to immunecomplex deposition incapillaries, venules andarterioles; includeshypersensitivity vasculitis

• Overall the most common type of

vasculitis• Etiologies

drugs: PCN, ASA,amphetamines, levamisole,thiazides, chemicals,immunizations

infections: Strep, Staph,endocarditis, TB, hepatitis

malignancy (paraneoplastic)• Clinical manifestations: abrupt

onset of palpable purpuraand transient arthralgiasafter exposure to the offendingagent; visceral involvementrare but can be severe

• Dx studies: ↑ ESR, ↓ complementlevels, eosinophilia; ✓ U/A;

skin biopsy →leukocytoclastic vasculitis w/oIgA deposition in skin (todistinguish from HSP); ifetiology not clear, considerANCA, cryoglobulins, hepatitisserologies, ANA, RF

• Treatment: withdrawal ofoffending agent ± rapidprednisone taper

Behçet’s syndrome (Curr RheumOpin 2010;12:429)• Systemic vasculitis affecting all

vessel sizes, a/w oral and/orgenital ulcers

• Epidemiology: usually young

adults (25–35 y); a/w HLA-B51in areas of highest prevalenceon the old Silk Road (Turkey,Middle East and other Asiancountries)

• Classification criteria (#1 + ≥2others is 91% Se & 96% Sp;Lancet 1990;335:1078)

1. recurrent oral aphthousulceration (≥3× in 1 y,usually 1st manifestation)

2. recurrent genital ulceration(labia in females, scrotum inmales)

3. eye lesions: uveitis, scleritis,retinal vasculitis, optic neuritis(may threaten vision)

4. skin lesions: pustules, papules,folliculitis, erythema nodosum(scarring)

5. pathergy test (prick forearmw/sterile needle → pustule)(not sensitive in Caucasians)

• Other clinical manifestations:most recur but are not chronicarthritis: mild, ± symmetric,

nondestructive, involvingknees and ankles

neurologic: usuallyinvolvement of midbrainparenchyma; peripheralneuropathy rare

vascular: superficial or deepvein thrombosis (25%);

arterial stenosis, occlusionand aneurysm can alsooccur; low incidence ofthromboembolism

• Dx studies: ↑ ESR/CRP; ulcerswab to r/o HSV; ulcer bxnonspecific; ophtho eval if sx

• Treatment (Rheumatology2007;46:736; Ann Rheum Dis2008;67:1656 & 2009;68:1528)mucocutaneous

mild: topical steroids,colchicine (esp. forerythema nodosum),dapsone

severe: oral steroids,steroid-sparing agents

arthritis: NSAIDs, colchicine,steroids, steroid-sparingagents

ocular: topical and/orsystemic steroids ±steroid-sparing agents

steroid-sparing: AZA, anti-TNF,CYC (large vessel and CNSds), CsA, MTX, IFNɑ-2A

venous thrombosis: steroidsand anticoagulation (carefulif aneurysm present)

IGG4-RELATED DISEASE

Definition & etiology (NEJM2012;366:539)• Responsible for tumor-like

inflammatory lesions ofnearly every organ/tissue

• Etiology unclear: ? autoimmune;unclear role of IgG4 Ab; mayhave h/o atopy

Clinical manifestations• Commonly pancreatitis, aortitis,

cholangitis, sialadenitis,orbital structures,retroperitoneal fibrosis

• Multiple lesions may be presentsynchronously or

metachronously

Diagnosis (Mod Pathol2012;25:1181)• Biopsy w/ specific

histopathology &immunohistochemistryfindings: lymphoplasmacyticinfiltrate w/ significant IgG4+plasma cell infiltrate, fibrosis,obliterative phlebitis

• ↑ serum IgG4 in 40%; notspecific seen in GPA,bronchiectasis, etc (ModernRheum 2012;22:419)

Treatment• Prednisone vs. rituximab

(Medicine 2012;91:57)

CRYOGLOBULINEMIA

Definition & types (Lancet2012;379:348)• Proteins that precipitate on

exposure to the cold andredissolve on rewarming,characterized by theircomposition

• Cryoglobulins=proteins thatprecipitate from serum andplasma when cooled

• Distinguish fromcryofibrinogenemia=proteins(eg, fibrin, fibrinogen) thatprecipitate only from plasma;found in autoimmune dis,

malignancies, infxns; unclearclinical significance

Etiologies• Infections (types II & III): viral

(HCV, HBV, HIV, HAV, EBV,CMV), bacterial (endocarditis,strep, etc.), fungal(coccidiomycosis, etc.) andparasitic (malaria, amoebiasis)

• Hematologic diseasestype I: MM, CLL,

Waldenström’stype II: B-cell lymphomas,

solid organ malignancies• Autoimmune syndromes (type III

> II): Sjögren’s syndrome,SLE, RA, PAN

• Essential (idiopathic) in 10% ofcases

• Renal transplant recipients (ClinNephrol 2008;69:239)

Pathophysiology• Chronic immune stimulation

and/or lymphoproliferation →cryoglobulin generation

• Type I: cryo precipitation inmicrocirculation →hyperviscosity & vascularocclusion

• Types II/III:defective/insufficient immunecomplex (IC) clearance → IC-mediated inflammation ofblood vessels w/ complementactivation → vasculitis

Clinical manifestations (systemicsx usually due to type II > III)• Most patients with

cryoglobulinemia are asx• Type I: hyperviscosity (cold

worsens sx) → H/A, visual

disturbance, livedo, digitalischemia

• Type II: vasculitis (sx notaffected by cold exposure)General: weakness, low-grade

feverDermatologic (54–80%): lower

extremity purpura, livedoreticularis, leg ulcers

Joint (44–70%): symmetric,migratory arthralgias ofsmall or medium joints

Renal (50%):glomerulonephritis(proteinuria, hematuria,ARF, HTN, edema)

Neurologic (17–60%):

peripheral neuropathy(polyneuropathy >mononeuritis multiplex)

Hematologic: anemia,thrombocytopenia, ↑ risk ofB-cell lymphoma

GI (5%): abdominal pain,hepatosplenomegaly,abnormal LFTs

Diagnostic studies• ✓ Cryoglobulins; must keep

blood warmed to 37°C at alltimes en route to lab; earlycooling causes false cryoglobulin, loss of RF and ↓↓complement

• Cryocrit is quantification ofcryoprotein, does not alwayscorrelate w/ disease activity

• False ↑ in WBC or plt onautomated CBC, due tocryoprecipitation

• Type I: ✓ serum viscosity,symptomatic if ≥4.0centipoise; complement levelsnormal

• Type II: ↓ C4 levels, variable C3levels, ↑ ESR, rheumatoidfactor (RF)

✓ HCV, HBV, & HIV serologies inall Pts w/ mixedcryoglobulinemia

Bx of affected tissue: hyaline

thrombi; vasculitis w/ mixedinflammatory infiltrates ofsmall vessels; leukocytoclasticvasculitis in purpuric lesions

Treatment (Autoimmun Rev2011;10:444; Arth Rheum2012;64:604; Blood 2012;119:5996)• Treat underlying disorder:

Lymphoproliferative disease:chemotherapy and/orradiation

HCV: antivirals ±immunosuppression forsevere disease

Connective tissue-relateddisease: DMARD/steroids ±

rituximab• Type I: Plasma exchange if

hyperviscosity• Type II: NSAIDs for control of

mild symptoms for Pts w/normal renal functionRituximab or

cyclophosphamide for majororgan involvement

Plasmapheresis or plasmaexchange in severe, life-threatening disease

AMYLOIDOSIS

The deposition of misfolded andinsoluble fibrous proteins innormal organs and tissues.

Diagnostic studies• If suspect AL → ✓ SIEP & UIEP

(↑ Se vs. SPEP & UPEP) & freelight chains, ± BM bx

• If suspect renal involvement ✓U/A (proteinuria)

• If suspect cardiac involvement: ✓ECG (↓ voltage, conductionabnl), echo (biventricularthickening with “granularsparkling” appearance; ↑ wallw/o ↑ volt 75% Se, 95% Sp),MRI

• Biopsy (abdominal SC fat pad,rectal or affected tissue) →apple-green birefringence onCongo red stain; fat pad bxSe 60–85%, Sp 90–100%

• Genetic testing for hereditaryforms

Treatment• AL: ? high-dose melphalan →

auto HSCT if limited organdysfxn (NEJM 2007;357:1083);o/w low-dose melphalan +dexamethasone; novel agents(eg, bortezomib, lenalidomide,thalidomide) being evaluated(J Hematol Oncol 2011;4:47)

• AA: Rx underlying disease;colchicine for FMF esp. toprevent progressive renaldisease (NEJM 2007;356:23);eprodisate promising for renaldisease (NEJM 2007;356:2349)

• For hereditary amyloidoses inwhich amyloid precursorprotein is produced by theliver (eg, TTR), liver

transplantation may preventfurther deposition

• Cardiac involv.: diuretics; avoiddig & CCB; avoid vasodilators;? ICD for 1° prevention

• Heart, kidney and liver Tx maybe considered in those w/advanced disease

Prognosis• AL amyloid: median survival

~12–18 mo; if cardiacinvolvement, median survival~6 mo

• AA amyloid: median survival~11 y (NEJM 2007;356:2361)

CHANGE IN MENTAL STATUS

Definitions (description ofpatient & timing is most helpful)• Unresponsive: implies ↓ arousal

or ability to follow commands,specify w/ exam

• Delirium (aka acute confusionalstate or encephalopathy):acute change in attention andconsciousness withfluctuations. May includesleep–wake dysregulation,autonomic changes, abnormalsensory perception andchanges in affect as additionalfeatures.

• Dementia: impaired cognition,

often incl. memory. Usuallychronic & progressive,eventually encompassing moreanatomical & functional partsof the nervous system.

Initial evaluation• History (witness & background

crucial): time course, previousillnesses including dementia orpsych; head trauma; meds,drug/alcohol use;infection/immune status

• General physical exam: vitalsigns, signs of trauma,asterixis, stigmata of liverdisease, embolic phenomena,signs of drug use, nuchalrigidity (may be present inmeningitis or SAH, but do nottest if possible trauma/cervicalspine fracture)

• Neurologic exam (mostmeaningful offsedatives/paralytics): look for

focality or s/s of ↑ ICP (eg,HA, vomiting, papilledema,unilateral dilated pupil, ↑ BP)

Initial treatment• Resuscitation, control airway,

monitor vital signs, fingerstickglucose, IV access

• Immobilization of C-spine ifconcern for cervical trauma

• Thiamine (100 mg IV) prior todextrose to prevent exacerb. ofWernicke’s encephalopathy

• Dextrose (50 g IV push)• Naloxone 0.01 mg/kg if opiates

suspected; supportive careimportant in nearly all toxcases

• If concern for ↑ ICP ±

herniation: ↑ head of bed;osmotherapy w/ mannitol orhypertonic saline; ↑ventilation; dexamethasone fortumor edema; c/s neurosurgery(? decompress)

Diagnostic studies (Continuum2011;17:967)• Labs: CBC, electrolytes, BUN/Cr,

LFTs, NH3, tox screen, TSH,B12, ABG, U/A, ECG

• Imaging: head CT, consider MRI;radiographs to r/o C-spinefracture; CXR

• Lumbar puncture to r/omeningitis, SAH or

noninfectious inflammation(eg, autoimmune)

• EEG to evaluate fornonconvulsive seizures,toxic/metabolicencephalopathy

Further treatment of delirium(Annals 2011;154:746)• Treat underlying acute illness,

eliminate precipitating factors,provide supportive care

• Address sensory & cognitiveimpairments, increasefamiliarity

• Decrease/preventinfection/restraints if possible,

remove lines/catheters ifunnecessary

• Promote good sleep: reduce noise& night-time interventions;selective med if necessary

• Meds: consider antipsychotics,avoid benzos except foralcohol withdrawal or seizures

ANOXIC BRAIN INJURY

Prevalence (NEJM2012;367:1912)• Pts with at least 5 min of

cerebral hypoxia at risk• 1.5 million cardiac arrests per

year in U.S.; for inPt arrest,~20% survival, ~70% of Ptswho survive will have a goodlong-term neurologic outcome

Initial evaluation (Circulation2010:S768)• Neuro exam: arousal/verbal, eyes

& other cranial nerves, motorresponse to pain

• Imaging: usually not informative

w/in first day after arrest, butshould be done prior toinitiating hypothermia ifpatient found down or has hadhead trauma

Induced hypothermia(Circulation 2008;118:2452 &2013;127:244)• Indications: comatose (eg, no

meaningful response to verbalstimuli) <6 h followingcardiac arrest (not isolatedresp. arrest). Fully studied onlyin VT/VF, but consider afterasystole or PEA arrest or 6–12h after cardiac arrest.

• Exclusion: pregnancy, CVinstability despitepressors/assist devices, othercause of coma, persistent ↓ O2

• Relative contraindications: majorhead trauma,coagulopathy/bleeding, majorsurgery <14 d, systemicinfection/sepsis

• Method: target temp 32–34°C ×24 h (from time of initiation ofcooling). Can use cold salineinfusions; ice packs to thehead, neck and torso; coolingblankets; cooling vest orendovascular catheter ifavailable. Goal to achieve

target temp <6 h. Startrewarming 24 h after coolingis initiated (rewarm no fasterthan 0.5°C per h).

• Complicationscardiac dysrhythmias

(bradycardia most common):if signif dysrhythmia orhemodynamic instability,d/c cooling and rewarmpatient

coagulopathy: Pts can receivefibrinolytics, GP IIb/IIIainhibitors, etc., and stillundergo cooling. ✓ PT andPTT.

infection: ✓ surveillance blood

cultures during coolinghyperglycemia during cooling,

hypoglycemia w/rewarming; stop insulin ifglc <200 mg/dL

hypokalemia during cooling,hyperkalemia w/rewarming; keep K 4–5mEq/L

Ongoing evaluation• Neuro exam: daily focus on coma

exam. No exam finding isreliable <24 h or on sedation.Pt needs to be off sedation foran adequate time to evaluate(depends on doses used,

duration of Rx, metabolicprocesses in the individual Pt).

• Labs: daily CBC, PT/PTT,electrolytes. Serum neuron-specific enolase (NSE) on days1–3

• Imaging: noncontrast CT 24 hafter arrest; if unrevealing,consider MRI around days 3–5

• EEG: consider in all to excludeseizures or myoclonus; greatestrisk during rewarming

• Somatosensory evoked potentials(SSEP): helpful for predictionof poor outcome if corticalresponses are absentbilaterally; perform 48 h after

arrest (72 h if cooled)

Prognosis (Neuro 2006;67:203;NEJM 2009;361:605)• Prior to cooling era, uniformly

poor prognosis could bepredicted at 72 h only in Ptswho have absent pupillary andcorneal reflexes, and no motorresponse to pain; or withabsent SSEPs at 48 h. Withcooling, it is less clear if theprior measures are as reliable.

