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Resuscitation
jo u r n al hom ep age:w w w . e l s e v i e r . c o m / l o c a t e / r e s u s c i t a t i o n
Prognostication
in
comatose
survivors
of
cardiac
arrest:
An
advisory
statement
from
the
European
Resuscitation
Council
and
the
European
Society
of
Intensive
Care
Medicine
夽
Claudio
Sandroni
a,∗,
Alain
Cariou
b,
Fabio
Cavallaro
a,
Tobias
Cronberg
c,
Hans
Friberg
d,
Cornelia
Hoedemaekers
e,
Janneke
Horn
f,
Jerry
P.
Nolan
g,
Andrea
O.
Rossetti
h,
Jasmeet
Soar
iaDepartmentofAnaesthesiologyandIntensiveCare,CatholicUniversitySchoolofMedicine,LargoGemelli8,00168Rome,Italy bMedicalICU,CochinHospital(APHP),ParisDescartesUniversity,Paris,France
cDepartmentofClinicalSciences,DivisionofNeurology,LundUniversity,Lund,Sweden
dAnaesthesiologyandIntensiveCareMedicine,SkåneUniversityHospital,LundUniversity,Lund,Sweden eIntensiveCare,RadboudUniversity,NijmegenMedicalCentre,Nijmegen,TheNetherlands
fIntensiveCare,AcademicMedicalCenter,Amsterdam,TheNetherlands
gDepartmentofAnaesthesiaandIntensiveCareMedicine,RoyalUnitedHospital,Bath,UK hDepartmentofClinicalNeurosciences—CHUVandUniversityofLausanne,Switzerland iDepartmentofAnaesthesiaandIntensiveCareMedicine,SouthmeadHospital,Bristol,UK
a
b
s
t
r
a
c
t
Objectives:Toreviewandupdatetheevidenceonpredictorsofpooroutcome(death,persistentvegetativestateorsevereneurologicaldisability)inadult comatosesurvivorsofcardiacarrest,eithertreatedornottreatedwithcontrolledtemperature,toidentifyknowledgegapsandtosuggestareliable prognosticationstrategy.
Methods:GRADE-basedsystematicreviewfollowedbyexpertconsensusachievedusingWeb-basedDelphimethodology,conferencecallsandface-to-face
meetings.Predictorsbasedonclinicalexamination,electrophysiology,biomarkersandimagingwereincluded.
Resultsandconclusions:Evidencefromatotalof73studieswasreviewed.Thequalityofevidencewasloworverylowforalmostallstudies.Inpatientswho arecomatosewithabsentorextensormotorresponseat≥72hfromarrest,eithertreatedornottreatedwithcontrolledtemperature,bilateralabsence
ofeitherpupillaryandcornealreflexesorN20waveofshort-latencysomatosensoryevokedpotentialswereidentifiedasthemostrobustpredictors.
Earlystatusmyoclonus,elevatedvaluesofneuronspecificenolaseat48–72hfromarrest,unreactivemalignantEEGpatternsafterrewarming,and
presenceofdiffusesignsofpostanoxicinjuryoneithercomputedtomographyormagneticresonanceimagingwereidentifiedasusefulbutlessrobust
predictors.Prolongedobservationandrepeatedassessmentsshouldbeconsideredwhenresultsofinitialassessmentareinconclusive.Althoughnospecific combinationofpredictorsissufficientlysupportedbyavailableevidence,amultimodalprognosticationapproachisrecommendedinallpatients.
©2014TheAuthors.PublishedbyElsevierIrelandLtd.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense
(http://creativecommons.org/licenses/by-nc-nd/3.0/).
1. Introduction
Severeneurologicalimpairmentcausedbyhypoxic-ischaemic braininjury iscommonafterresuscitationfromcardiacarrest.1 Earlyidentificationofpatientswithnochanceofagood neurologi-calrecoverywillhelptoavoidinappropriatetreatmentandprovide informationforrelatives.
夽 ThismanuscripthasbeenendorsedbytheEuropeanResuscitationCouncil(ERC) andtheEuropeanSocietyofIntensiveCareMedicine(ESICM).Thisarticleisbeing simultaneouslypublishedinResuscitationandIntensiveCareMedicine[ISSN: 0342-4642(printversion)ISSN:1432-1238(electronicversion)].
∗ Correspondingauthor.
E-mailaddress:[email protected](C.Sandroni).
In 20062 a landmark review from the Quality Standards Subcommittee of the American Academy of Neurology (AAN) recommendedasequentialalgorithmtopredictpoorneurological outcome in comatose survivors within the first 72h after car-diopulmonary resuscitation (CPR). According to that algorithm, thepresenceofmyoclonusstatusepilepticusonday1,thebilateral absence of the N20 wave of somatosensory evoked potentials (SSEPs)orabloodconcentrationofneuronspecificenolase(NSE) above33mcgL−1 atdays1–3, andabsentpupillaryandcorneal reflexes or a motor response nobetter than extension (M1–2) atday3accuratelypredictedpooroutcome.However,theAAN recommendationsneedupdating:
1.TheAAN2006reviewwasbasedonstudiesconductedbeforethe adventoftherapeutichypothermia(TH)forpost-resuscitation http://dx.doi.org/10.1016/j.resuscitation.2014.08.011
0300-9572/©2014TheAuthors.PublishedbyElsevierIrelandLtd.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/ by-nc-nd/3.0/).
care.BothTHitself andsedatives orneuromuscularblocking drugsusedtomaintainitmaypotentiallyinterferewith prognos-ticationindices,especiallyclinicalexamination.3Thepredictive valueofthoseindicesthereforeneedstobere-evaluatedin TH-treatedpatients.
2.Studiesconductedbothbefore4andafter5,6theAAN2006review showedthatthepreviouslyrecommendedthresholdsfor out-comepredictionusingbiomarkerswereinconsistent.7
3.EvidenceforsomeprognostictoolssuchasEEG8 andimaging studieswaslimitedatthetimeofthe2006AANreview, and needsre-evaluation.
