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Resuscitation
jo u r n al h om 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
Clinical Paper
Determinants of cognitive outcome in survivors of out-of-hospital cardiac arrest 夽
Marte Ørbo
a,∗, Per M. Aslaksen
b,c, Kristina Larsby
d, Lena Norli
a, Christoph Schäfer
a, Pål M. Tande
d, Torgil R. Vangberg
e,f, Audny Anke
a,faDepartmentofRehabilitation,DivisionofRehabilitationServices,UniversityHospitalofNorthNorway,Tromsø,Norway
bDepartmentofPsychology,FacultyofHealthSciences,UiT,TheArcticUniversityofNorway,Tromsø,Norway
cDepartmentofChildandAdolescentPsychiatry,DivisionofChildandAdolescentHealth,UniversityHospitalofNorthNorway,Tromsø,Norway
dDepartmentofCardiology,DivisionofCardiothoracicandRespiratoryMedicine,UniversityHospitalofNorthNorway,Tromsø,Norway
eDepartmentofRadiology,DivisionofDiagnosticServices,UniversityHospitalofNorthNorway,Tromsø,Norway
fDepartmentofClinicalMedicine,FacultyofHealthSciences,UiT,TheArcticUniversityofNorway,Tromsø,Norway
a r t i c l e i n f o
Articlehistory:
Received8April2014
Receivedinrevisedform7August2014 Accepted8August2014
Keywords:
Cardiacarrest Resuscitation Hypothermia
Neuropsychologicaltests Cognitiveimpairments
a b s t r a c t
Aim:Todescribecognitivefunctioningwithneuropsychologicaltestsandexaminepredictorsofcognitive outcomeinadultsurvivorsofout-of-hospitalcardiacarrest(OHCA)ofcardiaccause.
Method:ThestudywasprospectiveandtookplaceattheUniversityhospitalofNorth-Norway.Only patientseligibleofneuropsychologicalassessmentthreemonthsafterOHCAwereaskedtoparticipate.
Cognitivetestperformancewascomparedtolargesamplesofage-correctednormativedata.Generallin- earmodelswereusedtodeterminepredictorsofacognitivecompositescoreandperformanceonseparate cognitivetests.Thepredictorsassessedwerecomaduration,hypothermiatreatmentandtimetorestora- tionofspontaneouscirculation.Weaimedtocontrolfordemographicvariables,medicalcomorbidityand affectivesymptoms.
Results:45survivors(4women)completedtheassessment.Neuropsychologicaltestsoffinemotor functioning,memory,attentionandexecutivefunctionsweresignificantlybelownormativemeans.
Dependingonthetest,impairmentrangedfrom9to31%.Fortwenty-fivesurvivors(56%),allcogni- tivetestswerewithinthenormalrange.Shortercomadurationandinducedhypothermiatreatment wereassociatedwithfavourablecognitiveoutcomesandexplained45%ofthevariabilityinthecogni- tivecompositescore.Comadurationwaspredictiveacrossallcognitivetests,hypothermiatreatmentof specifictestsofmemory,attentionandexecutivefunctioning.
Conclusions:Cognitiveoutcomewasnormalinmorethanhalfofthesurvivors.Shortercomadurationand inducedhypothermiawereassociatedwithfavourablecognitiveoutcomesintheparticipatingsurvivors threemonthsafterOHCA.
Institutionalprotocolnumber:2009/1395.
©2014ElsevierIrelandLtd.Allrightsreserved.
1. Introduction
Survivors of out-of-hospital cardiac arrest (OHCA) are at riskofcognitiveimpairmentsresultingfromhypoxic–ischaemic encephalopathy.1Concernexiststhatpersistent,mildtomoderate cognitivedisabilityisunderdiagnosedbecausesensitivemeasures arenotsystematicallyappliedduringoutcomeevaluations.1–4
夽ASpanishtranslatedversionofthesummaryofthisarticleappearsasAppendix inthefinalonlineversionathttp://dx.doi.org/10.1016/j.resuscitation.2014.08.010.
∗Correspondingauthorat:DepartmentofRehabilitation,DivisionofRehabilita- tionServices,UniversityHospitalofNorthNorway,9038Tromsø,Norway.
E-mailaddresses:Marte.Orbo@unn.no,marte.orbo@hotmail.com(M.Ørbo).
Clinicalneuropsychologicalassessmentprovidesstandardised, objective and reliable measures of cognitive functioning using psychometrically sophisticated and well-validated procedures.
