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Transcript of Pocketmedecin2014 140508113544-phpapp01
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PocketMEDICINE
Fifth Edition
Edited byMARC S. SABATINE, MD, MPHASSOCIATE PROFESSOR OF
MEDICINE
HARVARD MEDICAL SCHOOL
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The MassachusettsGeneral HospitalHandbook of InternalMedicine
HealthPhiladelphia • Baltimore• New York • LondonBuenos Aires • HongKong • Sydney • Tokyo
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Executive Editor: Rebecca GaertnerProduct Manager: Kristina OberleVendor Manager: BridgettDoughertyManufacturing Coordinator: BethWelshMarketing Manager: KimSchonbergerCreative Director: Doug SmockProduction Service: Aptara, Inc.
© 2014 by LIPPINCOTT WILLIAMS &WILKINS, a WOLTERS KLUWER businessTwo Commerce Square2001 Market StreetPhiladelphia, PA 19103 USALWW.com
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All rights reserved. This book isprotected by copyright. No part ofthis book may be reproduced inany form by any means, includingphotocopying, or utilized by anyinformation storage and retrievalsystem without written permissionfrom the copyright owner, exceptfor brief quotations embodied incritical articles and reviews.Materials appearing in this bookprepared by individuals as part oftheir o cial duties as U.S.government employees are notcovered by the above-mentionedcopyright.
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Printed in China
Not authorised for sale in UnitedStates, Canada, Australia, NewZealand, Puerto Rico, and UnitedStates Virgin Islands.
Library of Congress Cataloging-in-Publication Data
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
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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
compilation. II. Title.[DNLM: 1. Internal Medicine–
Handbooks. 2. Clinical Medicine–Handbooks. WB 39]
RC55616–dc23
2013019655DISCLAIMER Care has been takento con rm the accuracy of theinformation presented and to
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describe generally acceptedpractices. However, the authors,editors, and publisher are notresponsible for errors or omissionsor for any consequences fromapplication of the information inthis book and make no warranty,expressed or implied, with respectto the currency, completeness, oraccuracy of the contents of thepublication. Application of theinformation in a particularsituation remains the professionalresponsibility of the practitioner.
The authors, editors, andpublisher have exerted every e ortto ensure that drug selection and
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dosage set forth in this text are inaccordance with currentrecommendations and practice atthe time of publication. However,in view of ongoing research,changes in governmentregulations, and the constant owof information relating to drugtherapy and drug reactions, thereader is urged to check thepackage insert for each drug forany change in indications anddosage and for added warningsand precautions. This isparticularly important when therecommended agent is a new orinfrequently employed drug.
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Some drugs and medical devicespresented in the publication haveFood and Drug Administration(FDA) clearance for limited use inrestricted research settings. It is theresponsibility of the health careprovider to ascertain the FDAstatus of each drug or deviceplanned for use in their clinicalpractice.
To purchase additional copies ofthis book, call our customer servicedepartment at (800) 638-3030 orfax orders to (301) 223-2320.International customers should call(301) 223-2300.
Visit Lippincott Williams &
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Wilkins on the Internet: atLWW.com. Lippincott Williams &Wilkins customer servicerepresentatives are available from8:30 am to 6 pm, EST.
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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
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Acute Coronary SyndromesPA Catheter and Tailored TherapyHeart FailureCardiomyopathiesValvular Heart DiseasePericardial DiseaseHypertensionAortic AneurysmsAcute Aortic SyndromesArrhythmiasAtrial FibrillationSyncopeIntracardiac DevicesCardiac Risk Assessment forNoncardiac SurgeryPeripheral Artery Disease
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PULMONARYQIan J. Barbash, Kathryn A. Hibbert,
Atul MalhotraDyspneaPulmonary Function TestsAsthmaAnaphylaxisChronic Obstructive PulmonaryDiseaseHemoptysisBronchiectasisSolitary Pulmonary NoduleObstructive Sleep ApneaInterstitial Lung DiseasePleural EffusionVenous ThromboembolismPulmonary Hypertension
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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
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HepatitisAcute Liver FailureCirrhosisHepatic Vascular DiseaseAscitesBiliary Tract Disease
NEPHROLOGYAndrew S. Allegretti, Andrew L.
Lundquist, Hasan BazariAcid-Base DisturbancesSodium and Water HomeostasisPotassium HomeostasisRenal FailureGlomerular DiseaseUrinalysisNephrolithiasis
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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
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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
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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
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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
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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
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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
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RadiologyEchocardiography & CoronaryAngiographyPeripheral Blood Smears &LeukemiasUrinalysis
ACLS
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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
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CancerCareHematology/Oncology Program
Ian J. Barbash, MDInternal Medicine Resident,
Massachusetts General Hospital
Nesli Basgoz, MDAssociate Chief and Clinical
Director, Infectious DiseaseDivision, Massachusetts GeneralHospital
Associate Professor of Medicine,Harvard Medical School
Hasan Bazari, MDClinical Director, Nephrology Unit,
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Massachusetts General HospitalProgram Director, Internal
Medicine Residency,Massachusetts General Hospital
Associate Professor of Medicine,Harvard Medical School
Michael P. Bowley, MD, PhDNeurology Resident, Partners
Neurology Residency
Andrew M. Brunner, MDInternal Medicine Resident,
Massachusetts General Hospital
Neal A. Chatterjee, MDInternal Medicine Resident,
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Massachusetts General Hospital
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
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ResidencyAssistant Professor of Neurology,
Harvard Medical SchoolAssistant Neurologist,
Massachusetts General Hospital
Andrew S. de Lemos, MDTransplant Hepatology Fellow,
Massachusetts General Hospital
Daniel J. DeAngelo, MD, PhDAdult Leukemia Program, Dana-
Farber Cancer Institute &Brigham and Women’s Hospital
Associate Professor of Medicine,Harvard Medical School
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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,
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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
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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,
Massachusetts General Hospital
Stella K. Kim, MDDirector, Clinical Research in
Opthalmology
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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,
Massachusetts General Hospital
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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
Associate Professor of Medicine,Harvard Medical School
Michael Mannstadt, MDAttending Physician, Endocrine
Unit, Massachusetts GeneralHospital
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Assistant Professor of Medicine,Harvard Medical School
Eli Miloslavsky, MDRheumatology Fellow,
Massachusetts General Hospital
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
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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,
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Harvard Medical School
Ada Stefanescu, MD, CMInternal Medicine Resident,
Massachusetts General Hospital
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
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Zachary S. Wallace, MDInternal Medicine Resident,
Massachusetts General Hospital
Ana A. Weil, MD, MPHInternal Medicine Resident,
Massachusetts General Hospital
Marc N. Wein, MD, PhDEndocrinology Fellow,
Massachusetts General Hospital
Zachary A. Zator, MDInternal Medicine Resident,
Massachusetts General Hospital
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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
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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
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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.
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DENNIS A. AUSIELLO, MDPhysician-in-Chief, Massachusetts
General HospitalJackson Professor of Clinical
Medicine, Harvard Medical School
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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
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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
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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
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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.
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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
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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.
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I hope that you nd PocketMedicine useful throughout thearduous but incredibly rewardingjourney of practicing medicine.
MARC S. SABATINE, MD, MPH
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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
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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,
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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
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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
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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,
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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
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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,
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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
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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
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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)
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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)
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• 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)
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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
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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)
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• 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′,
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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
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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)
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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
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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
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CHEST PAIN
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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
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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
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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)
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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
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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.
