THERAPEUTIC HYPOTHERMIA AFTER CARDIAC ARREST

THERAPEUTIC THERAPEUTIC HYPOTHERMIA AFTER HYPOTHERMIA AFTER

CARDIAC ARRESTCARDIAC ARRESTAdam Oster R3Adam Oster R3

Resident Oral PresentationResident Oral PresentationNovember 13, 2003November 13, 2003

Therapeutic Hypothermia Post Therapeutic Hypothermia Post Cardiac ArrestCardiac Arrest

►Guiding questionsGuiding questions►Supporting scienceSupporting science►Preliminary studiesPreliminary studies►Clinical trialsClinical trials►Cooling technology Cooling technology ►Who to coolWho to cool►When to coolWhen to cool►How long to coolHow long to cool

Therapeutic Hypothermia Post Therapeutic Hypothermia Post Cardiac ArrestCardiac Arrest

►Baseline cardiac arrest dataBaseline cardiac arrest data►Physiology of CAPhysiology of CA►Preliminary studies of induced HTPreliminary studies of induced HT►Recent clinical trialsRecent clinical trials►Cooling TechnologyCooling Technology►The Future…The Future…

Promising Therapies?Promising Therapies?►Thiopental Thiopental ►SteroidsSteroids►Calcium channel antagonistsCalcium channel antagonists►Glutamate channel antagonistsGlutamate channel antagonists►NimodipineNimodipine►LidoflazineLidoflazine►PEG-SODPEG-SOD►Mg +/-ativanMg +/-ativan

OPALS DataOPALS Data1991-19971991-1997

► 9273 out-of-hospital CA9273 out-of-hospital CA 38.6% VF/pVT38.6% VF/pVT

►27% ROSC27% ROSC►21% admitted to hospital21% admitted to hospital►9% survival to discharge9% survival to discharge►15% poor neurologic outcome *15% poor neurologic outcome *

*not OPALS data*not OPALS data

7% of all pre-hospital CA return home to 7% of all pre-hospital CA return home to independent livingindependent living Eisenberg, M. Annals of Emergency Medicine, 1990.Eisenberg, M. Annals of Emergency Medicine, 1990.

VF/VTVF/VTCognitive SequelaeCognitive Sequelae

►Outcome of patients surviving to Outcome of patients surviving to hospital post-VF/VT with GCS =/<9hospital post-VF/VT with GCS =/<9 Best estimates (based on control group in Best estimates (based on control group in

two large trials)two large trials)►Mortality at 6 moMortality at 6 mo 55%-68% 55%-68%►Neurologic outcome at 6 moNeurologic outcome at 6 mo

26-40% poor outcome [CPC 3/4]26-40% poor outcome [CPC 3/4]

Cardiac Arrest:Cardiac Arrest:Cognitive Sequelae Cognitive Sequelae

► Graves, J. Resuscitation 1997Graves, J. Resuscitation 1997 Sweden 1980-1993 Sweden 1980-1993 N=3754N=3754

► 9% survived to discharge9% survived to discharge► 21% mortality at 1yr21% mortality at 1yr► 56% by 5yrs56% by 5yrs► 82% by 10yrs82% by 10yrs

► Cerebral Performance Category on discharge, N=320Cerebral Performance Category on discharge, N=320► 1 53%1 53%► 2 21%2 21%► 3 24%3 24%► 4 2%4 2%

Adam Oster

all comers with CAnot reported percent in coma post resuscitation CPC 1 good cerebral performace2 moderate cerebral disability3 severe disability4 persistent veg state5 death1/2 considered a good outcome

Cardiac Arrest:Cardiac Arrest:Cognitive SequelaeCognitive Sequelae

►Bur, A. Intensive Care Medicine, 2001.Bur, A. Intensive Care Medicine, 2001. Patients admitted Patients admitted post-VF CApost-VF CA, N=276 , N=276

(out of 1254)(out of 1254)►50% mortality at 6mo50% mortality at 6mo►87% good neurologic outcome87% good neurologic outcome►Age, duration of ROSC, time to EMS, time to 1Age, duration of ROSC, time to EMS, time to 1stst

defib, and amount of epi all significantly defib, and amount of epi all significantly related to CPC category.related to CPC category.

