Canadian Guidelines for the use of targeted temperature management (therapeutic hypothermia) after cardiac arrest

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Resuscitation

j o ur na l h o me p a g e:ww w . e l s e v i er . c o m / l o c a t e / r e s u s c i t a t i o n

Canadian Guidelines for the use of targeted temperature management (therapeutic hypothermia) after cardiac arrest: A joint statement from The Canadian Critical Care Society (CCCS), Canadian Neurocritical Care Society (CNCCS), and the Canadian Critical Care Trials Group (CCCTG)

Daniel Howes

^a^,^b^,∗

, Sara H. Gray

^d

, Steven C. Brooks

^a^,^p

, J. Gordon Boyd

^b^,^e

, Dennis Djogovic

^f

, Eyal Golan

^g,h

, Robert S. Green

ⁱ

, Michael J. Jacka

^j

, Tasnim Sinuff

^k,l

, Timothy Chaplin

^a

, Orla M. Smith

^m

, Julian Owen

ⁿ

, Adam Szulewski

^a

, Laurel Murphy

ⁱ

, Stephanie Irvine

^b

, Draga Jichici

^o

, John Muscedere

^b,c

aDepartmentofEmergencyMedicineQueen’sUniversity,Kingston,ON,Canada

bQueen’sUniversity,Kingston,ON,Canada

cDepartmentofMedicineQueen’sUniversity,Kingston,ON,Canada

dDivisionofEmergencyMedicine,DepartmentofMedicine,andtheInterdepartmentalDivisionofCriticalCare,UniversityofToronto,Toronto,ON,Canada

eDivisionofNeurologyDepartmentofMedicineQueen’sUniversity,Kingston,ON,Canada

fDivisionofCriticalCareMedicineandDepartmentofEmergencyMedicine,UniversityofAlberta,Edmonton,AB,Canada

gInterdepartmentalDivisionofCriticalCareandDepartmentofMedicine,UniversityofToronto,Toronto,ON,Canada

hInstituteofHealthPolicy,ManagementandEvaluation,UniversityofToronto,Toronto,ON,Canada

iDepartmentofEmergencyMedicine,DepartmentofCriticalCareMedicine,DalhousieUniversity,Halifax,NS,Canada

jDepartmentsofAnesthesiologyandCriticalCare,UniversityofAlbertaHospital,Edmonton,AB,Canada

kInterdepartmentalDivisionofCriticalCareMedicine,UniversityofToronto,Toronto,ON,Canada

lDepartmentofCriticalCareMedicineandSunnybrookResearchInstitute,SunnybrookHealthSciencesCentre,Toronto,ON,Canada

mCriticalCareDepartment,KeenanResearchCentre,LiKaShingKnowledgeInstitute,St.MichaelsHospital,Toronto,ON,Canada

nMcMasterUniversityandHamiltonHealthSciences,Hamilton,ON,Canada

oDepartmentofNeurologyandCriticalCareMedicine,McMasterUniversity,Hamilton,ON,Canada

pRescu,LiKaShingKnowledgeInstitute,St.Michael’s,Toronto,ON,Canada

a r t i c l e i n f o

Articlehistory:

Received29June2015

Receivedinrevisedform25July2015 Accepted30July2015

Keywords:

Therapeutichypothermia Targetedtemperaturemanagement Postcardiacarrestsyndrome Cardiacarrest

Introduction

Since the publication of two landmark articles in 2002,^1,2 the practice of controlling a patient’s core temperature after

∗ Correspondingauthorat:DepartmentofEmergencyMedicine,Queen’sUniver- sity,Empire3,KingstonGeneralHospital,76StuartSt.,Kingston,ON,CanadaK7L 2V7.

E-mailaddress:howesd@kgh.kari.net(D.Howes).

resuscitationfromcardiacarresthasbeenanimportanttherapeu- ticoption.TargetedTemperatureManagement(TTM),previously knownastherapeutichypothermiaorprotectivehypothermia,³is wellrecognizedandacceptedaspartofpost-resuscitativecare.^4,5It involvesactivetreatmentthattriestoachieveandmaintainaspe- ciﬁcbodytemperatureforaspeciﬁcdurationinanefforttoimprove neurologicoutcomes.

Sincethepublicationof thesearticlestherehasbeenexten- siveresearch publishedwiththe goalof better elucidatingthe target population and reﬁnement of the technique. Much has

http://dx.doi.org/10.1016/j.resuscitation.2015.07.052

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beenpublishedsincethepreviousCanadianGuidelinesin2006,⁶ which predated the use of the Grading of Recommendations Assessment,DevelopmentandEvaluation(GRADE)WorkingGroup recommendations.⁷The2010InternationalLiaisonCommitteeon Resuscitation(ILCOR)guidelines⁵recommendTTMasacomponent ofpost-resuscitationcare, butdo not addresssomeofthe spe- ciﬁcimplementationissuesfacedbyclinicians.Thepublicationofa largerandomizedtrial⁸in2013hasstimulatedfurtherdiscussion, debate,andclinicaluncertainty.

Giventheadvancingliteraturebase,werevisedtheCanadian guidelinestoensurethattheyreﬂect thecurrentevidence.The guidelinesthatfollowweredevelopedasapracticalguideforclini- cians.Theyaremeanttoaddressthetreatmentdecisionsphysicians facewhendecidingwhethertouseTTM,whencaringforthecooled patient,andwhenprognosticatingafterTTM.AlthoughTTMhas beenstudiedfor otherpathologiesand in pediatricagegroups, we addressedonlythe useofTTM after cardiacarrest inadult patients.

Thecareofpost-resuscitationpatientscaninvolvea number ofclinicalenvironmentsandprovidergroups.Itisimportantthat thesegroupsshareasimilarapproach.Hence,theseguidelineswere developedbyacommittee,withrepresentationfromtheCanadian AssociationofEmergencyPhysicians(CAEP),theCanadianCriti- calCareSociety(CCCS),theCanadianNeurocriticalCareSociety (CNCCS),andtheCanadianCriticalCareTrialsGroup(CCCTG).The purposeoftheseguidelinesistoadviseclinicianswithevidence basedrecommendationsfrominformedexpertswithconsideration ofcurrentresearch,Canadianvalues,ourhealthcaresystem,and therangeofclinicalenvironmentswhereTTMmaybeused.

Methods

WeusedtheGRADE^9–13andtheAGREEII¹⁴(AppraisalofGuide- lines for Research &Evaluation II) recommendations toinform theTTM guideline developmentprocess.The methodologywas approvedbyrepresentativesofthefourcontributingorganizations.

EachSocietyhadrepresentationontheguidelinecommitteefrom thebeginningoftheprocess.