4.TheAAN2006reviewandpreviousreviewsdidnotadequately addresssomeimportantlimitationsofprognosticationstudies, suchastheriskof‘self-fulfillingprophecy’,whichisabias occur-ringwhenthetreatingphysiciansarenotblindedtotheresultsof theoutcomepredictoranduseittomakeadecisiontowithdraw life-sustainingtreatment(WLST).9
Giventhelimitationsofthecurrentliteratureandtheneedfor up-to-dateclinicalguidance,membersoftheEuropean Resuscita-tionCouncil(ERC)andtheTraumaandEmergencyMedicine(TEM) SectionoftheEuropeanSocietyofIntensiveCareMedicine(ESICM) plannedanAdvisoryStatementonNeurologicalPrognosticationin comatosesurvivorsofcardiacarrest.Theaimsofthisstatementare to:
1.Update and summarise theavailable evidence on this topic, includingthatonTH-treatedpatients;
2.Providepracticalrecommendationsonthemostreliable prog-nosticationstrategies,basedonamorerobustanalysisofthe evidence,inanticipationofthenextERCGuidelineson Resusci-tationtobepublishedinOctober2015;
3.Identify knowledge gaps and suggest directions for future research.
2. Methods 2.1. Panelselection
Thepanelforthis AdvisoryStatementincludedmedical spe-cialistsexperiencedinthemanagementofcomatoseresuscitated patients.Allthepanelmembersareauthorsoforiginalstudieson prognosticationinpost-resuscitationcareorhaveprevious expe-rienceinguideline developmentorsystematic evidencereview. Panel members completeda conflictof interest declaration, as recommended.10,11
2.2. Groupprocess
Followinganinitialconferencecallandaface-to-facemeeting, thepanelmembersagreedoncriteriaforstudyinclusion,grading methods,andtheprocesstimeline.Subsequentconsensusonthe evidenceandtherecommendationswasachievedusinga Web-basedDelphimethod.Thedocumentwaswrittenusinga Web-basedcollaborativeprocessandcollectivelyreviewedforcontent andwording.Afinalface-to-facemeetingwasheldtofinalisethe statements.
2.3. Inclusioncriteriaanddefinitions
Giventhepaucityofevidenceonneurologicalprognostication in children with coma after cardiac arrest, the evidence eval-uationwas restrictedto adults. Inclusion criteria are described in detail elsewhere.12 Briefly, all studies on adult (≥16 years) patientswhowerecomatosefollowingresuscitationfromcardiac
arrestand weretreatedwithTH wereconsideredforinclusion. Patientsdefinedasunconscious,unresponsive,orhavingaGlasgow ComaScalescore(GCS)13≤8wereconsideredascomatose. Stud-iesincludingnon-comatosepatientsorpatientsinhypoxiccoma fromcausesotherthancardiacarrest(e.g.,respiratoryarrest, car-bonmonoxideintoxication,drowningandhanging)wereexcluded, exceptwhenasubpopulationofcardiacarrestpatientscouldbe evaluatedseparately.
Studieswereconsideredfor inclusionregardlessof boththe causeofarrestandtreatmentwithTH.Poolingofdatawas strat-ified according totiming of prognostication and TH treatment. PoorneurologicaloutcomewasdefinedasaCerebralPerformance Category(CPC)14of3to5(severeneurologicaldisability, persis-tent vegetative stateor death) asopposed toCPC 1–2(absent, mildormoderateneurologicaldisability;seeESMAppendix1for adetailedCPCdescription).InsomestudiesaCPC4–5wasdefined as a poor outcome. When original data were not available to correctoutcome asCPC3–5, a CPC4–5wasacceptedasa sur-rogatepooroutcome,assigningthestudyanindirectnessscore. WhentheoutcomewasexpressedusingamodifiedRankinScore (mRS)15anequivalentCPCwascalculatedbasedontheequivalence mRS≥4=CPC≥3.16
2.4. Datasource
Results fromthree recent systematic reviews7,12,17 on post-arrestprognosticationwereusedasadatasource.Oneofthese7 included50 studies on2828 patientsnot treated with TH,the twootherreviews12,17includedatotalof39studiesin2564 TH-treated patients. In order to identify further studies published duringthegradingandconsensusprocess,theautomaticalert sys-temofPubMedwasmaintainedactiveandthetablesofcontents ofrelevant Journalswerescreened.Thisledtoinclusion offive additionalstudies.18–22
2.5. Grading
Grading was made according to the Grading of Recom-mendations Assessment, Development and Evaluation(GRADE) criteria.23–28Thegradingprocessforincludedstudiesisdescribed indetailintheESMAppendix2.
2.5.1. Qualityofevidence
AccordingtoGRADE,thequalityofevidence(QOE)wasgraded ashigh,moderate,loworverylowaccordingtothepresenceof limitations,indirectness,inconsistencyandimprecision. Publica-tionbiaswasnotconsidered,giventhedifficultyofmeasuringitin prognosticstudies.29
Giventheimportanceoftheriskofself-fulfillingprophecy, lim-itationsweregradedasseriouswhenthetreatingteamwasnot blindedtotheresultsofthepredictorofpooroutcomethatwas beingstudied,andveryseriouswhentheinvestigatedpredictor wasusedtodecidetoWLST.
Imprecisionwasgradedasseriouswhentheupperlimitofthe 95%confidenceintervals(CIs)oftheestimateofthefalsepositive rate(FPR)wasgreaterthan5%,andveryseriouswhenthisvalue wasmorethan10%.Confidenceintervalswerecalculatedusingthe Fdistributionmethod,accordingtoBlyth.30
Thisadvisorystatementcoversthefourmaincategoriesof prog-nostictests: clinicalexamination,electrophysiology,biomarkers andimaging.TherelevantEvidenceProfiletablesareincludedin theESMAppendixes3a–d.
2.5.2. Recommendations
Recommendationsinthisdocumentarestatedaseitherstrong (‘werecommend’)orweak(‘wesuggest’).24,25Thestrengthofthe
recommendationswasbasedonthefollowingfactors25:(1)the balancebetweentrueandfalsepredictionsgivenbythattest,i.e. thetestperformanceasestimatedbyitssensitivityandspecificity; (2)theconfidenceinthemagnitudeoftheestimates(i.e.,thequality ofevidence);(3)theresourceuse,i.e.thecostofthestrategyunder evaluation.
3. Clinicalexamination 3.1. Evidence(ESMtable1) 3.1.1. Ocularreflexes
Bilateral absence of pupillary light reflex immediately after recoveryofspontaneouscirculation(ROSC)31–33hasaverylimited valueinpredictingpooroutcome(FPRis8[1–25]).Conversely,at 72hfromROSC,3,18,33–40abilaterallyabsentpupillarylightreflex predictspooroutcomewith0%FPR,bothinTH-treatedandin non-TH-treatedpatients(95%CIs0–2and0–8,respectively);however, itssensitivityislow(24%and18%respectively).