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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
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(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),
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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
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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
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• 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
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• 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
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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
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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
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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
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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)
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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
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• 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
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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
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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
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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):
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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
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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
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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
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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
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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
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• 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; ↓
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w/ DES vs. BMS.
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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)
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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,
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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
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• 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
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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%)
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• 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)
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• 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/
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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)
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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
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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
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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
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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
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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
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Figure 1-2 Approach toUA/NSTEMI
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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-
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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
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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
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• 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
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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
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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)
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LV failure (~25%)• Diurese to achieve PCWP 15–20
→ ↓ pulmonary edema, ↓myocardial O2 demand
• ↓ Afterload → ↑ stroke volume &CO, ↓ myocardial O2 demand
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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)
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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
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≥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/
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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)
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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,
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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
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• 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
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or PCI) and ~20% w/o• Predictors of mortality: age, time
to Rx, anterior MI or LBBB,heart failure (Circ2000;102:2031)
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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
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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
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? 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
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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)
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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
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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,
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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)
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(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,
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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-
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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
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• 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)
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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
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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
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• 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,
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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
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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
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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.
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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
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>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
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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,
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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
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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)
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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)
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• 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
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History• Low output: fatigue, weakness,
exercise intolerance, Δ MS,anorexia
• Congestive: left-sided →dyspnea, orthopnea,
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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
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>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)
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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.,
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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: ↑
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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)
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• 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
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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
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• 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”)
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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
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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 →
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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
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• 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
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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
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• Utility of BNP-guided Rx remainsdebated (Circ 2013;301:500 &509)
• Implantable PA pressure sensorin NYHA III → ~30% ↓ risk ofhosp (Lancet 2011;377:658)
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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
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• 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
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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
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(neutral endopeptidase)inhib under study (Lancet2012;380:1387)
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CARDIOMYOPATHIES
Diseases with mechanical and/orelectrical dysfunction of the
myocardium
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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
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• 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
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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
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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
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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
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(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
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(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%),
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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
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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
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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
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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),
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ischemic/GCM (worst)
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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)
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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
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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.,
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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
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• 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
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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)
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• 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
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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
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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,
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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)
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• First-degree relatives: periodicscreening w/ echo, ECG (astiming of HCMP onsetvariable). Genetic testing ifknown mutation.
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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
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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
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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.
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~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
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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;
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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
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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, ±
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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, ↑
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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)
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• 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
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cases
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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
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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;
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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
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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)
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Diagnostic studies• ECG: may see LVH, LAE, LBBB,
AF (in late disease)
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• 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
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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)
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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
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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
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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
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nonoperative Pts, 44% ↓mortality vs. standard Rx(NEJM 2012;366:1696)
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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
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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
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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
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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)
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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
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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)
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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
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• 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)
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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
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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,
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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
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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)
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Diagnostic studies (NEJM2005;352:875)• ECG: may see LAE, LVH, ± atrial
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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
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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
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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
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• 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
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LV dysfxn: ACEI, bB, ± BiVpacing; maintain SR
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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,
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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
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• 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 expi- ration, ↑w/ exercise; severityproportional to duration (notintensity) of murmur
• Opening snap (high-pitched
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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)
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Diagnostic studies• ECG: LAE (“P mitrale”), ± AF, ±
RVH• CXR: dilated LA (straightening
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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
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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
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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
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<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
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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
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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
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2007:116:1736)• Aspirin or anticoagulation if
prior neurologic event or atrialfibrillation
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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)
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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.
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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
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• 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 →
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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
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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
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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
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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)
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HEART VALVES (superior view,JAMA 1976;235:1603)
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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
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characterized by increasedventricular interdependence
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PERICARDITIS ANDPERICARDIAL EFFUSION
Clinical manifestations (NEJM2004;351:2195)• Pericarditis: retrosternal chest
pain that is pleuritic,positional (↓ by sitting
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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
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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
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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;
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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
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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,
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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
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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
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• 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)
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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,
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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 → ↓
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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
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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
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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
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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
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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
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consider removing just enoughfluid to reverse PEA en routeto emergent surgery)
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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
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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
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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
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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,
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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
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(Circ 2011;124:1830)
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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;
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>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).
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• 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
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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,
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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
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• 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
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<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-
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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
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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
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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;
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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
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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:
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salt and fluid restriction, ±diuretics
Endocrine etiologies: see“Adrenal Disorders”
• Pregnancy: methyldopa,labetalol, nifedipine,hydralazine; avoid diuretics; �ACEI/ARB
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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
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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
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• 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
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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
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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
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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,
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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
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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-
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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
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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
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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; ↑
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>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
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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)
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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)
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• 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
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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.
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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
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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):
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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
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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),
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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-
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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)
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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
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• 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
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• 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,
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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
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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
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• 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 &
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PPM for brady
AV dissociation• Default: slowing of SA node
allows subsidiary pacemaker(eg, AV junction) to take over
• Usurpation: acceleration of
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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
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bradycardia due to reversiblecause (bB/CCB O/D, Lyme,myocarditis, SBE, s/p cardiacsurgery/trauma), TdP, acuteMI (sx brady, high grade AVB)
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SUPRAVENTRICULARTACHYCARDIAS (SVTS)
Arise above the ventricles, ∴ narrowQRS unless aberrant conduction or
pre-excitation.
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Figure 1-4 Approach to SVT(adapted from NEJM2012;367:1438)
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• Catheter ablation: high overall
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success rate (AFL/AVNRT~95%, AVRT ~90%, AF~80%)Complications: stroke, MI,
bleeding, perforation,conduction block (JAMA2007;290:2768)
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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
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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-
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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
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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 →
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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
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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 =
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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)
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• 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
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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
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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
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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
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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
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<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)
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• Radiofrequency ablation ifisolated VT focus or ifrecurrent VT triggering ICDfiring; ablation before ICDimplantation ↓ discharge rateby 40% (Lancet 2010;375:31)
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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
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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
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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
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before anticoag, TFTs; r/o MInot necessary unless otherischemic sx
Figure 1-5 Approach to acuteAF
(Adapted from NEJM2004;351:2408; JACC2006;48:e149)
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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
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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
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Cardioversion• Consider pharm or electrical
cardioversion w/ 1st AFepisode or if sx;if AF >48 h, 2–5% risk stroke
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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;
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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
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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)
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• 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.
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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)
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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
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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° =
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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%)
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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
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• 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),
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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
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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.
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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
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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
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• 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)
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• 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
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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;
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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
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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
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High-risk features (usually admitw/ telemetry & testing; J EmergMed 2012;42:345)• Age >60 y, h/o CAD, HF/CMP,
valvular or congenital heart
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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,
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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
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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
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• ✓ state driving laws and MDreporting requirements.Consider appropriateness of Ptinvolvement in exercise/sport,operating machinery, high-riskoccupation (eg, pilot).
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INTRACARDIAC DEVICES
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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 +
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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)
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• 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)
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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–
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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)
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• 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.
