PostoperativeCognitionandBurstSuppression

JamieSleighDepartmentofAnaesthesia,UniversityofAuckland,WaikatoHospital,Hamilton,New

Zealand

ConflictsofInterest

• None

PlanofTalk

• WhatisPOD/POCD?– &howwe(failto)measureit

• WhatisBurstSuppression(BSupp)– &howwe(failto)measureit

• Howaretheylinkedclinically?–Observationalstudies

• IsBSupp animportantcauseofPOD?– Meta-analyses– ENGAGES

• Conclusions– weareinastateofepistemologicalfailure

ConfusionaboutDelirium:Whatarewetalkingabout?

• Delayedneurocognitiverecovery…– Delirium =acutefluctuations• PACU-Delirium(hrs)• PostoperativeDelirium(dys)

– POCD• Prolonged<1(=mild)<2(=severe)SDbelowonpsychometrictests

EveredLetal.BrJAnaesth.2018Nov;121(5):1005-1012.doi:10.1016/j.bja.2017.11.087.Epub 2018Jun15.Recommendationsforthenomenclatureofcognitivechangeassociatedwithanaesthesia andsurgery-2018.

Flavoursandtimecourseofcognition

GA PACU-D(hrs)

POD(days)

POCD(weeks-months-years)

Cognition

Doesitmatter?Deliriumisassociatedwithfour-foldmoredeath

• Q:Isitamarkeroramediator?• A:probablyamarker…forhip#• Hamiltonetal.ASystematicReviewandMeta-analysis Examining the

ImpactofIncidentPostoperativeDeliriumonMortality(Anesthesiology2017)

Delirium

AgeASA

SurgeryDeath

MeasurementofDelirium(s)isunsatisfactory• Acute(fluctuating)disturbanceof:– Attention toenvironment

• Hyper- orhypo-active– Cognition/perception

• Diagnosis (expertsdisagreebyatleast25%,nurseassessment47%sensitive...)– DSM-5– Impression/notes,cognitivetests,Nu-DESC– RichmondAgitation-SedationScale(RASS)=arousal

– 3D-CAM andCAM-ICU(ConfusionAssessmentMethodfortheIntensiveCareUnit)=content

Deliria

ThepresentdayDx of‘delirium’iscomparabletotheDx of‘fever’;ortheDx of‘cancer’

CanwepredictwhowillgetPOD?

• Pre-operativestates

• IntraoperativeDrugs

• IntraoperativeEEGPatterns

EEGTrajectoriesduringAnesthesiaEmergenceareAssociatedwithDeliriuminthePost-AnesthesiaCareUnit,anEarlySignofPostoperativeComplications

Hesse,Sleigh,Garciaetal.BJA2019

• N=626– 125PACU-D• Pre-existingneuropathology• Durationandtypeofoperation• MaintenanceBurstsuppression(OR=1.86)

• Nospindles/alphaemergencetrajectory(OR=1.8to6.5)

• Ketamine/N2O(OR=6.51)

PACUDelirium OddsRatio ORScalingAbsent(n=501) Present(n=125) p-Value* OR(95%CI) Factor*

ProcedureCharacteristicsSurgical Discipline

ENT 2%Ɨ 3% 0.2516General 32% 34% 0.7873Gynecology 11% 14% 0.4917Orthopedics,notSpine 22% 13% 0.0242 0.52(0.30- 0.92)Plastic 3% 3% 0.9145SpineSurgery 1% 6% 0.0085 4.19(1.44- 12.17)Thoracic 1% 2% 0.7210Urology 12% 10% 0.5435Vascular 11% 12% 0.8452Other 3% 4% 0.5686

Surgical RiskMinimally Invasive Procedure 31% 30% 0.8187CardiacRiskScale 2(2,2) Ɨ 2 (2,2) 0.2551Severity Grade 2(2,2) 2(2,2) 0.6327

ProcedureDuration(min) 82.15(42,129) 112.775(62.725,179) 0.0001 2.49(1.57- 3.95) 180min

Pre- &Intra-operativeMedicationsPreoperativeMidazolam 61% 64% 0.8905PreoperativeMidazolam Dose(mg) 2(2,2) 2(2,2) 0.7449Pre/IntraoperativeOpioids(FentanylEquiv.,mcg) 250(154.1667,350) 309.1667(200,475) 0.0046 2.48(1.32- 4.65) 750mcgPre/IntraoperativeOpioids(FentanylEquiv.,mcg/kg) 2.8233(1.7655,4.3044)3.7805(2.1529,5.6684) 0.0013 2.50(1.43- 4.36) 8mcg/kgEtomidateInduction 4% 4% 0.8097Maintenance Anesthetics