Adam Oster

again no breakdown of GCS on arrival to see the neuro outcome of these patients

Cardiac Arrest:Cardiac Arrest:Cognitive Sequelae and QOLCognitive Sequelae and QOL

►Granja, C. Resuscitation, 2002.Granja, C. Resuscitation, 2002. Compared CPC and QOL post-CACompared CPC and QOL post-CA QOR survey administered at 6mo, QOR survey administered at 6mo,

N=24N=24/97/97 N=97 admitted after CAN=97 admitted after CA

►36 (37%) discharged from hospital36 (37%) discharged from hospital►12 more died before 6mo12 more died before 6mo►5 LTFU5 LTFU►Questionnaire administered to 19Questionnaire administered to 19

No significant differences compared to other non-CA No significant differences compared to other non-CA ICU survivorsICU survivors

Adam Oster

raises an interesting question of whether the goal of ACLS is to return people to pre-arrest CPC or to have a high QOL

Cardiac Arrest PhysiologyCardiac Arrest Physiology►4 stages 4 stages

Pre-arrestPre-arrest ArrestArrest ResuscitationResuscitation Post-resuscitationPost-resuscitation

How Effective is CPR?How Effective is CPR?►CPR cardiac outputCPR cardiac output

optimally carried-out up to 60%optimally carried-out up to 60% realistically 20-30%realistically 20-30% CO inversely proportional to duration of CO inversely proportional to duration of

CA preceding initiation of CPRCA preceding initiation of CPR animal models;animal models;

►50% pre-arrest CBF if <2mins50% pre-arrest CBF if <2mins►0% if >10mins0% if >10mins

Cardiac Arrest PhysiologyCardiac Arrest Physiology► Arrest and Resuscitative PhasesArrest and Resuscitative Phases

No to low-flow state tolerated for approx 5minsNo to low-flow state tolerated for approx 5mins Brain O2 stores lost in 20secsBrain O2 stores lost in 20secs ATP and glucose in 5 minsATP and glucose in 5 mins cells revert to anaerobic metabolismcells revert to anaerobic metabolism Major mechanism of injury is Ca influxMajor mechanism of injury is Ca influx

► multiple biochemical pathways are initiatedmultiple biochemical pathways are initiated► loss of normal cellular ionic gradientsloss of normal cellular ionic gradients► tissues most susceptible -- tissues most susceptible --

brain (esp. hippocampus, cerebral cortex and cerebellum)brain (esp. hippocampus, cerebral cortex and cerebellum)Ross. Journal of Cerebral Blood Flow and Metabolism, 1993.Ross. Journal of Cerebral Blood Flow and Metabolism, 1993.

Adam Oster

considerable evidence that part of the neurologic injury occurs after ROSC = reperfusion injury

Cerebral Blood FlowCerebral Blood Flow►Post-arrest CBFPost-arrest CBF

Reperfusion injuryReperfusion injury►After initial increase, CBF reduced to 50% After initial increase, CBF reduced to 50%

normal for 90mins to 24hrs in normotensive normal for 90mins to 24hrs in normotensive ptspts

►Heterogenous CBFHeterogenous CBF►Increase in cerebral O2 uptakeIncrease in cerebral O2 uptake

Bottiger, et al., Resuscitation 1997.Bottiger, et al., Resuscitation 1997.

Some evidence of raised ICP and cerebral Some evidence of raised ICP and cerebral edemaedema post-ROSC.post-ROSC.

Morimoto, et.al., Critical Care Medicine, 1993.Morimoto, et.al., Critical Care Medicine, 1993.

Adam Oster

evidence that cerebral O2 demand is increased but that CBF is decreased for 12-24hrs post ROSC despite normal MAP.

Effects of HyperthermiaEffects of Hyperthermia►Hickey, R. Critical Care Medicine. Hickey, R. Critical Care Medicine.

2003.2003. Hyperthermia exacerbates histologic Hyperthermia exacerbates histologic

neuronal damage post-hypoxic arrest in neuronal damage post-hypoxic arrest in rats.rats.

Hypothermia PhysiologyHypothermia Physiology►How could hypothermia help?How could hypothermia help?

7% reduction in cerebral metabolic rate (CMRO2) 7% reduction in cerebral metabolic rate (CMRO2) for every 1 degree reduction in brain temp.for every 1 degree reduction in brain temp.

► In part due to reduction in electric activityIn part due to reduction in electric activityCritical Care Medicine, 1996Critical Care Medicine, 1996

Suppresses many chemical reactionsSuppresses many chemical reactions► Reduction in oxidative damageReduction in oxidative damage► Reduces free calcium shiftsReduces free calcium shifts► Maintains mitochondrial functionMaintains mitochondrial function► Reduces excitatory glutamate releaseReduces excitatory glutamate release

Journal of Cerebral Blood Flow, 2000.Journal of Cerebral Blood Flow, 2000.

Hypothermia PhysiologyHypothermia Physiology►CNS effects of IHCNS effects of IH

Cerebral metabolic rate for O2 is the major Cerebral metabolic rate for O2 is the major determinant of CBFdeterminant of CBF

►May improve flow to selective ischemic areas of May improve flow to selective ischemic areas of the brainthe brain

Decreases ICPDecreases ICP►Likely due to global cerebral vasoconstriction Likely due to global cerebral vasoconstriction

and decreased IC blood volumeand decreased IC blood volume Critical Care Medicine, 1984.Critical Care Medicine, 1984.

