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CaringfortheCriticallyIllPatient | June2,2010
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AssociationBetweenArterialHyperoxiaFollowing
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ResuscitationFromCardiacArrestandInHospital GetPermissions GetAlerts
Mortality FREE SubmitaLetter Slideset(.ppt)
J.HopeKilgannon,MDAlanE.Jones,MDNathanI.Shapiro,MD,MPHMarkG.Angelos,MDBarryMilcarek, SupplementalContent
PhDKrystalHunter,MBAJosephE.Parrillo,MDStephenTrzeciak,MD,MPHfortheEmergencyMedicine
ShockResearchNetwork(EMShockNet)Investigators
11,742 251
[+]AuthorAffiliations Views Citations

JAMA.2010303(21):21652171.doi:10.1001/jama.2010.707. TextSize: A A A
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ABSTRACT|METHODS|RESULTS|COMMENT|CONCLUSIONS|ARTICLE
SeeAlso...
INFORMATION|REFERENCES
Editorial
Context Laboratoryinvestigationssuggestthatexposuretohyperoxiaafterresuscitationfromcardiac TitratingOxygenDuringandAfter
arrestmayworsenanoxicbraininjuryhowever,clinicaldataarelacking. CardiopulmonaryResuscitation
JAMA.2010303(21):21902191.
ObjectiveTotestthehypothesisthatpostresuscitationhyperoxiaisassociatedwithincreasedmortality.
doi:10.1001/jama.2010.715.
Design,Setting,andPatientsMulticentercohortstudyusingtheProjectIMPACTcriticalcare
databaseofintensivecareunits(ICUs)at120UShospitalsbetween2001and2005.Patientinclusion
ArticlesRelatedByTopic
criteriawereageolderthan17years,nontraumaticcardiacarrest,cardiopulmonaryresuscitationwithin24
hourspriortoICUarrival,andarterialbloodgasanalysisperformedwithin24hoursfollowingICUarrival.
FilterByTopic>
Patientsweredividedinto3groupsdefinedaprioribasedonPaO2onthefirstarterialbloodgasvalues
obtainedintheICU.HyperoxiawasdefinedasPaO2of300mmHgorgreaterhypoxia,PaO2oflessthan
SuccessfulResuscitationFromIn
60mmHg(orratioofPaO2tofractionofinspiredoxygen<300)andnormoxia,notclassifiedashyperoxia
HospitalCardiacArrestWhatHappens
orhypoxia.
Next?
MainOutcomeMeasureInhospitalmortality. JAMA.2015314(12):12381239.
doi:10.1001/jama.2015.11735.
ResultsOf6326patients,1156hadhyperoxia(18%),3999hadhypoxia(63%),and1171hadnormoxia
(19%).Thehyperoxiagrouphadsignificantlyhigherinhospitalmortality(732/1156[63%95%confidence RacialDifferencesinSurvivalAfterIn
interval{CI},60%66%])comparedwiththenormoxiagroup(532/1171[45%95%CI,43%48%] HospitalCardiacArrest
proportiondifference,18%[95%CI,14%22%])andthehypoxiagroup(2297/3999[57%95%CI, JAMA.2009302(11):11951201.
56%59%]proportiondifference,6%[95%CI,3%9%]).Inamodelcontrollingforpotentialconfounders doi:10.1001/jama.2009.1340.
(eg,age,preadmissionfunctionalstatus,comorbidconditions,vitalsigns,andotherphysiologicalindices), [+]ViewMore
hyperoxiaexposurehadanoddsratiofordeathof1.8(95%CI,1.52.2).

