1/1/2015 www.medscape.

com/viewarticle/836268_print

www.medscape.com

IsEpinephrineDuringCardiacArrestAssociated
WithWorseOutcomesinResuscitatedPatients?
FlorenceDumas,MD,PHD,WulfranBougouin,MD,MPH,GuillaumeGeri,MD,MSC,Lionel
Lamhaut,MD,AdrienBougle,MD,FabriceDaviaud,MD,TristanMorichauBeauchant,MD,JulienRosencher,MD,Eloi
Marijon,MD,PHD,PierreCarli,MD,PHD,XavierJouven,MD,PHD,ThomasD.Rea,MD,MPH,AlainCariou,MD,PHD
JAmCollCardiol.201464(22):23602367.

AbstractandIntroduction
Abstract

BackgroundAlthoughepinephrineisessentialforsuccessfulreturnofspontaneouscirculation(ROSC),theinfluence
ofthisdrugonrecoveryduringthepostcardiacarrestphaseisdebatable.

ObjectivesThisstudysoughttoinvestigatetherelationshipbetweenprehospitaluseofepinephrineandfunctional
survivalamongpatientswithoutofhospitalcardiacarrest(OHCA)whoachievedsuccessfulROSC.

MethodsWeincludedallpatientswithOHCAwhoachievedsuccessfulROSCadmittedtoacardiacarrestcenter
fromJanuary2000toAugust2012.Useofepinephrinewascodedasyes/noandbydose(none,1mg,2to5mg,>5
mg).AfavorabledischargeoutcomewascodedusingaCerebralPerformanceCategory1or2.Analyses
incorporatedmultivariablelogisticregression,propensityscoring,andmatchingmethods.

ResultsOfthe1,556eligiblepatients,1,134(73%)receivedepinephrine194(17%)ofthesepatientshadagood
outcomeversus255of422patients(63%)inthenontreatedgroup(p<0.001).Thisadverseassociationof
epinephrinewasobservedregardlessoflengthofresuscitationorinhospitalinterventionsperformed.Comparedwith
patientswhodidnotreceiveepinephrine,theadjustedoddsratioofintactsurvivalwas0.48(95%confidenceinterval
[CI]:0.27to0.84)for1mgofepinephrine,0.30(95%CI:0.20to0.47)for2to5mgofepinephrine,and0.23(95%CI:
0.14to0.37)for>5mgofepinephrine.Delayedadministrationofepinephrinewasassociatedwithworseoutcome.

ConclusionsInthislargecohortofpatientswhoachievedROSC,prehospitaluseofepinephrinewasconsistently
associatedwithalowerchanceofsurvival,anassociationthatshowedadoseeffectandpersisteddespitepost
resuscitationinterventions.Thesefindingssuggestthatadditionalstudiestodetermineifandhowepinephrinemay
providelongtermfunctionalsurvivalbenefitareneeded.

Introduction

Internationalresuscitationguidelinesrecommendadministeringepinephrineevery3to5minduringcardiacarrest
resuscitationregardlessoftheinitialrhythm. [1]Thealphaadrenergiceffectsofepinephrinecanincreasecoronaryand
cerebralperfusionpressureduringtheresuscitationperiod[2,3]andsubsequentlyhelpachievereturnofspontaneous
circulation(ROSC).However,epinephrinemayexertadverseeffectsduringthepostresuscitationphaseand
contributetomyocardialdysfunction,increasedoxygenrequirements,andmicrocirculatoryabnormalities. [48]

AlthoughepinephrinecanincreasethelikelihoodofachievingROSC,thebalanceoftheeffectsofepinephrineon
longtermsurvivalremainsuncertain.Arandomizedstudyfoundnooverallsurvivaleffectofmedicationtreatmentsthat
includedepinephrine. [9]Inalargeobservationalstudy,epinephrinewasassociatedwithalowerlikelihoodoflongterm
survival. [10]Ineachofthesestudies,epinephrinewasassociatedwithagreaterlikelihoodofROSC,buttheearly
potentialbenefitdidnottranslateintoagreaterlikelihoodoflongtermsurvivalbecauseoutcomesamongthe
epinephrinetreatedpatientswereworseduringthepostresuscitationphase.

Wesoughttobetterunderstandthepotentialadverseeffectsofepinephrinewhenusedduringthepostresuscitation
phase.Weevaluatedtherelationshipbetweenuseofepinephrineduringresuscitationandsurvivalamongacohortof
http://www.medscape.com/viewarticle/836268_print 1/13
1/1/2015 www.medscape.com/viewarticle/836268_print

patientsresuscitatedfromoutofhospitalcardiacarrest(OHCA)andadmittedtothehospitalwithROSC.Wealso
evaluatedwhetherevidencebasedpostresuscitationinterventions,suchascoronaryreperfusionorhypothermia,may
influencethisepinephrinesurvivalrelationship.