Decreases amount of excitatory neurotransmittersDecreases amount of excitatory neurotransmitters Anaesthesia, 1994.Anaesthesia, 1994.

Hypothermia PhysiologyHypothermia Physiology►CVS Effects of IHCVS Effects of IH

With shivering mechanism blocked…With shivering mechanism blocked…► Decrease HRDecrease HR► Increases SVRIncreases SVR► SV and MAP constantSV and MAP constant► Osbourne wave at 33 degOsbourne wave at 33 deg

Hypothermia PhysiologyHypothermia Physiology►Respiratory Effects of IHRespiratory Effects of IH

?increased risk of pneumonia?increased risk of pneumonia►Does not appear to if <24hrsDoes not appear to if <24hrs

Hypothermia PhysiologyHypothermia Physiology►Renal effects of IHRenal effects of IH

Decreased resorbtion of solute causes Decreased resorbtion of solute causes osmotic diuresisosmotic diuresis

K shifts into cellsK shifts into cells Decreased phosphateDecreased phosphate

Hypothermia PhysiologyHypothermia Physiology►Acid-Base/ABG correctionAcid-Base/ABG correction

When ABG corrected for temp, looks like a When ABG corrected for temp, looks like a respiratory alkalosisrespiratory alkalosis

►Controversial whether ABGs should be Controversial whether ABGs should be corrected for temp but currently they are not corrected for temp but currently they are not correctedcorrected

►Some evidence for better outcome (animal Some evidence for better outcome (animal studies) if you do correct for temp and manage studies) if you do correct for temp and manage pH pH decreased cerebral infarct volume and decreased cerebral infarct volume and amount of edema formed.amount of edema formed.

► Anesthesiology, 2002.Anesthesiology, 2002.

Hypothermia PhysiologyHypothermia Physiology►GI effects of IHGI effects of IH

Decreased motilityDecreased motility Decreased insulin release causes increase Decreased insulin release causes increase

in glucose. All patients require insulin to in glucose. All patients require insulin to avoid the complications of hyperglycemia.avoid the complications of hyperglycemia.

Induced Hypothermia TrialsInduced Hypothermia Trials► Bigelow, 1950.Bigelow, 1950.► Benson et al., 1955.Benson et al., 1955.► Williams and Spencer, 1958.Williams and Spencer, 1958.► Bernard et al. Annals of Emergency Bernard et al. Annals of Emergency

Medicine, 1997.Medicine, 1997.► Yanagawa et al. Resuscitation, 1998.Yanagawa et al. Resuscitation, 1998.► Zeiner, et al. Stroke, 2000Zeiner, et al. Stroke, 2000► Holzer et al. NEJM, 2002. Holzer et al. NEJM, 2002. ► Bernard et al. NEJM, 2002.Bernard et al. NEJM, 2002.

Adam Oster

hypothermia for cerebral protection has been used since the 1950ssimple chemistry that reduction of 10deg slows biochemical rxn by 50%Bigelow used prospective hypothermia in open-heart surgery.Benson cooled 4 pts to 30-33 post in-hospital CA for 24-72hrs --> all 4 recovered

Neurologic Outcome Neurologic Outcome MeasurementsMeasurements

►Glasgow Outcome ScoreGlasgow Outcome Score►Cerebral Performance CategoryCerebral Performance Category►Physiatrist assessment of best Physiatrist assessment of best

discharge locationdischarge location

Adam Oster

effectively identical for our purposescombined 1 and 2 = good outcome in most of these studies = live independently and work at least part-timeGOS1 normal/minimal disability2 mod disability3 conscious, severe disability4 vegetative5 deadCPC1 good recovery2 mod disability3 severe disability4 vegetative5 deadPhysiatrist assessmentsimilar categories (discharged home or to rehab considered good outcome)although it is possible to image a person discharged to a nursing home because of lack of social supports

Bernard et al., Bernard et al., Annals of Emergency Medicine, Annals of Emergency Medicine,

1997.1997.►Prospective, consecutive case series Prospective, consecutive case series

compared to consecutive historic control compared to consecutive historic control groupgroup

►ROSC post-CA (included non-VF/VT)ROSC post-CA (included non-VF/VT)►Exclusion Exclusion

SBP <90 with pressorsSBP <90 with pressors Decreased LOC possibly due to trauma or Decreased LOC possibly due to trauma or

CVACVA Age <16, possibly pregnantAge <16, possibly pregnant

►N=22N=22


1997.1997.► Intubation/paralysis and sedationIntubation/paralysis and sedation►Surface cooling with ice packs to 33deg for Surface cooling with ice packs to 33deg for

12hrs then actively rewarmed12hrs then actively rewarmed►Thrombolysis as indicated (no angioplasty)Thrombolysis as indicated (no angioplasty)►Similar protocoled ICU managementSimilar protocoled ICU management►Glasgow Outcome Scale estimated by Glasgow Outcome Scale estimated by

unblinded chart review based on data at unblinded chart review based on data at time of hospital dischargetime of hospital discharge

Adam Oster

at 72 hrs a decision was made whether to transfer to CCU unless continued ICU care was necessary, trach and tx to ward if still in coma and if coma and no BS reflexes, withdrawl of care.