Isof lurane 1% 2% 0.2201Sevof lurane 83% 76% 0.1009Desf lurane 16% 17% 0.8216Maintenance PropofolBolus(es) 9% 9% 0.8709Maintenance PropofolInfusion,non-TIVA 3% 10% 0.0016 3.34(1.58- 7.09)TIVA 2% 3% 0.2448AdjunctAnesthetic(s) 3% 10% 0.0012 3.74(1.68- 8.30)

Ketamine 1% 4% 0.0256 4.18(1.19- 14.67)NitrousOxide 2% 6% 0.0210 3.28(1.20- 8.99)

NeuromuscularBlockadeSuccinylcholine 17% 30% 0.0012 2.10(1.34- 3.29)Non-DepolarizingNeuromuscularBlock 59% 59% 0.7633Non-DepolarizingNMBwithoutReversal 10% 15% 0.1160

AnesthesiaDuration(min) 104(60,159) 148.5(93.1917,208.5) <0.0001 2.74(1.81- 4.15) 180min

Intra- &Post-operativePatientCharacteristicsIntraoperativeEEG

AnyBurstSuppresionDuringPeri- Induction 33% 39% 0.1120AnyBurstSuppresionDuringMaintenance 35% 43% 0.0176 1.72(1.10-2.70)AnyBurstSuppresion 68% 66% 0.1182

AccuracytoName andLocation <0.0001 0.32(0.25-0.40)0 15% 54%1 11% 19%2 71% 25%

AnyPainScore> 4 57% 54% 0.9052

PACUDelirium OddsRatio ORScalingAbsent(n=501) Present(n=125) p-Value* OR(95%CI) Factor*

Demographics

Age (years) 56(44,67) Ɨ 63(50,71) 0.0045 2.55(1.34-4.85) 50years

Female 39%Ɨ 41% 0.6406Weight (kg) 87.2(75.6,103.15) 86.45(71.15,100.75) 0.1825BMI 29.2(25.2,33.5) 28.95(24,33.65) 0.6370ASAPhysical Status 0.0067 1.48(1.11-1.96)

1 11% 10%2 44% 30%3 43% 53%4 2% 7%

ComorbidConditionsRespiratoryDisease 17% 22% 0.1590

Asthma 11% 10% 0.6560COPD 7% 14% 0.0186 2.10(1.13- 3.88)

CardiovascularDisease 50% 62% 0.0178 1.62(1.09- 2.42)CHF 3% 3% 0.8083Hypertension 48% 59% 0.0221 1.59(1.07- 2.37)Hxof MI 5% 10% 0.0428 2.11(1.02- 4.35)

Strokeand/orNeurodegenerative Disease** 4% 15% <0.0001 4.55(2.33- 8.88)Hxof CVA 3% 12% 0.0001 4.42(2.10- 9.31)Dementia 0% 3% 0.0125 16.53(1.83-149.22)MildCognitiveImpairment 1% 2% 0.0873 4.08(0.81- 20.47)

Hxof Seizures 3% 5% 0.3862Hxof Anxiety 6% 10% 0.1051ChronicPain 19% 23% 0.2427Depression 14% 14% 0.9935Hxof Cancer 13% 17% 0.2413ChronicRenalInsuff iciency 7% 16% 0.0019 2.54(1.41- 4.57)Diabetes 16% 20% 0.3353Liver Disease 4% 6% 0.1651

Sleep HistoryObstructiveSleep Apnea(OSA) 14% 15% 0.7252OtherSleep Disorder(notOSA) 2% 4% 0.1988EpworthSleepinessScale 5(2,7) 5(2,8) 0.0612 1.05(1.00- 1.11)STOP-BangScore 3(2,4) 4(3,5) 0.2124

MedicationUseDaily BenzodiazepineUse 2% 3% 0.2516Daily OpioidUse 8% 10% 0.5587

Social HistorySmoker, CurrentorPrevious 42% 50% 0.1427AlcoholUse 30% 22% 0.0807 0.66(0.42- 1.05)AlcoholorOtherSubstanceAbuse,CurrentorPrevious 12% 18% 0.0733 1.63(0.95- 2.79)