Methods
StudyDesign,Patients,andSetting

WeperformedacohortinvestigationofallpatientswhoexperiencednontraumaticOHCA,achievedROSC,andwere
subsequentlyadmittedtoalargeParisiancardiacarrestreceivinghospitalfromJanuary2000toAugust2012.The
appropriateinstitutionalreviewboardapprovedthestudy.

ManagementofOHCAinvolvesmobileemergencyunitsandfiredepartmentsthatprovidebasicandadvancedcardiac
lifesupport(ACLS).Insuspectedcasesofcardiacarrest,theclosestemergencyunitisdispatchedtothescene.
Outofhospitalresuscitationisperformedbyanemergencyteam,whichincludesatleast1emergencyphysician
trainedaccordingtointernationalguidelines. [1]Whenused,epinephrineisadministeredpromptlyatthebeginningof
ACLSorlaterifrequired.Patientsinwhomtheresuscitationprocessfailsarenottransportedtothehospital.Most
patientswhoachieveROSCarebroughttothecardiacarrestreceivinghospitalandadmittedtotheintensivecare
unit,wheretheyaretreatedaccordingtostandardresuscitativeguidelinesincludingcoronaryangiographyandmild
therapeutichypothermia.Proceduresofpostcardiacarrestcarehavebeendescribedpreviously. [11]Earlycoronary
reperfusionandtargetedtemperaturemanagementarethemostimportantcomponentsoftheseprocedures.

DataCollection

ThestudyhospitalmaintainsanongoingregistryofallpatientswithOHCAwhoareadmittedwithROSC.Information
isprospectivelycollectedaccordingtoUtsteinrecommendations. [12]Theregistryincludescharacteristicssuchas
age,sex,cardiovascularriskfactors(hypertension,diabetesmellitus,andcurrentsmoking),locationofcardiac
arrest,witnessedstatus,bystandercardiopulmonaryresuscitation(CPR),andinitialcardiacrhythmasrecordedby
theautomateddefibrillator(ventricularfibrillation[VF]/ventriculartachycardia[VT]orpulselesselectrical
activity/asystole).Theemergencymedicalservicerecordisusedtodeterminethetimeintervalbetweenthe
emergencycallandsuccessfulROSCaswellasuseofepinephrine,thetimingofthefirstadministrationaftercardiac
arrest,andthetotaldose.Hospitaldataduringthepostresuscitationphaseincludeinitiallaboratoryvalues,suchas
bloodlactatelevels(mmol/l),andprocedures,suchastherapeutichypothermia,coronaryangiography,and
percutaneouscoronaryintervention(PCI).

Postresuscitationshockwasdefinedastheoccurrenceorpersistenceofarterialhypotension(meanarterial
pressure<60mmHgorsystolicbloodpressure<90mmHg)sustainedformorethan6hafterROSCdespite
adequatefluidresuscitationandcontinuousvasopressorinfusion. [13]Thedefinitiveetiologyofthecardiacarrestwas
confirmedathospitaldischarge,consideringallavailabledataobtainedduringhospitalstay.Acutecoronary
syndromesand/orprimaryventriculararrhythmiawereconsideredcardiacetiology.Allothercauseswereconsidered
tobeextracardiaccauses.Theprimaryoutcomewasfavorableneurologicaloutcomeatdischarge,definedasa
CerebralPerformanceCategory(CPC)of1or2.

StatisticalAnalysis

CategoricalvariablesweresummarizedwithproportionsandcomparedusingPearsonchisquaretestorFisherexact
test.Continuousvariablesweredescribedwithmedians(andquartiles)ormeansandcomparedusingStudentttest
orthenonparametricWilcoxontest.Useofepinephrinewasclassifiedbothdichotomously(anyepinephrinevs.no
epinephrine)andasadosevariabledividedinto4categories:none,1mg,2to5mg,and>5mg.

Weusedmultivariablelogisticregressiontoevaluatetheassociationbetweenepinephrineandfavorableneurological
survivalwhileadjustingforpotentialconfounders.Wealsosetupapropensitymodeltoevaluatetherelationship
betweenepinephrineandoutcome.Thepropensityofreceivingepinephrinewasdeterminedusingpretreatment
http://www.medscape.com/viewarticle/836268_print 2/13
1/1/2015 www.medscape.com/viewarticle/836268_print

characteristics.Inanefforttocontrolforconfounding,wealsouseddifferentmethods [14,15]thatincludedalogistic
regressionmodeladjustedforthepropensityscore,2conditionallogisticregressionanalysesaftermatchingonthe
propensityscoreina1:1manner,stratificationonquintilesofpropensityscore,andaninverseprobabilityof
treatmentweightedlogisticregressionmodel.Here,weperformedanadditionalanalysisbasedon1,000bootstrap
samplesdrawnwithreplacementfromthestudypopulation.Atthisstep,allmodelswereadjustedonhospital
potentialconfounders:PCI,therapeutichypothermia,bloodlactatelevel,andoccurrenceofpostcardiacarrest
shock.