ConclusionAmongpatientsadmittedtotheICUfollowingresuscitationfromcardiacarrest,arterial RelatedCollections
hyperoxiawasindependentlyassociatedwithincreasedinhospitalmortalitycomparedwitheitherhypoxia
ornormoxia. CardiacArrest/Resuscitation
Cardiology
Suddencardiacarrestisthemostcommonlethalconsequenceofcardiovasculardisease.Evenifreturnof CriticalCare/IntensiveCareMedicine
spontaneouscirculation(ROSC)fromcardiacarrestisachieved,approximately60%ofpatientswillnot EmergencyMedicine
survivetohospitaldischarge. 1,2Thehighmortalityisattributedtothepostcardiacarrestsyndrome,which
involvesglobalischemiareperfusioninjury,myocardialstunning,andanoxicbraininjury. 3Therecent
PubMedArticles
4,5
successoftherapeutichypothermiaforpostROSCneuroprotection4,5hasincreasedmomentumfor
Conservativeoxygentherapyin
investigatingpostROSCfactorsthatcanimproveoutcomes.
mechanicallyventilatedpatientsfollowing
cardiacarrest:Aretrospectivenestedcohort
InthesearchformodifiablepostROSCfactors,theroleofsupplementaloxygen,whichisoften
study.Resuscitation2016101():10814.
administeredinhighconcentrationstopatientsaftercardiacarresthascomeintocontroversy. 6Thereisa
Hyperoxiatoxicityaftercardiacarrest:What
paradoxwithoxygenwhendeliveredtotheinjuredbrain.Toolittleoxygenmaypotentiateanoxicinjury.
istheevidence?AnnIntensiveCare
Toomuchoxygenmayincreaseoxygenfreeradicalproduction,possiblytriggeringcellularinjuryand
20166(1):23.
apoptosis. 7 Althoughnumerouslaboratoryinvestigationssupportthepotentiallydetrimentaleffectsof
hyperoxiaexposureafterROSCfromcardiacarrest,clinicaldataarelacking. ViewMore
Resultsprovidedby:
TheincidenceofpostROSChyperoxiaandsubsequentoutcomesinpatientswhosurvivedcardiacarrestto
intensivecareunit(ICU)admissionarereportedherein.Theoverallaimwastodeterminewhetherexposure
tohyperoxiaafterROSCfromcardiacarrestwasassociatedwithpoorclinicaloutcome.Specifically,for Jobs
patientswhosurvivedcardiacarresttoICUadmission,theobjectivesweretodetermine(1)whetherthe
EpidemiologyPhysicianLeadership
presenceofpostROSChyperoxia(definedasPaO2300mmHg)wasacommonoccurrence(2)whether
Positions
postROSChyperoxiawasassociatedwithlowersurvivaltohospitaldischargeand(3)whetherpostROSC
UTSouthwesternMedicalCenteratDallas
hyperoxiaremainedsignificantlyassociatedwithinhospitaldeathafteradjustmentforapredefinedsetof
DeptofInfectiousDisease
confoundingvariablesinamultivariableanalysis.
Dallas,TX

LargeMinnesotaOBGYNClinicSeeksBC/BE
METHODS OBGYNToJoinGrowingPractice(OB)CPH#
213672
ABSTRACT|METHODS|RESULTS|COMMENT|CONCLUSIONS|ARTICLE
Comphealth
INFORMATION|REFERENCES
MN

ProjectIMPACT(CernerCorporation,KansasCity,Missouri)isalargeadministrativedatabase(initially MoreListingsat
developedbytheSocietyofCriticalCareMedicine)designedforcriticalcareunitsacrossalldisciplines. JAMACareerCenter.com>
AdultICUsfrom131UShospitalsparticipateinProjectIMPACTanddatafrommorethan400000patients
havebeencollected.Participatinginstitutionsuploaddataquarterlytoacentralrepository.Datafields
includehospitalandICUorganizationalcharacteristics,admissionsource(eg,emergencydepartmentvs JAMAevidence.com
inpatient),demographics,physiologicaldata(includinghemodynamicindicesandlaboratoryvalues),
procedures,complications,hospitalandICUlengthofstay,andoutcomes.Alldataarecollectedby TheRationalClinicalExamination:Evidence
dedicatedonsitepersonnelwhomustbetrainedandcertifiedbyProjectIMPACT,whichrequirespassinga BasedClinicalDiagnosis
writtencertificationexaminationtoensureuniformityinbothdatabasedefinitionsandentry.Onsitedata QuickReference
collectorsreceiveadditionalcertificationfromProjectIMPACTasaprerequisitetocollatinganduploading
TheRationalClinicalExamination:Evidence
data.TheinstitutionalreviewboardatCooperUniversityHospital(Camden,NewJersey)approvedthis
BasedClinicalDiagnosis
study.
QuickReference