Assessmenthasbeenprovenusefulfordifferentialdiagnosispur- poses, for allocating rehabilitationresources and for predicting patients’ real-world activities after brain injury in general and hypoxic–ischaemicinjuryspecifically.5–10
Fewprevious prospectivestudies have investigated residual cognitive deficits in OHCA survivors using standard neuropsy- chologicalmeasures.Systematicreviewsoftheresearchliterature concludethat only fiveprospective,qualitatively soundstudies areinformativeofcognitiveoutcomeafterOHCA.1,11Fromthese studies,it can begeneralisedthat cognitiveimpairments occur in 20–50% of survivors and are most often mild to moderate http://dx.doi.org/10.1016/j.resuscitation.2014.08.010
0300-9572/©2014ElsevierIrelandLtd.Allrightsreserved.
in severity. Simultaneous impairment in executive functions, attention and memoryfunctions are most frequentlyreported, as are deficits in fine-motor functioning and visual–spatial conceptualisation.1,4,5,11–15
Thevariability in cognitiveoutcomeseverity isreliably pre- dictedbythe durationof unconsciousness.Patients who spend shorterperiodsin comaandthoseawakeat hospitaladmission havethebestcognitiveprospects.1,4,5,11,12 Inconsistentandcon- tradictory results have been reported regarding the impact of resuscitationtimes, demographic variables and medicalcomor- biditiesoncognitiveoutcome.1,4,5,12,13,15Therapeutichypothermia isrecommendedforallpatientswithashockablecardiacrhythm whoremainunconsciousafterrestorationofspontaneouscircula- tion(ROSC).16Hypothermiatreatmenthasincreasedsurvivalrates and reducedtheprevalenceofsurvivors withseverefunctional disability.17–19Onlytwostudieshaveinvestigatedtheimpactof hypothermiatreatmentoncognitivefunctioning usingstandard neuropsychological measures, and no significant effects could be documented.1,11,14 Thereis still noevidence that therapeu- tichypothermia reducestheriskof mildtomoderate cognitive impairment.20
In the present prospective study, neuropsychological tests wereadministered 45 OHCA survivors three monthsafter suc- cessful resuscitation. Our first aim was to describe cognitive functioningwithneuropsychologicaltests.Weexpectedtestsof memory,attentionandexecutivefunctionstobemostfrequently impaired.11,21Oursecondaimwastoidentifypredictorsfromthe acutestagethatcouldaccountforvariabilityincognitiveoutcome.
Thepredictorsexaminedwerecomaduration,timetoROSCand hypothermiatreatment.Wecontrolledfordemographicvariables, previouscardiacdiseaseand affectivesymptomsthat caninflu- encecognitiveperformance.9Wehypothesisedthatcomaduration wouldpredictoutcomeseverity.22
2. Methods 2.1. Patients
Weaimedtoprospectivelyincludeallsurvivorsofsudden,non- traumatic, normothermic OHCA of presumed cardiac aetiology, aged18–85years,dischargedalivefromthecardiacwardatthe UniversityHospitalofNorth-NorwaybetweenAugust2010and September2013andwhowereabletoperformneuropsychological testingthreemonthspost-resuscitation.
The hospital is the regional hospital of the northern health regioninNorway,coveringthethreenorthernmostcountieswith acombinedpopulationof456,000distributedoverageographic areaof112,000km2.Thehospitalserves smallerlocal hospitals inaregionalmanner.Accordingtohospitalrecords197patients weretreatedatthecardiacwardforanOHCAinthestudyperiod.
Patientsthatdiedbeforeorduringhospitaladmissionwerenot registered.129oftheseOHCA’swereofcardiaccausewithsurvival todischarge.Predefinedexclusioncriteria(Fig.1)weredesigned tocontrolforsuboptimalcognitivefunctioningpriortoOHCAor conditions that might have interfered with thevalidity of test recordings.ThestudywasapprovedbyTheRegionalCommittee forMedicalResearchEthicsinNorth-Norway,institutionalprotocol number2009/1395.