TheChairandall13membersoftheguidelinecommitteewere required to declare potential conﬂicts at the beginning of the projectandagainbeforeeachstageoftheDelphiprocess.Potential conﬂictsweresharedwithallmembersofthecommittee.Noneof thememberswerefromindustry;therewasnoindustryfundingor presenceduringanyportionoftheguidelinedevelopmentprocess.

Supportfortheprojectcamefromanunrestrictedgrantfromthe KingstonResuscitationInstitute.

Aworkinggroupcreateda draftsetofclinicalquestions.Cli- nicians representingcommunity,tertiary,and academiccenters fromacrossCanadawereaskedforadditionalclinicalquestions usingonlinesurveys.Thecompletesetofquestionswasorganized intocategoriesandassignedtoasectionlead.Theguidelinecom- mitteewascomprisedoftheChairandeightsectionleads.Section leadswereresponsibleforcoordinatingtheworkoftheirteamin theliteraturesearch,extractionandgradingoftheliterature,and formulationofthedraftrecommendations.

Individualliteraturesearchesaddressedeachclinicalquestion.

Thevariablenatureoftheclinicalquestionsprecludedtheuseofa singlesearchstrategy,butasamplesearchstrategywasprovided tosectionleadstopromoteconsistencyanduniformrigor.Sec- tionleadsdevelopedtheliteraturesearcheswiththeassistanceof amedicallibrarianorotherindividualtrainedinmedicalsearch strategydevelopment.SearcheswereperformedusingEMBASE, Medline,CochranedatabaseofSystematicReviews,CochraneCen- tralRegisterofControlledTrialsandtheCochraneMethodology Registerdatabasesfrominception toDecember31, 2013.Titles

andabstractsofthesearchresultswerescannedbytwoindepen- dentreviewersforeachsection.Articlesidentiﬁedforinclusionby atleastonereviewerunderwentdetailedreviewbybothreview- ers.Additionalreferencesweresoughtfrompersonallibrariesof thesectionauthors,andbyscanningthereferencesofsystematic reviews,meta-analyses,andincludedarticles.

Articlesweresummarizedonastandardizedextractionform thatincludedtheabstract,identiﬁcationofindustryfunding,level of evidence, and reviewer comments. A level of evidence was assigned toindividual articlesusing a standardized assessment tool¹⁵(Fig.1).

Sectionleadsthendraftedrecommendationsforeachclinical questionbasedontheirreviewoftheliterature.Draftrecommen- dations,theextractedliteraturereviewresultsandtheleadauthors’

conﬂictof interest statements werecirculated to theguideline committee. To achieve our goal of developing clinically help- ful guidelines,equivocalrecommendations wereavoidedwhere possible.Whenthequalityof evidencewaslow we considered physiologicrationaleandclinicalexpertise.

ThecommitteeusedacombinationofDelphimethodologyand nominalgrouptechniquemodifiedfromJaeschke¹⁶andHsu¹⁷to developthefinalrecommendations.Earlyroundswereconducted electronically and by teleconference. The final roundwas con- ductedasanin-personmeetingofallsectionleadsduringatwo-day periodinSeptember2014.

Theguidelinecommitteeconsideredthebodyofliteratureto assigna‘QualityofEvidence’designationforeachrecommenda- tion.Committeememberswereaskedtoconsiderthelikelihood thatfutureevidencemightchangetherecommendation.Thelevel ofevidenceforeacharticle,thedirectnessoftheevidence,consis- tencyandquantityofevidencewereconsideredwhenmakinga designationofhigh,moderate,loworverylow(Fig.2).Thecom- mitteeconsolidatedthe“low”and“verylow”designationsintoa single“low”categoryforclarity.¹⁸

Recommendations were identiﬁed as strong or conditional based on consideration of the quality of the evidence, balance betweendesirableand undesirable outcomes,Canadiansocietal values of potential outcomes, feasibility and cost. Fig. 3 pro- vides further details on how the committee considered these factors.

The voting process conducted by members of the guideline committeewasanonymousduringtheelectronicDelphiprocess and transparent duringthein-person meeting.The ﬁnal word- ingofeachrecommendationwasachievedthroughconsensus.For clarity,thephrase“Werecommend...”wasreservedfor strong recommendationsand“Wesuggest...”forconditionalrecommen- dations.Apriori,itwasdecidedthatassignmentofthequalityof evidencewouldrequireasimplemajority,butthatthestrength ofarecommendationwouldrequirean80%majorityforastrong recommendation.Memberswererequiredtobepresentandtopar- ticipateinthediscussionofarecommendationtobeentitledtovote atthein-personmeeting.

Thedraftmanuscriptwascirculatedtoallmembersofthecom- mitteeforﬁnaleditorialsuggestions.Anindependentreviewerwho wasnotinvolvedinthedevelopmentoftheguidelinesreviewedthe documentusingtheAGREEIIassessmenttool.Theﬁnalmanuscript wassubmittedtothesponsoringSocietiesforendorsement.The Canadian Association of Emergency Physicians (CAEP) initially reviewedadraftoftheguidelinesbutwewereunabletocomplete theirinternalreviewprocessbeforepublication.

Recommendations

Theclinicalquestionsandrecommendationsofthecommittee aresummarizedinTable1.

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Fig.1.Determinationoflevelofevidenceforeachindividualpublication.AdaptedfromDellinger.¹⁵

Fig.2. DeﬁnitionsforQualityofEvidenceusedforaRecommendation.AdaptedfromGuyatt.⁹

Fig.3. Deﬁnitionsusedbythecommitteetoassignthestrengthofarecommendation.AdaptedfromJaeschke¹⁶andGuyatt.¹⁰

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Table1

Summaryofrecommendations CT—computedtomography,ECG—electrocardiogram,EEG—electroencephalogram, MAP—meanarterialpressure,N/A—notapplicable, PEA—pulselesselectrical activity, ROSC—return of spontaneous circulation, TTM—Targeted Temperature Management, VF—ventricular ﬁbrillation, VT—ventricular tachycardia.

Clinicalquestion Recommendation Strengthof

recommendation

Qualityof evidence ShouldIuseTTMinmyclinical

practice?

WerecommendthatTTMbeusedforneuro-protectionineligible adultpatientsafterresuscitationfromcardiacarrest

Strong High

Whichpresentingrhythmsareeligible forTTM?

WerecommendthatpatientswithapresentingrhythmofVFor pulselessVTareeligibleforTTM

Strong High

WesuggestthatpatientswithapresentingrhythmofPEAor asystoleareeligibleforTTM

Conditional Low

Arein-hospitalandout-of-hospital patientseligibleforTTM?