TheICUsinProjectIMPACTrepresentawidescopeofpracticeenvironments,includingmedical,surgical, Allresultsat
andmultidisciplinaryICUs.Theinstitutionsareheterogeneousintermsofhospitalsize,type(communityvs JAMAevidence.com>
academicprivatevspublic),andlocation(urban,suburban,orrural).Participatinghospitalsarenot
restrictedtoanyparticulargeographicregion.
Advertisement

AdultpatientswhosustainednontraumaticcardiacarrestandwereadmittedtotheICUataparticipating
centerbetween2001and2005wereincluded.Specifically,inclusioncriteriawereageolderthan17years,
nontraumaticcardiacarrest,cardiopulmonaryresuscitationwithin24hourspriortoICUarrival,and
arterialbloodgasanalysisperformedwithin24hoursfollowingICUarrival.

Thefollowingvariableswereabstracted:demographics,comorbidities,preadmissionfunctionalstatus,site
oforiginpriortoICUarrival,hospitalcharacteristics,mostabnormalphysiologicalparameters(including
vitalsigns,otherhemodynamicindices,andlaboratorytests)overthefirst24hoursintheICU,firstarterial
bloodgasresultoverthefirst24hoursintheICU,lifesupportinterventions(eg,vasopressoruse),vital
statusathospitaldischarge(aliveordead),andfunctionalstatusathospitaldischarge.TheProjectIMPACT
participationmanualspecifiesthatrace/ethnicitydatabeabstractedfromtheregistrationinformationatthe
timeofhospitaladmission.Race/ethnicitywasincludedasastudyvariablebecausepriordatahave
suggestedanassociationbetweennonwhiteraceandpooroutcome.Statisticalanalyseswereconducted
usingSPSSsoftwareversion15.0.1(SPSSInc,Chicago,Illinois).

Continuousdataarepresentedasmeansandstandarddeviationsormediansandinterquartileranges
(IQRs)asappropriatebasedondistributionofthedatacategoricaldataarereportedasproportionsand
95%confidenceintervals(CIs).Forthepurposesofthisanalysis,thecohortwasdividedinto3exposure
groupsdefinedaprioribasedonPaO2onthefirstarterialbloodgasvaluesobtainedintheICU.Hyperoxia
wasdefinedasPaO2of300mmHgorgreater8 hypoxia,PaO2oflessthan60mmHg(orratioofPaO2to
fractionofinspiredoxygen[FIO2]<300)9andnormoxia,casesnotclassifiedashyperoxiaorhypoxia.
Theseclassificationsweredefinedinawrittenprotocolbyconsensusofallauthorspriortoqueryingthe
databaseoranalyzinganydata.

Theprimaryoutcomemeasurewasinhospitalmortality.Theoccurrenceofoutcomeswerecompared
betweenthegroupsusingthe 2testorthebinomialtestforthedifferenceinproportionswithBonferroni
correctionformultiplepairwisecomparisons(ie,for3groups,levelof.05dividedby3or.017).Fordaysto
primaryoutcomeanalysis,KaplanMeiersurvivalestimatesandlogranktestswereusedtocomparethe
hyperoxiaandnormoxiagroups.

Oddsratios(ORs)werecalculatedtodetermineindependentpredictorsofmortality.Giventhedichotomous
outcome,multivariablelogisticregressionmodelingwasused.Theanalysisproceededin2stages.Inthe
firststage,significantriskfactorswereidentifiedfromthecandidatevariablesinthesecondstage,potential
hospitaleffectswereassessed(ie,correlationamongpatientssampledwithinhospitalclusters).Allpatient
orienteddatainTable1wereconsideredtobepotentialcandidatevariablesforthemodel.Theregression
modelwasrunin5stepswithinhospitalmortalityastheoutcome.Ateachstep,aPvalueoflessthan.05
wasusedasthecriterionforretentioninthemodel.