1997.1997.► ResultsResults

2 groups comparable at entry2 groups comparable at entry► Similar incidences of witnessed collapse, time to CPR, Similar incidences of witnessed collapse, time to CPR,

ROSC, VF as presenting rhythm, brainstem reflexesROSC, VF as presenting rhythm, brainstem reflexes► None in NT group received thrombolysis vs 4 in MH groupNone in NT group received thrombolysis vs 4 in MH group

MortalityMortality► MH 10 vs NT 17 (45% vs 77% ARR 32% MH 10 vs NT 17 (45% vs 77% ARR 32% NNT 3), sig. NNT 3), sig.

Good neurologic outcomesGood neurologic outcomes (GOS1/2) (GOS1/2)► MH 11 vs NT 3 (50% vs. 13.7, ARR 36% MH 11 vs NT 3 (50% vs. 13.7, ARR 36% NNT 2.7), sig. NNT 2.7), sig.

Adverse EventsAdverse Events► No difference between groupsNo difference between groups

Adam Oster

good neurologic outcome = discharge directly homemoderate disability = discharged to a rehab facility awake and alert but requiring assistance with ADLsno OR or confidence intervals pubilshed


1997.1997.► Study limitationsStudy limitations

Small numbersSmall numbers Historic controlsHistoric controls

► Some pre-hospital data unavailable (eg EMS to ROSCSome pre-hospital data unavailable (eg EMS to ROSC► Unclear if post-resuscitation protocols similarUnclear if post-resuscitation protocols similar

Non-blinded assessment of outcome Non-blinded assessment of outcome classification classification biasbias

Underpowered to find difference in adverse eventsUnderpowered to find difference in adverse events► StrengthsStrengths

MH feasible and likely safe MH feasible and likely safe May have effect on mortality and neurologic May have effect on mortality and neurologic

outcomeoutcome

Yanagawa, et al. Yanagawa, et al. Resuscitation, 1998Resuscitation, 1998

► Consecutive, patients with ROSC post-CA, Consecutive, patients with ROSC post-CA, N=13N=13► Compared to historic normothermic control Compared to historic normothermic control

group.group.► Similar exclusion criteriaSimilar exclusion criteria► Intubated/paralyzed/sedated as per protocolIntubated/paralyzed/sedated as per protocol► MH cooled to 33 deg for 48hrs using cooling MH cooled to 33 deg for 48hrs using cooling

blankets and EtOH on skinblankets and EtOH on skin► Passively rewarmed over 3-4 daysPassively rewarmed over 3-4 days► GOS at 6 mo (not blinded to treatment)GOS at 6 mo (not blinded to treatment)

Adam Oster

pilot study to test feasibility of MH and determine backgroup numbers

Yanagawa, et al. Yanagawa, et al. Resuscitation, 1998Resuscitation, 1998

►ResultsResults Groups had different incidences of cardiac Groups had different incidences of cardiac

(vs pulmonary) etiology of arrest(vs pulmonary) etiology of arrest Stat sig difference in witnessed collapse Stat sig difference in witnessed collapse

(10 vs 3, in MH group)(10 vs 3, in MH group) No difference in mortalityNo difference in mortality 3 vs 1 with GOS 1/23 vs 1 with GOS 1/2 Stat sig. increase in pulmonary Stat sig. increase in pulmonary

complications in MH group complications in MH group

Zeiner, A. et al., Zeiner, A. et al., Stroke, 2000.Stroke, 2000.

► Prospective, multicentered.Prospective, multicentered.► Historic controlsHistoric controls► Included only post-VFIncluded only post-VF► ExclusionExclusion

CA <5 or >15 mins or 60 mins without ROSC CA <5 or >15 mins or 60 mins without ROSC Post-resuscitation SBP<60 or SaO2<85Post-resuscitation SBP<60 or SaO2<85 Pts having subsequent CA within 6moPts having subsequent CA within 6mo

► Cooled to 33deg via external head and body Cooled to 33deg via external head and body for 24hrs then passively rewarmedfor 24hrs then passively rewarmed

► CPC at 6moCPC at 6mo

Zeiner, A. et al., Zeiner, A. et al., Stroke, 2000Stroke, 2000

►ResultsResults 31 pts MH31 pts MH

►4 excluded from analysis4 excluded from analysis►11 died (mortality 41%)11 died (mortality 41%)►CPC 1/2 14 (52%)CPC 1/2 14 (52%)►CPC 3/4 2 (7%)CPC 3/4 2 (7%)

No formal comparison with historic No formal comparison with historic controlscontrols

Adam Oster

just said that compared with historic controls represents a 2 fold improvement in outcome

Bernard et al. and Holzer et al., Bernard et al. and Holzer et al., NEJM, 2002.NEJM, 2002.