2.2. Procedure
Theprocedurewasaneuropsychologicalexaminationconsist- ingof ananamnestic interview,neuropsychological testing and completionoftheHospitalAnxietyandDepressionScale(HADS).23 Thepatients’workandlivingsituationsbeforeOHCAandatthe
timeofassessmentwererecorded.Theprocedurelastedapprox- imately 3h, including breaks.Theassessments wereconducted by different certified neuropsychologists at the Department of Rehabilitationwheretheassessmenttookplace.TheHospitalAnx- ietyDepressionScale(HADS)wasincludedtoscreenforaffective symptoms,whichcaninfluencetheoutcomeofcognitivetests.24 Neuropsychologicaltestswereselectedtocoverseveralcognitive domainssuchaspsychomotorspeed,attention,workingmemory, executivefunctions,fine-motorfunctions,verbal-andvisuallearn- ingandmemoryinadditiontoindicatorsofgeneralintelligence.
Alltestshavewell-establishedtestproceduresandareavailable inNorwegiantranslations.Thepublishednormsusedinthisstudy arewell-known,andthedatausedforeachtestarebasedonlarge samplesofage-matchedsubjects.Table2displaystheneuropsy- chologicaltestsincluded.
Medicaldata,dataconcerningtheOHCAandresuscitationwere collectedfromthepatient’smedicalrecordswhereresuscitation variables arerecordedaccordingtotheUtsteincriteria.31 Coma durationwascalculatedfromestimatedtimeofarresttoanydocu- mentationofpurposefulbehaviour.Therapeutichypothermiawas, according to the medical records, performed as recommended byinternationalguidelinesforhypothermiatreatment16wherea bodytemperatureof32–34◦Cwasreachedassoonaspossiblefor patientsthatremainunconsciousafterROSC,unlesscontraindica- tionsforhypothermiawerepresent.16
2.3. Statisticalanalyses
Allcontinuousvariables usedinthestatisticalanalyseswere normallydistributedaccordingtotheKolmogorov–Smirnovtest.
Correlation analyses were performed using Pearson product- moment correlations (two-tailed). Group comparisons were performedusinggenerallinearmodelanalysisofvariance. Raw scoresfromthedifferentneuropsychologicaltestswerefirsttrans- formedtonormativescores(T-scores,Wechslerscoresorscaled scores)usingage-correctedpublishednormativedata.Then,alltest scoreswerestandardisedtoZ-scores(mean=0,SD=1)toallowfor comparisonsbetweentestscoresfromdifferentdistributions.One- samplet-testswereusedtoexaminewhethertheZ-scoresforthe meanofeachneuropsychologicaltestweresignificantlydifferent from0.Thecut-offforimpairedversusnormalperformancefor themeanoftheseparateneuropsychologicaltests(displayedin Table3)wassetto≤−1.5standarddeviations(SDs)belowthenor- mativemean.Acut-offof≤−1.5SDwasdeemedmorereasonable thanacut-offof≤−1.0SDbecausealargenumberofsubtestswere administeredtoeachpatient.10
Thecut-offcriteriafortheHADStotalscoreweresetto15points.
Aneight-pointcut-offwasusedforboththedepressionandthe anxietysubscaleswhentheywereassessedseparately.23
Toreducethenumberofdependentvariablesintheregression analyses,asinglecognitivecompositescorewascalculatedusing themeanoftheZ-scoresacrossallneuropsychologicaltests.When usingZ-scores,allincludedtestsweightequallyinthecomposite scoreduetonormalisation.IQwasnotincludedinthecognitive compositescore.Overlappingvarianceacrossneuropsychological testsiswellknown,evenwheneachtestisdesignedtotargetone mainfunction,andthesamplesizewasnotlargeenoughtoassign differenttestscorestoseparatefunctionaldomainsusingfactor analysis.9,11 Thecompositescoregivesaconvenientestimateof averagecognitiveperformanceacrosstestsforeachindividualto beusedintheregressionanalysis,howeveritisnotinformative aboutdomainspecificimpairmentsandhasnonormativedata.