Werecommendthatpatientswhosufferout-of-hospitalcardiac arrestareeligibleforTTM

Strong High

Werecommendthatpatientswhosufferin-hospitalcardiacarrest areeligibleforTTM

Strong Low

CanTTMbeusedaftercardiacarrest fromnon-cardiaccauses?

Werecommendthatpatientswhosufferacardiacarrestofknown cardiaccauseorofanunknowncauseareeligibleforTTM

Strong High

Wesuggestthatpatientswhosufferacardiacarrestfroma non-cardiaccauseareeligibleforTTM

Conditional Low

CanTTMbeusedinpregnantwomen? WesuggestthatpregnantpatientsareeligibleforTTM Conditional Low ShouldIobtainaCTscanpriorto

institutingTTM?

Werecommendthatimagingofthebrainisnotroutinelyrequired beforetheinitiationofTTM

Strong Low

Whatconstitutesunresponsivenessfor eligibilityforTTM?

Werecommendthatpatientswhoarecomatoseanddonotrespond toverbalcommandsaftercardiacarrestbeconsideredforTTM

Strong Low

HowlongshouldIwaitafterROSC beforeassessingresponsiveness?

Werecommendthatassessmentofapatient’slevelof consciousnessforthepurposeofdeterminingeligibilityforTTM shouldbecompletedwithoutdelayafterROSC

Strong Low

Whatarethecontraindicationsforthe useofTTM?

Werecommendthatuncontrolledbleedingandrefractoryshockbe consideredcontraindicationsforTTM

Strong Low

Wesuggestthathypotension(MAP<60mmHg)isnotanabsolute contraindicationtoTTM.Wesuggestaggressiveresuscitationofthe patientwiththeaimofimprovingMAPandperfusion

Conditional Low

WesuggestthatpatientswithsevereinfectiondonotundergoTTM Conditional Low WerecommendthatadvancedageisnotacontraindicationforTTM Strong Low Werecommendthattheneedforurgentcoronaryangiographyor

percutaneouscoronaryinterventionshouldnotbeconsidereda contraindicationforTTM

Strong Low

CanTTMbeusedinpatientsin

‘electricalstorm’?

Wesuggestthatrecurrentventricularﬁbrillationorventricular tachycardianotbeconsideredacontraindicationtoTTM

Conditional Low

Whatconsultationsarerequiredprior toinstitutingTTM?

WerecommendthatTTMbeinitiatedbytheﬁrstprovider knowledgeableandtrainedintheprocess,andthatconsultation withanyparticularspecialtyproviderpriortotheinitiationofTTM isnotrequired

Strong Low

Whatsettingsarereasonablefor initiatingTTM?Shouldpatientsbe transferredtospecializedcenters beforereceivingTTM?

WerecommendthatTTMcanbeinitiatedinanymedical environmentwiththenecessarysupports,includingprehospital, emergencydepartment,andcriticalcareunit

Strong Moderate

HowsoonshouldTTMbeinitiated? Werecommendthatcliniciansattempttoachievetarget temperatureasrapidlyaspossible

Strong Low

HowlatecanTTMbestartedwitha reasonableexpectationofaneffect?

Wesuggestthatinsituationswheretherehasbeenanunavoidable delay,theremaybebeneﬁtfromTTMeightormorehoursafter ROSC

Conditional Low

Whattemperatureshouldpatientsbe cooledto?

WesuggestthatpatientsundergoingTTMbecooledtoatarget temperaturebetween32^◦Cand34^◦C

Conditional High

Howshouldcoretemperaturebe monitored?

Werecommendthatcoretemperaturebecontinuouslymonitored duringthecoolingandrewarmingphasesofTTM

Strong Low

Werecommendthatesophageal,nasopharyngeal,bladder, endotrachealcuffandpulmonaryarterytemperaturesensorsare acceptableoptionsformonitoringcoretemperature

Strong Moderate

Whatisthebestmethodtousetocool patients?

WedonotrecommendaspeciﬁccoolingmethodforTTM N/A Low

ShouldTTMpatientsreceiveseizure prophylaxis?

Wesuggestagainsttheroutineuseofanticonvulsantmedications forseizureprophylaxisinpatientsundergoingTTM

Conditional Low

ShouldTTMpatientshaveanEEG? WesuggestthatpatientswhoundergoTTMreceivecontinuousEEG monitoringwhereitisavailable

Conditional Low

DoallTTMpatientsrequiresedation andanalgesia?

WerecommendthatpatientsundergoingTTMshouldreceive sedationandanalgesia

Strong Low

DoallTTMpatientsrequireparalytic agents?

Wesuggestthatparalyticsbeusedduringinductionand rewarmingphasesofTTM,tofacilitatetighttemperaturecontrol andtopreventshivering

Conditional Low

WhatECGabnormalitiescanbe expectedfromTTMandhowshould theybetreated?

WesuggestmonitoringoftheQTcintervalinpatientsundergoing TTM

Conditional Low

WesuggestcautioususeofmedicationsthatmayprolongtheQTc intervalinpatientsundergoingTTM

Conditional Low

Wesuggestthatanti-arrhythmicagentsbeusedonlyforthe treatmentofmalignantorhemodynamicallysigniﬁcant arrhythmias

Conditional Low

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Table1(Continued)

Clinicalquestion Recommendation Strengthof

recommendation

Qualityof evidence Whatshouldbedonewhenpatients

undergoingTTMdevelop hemodynamicinstability?

WesuggestthathemodynamicinstabilitydevelopingduringTTM thatisrefractorytoaggressiveresuscitationbeconsideredacause fordiscontinuingtherapy

Conditional Low

HowshouldItreatbradycardiainthe patientundergoingTTM?

WesuggestthatbradycardiaduringTTMnotbetreatedroutinely unlessitiscausinghemodynamicinstability

Conditional Low

HowshouldIdealwithhypokalemiain thepatientundergoingTTM?

Wesuggestthatpotassiumlevelsbekeptabove3.0mmoll⁻¹ duringthehypothermicphaseofTTM

Conditional Low

ShouldpatientsundergoingTTM receiveprophylacticantibiotics?

Wesuggestagainsttheroutineuseofprophylacticantibioticsin patientstreatedwithTTM

Conditional Low

CanProcalcitoninbeusedtomonitor forinfectioninpatientsundergoing TTM?

WerecommendagainsttheuseofProcalcitoninforthediagnosisof infectioninpatientstreatedwithTTM

Strong Low

Shouldbehaveacarebundleforour TTMpatients?

Wesuggestthatstandardordersetsandcarebundlesbeutilized fortheinitiationandcareofpatientsundergoingTTM

Conditional Low

ShouldpatientsundergoingTTMbe fed?