Weassessedfordifferencesintheepinephrineoutcomeassociationamongsubgroupsbyincludinganinteraction
(crossproduct)termbetweentheuseofepinephrineandthecovariateofinterest(initialrhythm,intervals,post
cardiacarrestshock,etiology,coronaryangiography,andtherapeutichypothermia).Becausetheperiodofstudywas
morethanadecade,weperformedanancillaryanalysisontheperiodofinclusion,especiallybeforeandafter2005,
theyearofremovedandnewguidelinesconcerningprehospitalcare. [16]Finally,anancillaryanalysiswasperformed
focusingontheintervalsbetweencardiacarrestandACLS(firstadministrationofepinephrine).

Alltestswere2sided.Apvalue0.05wasconsideredstatisticallysignificant.Allanalyseswereperformedusing
Stata11.2/SEsoftware(CollegeStation,Texas).

Results
Duringthestudyperiod,1,646patientsachievedROSCandwereadmittedtothehospital.Ofthese,90(5.5%)had
missingepinephrinestatusandwereexcludedfromtheanalysis.

Onaverage,thecohortwas6016yearsofage,71%(1,112of1,556)weremale,and54%(845of1,556)presented
withaninitialshockablerhythm.Coronaryangiographywasperformedin63%(961of1,534)andPCIin44%(423of
961).Approximately70%ofpatients(1,083of1,556)underwenttherapeutichypothermia.

NearlythreefourthsofpatientsreceivedepinephrineaspartofOHCAresuscitation().Patientcharacteristicsdiffered
accordingtoepinephrinestatus.Thosereceivingepinephrinehadlessfavorableprognosticcharacteristicsfor
example,theywereolder(p=0.02),lesslikelytohaveawitnessedevent(p=0.006),werelesslikelytopresentwith
ashockablerhythm(p<0.001),andhadalongerdurationofresuscitation(p<0.001).

Table1.BaselineCharacteristicsAccordingtoUseofEpinephrine

TreatmentWithEpinephrine(n= TreatmentWithoutEpinephrine(n p

1,134) =422) Value

Age,yrs 60.3(16) 58.3(16) 0.02

Male 797(70) 315(75) 0.09

Hypertension 408(40) 124(32) 0.003

Diabetesmellitus 185(18) 47(12) 0.004

Smoking 380(43) 163(45) 0.35

Witnessedstatus 945(87) 371(92) 0.006

BystanderCPR 480(43) 201(49) 0.05

Publiclocation 306(27) 185(44) <0.001

Initialshockablerhythm 554(49) 291(69) <0.001

Resuscitationlength<20
373(38) 299(80) <0.001
http://www.medscape.com/viewarticle/836268_print 3/13
1/1/2015 www.medscape.com/viewarticle/836268_print

min*

PCI 277(24) 146(35) <0.001

Hypothermia 765(67) 318(75) 0.003

Bloodlactate>5.2mmol/l
652(63) 94(23) <0.001
1*

Postcardiacarrestshock 750(66) 191(45) <0.001

Valuesaren(%).*Summarizedwithitsmedian.

CPR=cardiopulmonaryresuscitationPCI=percutaneouscoronaryintervention.

Ofthe1,556patientsincludedinthisstudy,482(31%)hadoverallsurvivaltohospitaldischargeand449(29%)had
survivalwithgoodneurologicaloutcome.Survivalwithgoodneurologicaloutcome(CPC1or2)waslesslikelyamong
thosewhoreceivedepinephrinecomparedwiththosewhodidnotreceiveepinephrine(194of1,134[17%]vs.255of
422[60%],respectivelyp<0.001)(Figure1).

Figure1.

PatientFlow

PatientoutcomesarepresentedaccordingtotreatmentwithorwithoutEPIduringresuscitation.EPI=epinephrine.

Afteradjustingforthedifferentconfounders,useofepinephrinewasnegativelyassociatedwithfavorableneurological
http://www.medscape.com/viewarticle/836268_print 4/13
1/1/2015 www.medscape.com/viewarticle/836268_print

outcome(adjustedoddsratio[aOR]:0.3295%confidenceinterval[CI]:0.22to0.47),evenafteradjustingforhospital
interventions.Furthermore,thehospitalpredictivefactorsforgoodoutcomewerePCI(aOR:0.8895%CI:1.34to
2.65),bloodlactatelevel>5.2mmol/l1(aOR:0.4195%CI:0.29to0.58),andtheoccurrenceofpostcardiacarrest
shock(aOR:0.6695%CI:0.48to0.92).Therapeutichypothermiawassignificantlyassociatedwithgoodoutcome
onlyafterrestrictinganalysestopatientswithVF/VT(aOR:1.6995%CI:1.04to2.75)(OnlineTable1
http://content.onlinejacc.org/data/Journals/JAC/931793/09036_mmc1.docx?v=635526387090300000).