Table1.BaselineCharacteristicsoftheStudyPatients a

ViewLarge|SaveTable|DownloadSlide(.ppt)

Step1considereddemographics.Forentryintothemodel,agewascodedbydeciles.Step2includedpatient
characteristics(otherthandemographics)priortocardiacarrest.Preadmissionfunctionalstatuswascoded
asindependentornonindependent.SiteoforiginpriortoICUadmissionwasemergencydepartmentor
hospitalinpatient.Step3includedpreadmissioncomorbidconditions.Step4includedpatientphysiological
dataaftercardiacarrest.Hypotension(systolicbloodpressure<90mmHg)onICUadmissionandinotrope
requirementwerecodedasbinary(yesorno)variables.Forthehighestheartrate,eachpatientwascodedas
beingaboveorbelowthemedianfortheentirecohort.Inthefinalstepoftheregressionmodel,the
predictiveeffectsoninhospitalmortalitywereassessedforhyperoxiaandhypoxia.Thehyperoxiaand
hypoxiagroupswereeachcodedasacontrastvariableagainstnormoxia.Thefifthstepprovidesa
significancetest,OR,anda95%CIaroundtheORfortheprimarycovariateofinterest,whichwasexposure
tohyperoxia.Theresultssummarizetheeffectandareadjustedforallothervariablesincludedintheearlier
stepsofthemodel.

Generalizedestimatingequationswereusedtoaccountforpotentialcorrelationinmortalityratesamong
patientssampledwithinhospitalclusters.Threealternativestotheindependenceassumption(no
association)wereexaminedforwithinhospitalcorrelation.Thequasilikelihoodindependencecriterion
wasusedtodeterminethebestworkingcorrelationstructureassumption.First,anexchangeable(or
compoundsymmetry)patternwastested,assumingidentical(butunknown)correlationbetweenvariables
inthemodelandmortalityoverpatientsclusteredinhospitals.Next,anunstructuredpatternwastested,
assumingnonidenticalcorrelationbetweenvariablesinthemodelandmortalityoverpatientsclusteredin
hospitals.Lastly,anautoregressivepatternwastested,assumingdecreasingcorrelationbetweenthe
variablesinthemodelandmortalityoverpatientsclusteredinhospitals.Comparedwiththeindependence
assumption,noneofthesealternativecorrelationstructuresimprovedthemodelfit,suggestingthata
significanthospitaleffectwasnotpresentinthemodel.

Totestifhyperoxiaexposureremainedasignificantindependentpredictorofinhospitaldeathwhenthe
propensityofindividualstobeexposedtohyperoxiawasadjustedfor,asensitivityanalysiswasperformed
usingpropensityscores(themethodsofthepropensityscoreanalysisappearineMethods).Apreplanned
secondaryanalysisalsowasperformedthatwasidenticaltotheunivariableanalysisbutusedahigherPaO2
cutofftodefinehyperoxia(400mmHgratherthan300mmHg). 1113

Assumingaratioofapproximately3patientsinthehypoxiagroupforevery1patientinthenormoxiaand
hyperoxiagroups,thesamplesizethatwasanalyzedallowedgreaterthan80%powertodetectasignificant
differenceinproportionsbetweenthegroups(assuminganlevelof.017whenadjustedformultiple
comparisons).

RESULTS
ABSTRACT|METHODS|RESULTS|COMMENT|CONCLUSIONS|ARTICLE
INFORMATION|REFERENCES

Therewere8736patientsthatmetthefirst3inclusioncriteriaofageolderthan17years,nontraumatic
cardiacarrest,andcardiopulmonaryresuscitationpriortoICUarrival.Therewere2410patientswhodidnot
havearterialbloodgasvaluesobtainedwithinthefirst24hoursintheICUandwerethusexcludedfromthe
study.Theremaining6326patientswerefrom120hospitals.Themediannumberofcardiacarrestcasesper
hospitalwas41(IQR,1772).BaselinecharacteristicsforallgroupsappearinTable1andTable2.Patients
werepredominantlywhiteandfromcommunity,nonacademichospitals.Sixtysixpercent(n=4146)of
patientswerelivingindependentlypriortohospitaladmissionand43%(n=2747)wereadmittedtotheICU
fromanemergencydepartment.Themostcommoncomorbidconditionwasseverecardiovasculardisease
(eg,NewYorkHeartAssociationclassIVn=732patients).Ofthe6326patients,1156wereinthe
hyperoxiagroup(18%),3999wereinthehypoxiagroup(63%),and1171wereinthenormoxiagroup(19%).