Abilaterallyabsentcornealreflexisslightlylessspecificthanthe pupillaryreflexforpredictionofpooroutcome.Onereasonforthis couldbethesensitivityofthecornealreflextointerferencefrom residualeffectsofsedatives3orneuromuscularblockingdrugs.At 72hfromROSC,theFPRwas5[0–25]%inonestudy35in non-TH-treatedpatientsand4[1–7]%in 7studies3,18,36–40in TH-treated patients;sensitivitieswere29%and34%respectively.
3.1.2. Motorresponsetopain
In non-TH-treatedpatients35,41 an absentor extensormotor responsetopain, correspondingtoamotor score 1or2 ofthe GlasgowComa Scale(M≤2)at 72hfrom ROSChasa high(74 [68–79]%)sensitivityforpredictionofpooroutcome,buttheFPRis alsohigh(27[12–48]%).SimilarresultswereobservedinTH-treated patients.3,18,36–40,42–44Likethecornealreflex,themotorresponse canbesuppressedbytheeffects ofsedativesorneuromuscular blockingdrugs.3
Onlyafewprognosticationstudies3,18,21,38,42,44 reported sus-pensionofsedationbeforeclinicalexaminationandnostudyruled outresidualeffectsofneuromuscularblockingdrugsusing objec-tivemeasurementssuchasmediannervestimulationtrain-of-four. Nostudyevaluatedtheinterobserveragreementinclinical exam-ination.In comadue tomultiplecausesthis agreementis only moderate(kappafrom0.42to0.79).45
Whilepredictorsofpooroutcomebasedonclinicalexamination areinexpensiveandeasytousetheycannotbeconcealedfromthe treatingteamandthereforetheirresultsmaypotentiallyinfluence clinicalmanagementandcauseaself-fulfillingprophecy.
3.2. Recommendations Werecommend:
• Usingthebilateralabsenceofbothpupillaryandcornealreflexes at72hormorefromROSCtopredictpooroutcomeincomatose survivors from cardiac arrest, either TH-treated or non-TH-treated.
• Prolongingobservationofclinicalsignsbeyond72hwhen inter-ferencefromresidualsedationorparalysisissuspected,sothat thepossibilityofobtainingfalsepositiveresultsisminimised.
Wedonotsuggestusinganabsentorextensormotorresponse topain(M≤2)alonetopredictpooroutcomeinthosepatients, givenitshighfalsepositiverate.However,duetoitshigh sensi-tivity,thissignmaybeusedtoidentifythepopulationwithpoor
neurological status needing prognostication or to predict poor outcomeincombinationwithothermorerobustpredictors. 3.3. Knowledgegaps
• Prospectivestudiesareneededtoinvestigatethe pharmacoki-neticsofsedativedrugsand neuromuscularblockingdrugsin post-cardiacarrestpatients,especiallythosetreatedwith con-trolledtemperature.
• Clinical studies are needed to evaluatethe reproducibilityof clinicalsignsusedtopredictoutcomeincomatosepost-arrest patients.Inparticular,clinicalexaminationtendsto underesti-matethepresenceofpupillaryreflex,whichcanbedetectedand quantifiedusingpupillometry.46,47
4. Myoclonusandstatusmyoclonus 4.1. Evidence(ESMtable1)
Myoclonusisaclinicalphenomenonconsistingofsudden,brief, involuntaryjerkscausedbymuscularcontractionsorinhibitions. Aprolongedperiodofcontinuousandgeneralisedmyoclonicjerks iscommonly describedasstatusmyoclonus.Thereis no defini-tiveconsensusontheduration orfrequency ofmyoclonic jerks requiredtoqualifyasstatusmyoclonus,howeverin prognostica-tionstudiesincomatosesurvivorsofcardiacarresttheminimum reporteddurationis30min.Thenamesanddefinitionsusedfor statusmyoclonusvaryamongthosestudies(seeESMAppendix4). Termslikestatus myoclonus,myoclonicstatus, generalised sta-tusmyoclonicus,andmyoclonus(ormyoclonic)statusepilepticus have been used interchangeably. Although theterm myoclonic statusepilepticusmaysuggestanepileptiformnatureforthis phe-nomenon, in post-anoxic comatosepatients clinical myoclonus is only inconsistently associated with epileptiform activity on EEG.48,49
In comatose survivors of cardiac arrest treated with TH,21,42,44,48,50,51 the presence of myoclonic jerks (not status myoclonus)within72hfromROSCisnotconsistentlyassociated withpooroutcome(FPR5[3–8]%;sensitivity33%).Inonestudy,36 presenceofmyoclonicjerkswithin7daysfromROSCwas com-patiblewithneurologicalrecovery(FPR113–26%;sensitivity54%).
A status myoclonus starting within 48h from ROSC was consistentlyassociatedwithapooroutcome(FPR0[0–4]%; sen-sitivity15%)inprognosticationstudiesmadein non-TH-treated patients,35,52,53andisalsohighlypredictive(FPR0.5%[0–3]; sen-sitivity16%)inTH-treatedpatients.3,48,54 However,severalcase reportsofgoodneurologicalrecoverydespiteanearly-onset, pro-longedandgeneralisedmyoclonushavebeenpublished.Insome of these cases,55–60 myoclonus persisted after awakening and evolvedintoachronicactionmyoclonus(Lance-Adamssyndrome). Inothers61,62itdisappearedwithrecoveryofconsciousness.The exacttimewhenrecoveryofconsciousnessoccurredinthesecases mayhavebeenmaskedbythemyoclonusitselfandbyongoing sedation.
4.2. Recommendations Wesuggest:
• Usingthetermstatusmyoclonus52toindicateacontinuousand generalisedmyoclonuspersistingfor≥30minincomatose sur-vivorsofcardiacarrest
• Usingthepresenceofastatusmyoclonuswithin48hfromROSC incombinationwithotherpredictorstopredictpooroutcome in comatose survivors of cardiac arrest, either TH-treated or non-TH-treated
• Evaluatingpatientswithpost-arreststatusmyoclonusoff seda-tionwheneverpossible;inthosepatients,EEGrecordingcanbe usefultoidentifyEEGsignsofawarenessandreactivity61andto revealacoexistentepileptiformactivity.
4.3. Knowledgegaps
• Aconsensus-based,uniformnomenclatureanddefinitionfor sta-tusmyoclonusisneeded.
• Thedistinctivepathophysiologicalandelectrophysiological fea-turesofpostanoxicstatusmyoclonus,incomparisonwithmore benign forms of myoclonus,likethe Lance-Adams syndrome, needtobefurtherinvestigated.