Thelogisticmodelusedtoestimatethepropensityscoreforreceivingepinephrineusingallavailablecovariates
yieldedaCstatisticof0.80.Fromthepropensityscore,228pairsoftreatedandnontreatedpatientswerematched,
andtheinterventiongroupwassimilarwithregardtocovariatescomparedwiththenontreatedgroup(OnlineTables2
and3http://content.onlinejacc.org/data/Journals/JAC/931793/09036_mmc1.docx?v=635526387090300000).Inthis
matchedanalysis,68of228patients(30%)inthetreatedgrouphadagoodoutcomewhereas138of228patients
(61%)inthenontreatedgroupweredischargedwithCPC1or2(p<0.001).Thenegativeassociationbetweenthe
useofepinephrineandoutcomepersistedafterstratifyingonquintilesofpropensityscoreandafteruseofweighted
models().Similarly,useofepinephrinewasassociatedwithloweroddsofsurvivalbeforeandafterthechangein
guidelinesin2005.

Table2.MultivariateModelsTestingtheAssociationBetweenUseofEpinephrineandGoodNeurologicalOutcome

OddsRatio 95%ConfidenceInterval pValue

Crudeassociation 0.14 0.100.17 <0.001

Standardlogisticregression* 0.32 0.220.47 <0.001

AdjustmentonPS 0.35 0.240.50 <0.001

CrossmatchingPS 0.33 0.190.58 <0.001

ProbabilityofPS

0.20.4 0.44 0.171.12 0.09

0.40.6 0.29 0.150.57 <0.001

0.60.8 0.30 0.150.62 0.001

0.81 0.31 0.160.60 0.001

IPTWPS 0.18 0.130.27 <0.001

SMRPS 0.18 0.130.26 <0.001

Yearofinclusion

Beforeorin2005 0.38 0.210.70 0.002

After2005 0.29 0.180.47 <0.001

*Adjustedaccordingtobaselinecharacteristics(age,sex,hypertension,diabetesmellitus,smoking,witnessed
status,bystanderCPR,lengthofresuscitation)andhospitalcovariates(i.e.,PCI,hypothermia,postcardiacarrest
shock,bloodlactatelevel).Adjustedonpropensityscoreandhospitalcovariates.Adjustedonhospitalcovariates.

AbbreviationsasinTable1.IPTW=inverseprobabilityoftreatmentweightingPS=propensityscoreSMR=
standardmortalityratio.

Whenfocusingonthetimeintervalsbetweencollapseandfirstuseofepinephrine,weobservedthatACLSdelays
weresimilarinpatientstreatedwithorwithoutepinephrine(13.610.1minvs.13.69.8minp=0.98)andthatthe

http://www.medscape.com/viewarticle/836268_print 5/13
1/1/2015 www.medscape.com/viewarticle/836268_print

delayforfirstadministrationoftreatment,ifappropriate,was16.110.6minaftercollapse.Althoughlongerintervals
forACLSwereassociatedwithworseoutcome,theinfluenceofepinephrineremainedadversewhateverthedelay
(OnlineFigure1http://content.onlinejacc.org/data/Journals/JAC/931793/09036_mmc1.docx?v=635526387090300000)
(pforinteraction=NS).

Moreover,thedelaybetweencardiacarrestandfirstdoseofepinephrinewaslinearlyrelatedtoabadoutcome.
Patientsinwhomepinephrinewasgivenwithinthefirst9minaftercardiacarresthadabetteroutcome(aOR:0.54
95%CI:0.32to0.91)comparedwiththosewhoreceivedtreatmentbetween10and15min(aOR:0.3395%CI:0.20
to0.56),between16and22min(aOR:0.2395%CI:0.12to0.43),and>22minaftercardiacarrest(aOR:0.1795%
CI:0.09to0.34)(OnlineFigure2http://content.onlinejacc.org/data/Journals/JAC/931793/09036_mmc1.docx?
v=635526387090300000).

Theadverseassociationbetweenuseofepinephrineandsurvivalwasevidentacrosssubgroupsdefinedbyinitial
rhythm,lengthofresuscitationandpostresuscitationcare(includinghypothermiaandPCIstatus),andthepresence
orabsenceofpostresuscitationshock(Figure2).Forexample,theaORforuseofepinephrineandneurologically
intactsurvivalwas0.31(95%CI:0.20to0.48)amongthosewhounderwenttherapeutichypothermiaand0.37(95%
CI:0.15to0.92)amongthosewhodidnotundergotherapeutichypothermia.Inaddition,weobservedastepwise
doseassociationwithdecreasingoddsofsurvivalwithCPC1or2associatedwithanincreasingdoseofepinephrine.
Overall,comparedwithpatientswhodidnotreceiveepinephrineduringresuscitation,theaORofintactsurvivalvaried
bydoseofepinephrine:0.48(95%CI:0.27to0.84)for1mg,0.30(95%CI:0.20to0.47)for2to5mg,and0.23
(95%CI:0.14to0.37)for>5mg(Figure3).Asimilardoserelationshipwasobservedacrosstheapriorisubgroups
(OnlineFigures3Ato3Chttp://content.onlinejacc.org/data/Journals/JAC/931793/09036_mmc1.docx?
v=635526387090300000).

http://www.medscape.com/viewarticle/836268_print 6/13
1/1/2015 www.medscape.com/viewarticle/836268_print

Figure2.