• Otherwise, prognosis requiresmultifactorial approachconsidering exam, age,comorbid diseases, ancillary

data (NSE, EEG, SSEP; imagingis less reliable for pooroutcome)

• When in doubt, err on the side ofgiving more time (esp. inyounger Pts and inducedhypothermia Pts)

SEIZURES

Definitions (NEJM2003;349:1257; Epilepsia2010;51:676)• Seizure = abnormal,

paroxysmal, excessivedischarge of CNS neurons;occurs in 5–10% of thepopulation; can rangeclinically from dramatic tosubtle

• Epilepsy = recurrentunprovoked seizures; 0.5–1.0%of population

• Generalized seizures (involvesbrain diffusely)

Tonic-clonic (grand mal): tonicphase (10–20 sec) withcontraction of muscles(causing expiratory moan,cyanosis, pooling ofsecretions, tongue biting) →clonic phase (~30 sec) withintermittent relaxing andtensing of muscles

Absence (petit mal): transientlapse of consciousness w/oloss of postural tone, usupedi

Myoclonic (infantile spasms &juvenile myoclonicepilepsy): sudden, briefcontraction

• Focal (partial) seizures(involves discrete brain area,implies a structural lesion)Simple (w/o Δ MS) vs. complex

(w/ Δ MS): motor, sensoryand/or autonomic

Focal with secondarygeneralization: starts focal,becomes generalized

Differential diagnosis• Syncope (Lancet Neurol

2006;5:171)

• Nonepileptic seizure (NES, aka“psychogenic”): may see side-to-side head turning,asymmetric large-amplitudelimb movements, diffuseshaking w/o LOC, and cryingor talking during event

• Other: metabolic disorders (eg,alcoholic blackouts,hypoglycemia), migraine, TIA,transient global amnesia,narcolepsy (cataplexy),nonepileptic myoclonus, tics,asterixis

Etiologies (varies strongly byage)

• Alcohol withdrawal, illicit drugs,meds (eg, β-lactams,bupropion, tramadol,metronidazole, meperidine,CsA, antidep., clozapine canlower seizure threshold)

• Brain tumor or penetratingtrauma

• Cerebrovascular disease,including subdural hematomas,hypertensive encephalopathy

• Degenerative disorders of theCNS (eg, Alzheimer’s)

• Electrolyte (hyponatremia) &other metabolic (eg, uremia,liver failure, hypoglycemia)

• Idiopathic (in ~60%)

Clinical manifestations• Aura (sec to mins): premonition

with paresthesias, focal motorcontractions, abnormalsmells/tastes, fear,depersonalization, déjà vu,autonomic changes,automatisms

• Ictal period (sec to mins): tonicand/or clonic movements ofhead, eyes, trunk or extrem.

• Postictal period (mins to h):slowly resolving period ofconfusion, disorientation, andlethargy. May be accompaniedby focal neurologic deficits(Todd’s paralysis).

• Status epilepticus: continuoustonic-clonic seizure ≥30 minor repeated seizures w/oresolution of postictalencephalopathy.Complications includeneuronal death,rhabdomyolysis and lacticacidosis.

• Nonconvulsive statusepilepticus: alteration ofawareness (ranging fromconfusion to coma) w/o motormanifestations of seizure. Dxwith EEG.

Clinical evaluation

• Seizure: patient usually w/orecollection, must talk towitnessesunusual behavior before

seizure (ie, an aura)type & pattern of abnl

movements, incl. headturning & eye deviation(gaze preference usuallyaway from seizure focus)

loss of responsiveness• HPI: recent illnesses/fevers, head

trauma, sleep deprivation,medication compliance

• PMH: prior seizures or FHx,prior meningitis/encephalitis,prior stroke or head trauma

• Medications, alcohol and illicitdrug use

• General physical exam shouldinclude the skin, looking forneuroectodermal disorders (eg,neurofibromatosis, tuberoussclerosis) that are a/w seizures

• Neurologic exam should look forfocal abnormalities →underlying structuralabnormality

Diagnostic studies (Neurology2007;69:1996)• Laboratory: full electrolytes,

BUN, Cr, glc, LFTs, tox screen,medication levels

• EEG: during seizure can capturerepetitive rhythmic activity(generalized seizures willtypically have abnl EEG;partial may not); interictalEEG normal in 50% of Pts w/epilepsy, and interictalepileptiform activity (spikes orsharp waves) seen in only 25%of Pts w/ epilepsy but up to2% of normal population;sleep deprivation and repeatedstudies ↑ dx yield of EEG; videomonitoring may help w/nonepileptic seizures

• MRI to r/o structuralabnormalities; ↑ Se w/ fine

coronal imaging of frontal &temporal lobes

• LP (if no space-occupying lesionon imaging): if suspectmeningitis (eg, fever, ↑ WBC,nuchal rigidity) or encephalitisand in all HIV Pts

Treatment (Lancet2006;367:1087 & 2007;369:1000,1016; NEJM 2008;359:166)• Treat any underlying causes,

including CNS infections,intoxication, withdrawal, etc.

• Antiepileptic drug (AED) therapyis usually reserved for Pts w/underlying structural

abnormality or an idiopathicseizure plus (i) statusepilepticus on presentation,(ii) focal neurologic exam, (iii)postictal Todd’s paralysis or(iv) abnormal EEG

• After 1st unprovoked sz, if EEGand MRI nl → 65% sz-free at 5y (Lancet Neurol 2006;5:317)

• For Pts w/ infrequent seizures,early (vs. delayed)intervention w/ AED ↑ time toseizure recurrence, but has noeffect on long-term seizure-freestatus (Lancet 2005;365:2007)

• AED choice dependent on type ofseizure, side effects, cost,

mechanism of elimination (ifhepatic or renal insufficiency),teratogenesis and druginteractions

• Introduce gradually, monitorcarefully

• May consider withdrawal ifseizure-free (typically for atleast 1 y) and normal EEG

• Individual state laws mandateseizure-free duration beforebeing allowed to drive

Status epilepticus (consultneurology)• Place Pt in semiprone position to

↓ risk of aspiration• Oral airway or, if prolonged,

endotracheal intubation• IV access, start normal saline

infusion• STAT labs including glc, Na, Ca,

serum & urine toxicologyscreen, anticonvulsant levels

• Thiamine (100 mg IV) prior todextrose to prevent Wernicke’sencephalopathy

• Dextrose (50 g IV push)

ALCOHOL WITHDRAWAL

Pathophysiology• Alcohol is a CNS depressant• Chronic use → insensitivity to

inhibitory neurotransmitter g-aminobutyric acid (GABA)

• Abrupt alcohol cessation → CNSoveractivity

Clinical manifestations• Minor withdrawal sx (6–48 h

after last drink): mild anxiety,tremulousness, HA

• Withdrawal seizures: typicallyw/in 48 h after last drink; ifunRx’d, 1⁄3 → delirium

tremens• Alcoholic hallucinosis: isolated

hallucinations (typicallyvisual) 12–48 h after last drink

• Delirium tremens (DT):disorientation, agitation,hallucinations, ↑ HR & BP,fever, diaphoresis; begins 48–96 h after last drink, lasts 5–7d

• Consider other dx: CNS infxn orbleed, sz, drug O/D,coingestions, acute liverfailure, GIB

Clinical Institute WithdrawalAssessment scale for alcohol

(CIWA-Ar)• Assign points for each of the 10

criteria; each criteria is scored0–7 except orientation which isscored 0–4; add points tocalculate score

Treatment (NEJM2003;348:1786)• Benzodiazepines (BDZ)

Drug: diazepam (long-actingw/ active metab; ↓ risk ofrecurrent withdrawal),lorazepam (short half-life),chlordiazepoxide, oxazepam(no active metab; good ifcirrhosis)

Route: start IV, transition toPO

Dosing: typically start w/diazepam 10–15 mg IV q10–15min (or lorazepam 2–4mg IV q15–20min) untilappropriate sedationachieved, then titrate toCIWA-Ar scale, evaluatingq1h until score <8 × 8 h,

then q2h × 8 h, and ifstable, then q4h (JAMA1994;272:519)

• If refractory to BDZ prn, considerBDZ gtt, phenobarbital orpropofol (& intubation)

• Avoid haloperidol (↓ seizurethreshold) or βB/central ɑ2-agonists (mask sx)

• Mechanical restraints as neededuntil chemical sedationachieved

• Volume resuscitation as needed;thiamine then glc to preventWernicke’s encephalopathy(ataxia, ophthalmoplegia,

short-term memory loss);replete K, Mg, PO4

• Prophylaxis: if min sx or asx (ie,CIWA score <8) but prolongedheavy EtOH consumption orh/o withdrawal seizures or DTs→ chlordiazepoxide 25–100 mg(based on severity of EtOHuse) q6h × 24 h, then 25–50mg q6h × 2 d

STROKE

ISCHEMIC STROKE

Etiologies• Embolic (~75%): artery →

artery, cardioembolic,paradoxical (NEJM2007;357:2262), cryptogenic

• Thrombotic (~25%): large vessel(atherosclerosis) vs. smallvessel (“lacunar,”lipohyalinosis of small arteries,often related to HTN,hyperlipidemia, & DM)

• Other: dissection, vasculitis,vasospasm, prothromboticstates, hypoperfusion, genetic

Clinical Manifestations• Timing: embolic → sudden onset;

thrombotic → stuttering course

Transient ischemic attack (TIA)• Sudden deficit due to cerebral

ischemia; no stroke onimaging; sx resolve <24 h

(most <1 h)• Ddx: seizure, migraine,

hypoglycemia, amyloid spells,TGA, anxiety

• Risk of subsequent stroke perABCD2: Age ≥60 y (+1); BP≥140/90 (+1); Clin features:unilat. weak. (+2), speechimpair. w/o weakness (+1);Duration ≥60 (+2) or 10–59min (+1); DM (+1)risk of stroke at 48 h: low risk

(0–3) = 1.0%; moderate (4–5) = 4.1%; high (6–7) =8.1%

Physical exam

• General: assess for arrhythmias,murmurs, carotid & subclavianbruits, peripheral emboli

• Neurologic exam, NIH strokescale(http://www.ninds.nih.gov/doctors/NIH_Stroke_Scale.pdf

Acute workup (w/in 8 h foranterior and w/in 24 h forposterior circulation)• Electrolytes, Cr (relevant for

contrast); glc, CBC, coags (seeexclusion criteria for lysis)

• Cardiac biomarkers, 12-lead ECG,tox screen

• STAT CT to r/o ICH prior to lysis(Se MRI, faster, more widely

http://www.ninds.nih.gov/doctors/NIH_Stroke_Scale.pdf

available)early signs: hyperdense artery,

loss of gray-whitedifferentiation, edema,insular ribbon

CT can be nl in first hrs aftersx onset, not Se for smallstrokes & brainstem strokes

obtain CT-angio head & neckor CT perfusion ifendovascular interventionindicated

Workup to assess foretiology/modifiable risk factors• Cardiac: Holter to assess for

arrhythmias; echo to assess for

thrombus or vegetation, w/bubble study to assess forPFO/atrial septal aneurysm ifsuspected embolic stroke

• Vessel imaging: carotid U/S andDoppler (if no vessel imagingobtained in acute eval)

• Labs: lipids, HbA1c, TSH,homocysteine, Lp(a),hypercoag w/u (if <65 y orcryptogenic stroke; ideallydrawn before startinganticoag), ESR/CRP, blood cxif s/s systemic infection

• MRI helpful if dx of strokeunclear (esp. post circ) or todefine stroke subtype, age,

exact sizeDWI bright/ADC dark =

earliest finding in acuteischemia (~ w/in mins, upto days)

T2-FLAIR: hyperintense w/inhrs, persists for wks; PWIdifferentiates irreversiblyinfarcted core vs. viablepenumbra; T1 fat-sat (neckvessels) if suspicious fordissection

Acute treatment of ischemicstroke (NEJM 2011;364:2138;Stroke 2013;44:870)• Thrombolysis (IV): tPA 0.9

mg/kg (max 90 mg), w/ 10%as bolus over 1 min, rest over1 hconsider if onset w/in 4.5 h, �

ICH, � contraindic. (incl.current/prior ICH; headtrauma or stroke w/in 3 mo;intracranial neoplasm, AVMor aneurysm; recentintracranial/intraspinalsurgery; active internalbleeding; noncompressiblearterial puncture; ↑ BP;multilobar infarct; plt<100k, INR >1.7, on Xainhib, PTT >40, glc <50)

0–3 h: 12% absolute ↑ in good

neuro outcome (min/nodisability), 5.8% absolute ↑in ICH, trend toward 4%absolute ↓ mortality

3–4.5 h: 7.2% absolute ↑ ingood neuro outcome, 1.8%absolute ↑ in ICH, �mortality benefit (nb, trialexcluded patients withprevious strokes + DM)

tenecteplase 0.25 mg/kg IVbolus promising (NEJM2012;366:1099)

• Endovascular (eg, intra-arteriallysis, thrombectomy): w/oproven benefit overthrombolysis IV alone (NEJM

2013;368:893, 904, 914); thusstill experimental, ? considerfor major vascular occlusions(distal ICA, prox MCA, espbasilar given high mortality ordisability untreated)

• BP: lower to <185/110 toconsider lysis; if lyse keep<180/105 × 24 h (considerlabetalol or nicardipine), o/wpermissive HTN unless>220/120 or sx; if sx HoTNconsider vasopressors

• Initiate ASA w/in 24–48 h; avoidanticoagulation w/in 24 h oflysis; see below for long-termRx

• Cerebral edema → herniation:often occurs 1–5 d post largeMCA or cerebellar strokes, ↑risk in young. Temporize:elevate HOB >30°; mannitol± 23% NaCl.Hemicraniectomy ↓ mortality(Lancet Neurol 2007, 6:215).Neurosurgery consult in selectMCA and all large cerebellarstrokes.

Secondary stroke prevention(NEJM 2012;366:1914)• Antiplatelet therapy: different

agents likely have similarefficacy

ASA ↓ death & repeat stroke;equal to warfarin innonembolic stroke (NEJM2001;345:1444)

ASA + dipyrimadole: sup toASA (Lancet 2006;367:1665),but bid dosing, HA → ↓compliance

clopidogrel: marginally sup toASA, slightly ↑ ICH (Lancet1996:348:1329)

cilostazol: superior to ASA, lessbleeding (Lancet Neurol2010;9:959)

clopidogrel + ASA not moreeffective than ASA alone and↑ ICH (Lancet 2004;364:331)

• Anticoagulation (AC): notroutinely indicatedIndications:

cardiac/paradoxical emboli(except bacterialendocarditis); long segmentextradural dissections;hypercoag state; bridge toCEA in sx carotid stenosisw/ongoing TIAs.

INR goal 2–3 for warfarin.Consider LMWH in Ptsw/malignancy.

Hold off on AC in largestrokes for ~2–4 wk givenrisk of hemorrhagicconversion.

• Long-term SBP target 120–139mmHg ( JAMA 2011;306:2137)

• Statin: ↓ recurrent stroke w/atorvastatin 80 mg, LDL goal<70 (NEJM 2006;355:549)

• Fluoxetine: ? improved motorrecovery after 3 mo (LancetNeurol 2011;10:123)

• Carotid revascularizationCEA (if surgical morbidity &

mortality ≤6%) indicatedfor:

sx stenosis 70–99%(benefit ↑ for males,>75 y, ≤2 wk fromstroke) → 65% ↓ RR ofrepeat stroke, slight

benefit for 50–69%stenosis (NEJM1991;325:445; Lancet2004;363:915)

asx stenosis 70–90%, <79y: 50% ↓ RR of repeatstroke (Lancet2004;363:1491 &2010;376:1074)

stenting: compared w/ CEA,periprocedural risk of stroke↑ (esp. in elderly) & MI ↓(although many asx),subsequent rates of strokesimilar (NEJM 2010;363:11;Lancet 2010;376:1062)

Patent foramen ovale (PFO; in~27% of population) (NEJM2005;353:2361)• ↑ stroke risk: ≥4 mm separation,

R→L shunting at rest, ↑ septalmobility, atrial septalaneurysm

• If PFO & stroke/TIA: no benefitof warfarin over ASA (Circ2002;105:2625), but consider ifat high risk for or has DVT/PE.No sig benefit shown for PFOclosure so far, albeit studiessmall & w/ favorable trends(NEJM 2012;366:991;2013:1083 & 1092).

INTRACRANIAL HEMORRHAGE(ICH)

Classification by location• Hemorrhagic strokes:

intraparenchymal hemorrhage(IPH) & subarachnoidhemorrhage (SAH)

• Other ICH: epidural hematoma(EDH) & subdural hematoma(SDH)

Etiologies• AVM, aneurysm, cerebral venous

sinus thrombosis → IPH orSAH

• HTN (basal ganglia, cerebellum,brainstem), cerebral amyloid

(lobar), tumor (esp. w/melanoma, renal cell CA,chorio-CA, thyroid CA) → IPH

• Trauma → all locations (nb, IPHor SAH caused by traumatechnically not a stroke)

Clinical manifestations (LancetNeurol 2005;4:662; BMJ2010;341:c5204)• ↓ consciousness, N/V, HA,

progressive focal neurologicdeficits

• SAH: thunderclap HA, onset w/exertion; nuchal pain/rigidity;LOC. EDH: initial lucidinterval.