Linearstepwiseregressions(backwards selection)werecon- ducted using the cognitive composite score as the dependent variableandthefollowingpredictors:comaduration(inhours), timetoROSC(inminutes),previouscardiacdisease(yes/no),HADS
Discharged alive after OHCA due to cardiac cause
October 2010 –September 2013 N= 129
Included N=45
Excluded due to predefined criteria
Age above 85 years, n = 2 Severe anoxic brain injury, n = 8
Tourists/living abroad, n = 10 Non-fluent in Norwegian language, n = 1
Other severe somatic illness, n = 7 Psychiatric disorder / neurological disease / learning disabilities / drug/alcohol abuse, n = 18
Died before 3 months after OHCA N = 4
Lost to follow-up
Transferred to further treatment and rehabilitation/mild anoxic injury suspected, n = 6
Discharged to own home –no brain injury suspected and not asked to participate, n = 13
Refused to participate
Reasons:
Long travelling distance, n = 2 The examination felt unnecessary due to self-
reported good functioning, n = 10 Did not want to participate in research, n = 2
No show, n = 1 Eligible for the study
N=79
Fig.1.Overviewofenrolmentandexclusion.InadditiontothepredefinedexclusioncriteriashowninFig.1,previouscardiacarrestandcardiacsurgeryduringthelastyear beforeOHCAweresetaspredefinedreasonsforexclusion.Noneofthepatientsincludedhadexperiencedpreviouscardiacarrestnorhadtheycardiacsurgeryinthelast yearbeforeOHCA.
Table1
Characteristics of the sample. N=45. CPR=cardiopulmonary resuscita- tion. DC=direct current. VF=ventricular fibrillation. AF=atrial fibrillation.
ROSC=return of spontaneous circulation. PCI=percutaneous coronary inter- vention. CABG=coronary artery bypass grafting. ICD=implanted cardioverter defibrillator.
Variable Number(%) Mean(SD) Min–max
BaselineinfoofpatientsbeforeOHCA(N=45)
Age 60.4(12.4) 18–83
Age>70years 9(20)
Male 41(91.1)
Female 4(8.9)
Maritalstatus
Married 36(80)
Unmarried 9(20)
Yearsofeducation 11.5(4) 5–22
Education>12years 15(33.3)
Employed 23(51.1)
Notemployed 22(48.9)
Anypreviousdiagnosedcardiaccondition
Yes 21(46.7)
No 24(53.3)
Previouslydiagnosedcardiaccondition Myocardialinfarction 10(22.2)
Ischaemia 2(4.4)
Hypertension 9(20)
Diabetes
Yes 3(6.7)
No 42(93.3)
Cardiacarrestandresuscitation Witnessedarrest
Yes 44(97.8)
No 1*(2.2)
BystanderCPR
Yes 45(100)
No 0(0)
NumberofDCshocks(n=45) 2.7(2.4) 1–11 Firstregisteredcardiacrhythm
VF 43(95.6)
AF 1(2.2)
Asystole 1(2.2)
MinutestoROSCfromcollapse 17.6(12.5) 1–60 Minutesfromcollapseto
ambulancearrival
12 1–40
Presumedcauseofarrest
Infarction 36(80)
Arrhythmia 7(15.6)
Unknown 2(4.4)
Comadurationinhours 39.9(51) 2minto
192h Cardiactreatment
Awakeuponadmission 13(28.9) Hypothermiatreatment
Yes 19(42.2)
No** 26(57.8)
PCI
Yes 36(80)
No 9(20)
CABG
Yes 2(4.4)
No 43(95.6)
ICDimplantationafterarrest
Yes 15(33.3)
No 30(66.7)
Neurologicaldeficits(paresis)
Yes 3(6.7)
No 42(93.3)
Table1(Continued)
Variable Number(%) Mean(SD) Min–max
Lengthofhospitalstayindays
IntensiveCareUnit 5.05(3.97) 1–14
CardiacWard 12.05(7.25) 5–41
*Thepatientwithanunwitnessedarrestdisplayedneuropsychologicalscores withinthenormalrangeandhadnoneurologicaldeficitsat3monthspost-arrest.
**Forthe14patientsunconsciousatadmissionthatdidnotreceivehypothermia treatment,thefollowingcontraindicationswerepresent:pneumonia(n=3),proba- bleseverebleedings(n=4),uncertainlevelofconsciousnessafteradmission(n=4), surgicalprocedures(n=3).
Table2
Overviewoftheneuropsychologicaltestsusedinthepresentstudy.
Testname Cognitivedomains
CaliforniaVerbalLearningTest II.26
Verballearning(ListATrials1–5), memoryinterference(ListB),short- andlongtermmemory(freeandcued recallofListA)andlong-term recognitionofListA.
Rey’scomplexFigureTest.28 Visuo-spatialability,short-and long-termvisualmemory(copy-trial, immediaterecall,delayedrecalland visualrecognition)
WechslerMemoryScale-329: MemorySpan:Verbal-and Visualspan,bothforwards andbackwards.
Attentionandworkingmemory.