►Two (European and Australian) Two (European and Australian) prospective, randomised controlled trials prospective, randomised controlled trials of MH post VF/VT CA.of MH post VF/VT CA.

►Similar inclusion and exclusion criteriaSimilar inclusion and exclusion criteria►Primary outcome was neurologic function Primary outcome was neurologic function

at 6 mo or discharge from hospitalat 6 mo or discharge from hospital►Differences: Differences: cooling methodology, cooling methodology,

initiation of IH, total duration of initiation of IH, total duration of cooling and blinding of evaluators.cooling and blinding of evaluators.

Bernard et al., Bernard et al., NEJM, 2002.NEJM, 2002.

►Australian TrialAustralian Trial►Only included VF-resuscitated out-of-Only included VF-resuscitated out-of-

hospital pts who remained hospital pts who remained unresponsiveunresponsive Did not specify duration of CADid not specify duration of CA

►Exclusion criteria…Exclusion criteria…►Odd-even day randomization Odd-even day randomization ►Pre-hospital initiation of coolingPre-hospital initiation of cooling►Thrombolysis as indicatedThrombolysis as indicated

Adam Oster

exclusion criteriaSBP<90 with pressorsage <50 woman ?pregnant <18menpossible other etiologies of CAif ICU bed unavailablerandomisation =?psuedorandomisation


► Ice packs to head, neck, torso and limbsIce packs to head, neck, torso and limbs►MH for 12hrs with sedation and paralysisMH for 12hrs with sedation and paralysis►Actively re-warmed with heating blanket Actively re-warmed with heating blanket

at 18hrsat 18hrs►After 24hrs patient care followed usual After 24hrs patient care followed usual

ICU protocolsICU protocols►Blinded assessment by Physiatrist when Blinded assessment by Physiatrist when

pt ready for d/c from hospital (good vs pt ready for d/c from hospital (good vs poor outcome)poor outcome)


►84 pts eligible over 33mo84 pts eligible over 33mo►7 excluded from analysis7 excluded from analysis►77 pts 77 pts 43 (MH), 34 (NT) 43 (MH), 34 (NT)

Groups statistically different in rates of Groups statistically different in rates of bystander CPR (NT>MH)bystander CPR (NT>MH)

►72 treated correctly72 treated correctly► Intention-to-treat analysisIntention-to-treat analysis►Median time to target temp from Median time to target temp from

ROSC, 120minROSC, 120min


►ResultsResults Good neuro outcome at discharge Good neuro outcome at discharge

(MH vs NT)(MH vs NT)►49% vs 26%, p=0.045 (n=21 vs 9)49% vs 26%, p=0.045 (n=21 vs 9)

ARR 23% ARR 23% NNT 4 NNT 4 OROR for good outcome with MH was for good outcome with MH was 5.255.25 (1.47-18.5), (1.47-18.5),

p=0.01p=0.01 Mortality (MH vs NT)Mortality (MH vs NT)

►51% vs 68% (95% CI crosses 1)51% vs 68% (95% CI crosses 1) Complication rateComplication rate

►Not statedNot stated


► Take homeTake home Small studySmall study Randomization method Randomization method Neurologic benefitNeurologic benefit Mortality benefit not statistically sigMortality benefit not statistically sig

► ?underpowered?underpowered Unblinded treating physicians may have Unblinded treating physicians may have

introduced treatment biasintroduced treatment bias Unable to confirm that outcome assessors were Unable to confirm that outcome assessors were

blinded to treatment assignmentblinded to treatment assignment Did not publish complication rateDid not publish complication rate

Holzer et al. Holzer et al. NEJM, 2002.NEJM, 2002.

► Consecutive pts, with witnessed VF/VT CA, Consecutive pts, with witnessed VF/VT CA, >18yrs, CA duration>5 and <15mins, >18yrs, CA duration>5 and <15mins, ROSC<60minsROSC<60mins

► Exclusion criteria…Exclusion criteria…► No thrombolysisNo thrombolysis► Randomised to MH (33 deg) using a cooling Randomised to MH (33 deg) using a cooling

blanket (TheraKool®) +/- ice packs if requiredblanket (TheraKool®) +/- ice packs if required► Cooling for 24hrs, followed by passive Cooling for 24hrs, followed by passive

rewarmingrewarming► Standard, protocoled intensive careStandard, protocoled intensive care

Adam Oster

excluded ifhypothermiccardiogenic shock MAP<60 >30minand if SaO2 <85% >15mincoma priorpregnantGCS>9pre-arrest terminal illness