Workup• STAT CT brain, angio (CT-A or

conventional) if suspicious forvascular source

• LP to ✓ for xanthochromia if noevidence of ICH on CT andsuspicious for SAH

• Coags (PT, PTT, INR)

Management• Reverse coagulopathies w/ vit K

& FFP, goal INR <1.4. Plt goal>100k; no clear evidence forplt transfusion if on ASA butmay consider with expandingICH; DDAVP if uremic.

• HOB elevation to 30–45°; strict

BP control w/ arterial line, usenicardipine or labetalol gtt,goal SBP <160, foraneurysmal SAH <140, unlessrisk for hypoperfusion b/c ofcrit carotid stenosis

• SAH: surgical clipping vs.endovascular coiling(depending on location,comorbidities) ofaneurysm/AVM; nimodipine to↓ risk of vasospasm (monitorw/ TCDs), seizure Ppx

• Surgical evacuation: any EDH;SDH if >1 cm or rapidexpansion; IPH: consider inyounger Pts w/ ICH, data

controversial, potential benefitin superficial IPH (Lancet2005, 365:387)

• Venous sinus thrombosis: startanticoagulation, manage ↑ ICPand seizures as needed

WEAKNESS &NEUROMUSCULAR

DYSFUNCTION

PERIPHERAL NEUROPATHIES

Etiologies• Mononeuropathy (one nerve):

entrapment, compression,trauma, DM, Lyme.

Commonly seen: mediann. (carpal tunnelsyndrome); ulnar n. (atelbow or wrist);common peroneal n. (atknee with habitual legcrossing); lateralfemoral cutaneous n. (atinguinal ligament).

• Mononeuropathy multiplex(axonal loss of multiple,

separate, noncontiguousnerves):vasculitides, sarcoid, DM,

Lyme, Sjögren, hereditaryneuropathy with pressurepalsies

• Small fiber neuropathy:(unmyelinated or thinlymyelinated nerves): idiopathic,DM, CTD, alcohol, sarcoid,thyroid dysfxn, B12 defic,paraproteinemia, paraneo,celiac, hered.

• Polyneuropathy (multiplesymmetric nerves, generallylength dependent)

Demyelinatingacute: acute inflammatory

demyelinatingpolyneuropathy (AIDP) =Guillain-Barré

subacute: meds (paclitaxel),paraneoplastic

chronic: idiopathic, DM,CIDP, hypothyroidism,toxins, paraproteinemia,hereditary

Axonalacute: acute motor axonal

neuropathy (AMAN),porphyria, vasculitis,uremia

subacute: DM, meds

(cisplatin, paclitaxel,vincristine, INH, ddI),EtOH, sepsis, paraneo.

chronic: DM, uremia, lead,arsenic, HIV,paraproteinemia, B12 defic

Clinical manifestations• Weakness, fasciculations,

numbness, dysesthesias(burning/tingling), allodynia

• ± Autonomic dysfxn (orthostasis,bowel/bladderretention/incontinence,impotence)

• Depressed or absent DTRs (maybe normal in small fiber

neuropathy)

Diagnostic studies• Distal symmetric

polyneuropathy: start w/HbA1C or glc tolerance test,B12, SPEP + SIEP

• EMG & NCS (often no change infirst 10–14 d or in small fiberneuropathy)

• Electrolytes, BUN/Cr, CBC, TSH,LFTs, ANA, anti-Ro, anti-La,ESR, HIV, Cu, Lyme titers,genetic testing and heavymetal screening as indicatedby clinical history and exam

• Autonomic testing/skin bx (small

fiber), nerve bx(mononeuropathy multiplex)

• MRI if possible radiculopathy orplexopathy (after EMG)

Treatment of neuropathic pain• Pharmacologic: pregabalin,

gabapentin, TCAs(nortriptyline, amitriptyline),SSRIs (duloxetine,venlafaxine), tramadol, topicalanalgesics (lidocaine,capsaicin), opiates

• Nonpharmacologic:transcutaneous electrical nervestimulation (TENS)

GUILLAIN-BARRÉ SYNDROME(GBS)

Definition & epidemiology• Acute inflammatory

demyelinating polyneuropathy(AIDP)

• Incidence 1–2 per 100,000; mostcommon acute/subacuteparalysis

• Precipitants in 60%: viral illness(CMV, EBV, HIV), URI(Mycoplasma), gastroenteritis(Campylobacter), Lyme,immunizations (no proven riskw/ current), surgery


• Distal sensory dysesthesias andnumbness often firstsymptoms, back pain alsocommon

• Ascending symmetric paralysisover hours to days; plateau in1–3 wk

• Hypoactive then absent reflexes• Resp failure requiring mech vent

occurs in 30%; autonomicinstability & arrhythmias in50%

• Fisher variant: ophthalmoplegia,ataxia, areflexia; associatedwith anti-GQ1b antibodies

Diagnostic studies (results may

be normal in first several days)• LP: albuminocytologic

dissociation = ↑ protein w/opleocytosis (<10 WBCs) seenin up to 50% of Pts in 1st wk,75% by 3rd wk of symptoms

• EMG & NCS: ↓ nerve conductionvelocity, conduction block,prolonged F wave latency

• FVC & NIF: to assess for risk ofrespiratory failure (cannot relyon PaO2 or SaO2)

Treatment• Plasma exchange (Coch Data Syst

Rev 2002;2:CD001798) or IVIgof equal efficacy and no

additional benefit with both(Neuro 2012;78:1009), steroidsnot beneficial

• Supportive care with monitoringin ICU setting if rapidprogression or resp. failure

• Watch for autonomicdysfunction: labile BP,dysrhythmias (telemetry)

• Most recover near baseline;axonal variant (~5%) withincomplete recovery; 3–5%mortality

MYASTHENIA GRAVIS

Definition & epidemiology• Autoimmune disorder with Ab

directed against acetylcholinereceptor (AChR) in NMJ

• Prevalence: 1 in 7500; affects allages, peak incidence 20s–30s(women), 60s–70s (men)

Clinical manifestations• Fluctuating weakness w/

fatigability (worse w/ repetitiveuse, relieved by rest)

• Cranial muscles involved early →ocular (ptosis, diplopia) in50%; bulbar (difficultychewing, dysarthria,

dysphagia) in 15%. Oftenlater progresses togeneralized weakness.

• Limb weakness proximal >distal; DTRs preserved;minimal/no atrophy

• Exacerbations triggered bystressors such as URI, surgery,pregnancy or postpartum,meds (eg, aminoglycosides,procainamide, phenytoin);prednisone can worsen acutely

• Myasthenic crisis = exacerbation→ need for respiratoryassistance

• Cholinergic crisis = weaknessdue to overtreatment with

anticholinesterase medications;may have excessive salivation,abdominal cramping anddiarrhea; rare at normal doses

Diagnostic studies• Bedside: ptosis at baseline or

after >30 sec of sustainedupgaze, improved with icepack over eyes for 2–5 min, Se77%, Sp 98%

• Neostigmine test: temporary ↑strength; false & occur;premedicate w/ atropine

• EMG: ↓ response with repetitivenerve stimulation (vs. ↑response in Lambert-Eaton)

• Anti-AChR Ab: Se 80%, 50% ifocular disease only; Sp >90%;muscle specific receptortyrosine kinase (MuSK) Abaccount for most AchR Ab cases

• CT or MRI of thorax to evaluatethymus (65% hyperplasia, 10%thymoma)

Treatment• Thymectomy if thymoma; may

lead to improvement in up to85% Pts w/o thymoma

• Cholinesterase inhibitors (eg,pyridostigmine) are most rapidacting (benefit in 30–60 min)

• Immunosuppression: prednisone(benefit in wks) ±azathioprine,cyclophosphamide (benefit in6–12 mo)

• Myasthenic crisis: treatprecipitantconsider d/c anticholinesterase

if suspect cholinergic crisisimmunosuppression with

glucocorticoids (inmonitored setting as risk forinitial worsening)

IVIg or plasmapheresis ofequal efficacy (Ann Neurol2010;68:797)

ICU if rapid or severe (follow

FVC, NIF)

MYOPATHIES

Etiologies• Hereditary: Duchenne, Becker,

limb-girdle, myotonic,metabolic, mitochondrial

• Endocrine: hypothyroidism,hyperparathyroidism, Cushingsyndrome

• Toxic: statins, fibrates,glucocorticoids (incl. criticalillness myopathy), zidovudine,alcohol, cocaine, antimalarials,colchicine, penicillamine

• Infectious: HIV, HTLV-1,trichinosis, toxoplasmosis

• Inflammatory (see

“Rheumatology”):polymyositis, dermatomyositis,inclusion body myositis

Clinical manifestations• Progressive or episodic weakness

(not fatigue)• Weakness most often symmetric,

proximal > distal (stairs,rising from sitting, etc.)

• ± Myalgias (though notprominent or frequent),cramps, myotonia (impairedrelaxation)

• May develop eitherpseudohypertrophy(dystrophies) or mild muscle

atrophy• Assoc. organ dysfxn: cardiac

(arrhythmia, CHF), pulmonary(ILD), dysmorphic features

Diagnostic studies• CK, aldolase, LDH, electrolytes,

ALT/AST, PTH, TSH, ESR, HIV• Autoantibodies (anti-Jo1,

antisynthetase, anti-Mi-2, anti-SRP, ANA, RF)

• EMG/NCS: low-amplitude,polyphasic units with earlyrecruitment, ± fibrillationpotentials

• Muscle biopsy, molecular genetictesting (where indicated)

HEADACHE

Primary headache syndromes(International Headache SocietyClassification)• Tension-type: constant pressure,

freq bilateral; a/w myofascialsensitivity in neck or headTriggers: stress, sleep

deprivation, dehydration,hunger

Treatment: OTC analgesics(NSAIDs, acetaminophen;risk of med overuse HA!) forepisodic; TCAs for chronic

• Cluster HA and trigeminalautonomic cephalgias (TACs)

Characterized by unilateralrhinorrhea, red/tearing eye,miosis/ptosis, lid edema,sweating, differentiated bytiming

Cluster: > , unilateral eyepain, attacks 15 min–3 h,worsened by EtOH. Ppx:CCB (verapamil). Rx: high-flow O2, sumatriptan IN/SC,lidocaine IN.

Paroxysmal hemicrania: similarto cluster, but > , attacks2–45 min. Rx: indomethacin.

Hemicrania continua: > ,icepick-like pain lasting >3

mo. Rx: indomethacin.Short-lasting unilateral

neuralgiform HA w/conjunctival injection andtearing (SUNCT): > ,excruciating, stabbing,electrical pain, 5 sec–6 min,up to 200×/d. Rx:lamotrigine, gabapentin,topiramate.

• Migraine: see below

Secondary causes of headaches• Traumatic: postconcussion, SAH,

SDH, postcraniotomy• ↑ ICP: mass (tumor, abscess,

vascular malformations, ICH),

hydrocephalus, idiopathicintracranial hypertension(pseudotumor cerebri), altitudeassociated cerebral edema

• ↓ ICP: post-LP headache, CSFleak/dural tear, overshunting

• Vascular causes: stroke (esp.posterior circ), dissection,vasculitis (incl. temporalarteritis), reversible cerebralvasoconstriction syndrome(RCVS), ICH, venous sinusthrombosis

• Meningeal irritation: meningitis,SAH

• Trigeminal neuralgia• Extracranial: sinusitis, TMJ

syndrome, glaucoma• Systemic causes: hypoxia,

hypercapnia, dialysis HA,HTN, hypoglycemia, ↓TSH

• Medication overuse (analgesics),withdrawal (caffeine, opioids,estrogen)

Clinical evaluation ( JAMA2006;296:1274)• History: onset (sudden vs.

gradual), quality, severity,location, duration, triggers,alleviating factors, positionalcomponent, hormonal triggers(menstruation), precedingtrauma, associated sx (visual

Δs, “floaters,” N/V,photophobia, focal neurologicsx)

• Medications (analgesics),substance abuse (opioids,caffeine)

• General and neurologic exam(fundoscopic exam, visualfields)

• Warning signs (should promptneuroimaging)explosive onset (vasc); “worst

HA of my life” (SAH, RCVS);meningismus (SAH, infxn)

positional: lying > standing (↑ICP); N/V (↑ ICP; migraines)

visual sx: diplopia, blurring, ↓

acuity (GCA, glaucoma, ↑ICP); eye pain (glaucoma,cluster)

abnl neuro exam (struct. lesion,poss. in migraine); ↓consciousness (± fever):infxn, ICH

age >50 y; immunosuppression(CNS infections, PRES)

• LP if suspicious for SAH (✓ forxanthochromia), pseudotumor(✓opening press); image first!

MIGRAINE

Epidemiology: affects 15% ofwomen and 6% of men; onsetusually by 30 y

Definition & clinicalmanifestations (Lancet2004;363:381; JAMA2006;296:1274)• H/o ≥5 attacks lasting 4–72 h

and with (a) N/V orphotophobia & phonophobia,and (b) ≥2 of following:unilat., pulsating, mod–severeintensity, aggravated byroutine activity

• Migraine w/o aura (64%): most

common, previously called“common” migraine

• Typical aura w/ migraine (18%):visual aura (scotomata withjagged/colored edge) precedesHA, can also be reversiblesensory or speech symptoms,<1 h

• Complicated: accompanied bystereotypical neurologic deficitthat may last hrs (DDx includesstroke: in migraine onset israther gradual, sx spread overmins)

• Precipitants: stress, hunger, foods(cheese, chocolate) and foodadditives (MSG), fatigue,

alcohol, menstruation, exercise

Treatment (NEJM 2002;346:257)• Eliminate precipitants• Prophylaxis: TCA, βB, CCB,

valproic acid, topiramate( JAMA 2004;291:965),gabapentin

• Abortive therapy: ASA,acetaminophen, caffeine, high-dose NSAIDsmetoclopramide IV,

prochlorperazine IM or IV,valproate IV, steroids

5-HT1 agonists (“triptans”):most specific therapy,contraindicated if

complicated migraine, CAD,prior stroke. Triptan +NSAID stronger than eitheralone ( JAMA2007;297:1443)

ergotamine,dihydroergotamine: use withcaution in Pts w/ CAD

BACK AND SPINAL CORDDISEASE

Differential diagnosis of backpain• Musculoskeletal:

musculoligamentous “strain”(experienced by up to 80% ofpopulation at some time), OA,RA, spondylolisthesis,vertebral fx, inflammatoryspondyloarthritis (ankylosingspondylitis, reactive,psoriatic), myofascial painsyndrome

• Spinal cord (myelopathy)/nerveroot (radiculopathy):

Degenerative/traumatic: discherniation, spondylosis,vertebral fx and subluxation

Neoplastic: lung, breast,prostate, RCC, thyroid,colon, multiple myeloma,lymphoma

Infectious (also see ID section):osteomyelitis, epiduralabscess, zoster, Lyme, CMV,HIV

• Referred pain from visceraldisease: (quality of pain canbe important to distinguish)GI: PUD, cholelithiasis,

pancreatitis, pancreaticcancer

GU: pyelonephritis,nephrolithiasis, uterine orovarian cancer, salpingitis

Vascular: aortic dissection,leaking aortic aneurysm

Initial evaluation• History: location, radiation,

trauma, wt loss, cancer hx,fever, immunocompromised,neurologic symptoms, saddleanesthesia, incontinence,urinary retention, IV drug use

• General physical exam: localtenderness, ROM, signs ofinfection or malignancy,signs of radiculopathy

(experienced assharp/lancinating painradiating into limb):Spurling sign (radicular pain

w/ downward force toextended & ipsilaterallyrotated head): 30% Se,93% Sp

straight leg raise (radicularpain at 30–70°):ipsilateral: 92% Se, 28%Sp; crossed (contralateralleg raised): 28% Se, 90%Sp