Delis–KaplanExecutive FunctioningSystem(D–K)27:
D–KTrail–MakingTest1–5. Psychomotorspeedandexecutive functioning.
D–KColor-Word.27 Executivefunctioning.Selective attentionandresponseinhibition.
D–KVerbalFluency.27 Executivefunctioning.Rapidword generationandverbalflexibility.
GroovedPegboard25–both hands.
Finemotorfunctioning.
WechslerAbbreviatedScaleof Intelligence(WASI).30 Subtests:
MatrixReasoning,Block Design,Vocabularyand Similarities.
Generalcognitiveability(IQ).
scoresandhypothermiatreatment(yes=1,no=0).Tocontrolfor thepotentialconfoundingwithyearsofeducationandage,these variableswereincludedintheinitialmodel.9Otherpossiblepre- dictorvariablessuchassex,maritalstatus,initialcardiacrhythm, observedcardiacarrest,bystanderresuscitationandcardiactreat- ment(PCI/CABG)wereomittedbecauseofverylittlevariability(see Table1).Amultivariategenerallinearmodelwasusedtofurther examinetheimpactofthesignificantpredictorvariablesfromthe regressionanalysisontheseparateneuropsychologicaltests.
Missingdatafortwopatientswerereplacedbytheindividual mean.Missingdatawerefoundintwotestsforonepatientandin threetestsforanother.Thus,fivevalueswerereplacedwiththe meanofthevariableforwhichdataweremissing.Alldatawere analysedusingtheIBMSPSSv.21package.Ap-value≤0.05was consideredsignificantforallanalyses.
3. Results
3.1. Samplecharacteristics
Afterexclusion duetothepredefinedcriteria,losstofollow- upandrefusaltoparticipate(Fig.1),45survivorscompletedthe neuropsychologicalassessment threemonthspost-resuscitation.
Demographicandclinicalcharacteristicsoftheincludedsurvivors aredisplayedinTable1.
Table3
Neuropsychologicalresults.SD:standarddeviation.AllscoresaredisplayedastransformedZ-scorestoallowcomparisonbetweentests(mean=0,standarddeviation=1), withtheexceptionofWASIIQ,whichisdisplayedintermsofWechslerscores(normativemean=100,standarddeviation=15).CVLTII:CaliforniaVerbalLearningTestII.
WMS-3:WechslerMemoryScale3.DK=Delis–KaplanExecutiveFunctionSystem.WASI:WechslerAbbreviatedScaleofIntelligence.
Variable Mean SD Min Max %Below1.5SD
CVLTII −.53* 1.05 −3.17 1.42 13.3
Rey’scomplexfigure −.16 1.77 −3.33 2.17 30.8
WMS-3MemorySpan −.27 1.09 −3.67 1 9.8
DKTrail-Makingtest −.10 1.10 −3.60 1.60 8.9
DKColor-Word −.40* 1.23 −4.0 1.75 15.4
DKVerbalFluency −.26 1.30 −4.0 2.25 12.5
GroovedPegboard −.66* 1.02 −3.25 1.5 12.2
Cognitivecompositescore −.31* .94 −3.22 1.02 13.3
WASIIQ 99.39 13.23 65 126 15.9
* Z-scoresthataresignificantly(p<0.05)differentcomparedwiththeexpectednormativevalue(0).
3.2. Functionaloutcome
OfthetwentypatientswhowereworkingpriortotheirOHCA, four(9%)hadreturnedtoworkatthetimeoftheneuropsychologi- calassessment.Allofthesurvivorshadbeenindependentintheir dailylifepriortothecardiacarrest.Thelivingsituationatfollow- upwasunalteredin43patients,whiletwopatientsstillreceived in-hospitalrehabilitation.
TotalHADSscoresweregenerallylowindicatingabsenceofclin- icalsignificantsymptomsofanxietyordepression(meanHADS total=4.8,SD=4.41,min=0,max=16).Fivepatients(11.1%)scored above the cut-off on the HADS anxiety subscale (mean=3.13, SD=2.93, min=0, max=11) indicating increased anxiety level.
Noneofthepatientsscoredabovethecut-offonthedepression subscale(mean=1.68,SD=1.94,minimum=0,max=6).