►Primary OutcomePrimary Outcome Blinded assessment of neurologic status Blinded assessment of neurologic status

within 6mo (Cerebral Performance Category)within 6mo (Cerebral Performance Category)►Secondary OutcomeSecondary Outcome

MortalityMortality Rate of complicationsRate of complications

► Intention-to-treat analysis for mortality Intention-to-treat analysis for mortality outcome onlyoutcome only


► ResultsResults 3551 pts eligible 3551 pts eligible

► 34263426 did not meet inclusion criteria did not meet inclusion criteria► 3030 excluded for other reasons excluded for other reasons► 8% enrolled,8% enrolled, 275 275 175 MH, 138 NT. 175 MH, 138 NT.► Groups different at baseline for DM/CAD and receipt of Groups different at baseline for DM/CAD and receipt of

BLS (all higher in NT group), none stat sig.BLS (all higher in NT group), none stat sig.► Median time to cooling Median time to cooling 105mins105mins► Median time between ROSC and attainment of target Median time between ROSC and attainment of target

temp, temp, 8hrs8hrs► Target temp not reached in 19ptsTarget temp not reached in 19pts► Hypothermia discontinued early in 14 ptsHypothermia discontinued early in 14 pts


► ResultsResults Favorable neurologic outcomeFavorable neurologic outcome CPC1/2 (MH vs CPC1/2 (MH vs

NT)NT)► 55% vs 39%, (RR 1.47, 95% CI 1.09-1.82)55% vs 39%, (RR 1.47, 95% CI 1.09-1.82)

ARR 16% ARR 16% NNT 6.25 (4-25) NNT 6.25 (4-25) Mortality (MH vs NT)Mortality (MH vs NT)

► 41% vs 55%, (RR 0.74, 0.58-0.95) 41% vs 55%, (RR 0.74, 0.58-0.95) ► ARR 14% ARR 14% NNT 7 (4-33) NNT 7 (4-33)

Complication ratesComplication rates different between groups but different between groups but not statistically significant (approx 70% of patients not statistically significant (approx 70% of patients in both groups)in both groups)

► 22% more complications MH group (pneumonia NNH=12, 22% more complications MH group (pneumonia NNH=12, sepsis NNH=14)sepsis NNH=14)

Adam Oster

if you included the pts in MH group who were excluded from analysis in the complication get a rate of 1.5/pt vs 1.1/pt in NT groupNB.could not verify blinding of evaluators


►Take homeTake home Larger studyLarger study Neurologic and mortality benefitNeurologic and mortality benefit

►NNT 6-7 for each end-pointNNT 6-7 for each end-point Establishes that there is a higher rate of Establishes that there is a higher rate of

complicationscomplications Unblinded treating physicians Unblinded treating physicians Could not verify blinding of outcome Could not verify blinding of outcome

assessments.assessments.

Holzer and BernardHolzer and BernardTrial Feature Holzer Bernard

inclusion differences witnessed VF/VT witnessed VF

Exclusion >5 <15 mins to first BLS no restriction to time to BLS

N= 275 77

Randomization stratified according to centre even-odd day

Initiation of cooling hospital pre-hospital

Lytics? no yes

cooling device Mattress (TheraKool) ice-packs (CoolCare)

Duration of cooling 24 12

Goal temp 33 33 =/-1

Rewarming passive actively at 18hrs

Primary end-point favourable outcome within 6mo at hospital discharge

Result 55% vs 39% 49% vs 26%

NNT 6.25 4

Mortality 41% vs 55% 51% vs 68%

Complications NS not stated

Lingering questionsLingering questions►Were groups randomised for Were groups randomised for allall

important prognostic features?important prognostic features? Ie brains stem reflexes, glucIe brains stem reflexes, gluc

►Blinding of outcome evaluatorsBlinding of outcome evaluators How big a deal is not blinding the treating How big a deal is not blinding the treating

and outcome physicians?and outcome physicians?►Optimal time of initiation of coolingOptimal time of initiation of cooling►Re-warming strategyRe-warming strategy►Cooling techniqueCooling technique

Were groups randomised for all Were groups randomised for all important prognostic features?important prognostic features?

►Longstreth. NEJM, 1993.Longstreth. NEJM, 1993.►4 criterion model that predicts neurologic 4 criterion model that predicts neurologic

recovery (awakening) after out-of-hospital VF recovery (awakening) after out-of-hospital VF or asystolic CAor asystolic CA

►Retrospectively derived and testedRetrospectively derived and tested►Predictor variables from ICU admission notePredictor variables from ICU admission note►Median time 2.7days (longest 100days)Median time 2.7days (longest 100days)►N=389N=389

50% survived to discharge50% survived to discharge 209 209 awakenedawakened

Adam Oster

outcome variable was ability to follow commands or speak comprehensibly

Longstreth. NEJM, 1993.Longstreth. NEJM, 1993.►Predictor variablesPredictor variables

Motor response (0-4) Motor response (0-4) ►absent, extensor, flexor, non-posturing, absent, extensor, flexor, non-posturing,

withdraws or localizes.withdraws or localizes. Pupillary light response (3x)Pupillary light response (3x) Spontaneous eye movementsSpontaneous eye movements Glucose <20mmol/LGlucose <20mmol/L

Longstreth. NEJM, 1993.Longstreth. NEJM, 1993.