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CARDIAC RISK ASSESSMENTFOR NONCARDIAC SURGERY
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Preoperative evaluation
Figure 1-7 ACC/AHA approachto preoperative cardiovascularevaluation for noncardiacsurgery
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Preoperative testing andassessment• ECG if ≥1 risk factor and
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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
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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
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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
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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)
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• ? 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
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>1 risk factor for CAD.• ✓ Postop troponin only if new
ECG Δs or chest painsuggestive of ACS
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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
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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
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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
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<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,
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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
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or surgery
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NOTES
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DYSPNEA
Evaluation• History: quality of sensation,
tempo, positional dependence,exac./allev. factors, exertion
• Cardiopulmonary exam, SaO2,CXR (see Appendix &
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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)
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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”
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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
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surface area for gas exchange;helps differentiate causes ofobstructive and restrictivediseases and screens forvascular disease & early ILD
Figure 2-1 Approach toabnormal PFTs
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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
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• 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
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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
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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
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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
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• 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
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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
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(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
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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 (↑
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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)
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• 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
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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
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• 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)
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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,
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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
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tiring
Initial treatment (NEJM2010;363;755)• Oxygen to keep SaO2 ≥90%• Inhaled SABA (eg, albuterol) by
MDI (4–8 puffs) or nebulizer
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(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
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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
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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
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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
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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
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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
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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
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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
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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:
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allergen avoidance, instructionand Rx for EpiPen, allergistf/u
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CHRONIC OBSTRUCTIVEPULMONARY DISEASE
Definition and epidemiology(NEJM 2004;350:26)• Progressive airflow limitation
caused by airway andparenchymal inflammation
Pathogenesis (Lancet
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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
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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, ↓
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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:
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↑↑ 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
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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: ↑
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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)
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• 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
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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)
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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
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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)
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• 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)
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EXACERBATION
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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
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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,
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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 ↑
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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
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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
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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
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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)
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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
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• 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)
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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
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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
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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
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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
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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
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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), ↓
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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)
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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,
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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,
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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,
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VATS, open) if no clearprecipitant and w/uunrevealing
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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
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• Löfgren’s syndrome: erythemanodosum + hilar adenopathy+ arthritis (good prognosis)
• Diagnostic studies: LN bx →noncaseating granulomas +multinucleated giant cells18FDG PET can be used to
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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-
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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:
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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
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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
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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-
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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
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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
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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
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• 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)
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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:
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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
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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
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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
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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
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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
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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%):
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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
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• 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,
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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
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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
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>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
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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
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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
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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,
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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 →
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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
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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
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listed above): mostcommonly malig, empyema,TB, PE. ✓ s/s malig, chestCT (I+), ADA or IFN-grelease assay; considerthoracoscopy.
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Treatment• Symptomatic effusion:
therapeutic thoracentesis, treatunderlying disease process
• Parapneumonic effusion (Chest
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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
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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,
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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
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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
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• 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
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• 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
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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
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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
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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,
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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
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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%
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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% &
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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%
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(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
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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)
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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
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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
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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
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(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
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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)
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• 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).
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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
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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
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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;
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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
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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)
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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
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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
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(Circ 2008;117:1711)
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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:
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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
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Clinical manifestations• Dyspnea, exertional syncope
(hypoxia, ↓ CO), exertionalchest pain (RV ischemia)
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• 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
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(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), ↓
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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
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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
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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
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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
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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)
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• 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
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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
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• 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
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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)
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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
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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
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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 →
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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.
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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)
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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)
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Tailoring the ventilator settings• To improve oxygenation: options
include ↑ FiO2, ↑ PEEPFirst, ↑ FiO2. If >0.6 and
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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
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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
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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,
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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
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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
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(~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.
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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
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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)
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• 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)
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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
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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 ↑
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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)
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• 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
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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 → ↑
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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 ↑
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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)
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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
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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)
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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 ✓
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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
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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
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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
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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)
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• 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)
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• 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
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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
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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)
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NOTES
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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)
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Achalasia• Etiologies: idiopathic (most
common), pseudoachalasia(due to GE jxn tumor), Chagas
• Sx: dysphagia (solid & liquid),chest pain (1/3 of Pts),regurgitation
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• 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;
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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
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on bx & exclude GERD (eg,empiric PPI trial). Rx: 3Ds:Diet (elim milk, soy, eggs,wheat, nuts, fish); Drugs(swallow inh steroids),Dilation
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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
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• 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)
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>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
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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
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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.
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High-grade dysplasia: U/S tor/o invasive cancer;endoscopic mucosalresection of any visiblemucosal irregularity +ablation of dysplasia(radiofrequency orphotodynamic).
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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 gastro- paresis,
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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
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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
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• 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
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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
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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%)
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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
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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
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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
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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
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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
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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
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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)
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• 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
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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
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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
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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
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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
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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
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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
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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
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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)
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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
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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
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DIARRHEA, CONSTIPATION ANDILEUS
ACUTE DIARRHEA (<4 wk)
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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
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• 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
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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
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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
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of sx onset)avoid abx if suspect E. coli
O157:H7 as may ↑ risk ofHUS
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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)
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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
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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
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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,
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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%
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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
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2013;368:407)• Probiotics may prevent CDAD by
66% in non-immunosuppressedPts (Annals 2012;157:878)
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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, discom- fort,
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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
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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.
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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)
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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
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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 &
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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
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• 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
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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
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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
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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
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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:
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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
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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)
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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
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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),
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methylnaltrexone (for smallbowel, ? colonic)
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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
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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,
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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
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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,
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rehydrating and repleting
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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%
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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)
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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
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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)
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• 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
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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.
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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
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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
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• 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
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vasopressin infusion orembolization
• Surgery: if above modalities fail& bleeding is persistent &hemodynamically significant
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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)
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• 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
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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,
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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
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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
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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
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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
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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
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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
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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 ↓
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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
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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
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2008;371:660; NEJM2010;362:1383).
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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
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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.
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• 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).
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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
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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
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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
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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% ↑
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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;
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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
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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
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for abd pain excluded
Prognosis• Mortality 20 to >70% if bowel
infarcted; dx prior toinfarction strongest predictorof survival
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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
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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
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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
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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
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• 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
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• 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,
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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,
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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)
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• 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
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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
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dx. Helps exclude other dx,stage severity, & r/ocomplications. CT w/ IVcontrast on day 3 ofpresenta- tion 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
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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,
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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.
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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,
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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
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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
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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
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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
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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)
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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
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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,
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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.
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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
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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)
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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;
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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:
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↑↑ 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
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• 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;
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ANA, ASMA, ALKM; anti-tissuetransglutaminase;ceruloplasmin & ɑ1-AT; TSH;vascular abnl (U/S w/Doppler)
Figure 3-4 Approach toabnormal liver tests withcholestatic pattern
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Figure 3-5 Approach toabnormal liver tests with isolatedhyperbilirubinemia
Figure 3-6 Approach toabnormal liver tests withinfiltrative pattern
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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
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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
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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
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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)
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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)
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• 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)
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• 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
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(<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
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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
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• Treatment for acute HBV:
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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
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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
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• 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)
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• 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,
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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
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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
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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
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(� 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, µRNA-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),
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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)
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• 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
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• 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)
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• Extrahepatic sx: arthritis,pancreatitis, neuro (GBS,inflam polyradic.,meningoenceph.)
Other viruses (HGV, CMV, EBV,HSV, VZV)
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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
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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
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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
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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 ×
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[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,
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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
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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
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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
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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
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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 ↑
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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
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2010;362:1675). Pentoxifyllineunder study (Hep2011;54:1610).