NeuropsychologicalresultsaredisplayedinTable3.TheCVLT-II, theGroovedPegboardandtheD-Kefs’Color-WordTestscoreswere significantlylowercomparedwithnormativevaluesfromtherefer- encepopulations.Dependingonthetest,impairmentrangedfrom 9to31%whenthecut-offforimpairmentwas≤−1.5SDfromthe normativemean.Twenty-fivepatients(55.6%)hadallaveragetests
scoresabovethecut-off,indicatingabsenceofanycognitiveimpair- ment.Sixpatients(13%)hadmorethanthreeaveragetestscores below−1.5SD,andfourteenpatients(31%)hadoneortwoaverage testsscoresatorbelowthecut-off.Wesuggestthatthisgivesan indicationofthenumberofsurvivorsintheunimpaired,moderate toseverelyimpairedandmildimpairmentrange.Ifthisselected testbatteryconsistingof6neuropsychologicaltestswithanaver- agecorrelationofr=.54hadbeenusedinageneralpopulation,the percentageofthepopulationexpectedtoproduce1ormoretest scoresbelow−1.5SDwouldbe18.64%.Thisassumptionwasbased ondataestimatingtheproportionofcognitiveimpairmentinthe generalpopulationwhentheaveragecorrelationbetweenthetests isr=.50.32,33
3.3. Associationsofdemographicandmedicalfactorswith functionaloutcome
ThemeantimefromOHCAtoneuropsychologicalexamination was114days(range80–131).Therewasnosignificantcorrelation betweentimetoadministrationoftestingandthecognitivecom- positescore(r=0.23,p=0.3).Significantcorrelationsbetweenthe
Table4
Stepwiseregressionanalyseswiththecognitivecompositescoreasthedependentvariable.Comadurationisdisplayedinhours.Hypothermiatreatmentwascodedas0=no (hypothermiatreatment)and1=yes.Apreviouslydiagnosedcardiacconditionwascodedas0=yes(previouscardiaccondition)and1=no.TimetoROSCindicatesthetime inminutesfromcollapsetothereturnofspontaneouscirculation.Excludedvariableswereremovedinthesecondstepoftheanalysisforregressions1and2.Collinearity statisticsdisplayedvarianceinflationfactors(VIFs)<1.04forthesignificantpredictorsinregression1andVIFs<1.01forregression2.Nooutliersmorethan2standard deviationsfromtheregressionlineweredetectedinthesignificantmodels.
Regression1:Allpatients.(R2=.45,F(2,44)=17.34,p<0.001),n=45.
Includedvariables B t ˇ p
Comaduration −.01 −5.81 −.68 <.001
Hypothermia .44 2.06 .24 .046
Excludedvariables B t Partialcorrelation p
Yearsofeducation .15 1.26 .19 .21
Previouslydiagnosedcardiaccondition .17 1.47 .22 .15
TimetoROSC −.20 −1.73 −.26 .09
Ageabove70 .004 .03 .005 .97
HADS −.11 −.88 −.14 .38
Regression2:Patientswhowereunconsciousuponadmission.(R2=.48,F(2,31)=13.55,p<0.001),n=32.
Includedvariables B t ˇ p
Comaduration −.01 −4.55 −.61 <.001
Hypothermia .56 2.08 .28 .046
Excludedvariables B t Partialcorrelation p
Yearsofeducation .01 .08 .02 .94
Previouslydiagnosedcardiaccondition .17 1.23 .22 .23
TimetoROSC −.18 −1.39 −.26 .17
Ageabove70 .03 .21 .04 .84
HADS −.06 −.44 −.08 .66
Table5
Multivariate linear analysis of variance. The association between significant predictors(coma duration inhoursand hypothermia treatment)forthecog- nitive compositescore andperformance onspecific neuropsychologicaltests.
CVLTII:CaliforniaVerbalLearningTestII.WMS-3:WechslerMemoryScale3.
DK=Delis–KaplanExecutiveFunctionSystem.2=etasquared.