Table2.BaselineCharacteristicsoftheStudyHospitals a

ViewLarge|SaveTable|DownloadSlide(.ppt)

Physiologicaldataoverthefirst24hoursintheICUforallgroupsaredisplayedinTable3.Sixtypercentof
patientsrequiredavasopressoragent(eg,continuousinfusionofdopamine,norepinephrine,epinephrine,
orphenylephrine)theoverallmean(SD)forlowestsystolicbloodpressurewas85(22)mmHg.Forall
patients,themean(SD)hightemperaturewas38C(3C)andforlowtemperaturewas36C(3C).The
medianICUlengthofstayforsurvivorstohospitaldischargewas4days(IQR,28days)andfor
nonsurvivorswas2days(IQR,15days).Themedianhospitallengthofstayforsurvivorswas12days(IQR,
722days)andfornonsurvivorswas4days(IQR,111days).

Table3.AbnormalVitalSignsintheFirst24HoursintheIntensiveCareUnitandInterventions

ViewLarge|SaveTable|DownloadSlide(.ppt)

Overall,56%ofpatients(n=3561)mettheprimaryoutcomeofinhospitalmortality(Table4).Mortality
washighestinthehyperoxiagroup(732/115663%[95%CI,60%66%])comparedwiththehypoxiagroup
(2297/399957%[95%CI,56%59%])andthenormoxiagroup(532/117145%[95%CI43%48%]).The
hyperoxiagrouphadsignificantlyhigherinhospitalmortalitycomparedwiththenormoxiagroup
(proportiondifference,18%[95%CI,14%22%]P<.001).Mortalityalsowassignificantlyhigherinthe
hyperoxiagroupcomparedwiththehypoxiagroup(proportiondifference,6%[95%CI,3%9%]P<.001).
OnKaplanMeieranalysis,thesurvivalfractionsforthehyperoxiaandnormoxiagroupsdiverged
significantlyovertime(logrankP<.001Figure).Inaddition,amonghospitalsurvivors,patientswith
hyperoxiahadasignificantlylowerproportionofdischargesfromthehospitalasfunctionallyindependent
comparedwithpatientswithnormoxia(29%vs38%,respectivelyproportiondifference,9%[95%CI,
3%15%]P=.002Table4).

Table4.OutcomesofStudyPatients

ViewLarge|SaveTable|DownloadSlide(.ppt)

Figure.InHospitalDeathBetweenHyperoxiaandNormoxia
 ViewLarge|SaveFigure|DownloadSlide(.ppt)

Nineriskfactorsprovedtobesignificantlyassociatedwithinhospitaldeathonmultivariablelogistic
regressionanalysis.Significantdemographicandotherfactorspriortocardiacarrestincludedage,
nonindependentpreadmissionfunctionalstatus,emergencydepartmentorigin,activechemotherapy,and
chronicrenalfailure.SignificantphysiologicalfactorsincludedhypotensiononICUarrival,tachycardia,
andhypoxia.Exposuretohyperoxiawasfoundtobeasignificantpredictorofinhospitaldeath(OR,1.8
[95%CI,1.52.2]Table5).Thisisanindependenteffectthatpersistsafteradjustingforallothersignificant
riskfactors.Inthesensitivityanalysisadjustingthemodelforpropensityscores,theORand95%CIsfor
hyperoxiaexposuredidnotchange(seeeResultsandeTable1).

Table5.MultipleLogisticRegressionModelWithInHospitalMortalityastheDependentVariablea

ViewLarge|SaveTable|DownloadSlide(.ppt)

InthesecondaryanalysisusingaPaO2of400mmHgorgreatertodefinethehyperoxiagroup,mortality
wasevengreaterinthehyperoxiagroup(377/54969%[95%CI,65%72%])comparedwiththehypoxia
group(2297/399957%[95%CI,56%59%])andthenormoxiagroup(887/177850%[95%CI,
48%52%]).Thehyperoxiagrouphadsignificantlyhigherinhospitalmortalitycomparedwiththe
normoxiagroup(proportiondifference,19%[95%CI,14%24%]P<.001).Mortalityalsowassignificantly
higherinthehyperoxiagroupcomparedwiththehypoxiagroup(proportiondifference,12%[95%CI,
8%16%]P<.001).