• Neurologic exam: full motor(including sphincter tone),sensory (including perineal

region) and reflexes includinganal (S4) and cremasteric (L2)

• Laboratory (depending onsuspicion): CBC, ESR, Ca, PO4,AФ, CSF

• Neuroimaging: low yield ifnonradiating pain, high false

rate (incidental spondylosis)depending on suspicion: X-rays, CT or CT myelography,MRI, bone scan

• EMG/NCS: may be useful todistinguish root/plexopathiesfrom peripheral neuropathies

SPINAL CORD COMPRESSION

Clinical manifestations• Acute: flaccid paraparesis and

absent reflexes (“spinalshock”)

• Subacute–chronic: spasticparaparesis and hyperactivereflexes

• Posterior column dysfunction inlegs (loss of vibratory sense orproprioception)

• Sensory loss below level of lesion• Bilateral prominent Babinski

responses ± ankle clonus

Evaluation & treatment• Empiric spine immobilization

(collar, board) for all traumapatients

• STAT MRI (at and above clinicalspinal level, pre- andpostgadolinium) or CTmyelogram

• Emergent neurosurgical and/orneurology consultation

• Urgent radiation therapy ±surgery for compression if dueto metastatic disease

• High-dose steroids depending oncause:Tumor: dexamethasone 16

mg/d IV (usually 4 mg q6h)with slow taper over wks

Trauma: methylprednisolone

30 mg/kg IV over 15 minthen 5.4 mg/kg/h × 24 h (ifstarted w/in 3 h of injury) or× 48 h (if started 3–8 hafter injury) ( JAMA1997;277:1597)

NERVE ROOT COMPRESSION

Clinical manifestations• Radicular pain aggravated by

activity (esp. bending,straining, coughing), relievedby lying

• Sciatica = radicular painradiating from buttocks downlateral aspect of leg, often toknee or lateral calf ±numbness and paresthesiasradiating to lateral foot

Treatment of nerve rootcompression• Conservative: avoid

bending/lifting; NSAIDs; Rxneuropathic pain (see

“Peripheral Neuropathies”);physical therapy

• Spinal epidural steroid injections(ESI): limited short-term reliefof refractory radicular pain

• Surgery: cord compression orcauda equina syndrome;progressive motor dysfunction;bowel/bladder dysfunction;failure to respond toconservative Rx (NEJM2007;356:2245)

SURGICAL ISSUES

ABDOMINAL PAIN

Figure 10-1 Etiologies ofabdominal pain based onlocation

Initial evaluation• History: onset of pain, location,

exacerbating/relieving factors• Assoc. sx: fevers/chills, N/V, Δ in

bowel habits(diarrhea/constipation, stooldiam. or color, hematochezia,melena), jaundice, Δ in urinecolor, Δ in wt, menstrual hx inwomen

• PMHx: previous incisions orabdominal surgeries; Ob/Gynhx

• Exam: VS; general posture of Pt;comprehensive abdominal

exam specifically looking forsigns of peritonitis, whichinclude rebound tendernessand involuntary guarding,abdominal wall rigidity, painw/ percussion/minimalpalpation; presence of hernias;rectal/pelvic

• Labs: CBC, electrolytes, LFTs,amylase/lipase, pregnancy test

• Imaging: depends on suspectedetiology, may include RUQU/S for biliary/hepaticdisease, KUB for intestinalobstruction, CT for pancreatitisor intestinal disease. Do notdelay resucitation or surgical

consultation for ill Pt whilewaiting for imaging.

ACUTE ABDOMEN

Definition• Acute onset abdominal pain that

portends need for urgentsurgery

Etiologies• Perforated viscous → peritonitis

(perforated ulcer, complicateddiverticulitis, trauma)

• Intraperitoneal bleed• Bowel obstruction (adhesions

from previous surgeries,malignancies, hernias)

• Mimics: severe pancreatitis canresemble peritonitis; renalcolic causes severe abdominal

pain but not abdominalrigidity

Initial evaluation• H&P as above• Labs as above plus: PT/INR, PTT,

type & screen• Imaging: KUB (upright) or if

stable, CT abomen/pelvis w/IV contrast (IV/PO if suspectobstruction)

Initial management• Immediate surgical consultation

for suspected acute abdomen• NPO, start IV fluids (NS or LR)• Broad spectrum abx if

perforation suspected

EXTREMITY EMERGENCIES

Acute limb ischemia (see“Peripheral Artery Disease” fordetails)• Definition: sudden ↓ in perfusion

causing threat to limb viability• Evaluation: detailed vascular

exam; CT angiography orarteriography

• Initial management: anticoag forembolism/thrombosis;immediate surgicalconsultation

Compartment syndrome (ClinOrthop Relat Res 2010;468:940)• Definition: ↑ intracompartmental

pressure w/ compressiveclosure of venules → ↑hydrostatic force resulting infurther increases incompartment pressure

• Etiologies: orthopedic (fracture),vascular (ischemia-reperfusion), iatrogenic (eg,vascular injury inanticoagulated Pt), soft tissueinjury (eg, prolonged limbcompression)

• Clinical manifestations: pain esp.on passive movement,swollen/tense compartment,paraesthesia, pallor,pulselessness, paralysis (late)

• Evaluation: ✓ compartmentpressures (needle manometry),ICP >30 or difference betweendiastolic pressure and ICP of>10–30 is diagnostic

• Treatment: fasciotomy

SURGICAL TUBES, DRAINS,WOUNDS

Tracheostomy (Otolaryngol HeadNeck Surg 2013;148:6)• Inserted either percutaneously or

surgically• Monitor for secretions and

suction frequently• Typically a cuffed tube, which

creates a tight seal to facilitateventilation throught tube

• Speaking valve (eg, Passy-Muir):1-way valve that allowsinhalation through tube, butexhalation around tubethrough vocal cords (nb, cuff

should not be inflated)• 1st routine tube change for

percutaneously placed tubesshould be ~10 d postop,whereas surgically placedtubes can be changed >5 dpostop and should be overseenby experienced personnel

• Accidental dislodgement of tube:intubate from above (if

airway/vent necessary &anatomically possible)

w/in 7 d of placement:emergent surgicalconsultation

>7 d after placement: replacewith a similar size tube or

smaller

Chest tubes (Eur J CardiothoracSurg 2011;40:291)• Inserted for PTX, chest trauma or

after thoracic surgery fordrainage of air/ fluid fromthoracic cavity. Tubes rangefrom small 10-Fr cathetersplaced for spontaneous PTX tolarge bore tubes (28–32 Fr)placed after pulmonaryresections.

• Connected to 3-chamber chestdrainage system:1st: collection chamber for

pleural fluid

2nd: water seal chamber usedto allow air to exit pleuralspace on exhalation andprevent air from entering oninhalation

3rd: suction control chamberwhich regulates suctiontransmitted to pleural space

• Monitor for ouput and presenceof air leak (indicated bybubbling in water seal chamber)

• Removal determined by overalldaily outputs and presence ofair leak

• If accidentally removed ordislodged so not functional,tube should be completely

removed and an occlusivedressing (eg, 4 × 4 coveredw/ Tegederm or silk tape)should be placed rapidly oversite. CXR STAT; new tubeshould be placed if persistentPTX.

Gastrostomy/jejunostomy tubes(Paediatr Child Health2011;16:281)• Placed for tube feedings,

hydration and delivery ofmedications

• Securely anchor to skin toprevent inadvertent removal

• Surrounding skin should be kept

dry to prevent breakdown• Should not be removed for ≥6–8

wk to allow establishment ofmature gastrocutaneous tract

• Obstructed tubes can be clearedby flushing with agents such ascarbonated water, meattenderizer, pancreaticenzymes. ↓ obstruction byflushing before & after medsand flushing q4–6h whenreceiving continuous feeds.

• If becomes inadvertentlyremoved a foley catheter ofsimilar size or smaller shouldbe placed in the tractimmediately to prevent stoma

from closing. Tube thenreplaced and confirmed viafluoro study w/ gastrograffin.

Suture/staple removal• Should be done in consultation

w/ surgical team• Timing of removal depends on

location of wound: wait 3–4 dbefore removal from face, 6 dfor scalp, 7 d for chest,abdomen & arms, 10 d forback & legs, 14 d for hands

• Should not be removed if there isevidence of wound separationduring removal!

• After removal, wound should be

reapproximated w/ steri-strips

MAXIMIZING A SURGICALCONSULT

• For ill Pt, call surgical consultearly, do not wait for labs &imaging results

• If potential surgical emergency,make Pt NPO, start IVF, ✓coags, type & screen

• Have appropriate-level MD whoknows & has examined Pt callconsult

OB/GYN ISSUES

VAGINAL BLEEDINGAbnormal bleeding from lower (vulva,vagina, cervix) or upper genital tract

(uterus)

Etiologies• Premenopausal

Not pregnant: menses,dysfunctional uterinebleeding (menorrhagia),leiomyoma, polyp, trauma,cervical dysplasia/cancer(rare), endometrialhyperplasia/cancer (rare)

Pregnant

1st trimester: threatenedabortion, spont.abortion (missed,incomplete orcomplete), ectopicpregnancy, molarpregnancy (partial orcomplete hydatidiformmole)

2nd or 3rd trimester:preterm labor, placentaprevia, placentalabruption

• Postmenopausal: atrophy, polyp,leiomyoma, endometrialhyperplasia/cancer, cervicaldysplasia/cancer

History & exam• Age, menopausal status,

gestational age if preg.;volume & duration of currentbleeding

• If premenopausal: menstrual hxincluding age of onset, intervalbetween & duration of menses,any assoc. sx and LMP toassess timing of menstrualcycle

• Past Ob/Gyn hx (any structuralabnl, STD and contraception)

• Health maint. (Pap smear, HPVscreening); domestic violence;anticoag or antiplt meds

• General physical & abdominal

exam (incl. tenderness,masses)

• Pelvic exam: external (quantityof bleeding seen on vulva, anylesions, any trauma); also, w/assistance from Ob/Gyn,speculum exam (quantity ofbleeding; cervical os open orclose and if open, dilation; anypolyps) & bimanual exam(uterine size and tenderness,adnexal mass and tenderness)

Laboratory evaluation &imaging• Urine (rapid test) & serum

pregnancy test (bhCG);

Hct/hemoglobin• Pelvic U/S: visualize intrauterine

preg to r/o ectopic; if preg.,intrauterine not seen, & bHCG> discrim. zone → concern forectopic; if bHCG < discrim.zone → follow bHCG; nlplacental position to r/oplacenta previa and likelysevere abruption

• Ectopic pregnancy is life-threateningdiagnosis, ∴ must rule out if Ptpregnant

VAGINAL DISCHARGEFluid or mucus from vagina, cervix or

uterus

Etiologies• Infectious: bacterial vaginosis,

candida vulvovaginitis,trichomoniasis

• Noninfectious: physiologic (inpreg. or non-preg.), rupture ofmembranes, foreign-body rxn

Initial evaluation• Age, LMP, gestational age if

preg. or menopausal status• Discharge quantity, color,

consistency, odor, assoc. sx

(itchiness, redness, abd/pelvicpain)

• Past gyn hx incl STD andcontraception usage (condoms↓ STD risk)

• Tampon or condom use as riskfactors for retained foreignbody

• Pelvic exam: external (quantity &quality of discharge on vulva,any lesions); speculum(discharge, appearance ofcervix), bimanual (cervicalmotion tenderness)

• Laboratory: pH of discharge;microscopy (saline & KOH wetmounts); urine pregnancy test

Treatment• Bacterial vaginosis: oral or

vaginal metronidazole orclindamycin

• Candida vulvovaginitis: oral ortopical antimycoticmedications

• Trichomoniasis: oralmetronidazole

ADNEXAL MASS IN NON-PREGNANT WOMAN

Mass arising from ovary, fallopiantube or surrounding connective tissue

Etiologies• Ovarian: functional (follicular

and corpus luteum) orhemorrhagic cyst,endometriomas, ovariantorsion, tubo-ovarian abscess,benign & malignant ovariantumors

• Fallopian tube: paratubal cyst,hydrosalpinx, ovarian torsion,tubo-ovarian abscess

Initial evaluation• LMP / menopausal status;

associated sx of abd/pelvicpain, FHx of gyn cancers

• Abd exam (distension,tenderness, masses); bimanual(uterine or adnexal masses)

• Preg. test if premenopausal (if ,then mass likely pregnancy);CA-125 if postmenopausal

• Pelvic U/S (even if mass firstidentified on CT as U/S is bestmodality); U/S appearance ofmass most important factorused to determine risk ofmalignancy

OPHTHALMIC ISSUES

ACUTE VISUAL CHANGES

Description & commonetiologies of other visualchanges• Fluctuation in vision (ie,

blurry): med-inducedrefractive error (eg, systemicsteroids, chemotherapy),hyperglycemia, dry eye

(common)• Double vision (diplopia): fixed

double vision w/ophthalmoplegia from orbitalprocess or cranial nerve palsy.Transient “diplopia” due tofatigue or sedation.

• Visual field defect: bilateral(homonymous → contral. CNSlesion; bitemporal → pituitary,glaucoma or toxic/nutritional);unilateral (ipsilat. orbital,retinal or optic nerve prob)

• Floaters: vitreous detachment(common, benign); retinaldetachment (uncommon,“flashing lights,” unilateral

visual field defect);hemorrhage; intraocularlymphoma

RED EYE

OTHER DIAGNOSES

Optic nerve disorders• Ischemic optic neuropathy:

p/w acute unilat. visual loss,altitudinal field defect anterior:a/w GCA; non-arteritic a/wHTN, hyperchol., DM,thrombophilia posterior (veryrare): seen after severe bloodloss; hypotension duringsurgery

• Optic neuritis: often p/w unilat.central scotoma, pain withEOM,↑ visual loss over days;a/w demyelinating disease(eg, MS), also seen w/

sarcoidosis & CTD

Ocular motor palsies• CN III palsy: EOM restricted in

all directions except laterally(eye is “down & out”); a/wptosis & mydriasis; seen w/uncal herniation, aneurysm ofpost com art., GCA, HTN, DM

• CN IV palsy: upward deviation &lack of depression onadduction; congenital 4th (nodiplopia); a/w trauma, postfossa tumor (vertical diplopia,better with head tilt)

• CN VI palsy: failure of abduction(eye is “turned in”), horizontal

diplopia worse at distancethan near, worse w/ gaze toaffected side; a/w ↑ ICP, HTN,diabetes, trauma

Other Dx• Orbital cellulitis: p/w fever,

proptosis, ↓ EOM, sinusitis;requires emergent abx & referralto ophtho; differentiate frompreseptal cellulitis by presenceof pain w/ eye movement,proptosis, pupil reaction abnl,ophthalmoplegia, ± visualchanges

• SJS/TEN/facial burn/acuteGVHD:

conjunctival/lid/corneainvolvement → may lead tocorneal perforation,permanent vision loss; emergophtho consult

INITIAL EVALUATION• Ocular presentation: onset

(sudden or progressive) &duration of sx; unilateral vs.bilateral; pain; photophobia;discharge; Δ in near (eg, book)or far (eg, TV across room)vision

• Pre-existing ocular conditions,eye meds (incl any Ds), recenth/o ocular surgery

• Ocular exam: vision (✓with Pt’scorrection [glasses/contacts])w/ each eye; pupillary exam;EOM; confrontation visualfields (important if suspectCNS problem)

• Overall status: VS,immunocompromised, s/s ofinfxn, h/o malignancy, CNSissues, Δ in meds, CBC, coags

ICU MEDICATIONS

F i g u r e 11-1 ACLS pulmonaryedema, hypotension or shockalgorithm

ANTIBIOTICS

The following tables of spectra ofactivity for different antibiotics are

generalizations.Sensitivity data at your own

institution should be used to guidetherapy.

