The acute respiratory distress syndrome.docx

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