5. BilateralabsenceofSSEPN20wave 5.1. Evidence(ESMtable2)
In non-TH-treated post-arrest comatose patients, bilateral absenceoftheN20waveofshort-latencysomatosensoryevoked potentials(SSEPs)predictsdeathorvegetativestate(CPC4–5)with 0[0–5]% FPR as earlyas 24hfrom ROSC,35,63,64 and it remains predictiveduringthefollowing48hwithaconsistentsensitivity (45–46%).4,35,63,65,66Amongatotalof287patientswithnoN20SSEP waveat≤72hfromROSC,therewasonlyonefalsepositiveresult67 (positivepredictivevalue99.7[98–100]%).
InTH-treatedpatients,abilaterallyabsentN20waveaccurately predictspoor outcomeboth during TH (FPR0[0–2]%)and after rewarming(at72hfromROSC)(FPR0.4[0–2]%),eveniftwoisolated casesoffalse positivepredictionhavebeenreported.68,69Inthe largestobservationalstudyonSSEPinTH-treatedpatients,38three patientswitha bilaterallyabsentN20duringTH rapidly recov-eredconsciousnessafterrewarming and ultimately had a good outcome.Inapost-hocassessment,twoexperienced neurophysiol-ogistsreviewedblindlytheoriginaltracingsandconcludedthatthe SSEPrecordingswereundeterminablebecauseofexcessivenoise. Correctionoftheresultsafterthis reassessmentledtoa FPRof 0[0–3]%.
InterobserveragreementforSSEPsinanoxic-ischaemiccomais moderatetogoodbutisinfluencedbynoise.70,71
Inmostprognosticationstudies,absenceoftheN20waveafter rewarming has been used–alone or in combination–asa crite-rionfordecidingonWLST,withaconsequentriskofself-fulfilling prophecy(seeESMAppendix3b).SSEPresultsaremorelikelyto influencephysicians’andfamilies’WLSTdecisionsthanthoseof clinicalexaminationorEEG.72
5.2. Recommendations Werecommend:
• UsingbilateralabsenceofN20SSEPwaveat≥72hfromROSCto predictpooroutcomeincomatosesurvivorsfromcardiacarrest treatedwithcontrolledtemperature.
Wesuggest:
• Using SSEP at ≥24h after ROSC to predict poor outcome in comatosesurvivorsfrom cardiacarrest not treatedwith con-trolledtemperature.
SSEPrecordingrequiresappropriateskillsandexperience,and utmostcareshouldbetakentoavoidelectricalinterferencefrom muscleartefactsorfromtheICUenvironment.
5.3. Knowledgegaps
• MostofprognosticaccuracystudiesonSSEPsinpost-anoxiccoma werenotblinded,whichmayhaveledtoanoverestimationofthe SSEPprognosticaccuracyduetoaself-fulfillingprophecy.Blinded studieswillbeneededtoassesstherelevanceofthisbias. 6. Electroencephalogram(EEG)
6.1. Evidence(ESMtable2) 6.1.1. AbsenceofEEGreactivity
InTH-treatedpatients,absenceof EEGbackgroundreactivity duringTHisalmostinvariablyassociatedwithpooroutcome(FPR 2[1–7]%;21,44,50)whileafterrewarmingat48–72hfromROSCit predicts apooroutcome with0[0–3]% FPR.42,44,50 However,in onestudyinposthypoxicmyoclonus48threepatientswithnoEEG reactivityafterrewarmingfromTHhadagoodoutcome.Among fourprognosticationstudiesonabsentEEGreactivityaftercardiac arrestincludedinthisdocument,three21,42,44weremadebythe samegroupofinvestigators.LimitationsofEEGreactivityinclude beingoperatordependentandnon-quantitative,andlacking stan-dardisation.TechniquesforautomatedanalysisofEEGbackground reactivityareunderinvestigation.73
6.1.2. Statusepilepticus
InTH-treatedpatients,thepresenceofstatusepilepticus(SE), i.e.,aprolongedepileptiformactivity,duringTHorimmediately afterrewarming51,54,74isalmostinvariablyfollowedbypoor out-come(FPRfrom0%to6%).Amongthosepatients,absenceofEEG reactivity51,75oradiscontinuousEEGbackground76predictedno chanceofneurologicalrecovery.AllstudiesonSEincludedonly afewpatients.DefinitionsofSEwereinconsistentamongthose studies(seeESMAppendix5).
6.1.3. LowvoltageEEG
Accordingtorecentguidelines,77thevoltageofbackgroundEEG isdefinedaslowwhenmostorallactivityis<20V(measured frompeaktotrough)inlongitudinalbipolarwithstandard10–20 electrodes,whilesuppressionisdefinedasallvoltagebeing<10V. Intwo studies35,67 innon-TH-treatedpatients,a low-voltage EEG(≤20–21V)at1-3daysafterROSCpredictedpooroutcome with0[0–6]%FPR.Inoneofthesestudies,35however,thepresence ofthisEEGpatternwasusedasacriterionforWLST.
Intwostudies76,78inTH-treatedpatientsaflatorlow-voltage tracingoncontinuousEEGrecordedduringTHorimmediatelyafter rewarmingwasinconsistentlyassociatedtoapooroutcome(FPR from0%to6%).Intwostudies79,80abispectralindex(BIS)value of6orlessrecordedduringTH,correspondingtoaflator low-amplitudeEEG,predictedpooroutcomewith0%[0–6]FPR,while higherBISvalueswerelessspecific.81However,inasubsequent study82aBIS≤6wasnot100%reliable(FPR17%7–32).Thereis lim-itedevidence76,82onthepredictivevalueoflowEEGvoltageafter rewarmingfromTH.
AmplitudeoftheEEGsignalmaydependontheeffectofdrugs, bodytemperature,andonavarietyoftechnicalconditionssuchas skinandscalpimpedance,inter-electrodedistances,size,typeand placementoftheexploringelectrodes,andtypeoffiltersadopted, aswellaspatient-specificissues.83
6.1.4. Burst-suppression
Accordingtoarecentdefinition,77burst-suppressionisdefined asmorethan50%oftheEEGrecordconsistingofperiodsofEEG voltage <10V, with alternating bursts. In comatose survivors of cardiac arrest, either TH-treated or non-TH-treated, burst-suppressionisusuallyatransientfinding.Duringthefirst24–48h
afterROSC67innon-TH-treatedpatientsorduringTH44,78,84 burst-suppressioniscommonanditmaybecompatiblewithneurological recovery while at ≥72h from ROSC35,76,85 a persisting burst-suppressionpatternislesscommon,butisconsistentlyassociated withpooroutcome.Inonecase61agoodrecoverywasreported despiteanEEGburst-suppressionpatternrecordedat72hfrom ROSC;inthatcase,EEGreactivitywasmaintained.Definitionsof burst-suppressionwereinconsistentamongprognostication stud-ies(seeESMAppendix6).