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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,
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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
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• 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
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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
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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
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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
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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
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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
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(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)
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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
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• 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%
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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
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• 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
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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
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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
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(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
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(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,
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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
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• 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%
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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)
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↓ 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%,
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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%
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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 ↑
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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
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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
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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-
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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
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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
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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;
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(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
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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
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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)
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• 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,
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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
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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)
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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; ↑
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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
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• 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
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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
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• 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
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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
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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,
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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
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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
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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 +
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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
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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
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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)
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(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
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(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, ↑
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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
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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,
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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,
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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,
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colectomy may ↓ recurrence
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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,
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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
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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),
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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.
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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;
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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
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(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)
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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
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ASCITES
Pathophysiology• Portal hypertension → systemic
vasodilatation (? due torelease of NO) → ↓ effectivearterial volume → renal Naretention
• ↓ serum oncotic pressure fromhypoalbuminemia; ↑ hepaticlymph production
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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
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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
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(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%
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(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 +
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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)
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• 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,
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30% GNR; Rx: vanc + gent (IVload, then administer in PD)
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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,
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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%)
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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
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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
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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,
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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
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• Gallstone ileus: SBO (usually atterm ileum) due to stone inintestine that passed thrufistula
• Gallbladder carcinoma (~1% inU.S.)
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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,
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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;
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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%
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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
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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:
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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
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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
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• 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)
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• CCY typically w/in 6 wk unlesscontraindication (>15% Ptswill develop indication forCCY if left unRx’d)
Complications• Cholangitis, cholecystitis,
pancreatitis, stricture
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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
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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
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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.
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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
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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
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Workup• Determine primary disorder: ✓
pH, PaCO2, HCO3
• Determine if degree ofcompensation is appropriate
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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
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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
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met. acid. + met. alk.• Cannot have resp. acid.
(hypoventilation) and resp.alk. (hyperventilation)simultaneously
Figure 4-1 Acid-basenomogram
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• ABG vs. VBG: concordant for pH(~0.04), HCO3 (~2 mEq) butnot PaCO2 (~8±17 mmHg)
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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)
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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
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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
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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; ∴
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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
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glycol: early on, OGprecedes AG; later OGmay be nl with AG
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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
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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)
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• 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 ↑
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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:
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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
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Treatment of severe metabolicacidoses (pH <7.2) (Nat RevNephol 2012;8:589)• DKA: insulin & IVF; AKA:
dextrose, IVF, replete K, Mg,PO4 as needed
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• 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
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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
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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 →
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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)
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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
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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
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→ ↑ HCO3 excretion → ↑ Naexcretion; negativelycharged HCO3 “drags” Na+along)
If UCl >20 and volume replete,✓ blood pressure
Figure 4-3 Approach tometabolic alkalosis
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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
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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
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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
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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
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ventilation (eg, CPR, severeHoTN) → ↓ delivery of CO2 tolungs for excretion; low PaCO2
but ↑ tissue CO2
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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
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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),
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hyperkalemia action: iso-osmotic reabsorption ofsodium in exchange forpotassium or H+
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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
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>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 =
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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
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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
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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
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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
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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)
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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
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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
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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)
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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
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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
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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 →
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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
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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
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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
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(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)
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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
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w/o access to H2O
Workup• ✓ Uosm, UNa, volume status (vital
signs, orthostatics, JVP, skinturgor, BUN, Cr)
Figure 4-5 Approach tohypernatremia
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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)
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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
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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: ↑
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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
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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
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frequently• DI and osmotic diuresis: see
“Polyuria” section below• Na overload: D5W + diuretic
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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
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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
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(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
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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
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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;
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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
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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
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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,
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daily intake ~100 mEq)
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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:
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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
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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-
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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
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• ✓ 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
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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
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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)
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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
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• 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,
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↓ 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,
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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
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2008;19:424)
• Rate of onset important to notewhen establishing a treatmentplan
• Calcium helps prevent/treatcardiac complications; ∴should be initial Rx, esp. if
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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
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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;
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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
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• 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)
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Contrast-induced acute kidneyinjury (CIAKI)• Risk factors: CKD, DM, CHF, age,
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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
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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
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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
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• 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
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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
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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
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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%),
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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)
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Treatment (Annals 2009;150:ITC2-1; NEJM 2010;362:57)• General: nephrology referral
when GFR <30 and access
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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
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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
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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
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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
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calcium-sensing receptoragonist) if PTH remainselevated despite phosphorusbinders ± vit. Δ analogue(NEJM 2004;350:1516; NDT2011;26:1327)parathyroidectomy
• Consider transplantevaluation
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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
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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%
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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
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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
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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.
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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
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• 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)
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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
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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,
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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.
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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
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(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
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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)
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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
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(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–
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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
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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 &
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dyslipidemia (immunosuppmeds)
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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
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• Progression: acute GN days;rapidly progressive GN (RPGN)
wks; chronic GN mos; cansimply have asx hematuria
• Crescentic GN (pathologicdescription) RPGN (clinicaldescription)
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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
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• 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)
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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)
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• 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
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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)
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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
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• Treatment: ACEI/ARB, ± fishoils (JASN 1999;10:1772);steroids (JASN 2012;23:1108);± cytotoxic therapy forcrescentic GN and nephroticsx, consider for progressivechronic GN
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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,
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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, &
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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
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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
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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.
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→ 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 ±
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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)
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URINALYSIS
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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
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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
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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
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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
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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 ±
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contrast (r/o nephrolithiasisand neoplasia of uppertract), cystoscopy (r/obladder neoplasia, esp. ≥35y), ± MRI, retrogradepyelogram, U/S
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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
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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
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• 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
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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
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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)
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• 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
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• Magnesium ammoniumphosphate: antibiotics to treatUTI, urologic intervention,acetohydroxamic acid: ureaseinhibitor, reserve forexperienced clinician, poorlytolerated
• Cystine: urine alkalinization (K-citrate), D-penicillamine,tiopronin
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NOTES
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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),
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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
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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,
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LFTs, BUN and Cr, TFTs, Hbelectrophoresis, enzymeanalyses, gene mutationscreens
• Bone marrow (BM) aspirateand biopsy (bx) withcytogenetics as indicated
Figure 5-1 Approach toanemia
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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:
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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
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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
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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
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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 ( =
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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
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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
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(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
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(w/ iron-laden mitochondria)in BM
• Treatment: treat reversiblecauses; trial of pyridoxine,supportive transfusions forsevere anemia; high-dosepyridoxine for some hereditarycases
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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
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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
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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
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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
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thymus enlarged; IVIg ifparvovirus infection;immunosuppression if CLL oridiopathic; supportive carewith PRBC transfusions; ?erythropoietin receptor agonistif due to antierythropoietin Ab(NEJM 2009;361:1848)
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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,
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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,
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↑ 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
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cells; absorbed in terminalileum
• Etiologies: malnutrition(alcoholics, vegans),pernicious anemia (PA,autoimmune dis- ease 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
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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
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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
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• Reticulocytosis• Other causes: hypothyroidism;
MDS; meds that impair DNAsynthesis (zidovudine, 5-FU,hydroxyurea, Ara-C);hereditary orotic aciduria;Lesch-Nyhan syndrome.