WerecommendthatpatientsundergoingTTMreceiveenteral nutrition

Strong Moderate

Wesuggestthatcaloricintaketargetsbecalculatedas75%of normothermictargetsduringthehypothermicphaseofTTMif calorimetryisnotbeingused

Conditional Low

Whenshouldrewarmingbeinitiated? Wesuggestthatrewarmingshouldbegin24hafterthepatient reachesthetargettemperature

Conditional Low

HowrapidlyshouldTTMpatientsbe rewarmed

Wesuggestthatpatientsshouldberewarmedatarateof 0.25–0.5^◦Cperhour

Conditional Low

Howshouldfeverbemanagedafter rewarmingfromTTM?

Wesuggestthathyperthermiashouldbepreventedforatleast72h postarrest

Conditional Low

HowlongafterROSCshouldIwait beforeprognosticatinginpatientswho havereceivedTTM?

Werecommendthataclinicalneurologicexaminationforthe purposeofprognosticationnotbeperformedearlierthan72hafter returnofspontaneouscirculation

Strong Moderate

Wesuggestthatwhenthereisaconcernofresidualmedication effect,clinicalneurologicexaminationforprognosticationshould bedeferreduntiltheclinicianisconﬁdentthattheconfounding effectsarenolongerpresent

Conditional Low

Whatadjunctivetestingisrequiredto makeaprognosisaftertheuseofTTM?

Wesuggestthatadjunctivetestingisnotroutinelyrequiredto identifypoorneurologicaloutcomeinpatientsafterTTM

Conditional Low

Wesuggestthatsomatosensoryevokedpotentialsandcontinuous EEGcanfacilitateprognosticationinspeciﬁccircumstances

Conditional Low

Isconsultationwithaneurologist requiredforprognosticationafterthe useofTTM?

Werecommendthataneurologicconsultationisnotroutinely requiredforprognosticationaftertheuseofTTM

Strong Low

IndicationsandContraindications

WerecommendthatTargetedTemperatureManagement(TTM) be used for neuro-protection in eligible adultpatients after resuscitationfromcardiacarrest.

Qualityofevidence:High

Strengthofrecommendation:Strong

Werecommendthatpatientswithapresentingrhythmofven- tricularﬁbrillation(VF)orpulselessventriculartachycardia(VT) areeligibleforTTM.

Wesuggestthatpatientswithapresentingrhythmofpulseless electricalactivity(PEA)orasystoleareeligibleforTTM.

Qualityofevidence:Low

Strengthofrecommendation:Conditional

The highest level of evidence we identiﬁed that addressed whetherornottouseTTMwasfromtworandomizedcontrolled trials(RCTs).^1,2Thesetrialsdemonstratedadecreaseinmortality andimprovementinneurologicoutcomeinpatientswithapre- sentingrhythmofVForpulselessVTwhoweretreatedwithTTM.

TheHypothermiaAfterCardiacArrest(HACA)trial²foundfavorable neurologicoutcomeatsix-monthsincreasedfrom39%inthecon- trolgroupto55%inTTMgroup(riskratio1.40,95%CI1.08–1.81).

Bernardetal.¹foundthatsurvivalwithgoodneurologicfunction was26%inthecontroland49%intheTTMgroup(p=0.046).The literaturereviewalsoidentiﬁedasigniﬁcantvolumeoflowerlevel evidencesupportingtheuseofTTMaftercardiacarrest.

The committee discussed the HACA and Bernard trials extensively.Therewereanumberofpotentialflawsinthemethod- ology identified, which have been identified previously in the literature,^19,20leadingsomecommitteemembers todowngrade oneorbothofthestudiestolevelB.Afterconsiderationofthese trialstogetherwiththelargevolumeofobservationalevidence,the committeefoundthequalityofevidencetobehighfortheuseof TTMwhenthepresentingrhythmisVFofpulselessVT.

Onthebasisofthequalityoftheevidence,treatmenteffect, thevaluesocietyplacesonneurologicfunctionandrelativecost- effectivenessthecommitteearrivedatastrongrecommendation fortheuseofTTMaftercardiacarrestforpatientswhopresent inVForpulselessVT.Particularnotewasmadethat‘presenting rhythm’maynotbethebestmethodofstratifyingcardiacarrests.

Itisusedasasurrogate-markerforcardiacarrestseverity,patho- genesis, or prognosis; however the basis for this is not well established.

ThecommitteefoundthequalityofevidencecomparingTTMto normothermiaforpatientspresentingwithPEAandasystoletobe low.Althoughsomeevidencehasreportedreasonablesurvival^8,21 thecommitteeassignedaconditionalrecommendationforpatients presentinginasystoleandPEA.Discussionfocusedontheinappro- priateuseofpresenting rhythmasdeterminantoftherapy, and lowriskofharmfromTTM.Thecommitteediscussedthepossibil- ityofreducedmortalitybutanincreaseinthenumberofpatients withapoorneurologicoutcome.Theuncertaintyofthispossibility andlowqualityofevidenceinthispatientgroupresultedinthe conditionalrecommendation.

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Werecommendthatpatientswhosufferout-of-hospitalcar- diacarrestareeligibleforTTM.

Werecommendthatpatientswhosufferin-hospitalcardiac arrestareeligibleforTTM.

The best evidence demonstrating the beneﬁcial effects of TTM enrolled patients who had suffered cardiac arrest out-of- hospital.^1,2Onthebasisofthisevidence,thecommitteeassigned ahighqualityofevidenceandastrongrecommendationforthe eligibilityofthesepatients.

TheevidencefortheuseofTTMforin-hospitalcardiacarrest is considerablyweaker.One investigationofin-hospital cardiac arrestsfoundanincreaseinmortalityfrom40%to61%(notstatis- ticallysigniﬁcant)whenpatientsweretreatedwithTTM.²²Other studieshavenotdemonstratedadifferenceinmortalitywiththe useofTTM.^21,23,24Althoughthequalityofevidencewaslow,the committeefeltthatlocationofthecardiacarrestlackedsufﬁcient discriminativeabilityasanoutcomepredictortobeusedtoestab- lisheligibility,andrecommendsthatallpatientswhohaveacardiac arrest,includingthoseoccurringin-hospital,beconsideredeligible forTTM.

Werecommendthatpatientswhosufferacardiacarrestof knowncardiaccauseorofanunknowncauseareeligiblefor TTM.

Wesuggestthatpatientswhosufferacardiacarrestfroma non-cardiaccauseareeligibleforTTM.