►Test CohortTest Cohort Cutoff of >/=4 maximized sensitivity (0.92) Cutoff of >/=4 maximized sensitivity (0.92)

and specificity (0.65). and specificity (0.65). NPV 0.84 PPV .80NPV 0.84 PPV .80 44 errors in classification44 errors in classification

►Majority were of predicted awakening in patients Majority were of predicted awakening in patients who never awakenedwho never awakened

►16 patients predicted not to awaken who did 16 patients predicted not to awaken who did awakenawaken

12 with severe neurologic defecits12 with severe neurologic defecits 4 awakened within 36hrs and made a good 4 awakened within 36hrs and made a good

recovery and returned to pre-arrest functioning.recovery and returned to pre-arrest functioning.

Adam Oster

neither study presented data on baseline BS reflexesbut should this have been accounted for by adequate randomisation?Also time to ROSC presented and equal but are these proxies for neurologic examination

Non-blinding of treating Non-blinding of treating physicians – introduction of physicians – introduction of

bias?bias?►Schulz, K. Empirical Evidence of Bias. Schulz, K. Empirical Evidence of Bias.

JAMA, 1995.JAMA, 1995. Observational meta-analysis which Observational meta-analysis which

assessed the methodological quality of assessed the methodological quality of 250 controlled studies on a specific topic 250 controlled studies on a specific topic

Determined the associations between Determined the associations between those assessments and the published those assessments and the published treatment effects.treatment effects.

Schulz, K. Empirical Evidence of Schulz, K. Empirical Evidence of Bias. JAMA, 1995.Bias. JAMA, 1995.

►Controlling for allocation concealmentControlling for allocation concealment Trials that were not double-blinded had Trials that were not double-blinded had

OR that were 17% higher than those trials OR that were 17% higher than those trials that were double-blindedthat were double-blinded

Timing of cooling.Timing of cooling.►When should cooling be initiated?When should cooling be initiated?►When is it When is it too latetoo late for cooling to be for cooling to be

beneficial?beneficial?

When should cooling be When should cooling be initiated?initiated?

► Kuboyama et al. Critical Care Medicine, 1993.Kuboyama et al. Critical Care Medicine, 1993. Prospective, randomised and controlled dog studyProspective, randomised and controlled dog study N=18N=18 VF arrest 12.5min VF arrest 12.5min CPB CPB defib <5min defib <5min

randomised randomised standard ICU care for 96hrs standard ICU care for 96hrs 3 groups3 groups

► NT controlNT control► Immediate IH to 24 deg for 60minsImmediate IH to 24 deg for 60mins► Delayed IH for 15mins then maintained for 60minsDelayed IH for 15mins then maintained for 60mins

better overall performance category in group 2 (NS) better overall performance category in group 2 (NS) and improved brain histologic score.and improved brain histologic score.

Adam Oster

little data and no human studies.2 dog studies and this is the best.CPB=cardiopulmonary bypassNo data on when it is too late to initiate cooling

Clinical Feasibility StudiesClinical Feasibility StudiesHow to coolHow to cool

►External blanketsExternal blankets► Ice-packs Ice-packs

►Cranial coolingCranial cooling►Cold fluid IV infusionCold fluid IV infusion

Clinical Feasibility StudiesClinical Feasibility Studies►Felberg, et al. Circulation, 2001.Felberg, et al. Circulation, 2001.

2 Cooling blankets (RK-2000, Thermia) 2 Cooling blankets (RK-2000, Thermia) Initiation to goal temp took median time Initiation to goal temp took median time

of 300min (goal 120mins).of 300min (goal 120mins). Approximately 0.3C/hrApproximately 0.3C/hr

Clinical Feasibility StudiesClinical Feasibility Studies►Callaway, et al., Resuscitation, 2002.Callaway, et al., Resuscitation, 2002.