PreviousHeavy AlcoholUse 5% 10% 0.0428 2.11(1.02- 4.35)Heavy AlcoholUse(>14drinks/week) 4% 5% 0.5309

BURSTSUPPRESSION

(Caveats:Measurementissues&differentflavours ofBSupp)

Caveat#1: ProblemswithautomaticBurstSuppressionDiagnosis

• N=41(PODn=7)• Sedline=27minvsVisual=74min• Visualassessment=PostOperativeDelirium(CAM)

• MachineBSR=NO correlationwithpostoperativedelirium

W.G.Muhlhofer etal

Caveat#2:Wedon’tseealotinthefrontalEEG• Localcorticaldynamicsofburst

suppressionintheanaesthetizedbrain.Lewisetal.Brain2013,

• MoremarkedsuppressioninPosteriorChannels

FrontalChannels

PosteriorChannels

Courtesy:MatthiasKreutzerandStephanKratzer.TUM

Caveat#3:TherearedifferentspeciesofBSupp thatgiveyouthesamenumber(&thalamicvscorticaletc)

FewLongSuppressions

ManyShortSuppressions

IsBSupp associatedwithPOD?

Observationalstudies• Intraoperativeburstsuppressionisassociatedwithpostoperativedeliriumfollowingcardiacsurgery:a

prospective,observationalstudy.Soehle (ROC=0.73)• IntraoperativeElectroencephalogramSuppressionPredictsPostoperativeDelirium.Fritz(OR1.22per

minuteBurstSuppression)• Intraoperativeelectroencephalogramsuppressionatlowervolatileanaesthetic concentrationspredicts

postoperativedeliriumoccurringintheintensivecareunit.Fritz (OR=2.6->2.2adjusted)• Predictingpostoperativedeliriumandpostoperativecognitivedeclinewithcombinedintraoperative

electroencephalogrammonitoringandcerebralnear-infraredspectroscopyinpatientsundergoingcardiacinterventions.Momeni (OR=2.2)

Au contraire:

Can Intraoperative Processed EEG Predict Postoperative Cognitive Dysfunction in the Elderly? Stacie Deiner. Clinical Therapeutics/Volume 37, Number 12, 2015

• “PatientswhodevelopedPOCDspentlesstimeinEEGburstsuppressionandlesstimeindeepstates.”• “BurstsuppressionmaybeprotectiveforPOCD.”

PostoperativedeliriuminasubstudyofcardiothoracicsurgicalpatientsintheBAG-RECALLclinicaltrial.WhitlockELetal.A&A2014

• Lowaveragevolatileanestheticdose,intraoperativetransfusion,ASAphysicalstatus,andEuropeanSystemforCardiacOperativeRiskEvaluationwereidentifiedasindependentpredictorsofdelirium.

• “Theassociationbetweenlowanestheticconcentrationanddeliriumisasurprisingfindingandcouldreflectthatpatientswithpoorhealtharebothmoresensitivetotheeffectsofvolatileanestheticdrugsandarealsomorelikelytodeveloppostoperativedelirium.”

CanwethenactuallypreventPODbyalteringourGAdelivery?

RCTs

ProcessedElectroencephalogramMonitoringandPostoperativeDelirium:ASystematicReviewandMeta-analysis.MacKenzie KK,Britt-SpellsAM,SandsLP,LeungJ,Anesthesiology.2018Sep;129(3):417-427.

• 5RCTs(lowbiasin3) n=2654• UseofEEG…POD OR=0.62

– POCD:OR=0.69

• 6RCTs(n=2929)– BISreducessevendayPODand12weekPOCD(RR=0.71,NNT=17)– Lesscomplications (RR=0.51)

Cerebralmonitoringofanaesthesiaonreducingcognitivedysfunctionandpostoperativedelirium:asystematicreviewChunmei LuoandWeiwuZouJIntMedRes.2018Oct;46(10):4100–4110

Processedelectroencephalogramandevokedpotentialtechniquesforameliorationofpostoperativedeliriumandcognitivedysfunctionfollowingnon-cardiacandnon-neurosurgicalproceduresinadults Punjasawadwong Y,etalCochraneSystematicReview- 2018

BILLSHIPLEY.CauseandCorrelationinBiology:AUser'sGuidetoPathAnalysis,StructuralEquationsandCausalInferencewithR2nded.UnitedKingdom: CambridgeUniversityPress.