TheHACA²andBernard¹trialsincludedpatientswhosearrest wasknown tobe cardiac in origin,or of unknown cause.This is also the inclusion practice for much of the observational research.Onthebasisofthisevidence,thecommitteearrivedat astrongrecommendationforthetreatmentofthesepatientswith TTM.

Wedidnotﬁndthesamelevelofevidenceforarrestsknownto befromanon-cardiaccause.Therearesmallcaseseriesandcase reportsdescribingvariableneurologicaloutcomeswhenTTMwas usedaftercardiacarrestassociatedwithvariousetiologies.^25–38 Acase series of14 consecutivecomatosesurvivors ofasphyxia thatweretreatedwithTTMobservedasurvivalrateof65%.²⁵In anotherretrospectivecohortstudyof16unconsciouspatientsafter nearhanging,13patientsreceivedTTMand12ofthemhadpoor neurologicaloutcomes.³⁸

Thecommitteefoundthequalityoftheevidencetobelow.We madeaconditionalrecommendationthatthesepatientsbeconsid- eredeligibleforTTMbasedontheopinionthatintheabsenceof othercontraindications,theanoxicbraininjurysufferedfromthe cardiacarrestmayrealizebeneﬁtfromTTMinthesamewayas patientswhosearrestwascardiacinorigin.Therewassigniﬁcant concernamongcommitteemembersthatthispatientpopulation mightbemorelikelytohaverelativecontraindicationstoTTM,but consideredthisissueseparately.

WesuggestthatpregnantpatientsareeligibleforTTM.

Pregnantpatientswereexcludedfromtrialsdemonstratingben- eﬁtfromtheuseofTTM.¹ThequalityofevidencesupportingTTMin pregnantpatientswasfoundtobelow.Casesofpregnantpatients who were cooled after cardiac arrest have been reported.^39–41 Two resulted in normal fetal delivery, the third in fetal demise.

The committee found that the lack of evidence and lack of goodphysiologicinformationmadeaddressingthisclinicalques- tionchallenging.Ultimately,whenfacedwithapregnantpatient otherwiseeligibleforTTM,themajorityofcommitteemembers wouldcoolthepatient.Thepaucityofevidenceforeffectandsafety inthispopulationandconcernsforpotentialharmresultedina conditionalrecommendation.

Werecommendthatimagingofthebrainisnotroutinely requiredbeforetheinitiationofTTM.

There wasno high-level literature that evaluated this issue directly.Oneprospectivestudy⁴²failedtodemonstrateadiffer- enceindoortocoolingtimewhencomputertomography(CT)scan oftheheadwasperformedpriortoICUadmission,comparedto afteradmissionornotatall.Thecommitteefoundthequalityof evidenceforthisrecommendationtobelow.

Theconsensusofthecommitteewasthatalthoughbrainimag- ing may play an important role in the management of these patients at some point during their care, it is not routinely required prior to the initiation of TTM. Routine CT scanning prior to TTM could signiﬁcantly delay its initiation, particu- larlyinsettings thatrequiretransport toanothercentre. It isa reasonable option tocool simultaneously with CT scanning. In cases where there is a strong suspicion of intracranial bleeding, it is reasonable to delay TTM initiation until a CT scan is obtained.

Werecommendthatpatientswhoarecomatoseanddonot respondtoverbalcommandsaftercardiacarrestbeconsidered forTTM.

Werecommendthatassessmentofapatient’slevelofcon- sciousness(LOC)forthepurposeofdeterminingeligibilityfor TTMshouldbecompletedwithoutdelayafterreturnofsponta- neouscirculation(ROSC).

Thepurposeofdetermininglevelofconsciousnessistoiden- tify patientswithout signiﬁcant neurologic injury sothat TTM maybewithheldaccordingly.Thetimingofthisassessmentasa componentofTTMeligibilitywasnotdirectlyaddressedinthelit- erature.ThereviewerslookedtotheHACA²andBernard¹studies andfoundthatthetimingwasnotwelldeﬁnedineitherstudy.Nei- therofthesetrialsimposedanintentionaldelayperiodbeforethe assessment.

Thereviewerslookedtostudiesdemonstratingaclinicalbenefit fromTTMfortheirdefinitionofneurologicdysfunctionandfound significantvariation.IntheBernardtrial,¹patientswereincluded iftheyhad“persistentcoma”butthetermwasnotfurtherdefined inthepaper.IntheHACAtrial,² patientswereexcludedifthey wereableto“respondtoverbalcommandsafterROSCandbefore randomization”.IntheRCTbyLaurentetal.,⁴³patientswerenot randomizediftheywerefoundtorespondtoverbalcommands afterROSC.

Thecommitteegavethisasastrongrecommendationdespite the low level of evidence. This was based on the perceived importance of avoiding delay and the very low risk of harm in early initiation of TTM. The committee recognized it is not uncommon for some patients to have early and rapid improvements in LOC during the immediate period following ROSC. If such an improvement occurs TTM could reasonably be aborted. The committee was particularly cognizant of the value that members of society place on avoiding even small neurologic insults, and the low level of risk associated with TTM.

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Werecommendthatuncontrolledbleedingandrefractory shockbeconsideredcontraindicationsforTTM.

We suggest that hypotension (MAP<60mmHg) is not an absolutecontraindicationtoTTM.Wesuggestaggressiveresus- citationof the patient with the aim of improving MAPand perfusion.

Wesuggestthatpatientswithsevereinfectionshouldnot undergoTTM.

Werecommendthatadvancedageisnotacontraindication forTTM.

Werecommendthattheneedforurgentcoronaryangiog- raphyor percutaneouscoronary interventionshould not be consideredacontraindicationforTTM.

Forthepurposeofidentifyingcontraindications,thereview- erssoughtreportsofadverseeffectsandreviewedtheexclusion criteriaofthearticlesthatdemonstratedbeneﬁtfromTTM.

Bleeding

Patientswereexcluded fromtheHACAstudy² iftheyhad a

“knownpre-existingcoagulopathy”.Theyfoundthat 19%inthe normothermiagroupand26%inthetreatmentgroupexperienced bleedingofanykind.Thedifferencewasnotstatisticallysigniﬁ- cant.IntheBernardstudy,¹patientswerenotexcludedonthebasis ofbleedingorpre-existingcoagulopathy.Therewerenoreported bleedingcomplicationsineitherarmofthestudy.IntheNielsen trial,⁴⁴therewasnodifferenceinbleedingdetectedbetweenthe groupcooledto36^◦Candthegroupcooledto33^◦C.