6.2. Recommendations Wesuggest:
• UsingEEG-basedpredictorssuchasabsenceofEEGreactivityto externalstimuli,presenceofburst-suppressionorstatus epilep-ticusat≥72hafterROSCtopredictpooroutcomeincomatose survivorsfromcardiacarrest.
• Usingthesepredictorsonlyincombination(i.e.presenceof burst-suppressionorstatusepilepticusplusanunreactivebackground) andcombiningthemwithotherpredictors,sincethesecriteria lackstandardisationandtherelevantevidenceislimitedtoafew studiesperformedbyexperiencedelectrophysiologists
• Notusinga low EEGvoltagetopredictoutcome incomatose survivorsofcardiacarrest,becauseofthelimitedevidenceand theriskofinterferencefromhypothermia,ongoingsedationand technicalfactors.
Werecommendnotusingburst-suppressionfor prognostica-tionduringthefirst24–36hafterROSCorduringTHincomatose survivorsofcardiacarrest.
Apartfromitsprognosticsignificance,recordingofEEG—either continuousorintermittent—incomatosesurvivorsofcardiacarrest bothduringTHandafterrewarmingishelpfultoassessthelevel ofconsciousness—whichmaybemaskedbyprolongedsedation, neuromusculardysfunctionormyoclonus—andtodetectandtreat non-convulsiveseizures8whichmayoccurinaboutonequarterof comatosesurvivorsofcardiacarrest.54,76,86
6.3. Knowledgegaps
• Largerprospectivestudiesontheprevalenceandthepredictive valueofEEGchangesincomatosesurvivorsofcardiacarrestare needed,especiallyinpatientswhohavebeenrewarmedfrom controlledtemperature.
• ThedefinitionofSEandthemodalitiesforelicitingandevaluating EEGreactivityneedstandardisation.Infuturestudies,definitions ofburstsuppressionandlow-voltageEEGshouldcomplywith recentrecommendations.77
• ItisnotclearwhetherpostanoxicSEisonlyamarkerofbrain injuryorwhetheritcontributesdirectlytoneurologicalinjury, norifantiepileptictreatmentsmaypotentiallyimproveits out-come.
7. Biomarkers
NSEandS-100Bareproteinbiomarkersthatarereleased fol-lowinginjurytoneuronsandglialcells,respectively.Bloodvalues ofNSEorS-100Baftercardiacarrestarelikelytocorrelatewiththe extentofanoxic-ischaemicneurologicalinjuryfromcardiacarrest and,therefore,withtheseverityofneurologicaloutcome.
AdvantagesofbiomarkersoverbothEEGandclinical examina-tionincludequantitativeresultsandlikelyindependencefromthe effectsofsedatives.Theirmainlimitationasprognosticatorsisthat itisdifficulttofindaconsistentthresholdforidentifyingpatients
destinedtoapooroutcomewithahighdegreeofcertainty.Infact, serumconcentrations ofbiomarkers arepersecontinuous vari-ables,whichlimitstheirapplicabilityforpredictingadichotomous outcome,especiallywhenathresholdfor0%FPRisrequired. 7.1. Evidence(ESMtable3)
7.1.1. Neuron-specificenolase(NSE)
Innon-TH-treatedpatientsthe2006AANreview2identifiedan NSEthresholdof33mcgL−1atdays1to3fromROSCasan accu-ratepredictorofpooroutcomewith0%FPR.However,inastudy4 includedinthatreviewthis thresholdwas47.6mcgL−1 at24h, while ina largecohort study5 publishedaftertheAANreview, thisthresholdwas65.0mcgL−1at48hand80mcgL−1at72h.In threeotherstudies,3,63,87 valuesofNSEbetween65mcgL−1 and
85mcgL−1at3-5dayswerereportedascompatiblewithrecovery ofconsciousness.
In TH-treated patients the threshold for 0% FPR varied between38.1mcgL−1and80.8mcgL−1at24h,20,74,88–90between 25mcgL−1and151.5mcgL−1 at48h,20,22,38,74,88–93andbetween 27.3mcgL−1and78.9mcgL−1at72h.6,90,91However,the distribu-tionofNSEvaluesinavailablestudies5,6,22,38,88,91indicatesthatNSE valuesabove60mcgL−1at48–72hfromROSCareveryrarely asso-ciatedwithgoodoutcome.Limitedevidence20,89,94suggeststhat thediscriminativevalueofNSElevelsat48–72hishigherthanat 24h.
7.1.2. S-100B
S-100BislesswelldocumentedthanisNSE.AsforNSE, inconsis-tencieswerefoundinitsthresholdsfor0%FPR.Innon-TH-treated patients, these thresholds ranged from 0.19 to 5.2mcgL−1 at 24h4,92,95 andfrom0.12to0.25mcgL−1 at48h.92,96,97Precision wasverylowinallstudies.
InTH-treatedpatients,thethresholdsfora0%FPRrangedfrom 0.18 to1.15mcgL−1 at24hafterROSC,90,92,98 andfrom0.30 to 2.15mcgL−1at48h.82,90Finally,inonestudy90thethresholdfor 0%FPRat72hwas0.92mcgL−1.
The main reasonsfor the observed variability in biomarker thresholds may include the use of heterogeneous measure-menttechniques,99,100thepresenceofextra-neuronalsourcesof biomarkers(haemolysisandneuroendocrinetumoursforNSE,101 muscle and adipose tissue breakdown for S-100B102), and the incompleteknowledgeof thekineticsoftheirblood concentra-tionsinthefirstfewdaysafterROSC.Someevidence89,90,94suggests thatnotonlythebiomarkers’absoluteconcentrationsbutalsotheir trendsovertimemayhavepredictivevalue.
7.2. Recommendations Wesuggest:
• UsinghighserumvaluesofNSEat48–72hfromROSCin combina-tionwithotherpredictorsforprognosticatingapoorneurological outcomeincomatosesurvivorsfromcardiacarrest,either TH-treated or non-TH-treated. However, no threshold enabling predictionwithzeroFPRcanberecommended.