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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
Clinical manifestations
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• 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
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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
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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 &
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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)
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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
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• 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
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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
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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
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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
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• 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
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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
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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
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• 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
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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,
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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
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• 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
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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
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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
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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
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abnormality; urgent plasmaexchange for TTP
Hypersplenism• Stasis/trapping in spleen → mf
attack & remodeling of RBC →spherocytosis → hemolysis
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DISORDERS OF HEMOSTASIS
Figure 5-3 Approach toabnormal hemostasis
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Figure 5-4 Coagulation Cascade
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Purpura (nonblanching purple/redlesions due to extravasation ofRBCs into dermis)• Nonpalpable (macular; ≤3 mm
in diameter = petechiae; >3mm = ecchymoses)platelet disorder:
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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
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or S deficiency or APS (seesection on DIC)
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PLATELET DISORDERS
THROMBOCYTOPENIA (PLTCOUNT <150,000/µL)
Etiologies• ↓ production
hypocellular bone marrow:aplastic anemia (qv), rarelyMDS, drugs (eg, thiazides,antibiotics), alcohol,cirrhosis
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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
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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
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• 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
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“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
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• 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
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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:
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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
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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
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• 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
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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
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(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
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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 (✓
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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
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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
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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
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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
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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
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(NEJM 2006;354:1927)
Disseminated intravascularcoagulation (DIC): see“Coagulopathies”
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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)
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(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, ↓
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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
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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
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interactions withendothelium), considerholding anti-plt agents
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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; ∴
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↓ 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)
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• 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),
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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.
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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
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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
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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
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HYPERCOAGULABLE STATES
Suspect in Pts with venous or arterialthrombosis at young age or unusuallocations, recurrent thromboses or
pregnancy loss or FHx
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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,
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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)
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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
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(≥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/
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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
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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
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• 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,
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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)
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DISORDERS OF LEUKOCYTES
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TRANSFUSION THERAPY
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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
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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
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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;
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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”
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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)
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• 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
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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);
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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,
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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
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55–75)Hypoplastic MDS (rare) → can
considerimmunosuppression (CsA,ATG, prednisone)
• Prognosis: IPSS correlates withsurvival and progression toAML
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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
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(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
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frequency; genetic lesions areuseful as a clonal marker anddx tool
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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);
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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
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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
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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
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• 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-
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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
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previous cytoreductive chemo)
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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
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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
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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
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• Low-risk Pts have overallsurvival control population.Risk of transformation intoacute leukemia ~2–3%.
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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
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• 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
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→ 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
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• 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;
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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
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(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).
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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
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• 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),
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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
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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)
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• 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
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• 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
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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
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• Cytogenetics: important forprognosis. Intermed. risk = nofavorable/unfavorablefeatures.
Treatment (Blood 2010;115:453;JNCCN 2012;10:984; Lancet
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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) =
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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)
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• 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/
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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,
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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
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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
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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)
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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
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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)
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• 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
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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)
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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)
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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
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“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
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(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-
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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 &
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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
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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
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• 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-
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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
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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):
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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)
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• 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
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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
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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
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(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
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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
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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
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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
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receptor; correlated w/unmutated IgVH)
CD38 >30% or CD49d <30%(correlated with unmutatedIgVH)
higher β2-microglobulin levels(correlate with disease stageand tumor burden)
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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
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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
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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
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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
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(Blood 2006;107:52; JCO2007;25:3746); has role toassess PR/CR aftertreatment.
Head CT/MRI only ifneurologic symptoms.
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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
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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
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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
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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
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echo/stress at 10 y(controversial)
pulmonary toxicity (ifbleomycin)
hypothyroidism (if RT), ∴annual TSH (if neck RT)
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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
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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;
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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
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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,
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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
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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-
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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
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• Aggressive: ↑ chance of cure, butoverall worse prognosis
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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,
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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
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CHOP (often CD20–), but poorprognosis.
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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 ↑
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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
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• 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
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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
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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
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• 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
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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 =
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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
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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),
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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
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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
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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 →
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myelosuppression;lenalidomide → low plts &thromboembolism; bortezomib→ periph. neuropathy; steroids→ hyperglycemia, infxn
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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/
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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)
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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”)
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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
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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
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• 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
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anemia): rituximab ±chemotherapy (eg,cyclophosphamide,chlorambucil, fludarabine,cladribine, bendamustine) orbortezomib
• Thalidomide, alemtuzumab,everolimus, ibrutinib & auto-HSCT are investigational Rx
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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
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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
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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;
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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
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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
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(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 ↓
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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,
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~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
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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
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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
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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
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+ 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,
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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)
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• 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)
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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-
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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
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• 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
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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 =
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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
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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;
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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
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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;
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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
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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
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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)
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+ 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
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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
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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)
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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
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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
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(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
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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)
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• 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
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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,
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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
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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
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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%);
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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
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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)
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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/
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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.
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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
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(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
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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
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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
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premenopausal; pureantiestrogens (fulvestrant) ifpostmenopausal
Prevention (with selectiveestrogen receptor modulator[SERM] or AI)• Tamoxifen: ↓ risk contralat.
breast CA as adjuvant Rx.
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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)
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• BRCA1/2 : intensifiedsurveillance as describedabove. Prophylactic bilat.mastectomy → ~90% ↓ risk;bilat. salpingo-oophorectomy ↓risk of ovarian and breastcancer.
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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
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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
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• 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
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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,
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high Gleason grade orclinically advanced tumorabdomen-pelvis CT: inaccuratefor detecting extracapsularspread and lymph node metsendorectal coil MRI: improvesassessment of extracapsularspread
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Prognosis• PSA level, Gleason grade and age
are predictors of metastaticdisease
• In surgically treated Pts, 5-y
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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
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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)
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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
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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%
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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
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• 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
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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
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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
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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,
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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).
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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, ↑
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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)
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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
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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 tofol- low response to therapyand detect recurrence; not ascreening tool
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• ChemotherapyFOLFOX (5-FU + leucovorin
+ oxaliplatin), FOLFIRI orCapeOx (NEJM2004;350:2343)
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± 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).
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CHEMOTHERAPY SIDE EFFECTS
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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%
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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
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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)
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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;
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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-
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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
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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)
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• 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
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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.
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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
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mucinous material. Uncertainprogression to cancer (? 5–20y). Surgery based on age, size,location, dysplasia.
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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,
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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
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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,
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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
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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
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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
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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
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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)
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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
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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
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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),
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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
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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
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compression → surgery; if notsurgical candidate → RT
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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
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• 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
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• 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
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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
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CANCER OF UNKNOWNPRIMARY SITE
• Bony mets: common primarytumors include breast, lung,thyroid, kidney, prostate
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NOTES
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PNEUMONIA
Clinical manifestations• “Typical”: acute onset of fever,
cough w/ purulent sputum,dyspnea, consolidation on CXR
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• “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,
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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
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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
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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:
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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:
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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
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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
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points), arterial pH <7.35 (2points) score ≥3 points has Se~60–90% & Sp 45–75% forneed for ICU care (CID2008;47:375)
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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)
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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.;
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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,
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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
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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
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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:
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oseltamivir 75 mg PO daily ×10 d
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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
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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 ↑
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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)
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• 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
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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
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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
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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;
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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
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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
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(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;
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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,
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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 =
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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
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• 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
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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
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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
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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
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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).
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• 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
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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
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• 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:
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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
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• 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
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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)
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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
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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:
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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
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• 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)
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OTHER CUTANEOUS INFECTIONS
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“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)
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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)
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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)
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• 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
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• Management bymultidisciplinary teamimproves outcomes (Circulation2006;113:e463)
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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
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• 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
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• 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
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• 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])
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• Type II: PCN + clinda. If ↑ riskof CA-MRSA, + vanco. Ifconcern for strep, IVIG.