Hypothermiainducesamildbleedingdiathesiswitheffectson plateletcountandfunction,effectsonclottingfactorsandother componentsoftheclottingcascade.^45,46Theriskofbleedingmust beweighedagainstthepotentialneurologicbeneﬁtsonacaseby casebasisbasedontheseverityandlocationofthebleeding.The committeefeltthatitisprudenttowithholdTTMinpatientswho arehavingactivesigniﬁcantbleeding(e.g.severeGIbleed,intracra- nialhemorrhage)untilthatbleedingiscontrolled.

Shock

ThereisnodatafromRCTstosupporttheuseofTTMinpostcar- diacarrestpatientswithpersistenthypotension(SBP<90mmHg or MAP<60). There is evidence from a non-randomized study evaluatingTTM to33^◦C for patients in cardiogenic shock who werenotpost-arrest.TheyfoundTTMresultedinreducedheart- rate,increasedMAP,increasedejectionfraction,increasedinotropy and reduced vasopressor and inotrope requirements.⁴⁷ Several othernon-randomizedstudiesprovideweakevidencedemonstrat- ingreducedor similarcatecholaminerequirementstomaintain bloodpressureinpatientstreatedwithTTMtoagoalof32–34^◦C compared withnormothermic patients aftercardiac arrest.^48,49 Sub-groupanalysisofone observationalstudyfoundbeneﬁtfor patientswithshockwhoreceivedTTM.⁵⁰

Thecommitteeconsideredthatinsomeclinicalsituationsthe beneﬁtsofTTMcouldbeoutweighedbyfurtherneurologicdam- ageduetohypoperfusion,butfoundlittletosupportthisoccurring.

Therewasagreementthatpatientsshouldnotbecooledifthey

arepersistentlyhypotensivedespitefullresuscitativeefforts(e.g.

ﬂuids,inotropes, vasopressorsand mechanical support as indi- cated). Bradycardia without hypotension or hypoperfusion was notconsideredacontraindication,andisexpectedwithinduced hypothermia. The committee agreedthat the need for volume resuscitation,vasopressororinotropicmedications,ormechani- calsupporttotreatshockshouldnotbecontra-indicationstoTTM ifreasonablebloodpressureandperfusiongoalscanbeachieved (SBP>90mmHgorMAP>60mmHg).

Infection

Hypothermiaimpairsimmunefunction.^51–53Theeffectofthera- peutichypothermiaforpatientswhosuffercardiacarrestasaresult ofseveresepsisorsepticshockisnotknown.Itisconceivablethat theimmunesuppressioncausedbytherapeutichypothermiamay bebeneﬁcialforpatientswithoverwhelmingsepsisbyattenuat- ingadestructive,mal-adaptiveinﬂammatoryresponse.Itisalso possiblethathypothermiamediatedimmune suppressioncould bedetrimentalifitimpairstheabilitytoclearinfection.

Thecommitteemembersfeltthatsepsisandsepticshockshould beconsideredrelativecontra-indicationstoTTMbecauseofalack ofdemonstratedbeneﬁtandconcernforpotentialharm.

Age

ThereisapaucityofevidencefortheuseofTTMintheelderly (>75years).ElderlypatientswereexcludedfromtheHACAtrial.² PatientsintheBernardstudy¹wereasoldas89,butthenumber ofincludedpatients>75isnotclear.Atleastonecaseseries⁵⁴has reportedoutcomesinanelderlygroupofpatients.In30patients

>75,halfofthemhad“goodneurologicoutcome”.

Itwastheopinionofthecommitteethatwithoutevidenceor biologic rationale for increased harm fromTTM in theelderly, agealone should notbe considereda contraindication to TTM.

Co-morbidities,baselinequalityoflifeandpreviouslyexpressed wishesmustbeconsideredcarefullywhendeterminingsuitability forallaggressivecriticalcare,includingTTM.

Percutaneouscoronaryinterventions

Severalreports havedemonstratedthefeasibilityandpoten- tialbeneﬁtofperformingurgentangiographyandpercutaneous coronaryinterventioninconjunctionwithTTMforpatientswith suspected ACS causing cardiac arrest.^55–57 These small, non- randomizedreportsprovidelowlevelevidencetosuggestthatTTM canbeinducedpriortoandduringPCIwithoutdelayingdoor-to- balloontime.

Althoughtherehasbeenconcernexpressedthathypothermia mayresultinincreasedmyocardialirritability,thishasnotbeen demonstratedattemperaturesabove30^◦C.Thereissomesugges- tionthatcoretemperaturesinthetargetrangemay,infact,result inmembranestabilization.

ThecommitteememberswereoftheopinionthatTTMshould beinitiatedassoonaspossibleforeligiblepatients,includingthose requiringurgentcoronaryangiography.Thereisnoneedtodelay TTMforPCI.

Wesuggestthatrecurrentventricularﬁbrillationorventri- culartachycardianotbeconsideredacontraindicationtoTTM.

Despitebeingahighriskpopulation,clinicallysigniﬁcantcar- diacarrhythmias are rare in patientstreated with TTM.^1,2,58,59 Animalandhumanstudieshavedemonstrated bothareduction in theelectrical threshold requiredfor successful deﬁbrillation,

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as well as improved deﬁbrillation success during hypothermic resuscitation.^60–62

Thecommitteefeltthatgiventhelackofevidencetosuggest harmandthepotentialforneurologicbeneﬁtfromTTM,itwould bereasonabletoinitiateormaintainTTMinpatientswithrecurrent VF/VT.Basedonthelowlevelofevidencethecommitteeassigned aconditionalstrengthofrecommendation.

WerecommendthatTTMbeinitiatedbytheﬁrstprovider knowledgeableandtrainedintheprocess,andthatconsultation withanyparticularspecialtyproviderpriortotheinitiationof TTMisnotrequired.

Thereisnodatafromcontrolledstudiesexaminingtheeffect of one type of care provider over anotherwith respect tothe inductionofTTMforpostcardiacarrestsyndrome.Feasibilityof TTMinductionforpostcardiacarrestpatientshasbeendemon- stratedbystudiessetintheprehospital,emergencydepartment, catheterizationlaboratoryandintensivecaresettings.Paramedics, emergency physicians, cardiologistsand critical carespecialists havealldemonstratedtheabilitytoinitiateTTM.

Despite the low quality of evidence supportingthis recommendation,thecommitteefeltthatastrongrecommendationwas importanttoemphasizethatroutinedelayininitiatingTTMinorder todeferthecaretoanothergroupofcaregiverscreatesanunneces- sarybarrierandmaynotbeinthepatient’sbestinterest.Incomplex orconfoundedsituations,consultationwithaspecialistmaybevery helpfulandisappropriate.

WerecommendthatTTMcan beinitiated inanymedical environmentwiththenecessarysupports,includingprehospi- tal,emergencydepartment,andcriticalcareunit.