FORMULAE AND QUICKREFERENCE

CARDIOLOGY

Fick cardiac outputOxygen consumption (L/min) =CO (L/min) × arteriovenous (AV)oxygen difference

CO = oxygen consumption/AVoxygen differenceOxygen consumption must bemeasured (can estimate w/ 125mL/min/m2, but inaccurate)AV oxygen di erence = Hb (g/dL)× 10 (dL/L) × 1.36 (mL O2/g ofHb) × (SaO2—SvO2)

SaO2 is measured in any arterialsample (usually 93—98%)SvO2 (mixed venous O2) ismeasured in RA, RV or PA(assuming no shunt) (nl ~75%)

PULMONARY

CXR in heart failure• ↑ cardiac silhouette (in systolic

dysfxn, not in diastolic)• Pulmonary venous hypertension:

cephalization of vessels (vesselssize > bronchi in upper lobes),peribronchial cuffing (fluidaround bronchi seen on end →small circles), Kerley B lines(horizontal 1—2-cm lines atbases), ↑ vascular pediclewidth, loss of sharp vascularmargins, pleural effusions(~75% bilateral)

• Pulmonary edema: ranges fromground glass to consolidation;often dependent and central,sparing outer third (“bat wing”appearance)

Dead space = lung units that areventilated but not perfused

Intrapulmonary shunt = lungunits that are perfused but notventilated

NEPHROLOGYAnion gap (AG) = Na − (Cl +HCO3) (normal = [alb] × 2.5;typically 12 ± 2 mEq)Delta-delta (ΔΔ) = [Δ AG (ie,calc. AG - expected) / Δ HCO3 (ie,24 - measured HCO3)]Urine anion gap (UAG) = (UNa +UK) − UCl

HEMATOLOGY

✓ PTT q6h after every Δ (t1⁄2 ofheparin ~90 min) and then qd orbid once PTT is therapeutic

✓ CBC qd (to ensure Hct and pltcounts are stable)

Warfarin-heparin overlaptherapy• Indications: when failure to

anticoagulate carries ↑ risk ofmorbidity or mortality

(eg, DVT/PE, intracardiacthrombus)• Rationale: (1) Half-life of factor

VII (3—6 h) is shorter thanhalf-life of factor II (60—72 h);

∴warfarin can elevatePT before achieving a trueantithrombotic state

(2) Protein C also hashalf-life less than that offactor II;∴theoretical concern ofhypercoagulable statebefore antithromboticstate

• Method: (1) Therapeutic PTT isachieved using heparin

(2) Warfarin therapy isinitiated(3) Heparin continueduntil INR therapeutic for≥2 d and ≥4—5 d ofwarfarin(roughly corresponds to

~2 half-lives of factor IIor a reduction to ~25%)

ABBREVIATIONS

5′-NT 5′-nucleotidase

6-MP 6-mercaptopurine

AAA abdominal aortic aneurysm

AAD antiarrhythmic drug

Ab antibody

ABE acute bacterial endocarditis

ABG arterial blood gas

abnl abnormal

ABPA allergic bronchopulmonaryaspergillosis

abx antibiotics

AC assist control

ACEangiotensin converting

enzyme

ACEI ACE inhibitor

ACIanemia of chronic

inflammation

ACL anticardiolipin antibody

ACLS advanced cardiac life support

ACS acute coronary syndrome

ACTHadrenocorticotrophic

hormone

ACV acyclovir

ADA adenosine deaminase

ADH antidiuretic hormone

ADL activities of daily living

AF atrial fibrillation

AFB acid-fast bacilli

AFL atrial flutter

AFP ɑ-fetoproteinAFTP ascites fluid total protein

AG aminoglycoside

anion gap

Ag antigen

AGN acute glomerulonephritis

AI aortic insufficiency

AIDS acquired immunodefic. synd.

AIH autoimmune hepatitis

AIHAautoimmune hemolytic

anemia

AIN acute interstitial nephritis

AIP acute interstitial pneumonia

AKI acute kidney injury

ALF acute liver failure

ALL acute lymphoblastic leukemia

ALS amyotrophic lateral sclerosis

ALT alanine aminotransferase

AMA anti-mitochondrial antibody

AMIanterior myocardial

infarction

AML acute myelogenous leukemia

amy amylase

ANA antinuclear antibody

ANCAantineutrophilic cytoplasmic

Ab

AoD aortic dissection

AoV aortic valve

APC activated protein C

APLacute promyelocytic

leukemia

APLA antiphospholipid AbAPS antiphospholipid Ab synd.

ARB angiotensin receptor blocker

ARDS acute resp distress synd.

ARV antiretroviral

ARVC arrhythmogenic RV CMP

AS aortic stenosis

ASA aspirin

ASD atrial septal defect

AST aspartate aminotransferase

asx

asymptomaticAT atrial tachycardia

ATII angiotensin II

ATIII antithrombin III

ATN acute tubular necrosis

ATRA all-trans-retinoic acid

AV atrioventricular

AVA aortic valve area

AVB atrioventricular block

AVNRTAV nodal reentrant

tachycardiaAVR aortic valve replacement

AVRT AV reciprocating tachycardia

a/w associated with

AZA azathioprine

Aϕ alkaline phosphatase

b/c because

BAL bronchoalveolar lavage

βB beta-blocker

BBB bundle branch block

BCx blood cultureBD bile duct

BDZ benzodiazepines

bili. bilirubin

BIPAPbilevel positive airway

pressure

BIV biventricular

BM bone marrow

bowel movement

BMD bone mineral density

BMI body mass indexBMS bare metal stent

BNP B-type natriuretic peptide

BOOPbronchiolitis obliterans with

organizing pneumonia

BP blood pressure

BPH benign prostatic hypertrophy

BRBPR bright red blood per rectum

BS breath sounds

BT bleeding time

BUN blood urea nitrogenbx biopsy

BYCEbuffered charcoal yeast

extract

C′ complement

c/s consult

c/w compared with

consistent with

CABGcoronary artery bypass

grafting

CAD coronary artery disease

CAH congenital adrenalhyperplasia

CALLA common ALL antigen

CAPDchronic ambulatory

peritoneal dialysis

CBC complete blood count

CBD common bile duct

CCB calcium channel blocker

CCl4 carbon tetrachloride

CCP cyclic citrullinated peptide

CCSCanadian Cardiovascular

SocietyCCY cholecystectomy

CD Crohn’s disease

CEA carcinoembryonic antigen

carotid endarterectomy

ceph. cephalosporin

CF cystic fibrosis

Cftx ceftriaxone

CFU colony forming units

CHB complete heart block

CHD congenital heart diseaseCHF congestive heart failure

CI cardiac index

CIAKI contrast-induced AKI

CIDPchronic inflammatory

demyelinatingpolyneuropathy

CJD Creutzfeldt-Jakob disease

CK creatine kinase

CKD chronic kidney disease

chronic lymphocytic

CLL leukemiaCMC carpometacarpal (joint)

CMLchronic myelogenous

leukemia

CMMLchronic myelomonocytic

leukemia

CMP cardiomyopathy

CMV cytomegalovirus

CN cranial nerve

CO carbon monoxide

cardiac outputCOP cryptogenic organizing PNA

COPD chronic obstructive pulm dis.

COX cyclo-oxygenase

CP chest pain

CPAP continuous positive airwaypressure

CPP cerebral perfusion pressure

CPPDcalcium pyrophosphate

dihydrate

Cr creatinine

CrAg cryptococcal antigen

CRC colorectal cancer

CrCl creatinine clearance

CRP C-reactive protein

CRTcardiac resynchronization

therapy

CsA cyclosporine A

CSF cerebrospinal fluid

CSM carotid sinus massage

CT computed tomogram

CTA CT angiogramCTD connective tissue disease

CV cardiovascular

CVA cerebrovascular accident

CVD cerebrovascular disease

collagen vascular disease

CVIDcommon variable

immunodefic.

CVP central venous pressure

CVVHcontinuous veno-venous

hemofiltration

CW chest wall

cx culture

CXR chest radiograph

CYC cyclophosphamide

d day

D death

∆MS change in mental status

DA dopamine

DAD diffuse alveolar damage

DAH diffuse alveolar hemorrhage

DAT direct antiglobulin test

DBP diastolic blood pressure

d/c discharge

discontinue

DCIS ductal carcinoma in situ

DCMP dilated cardiomyopathy

Ddx differential diagnosis

DES drug-eluting stent

DFAdirect fluorescent antigen

detection

DI diabetes insipidus

DICdisseminated intravascular

coagulation

diff. differential

DIPdesquamative interstitial

pneumonitis

distal interphalangeal (joint)

DKA diabetic ketoacidosis

DLCO diffusion capacity of the lung

DLE drug induced lupus

DM dermatomyositis diabetes mellitus

DMARDdisease-modifying anti-

rheumatic drug

DOE dyspnea on exertion

DRE digital rectal exam

DRESSdrug reaction w/ eosinophilia

& systemic symptoms

DSE dobutamine stress echo

DSTdexamethasone suppression

testDTRs deep tendon reflexes

DU duodenal ulcer

DVT deep vein thrombosis

dx diagnosis

EAD extreme axis deviation

EAV effective arterial volume

EBV Epstein-Barr virus

ECG electrocardiogram

ECMOextracorporeal membrane

oxygenation

ED emergency department

EDP end-diastolic pressure

EDV end-diastolic volume

EEG electroencephalogram

EF ejection fraction

EGD esophagogastroduodenoscopy

EGFRepidermal growth factor

receptor

EGPAeosinophilic granulomatosis

with polyangiitis

EI entry inhibitorEIA enzyme-linked immunoassay

ELISAenzyme-linked

immunosorbent assay

EM electron microscopy

EMB ethambutol

ENT ears, nose, & throat

EOMextraocular

movement/muscles

EP electrophysiology

Epo erythropoietin

EPS electrophysiology study

ERCPendoscopic retrograde

cholangiopancreatography

ERV expiratory reserve volume

ESP end-systolic pressure

ESRerythrocyte sedimentation

rate

ESRD end-stage renal disease

ESV end-systolic volume

ET endotracheal tube

essential thrombocythemiaEtOH alcohol

ETT endotracheal tube

exercise tolerance test

EUS endoscopic ultrasound

EVARendovascular aneurysm

repair

FDP fibrin degradation product

FEV1 forced expir. vol in 1 sec

FFP fresh frozen plasma

FHx family historyFI fusion inhibitor

FMD fibromuscular dysplasia

FMF familial Mediterranean fever

FNA fine needle aspiration

FOB fecal occult blood

FOBT fecal occult blood testing

FQ fluoroquinolone

FRC functional residual capacity

FSGSfocal segmental

glomerulosclerosis

FSH follicle stimulating hormone

FTI free thyroxine index

FUO fever of unknown origin

f/up follow-up

FVC forced vital capacity

G6PDglc-6-phosphate

dehydrogenase

GB gallbladder

GBMglomerular basement

membrane

GBS Guillain-Barré syndrome

GCA giant cell arteritis

GCS Glasgow coma scale

G-CSFgranulocyte colony

stimulating factor

GE gastroesophageal

gen. generation

GERDgastroesophageal reflux

disease

GFR glomerular filtration rate

GGT γ-glutamyl transpeptidaseGH growth hormone

GIB gastrointestinal bleed

GISTgastrointestinal stromal

tumor

glc glucose

GMCSFgranulocyte-macrophage

colony-stimulating factor

GN glomerulonephritis

GNR gram-negative rods

GnRHgonadotropin-releasing

hormone

GPAgranulomatosis w/

polyangiitis

GPC gram-positive cocci

GPIglycoprotein IIb/IIIa

inhibitor

GRAglucocorticoid-remediable

aldosteronism

GU gastric ulcer

GVHD graft-versus-host disease

h hour

H2RA H2-receptor antagonist

HA headache

HACA human antichimeric antibody

HAV hepatitis A virus

Hb hemoglobin

HBIG hepatitis B immunoglobulin

HBV hepatitis B virus

HCC hepatocellular carcinoma

HCMP hypertrophic cardiomyopathy

Hct hematocrit

HCV hepatitis C virusHCW health care worker

HD hemodialysis

HDL high-density lipoprotein

HDV hepatitis Δ virus

HELLPhemolysis, abnl LFTs, low

plts

HEV hepatitis E virus

HF heart failure

HGPRThypoxanthine-guanine

phosphoribosyl transferase

HHShyperosmolar hyperglycemic

state

HITheparin-induced

thrombocytopenia

HK hypokinesis

HL Hodgkin lymphoma

h/o history of

HOB head of bed

HoTN hypotension

hpf high power field

HPT hyperparathyroidismHR heart rate

HRThormone replacement

therapy

HS hereditary spherocytosis

HSCThematopoietic stem cell

transplantation

HSM hepatosplenomegaly

HSP Henoch-Schönlein purpura

HSV herpes simplex virus

HTN hypertension

HUS hemolytic uremic syndromehx history

I&D incision & drainage

IABP intra-aortic balloon pump

IBD inflammatory bowel disease

IBS irritable bowel syndrome

IC inspiratory capacity

ICa ionized calcium

ICDimplantable cardiac

defibrillator

ICH

intracranial hemorrhageICP intracranial pressure

ICU intensive care unit

IE infective endocarditis

IGF insulin-like growth factor

IGRA interferon-g release assay

II integrase inhibitor

IIP idiopathic interstitial PNA

ILD interstitial lung disease

IMIinferior myocardial

infarction

infxn infectioninh inhaled

INH isoniazid

INRinternational normalized

ratio

IPAA ileal pouch-anal anastomosis

IPF idiopathic pulmonary fibrosis

ITPidiopathic thrombocytopenic

purpura

IVB intravenous bolus

IVC inferior vena cava

IVDU intravenous drug use(r)

IVF intravenous fluids

IVIg intravenous immunoglobulin

JVD jugular venous distention

JVP jugular venous pulse

KUBkidney-ureter-bladder

(radiography)

KS Kaposi’s sarcoma

LA left atrium

long-acting lupus anticoagulant

LABA long-acting β2-agonist

LADleft anterior descending

coronary artery

left axis deviation

LAE left atrial enlargement

LAN lymphadenopathy

LAP left atrial pressure

leukocyte alkaline

phosphatase

LBBB left bundle branch block

LCA left coronary artery

LCIS lobular carcinoma in situ

LCx left circumflex cor. art.

LDH lactate dehydrogenase

LDL low-density lipoprotein

LE lower extremity

LES lower esophageal sphincter

LFTs liver function tests

LGIB lower gastrointestinal bleed

LH luteinizing hormoneLLQ left lower quadrant

LM left main coronary artery

LMWHlow-molecular-weight

heparin

LN lymph node

LOC loss of consciousness

LOS length of stay

LP lumbar puncture

lpf low power field

LR lactated Ringer’sLQTS long QT syndrome

LUSB left upper sternal border

LV left ventricle

LVAD LV assist device

LVEDP LV end-diastolic pressure

LVEDV LV end-diastolic volume

LVH left ventricular hypertrophy

LVOT left ventricular outflow tract

LVSD LV systolic dimension

mAb monoclonal antibody

MAC mitral annular calcification

Mycobacterium avium complex

MAHAmicroangiopathic hemolytic

anemia

MALTmucosa-assoc. lymphoid

tissue

MAO monoamine oxidase

MAP mean arterial pressure

MAT multifocal atrial tachycardia

MCD minimal change disease

MCPmetacarpal phalangeal

(joint)

MCTD mixed connective tissue dis.