COMMENT
ABSTRACT|METHODS|RESULTS|COMMENT|CONCLUSIONS|ARTICLE
INFORMATION|REFERENCES

InthislargemulticentercohortstudyofpatientsadmittedtoanICUafterresuscitationfromcardiacarrest,
wefoundthatpostROSCexposuretohyperoxiawasacommonoccurrence,asevidencedbythefirstarterial
bloodgasvaluesobtainedafterICUarrival.Inthiscohort,postROSChyperoxiawasassociatedwiththe
lowestsurvivalratetohospitaldischargeamongallpatients,includingthosewhohadhypoxia.After
controllingforapredefinedsetofconfoundingvariablesinamultivariableanalysis,wefoundthatexposure
tohyperoxiawasanindependentpredictorofinhospitaldeath.Thiseffectremainedrobustinsensitivity
analysesthatadjustedforhospitalfactorsandpropensityofhyperoxiaexposure.Additionally,wefoundthat
amonghospitalsurvivors,hyperoxiawasassociatedwithalowerlikelihoodofindependentfunctional
statusathospitaldischargecomparedwithnormoxia.Toourknowledge,thisisthefirstlargemulticenter
studydocumentingtheassociationbetweenpostROSChyperoxiaandpoorclinicaloutcome.Whilewe
acknowledgethatassociationdoesnotnecessarilyimplycausation,thesedatasupportthehypothesisthat
highoxygendeliveryinthepostcardiacarrestsettingmayhaveadverseeffects.

Reperfusionafteranischemicinsultisassociatedwithasurgeofreactiveoxygenspecies,whichmay
overwhelmhostnaturalantioxidantdefenses. 1517 Theoxidativestressfromthereactiveoxygenspecies
formedafterreperfusionmayleadtoincreasedcellulardeathbydiminishingmitochondrialoxidative
metabolism,disruptingnormalenzymaticactivities,anddamagingmembranelipidsthroughperoxidation. 7
Inclinicallyrelevantexperimentalmodelsofcardiacarrest,hyperoxiahasbeenshowntoworsenthe
severityofoxidativestress,causingagreaterlossofpyruvatedehydrogenasecomplex, 18 impairmentof
oxidativeenergymetabolism, 11andhigheroxidationofbrainlipids, 19culminatinginmoreseverebrain
histopathologicchangesandworseneurologicaldeficits. 12,19,20Inaddition,recentpreclinicaldatasuggest
thatearlypostischemichyperoxicreperfusionmayworsenbraininjuryviacellularinflammatoryreactions
intheneuronsortheirmicroenvironment(eg,activationofmicrogliaandastrocytes). 21Aftertheburstof
reactiveoxygenspeciesthatoccursintheinitialminutesafterreperfusion,oxidantstresscanbeperpetuated
inapersistentlyhyperoxicenvironment.Analogoustotheconceptthathyperoxiaexposuremaybe
associatedwithharmintheresuscitationofneonates, 22theongoingoxidantstressassociatedwith
hyperoxicreperfusionmaybecapableofworseninganoxicbraininjuryinadultpatientswithpostcardiac
arrestsyndrome.

CurrentAmericanHeartAssociationguidelinesforadultcardiopulmonaryresuscitationadvocate100%
inspiredoxygenduringresuscitativeeffortsbecausethismaymaximizethelikelihoodofachievingROSC. 23
However,aftercirculationissuccessfullyrestored,cliniciansfrequentlymaintainhighFIO2forvariable
periods. 24Ourstudyquantifiestheincidenceofpostcardiacarresthyperoxia.Nearly1in5patientshad
exposuretohyperoxia(PaO2300mmHg)postcardiacarrestandalmosthalfofthesepatientshadPaO2of
400mmHgorgreater.Therefore,arterialhyperoxiaappearstobeacommonoccurrenceinpatients
resuscitatedfromcardiacarrest.Thesedataprovideinsightintoapotentiallargescaleproblemin
postcardiacarrestcare.