Qualityofevidence:Moderate Strengthofrecommendation:Strong

Thereviewersfoundninearticles^63–71thataddressedTTMuse outsideoftheintensivecareunit. Mostwereintheprehospital setting,andmostsuggestedbothsafetyandfeasibility.

ThecommitteediscussedtheimplicationsofthestudybyKim⁶⁷ thatcomparedatreatmentgroupthatreceivedtwolitersof4^◦C salineintheprehospitalsettingcomparedtoacontrolgroupcooled inhospitalusingsurfaceorintravascularcooling.Therewasnodif- ferencein survivalor neurologicoutcome;however therewere suggestions of harm with the treatment group experiencing a higherrateofre-arrestandearlypulmonaryedema.Thecommit- teeattributedthesignalofpotentialharmtotheuseofcoldsaline ratherthantheinitiationofcoolingintheprehospitalsetting.

Itwastheopinionofthecommitteethatwithappropriatetrain- ingandsupport,TTMcanbesafelyprovidedinavarietyofmedical environments.Thestrengthoftherecommendationwasbasedon thepotentialbeneﬁttopatientsfromthetherapyandtheimpor- tanceofremovingsettingasabarriertoqualitycare.

Timing

Werecommend thatclinicians attempt to achieve target temperatureasrapidlyaspossible.

Thereviewerswereunabletoidentifyanyhighqualitystudies thatdirectlycomparedonetimetargettoanothertimetarget.Nine studiesinvolvedtimetotargetTH/TTMtemperature.1,2,70,72–77One retrospectivestudy⁷³foundaworseoutcomewithquickertimeto targettemperature.Therewasnoevidenceincorporatinganinten- tionaldelayintheinitiationofhypothermia.

Whenconsideringtheevidence,thecommitteechosenottogive signiﬁcantweighttotheﬁndingsofretrospectiveandobservational

studiesduetotheconfoundingissueofinjuryseverity.Therewas concernthatpatientswithmoresevereneurologicinjuryatROSC mayhavedisorderedautonomicfunction,includingimpairedther- moregulation.Thesepatientswouldbeexpectedtohavealower temperatureatpresentationandcoolmorequickly,resultingina shortertimetotargettemperature.

Whenmakingtherecommendationthecommitteespentcon- siderabletimediscussingthetimingoftherapyintrialsthatshowed benefitfromTTM,aswellastheimpactoftimedelayonthemech- anismsproposedforTTMbenefit.Thestrongrecommendationwas delivereddespitethelowqualityofevidencebasedontheconcern thatanydelaymayresultinprogressivedecreaseinbenefit,while theriskofharmprobablyremainsconstant.

We suggest that in situations where there has been an unavoidabledelay,theremaybebeneﬁtfromTTMeightormore hoursafterROSC.

Thereareclinicalsituationswhenthereisasignificantdelay betweenROSCand theopportunitytoinduceTTM. Thesecould includetransportfromasitethatdidnotprovideTTMordelays forprocedures.Thereviewersdidnotfindanyliteratureinvolving anintentionaltimedelayafterROSCbeforeinitiatingcooling.The HACAtrial,²whichdemonstratedasurvivalandneurologicbenefit, hadamediantimetotargetof8h(interquartilerange4–16h).

Thecommitteedidnotsetatimeperiodafterwhichpatients shouldnotbecooled,butfounditlikelythatthebeneﬁtsofTTM decreasewithtime.

Coolingprocess

WesuggestthatpatientsundergoingTTMbecooledtoatar- gettemperaturebetween32^◦Cand34^◦C.

Thetargettemperatureof32–34^◦Cbecamethestandardofcare basedprimarilyonthetwostudiespublishedin2002^1,2andfurther supportedbythreeotherstudiesthatshowedbeneﬁtofcoolingto this rangecomparedtonocooling.^78–80 Thechoiceoftempera- turetargetinthesestudieswasextrapolatedfromanimaldata,and demonstratedbeneﬁtwhencomparedtonotemperaturecontrol.

Threestudieshavespeciﬁcallyassessedthetargettemperaturefor therapeutichypothermiaaftercardiacarrest.^8,81,82Noneofthese studiesdemonstratedthatadifferenttargettemperatureleadsto improvedsurvivalorneurologicoutcomes.Thisissuegenerated extensivediscussion.Theprimaryissuedebatedbythecommit- teewaswhethertoextendtherangefrom32–34^◦Cto32–36^◦C basedontheresultsofthetrialpublishedbyNielsenetal.in2013.⁸ Thiswasalargemulticenterrandomizedcontrolledtrialcompar- ingatargetof36^◦Cto33^◦C,withaprimaryendpointofall-cause mortalitytotheendof thetrial.ItwasthelargestRCTonTTM todate,enrolling950patientsfrom36intensivecareunits.They foundahazardratiowithatargettemperatureof33^◦Cof1.06(CI 0.89–1.28;p=0.51).

Thetrialwasdesignedand analyzedasa superioritytrial.It is generally not appropriate to use a superiority trial to con- cludeequivalenceornon-inferiority,⁸³butthetrial’sclosepoint estimates and large size has led some to conclude effective demonstrationofnon-inferiority.^84,85Therearedesignandanal- ysisrequirementsforatrialtodemonstratenon-inferiority,well describedbytheConsolidatedStandardsofReportingTrials(CON- SORT)group^83,86andothers.^87–89Ultimately,thecommitteefound thestudyinappropriateforaﬁndingofnon-inferioritybecauseof theabsenceofadeﬁnedmarginofinferiority,inappropriateinclu- sioncriteria,andastudydesignlackingassaysensitivity.

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Innoninferiorityandequivalencetrials,aprestatedmarginof noninferiorityforthetreatmenteffectineachoutcomeisdefined.⁸³ Itis in relationtothismargin thattheanalysisis expressed.It isusuallybasedonaproportionofthebenefitthatthestandard grouppreviously demonstrated over placebo, but also requires somejudgementastowhatwouldbeconsideredclinicallymean- ingful.TheconfidenceintervalsintheNielsentrialincluderesults thatsomemightconsiderclinicallyimportant.

Enrollmentofpatientsinanoninferioritytrialshouldmatchas closelyaspossibletheenrollmentofthetrialswhenthereference treatmentdemonstrated superiority over controls.⁸³ A broader enrollmentincreasesthelikelihoodofincorrectlyconcludingnon- inferiority.TheNielsentrialincludedpatientsthatwouldnothave beenincludedintheBernardorHACAtrials,resultinginastudythat morecloselymatchesclinicalpracticebutmorelikelytoincorrectly concludenoninferiority.

