Postoperative Cognition and Burst Suppression · postoperative delirium occurring in the intensive...
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Postoperative Cognition and Burst Suppression Jamie Sleigh Department of Anaesthesia, University of Auckland, Waikato Hospital, Hamilton, New Zealand
Transcript of Postoperative Cognition and Burst Suppression · postoperative delirium occurring in the intensive...
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.