• Using utmostcare and preferably samplingat multiple time-pointswhenassessingNSEtoavoidfalsepositiveresultsdueto haemolysis.
7.3. Knowledgegaps
• Thereisaneedforstandardisationofthemeasuringtechniques forNSEandS-100incardiacarrestpatients.
• Littleinformationisavailableonthekineticsoftheblood concen-trationsofbiomarkersinthefirstfewdaysaftercardiacarrest. 8. Imaging
8.1. Evidence(ESMtable4) 8.1.1. BrainCT
BrainCTisoftenperformedinresuscitatedcomatosepatients, mainly to exclude further causes of coma, as subarachnoid haemorrhage.103ThemainCTfindingofglobalanoxic-ischaemic cerebral insult following cardiac arrest is cerebral oedema,104 whichappearsasareductioninthedepthofcerebralsulci(sulcal effacement)and an attenuation of the grey matter/white mat-ter(GM/WM)interface,duetoadecreaseddensityoftheGM.In onestudy,105thepresenceofthispatternonbrainCTperformed immediatelyafterresuscitationpredictedpooroutcomewith81% sensitivityand8%[0–38]FPR.TheattenuationoftheGM/WM inter-facehasbeenquantitativelymeasuredastheratio(GWR)between theGMandtheWMdensities.TheGWRthresholdbelowwhich pooroutcomewaspredictedwith0%FPRrangedbetween1.12and 1.22.20,33,106ThemethodsforGWRcalculationwereinconsistent amongstudies.
8.1.2. MRI
AdvantagesofMRIoverbrainCTincludeabetterspatial defi-nitionandahighsensitivityforidentifyingischaemicbraininjury; however,itsusecanbeproblematicinthemostclinicallyunstable patients.107
Theearliestpost-ischaemicMRIchangeishyperintensityin cor-ticalareasorbasalgangliaondiffusionweightedimaging(DWI) sequences.Intwosmallstudies,108,109thepresenceoflarge mul-tilobarchangesonDWIorFLAIRMRIsequencesperformedwithin fivedaysfromROSCwasconsistentlyassociatedwithdeathor veg-etativestatewhilefocal orsmallvolumelesionswerenot.93 In patientswithpooroutcomeafterresuscitationfromcardiacarrest, MRIcanrevealextensivechangeswhenresultsofotherpredictors suchasSSEPorocularreflexesarenormal.93,107
Apparent diffusion coefficient (ADC) is a quantitative mea-sure of ischaemic DWI changes. ADC values between 700 and 800×10−6mm2/sareconsideredtobenormal.107Several meth-odshavebeenusedtoquantifytheDWIchangesfollowingcardiac arrestinordertopredictoutcome.Measuredparametersinclude whole-brainADC,110 the proportion of brain volume with low ADC111andthelowestADCvalueinspecificbrainareas,suchasthe corticaloccipitalareaandtheputamen.88,112TheADCthresholds associatedwith0%FPRvaryamongstudies.Thesemethodsdepend partlyonsubjectivehumandecisioninidentifyingtheregionof interesttobestudiedandintheinterpretationofresults,although automatedanalysishasrecentlybeenproposed.19Accordingtoone study,109 theoptimaltimewindowforprognosticationbasedon ADCis3–5daysfromROSCinthecorticalstructuresand6–8days inthesubcorticalstructures.BoththetimingandseverityofMRI changesafterarrestdifferbetweencorticalareas.
AdvancedMRItechniques,suchasfractionalanisotropy113and axialdiffusivityindiffusion-tensor(DT)imaging114haverecently beentestedin humanstoevaluatethewhitematter disorgani-sationandtheaxonaldamagefollowingdiffuseanoxic-ischemic braininjury,respectively.Limitedevidenceshowsthesetechniques maybeusefultopredictoutcomeinpatientswhoarepersistently comatoseaftercardiacarrestandthattheiraccuracyiscomparable orsuperiortothatofADC.113
Allstudiesonprognosticationaftercardiacarrestusing imag-inghave a smallsample size witha consequentlow precision, and a very low quality of evidence. Most of those studies are
retrospective,andbrainCTorMRIhad beenmadeatdiscretion ofthetreatingphysician,whichmayhavecausedaselectionbias andoverestimatedtheirperformance.
8.2. Recommendations Wesuggest:
• UsingthepresenceofamarkedreductionoftheGM/WMratio orsulcaleffacementonbrainCTwithin24hafterROSCorthe presenceofextensivereductionindiffusiononbrainMRIat2-5 daysafterROSCtopredictapooroutcomeinpatientswhoare comatoseafterresuscitationfromcardiacarrestbothTH-treated ornon-TH-treated
• UsingbrainCTandMRIforprognosticatingpooroutcomeafter cardiacarrestonlyincombinationwithotherpredictors. • Usingbrainimagingstudiesforprognosticationonlyincentres
wherespecificexperienceisavailable,giventhelimited num-berofstudiedpatients, thespatialandtemporal variabilityof post-anoxicchangesinbothCTandMRI,andthelackof stan-dardisationforquantitativemeasuresofthesechanges.
8.3. Knowledgegaps
• Evidenceonimaging studiesin comatosesurvivorsofcardiac arrestislimitedbysmallsamplesizeandlikelyselectionbias. Largerprospectivestudiesareneededtoconfirmtheresultsof thecurrentlyavailablestudies.
• TheseverityofbrainCTandMRIchangesafterglobalischaemic injury willneeda standardiseddescription,e.g.using scoring systemssimilartothoseusedfortraumaticbraininjury.115 • Theprognosticvalueofquantitativevectorindicesderivedfrom
DTimaging,suchasfractionalanisotropy andaxialdiffusivity needtobeevaluatedinfuturestudies.
9. Self-fulfillingprophecy
Almostallprognosticationstudiesreviewedinthisdocument wereassignedaloworverylowqualityofevidence(seeEvidence ProfileTablesonESMAppendix3a–d)themainreasonbeingtherisk ofself-fulfillingprophecy.Infact,only9/73studies(12%)—threeof whicharefromthesamegroup—reportedblindingofthe treat-ingteamfromtheresultsofthepredictorunderinvestigation.In twoofthesestudies37,38resultsofthepredictor(absenceofN20 SSEPwave)recordedduringTHwerenotdisclosed,butifpatients remainedcomatoseafterrewarming,asecondSSEPwasperformed andresultsweredisclosedtothetreatingteam,whousedthis infor-mationfortreatmentdecisions.Atreatmentsuspensionpolicywas reportedin37/73studies(51%),althoughonly27ofthosestudies describedthecriteriaforWLST.In14/37studies(38%)the treat-mentsuspensionpolicywasbased,atleastinpart,ononeormore ofthepredictorsunderinvestigation(seeESMTable5).Treatment limitationswereappliedataminimumof3daysorlessfromcardiac arrestin12studiesandfrom3to7daysin9studies,whileinthe remainingstudiestheminimaldurationoflifesupportmeasures wasnotreported.