Assaysensitivityreferstotheabilityofaspecificclinicaltrial todemonstrateadifferenceifsuchadifferencetrulyexists,andis perhapsthegreatestchallengefornoninferioritytrials.⁸⁸Whena superioritytrialdemonstratesaneffectitalsoprovesassaysensi- tivity,butthisisnottrueforanoninferioritytrial.TheNielsentrial haddesignelementsappropriateina superioritytrialbut inap- propriatewhenanalyzingfornoninferiority.Thecommitteemade specificnotethattheintervention(cooling)wasnotstandardizedin itsmethodortherateachieved;therewasasignificantdelayafter ROSCbeforeinitiationoftemperaturecontrol;andrewarmingwas rapidcomparedtoprevioustrials.

Thesigniﬁcanceofeachoftheseissuesisunclear,butwhencon- sideredtogetherthecommitteefounditinappropriatetoconclude noninferiorityofatargettemperatureof36^◦C.

Thecommitteealsolookedforacompellingreasontoextend thetarget.Wedidnotfindareductionincostorresourcesbytar- geting36^◦C.Wefoundnoevidenceofharmreductiontopatients bytargeting36^◦C.Therewasnoreductioninadverseeventsby targeting36^◦C (specificallythere wasnosignificantdifferences foundinadverseeventsincludingbleeding,infectionandarrhyth- miasfromthe Nielsendata). Thecommittee alsodiscussedthe greaterriskofpotentialhyperthermiaduetodriftwhenselect- ingahighertargettemperature.Forthesereasons,thecommittee found insufficient cause to extend the recommended targeted temperaturerange.Whenconsideringtheoverall qualityofthe evidenceforthisrecommendation,thecommitteediscussedand considered the methodological shortcomings of the HACA and Bernardtrials. The potentialfor bias in thesestudies hasbeen welldiscussedelsewhere,^19,20andthecommitteewasparticularly concernedaboutthepotentialrolethatunblindedpalliationdeci- sionsmighthavehad.Theselimitationswererecognized,butwhen consideredincombinationwiththevolumeoflowerqualitysup- portingresearchthecommitteevotedtoassigna“high”quality fortheevidenceforthe32–34^◦Ctargetrange.It doesnot refer totheevidencefor whattheprecisetargettemperatureshould be.Inassigningstrengthtotherecommendation,63%ofthevot- ingmemberswereinfavorofastrongrecommendation.Thiswas belowourapriorirequirement ofan80%majorityfor astrong recommendation,andsotherecommendationwasassigneda‘conditional’strength.Thosein favorofthestrongrecommendation didsobasedonthequalityofevidence,lackofharm, thesoci- etalvalueplacedonsurvivalandimprovedneurologicoutcome, thesizeofthetreatmenteffect,aswellasthefeasibilityandlow costof therecommendation. Thedissentingopinion wasbased primarilyonacceptanceoftheNielsentrial,uncertaintywhether futureresearchmightdemonstratethatahighertargettempera- tureissaferforpatients,oreasierforphysicianstoachieve and maintain.

Ourunderstandingoftargettemperatureisstillimmature.We mightexpectthatthereisadoseeffectwithatherapeuticrange

fortemperaturemanagement.Theremaybeasubsetofpatients whobecomehemodynamicallyunstableattheusualtargetwho maytolerateandbeneﬁtfromatargetof36^◦C,butthecommittee concludedthatthereiscurrentlynotsufﬁcientevidencetochange thestandard‘dose’of32–34^◦C.

Werecommendthatcoretemperatureshouldbecontinu- ouslymonitoredduringthecoolingandrewarmingphasesof TTM.

Werecommendthatesophageal,nasopharyngeal,bladder, endotrachealcuffandpulmonaryartery temperaturesensors areacceptableoptionsformonitoringcoretemperature.

Qualityofevidence:Moderate Strengthofrecommendation:Strong

No studieshave attemptedto induceTTM withoutcontinu- ousmeasurementofcoretemperature.Continuousmonitoringis importanttoavoidsigniﬁcanttimespentoutsidethetargettem- peraturerange.

Oneobservationalstudyofcardiacarrestpatientsfoundthat esophageal, pulmonary artery and endotracheal tube cuff sen- sor measurements were similar,⁹⁰ while a second found that pulmonaryartery,bladderandnasopharyngealtemperaturemea- surementswerewellcorrelated.⁹¹

Two studies were performed in cardiopulmonary bypass patients. One found that esophageal, nasopharyngeal and pul- monaryarteryassessmentshadtheclosestcorrelationtocerebral temperature.⁹² The second paper found that nasopharyngeal temperatures did not correspond well to arterial temperature measurements.⁹³

Acasereportexaminedvarioustemperaturemeasurementsin aconscioussubjectundergoinginducedhypothermia,⁹⁴andfound thatesophagealmonitoringmostcloselyapproximatedpulmonary arterytemperaturesduringcoolingandrewarming.

Rectal probes have been reported to correlate poorly with esophagealtemperatureprobes⁹⁵andtobelessaccurateduring rewarmingphases.⁹⁴Tympanicmeasurementshavebeenfoundto notbeaccuratewhenicepacksareappliedtotheheadandneck,⁹⁶ andmayalsobeinaccurateduringrewarming.⁹⁴

WedonotrecommendaspeciﬁccoolingmethodforTTM.

Qualityofevidence:low

Strengthofrecommendation:norecommendation The literature review found a number of feasible cooling methods,1,32,43,69,97–117howevernospeciﬁcmethodofcoolinghas beenshowntoimprovepatientoutcomes.

Methodsvarysigniﬁcantlyintermsofeaseofuse,timetotar- gettemperature,temperaturevariability,costandavailability.It iscommontousemultiplecoolingmethodstoachieveTTM.Cli- niciansshouldconsiderhavingaprotocolindividualizedfortheir institution based onpatientfactors, easeof use, cost and local resources.

The committee was unable to make a speciﬁc recommendation on cooling method due to the range of clinical settings in which this therapy will be used. Surface cooling with ice-packs continues to be an acceptable method of inducing TTM, and is feasible in almost all clinical settings.

Centers with resources and sufﬁcient frequency might achieve shorter timetotarget temperature,tightertemperaturecontrol andimprovedconvenienceusingcommerciallyavailablecooling devices.

Asdiscussedpreviously,thetrialbyKim⁶⁷suggestspotential harmfromusing4^◦Csalineasacomponentofacoolingstrategy.

Thetrialcomparedatreatmentgroupthatreceivedtwolitersof4^◦C salineintheprehospitalsettingcomparedtoacontrolgroupcooled in-hospitalusingsurfaceorintravascularcooling.Therewasnodif- ferenceinsurvivalorneurologicoutcome,howeverthetreatment