NeurologicalOutcomeinTreatedandNontreatedPatientsAccordingtoSubgroups

TheadverseassociationbetweenuseofEPIandsurvivalwasevidentaccordingto(A)initialrhythm,(B)lengthof
resuscitation,(C)performanceofhypothermia,and(D)performanceofPCI.CI=confidenceintervalEPI=
epinephrinePCI=percutaneouscoronaryintervention.

http://www.medscape.com/viewarticle/836268_print 7/13
1/1/2015 www.medscape.com/viewarticle/836268_print

Figure3.

AssociationBetweenOutcomeandEarlyDoseofEPIandAccordingtotheInitialRhythm

Theoddsratioswereadjustedaccordingtobaselinecharacteristics(age,sex,hypertension,diabetesmellitus,
smoking,witnessedstatus,bystandercardiopulmonaryresuscitation,lengthofresuscitation),andhospitalcovariates
(PCI,hypothermia,postcardiacarrestshock,bloodlactatelevel).AbbreviationsasinFigure1and2.

Discussion
Inthislargecohort,useofepinephrineduringresuscitationofOHCAwasassociatedwithaworseneurological
outcomeduringthepostresuscitationperiodafteradjustmentforconfoundingfactors.Thisrelationshipwasrobustto
avarietyofdifferentmethodologicalapproachesdesignedtolimitconfounding.Theadverseassociationofepinephrine
wasnotmodifiedbypostresuscitationinterventionssuchasPCIortherapeutichypothermia.Importantly,thetiming
offirstadministrationandepinephrinedoseresponsebecamecriticalintermsofthepotentialbenefitofthisdrug
(CentralIllustration).

http://www.medscape.com/viewarticle/836268_print 8/13
1/1/2015 www.medscape.com/viewarticle/836268_print

CentralIllustration.

NeurologicalOutcomesofResuscitatedPatients

Administrationofepinephrineduringcardiacarrestisassociatedwithworseneurologicaloutcomesinresuscitated
patients.Thiseffectisconsistentinallsubgroupsofpatientsandincreasedwiththecumulateddosageanddelayof
thefirstadministration(associationbetweenepinephrineandworseneurologicaloutcomeatdischarge,expressedas
oddsratioswith95%confidenceintervals,adjustedonconfounders).

Evenifitisimpossibletocircumventinmanycases,useofepinephrinewasindependentlyassociatedwitha
decreasedlikelihoodofneurologicallyintactsurvivalamongpatientswhosuccessfullyachievedROSC.Although
epinephrineisknowntoincreaseROSCafterarrest, [17,18]itseffectsduringthepostresuscitationphaseonlater
outcomearenotclear,withpotentialforrelativeharm. [9,10,19]Thebenefitofthisdrugwhenusedduringthe
resuscitationperiodreliesontheimpliedvasostress,whichinturnmayalsopromotesecondarydetrimentaleffects
duringthepostcardiacarrestphase,combiningmyocardialdysfunction,ischemiareperfusion,andpostanoxic
injury. [20]Severalanimalstudiessupportthesemechanisms. [6,8,21,22]Furthermore,useofepinephrinewas
http://www.medscape.com/viewarticle/836268_print 9/13
1/1/2015 www.medscape.com/viewarticle/836268_print

associatedwithpostresuscitationshockandincreasedbloodlactatelevels.Previousclinicalstudies(both
randomizedandobservational)suggestedthatepinephrinemightworsensurvivalathospitaldischargeandlater
outcome. [9,10,19,2325]Thesestudiesconverged,suggestingapotentialriskofuseofepinephrine,especiallyin
VF/VTgroupshowever,theinvestigationswerenotstatisticallydefinitiveordidnotfocusontheroleofpost
resuscitationcare.

Onehypothesisisthatthepotentialadversepostresuscitationeffectsofepinephrinecouldbeattenuatedbyin
hospitalinterventionssuchasPCIorhypothermiatheserelationshipshavenotbeenfullyinvestigated. [23]By
focusingonpatientswithsuccessfulROSCandbyintegratingpostcardiacarrestcareintoouranalysis,we
assessedthespecificinfluenceofthedrugonthepostcardiacarrestperiodandconfirmedthatthisperiodisthe
timeframeduringwhichepinephrinemayrevealadverseeffects.Importantly,weobservedanegativeassociationof
epinephrineacrossallsubgroups,eveninpatientstreatedwithhospitalinterventionssuchasPCIandhypothermia.