ArecentconsensusstatementonthetreatmentofpostcardiacarrestsyndromebytheInternationalLiaison
CommitteeonResuscitationadvocatedtheavoidanceofunnecessaryarterialhyperoxiaandacontrolled
reoxygenationstrategytargetinganarterialoxygensaturationnottoexceed94%to96%. 24However,the
consensusstatementacknowledgedthatthisrecommendationwasbasedsolelyonpreclinicaldataand
identifiedtheroleofpostROSCoxygenationasacriticalknowledgegapforresuscitationscience. 24The
presentstudyprovidesimportantdatatohelpfillthisknowledgegap.Althoughitmaybeintuitivethat
adequateoxygenationisvital(andpersistenthypoxiashouldbeavoided)afterresuscitationfromcardiac
arrest,thepresentstudyquestionswhetheramoreisbetterstrategyforpostROSCoxygenationisactually
harmfulasopposedtobeneficial.Infact,thesedatasupportthehypothesisthatbothhyperoxiaandhypoxia
areharmfulandunderscoretheneedforclinicaltrialsofcontrolledreoxygenationinadultsresuscitated
fromcardiacarrest.

Weacknowledgeimportantlimitationsinthisstudy.First,thiswasapurelyobservationalstudytherefore,
wecanonlyidentifyassociationratherthancausation.Next,wedefinedhyperoxiaasPaO2of300mmHg
orgreaterbasedonPaO2levelsfromapreviouslypublishedexperimentalstudy, 8 buttheprecisePaO2level
associatedwithmaximalriskisunknown.Inaddition,ourdefinitionforthehypoxiagroupwasnotbased
onPaO2alonebutratherincludedtheratioofPaO2toFIO2asacomponentofthedefinition.Thiswas
necessarybecauseapatientwithnormalPaO2mayhaverequiredahighFIO2toachievetheobservedPaO2
value(ie,PaO2of65mmHgonaFIO2of1.0),andsuchapatientwouldbeathighriskofdeath,similarto
patientswithaPaO2oflessthan60mmHg.AlthoughourexposurevariableisbasedonthefirstPaO2value
measuredoverthefirst24hoursafterarrivalintheICU,thearterialbloodgasdatainProjectIMPACTare
notpreciselytimestamped.Thus,itispossiblethatsomeofthePaO2measurementswerenotobtainedearly
duringthepostresuscitationperiodspecifically,wedidnotcaptureintraarrestarterialbloodgasdata.
Laboratorydataindicatethatearlyexposuretohyperoxiaafterreperfusionworsensischemiareperfusion
injuryhowever,hyperoxiaexposureatlatertimepointsmaynot. 25Inthiscontext,thelimitationofthis
studythatlaterPaO2measurementsmaybeincludedinoursamplewouldbeexpectedtobiastheresults
towardthenull(ie,noassociationbetweenhyperoxiaexposureandincreasedmortality).

WealsorecognizethattheProjectIMPACTdatabasewasdesignedfromanICUperspective,andthusitdoes
notcapturevariablesintheUtsteinstyle26(eg,initialcardiacrhythm,noflowtime,cardiopulmonary
resuscitationquality)specifictothecardiacarresteventthatprecededtheadmissiontotheICU.However,
theICUperspectivemakesProjectIMPACTavaluablesourceofinformationonthistopicbecause
cardiopulmonaryresuscitationregistriesmaynotcollectPaO2dataafterROSC.Anotherlimitationworthyof
noteisthatourstudydidnotcapturewhetherornottherapeutichypothermiawasattempted.However,only
6%ofpatientshadalowestbodytemperatureunder34Cinthefirst24hoursafterarrivalintheICU,
indicatingthattherapeutichypothermiawasnotwidelyappliedinthiscohort.Althoughthepostulated
scientificbasisfortheassociationbetweenhyperoxiaexposureandoutcomeisrelatedtothedegreeof
anoxicbraininjury,wealsoacknowledgethathyperoxiacouldpotentiallybeassociatedwithextracerebral
deleteriousconsequencesthatwerenotascertainedinourstudy.Inaddition,ProjectIMPACTdoesnot
captureairwaypressuremeasurementsfromtheventilatorsthatcouldbeasurrogateforbarotrauma(such
aspeakorplateauairwaypressureorpositiveendexpiratorypressure).Finally,theremayhavebeen
unmeasuredconfoundersthatmayhaveinfluencedtheassociationbetweenoxygenationstatusand
mortality.