1. “Onemustbeabletorandomlyassignvaluesofthehypothesized“cause”totheexperimentalunitsindependentlyofanyattributes oftheseunits…”

2. “Assignmentmustbedirectandnotmediatedbyotherattributesoftheexperimentalunit”

“ThelogicofRCTshasweaknesseswhichseverelyrestrictstheirusefulnesstobiologists”

1. Oneisnot abletorandomlyassignvaluesof“BSupp” tothepatients,independentlyofanyBrainFrailty/CVS inthesepatients?

2. “Assignment[MAC]isnot directandis mediatedandmoderatedbythestate[BSupp/CVS/Frailty]ofthepatient”

ENGAGES:EffectofElectroencephalography-GuidedAnestheticAdministrationby255providers onPostoperativeDeliriumAmongOlderAdultsUndergoingMajorSurgery.Wildes etal.

JAMA2019

EEG+CVS/experienceguided• POD=26%(157/604)• MAC=0.69• BSRtime>1%=7min/264• TimeMAP<60mmHg=7min• Movements=22%• PONV=7.8%• SAEs=20%• Death=0.6%• Opioid=0.65• Ketamine=33• Cardiacarrest=1

Control- CVS/experienceguided?• POD=23%(140/609)• MAC=0.80• BSRtime>1%=13min/264• TimeMAP<60mmHg=7min• Movements=15%• PONV=8.9%• SAEs=21%• Death=3%(p=0.004,OR=0.2)• Opioid=0.58mg/kgmorphine• Ketamine=19(p=0.04)• Cardiacarrest=12(p=0.003)

Authors’Conclusions:atoddswiththemeta-analyses

• ‘TheprimaryfindingofthistrialwasthatEEGguidanceofanesthesia inolderadultsundergoingmajorsurgerydidnotdecreasetheincidenceofpostoperativedelirium,despitesuccessfullyreducinganesthetic exposure andduration ofEEGsuppression’

TheWebofCausality,Treatments,andOutcomes

• BSupp is associatedwithincreasedPOD.– SomehaveBSupp andnoPOD

– SomehavePODbutlittleBSupp

• MosthavefailedRx– 30-50%respondtoRx

SpecificConclusionsofENGAGES

• Most(~80%)patientshad>4minBsupp (shouldwetryharder?)

• ChangingtheaverageMACby12%- reducesBSupp burdenby30-50%- doesnotaltertheaveragerateofPOD.

• BSupp isassociatedwithPODforbothgroups.

• Wecan’tsaywhether(ornot)Bsupp causes POD.

“DoesBurstSuppressioncause POD?”or

“Can255anaesthesiaprovidersalterPOD?”

• EXPOSURE=IntraoperativeBSupp inbrain

• OUTCOME =Postoperativedelirium(POD)

• =>measurecorrelation

?

^%$&#@...thoseconfoundedconfounders!

• Afalsecorrelationbetweenexposure andoutcomemightexist,becauseofacommoncause(“brainfrailty”) X

PODandPOCD=additionalcomplexity

• Aswemovefurtherfromtheoperationtherearemoreconfoundersandexogenouscauses

• FrailtyMODERATESBSupp effects

Thisisactuallyamediator/moderatorproblem

• IsBSuppmediating MAC/FrailtyinteractionstocausePOD?

• TheexposureisMAC,notBsupp• TOTAL effectofGA=– Direct:MAC→PACU-D(hiddenbrain)

– Indirect:MAC→BSupp→PACU-D– minustheknownandunknownconfounder/moderator effects

RCT:ControlGroup• Youcan(partially)randomisetheexposure (MAC),notthemediator (BSupp).

• EEGishidden• MACisdrivenbyCVS&alltheotherconfoundersofexposureandoutcome.– thereispost-randomisationcorrelationbetweenRxandoutcome– failedRCTassumption

RCT:TreatmentGroup

• MACisdrivenbyEEG…&CVS&alltheotherconfoundersofexposureandoutcome

• ThelongandwindingroadtonegativeRCToutcomes:youbiastowardsnullwitheachstep…

• Toseeanyeffectyouneedallthelinksinthechaintobestrong.

?EEG

measurementandclinicianInterpretationandexpertise

?MAC-EEGcorrelation

&BSupp

measurement

???Strength

?Minimaleffects

Otherdrugs

AConfusionofConclusions1)BSupp ismostlyharmless,butsomeBSupp isevil2)BSupp is associatedwithPOD.