Itcouldbecontendedthatepinephrineshouldbeconsideredasurrogatemarkerofseverityratherthanan
independentpredictivefactor,complicatingthecurrentdebateonthebenefitofthisagent. [26]However,this
relationshiphasbeenalreadydescribedwhenlookingatobservationaldataandthefewrandomizedstudiesthatwere
recentlyperformed. [5,27]Wemademultiplemethodologicalefforts(usingpropensityscore,crossmatching,and
differentsensitivityanalysis)todiscriminatethespecificroleoftheintervention.Theresultswererobustregardlessof
themethodologicalapproach.Toourknowledge,thisisthefirststudydepictingsuchalinearrelationshipbetween
thedoseandoutcome,whichisconsistentwithanincreasingeffectoftheascendantdoseofthedrug.Somestudies
havepreviouslyshownthatrepeatedandincreaseddosesofepinephrinecouldworsenthechancesofsurvival. [28,29]

Beforeincriminatingthedrugitself,ourfindingsprobablyshouldprovokefurtherdiscussiononthemostappropriate
schemeoftreatmentanditsinteractionregardingtheresuscitationphases.Oursensitivityanalysesshowedthatthe
roleofepinephrinedidnotchangeaccordingtoACLSdelayorlengthofresuscitationbutwasclearlydependenton
thetimingoffirstadministration.Theselastfindingsareconsistentwithotherstudies,emphasizingthepotential
benefitofanearlydoseofepinephrine. [3032]

Moreover,theseobservationsconcurwithwhatWeisfeldtandBecker[33]previouslydescribedasthe3phasesof
resuscitationinVFarrest:"theelectricalphase"withinthefirstfewminutesafterarrest,inwhichepinephrineshould
notberequired"thecirculatoryphase,"duringwhichtimechestcompressionsandepinephrinecouldhelp
reperfusionandfinally"themetabolicphase,"whenthedrugmaybedetrimentalinregardtotheperipheralischemia
releaseofmassivelycytotoxicproteins.Assupportedbyourresults,itishighlyprobablethatpatientsreceivinglate
orrepeateddosesofepinephrinehavelittleorlowchanceofsurvival.Currently,noexistingalternativecanbringthese
patientsbackfromneardeathexceptmechanicalcirculatoryassistanceinveryselectcases.Altogether,the
schemeandtimingofadministrationmaybecrucialtoprovidetheappropriateeffectofepinephrine.

Thisstudyhighlightstheneedtoassessthequalityofresuscitation,suchasthequalityofCPRandACLSresponse,
[3436]toimproveclinicalpractice. [37,38]Wemaybeabletobetterunderstandtheroleofepinephrinewithcareful

investigationofitstiminganddoseinthecontextofintermediateoutcomessuchastheelectrocardiographic
waveformandrhythmtransition,endtidalcarbondioxide,andbrainperfusion. [31,39]Finally,ourresultshighlightthe
needforadditionalstudieswithdifferentschemesoftreatment,suchasthecombinationofepinephrinewithother
drugssuchasvasopressinorbetablockers. [40]

StudyLimitations

Thisstudyislimitedbyitsobservationaldesignconsequently,itprecludesanycausalrelationshipbetweenuseof
epinephrineandoutcome.However,weusedavarietyofanalyticalapproachestorigorouslyaddressconfounding.
Despiteourefforts,somepotentialconfoundersmaynothavebeenincludedforinstance,wedonothavereliable
timepointsforestablishmentofanintravenousorintraosseousline.Ourfindingsaredrawnfromasinglecenterand
maynotbegeneralizabletoallcommunities.

http://www.medscape.com/viewarticle/836268_print 10/13
1/1/2015 www.medscape.com/viewarticle/836268_print

Guidelineshavesupportedtheuseofadditionaloutcomeendpointssuchas90daysurvivalinevaluatingtreatment
effects.However,usingtheCPCscoreatdischargeappearstobeagoodindicatoroflongtermsurvival. [41]These
limitationsshouldbeconsideredinthecontextofthestrengthsofthisstudy:alargecohortwithdetailedinformation
ascertainedusingastandardapproachtodataabstractionregardingcareandoutcome.

Conclusions
InthislargecohortofpatientswhoachievedROSCafterOHCA,weobservedanadverseassociationbetween
epinephrineandneurologicallyintactsurvivaldespiterigorouseffortstoaddressconfoundingthisrelationshipwasnot
modifiedbyspecificpostresuscitationcaresuchashypothermiaorPCI.Asaresult,thesefindingssuggestthe
needforadditionalinvestigationstodetermineifandhowepinephrinemayprovidelongtermfunctionalsurvivalbenefit.