CONCLUSIONS
ABSTRACT|METHODS|RESULTS|COMMENT|CONCLUSIONS|ARTICLE
INFORMATION|REFERENCES

InthislargemulticentercohortofadultpatientsadmittedtotheICUafterresuscitationfromcardiacarrest,
wefoundthatexposuretohyperoxiaisacommonoccurrenceandanindependentpredictorofinhospital
mortality.Thesedatasupportthehypothesisthatpostresuscitationhyperoxiacouldbeharmfulandprovide
scientificrationaleforclinicaltrialsofcontrolledreoxygenationduringthepostresuscitationperiod.

ARTICLEINFORMATION
ABSTRACT|METHODS|RESULTS|COMMENT|CONCLUSIONS|ARTICLE
INFORMATION|REFERENCES

CorrespondingAuthor:StephenTrzeciak,MD,MPH,CooperUniversityHospital,OneCooperPlaza,
D363,Camden,NJ08103(trzeciakstephen@cooperhealth.edu).

AuthorContributions:DrsKilgannonandTrzeciakhadfullaccesstoallofthedatainthestudyand
takeresponsibilityfortheintegrityofthedataandtheaccuracyofthedataanalysis.

Studyconceptanddesign:Kilgannon,Jones,Shapiro,Angelos,Parrillo,Trzeciak.

Acquisitionofdata:Trzeciak.

Analysisandinterpretationofdata:Kilgannon,Jones,Shapiro,Milcarek,Hunter,Parrillo,Trzeciak.

Draftingofthemanuscript:Kilgannon,Trzeciak.
Criticalrevisionofthemanuscriptforimportantintellectualcontent:Kilgannon,Jones,Shapiro,
Angelos,Milcarek,Hunter,Parrillo,Trzeciak.

Statisticalanalysis:Kilgannon,Jones,Shapiro,Milcarek,Hunter,Trzeciak.

Obtainedfunding:Parrillo.

Administrative,technical,ormaterialsupport:Parrillo.

Studysupervision:Parrillo,Trzeciak.

FinancialDisclosures:DrTrzeciakreportedthathereceivesmaterialsupportforresearchfromIkaria
andservesasaconsultanttoSpectralDiagnostics,buthereceivesnopersonalremunerationfromany
commercialinterest.Noneoftheotherauthorsreportedfinancialdisclosures.

Funding/Support:DrKilgannonwassupportedbyacareerdevelopmentgrantfromtheEmergency
MedicineFoundation.DrJoneswassupportedbygrantGM76652fromtheNationalInstitutesofHealth
andtheNationalInstituteofGeneralMedicalSciences.DrShapirowassupportedinpartbygrant
HL091757fromtheNationalInstitutesofHealthandtheNationalHeart,Lung,andBloodInstituteand
grantGM076659fromtheNationalInstituteofGeneralMedicalSciences.DrTrzeciakwassupportedby
grantGM83211fromtheNationalInstitutesofHealthandtheNationalInstituteofGeneralMedical
Sciences.

RoleoftheSponsor:Thesponsorshadnoroleinthedesignandconductofthestudycollection,
management,analysis,andinterpretationofthedataandpreparation,review,orapprovalofthe
manuscript.

REFERENCES
ABSTRACT|METHODS|RESULTS|COMMENT|CONCLUSIONS|ARTICLE
INFORMATION|REFERENCES

1 PeberdyMA,KayeW,OrnatoJP,etal.Cardiopulmonaryresuscitationofadultsinthehospital:
areportof14,720cardiacarrestsfromtheNationalRegistryofCardiopulmonary
Resuscitation.Resuscitation.200358(3):297308
PubMed|LinktoArticle

2 StiellIG,WellsGA,FieldB,etalOntarioPrehospitalAdvancedLifeSupportStudy
Group.Advancedcardiaclifesupportinoutofhospitalcardiacarrest.NEnglJ
Med.2004351(7):647656
PubMed|LinktoArticle

3 NegovskyVA.Thesecondstepinresuscitationthetreatmentofthepostresuscitation
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