The acute respiratory distress syndrome.docx
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The acute respiratory distress syndrome.docx
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Theacuterespiratorydistresssyndrome
Reviewseries
Theacuterespiratorydistresssyndrome
MichaelA.Matthay,1LorraineB.Ware,2andGuyA.Zimmerman3
1CardiovascularResearchInstituteandDepartmentsofMedicineandAnesthesia,UCSF,SanFrancisco,California,USA.
2DivisionofAllergy,PulmonaryandCriticalCareMedicine,DepartmentofMedicine,VanderbiltUniversity,Nashville,Tennessee,USA.
3DepartmentofMedicine,DivisionofPulmonaryandCriticalCareMedicine,UniversityofUtah,SaltLakeCity,Utah,USA.
Theacuterespiratorydistresssyndrome(ARDS)isanimportantcauseofacuterespiratoryfailurethatisoftenasso-ciatedwithmultipleorganfailure.SeveralclinicaldisorderscanprecipitateARDS,includingpneumonia,sepsis,aspirationofgastriccontents,andmajortrauma.Physiologically,ARDSischaracterizedbyincreasedpermeabilitypulmonaryedema,severearterialhypoxemia,andimpairedcarbondioxideexcretion.Basedonbothexperimentalandclinicalstudies,progresshasbeenmadeinunderstandingthemechanismsresponsibleforthepathogenesisandtheresolutionoflunginjury,includingthecontributionofenvironmentalandgeneticfactors.Improvedsur-vivalhasbeenachievedwiththeuseoflung-protectiveventilation.Futureprogresswilldependondevelopingnoveltherapeuticsthatcanfacilitateandenhancelungrepair.
Introduction
Sincetheoriginaldescriptionoftheacuterespiratorydistresssyn-drome(ARDS)in1967,considerableprogresshasbeenmadeinunderstandingthepathogenesisandpathophysiologyofacutelunginjury(ALI)(1–4).Thelikelihoodofsurvivalisdeterminedbytheseverityoflunginjury,theextentofnonpulmonaryorgandysfunction,preexistingmedicalconditions,andthequalityofsupportivecare.BecauseARDSisacomplexsyndromewithabroadclinicalphenotype,ithasbeenchallengingtotranslatetheresultsofcellandanimalstudiestopharmacologictherapiesthatreducemortalityinhumans.Nevertheless,laboratory-basedinves-tigationshaveproducedvaluableinsightsintothemechanismsresponsibleforthepathogenesisandresolutionoflunginjury,andpreclinicalstudiespavedthewayforimportantimprovementsinsupportivecare.Twoofthesetherapies,lung-protectiveventila-tionandfluid-conservativemanagement,havereducedmortalityandmorbidity,respectively.ThisreviewofARDSwillfocusonsomeoftheseissues,includingnewinsightsintothemolecularmechanismsoflunginjuryandrepair.
Definitions,epidemiology,incidence,andmortalityCriteriaforthediagnosisofARDShaveevolved.Theoriginaldescriptionemphasizedrapidlyprogressiverespiratoryfailurefromnoncardiogenicpulmonaryedema,requiringmechanicalventilationbecauseofseverearterialhypoxemiaanddifficultybreathing(5).In1988,a4-pointscoringsystemprovidedaquan-titativeassessmentoflunginjuryseveritybasedonthedegreeofhypoxemia,thelevelofpositiveend-expiratorypressure(PEEP),staticrespiratorycompliance,andtheextentofradiographicinfiltrates(6),andthisscoringsystemhasbeenusefulforresearchandclinicaltrials.In1994,aconsensusconferencerecommendedsimplifiedcriteria:
arterialhypoxemiawithPaO2/FiO2ratiolessthan300mmHgandlessthan200mmHgtodefineALIandARDS,respectively,andbilateralradiographicopacitieswithoutevidenceofleftatrialhypertension(7).Thesecriteriahavebeenwidelyutilized,althoughsomeinvestigatorsbelievethatthedefi-nitionsshouldspecifythelevelofPEEPand/orthefractionofinspiredoxygen.Arecentreport—whatisnowcalledtheBerlindefinition—recommendsuseofthreecategoriesofARDS,based
onthedegreeofhypoxemia:
mild(200mmHg MostinvestigationshavefocusedonALIand/orARDSpatientswhoarealreadymechanicallyventilated.Recently,progresshasbeenmadeindiagnosingALIinspontaneouslybreathingpatientswhohavebilateralpulmonaryinfiltratesandarterialhypoxemiaandinwhomintravascularvolumeoverloadandcongestiveheartfailureareexcluded(9,10).Thisapproachfacilitatespatientidentificationandtestingofnewtherapiespriortotheneedformechanicalventilation.Figure1providesaclinicalvignettedescribingearlyrecognitionofALI. BacterialorviralpneumoniaisthemostcommoncauseofALIandARDS (1).Sepsisduetononpulmonaryinfections,aspira-tionofgastriccontents,andmajortraumawithshockalsocom-monlyprecipitatetheinjury.Lesscommonly,acutepancrea-titis,transfusions,drugreactions,andfungalandparasiticlunginfectionsarelinkedtoALIandARDS.Thecoexistenceoftwoormoreoftheseriskfactorscanenhancethelikelihoodofdevelop-ingALIorARDS (1). Aprospectiveepidemiologicstudyin1999–2000estimatedanannualincidenceofALIandARDSof190,000adultpatientsintheUnitedStates(11).ThereisasubstantialincidenceofALIandARDSinchildrenaswell(12,13).Datafrom2001–2008indicatethattheincidenceofALIand/orARDSinhospitalizedadultshasdeclined,perhapssecondarytomorewidespreaduseoflung-pro-tectiveventilation,reductionsinnosocomialinfections,andmoreconservativeuseofbloodproducts(14,15). Severearterialhypoxemia(PaO2/FiO2<100)andanincreaseinthepulmonarydeadspacefraction(>0.60)areassociatedwithhighermortality(16),asareshock,liverdysfunction,acutekid-neyinjury,ageover60years,andhigherseverityofillnessscores(17–19).BasedontheNIHHeart,LungandBloodInstitute(NHLBI)ARDSNetworktrials,60-daymortalityhasdeclinedfrom36%in1996–1997to26%in2004–2005(20).ThemostrecentARDSNetworkclinicaltrialsreporteda60-daymortality of22%inadultpatientsdespitehigherAPACHEIIIscoresanda Conflictofinterest: Theauthorshavedeclaredthatnoconflictofinterestexists. Citationforthisarticle: JClinInvest.2012;122(8): 2731–2740.doi: 10.1172/JCI60331. higherincidenceofshockatenrollmentcomparedwithapriortrialin2006(Figure2andref.4). Figure1 Chestradiographofapatientwithinfluenza-relatedpneumoniathatillustratesearlyALI,whichprogressedover48hourstomoreclassicALIthatrequiredpositive-pressureventilation.(A)Anterior-posteriorportablechestradiographofapreviouslyhealthy41-year-oldmanwhopresentedtotheemergencydepartmentwitha2-dayhistoryofmyalgiasandfever,aproductivecough,andshortnessofbreath.Chestauscultationrevealedralesandrhonchiposteriorlyinbothlungfields.Thechestradiographdemonstratespatchyinfiltratesintherightlowerlungfieldandalsointheleftlowerlungfield.(B)Anterior-posteriorchestradiograph48hoursafterthechestradiographinA,1hourafterendotrachealintubation(arrow)andinitiationofpositive-pressureventilationusingtheARDSNetworklung-protectiveventilationprotocol(97).Therewasmarkedprogressionofthebilateralradiographicinfiltrates,withdenseconsolidationintherightupper,rightlower,andleftlowerlungzones.Thepatient’shypoxemiasteadilyworsenedduringthe48hoursfollowinghisinitialpresentation,accompaniedbyanincreaseinrespiratoryrateto40breaths/minute.DiagnosticevaluationconfirmedH1N1influenzainfection.Allculturesforbacteriawerenegative.RecentclinicalinvestigationindicatesthatitispossibleinsomepatientstodiagnoseALIinanearlyphase(9),asshowninA,wellbeforetheprogressionofacuterespiratoryfailuretotheneedformechanicalventilation,asillustratedinB.EarlierdiagnosisofALIcouldfacilitatetestingoftherapeuticstrategiesthatmayhavetime-dependentefficacypriortothedevelopmentofestablishedALIthatrequiresintubationandmechanicalventilation. Environmentalandgeneticinfluences Environmentalandgeneticfactorsthatcontributetosusceptibil-ityandseverityofALIandARDShaveemergedasamajorresearchfocus.ChronicalcoholabuseincreasestheriskofALIandARDS (21)andmultipleorganfailureinsepticshock(22).Bothactiveandpassivecigarettesmokeexposure,asquantifiedbyplasmalev-elsofcotinine,havebeenindependentlyassociatedwiththedevel-opmentofALIaftersevereblunttrauma(23).Themechanismsmayincludeprimingeffectsofcigarettesmokeexposureonthelungendothelium,alveolarepithelium,orinflammatorycells. Variantsinmorethan25geneshavebeenassociatedwithdevel-opingALIand/orARDSandwithclinicaloutcomes(24)includingcommonvariantsofgenesthatregulateinflammation,coagula-tion,endothelialcellfunction,reactiveoxygenradicalgeneration,andapoptosis(25–29)—allprocessesthatareimportantinlunginjuryandrepair(2,30,31).Forexample,theFaspathwaymodu-latesapoptosis,inflammation,andepithelialcellinjury;inacan-didategenestudy,commongeneticvariantsinFaswereassociatedwithsusceptibilitytodevelopingclinicallunginjury(27).AfricanAmericanswithALIhaveahigherriskofdeathcomparedwithwhitepatients.AcandidategenestudyidentifiedafunctionalT-46Cpolymorphism(rs2814778)inthepromoterregionoftheDuffyantigen/receptorforchemokines(DARC)genethatwasassociatedwitha17%increasein60-daymortalityinAfrican-AmericanpatientsenrolledinARDSNetworkclinicaltrials.Plas-mainterleukin-8levelswereincreasedinthoseindividualswiththeDARCpolymorphism,supportingonemechanismcontribut-ingtoaworseclinicaloutcome(29). Geneticpolymorphismsthatpredisposeindividualsto
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