Prognosis• Generally fatal if untreated;
reported mortality 20–50%
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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
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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
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• Surgical exploration withdébridement, fasciotomiesand amputation if necessary
• Antibiotics: high-dose penicillinG 24 MU IV divided q2–3h +clinda 900 mg IV q8h
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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
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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)
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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)
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• 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)
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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
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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
Clinical manifestations
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• 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
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(w/ vertebral osteo andepidural abscess, may seeparaplegia 48–72 h after firstsigns)
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INFECTIONS OF THE NERVOUSSYSTEM
ACUTE BACTERIAL MENINGITIS
Definition• Bacterial infection of the
subarachnoid space
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Clinical manifestations (NEJM2006;354:44; Lancet2012;380:1684)• Fever (77%), headache (87%),
stiff neck (31%),
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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
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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
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• 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
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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
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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
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• Additional CSF studies based onclinical suspicion: AFB smear &cx, India ink prep,cryptococcal Ag, fungal cx,VDRL, PCR (eg, of HSV, VZV,enteroviral), cytology
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Prognosis• For community-acquired S.
pneumo mort. 19–37%; 30%have long-term neuro sequelae
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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
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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,
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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
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start empiric abx, wait for cxdata
• If suspect MTb:antimycobacterial Rx +dexamethasone (NEJM2004;351:1741)
• If suspect fungal: ampho lipidformulation, ± 5-fluorouracil
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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%):
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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,
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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
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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
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Treatment• HSV, VZV: acyclovir 10 mg/kg IV
q8h (often empiric Rx givenfrequency of HSV/VZV)
• CMV: ganciclovir ± foscarnet;supportive care for most otheretiologies
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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
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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
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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
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• 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
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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)
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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,
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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)
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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,
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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.
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• 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
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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
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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)
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• 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
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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
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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).
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• 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
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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
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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
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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
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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
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• PVE → 23% mortality• Aortic valve worse prognosis
than mitral valve
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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
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(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
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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
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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
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• 2° infxn: assess for primarysource of infection and treat.Source control essential forcure and to preventrecurrence.
• Persistently BCx: d/cindwelling catheters, considermetastatic infxn, infected
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thrombosis or infectedprosthetic material (joint,abscess, vascular graft,pacemaker, etc.)
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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
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• 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 &
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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
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• 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)
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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
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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,
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± 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,
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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
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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–
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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)
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• 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
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• ✓ 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,
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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
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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.).
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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,
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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)
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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 #
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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
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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 /
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• ARVs should be given inconsultation w/ HIV specialist(JAMA 2010;304:321)
• Counseling re: strict adherenceto ARVs is essential; genotype
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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
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(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);
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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)
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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
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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
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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
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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
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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
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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
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• 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–
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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.
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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
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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
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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,
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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)
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• 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,
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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.
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TICK-BORNE DISEASES
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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-
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Atlantic, northern CA• Humans contact ticks usually in
fields with low brush nearwooded areas
Diagnostic studies• Often a clinical dx esp. in early
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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
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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,
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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
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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
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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
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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
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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)
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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
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• 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
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• 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
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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
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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
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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
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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–
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14 d; empiric Rx may beneeded given challenges in dx
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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
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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
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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
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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,
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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
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(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
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• Up to 30% of cases remainundiagnosed, mostspontaneously defervesce (wksto mos)
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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, &
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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,
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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
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Treatment• Empiric abx are not indicated
(unless Pt neutropenic orcritically ill)
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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
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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
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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
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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.
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NOTES
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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
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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
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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
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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
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• 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
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• 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;
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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
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tumor doesn’t typically presentw/ DI
• Clinical manifestations: severepolyuria, mild hypernatremia(severe if ↓ access to H2O)
• Diagnostic studies: see “Sodiumand Water Homeostasis”
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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
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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)
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• 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
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compression of optic chiasm.• Treatment
If asx (no HA, galactorrhea,hypogonadal sx) µadenoma (<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
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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)
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• 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;
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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”
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↑ FSH & LH: usually non-fxn,presents as hypopituitarism b/cof compression effects
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THYROID DISORDERS
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Figure 7-1 Approach to thyroiddisorders
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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
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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)
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• 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,
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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,
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↓ 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:
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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
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hypothermia (T3 morearrhythmogenic); must giveempiric adrenal replace- menttherapy 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
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• 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)
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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
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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
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• 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
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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
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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
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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
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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
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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
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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
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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
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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 &
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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
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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
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(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-
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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
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methimazole for type 1;steroids for type 2 oftendifficult to distinguish so Rx forboth typically initiated ( JCEM2001;86:3) considerthyroidectomy in severely illpatient
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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
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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
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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;
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Am J Clin Pathol 2009;132:658)
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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
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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
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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)
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CRH, corticotropin-releasinghormone; DST, dexamethasonesuppression test; UFC, urinaryfree cortisol
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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;
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✓ 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)
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(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 +
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mineralocorticoid replacementif medical or surgicaladrenalectomy)
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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)
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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,
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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
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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
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(>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,
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measure aldo at end ofinfusion ( if aldo >5 ng/dL)
Figure 7-4 Approach tosuspected hyperaldosteronism
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Treatment• Adenoma → adrenalectomy vs.
medical Rx w/ spironolactoneor eplerenone
• Carcinoma → adrenalectomy• Hyperplasia → spironolactone or
eplerenone; GRA →glucocorticoids ±spironolactone
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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:
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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
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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-
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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)
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• 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
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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
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• 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 ↓
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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”)
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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
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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
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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
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• 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
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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
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excision
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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
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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
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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
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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.
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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
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× [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)
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HYPERCALCEMIA
Clinical manifestations (“bones,stones, abdominal groans andpsychic moans”)• Hypercalcemic crisis (usually
when Ca >13–15): polyuria,
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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
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• 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).
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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, ¶thyroidectomycontroversial.
Overall portends a poorprognosis
Diagnostic studies• Hyperparathyroidism and
malignancy account for 90%
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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
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↓ 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)
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• 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
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HYPOCALCEMIA
Clinical manifestations• Neuromuscular irritability:
perioral paresthesias, cramps, Chvostek’s (tapping facial
nerve → contraction of facialmuscles), Trousseau’s
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(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
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• 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
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wk). In chronic hypopara.,calcitriol is needed, consideralso thiazide.
• Chronic renal failure: phosphatebinder(s), oral Ca, calcitriol oranalogue (calcimimetic may beneeded later to preventhypercalcemia)
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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
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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
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• 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
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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
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with unexplained weight loss;can also be asymptomatic
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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
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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:
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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
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• 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 ¯ovascular complications ↓by strict glycemic control inT1D (NEJM 1993;329:997 &2005;353:2643) & T2D (Lancet
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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;
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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
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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
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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.