Preventionofself-fulfillingprophecybiaswouldrequire blind-ingoftestresultstothetreatingteamandprovidingsufficiently prolongedlifesupportinpatientswhodonotrecover conscious-ness after resuscitation and rewarming. Both those tasks are difficulttoaccomplish.Somepredictors, suchasresultsof clini-calexamination,cannotbeconcealedtothetreatingteam.Others, suchasEEG,shouldnotbeconcealedastheycanrevealthe pres-enceofpotentiallytreatablecomplications,likeseizures.Insome institutions,havingadedicatedinvestigatornotinvolvedinpatient
Fig.1.Suggestedprognosticationalgorithm.Thealgorithmisentered≥72hafterROSCif,aftertheexclusionofconfounders(particularlyresidualsedation),thepatient remainsunconsciouswithaGlasgowMotorScoreof1or2.Theabsenceofpupillaryandcornealreflexes,and/orbilaterallyabsentN20SSEPwaveindicatesapooroutcome isverylikely.Ifneitherofthefeaturesispresent,waitatleast24hbeforereassessing.Atthisstagetwoormoreofthefollowingindicatethatapooroutcomeislikely:status myoclonus≤48h;highneuronspecificenolasevalues;unreactiveEEGwithburstsuppressionorstatusepilepticus;diffuseanoxicinjuryonbrainCTand/orMRI.Ifnoneof thesecriteriaaremetconsidercontinuetoobserveandre-evaluate.
managementwhowillensureblindingofcollecteddatamaynotbe feasible.80Ontheotherhand,indefinitesupportivecarein poten-tiallyhopelesspatientsraisesbothethicalandfinancialconcerns. Evenwhentheriskofself-fulfillingprophecycannotbeavoided, however,inordertoadequatelyaccountforthisbiasitisdesirable thatfutureprognosticaccuracystudiesreportindetailthe crite-riaforwithdrawalorlimitationoflife-sustainingtreatment,ashas beendoneinrecenttrials.116
10. Practicalapproach:suggestedprognosticationstrategy Prognosticationisindicatedinpatientswithprolongedcoma after resuscitation. A thorough clinical examination should be performeddailytodetectsignsofneurologicalrecoverysuchas purposefulmovementsortoidentifyaclinicalpicturesuggesting thatbraindeathhasoccurred.
Following global post-anoxic injury, the brain will make a gradualrecovery.Brainstemreflexesreturnfirst,thenthemotor responsetopainand,finally,corticalactivityandconsciousness.117 Thisprocess is completedwithin 72h fromarrest.53,117 Conse-quently,inabsenceofresidualsedation,72hafterROSCseemstobe asuitabletimeforprognostication.However,inpatientswhohave receivedsedatives≤12hbeforethe72hneurologicalassessment, thereliability of clinicalexamination maybe reduced.3 Special caremustbetakeninTH-treatedpatients,sincehypothermia pro-longstheeffectsofbothopiates118 andneuromuscularblocking drugs.119,120
Beforedecisive assessment isperformed,major confounders mustbe excluded;121,122 apartfromsedation and neuromuscu-lar blockade, these include hypothermia, severe hypotension, hypoglycaemia, and metabolic and respiratory derangements. Sedativesandneuromuscularblockingdrugsshouldbesuspended long enough to avoid interference with clinical examination.
Short-actingdrugsarepreferredwheneverpossible.When resid-ual sedation/paralysis is suspected, considerusing antidotes to reversetheeffectsofthesedrugs.Becarefulifusingflumazenilto reversetheeffectsofbenzodiazepines,sincethisdrugmaylower theseizurethreshold.
Wesuggestusingtheprognosticationstrategyoutlinedinthe algorithmonFig.1inallcomatosepatientswithanabsentor exten-sormotorresponsetopainat≥72hfromROSC.Resultsofearlier prognostictestsshouldalsobeconsideredatthistimepoint.
Evaluatethemostrobustpredictorsfirst.Thesepredictorshave thehighest specificity and precision(FPR<5%with95%CIs <5% inpatientstreatedwithcontrolledtemperature)andhave been documented in >5 studies from at least three different groups ofinvestigators.Theyincludebilaterallyabsentpupillaryreflexes at≥72hfromROSCand bilaterallyabsentSSEPN20wave after rewarming (thislastsigncanbeevaluatedat ≥24hfromROSC inpatientswhohavenotbeentreatedwithcontrolled tempera-ture).Basedonexertopinion,wesuggestcombiningtheabsence ofpupillaryreflexeswiththoseofcornealreflexesforpredicting pooroutcomeatthistimepoint.Boththesepredictorsmaintain theirpredictivevalueirrespectiveofhypothermiatreatment.18
Ifnoneofthesignsaboveispresent,agroupoflessaccurate predictorscanbeevaluated,butthedegreeofconfidenceintheir predictionwillbelower.ThesehaveFPR<5%butwider95%CIs thanthepreviouspredictors,and/ortheirdefinition/thresholdis inconsistentinprognosticationstudies.Thesepredictorsinclude thepresenceofearlystatusmyoclonus(within48hfromROSC), highvaluesofserumNSEat48h-72hafterROSC,anunreactive malignantEEGpattern(burst-suppression,statusepilepticus)after rewarming,thepresenceofamarkedreductionoftheGM/WMratio orsulcaleffacementonbrainCTwithin24hafterROSCorthe pres-enceofdiffuseischemicchangesonbrainMRIat2–5daysafter ROSC.Basedonexpertopinion,wesuggestwaitingatleast24h
afterthefirstprognosticationassessmentandconfirming uncon-sciousnesswithM1-2beforeusingthissecondsetofpredictors. We alsosuggest combiningat leasttwo ofthese predictors for prognostication.