Sidebar
Perspectives

COMPETENCYINMEDICALKNOWLEDGE:Duringresuscitationofpatientswithoutofhospitalcardiacarrest,
administrationofepinephrinemayenhancethelikelihoodofreturnofspontaneouscirculationbutisassociatedwith
worseneurologicaloutcomesandtheimpactonlongtermsurvivalisuncertain.

TRANSLATIONALOUTLOOK:Additionalstudiesareneededtoassesstheimpactofothertreatmentstrategiesfor
patientswithoutofhospitalcardiacarrest,suchascombinationsofepinephrineandotherdrugs,ontimetoreturnof
spontaneouscirculation,neurologicaloutcomes,andlongtermsurvival.

References

1. NeumarRW,OttoCW,LinkMS,etal.Part8:adultadvancedcardiovascularlifesupport:2010American
HeartAssociationguidelinesforcardiopulmonaryresuscitationandemergencycardiovascularcare.Circulation
2010122:S72967.

2. YakaitisRW,OttoCW,BlittCD.Relativeimportanceofalphaandbetaadrenergicreceptorsduring
resuscitation.CritCareMed19797:2936.

3. MichaelJR,GuerciAD,KoehlerRC,etal.Mechanismsbywhichepinephrineaugmentscerebraland
myocardialperfusionduringcardiopulmonaryresuscitationindogs.Circulation198469:82235.

4. VandyckeC,MartensP.Highdoseversusstandarddoseepinephrineincardiacarrestametaanalysis.
Resuscitation200045:1616.

5. CallawayCW.Epinephrineforcardiacarrest.CurrOpinCardiol201328:3642.

6. TangW,WeilMH,SunS,NocM,YangL,GazmuriRJ.Epinephrineincreasestheseverityof
postresuscitationmyocardialdysfunction.Circulation199592:308993.

7. AngelosMG,ButkeRL,PanchalAR,etal.Cardiovascularresponsetoepinephrinevarieswithincreasing
durationofcardiacarrest.Resuscitation200877:10110.

8. RistagnoG,TangW,SunS,WeilMH.Cerebralcorticalmicrovascularflowduringandfollowing
cardiopulmonaryresuscitationaftershortdurationofcardiacarrest.Resuscitation200877:22934.

9. OlasveengenTM,SundeK,BrunborgC,ThowsenJ,SteenPA,WikL.Intravenousdrugadministrationduring
outofhospitalcardiacarrest:arandomizedtrial.JAMA2009302:22229.

http://www.medscape.com/viewarticle/836268_print 11/13
1/1/2015 www.medscape.com/viewarticle/836268_print

10. HagiharaA,HasegawaM,AbeT,NagataT,WakataY,MiyazakiS.Prehospitalepinephrineuseandsurvival
amongpatientswithoutofhospitalcardiacarrest.JAMA2012307:11618.

11. DumasF,GrimaldiD,ZuberB,etal.Ishypothermiaaftercardiacarresteffectiveinbothshockableand
nonshockablepatients?Insightsfromalargeregistry.Circulation2011123:87786.

12. JacobsI,NadkarniV,BahrJ,etal.Cardiacarrestandcardiopulmonaryresuscitationoutcomereports:update
andsimplificationoftheUtsteintemplatesforresuscitationregistries:astatementforhealthcare
professionals.Circulation2004110:338597.

13. LaurentI,MonchiM,ChicheJD,etal.Reversiblemyocardialdysfunctioninsurvivorsofoutofhospitalcardiac
arrest.JAmCollCardiol200240:21106.

14. AustinPC.Anintroductiontopropensityscoremethodsforreducingtheeffectsofconfoundingin
observationalstudies.MultivariateBehavRes201146:399424.

15. AustinPC.Atutorialandcasestudyinpropensityscoreanalysis:anapplicationtoestimatingtheeffectofin
hospitalsmokingcessationcounselingonmortality.MultivariateBehavRes201146:11951.

16. 2005AmericanHeartAssociationguidelinesforcardiopulmonaryresuscitationandemergencycardiovascular
care.Circulation2005112:IV1203.

17. ReddingJS,PearsonJW.Resuscitationfromasphyxia.JAMA1962182:2836.

18. MenegazziJJ,CallawayCW,ShermanLD,etal.Ventricularfibrillationscalingexponentcanguidetimingof
defibrillationandothertherapies.Circulation2004109:92631.

19. JacobsIG,FinnJC,JelinekGA,OxerHF,ThompsonPL.Effectofadrenalineonsurvivalinoutofhospital
cardiacarrest:arandomizeddoubleblindplacebocontrolledtrial.Resuscitation201182:113843.

20. NeumarRW,NolanJP,AdrieC,etal.Postcardiacarrestsyndrome:epidemiology,pathophysiology,
treatment,andprognostication.Aconsensusstatement.Circulation2008118:245283.

21. FriesM,WeilMH,SunS,etal.IncreasesintissuePco2duringcirculatoryshockreflectselectivedecreases
incapillarybloodflow.CritCareMed200634:44652.