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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: ↑
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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
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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
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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)
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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
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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
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• Insulin (eg, 10 U IV followed by0.05–0.1 U/kg/h)
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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
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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
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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
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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)
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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
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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
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• 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,
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↓ 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
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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
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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
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w/ motion/exercise• Physical exam (see table):
localize complaint and identifyobjective signs ofinflammation
• The physical exam is only 50–70%sensitive for detectinginflammatory arthritis
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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
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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
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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
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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/
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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
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(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
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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
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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
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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,
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malaise• Extra-articular manifestations
(18–41% of Pts) can occur atany time; ↑ frequency inseropositive (RF or anti-CCP)(Autoimmun Rev 2011;11:123)
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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
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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
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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
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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
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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)
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• Given ↑ r/o early CVmorbidity/mortality, ↓ risk w/lifestyle mgmt, lipid & DMscreening
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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/
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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,
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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 &
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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
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• 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
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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
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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
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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
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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
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• 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
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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
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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
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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)
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• 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
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>300 mg/d even in CKD)(Arthritis Rheum2012;64:2529; Arthritis CareRes 2012;64:1431)
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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;
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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
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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
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• “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)
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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
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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
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arthropathy
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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)
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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
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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
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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
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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
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Descriptions of skinmanifestations• Psoriasis: erythematous plaques
with sharply defined marginsoften w/ thick silvery scale
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• 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,
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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
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• 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,
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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
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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
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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
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• 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
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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
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inflammatory eye disease(may benefit from steroideye drops or intravitrealsteroid injections)
Treat underlying IBD whenappropriate
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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)
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• 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
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suspicious for bact. infxn;crystals do not r/o septicarthritis!
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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,
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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%),
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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%.
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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
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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
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• IV antibiotics × ≥2 wkfollowed by oral antibiotics;varies by clinical course µbiology
• 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
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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)
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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
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required.
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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
Clinical manifestations
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• 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
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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
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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
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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
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• 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
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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
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• 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
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CONNECTIVE TISSUE DISEASES
• Autoantibody testing is directedby clinical findings, asautoantibodies themselves donot define a particularconnective tissue disease
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• Overlap syndromes encompassingmore than one connectivetissue disorder may bereflected serologically by thepresence of multipleautoantibodies
see “Systemic Lupus Erythematosus”and “Rheumatoid Arthritis” for those
diseases
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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
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(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
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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
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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
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• 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 ↑
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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
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Treatment (Ann Rheum Dis2009;68:620)• Pulmonary Fibrosis:
cyclophosphamide (NEJM2006;354:2655), steroidsPAH: pulmonary vasodilators
(see “Pulm Hypertension”),
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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
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• 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.
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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
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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
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→ 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,
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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%
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• 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
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> 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%),
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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 ®eneration (required fordefinitive diagnosis)PM: endomysial inflam. (CD8
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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
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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
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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
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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;
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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
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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
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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,
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DMARDs, rituximab
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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
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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)
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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
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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
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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%)
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• 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
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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
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sympathectomy, ±anticoagulation
• Others: fish oil (1° RP only; Am JMed 1989;86:158), abx forinfected ulceration
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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
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assoc.; rare C1q & C2 defic.
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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%;
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ACL IgG/IgM, B2GP1, lupusanticoagulant), C3, C4
• If ↓ GFR, active sediment,hematuria or proteinuria →renal bx to guide Rx
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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)
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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
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after stopping medication
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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,
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myalgias, anorexia) commonto all
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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
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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;
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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
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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)
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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
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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
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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
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PMR:10–20 mg/d (SeminArthritis Rheum 2007;37:13)
• Monitoring: follow clinical status& ESR/CRP (Ann Rheum Dis2009;68:318)
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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
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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
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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
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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
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ANCA-ASSOCIATED SMALL-VESSEL VASCULITIS
Microvascular vasculitis (eg,capillaries, postcapillary venules, &
arterioles)
Differential diagnosis of ANCA• anti-PR3 (c-ANCA):
granulomatosis w/polyangiitis, eosinophilic
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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,
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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,
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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
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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
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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 +
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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
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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
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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
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• 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)
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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%),
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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
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• Treatment identical to that forGPA/MPA
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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
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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
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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
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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
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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;
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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
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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)
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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%);
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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
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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)
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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
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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
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(Medicine 2012;91:57)
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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,
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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)
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• 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
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• 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
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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%):
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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
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• 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
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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 ±
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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
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AMYLOIDOSIS
The deposition of misfolded andinsoluble fibrous proteins innormal organs and tissues.
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Diagnostic studies• If suspect AL → ✓ SIEP & UIEP
(↑ Se vs. SPEP & UPEP) & freelight chains, ± BM bx
• If suspect renal involvement ✓U/A (proteinuria)
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• 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 →
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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
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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)
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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,
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often incl. memory. Usuallychronic & progressive,eventually encompassing moreanatomical & functional partsof the nervous system.
Initial evaluation• History (witness & background
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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
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focality or s/s of ↑ ICP (eg,HA, vomiting, papilledema,unilateral dilated pupil, ↑ BP)
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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 ±
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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
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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,
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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
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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
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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.
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• 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
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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
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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,
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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
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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
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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)
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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)
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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
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• 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)
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• 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)
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• 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%)
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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).
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• 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
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• 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
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• 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
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• 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
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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
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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,
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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
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Status epilepticus (consultneurology)• Place Pt in semiprone position to
↓ risk of aspiration• Oral airway or, if prolonged,
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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)
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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
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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
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(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
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Treatment (NEJM2003;348:1786)• Benzodiazepines (BDZ)
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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,
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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,
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short-term memory loss);replete K, Mg, PO4
• Prophylaxis: if min sx or asx (ie,CIWA score <8) but prolongedheavy EtOH con- sumption orh/o withdrawal seizures or DTs→ chlordiazepoxide 25–100 mg(based on severity of EtOHuse) q6h × 24 h, then 25–50mg q6h × 2 d
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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
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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
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(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
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• 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
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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
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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,
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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
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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
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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
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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
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• 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
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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)
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• 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.
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• 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
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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)
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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).
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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
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(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.
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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
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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
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controversial, potential benefitin superficial IPH (Lancet2005, 365:387)
• Venous sinus thrombosis: startanticoagulation, manage ↑ ICPand seizures as needed
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WEAKNESS &NEUROMUSCULAR
DYSFUNCTION
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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,
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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)
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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
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(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
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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
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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)
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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
Clinical manifestations
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• 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
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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
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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
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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,
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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
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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)
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• 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)
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• 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
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FVC, NIF)
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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
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“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
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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)
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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)
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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
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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),
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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
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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
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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, ↓
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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!
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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
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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,
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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
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complicated migraine, CAD,prior stroke. Triptan +NSAID stronger than eitheralone ( JAMA2007;297:1443)
ergotamine,dihydroergotamine: use withcaution in Pts w/ CAD
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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):
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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
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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
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(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
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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
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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
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(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
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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)
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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
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Treatment of nerve rootcompression• Conservative: avoid
bending/lifting; NSAIDs; Rxneuropathic pain (see
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“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)
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SURGICAL ISSUES
ABDOMINAL PAIN
Figure 10-1 Etiologies ofabdominal pain based onlocation
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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
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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
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consultation for ill Pt whilewaiting for imaging.