MCV mean corpuscular volume

MDI metered dose inhaler

MDMA3,4-methylenedioxymetham-

phetamine (Ecstasy)

MDR multidrug resistant

MDS myelodysplastic syndrome

MEN multiple endocrine neoplasiaMG myasthenia gravis

MGUSmonoclonal gammopathy of

uncertain significance

MI myocardial infarction

min minute

min. minimal

MM multiple myeloma

MMEFR max. mid-expir. flow rate

MMF mycophenolate mofetil

MN membranous nephropathy

MNZ metronidazole

mod. moderate

MODS multiple organ dysfxn synd.

mo month

MPA microscopic polyangiitis

MPN myeloproliferative neoplasm

MPGNmembranoproliferative

glomerulonephritis

MR magnetic resonance

mitral regurgitation

MRA magnetic resonanceangiography

MRCPMR cholangio-

pancreatography

MRI magnetic resonance imaging

MRSA methicillin-resistant S. aureus

MS mitral stenosis

MTb Mycobacterium tuberculosis

MTP metatarsal phalangeal (joint)

MTX methotrexate

MV mitral valve

MVA mitral valve areaMVP mitral valve prolapse

MVR mitral valve replacement

Mϕ macrophage

N/V nausea and/or vomiting

NAC N-acetylcysteine

NAFLDnon-alcoholic fatty liver

disease

NASH non-alcoholic steatohepatitis

NG nasogastric

NGT nasogastric tubeNHL Non-Hodgkin lymphoma

NIDCM non-ischemic dilated CMP

NIF negative inspiratory force

NJ nasojejunal

nl normal

NM neuromuscular

NMJ neuromuscular junction

NNRTInon-nucleoside reverse

transcriptase inhibitor

NNT number needed to treat

NO nitric oxide

NPJTnonparoxysmal junctional

tachycardia

NPO nothing by mouth

NPV negative predictive value

NS normal saline

NSAIDnonsteroidal anti-inflam.

drug

NSCLC non-small cell lung cancer

NYHA New York Heart Association

NPPV noninvasive positive pressureventilation

NRTInucleoside reverse

transcriptase inhibitor

NSF nephrogenic systemic fibrosis

NTG nitroglycerin

NUD nonulcer dyspepsia

NVE native valve endocarditis

O&P ova & parasites

OA osteoarthritis

OCP oral contraceptive pill

O/D overdose

OG osmolal gap

OGT orogastric tube

OGTT oral glucose tolerance test

OI opportunistic infection

OM obtuse marginal cor. art.

OSA obstructive sleep apnea

OTC over-the-counter

o/w otherwise

PA pulmonary artery

PAC pulmonary artery catheter

PAD peripheral artery disease

PAN polyarteritis nodosa

PASP PA systolic pressure

PAVpercutaneous aortic

valvuloplasty

pb problem

PBC primary biliary cirrhosis

PCIpercutaneous coronary

intervention

PCN penicillinPCP

Pneumocystis jirovecipneumonia

PCR polymerase chain reaction

PCT porphyria cutanea tarda

PCWPpulmonary capillary wedge

pressure

PD Parkinson’s disease

peritoneal dialysis

PDA patent ductus arteriosus

posterior descending cor. art.

PE pulmonary embolismPEA pulseless electrical activity

PEEPpositive end-expiratory

pressure

PEF peak expiratory flow

PETpositron emission

tomography

PEx physical examination

PFO patent foramen ovale

PFT pulmonary function test

polyglandular autoimmune

PGA syndrome

PHT pulmonary hypertension

PI protease inhibitor

PID pelvic inflammatory disease

PIF prolactin inhibitory factor

PIP peak inspiratory pressure

proximal interphalangeal(joint)

PKD polycystic kidney disease

PM polymyositis

PMF primary myelofibrosisPMHx past medical history

PMI point of maximal impulse

PMLprogressive multifocal

leukoencephalopathy

PMN polymorphonuclear leukocyte

PMR polymyalgia rheumatica

PMVpercutaneous mitral

valvuloplasty

PMVTpolymorphic ventricular

tachycardia

PNA pneumonia

PNDparoxysmal nocturnal

dyspnea

PNHparoxysmal nocturnal

hemoglobinuria

PNS peripheral nervous system

PO oral intake

POBA plain old balloon angioplasty

POTSpostural orthostatic

tachycardia syndrome

PPD purified protein derivative

PPH primary pulmonary HTN

PPI proton pump inhibitors

Pplat plateau pressure

PPM permanent pacemaker

PPV positive predictive value

Ppx prophylaxis

PR PR segment on ECG

pulmonary regurgitation

PRBCs packed red blood cells

PRL prolactin

PRPPphosphoribosyl-I-

pyrophosphate

PRWP poor R wave progression

PS pressure support

pulmonic stenosis

PsA Pseudomonas aeruginosa

PSA prostate specific antigen

PSCprimary sclerosing

cholangitis

PSGNpost streptococcal

glomerulonephritisPSHx past surgical history

PSV pressure support ventilation

Pt patient

PT prothrombin time

PTApercutaneous transluminal

angioplasty

PTH parathyroid hormone

PTH-rP PTH-related peptide

PTT partial thromboplastin time

PTU propylthiouracilPTX pneumothorax

PUD peptic ulcer disease

PUVA psoralen + ultraviolet A

PV polycythemia vera

portal vein

PVD peripheral vascular disease

PVE prosthetic valve endocarditis

PVRpulmonary vascular

resistance

p/w present(s) with

PZA pyrazinamide

qac before every meal

qhs every bedtime

QoL quality of life

Qw Q wave

RA refractory anemia

rheumatoid arthritis

right atrium

RAA renin-angiotensin-aldosterone

RAD right axis deviation

RAE right atrial enlargement

RAI radioactive iodine

RAIU radioactive iodine uptake

RAS renal artery stenosis

RAST radioallergosorbent test

RBBB right bundle branch block

RBC red blood cell

RBF renal blood flow

RBV ribavirin

RCA right coronary artery

RCMP restrictive cardiomyopathy

RCT randomized controlled trial

RDW red cell distribution width

RE reticuloendothelial

RF rheumatoid factor

risk factor

RHD rheumatic heart disease

r/i rule in

RI reticulocyte index

RIBA recombinant immunoblotassay

RMSFRocky Mountain spotted

fever

r/o rule out

ROS review of systems

RPGNrapidly progressive

glomerulonephritis

RR respiratory rate

RRT renal replacement therapy

RT radiation therapy

RTA renal tubular acidosisRTX rituximab

RUQ right upper quadrant

RUSB right upper sternal border

RV residual volume

right ventricle

RVAD RV assist device

RVH right ventricular hypertrophy

RVOT RV outflow tract

RVSP RV systolic pressure

Rx therapy

RYGB roux-en-Y gastric bypass

SA sinoatrial

SAAGserum-ascites albumin

gradient

SAH subarachnoid hemorrhage

SAS sulfasalazine

SBEsubacute bacterial

endocarditis

SBO small bowel obstruction

SBP spontaneous bacterialperitonitis

systolic blood pressure

SBT spontaneous breathing trial

SC subcutaneous

SCD sudden cardiac death

SCIDsevere combined

immunodefic.

SCLC small cell lung cancer

s/e side effect

Se sensitivity

sec second

SERMselective estrogen receptor

modulator

sev. severe

SHBGsteroid hormone binding

globulin

SIADH synd. of inappropriate ADH

SIBOsmall intestine bacterial

overgrowth

SIEP serum immunoelectrophoresis

SIMVsynchronized intermittent

mandatory ventilation

SIRSsystemic inflammatory

response syndrome

SJS Stevens-Johnson syndrome

SLE systemic lupus erythematosus

SMA superior mesenteric artery

SMV superior mesenteric vein

SMX sulfamethoxazole

SOS sinusoidal obstructive synd.

s/p status post

Sp specificitySPEP serum protein electrophoresis

SR sinus rhythm

s/s signs and symptoms

SSCYSalmonella, Shigella,

Campylobacter, Yersinia

SSRIselective serotonin reuptake

inhibitor

SSS sick sinus syndrome

ST sinus tachycardia

STD sexually transmitted disease

ST-segment depressionSTE ST-segment elevation

SV stroke volume

SVC superior vena cava

SVR systemic vascular resistance

SVT supraventricular tachycardia

sx symptom(s) or symptomatic

T1D type 1 diabetes mellitus

T2D type 2 diabetes mellitus

T3RU T3 resin uptake

TAA thoracic aortic aneurysmTB tuberculosis

TBG thyroid binding globulin

TCA tricyclic antidepressant

TCD transcranial Doppler

TCN tetracycline

Tdap tetanus, diphtheria, pertussis

TdP torsades de pointes

TdTterminal deoxynucleotidyl

transferase

TEE transesophageal echo

TFTs thyroid function testsTG triglycerides

TGAtransposition of the great

arteries

TIA transient ischemic attack

TIBC total iron binding capacity

TINUtubulointerstitial nephritis

and uveitis

TIPStransjugular intrahepatic

portosystemic shunt

TLC total lung capacity

TMP trimethoprim

Tn troponin

TP total protein

TPMT thiopurine methyltransferase

TPN total parenteral nutrition

Tpo thrombopoietin

TPO thyroid peroxidase

TR tricuspid regurgitation

TRALItransfusion-related acute

lung injury

TRHthyrotropin releasing

hormone

TRS TIMI risk score

TRUS transrectal ultrasound

TS tricuspid stenosis

TSH thyroid stimulating hormone

TSIthyroid-stimulating

immunoglobulin

TSS toxic shock syndrome

transsphenoidal surgery

TTE transthoracic echo

TTKGtranstubular potassium

gradient

TTPthrombotic thrombocytopenic

purpura

TV tricuspid valve

Tw T wave

TWF T-wave flattening

TWI T-wave inversion

Tx transplant

TZD thiazolidinedionesU/A urinalysis

U/S ultrasound

UA unstable angina

uric acid

UAG urine anion gap

UC ulcerative colitis

UCx urine culture

UES upper esophageal sphincter

UFH unfractionated heparin

UGIB upper gastrointestinal bleed

UIP usual interstitial pneumonitis

ULN upper limit of normal

UOP urine output

UPEP urine protein electrophoresis

UR urgent revascularization

URI upper resp. tract infxn

UTI urinary tract infection

V/Q ventilation-perfusion

VAD ventricular assist device

VAP ventilator-associated PNA

VATSvideo-assisted thoracoscopic

surgery

VBI vertebrobasilar insufficiency

VC vital capacity

VD vessel disease

VDRLvenereal disease research

laboratory (test forsyphilis)

VEGFvascular endothelial growth

factorVF ventricular fibrillation

VLDL very-low-density lipoproteins

VOD veno-occlusive disease

VS vital signs

VSD ventricular septal defect

VT tidal volume

VT ventricular tachycardia

VTE venous thromboembolus

vWD von Willebrand’s disease

vWF von Willebrand’s factorVZV varicella zoster virus

w/ with

WBC white blood cell (count)

WCT wide-complex tachycardia

WHO World Health Organization

wk week

WMWaldenström’s

macroglobulinemia

WMA wall motion abnormality

w/o without

WPWWolff-Parkinson-White

syndrome

w/u workup

XRT radiation therapy

INDEX

AA-a gradient, 2-18, 11-5abdominal CT scan, P-7abdominal pain, 10-1acanthosis nigricans, 5-28accessory pathway, 1-33acetaminophen

as cause of metabolic acidosis, 4-2

hepatotoxicity, 3-19achalasia, 3-1acid-base disturbances, 4-1ACLS, ACLS-1acquired immunodeficiency

syndrome (AIDS), 6-17acromegaly, 7-2activated protein C

resistance, 5-11therapy, 2-23

acute coronary syndromes, 1-6acute interstitial nephritis, 4-12acute interstitial pneumonia, 2-10acute kidney injury, 4-12acute respiratory distress syndrome

(ARDS), 2-22acute tubular necrosis, 4-12Addison’s disease, 7-9adnexal mass, non-pregnant

woman, 10-3adrenal disorders, 7-7adrenal incidentalomas, 7-10

adrenal insufficiency, 7-9adrenal mass, 7-10advanced cardiac life support,

ACLS-1albuminuria, 4-13alcohol withdrawal, 9-5allergic bronchopulmonary

aspergillosis, 2-10alpha1-antitrypsin deficiency

as cause of cirrhosis, 3-24as cause of COPD, 2-5

alveolar gas equation, 11-5amaurosis fugax, 9-6amiodarone, thyroid disease and,

7-5amyloidosis, 8-22

cardiac manifestations, 1-19

anaphylaxis, 2-4anaplasmosis, 6-21anemia, 5-1

aplastic, 5-3autoimmune hemolytic, 5-5, P-13of chronic inflammation, 5-2Cooley’s, 5-2Fanconi’s, 5-3folate deficiency, 5-3hemolytic, 5-4iron deficiency, 5-1, P-13macrocytic, 5-3megaloblastic, 5-3, P-13microangiopathic hemolytic, 5-5microcytic, 5-1myelophthisic, 5-4normocytic, 5-2

pernicious, 5-3sickle cell, 5-4, P-14sideroblastic, 5-2

angina, 1-6angiodysplasia, 3-3angioplasty, 1-5anion gap, 4-2, 11-6ankylosing spondylitis, 8-7anoxic brain injury, 9-2antibiotics, 11-3antibodies

anticardiolipin, 5-11, 8-16anti-CCP, 8-3anti-centromere, 8-11anti-citrullinated peptide

(ACPA), 8-3anti-ds-DNA, 8-15

anti-GBM, 4-16antihistone, 8-15anti-Jo-1, 8-13anti-La, 8-14, 8-15anti-Mi-2, 8-13antimitochondrial, 3-24anti-MPO, 4-16, 8-18antineutrophil cytoplasmic

(ANCA), 4-16, 8-18antinuclear (ANA), 8-15antiphospholipid, 5-11anti-PR3, 4-16, 8-18anti-Ro, 8-14, 8-15anti-Scl-70, 8-11anti-Sm, 8-15anti-smooth muscle, 3-19anti-TPO, 7-3, 7-4, 7-5, 7-6

anti-U1-RNP, 8-14, 8-15autoantibodies, 8-2in connective tissue diseases, 8-

11anticoagulants, 5-6, 5-10anti-GBM disease, as cause of

glomerulonephritis, 4-16antiphospholipid syndrome, 5-11aortic aneurysm, 1-30aortic dissection, 1-31aortic insufficiency, 1-21aortic stenosis, 1-20aortoenteric fistula, 3-3arrhythmogenic RV

cardiomyopathy, 1-34arthralgias, 8-1arthritis, 8-1

IBD-associated (enteropathic), 8-8

infectious, 8-9osteoarthritis, 8-1psoriatic, 8-7reactive, 8-7rheumatoid, 8-3

asbestosis, 2-10ascites, 3-26

treatment of, in cirrhotics, 3-21aspergillosis, 6-4asplenia, 6-4asthma, 2-2asystole, ACLS-2atrial fibrillation, 1-32, 1-35atrial flutter, 1-32auto-PEEP, 2-20

AV block, 1-32AV dissociation, 1-32

Bbabesiosis, 6-21back pain, 9-11bacteremia, 6-14Barrett’s esophagus, 3-2Bartter’s syndrome, 4-5, 4-10, 7-8basophilia, 5-12basophilic stippling, 11-6Beck’s triad, 1-26Behçet’s syndrome, 8-20Bell’s palsy, 6-11Bernard-Soulier disease, 5-9berylliosis, 2-10bilevel positive airway pressure

(BiPAP), 2-20biliary tract disease, 3-27bite cells, 5-4, 11-6biventricular pacing, 1-16, 1-39blastomycosis, 6-3body surface area, 11-7Boerhaave syndrome, 1-3bone infections, 6-6bone marrow transplantation, 5-26bradycardia, 1-32, ACLS-1breast cancer, 5-30Brockenbrough sign, 1-18bronchiectasis, 2-7bronchiolitis obliterans with

organizing pneumonia, 2-10bronchitis, chronic, 2-5Brudzinski’s sign, 6-9

Brugada syndrome, 1-34B-type natriuretic peptide, 1-14, 2-

1Budd-Chiari syndrome, 3-25bundle branch blocks, 1-1burr cells, 11-6bursitis, 8-1, 8-10