22. DitcheyRV,LindenfeldJ.Failureofepinephrinetoimprovethebalancebetweenmyocardialoxygensupply
anddemandduringclosedchestresuscitationindogs.Circulation198878:3829.

23. OlasveengenTM,WikL,SundeK,SteenPA.Outcomewhenadrenaline(epinephrine)wasactuallygivenvs.
notgivenposthocanalysisofarandomizedclinicaltrial.Resuscitation201283:32732.

24. HerlitzJ,EkstromL,WennerblomB,AxelssonA,BangA,HolmbergS.Adrenalineinoutofhospital
ventricularfibrillation.Doesitmakeanydifference?Resuscitation199529:195201.

25. OngME,TanEH,NgFS,etal.Survivaloutcomeswiththeintroductionofintravenousepinephrineinthe
managementofoutofhospitalcardiacarrest.AnnEmergMed200750:63542.

26. PerkinsGD,CottrellP,GatesS.Isadrenalinesafeandeffectiveasatreatmentforoutofhospitalcardiac
arrest?BMJ2014348:g2435.

27. NolanJP,PerkinsGD.Istherearoleforadrenalineduringcardiopulmonaryresuscitation?CurrOpinCritCare
201319:16974.

http://www.medscape.com/viewarticle/836268_print 12/13
1/1/2015 www.medscape.com/viewarticle/836268_print

28. GueugniaudPY,MolsP,GoldsteinP,etal.Acomparisonofrepeatedhighdosesandrepeatedstandard
dosesofepinephrineforcardiacarrestoutsidethehospital.EuropeanEpinephrineStudyGroup.NEnglJMed
1998339:1595601.

29. ParadisNA,MartinGB,RosenbergJ,etal.Theeffectofstandardandhighdoseepinephrineoncoronary
perfusionpressureduringprolongedcardiopulmonaryresuscitation.JAMA1991265:113944.

30. KoscikC,PinawinA,McGovernH,etal.Rapidepinephrineadministrationimprovesearlyoutcomesinoutof
hospitalcardiacarrest.Resuscitation201384:91520.

31. KudenchukPJ.Earlyepinephrineinoutofhospitalcardiacarrest:issoonerbetterthannoneatall?
Resuscitation201384:8612.

32. GotoY,MaedaT,GotoYN.Effectsofprehospitalepinephrineduringoutofhospitalcardiacarrestwithinitial
nonshockablerhythm:anobservationalcohortstudy.CritCare201317:R188.

33. WeisfeldtML,BeckerLB.Resuscitationaftercardiacarrest:a3phasetimesensitivemodel.JAMA
2002288:30358.

34. WikL,KramerJohansenJ,MyklebustH,etal.Qualityofcardiopulmonaryresuscitationduringoutofhospital
cardiacarrest.JAMA2005293:299304.

35. OdegaardS,KramerJohansenJ,BromleyA,etal.Chestcompressionsbyambulancepersonnelonchests
withvariablestiffness:abilitiesandattitudes.Resuscitation200774:12734.

36. PytteM,KramerJohansenJ,EilevstjonnJ,etal.Haemodynamiceffectsofadrenaline(epinephrine)dependon
chestcompressionqualityduringcardiopulmonaryresuscitationinpigs.Resuscitation200671:36978.

37. ReaTD,PageRL.Communityapproachestoimproveresuscitationafteroutofhospitalsuddencardiacarrest.
Circulation2010121:113440.

38. TraversAH,ReaTD,BobrowBJ,etal.Part4:CPRoverview:2010AmericanHeartAssociationguidelinesfor
cardiopulmonaryresuscitationandemergencycardiovascularcare.Circulation2010122:S67684.

39. CallawayCW.Questioningtheuseofepinephrinetotreatcardiacarrest.JAMA2012307:1198200.

40. MentzelopoulosSD,MalachiasS,ChamosC,etal.Vasopressin,steroids,andepinephrineandneurologically
favorablesurvivalafterinhospitalcardiacarrest:arandomizedclinicaltrial.JAMA2013310:2709.

41. PhelpsR,DumasF,MaynardC,SilverJ,ReaT.Cerebralperformancecategoryandlongtermprognosis
followingoutofhospitalcardiacarrest.CritCareMed201341:12527.

AbbreviationsandAcronyms

ACLS=advancedcardiaclifesupport,aOR=adjustedoddsratio,CI=confidenceinterval,CPC=Cerebral
PerformanceCategory,CPR=cardiopulmonaryresuscitation,OHCA=outofhospitalcardiacarrest,PCI=
percutaneouscoronaryintervention,ROSC=returnofspontaneouscirculation,VF=ventricularfibrillation,VT=
ventriculartachycardia

JAmCollCardiol.201464(22):23602367.2014ElsevierScience,Inc.

2006AmericanCollegeofCardiology

http://www.medscape.com/viewarticle/836268_print 13/13