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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
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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
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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
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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)
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• Evaluation: ✓ compartmentpressures (needle manometry),ICP >30 or difference betweendiastolic pressure and ICP of>10–30 is diagnostic
• Treatment: fasciotomy
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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
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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
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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
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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
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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
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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
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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
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reapproximated w/ steri-strips
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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
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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
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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
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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
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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);
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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
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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
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(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
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Treatment• Bacterial vaginosis: oral or
vaginal metronidazole orclindamycin
• Candida vulvovaginitis: oral ortopical antimycoticmedications
• Trichomoniasis: oralmetronidazole
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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
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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
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OPHTHALMIC ISSUES
ACUTE VISUAL CHANGES
Description & commonetiologies of other visualchanges• Fluctuation in vision (ie,
blurry): med-inducedrefractive error (eg, systemicsteroids, chemotherapy),hyperglycemia, dry eye
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(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
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visual field defect);hemorrhage; intraocularlymphoma
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RED EYE
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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/
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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
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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:
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conjunctival/lid/corneainvolvement → may lead tocorneal perforation,permanent vision loss; emergophtho consult
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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)
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• Overall status: VS,immunocompromised, s/s ofinfxn, h/o malignancy, CNSissues, Δ in meds, CBC, coags
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ICU MEDICATIONS
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F i g u r e 11-1 ACLS pulmonaryedema, hypotension or shockalgorithm
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ANTIBIOTICS
The following tables of spectra ofactivity for different antibiotics are
generalizations.Sensitivity data at your own
institution should be used to guidetherapy.
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FORMULAE AND QUICKREFERENCE
CARDIOLOGY
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Fick cardiac outputOxygen consumption (L/min) =CO (L/min) × arteriovenous (AV)oxygen difference
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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%)
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PULMONARY
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CXR in heart failure• ↑ cardiac silhouette (in systolic
dysfxn, not in diastolic)• Pulmonary venous hypertension:
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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
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Intrapulmonary shunt = lungunits that are perfused but notventilated
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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
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HEMATOLOGY
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✓ 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)
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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
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(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
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~2 half-lives of factor IIor a reduction to ~25%)
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OTHER
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NOTES
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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
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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
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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
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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
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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
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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
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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
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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
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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
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BCx blood cultureBD bile duct
BDZ benzodiazepines
bili. bilirubin
BIPAPbilevel positive airway
pressure
BIV biventricular
BM bone marrow
bowel movement
BMD bone mineral density
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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
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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
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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
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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
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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
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CLL leukemiaCMC carpometacarpal (joint)
CMLchronic myelogenous
leukemia
CMMLchronic myelomonocytic
leukemia
CMP cardiomyopathy
CMV cytomegalovirus
CN cranial nerve
CO carbon monoxide
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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MNZ metronidazole
mod. moderate
MODS multiple organ dysfxn synd.
mo month
MPA microscopic polyangiitis
MPN myeloproliferative neoplasm
MPGNmembranoproliferative
glomerulonephritis
MR magnetic resonance
mitral regurgitation
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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
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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
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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
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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
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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
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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
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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
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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.
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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w/o without
WPWWolff-Parkinson-White
syndrome
w/u workup
XRT radiation therapy
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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
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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
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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
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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
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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
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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
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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
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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
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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
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(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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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eosinophilia, 5-12eosinophilic granulomatosis with
polyangiitis, 8-19as cause of asthma, 2-2as cause of glomerulonephritis,
4-16as cause of interstitial lung
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-
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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
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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,
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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
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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,
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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,
4-16as cause of interstitial lung
disease, 2-10Graves’ disease, 7-4Grey Turner’s sign, 3-13Guillain-Barré syndrome, 9-8
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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microangiopathic hemolyticanemia, 5-5
microscopic polyangiitis, 8-19as cause of glomerulonephritis,
4-16as cause of interstitial lung
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
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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
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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
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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
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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
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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
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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
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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
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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-
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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.)
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2 Normal lateral CXR.(Radiology 101, 3rd ed, 2009.)
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3 COPD: with hyperlucent,overinflated lungs and flatdiaphragms. (Radiology 101, 3rded, 2009.)
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4 Interstitial pulmonaryedema: with Kerley A, B, and Clines and cephalization of thevascular markings. (Fund. Diag.
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Radiology 3rd ed, 2006.)
5 Alveolar pulmonary edema.(Fund. Diag. Radiology 3rd ed,
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2006.)
6 Right upper lobepneumonia. (Radiology 101, 3rded, 2009.)
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7 Right middle lobepneumonia. (Radiology 101, 3rded, 2009.)
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8 Right lower lobe pneumonia(PA). (Radiology 101, 3rd ed,2009.)
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9 Right lower lobe pneumonia(lateral). (Radiology 101, 3rd ed,
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2009.)
10 Bilateral pleural effusions(curved arrows) and enlargedazygous vein (straight arrow)
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(PA). (Radiology 101, 3rd ed,2009.)
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11 Bilateral pleural effusions(curved arrows) (lateral).
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(Radiology 101, 3rd ed, 2009.)
12 Pneumothorax. (Radiology101, 3rd ed, 2009.)
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13 Normal chest CT at level ofpulmonary arteries(parenchymal windows).(Radiology 101, 3rd ed, 2009.)
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14 Bilateral PE (mediastinalwindows). (Radiology 101, 3rded, 2009.)
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15 Sarcoidosis withperilymphatic nodules. (Fund.Diag. Radiology 3rd ed, 2006.)
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16 Idiopathic pulmonaryfibrosis. (Fund. Diag. Radiology3rd ed, 2006.)
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17 Normal abdomen CT atlevel of liver & spleen. (Radiology101, 3rd ed, 2009.)
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18 Normal abdomen CT atlevel of pancreas. (Radiology 101,3rd ed, 2009.)
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Echocardiography
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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.
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(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
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rights reserved.)
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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-
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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.)
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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
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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.)
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4 Apical four-chamber view:Note that at some institutions theimage is re- versed 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
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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.)
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Coronary Angiography
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Peripheral Blood Smears
1 Normal smear.
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2 Hypochromic, microcyticanemia due to iron-deficiency.
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3 Macrocytic anemia due topernicious anemia; note macro-ovalocytes and hypersegmentedneutrophils.
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4 Spherocytes due toautoimmune hemolytic anemia.
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5 Sickle cell anemia.
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6 Schistocytes.
7 Teardrop shaped RBC(dacrocyte).
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8 Acanthocytes.
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9 Nucleated RBC.
10 Rouleaux.
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Leukemias
1 AML with Auer rod.
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2 ALL.
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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.
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of Oncol. 8th ed, 2008.
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Urinalysis
1 “Muddy brown” or granularcast (courtesy Nicholas Zwang,MD)
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2 Hyaline cast (courtesyNicholas Zwang, MD)
3 “Waxy broad” cast (courtesyNicholas Zwang, MD)
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4 Renal tubular epithelial cell(courtesy Nicholas Zwang, MD)
5 RBC cast. (Dis. of Kidney &
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Urinary Tract, 8th ed, 2006.)
6 WBC cast. (Clin. Lab.Medicine, 2nd ed, 2002.)
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7 Calcium oxalate crystals(courtesy Mallika Mendu, MD).Calcium monohydrate (arrow),calcium dihydrate (dashedarrow), and amorphous calciumcrystals (arrowhead)
8 “Struvite” magnesiumammonia phosphate crystals
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(courtesy Brett Carroll, MD)
9 Cystine crystals (Clin. Lab.Medicine, 1994.)
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10 Sulfadiazine “shock ofwheat” crystals (courtesyNicholas Zwang, MD)
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ACLS ALGORITHMS
Figure ACLS-1 ACLS TachycardiaAlgorithm
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Figure ACLS-2 ACLS BradycardiaAlgorithm
Figure ACLS-3 VF/Pulseless VT,Asystole & PEA Algorithms
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