Ccalciphylaxis, 7-11calcium disorders, 7-11calcium pyrophosphate dihydrate

deposition disease, 8-6cancer of unknown primary site, 5-

37Candida infections, 6-3carbon monoxide poisoning, 2-18

cardiac output, 1-12, 11-4cardiac resynchronization therapy,

1-16, 1-39cardiomyopathy, 1-17

arrhythmogenic RV, 1-17dilated, 1-17hypertrophic, 1-18peripartum, 1-17restrictive, 1-19

vs constrictive pericarditis, 1-27

Takotsubo, 1-17cardioversion, ACLS-1carotid revascularization, 9-7cauda equina syndrome, 9-11celiac disease, 3-6cellulitis, 6-6

central venous catheter-relatedinfections, 6-14

cerebrovascular disease, 9-6Chagas, 1-17Charcot’s triad, 3-28Chediak-Higashi syndrome, 5-9chemotherapy side effects, 5-34chest pain, 1-3chest tubes, 10-2Child-Turcotte-Pugh scoring system,

3-23cholangitis, 3-28cholecystitis, 3-27choledocholithiasis, 3-28cholelithiasis, 3-27cholera, 3-5cholestasis, 3-15

cholesterol emboli syndrome, 1-5chronic kidney disease, 4-13chronic obstructive pulmonary

disease (COPD), 2-5, P-1Churg-Strauss syndrome, 8-19

as cause of asthma, 2-2as cause of glomerulonephritis,

4-16as cause of interstitial lung

disease, 2-10Chvostek’s sign, 7-12cirrhosis, 3-21claudication, neurogenic vs.

vascular, 9-12clostridial myonecrosis, 6-7Clostridium difficile-associated

diarrhea, 3-6

coagulation cascade, 5-6coagulopathies, 5-10coarctation of aorta, 1-28coccidioidomycosis, 6-3cold calorics, 9-1colonoscopy, screening, 5-33colorectal cancer, 5-33coma, 9-1compartment syndrome, 10-2computed tomography

angiography, 1-3, 1-4confusion, 9-1connective tissue diseases, 8-11Conn’s syndrome, 7-8constipation, 3-8constrictive pericarditis, 1-26continuous positive airway

pressure (CPAP), 2-19, 2-20continuous veno-venous

hemofiltration, 4-15contrast-induced acute kidney

injury, 4-12conus medullaris syndrome, 9-11cord compression, 5-36, 9-11corneal acrus, 7-16coronary angiography, 1-5, P-13coronary arteries, P-13coronary artery bypass grafting

(CABG), 1-5coronary artery calcium score, 1-4coronary revascularization, 1-5Courvoisier’s sign, 5-35creatinine clearance, 11-6CREST syndrome, 8-12

Crohn’s disease, 3-10cryoglobulinemia, 8-21Cryptococcus, 6-3cryptogenic organizing pneumonia,

2-10crystal deposition arthritides, 8-5Cullen’s sign, 3-13Cushing’s reflex, 3-20Cushing’s syndrome, 7-7cutaneous leukocytoclastic angiitis,

8-20CXR/chest CT scan, 11-5, P-1, P-5cyanide poisoning, 2-18cyanosis, 2-18cystic fibrosis, 2-7cystitis, 6-5cytomegalovirus, 6-19

Ddactylitis, 8-7deep venous thrombosis, 2-13delirium, 9-1delirium tremens, 9-5delta-delta, 4-2, 11-6dementia, 9-1dengue, 6-23dermatomyositis, 8-12desquamative interstitial

pneumonia, 2-10diabetes insipidus, 4-8, 4-9diabetes mellitus, 7-13diabetic foot, 6-6diabetic ketoacidosis (DKA), 7-14dialysis, 4-15diarrhea, 3-5

Dieulafoy’s lesion, 3-3diffuse alveolar damage, 2-22diffuse alveolar hemorrhage, 2-10,

5-26diplopia, 10-4disc herniation, 9-12discriminant function, 3-19disseminated gonococcal arthritis,

8-10disseminated intravascular

coagulation (DIC), 5-10diuresis, 4-14diverticular disease, 3-9Döhle bodies, 11-6doll’s eyes, 9-1Dressler’s syndrome, 1-11, 1-25Duke treadmill score, 1-4

duodenal ulcer, 3-2dyslipidemias, 7-16dyspepsia, 3-2dysphagia, 3-1dyspnea, 2-1dysuria, 6-5

EEaton-Lambert syndrome, 5-28, 9-9echocardiography, P-9Ehlers-Danlos syndrome, 1-31ehrlichiosis, 6-21electrocardiography, 1-1encephalitis, viral, 6-11endocarditis, 6-12endomyocardial fibrosis, 1-19enthesitis, 8-7

eosinophilia, 5-12eosinophilic granulomatosis with

polyangiitis, 8-19as cause of asthma, 2-2as cause of glomerulonephritis,


disease, 2-10eosinophilic pneumonias, 2-10epidural abscess, 6-8epidural hematoma, 9-7epilepsy, 9-3erysipelas, 6-6erythema migrans, 6-20erythema multiforme, 6-23erythema nodosum, 2-9, 6-23, 8-20erythrocyte sedimentation rate, 8-

17erythromelalgia, 5-15esophageal reflux, 3-1esophageal ring, 3-1esophageal spasm, 1-3esophageal web, 3-1esophagitis, 3-1, 3-3essential thrombocythemia, 5-15ethylene glycol intoxication, 4-2exercise tolerance test, 1-4

Ffactor V Leiden, 5-11familial adenomatous polyposis, 5-

33familial hypocalciuric

hypercalcemia, 7-11

familial Mediterranean fever, 6-22Fanconi’s syndrome, 4-3Felty’s syndrome, 8-3fever

neutropenia and, 5-36Pel-Ebstein, 5-21

fever syndromes, 6-22fibromyalgia, 8-13Fitz-Hugh-Curtis syndrome, 8-10focal segmental glomerulosclerosis,

4-17folate deficiency, 5-3folliculitis, 6-6food poisoning, 3-5Forrester class, 1-11Fournier’s gangrene, 6-7fractional excretion of Na, 4-12,

11-6free H2O deficit, 4-8, 11-6fungal infections, 6-3furunculosis, 6-6

GGaisböck’s syndrome, 5-15Gallavardin effect, 1-20gallstone, 3-27gallstone ileus, 3-27gas gangrene, 6-7gastric antral vascular ectasia, 3-3gastric ulcer, 3-2gastritis, 3-3gastroesophageal reflux disease

(GERD), 3-1gastrointestinal bleeding, 3-3

gastrostomy tubes, 10-2giant cell arteritis, 8-17Gitelman’s syndrome, 4-5, 4-10, 7-8Glanzmann’s thromboasthenia, 5-9Glasgow Coma Scale, 9-1glomerulonephritis, 4-16glucagonoma

as cause of diabetes mellitus, 7-13

as cause of diarrhea, 3-7glucose-6-phosphate dehydrogenase

(G6PD) deficiency, 5-4glycemic control, in critical care, 2-

23goiter, 7-4, 7-5Goodpasture’s syndrome

as cause of alveolar hemorrhage,

2-10as cause of glomerulonephritis,

4-16Gottron’s papules, 8-13gout, 8-5graft-versus-host disease (GVHD), 5-

26, 5-27granulomatosis with polyangiitis,

8-18as cause of glomerulonephritis,


disease, 2-10Graves’ disease, 7-4Grey Turner’s sign, 3-13Guillain-Barré syndrome, 9-8

HHamman-Rich syndrome, 2-10Hashimoto’s thyroiditis, 7-4headache, 9-10heart failure, 1-14

with preserved EF, 1-16heart valve anatomy, 1-24Heinz bodies, 5-4, 11-6Helicobacter pylori infection, 3-2heliotrope rash, 8-13hematemesis, 3-3hematochezia, 3-3hematopoietic stem cell

transplantation, 5-26hematuria, 4-19hemochromatosis

as cause of cirrhosis, 3-23

as cause of DCMP, 1-17as cause of RCMP, 1-19

hemodialysis, 4-15hemolytic-uremic syndrome, 5-9hemophilia, 5-10hemoptysis, 2-7hemostasis disorders, 5-6Henoch-Schönlein purpura, 8-19

as cause of glomerulonephritis,4-16

heparin-induced thrombocytopenia,5-8

heparin nomograms, 11-7hepatic encephalopathy, 3-22hepatic hydrothorax, 2-11, 3-21hepatitis, 3-17

alcoholic, 3-19

autoimmune, 3-19ischemic, 3-19viral, 3-17

hepatocellular carcinoma, 3-22hepatopulmonary syndrome, 3-23hepatorenal syndrome, 3-22hereditary nonpolyposis colorectal

cancer, 5-33hereditary spherocytosis, 5-5Hermansky-Pudlak syndrome, 5-9herpes zoster, 6-11histoplasmosis, 6-3Howell-Jolly bodies, 11-6human immunodeficiency virus

(HIV), 6-17hyperaldosteronism, 7-8

as cause of hypokalemia, 4-10

as cause of metabolic alkalosis,4-4

hyperbilirubinemia, 3-16hypercalcemia, 7-11hypercapnia, 2-18hypercholesterolemia, 7-16hypercoagulable states, 5-11hypercortisolism, 7-7hyperhomocysteinemia, 5-11hyperkalemia, 4-11hypernatremia, 4-8hyperosmolar hyperglycemic state,

7-15hyperparathyroidism, 7-11

secondary, 4-14hyperpituitary syndrome, 7-2hyperprolactinemia, 7-2

hypersensitivity pneumonia, 2-10hypersensitivity vasculitis, 8-20hypersplenism, 5-5hypertension, 1-28hypertensive crisis, 1-29hyperthyroidism, 7-4hypertriglyceridemia, 7-16hypertrophic pulmonary

osteoarthropathy, 5-28hypoaldosteronism, 7-9

as cause of hyperkalemia, 4-11as cause of metabolic acidosis, 4-

3hypocalcemia, 7-12hypoglycemia, 7-15hypokalemia, 4-10hyponatremia, 4-6

hypoparathyroidism, 7-12hypopituitary syndromes, 7-1hypothermia, induced, 9-2hypothyroidism, 7-4hypoxemia, 2-18

IICU medications, 11-1ideal body weight, 11-7idiopathic interstitial pneumonia,

2-10idiopathic pulmonary fibrosis, 2-10IgA nephropathy, 4-17IgG4-related disease, 8-20ileus, 3-8immune thrombocytopenic

purpura, 5-7

impetigo, 6-6implantable cardiac defibrillator, 1-

16, 1-39inclusion body myositis, 8-12infections in susceptible hosts, 6-4inflammatory bowel disease, 3-10inflammatory markers, 8-2influenza, 6-2interstitial lung disease, 2-9intracardiac shunts, 11-4intracranial hemorrhage, 9-7intraductal papillary mucinous

neoplasm, 5-35intramural hematoma (aortic), 1-31iron deficiency, 5-1irritable bowel syndrome (IBS), 3-7ischemic colitis, 3-12

isopropyl alcohol intoxication, 4-3

JJaneway lesions, 6-12jaundice, 3-15Jod-Basedow effect, 7-6joint fluid, 8-1

KKaposi’s sarcoma, 6-19Kernig’s sign, 6-9ketoacidosis, 4-2kidney transplantation, 4-15Killip class, 1-11koilonychia, 5-1Kussmaul’s sign, 1-27

L

lactic acidosis, 4-2lactose intolerance, 3-6Langerhans cell granulomatosis, 2-

10left ventricular hypertrophy, ECG

criteria, 1-1left ventricular thrombus, 1-11leukemia, 5-17, P-14

acute lymphoblastic, 5-18acute myelogenous, 5-17acute promyelocytic, 5-18chronic lymphocytic, 5-20chronic myelogenous, 5-19hairy cell, 5-22

leukostasis, 5-17Libman-Sacks endocarditis, 8-15Liddle’s syndrome, 4-5, 4-10, 7-8

Light’s criteria, 2-11limb ischemia, acute, 1-41, 10-1lipodystrophy, 6-19liver failure, 3-20liver tests, abnormal, 3-15liver transplantation, 3-23Loeys-Dietz syndrome, 1-31Löffler’s endocarditis, 1-19Löffler’s syndrome, 2-10Löfgren’s syndrome, 2-9long QT syndrome, 1-34lung cancer, 5-28lupus anticoagulant, 5-11lupus pernio, 2-9Lyme disease, 6-20lymphadenopathy, 5-12lymphangioleiomyomatosis, 2-10

lymphocytic interstitialpneumonia, 2-10

lymphocytosis, 5-12lymphoma, 5-21

CNS, 6-19Hodgkin, 5-21non-Hodgkin, 5-22

Mmacro-ovalocytes, 5-3malabsorption, 3-6malaria, 6-23Mallory-Weiss tear, 3-3mammography, 5-30Marfan syndrome, 1-31mechanical ventilation, 2-19mechanic’s hands, 8-13

Meckel’s diverticulum, 3-4Meigs’ syndrome, 2-11, 3-26MELD score, 3-23melena, 3-3membranoproliferative

glomerulonephritis, 4-17membranous nephropathy, 4-17meningitis

acute bacterial, 6-9aseptic, 6-10

mental status, change in, 9-1mesenteric ischemia, 3-12metabolic acidosis, 4-2metabolic alkalosis, 4-4metabolic syndrome, 7-16methanol intoxication, 4-2methemoglobinemia, 2-18

microangiopathic hemolyticanemia, 5-5

microscopic polyangiitis, 8-19as cause of glomerulonephritis,


disease, 2-10migraine headache, 9-10milk-alkali syndrome, 7-11minimal change disease, 4-17Mirizzi’s syndrome, 3-27mitral regurgitation, 1-22mitral stenosis, 1-22mitral valve prolapse, 1-23mixed connective tissue disease

(MCTD), 8-14molluscum contagiosum, 6-18

monoclonal gammopathy ofuncertain significance, 5-25

monocytosis, 5-12mucinous cystic neoplasm of

pancreas, 5-35Mucor infection, 6-4multiple endocrine neoplasia

(MEN) syndromes, 7-2multiple myeloma, 5-24murmurs, eponymous

Austin Flint, 1-21Graham Steel, 2-14

Murphy’s sign, 3-27myalgias, 8-13myasthenia gravis, 9-9Mycobacterium avium complex,

disseminated, 6-19

mycosis fungoides, 5-22myelodysplastic syndromes, 5-14myelofibrosis, primary, 5-16myeloid neoplasms, 5-14myeloproliferative neoplasms, 5-15myocardial infarction (MI)

non ST elevation, 1-7ST elevation, 1-9

myocardial viability, 1-4myocarditis, 1-3, 1-17myopathies, 8-12, 9-9myositides, 8-13myxedema, 7-4

Nnecrotizing fasciitis, 6-7nephrogenic systemic fibrosis, 4-12

nephrolithiasis, 4-19nephrotic syndrome, 4-17nerve root compression, 9-11neuropathies, 9-8neutropenia, 5-12, 5-36, 6-4neutropenic enterocolitis, 5-36neutrophilia, 5-12New York Heart Association

classification, 1-14nonalcoholic fatty liver disease

(NAFLD), 3-19noninvasive ventilation, 2-20nonspecific interstitial pneumonia,

2-10nonulcer dyspepsia, 3-2nutrition, in hospitalized, 3-8

Oobstructive sleep apnea, 2-8ocular motor palsies, 10-4oculocephalic maneuver, 9-1Ogilvie’s syndrome, 3-8omega-3 fatty acids, 1-16, 7-16optic neuritis, 10-4optic neuropathy, ischemic, 10-4oral hairy leukoplakia, 6-18orbital cellulitis, 10-4orthostatic hypotension, 1-37Osler’s nodes, 6-12osmolal gap, 4-3, 11-6osteoarthritis, 8-1, 8-2osteomyelitis, 6-8

P

pacemakers, 1-39Paget’s disease

of bone, 7-11of breast, 5-30

Pancoast’s syndrome, 5-28pancreatic cancer, 5-35pancreatic insufficiency, 3-7pancreatitis, 3-13pancytopenia, 5-3panhypopituitarism, 7-1papillary muscle rupture, 1-10Pappenheimer bodies, 5-2paracentesis, 3-26paroxysmal nocturnal syndromes,