Comaduration Hypothermia
F 2 p F 2 p
CVLTII 20.35 .33 <.001 4.21 .09 .047
Rey’scomplexfigure 16.25 .28 <.001 .1 .003 .75 WMS-3Memoryspan 20.26 .33 <.001 4.38 .043 .10 DKTrail-Makingtest1–5 5.36 .12 .03 .14 .003 .71
DKColor-Word 12.70 .24 .001 13.76 .25 .001
DKVerbalFluency 6.37 .13 .02 7.24 .15 .01
GroovedPegboard 8.81 .18 .005 .49 .01 .49
cognitivecompositescoreandotherdemographicandresuscita- tionvariablesfromTable1werefoundforcomalength(r=−.45, p=.02)and for IQ (r=.62, p<0.001). There were no significant correlation between HADS scores and the cognitive composite score(r=.11,p=.48),orHADSandemploymentstatusatfollow-up (r=.29,p=.08).Employmentstatushadnosignificantcorrelation withthecognitivecompositescore(r=.09,p=.53).Lengthofhos- pitalstaywerenotcorrelatedwiththecognitivecompositescore (r=.27, p=.17) One-way ANOVA revealed nogroup differences in thecognitivecomposite score related toICD or thevariable
“previous cardiac disease”, PCI treatment, age above 70 years, hypothermiatreatmentorpatientsawakeuponhospitaladmis- sion(allF’s<3.6,allpvalues>.07).Nosignificantgroupdifferences betweenthepatientswhoreceivedtherapeutichypothermiaand thosewhodidnotwerefoundforanyofthefollowingvariables:IQ, age,education,“previouscardiacdisease”,PCI,comaduration,time toROSCorHADSscores(allF’s<1.82,allp-values>.19).Leavingout patientsawakeatadmissiondidnotsignificantlychangetheabove mentioneddifferences(allF’s<2.3,p-values>.14).
3.4. Generallinearmodels
Theregressionmodelexplained45%ofthevarianceinthecog- nitivecompositescore(R2=.45,F(2,44)=17.34,p<0.001).Coma durationandhypothermiatreatmenthadsignificantimpactonthe cognitivecompositescore.Leavingoutpatientswhowereawake upontheirarrivalatthehospitalandthereforenotconsideredfor therapeutichypothermiadidnotchangetheimpactofthesignifi- cantpredictorsfoundinthetotalsample(R2=.48,F(2,31)=13.55, p<0.001).Table4presentsthefullstatisticsofthemodels.
The results from the multivariate analysis are displayed in Table5.Comadurationhadasignificanteffectoneverycognitive test separately, while hypothermia treatment significantly pre- dictedbetterperformance onthefollowing cognitivetests:the CVLT-II,theMemoryspantestsfromWMS-IIIandtheColor-Word andtheVerbal-FluencytestsfromtheD-Kefsbattery.
4. Discussion
Weprospectivelyevaluatedcognitiveperformanceinasample of45adultOHCAsurvivorsthreemonthsaftersuccessfulresus- citationwith neuropsychological tests. Thescope wastwofold;
todescribecognitivefunctioninganddeterminepredictorsofthe variabilityincognitiveoutcome.
Smallsamplesizeandpossibleselectionbiasareobviouslim- itations.Thesurvivorsexaminedwerepredominantlymen.They survivedawitnessedcardiacarrest,ofcardiaccause,withinitial shockableregisteredcardiacrhythm.BystanderCPRwasinitiated and ROSCwasachieved within60min forall participants.It is affirmedthatOHCAvictimswhoreceiveCPRfromabystanderor
anemergencymedicalserviceprovider,andthosewhoarefound inshockablerhythms(VF/VT),andwhoachieveROSCbeforehos- pitaladmissionaremuchmorelikelytosurvivethatthosewhodo not.31,34Further,weincludedonlysurvivorsabletoperformneu- ropsychologicalassessmentafterthreemonths,whichisnotthe caseforeverycardiacarrestsurvivor.
Athree-monthintervalfromresuscitationtoneuropsychologi- caltestingwaschosenbecausecognitiverecoveryisassumedto belimitedafterthisperiodoftime,althoughitmightnotbethe end-point1,13,15,21Also,theremightbedifferenttrajectoriesofcog- nitiverecoveryfordifferentcognitivefunctions,differentpotential ofrecoveryaccordingtotheseverityofthehypoxiceventaswell andindividualdifferencesinrecoverypotential.22
A minority of the participating survivors had obvious cog- nitive disability with poor performance across a large number of neurocognitive test. The most commonresult was cognitive functioninginthenormalrangeorless-pronouncedimpairments.