NospecificNSEthresholdforpredictionofpooroutcomewith 0%FPRcanberecommendedatpresent,althoughinallthestudies weanalysedNSEvaluesgreaterthan60mcgL−1 at48–72hwere veryrarelyassociatedwithafalsepositiveprediction.Ideally,every laboratoryhospitalassessingNSEshouldcreateitsownnormal val-uesandcut-offlevelsbasedonthetestkitused.Careshouldbe takentoavoidhaemolysiswhensamplingNSE.
Althoughthemostrobustpredictorsshowednofalsepositives inmoststudies,noneofthemsingularlypredictspooroutcome withabsolutecertaintywhentherelevantcomprehensiveevidence isconsidered.Moreover,thosepredictorshaveoftenbeenusedfor WLSTdecisions,withtheriskofaself-fulfillingprophecy.Forthis reason,werecommendthatprognosticationshouldbemultimodal wheneverpossible,even inpresenceofone ofthesepredictors. Apartfromincreasingsafety,limitedevidence20,21,42,82also sug-geststhatmultimodalprognosticationincreasessensitivity.
Whenprolonged sedation and/or paralysis is necessary, for example,becauseoftheneedtotreatsevererespiratory insuffi-ciency,werecommendpostponingprognosticationuntilareliable clinicalexaminationcanbeperformed.Biomarkers,SSEPand imag-ingstudiesmayplayaroleinthiscontext,sincetheyareinsensitive todruginterference.
Whendealingwithanuncertainoutcome,cliniciansshould con-siderprolongedobservation.Absenceofclinicalimprovementover time suggestsa worse outcome.Although awakeninghasbeen describedas lateas 25 daysafterarrest,54,61,123 mostsurvivors willrecoverconsciousnesswithinoneweek.93,124–126Inarecent observationalstudy,12694%ofpatientsawokewithin4.5daysfrom rewarmingandtheremaining6%awokewithintendays.
11. Conclusions
Acarefulclinicalneurologicalexaminationremainsthe foun-dationforprognosticationofthecomatosepatientaftercardiac arrest.127 Adequatetime should begiven initially for theearly awakenerstoregainconsciousnessandtoavoidinterferencefrom residualeffectsofsedativesand/orneuromuscularblockingdrugs. Thisimplieswaitinguntil72hormoreafterROSCbeforepredicting pooroutcome, although someindicators can beevaluated ear-lier.Wheneverpossible,prognosticateusingmultiplepredictors, dependingonlocallyavailabletestsandexpertise.Iftheresults ofprognostictestsproduceconflictingresultsorprognostication isuncertain,werecommendfurtherclinicalobservationand re-evaluation.
Authorcontributions
Evidenceevaluation:AlainCariou,FabioCavallaro,Tobias Cron-berg,HansFriberg,CorneliaHoedemaekers,Janneke Horn,Jerry Nolan,AndreaRossetti,JasmeetSoar,ClaudioSandroni
Drafting of the manuscript: Claudio Sandroni, Jerry Nolan (Manuscript’sbodytextandFigure);FabioCavallaro,Tobias Cron-berg(Tables)
Revisionofthemanuscript:AlainCariou,HansFriberg,Cornelia Hoedemaekers,JannekeHorn,AndreaRossetti,JasmeetSoar
Datasearchandanalysis:FabioCavallaro,ClaudioSandroni. Conflictofintereststatement
• ClaudioSandroniisa memberoftheEditorialBoard, Resusci-tationJournal(unpaid);evidencerevieweroftheAdvancedLife
SupportTaskForce,InternationalLiaisonCommitteeon Resusci-tation(ILCOR)(unpaid).Heisthefirstauthoroftwosystematic reviewson prognostication in comatosepatients resuscitated fromcardiacarrest.
• AlainCariouistheDeputyofTraumaandEmergencyMedicine (TEM)SectionoftheEuropeanSocietyofIntensiveCareMedicine (ESICM);DelegatefromtheESICMintheGeneralAssemblyof theEuropeanResuscitationCouncil(ERC).Hereceivedacademic researchgrantsfromFrenchMinistryofHealthforconducting clinicalresearchinthefieldofcardiacarrest(alldatacontrolled bytheinvestigators).
• FabioCavallaroisaco-authoroftwosystematicreviewson prog-nosticationincomatosepatientsresuscitatedfromcardiacarrest. • TobiasCronbergistheCoordinatorofrecommendationson prog-nosticationaftercardiacarrest,SwedishResuscitationCouncil. Hereceivedacademicresearchgrantsfrommultiplenon-profit organisationsfortheconductofacognitivesub-studyandEEG sub-studyoftheTargetTemperatureManagementtrial(alldata controlledbytheinvestigators).
• HansFribergreceivedlecturefeesfromNatusInc(manufacturer ofNervusMonitor,cont.EEG/aEEG)andfromBardMedical.He receivedgrantsfromtheEUInterreg.ProgrammeIVAand aca-demicresearchgrantsfrommultiplenon-profitorganisationsfor theTargetTemperatureManagementtrial(alldatacontrolledby theinvestigators).Heisthechairoftheworkingparty“Careafter cardiacarrest”,SwedishResuscitationCouncil.
• CorneliaHoedemaekersisco-authorofasystematicreviewon diagnostictoolsforpredictionofpooroutcomeafter cardiopul-monaryresuscitation.
• JannekeHornreceiveda GrantfromtheDutchHeart Founda-tion(2007B039)forPROPACIIstudyandfromtheDutchBrain Foundation(14F06.48)forresearchonSSEPduringhypothermia treatmentaftercardiacarrest(datacontrolledbyinvestigatorand norestrictionsonpublication).Sheistheprincipalinvestigator ofPROPACIIstudyandco-authorofasystematicreviewon diag-nostictoolforpredictionofpooroutcomeaftercardiopulmonary resuscitation.
• JerryNolanistheEditor-in-Chief,JournalResuscitationand Vice-Chair,EuropeanResuscitationCouncil.
• AndreaRossettireceivedagrantfromtheSwissNationalScience Foundation(grantno.CR32I3143780).
• JasmeetSoaristheEditor,JournalResuscitation(Honorarium). HeismemberoftheExecutiveCommittee,ResuscitationCouncil (UK)(unpaid);Chairof theERCALSWorkingGroup(unpaid); Co-chairoftheALSILCORTaskForce(unpaid).
Acknowledgements
WegratefullythankDrs.SimonaGaudino,MD,neuroradiologist, andErikWesthall,MD,neurophysiologist,fortheiradvice. AppendixA. Supplementarydata
Supplementarydataassociatedwiththisarticlecanbefound, intheonlineversion,athttp://dx.doi.org/10.1016/j.resuscitation. 2014.08.011.
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