5-4patent foramen ovale, 9-7peptic ulcer disease (PUD), 1-3, 3-2

percutaneous coronaryintervention (PCI), 1-5

pericardial effusion, 1-25pericardial tamponade, 1-26pericarditis, 1-25periodic paralysis

hyperkalemic, 4-11hypokalemic, 4-10

peripheral smear, findings in, 11-6peritoneal dialysis, 4-15peritonitis, 3-26petechiae, 5-6pheochromocytoma, 7-10phlegmasia cerulean dolens, 2-13pica, 5-1pituitary disorders, 7-1pituitary tumors, 7-1

plasma cell dyscrasias, 5-24platelet disorders, 5-7pleural effusion, 2-11, P-4pleuritis, 1-3Plummer-Vinson syndrome, 5-1pneumoconioses, 2-10pneumocystis, 2-10Pneumocystis jiroveci pneumonia, 6-

19pneumonia, 6-1, P-2pneumothorax, P-4POEMS syndrome, 5-24polyarteritis nodosa, 8-18polycythemia vera, 5-15polydipsia, 4-9polyglandular autoimmune (PGA)

syndromes, 7-2

polymyalgia rheumatica, 8-13, 8-18polymyositis, 8-12polyuria, 4-9porphyria cutanea tarda, 3-18portal hypertension, 3-21portal vein thrombosis (PVT), 3-25portopulmonary hypertension, 2-

16, 3-23portosystemic encephalopathy, 3-

22Pott’s disease, 6-8, 6-15preexcitation, 1-33pregnancy, ectopic, 10-3preoperative risk assessment, 1-40prerenal azotemia, 4-12primary biliary cirrhosis, 3-24primary sclerosing cholangitis, 3-

24Prinzmetal’s angina, 1-6progressive multifocal

leukencephalopathy, 6-19prolactinoma, 7-1propylene glycol intoxication, 4-2prostate cancer, 5-32prostate-specific antigen (PSA)

testing, 5-32prostatitis, 6-5prosthetic heart valves, 1-24proteinuria, 4-18prothrombin mutation, 5-11pseudogout, 8-6pseudo-hypoparathyroidism, 7-12pseudo-Pelger-Huët cells, 5-14, 11-6pseudotumor cerebri, 9-10

pulmonary alveolar proteinosis, 2-10

pulmonary artery catheter, 1-12,11-4

pulmonary edemaCXR pattern in, 11-5, P-2treatment of, 1-15, 11-2

pulmonary embolism, 2-14, P-6pulmonary function tests, 2-1pulmonary hypertension, 2-16pulseless electrical activity, ACLS-2pulsus paradoxus, 1-26pure red cell aplasia, 5-2purified protein derivative (PPD)

test, 6-15purpura, 5-6pyelonephritis, 6-5

pyoderma gangrenosum, 3-10, 8-8

QQT interval, 1-1

Rradiculopathies, 9-11radioactive iodine uptake scan, 7-3Raynaud’s phenomenon, 8-14red eye, 10-4Reed-Sternberg cells, 5-21refeeding syndrome, 3-8Reiter’s syndrome, 8-7relapsing polychondritis, 8-4renal abscess, 6-5renal artery stenosis, 1-28renal failure, 4-12

renal osteodystrophy, 7-12renal replacement therapy, 4-15renal tubular acidosis, 4-3respiratory acidosis, 4-5respiratory alkalosis, 4-5respiratory bronchiolitis-associated

interstitial lung disease, 2-10respiratory failure, 2-18reticulocyte index, 5-1Reynold’s pentad, 3-28rheumatoid factor, 8-3Rhizopus infection, 6-4Richter’s syndrome, 5-20Rocky Mountain spotted tick fever,

6-21Roth spots, 6-12

Ssalicylate intoxication, 4-2Samter’s syndrome, 2-2sarcoidosis, 2-9, P-6

cardiac manifestations of, 1-19schistocytes, 5-5, 11-6, P-14sciatica, 9-11scleroderma, 8-11seizures, 9-3sepsis, 2-23seronegative spondyloarthritis, 8-7serum-ascites albumin gradient, 3-

26Sézary syndrome, 5-22Sheehan’s syndrome, 7-1shock, 1-13, 11-2

cardiogenic, 1-13

septic, 2-23sicca syndrome, 8-13sick euthyroid syndrome, 7-5sick sinus syndrome, 1-32silicosis, 2-10sinusoidal obstruction syndrome, 3-

25, 5-26Sjögren’s syndrome, 8-13smudge cells, 5-20soft tissue infections, 6-6solitary pulmonary nodule, 2-8spinal cord compression, 5-36, 9-11spinal stenosis, 9-12splenomegaly, 5-5spontaneous bacterial peritonitis,

3-26treatment of in cirrhosis, 3-22

spur cells, 11-6, P-14staple removal, 10-2statistics, 11-7status epilepticus, 9-4ST depression, 1-2ST elevation, 1-2stent thrombosis, 1-5steroids, in critical care, 2-23Still’s disease, adult onset, 6-22, 8-4stool osmotic gap, 3-7stress test, 1-4stroke, 9-6struma ovarii, 7-4subarachnoid hemorrhage, 9-7subdural hematoma, 9-7superior vena cava syndrome, 5-28suture removal, 10-2

syncope, 1-37syndrome of inappropriate

antidiuretic hormone(SIADH), 4-7

systemic lupus erythematosus(SLE), 8-15

systemic sclerosis, 8-11

Ttachycardias, 1-32, ACLS-1

atrial, 1-32atrioventricular reciprocating, 1-

32, 1-34AV nodal reentrant, 1-32multifocal atrial, 1-32nonparoxysmal junctional, 1-32sinus, 1-32

supraventricular, 1-32ventricular, 1-34, ACLS-1, ACLS-2wide-complex, 1-34

Takayasu’s arteritis, 8-17target cells, 11-6teardrop cells, 5-16, 11-6, P-14temporal arteritis, 8-17thalassemias, 5-2thrombocytopenia, 5-7thrombotic thrombocytopenic

purpura, 5-9thrush, 6-18thyroid disorders, 7-3thyroid function tests, 7-3thyroiditis, 7-4, 7-5thyroid nodules, 7-6thyroid storm, 7-4

TIMI risk score for UA/NSTEMI, 1-8

Todd’s paralysis, 9-3torsades de pointes, 1-34total body water, 11-6toxic megacolon, 3-6, 3-10toxic shock syndrome, 6-6toxoplasmosis, 6-19tracheostomy, 10-2transfusion-related acute lung

injury, 2-22, 5-13transfusion therapy, 5-13transient ischemic attack (TIA), 9-6trans-tubular potassium gradient,

4-10, 11-6tricuspid regurgitation, 1-24tropical sprue, 3-7

troponin, 1-3, 1-6Trousseau’s sign

of hypocalcemia, 7-12of malignancy, 5-35

tuberculosis, 6-15tularemia, 6-21tumor lysis syndrome, 5-37T wave inversion, 1-2typhilitis, 5-36typhoid fever, 6-23

Uulcerative colitis, 3-10ulcers, 3-2unstable angina, 1-7uremia, 4-13uremic bleeding, 5-9

urethritis, 6-5urinalysis, 4-18urinary tract infection, 6-5urine anion gap, 4-3urine dipstick, 4-18urine osmolality, 4-6urine sediment, 4-18, P-15usual interstitial pneumonia, 2-10uveitis, 8-7

Vvaginal bleeding, 10-3vaginal discharge, 10-3varices, 3-3, 3-22vasculitis, 8-17veno-occlusive disease

hepatic, 3-25, 5-26

pulmonary, 2-16venous thromboembolism, 2-13ventricular aneurysm, 1-11ventricular fibrillation, ACLS-2ventricular pseudoaneurysm, 1-11ventricular septal defect, 1-10Verner-Morrison syndrome, 3-7vestibular caloric stimulation, 9-1Virchow’s node, 5-35visual changes, 10-4visual field defect, 10-4vitamin B12 deficiency, 5-3vitamin Δ deficiency, 7-12vitamin K deficiency, 5-10von Willebrand’s disease, 5-9V/Q mismatch, 2-18

WWaldenström’s macroglobulinemia,

5-25warfarin loading nomogram, 11-7warfarin overdose, 5-10Wegener’s granulomatosis, 8-18

as cause of glomerulonephritis,4-16

as cause of interstitial lungdisease, 2-10

Wernicke’s encephalopathy, 9-5Whipple’s disease, 3-7Wilson’s disease, 3-24Wolff-Chaikoff effect, 7-5Wolff-Parkinson-White syndrome,

1-33

Xxanthelasma, 7-16xanthomas, 7-16

Yyellow-nail syndrome, 2-11

ZZenker’s diverticulum, 3-1Zollinger-Ellison syndrome, 3-2, 3-7zoster, 6-11zygomycetes, 6-4

Radiology

1 Normal PA CXR. The convexright cardiac border is formed bythe right atrium (straightarrows), and the curved arrowsindicate the location of thesuperior vena cava. The left

cardiac and great vessels borderwhat might be considered as fourskiing moguls. From cephalad tocaudad, the moguls are the aorticarch, the main and leftpulmonary arter-ies, the leftatrial appendage, and the leftventricle. (Radiology 101, 3rd ed,2009.)

2 Normal lateral CXR.(Radiology 101, 3rd ed, 2009.)

3 COPD: with hyperlucent,overinflated lungs and flatdiaphragms. (Radiology 101, 3rded, 2009.)

4 Interstitial pulmonaryedema: with Kerley A, B, and Clines and cephalization of thevascular markings. (Fund. Diag.

Radiology 3rd ed, 2006.)

5 Alveolar pulmonary edema.(Fund. Diag. Radiology 3rd ed,

2006.)

6 Right upper lobepneumonia. (Radiology 101, 3rded, 2009.)

7 Right middle lobepneumonia. (Radiology 101, 3rded, 2009.)

8 Right lower lobe pneumonia(PA). (Radiology 101, 3rd ed,2009.)

9 Right lower lobe pneumonia(lateral). (Radiology 101, 3rd ed,

2009.)

10 Bilateral pleural effusions(curved arrows) and enlargedazygous vein (straight arrow)

(PA). (Radiology 101, 3rd ed,2009.)

11 Bilateral pleural effusions(curved arrows) (lateral).

(Radiology 101, 3rd ed, 2009.)

12 Pneumothorax. (Radiology101, 3rd ed, 2009.)

13 Normal chest CT at level ofpulmonary arteries(parenchymal windows).(Radiology 101, 3rd ed, 2009.)

14 Bilateral PE (mediastinalwindows). (Radiology 101, 3rded, 2009.)

15 Sarcoidosis withperilymphatic nodules. (Fund.Diag. Radiology 3rd ed, 2006.)

16 Idiopathic pulmonaryfibrosis. (Fund. Diag. Radiology3rd ed, 2006.)

17 Normal abdomen CT atlevel of liver & spleen. (Radiology101, 3rd ed, 2009.)

18 Normal abdomen CT atlevel of pancreas. (Radiology 101,3rd ed, 2009.)

Echocardiography

1 Parasternal long-axis viewallows visualization of the rightventricle (RV), ven- tricularseptum (VS), posterior wall (PW)aortic valve cusps, left ventricle(LV), mitral valve, left atrium(LA), and ascending thoracicaorta (Ao). *Pulmonary artery.

(Top: From Mayo ClinicProceedings. [Tajik AJ, SewardJB, Hagler DJ, et al. Two-dimensional real-time ultrasonicimaging of the heart and greatvessels: Technique, imageorientation, structureidentification, and validation.Mayo Clinic Proceedings,1978;53:271–303], withpermission. Bottom: From Oh JK,Seward JB, Tajik AJ. The EchoManual, 3rd ed. Philadelphia:Lippincott Williams & Wilkins,2006. By permission of MayoFoundation for MedicalEducation and Research. All

rights reserved.)

2 Parasternal short-axis viewat the level of the aorta: LA,left atrium; PV, pul- monaryvalve; RA, right atrium; RVOT,right ventricular outflow tract.(Top: From Mayo ClinicProceedings. [Tajik AJ, SewardJB, Hagler DJ, et al. Two-

dimensional real-time ultrasonicimaging of the heart and greatvessels: Technique, imageorientation, structureidentification, and validation.Mayo Clinic Proceedings,1978;53:271–303], withpermission. Bottom: From Oh JK,Seward JB, Tajik AJ. The EchoManual, 3rd ed. Philadelphia:Lippincott Williams & Wilkins,2006. By permission of MayoFoundation for MedicalEducation and Research. Allrights reserved.)

3 Parasternal short-axis viewat the level of the papillarymuscles: AL, anterolateralpapillary muscle; PM,posteromedial papillary muscle;RV, right ventricle; VS,ventricular septum; LV, leftventricle. (Top: From Mayo Clinic

Proceedings. [Tajik AJ, SewardJB, Hagler DJ, et al. Two-dimensional real-time ultrasonicimaging of the heart and greatvessels: Technique, imageorientation, structureidentification, and validation.Mayo Clinic Proceedings,1978;53:271–303], withpermission. Bottom: From Oh JK,Seward JB, Tajik AJ. The EchoManual, 3rd ed. Philadelphia:Lippincott Williams & Wilkins,2006. By permission of MayoFoundation for MedicalEducation and Research. Allrights reserved.)

4 Apical four-chamber view:Note that at some institutions theimage is reversed so that theleft side of the heart appears onthe right side of the screen. LA,left atrium; LV, left ventricle; RA,right atrium; RV, right ventricle.(Top: From Mayo Clinic

Proceedings. [Tajik AJ, SewardJB, Hagler DJ, et al. Two-dimensional real-time ultrasonicimaging of the heart and greatvessels: Technique, imageorientation, structureidentification, and validation.Mayo Clinic Proceedings,1978;53:271–303], withpermission. Bottom: From Oh JK,Seward JB, Tajik AJ. The EchoManual, 3rd ed. Philadelphia:Lippincott Williams & Wilkins,2006. By permission of MayoFoundation for MedicalEducation and Research. Allrights reserved.)

Coronary Angiography

Peripheral Blood Smears

1 Normal smear.

2 Hypochromic, microcyticanemia due to iron-deficiency.

3 Macrocytic anemia due topernicious anemia; note macro-ovalocytes and hypersegmentedneutrophils.

4 Spherocytes due toautoimmune hemolytic anemia.

5 Sickle cell anemia.

6 Schistocytes.

7 Teardrop shaped RBC(dacrocyte).

8 Acanthocytes.

9 Nucleated RBC.

10 Rouleaux.

Leukemias

1 AML with Auer rod.

2 ALL.

3 CML.

4 CLL.

All photos excluding LeukemiasFig. 4: From Wintrobe’s Clin.Hematol. 12th ed, 2009: LeukemiasFig. 4 From Devita, Hellman, andRosenberg’s Cancer: Princip. & Prac.

of Oncol. 8th ed, 2008.

Urinalysis

1 “Muddy brown” or granularcast (courtesy Nicholas Zwang,MD)

2 Hyaline cast (courtesyNicholas Zwang, MD)

3 “Waxy broad” cast (courtesyNicholas Zwang, MD)

4 Renal tubular epithelial cell(courtesy Nicholas Zwang, MD)

5 RBC cast. (Dis. of Kidney &

Urinary Tract, 8th ed, 2006.)

6 WBC cast. (Clin. Lab.Medicine, 2nd ed, 2002.)

7 Calcium oxalate crystals(courtesy Mallika Mendu, MD).Calcium monohydrate (arrow),calcium dihydrate (dashedarrow), and amorphous calciumcrystals (arrowhead)

8 “Struvite” magnesiumammonia phosphate crystals

(courtesy Brett Carroll, MD)

9 Cystine crystals (Clin. Lab.Medicine, 1994.)

10 Sulfadiazine “shock ofwheat” crystals (courtesyNicholas Zwang, MD)

ACLS ALGORITHMS

Figure ACLS-1 ACLS TachycardiaAlgorithm

Figure ACLS-2 ACLS BradycardiaAlgorithm

Figure ACLS-3 VF/Pulseless VT,Asystole & PEA Algorithms

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