However,evenmilderformsofcognitivedeclinefollowingfrom OHCAcanhamperreturntoprevioussocialrolesandpremorbid leveloffunctioning.1,4,10,22,35Forthegroupasawhole,fine-motor functioning, aspects of memory, attention and executive func- tionsweresignificantlyimpaired,asexpectedbasedonprevious reports.1,11,12,14,15 Our results support that cognitive measures administeredafterOHCAshouldincludeafocusonexecutivefunc- tions,attentionandmemoryfunctions.20However,thesearehighly complicatedandinterrelatedneurocognitiveprocesses,5,21,36and thediagnosisofsubtlecognitivedeclinecanbechallenging.10,11 Atpresent,wedonotknowwhichcognitivetestsarebestableto diagnoseresidualneurocognitivedeficitsfollowingOHCA.8
Comaduration and hypothermia treatment were significant predictors forthecognitivecomposite score,andthetotalvari- anceexplainedwasapproximately45%forboththewhole-sample model andfor themodel consistingof onlypatientswho were unconsciousuponadmission.TimetoROSCwasnotasignificant predictor.Thelackofsignificancemaybearesultofthelimited samplesize.However,previousstudiesusingtimetoROSCasa predictorforneuropsychologicaltestsfoundbothgoodandpoor cognitiveoutcomesforthesamedelays.1,5,15
Weexpectedlongercomadurationtopredictworsecognitive outcome.1,4,5,11,12,22Accordingly,ouranalysisoftheimpactofcoma durationonseparatecognitivetestsshowedthatperformanceon allincludedtestswasnegativelyaffectedbylongercomaduration.
Wedidnotexpecttoobservehypothermiatreatmentasapredictor ofcognitiveoutcome.11,14Hypothermiatreatmentpredictedbetter cognitiveresultsonboththecognitivecompositescoreand the specificcognitivetests.
Large clinical trials have documented improved survival rates and better neurological outcomes after hypothermia treatment.17,18 It is currentlydebated whethercooling or tem- perature management in general is the central component in the outcome improvement observed.19 Whether controlling or manipulatingtemperatureinfluencesmilder,moresubtlecognitive impairmentshasnotbeendocumentedyet.19Thepresentdesignis unabletoshowthetrueeffectofhypothermiatreatmentoncogni- tiveoutcome.37Ourresultsmayindicatewhichcognitivefunctions aremostrelevanttoassessandwhichneuropsychologicalteststo includeinfuturescientificinvestigationsoftheimpactofhypother- miatreatmentortemperaturemanagementoncognitiveoutcome.
Inthepresentstudyhypothermiatreatmentwasactuallyastronger predictorcomparedwithcomadurationforperformanceonthe specificexecutivefunctiontests.
To reduce uncertainty about the cause of cognitive impair- ment,survivorswithvariouscomorbiditieswereexcludedfrom thisstudy.Suchexclusionsmostlikelyskewedboththecognitive scoresandHADSscoresinthepositivedirection.1,38Still,neuropsy- chologicaltestsarenotconclusiveaboutthecauseofimpairment.
Neithercantheydetangletheproportionofcognitivedeclinedue toOHCAfromotherfactors.Forinstance,alltheOHCAsurvivors haveexperiencedcriticalillnessandspenttimeasintensivecare patients,factorsthatareassociated withcognitiveimpairments regardlessofOHCA.39Simultaneously,studiescomparingcognitive performancebetweencardiacpatientswithoutOHCAandOCHA survivors,11,13,22haveshownOHCAsurvivorstoperformsignifi- cantlyworseinseveralcognitivedomainscomparedtothecontrols.
Thus,OHCAcancreatespecificcerebralinjuriesthatexplainasig- nificantproportionofthecognitiveimpairmentsobserved.40
Conclusively,thepresentstudyaddstotheexistingprospec- tiveneuropsychologicalreportsthatdofindcognitiveimpairments to be present in OHCA survivors with otherwise good func- tionalrecoverywhensensitiveneuropsychologicalmeasuresare appliedinoutcomeevaluations.22Futureneuropsychologicalstud- iesshouldfurtherinformaboutanabbreviatedselectionoftests mostsuitableofcognitivescreeningafterOHCA.8Comaduration isconsistentlyreportedasapredictorofcognitiveoutcomeafter OHCA,but additionalriskfactorsof cognitiveimpairmentsmay alsoexistinthispatientgroup.Thus,inclinicalpractice,thethresh- oldforreferringOHCAsurvivorstoneuropsychologicalassessment shouldbelow.5,6
Conflictofintereststatement
Theauthorsreportnoconflictsofinterest.
Acknowledgements
ThestudywasfinancedbytheNorwegianExtraFoundationfor HealthandRehabilitationthroughEXTRAfundsandbytheUniver- sityHospitalofNorthNorway.
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