….soyoushouldmakeplansifyouseeitintraoperatively3)Manipulation ofBSupp intraoperatively isofunclearbenefitbecause:

– ThemeasurementofBSupp ispoor– ThemeasurementofPODispoor– Theinteractionsofdrugswithbrainfrailtyisunclear.– OtherthingsaremoreimportantcausesofPOD

4)Whenweunderstandthebrainmechanismsproperly,wewillknowtheanswerstothesequestions5)“Pragmatic”EEGRCTsinanaesthesia arebiasedtowardsthenull,6)RCTscan’thelptodecidewhether‘BSupp causes POD’,becausemediatorsareconfounded

Acknowledgments

• JamesS.McDonnellFoundationGrant#220023046

• Manycollaborators:– LoganVoss,AmyGaskell,RebeccaPullon,Jono Termaat,GayMans,XavierVrydag,JoelWinders,DarrenHight,MoiraandAlistairSteyn-Ross,NicoMostert.

– PaulGarcia,MattWhalin,RobSanders,KatieWarnaby,MatthiasKreutzer,StephanKratzer,GerhardSchneider,IreneTracey,SaadJbabdi,MaxKelz,DavidLiley,Misha Perouansky,Aeyal Raz,MattBanks…

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Fittinggammadistributioncurvestoboxplots

MediationAnalysis:stochasticinterventionsonexposure– dir andindir fx

• Unveilmechs throughwhichcausaleffectsoperate• Atypicalmediationanalysisseekstounderstandwhether,andtowhatdegree,

theeffectofanexposureAonanoutcomeYinvolveschanginganintermediatevariableM.Howshouldsuchananalysisbedone?TheanswerdependsonwhatismeantbytheeffectofAonYthroughM(theindirecteffect).

• BinaryexposuresdecomposeAveRxeffectintodirectandindirect• Populationinterventioneffect–canidentifyDIRECTeffect• Thenatural(in)directeffectisnotidentifiableinRCT• Interventions->exposure=randomvariableconditionedonbaselinevariables• RealworldcontrastBsupp vsNone

• Sinceidentificationrequiresuntestableassumptions– mediators,unlikeexposures,cannotberandomized– sensitivityanalysesarerecommendedafter,oraspartof,effectestimation.Seee.g.,DingandVanderweele (2016);Imai,Keele,andTingley (2010);Imai,Keele,and

• Theidentificationofcausalmechanismsismuchmorechallengingthanidentificationoftheoverallcausaleffectofthetreatmentevenifthelatterhasbeenrandomized.Thereasonisthatweneedtoseparatelyidentifytheeffectofthemediatorontheoutcomeforthosewhoendogenouslyrespondtothetreatmentintermsofthemediator,whichisanon-randomsubsampleofthepopulationofinterest.Thetypicalsolutionistoassumesequentialignorability ofthemediatorwhichrequirestheresearchertoobserveallconfoundersthatjointlydeterminethemediatorandtheoutcomeofinterestconditionalonthetreatment

• Asanalternative,theliteratureproposestocombinethemainexperimentthatrandomizesthetreatmentandmeasuresitseffectonthemediatorandtheoutcomeofinterestwithanauxiliaryexperimentthatrandomizesthemediatorand/orthetreatmentconditionalonthemediatorinordertoidentifynaturaldirectandindirecteffects

ReformulationwithGAastheexposureDoesGAactthroughBsupp tocausePOD?

• AretheadverseeffectsofGAMEDIATEDthroughBSupp?

• 4coefficients– 2hidden• GA->POD– yup• GA->Bsupp(mediator)– yup• Mediatoraffectsoutcome?

GA+Bsupp ->POD• Completely/partialmediatedby

Bsupp =>ControlBsupp.– IfGAnotcorr cPOD=>complete– Soo whenyoucontrolformediator

inRCTyouBREAKthecausalpath….

ReformulationasperGAasexposureandcontrolBSupp

• Rx:GivedoseofGAtoavoidBSupp

• Cantestimatetotaleffectbecausecontrollingamediator(intermediate)

ReformulationasperGAasexposureandcontrolBSupp

• Cantestimateeffectbecausecontrollingamediator

CausalPathwaybetweenInterventionandOutcome

• whyaninterventionwasnotsuccessfulbyhelpingtoidentifypossibleimprovementsforthedesignandevaluationoffutureinterventionstudies.