External cranial cooling External cranial cooling ►Ice applied to head and necks of subjects with Ice applied to head and necks of subjects with

out-of-hospital arrests during CPRout-of-hospital arrests during CPR►Rate of temp decrease 0.06 +/-0.06 C/min Rate of temp decrease 0.06 +/-0.06 C/min

similar to control group without ice.similar to control group without ice.►Likely ineffectiveLikely ineffective

Adam Oster

all CA pts mildly hypothermic at entry 35.5

Clinical Feasibility StudiesClinical Feasibility Studies►Hachimi-Idrissi, et al. Resuscitation, Hachimi-Idrissi, et al. Resuscitation,

2001.2001. Helmet device Helmet device (Frigicap®)(Frigicap®) containing aqueous containing aqueous

glycerol placed around the head and neck. Kept glycerol placed around the head and neck. Kept in refrigerator prior to use. Changed Q1H.in refrigerator prior to use. Changed Q1H.

Clinical Feasibility StudiesClinical Feasibility Studies►Hachimi-Idrissi, et al. Resuscitation, Hachimi-Idrissi, et al. Resuscitation,

2001.2001. Mean starting temp 35.7Mean starting temp 35.7 Target bladder temp reached at median Target bladder temp reached at median

time of 180min after ROSC.time of 180min after ROSC. (Target median tympanic temp reached at (Target median tympanic temp reached at

60min)60min)

Clinical Feasibility StudiesClinical Feasibility Studies►Bernard, et al. Resuscitation, 2003.Bernard, et al. Resuscitation, 2003.

30cc/kg 4 deg LR over 30min for induction 30cc/kg 4 deg LR over 30min for induction followed by ice-packs followed by ice-packs

N=22 CA ptsN=22 CA pts No adverse events (including pulmonary No adverse events (including pulmonary

edema)edema) Median decrease in core (bladder) temp Median decrease in core (bladder) temp

1.6 deg1.6 deg

ILCOR Advisory StatementILCOR Advisory Statement►Nolan, J. et al., Circulation, 2003.Nolan, J. et al., Circulation, 2003.

Recommends MH in witnessed, out-of-Recommends MH in witnessed, out-of-hospital VF arrests with spontaneous hospital VF arrests with spontaneous ROSC who remain unconsciousROSC who remain unconscious

Cool to 32-34 degrees for 12 to 24hrsCool to 32-34 degrees for 12 to 24hrs

CCU (draft) ProtocolCCU (draft) ProtocolInclusionInclusion

► WitnessedWitnessed► VF or pVTVF or pVT► 18-75 yrs18-75 yrs

► <15min est to BLS<15min est to BLS► <60mins to ROSC<60mins to ROSC

► MAP>60 MAP>60

ExclusionExclusion► Initial T<30Initial T<30

► GCS>9GCS>9► Coma prior to CAComa prior to CA

► PregnantPregnant► Terminal illnessTerminal illness

► SaO2 < 85% SaO2 < 85% >15min>15min

► Shock (?)Shock (?)

CCU (draft) ProtocolCCU (draft) Protocol►Minimum of 10 covered ice packs +/- Minimum of 10 covered ice packs +/-

cooling blankets prncooling blankets prn►Maintain for 24hrsMaintain for 24hrs►Allow for passive re-warmingAllow for passive re-warming► Intubation/sedation/paralysisIntubation/sedation/paralysis►Document neurologic exam prior to Document neurologic exam prior to

initiation initiation

Take HomeTake Home► Appropriate patients are a highly selected Appropriate patients are a highly selected

sub-group (approx 8% of all-comers with sub-group (approx 8% of all-comers with CA)CA) Arrest of primary cardiac originArrest of primary cardiac origin WitnessedWitnessed First attempt at resuscitation <15minsFirst attempt at resuscitation <15mins ROSC<60minsROSC<60mins SBP>90 and SaO2>90%SBP>90 and SaO2>90% Remain unresponsiveRemain unresponsive Reasonable pre-arrest quality of life and life Reasonable pre-arrest quality of life and life

expectancyexpectancy Insufficient evidence to support ped useInsufficient evidence to support ped use

Take HomeTake Home► Timing of CoolingTiming of Cooling

As soon as possible after ROSC (animal studies) As soon as possible after ROSC (animal studies) ► But, likely beneficial even if delayed upto 6hrsBut, likely beneficial even if delayed upto 6hrs

?No longer than 16hrs after ROSC?No longer than 16hrs after ROSC► Target TemperatureTarget Temperature

More research neededMore research needed 33 deg +/- 1 deg33 deg +/- 1 deg

► Duration of CoolingDuration of Cooling More research neededMore research needed No longer than 24hrs (may not be any benefit No longer than 24hrs (may not be any benefit

from >12hrs)from >12hrs)

Adam Oster

approx 8-9% of all out-of-hospital CA patients

Take HomeTake Home►Cooling TechniqueCooling Technique

Unsure if any benefit from rapid induction Unsure if any benefit from rapid induction of MH vs gradual onsetof MH vs gradual onset

External cooling method (ie. Cooling External cooling method (ie. Cooling blanket +/- ice packs) are the simplest blanket +/- ice packs) are the simplest and have been tested.and have been tested.

Other strategies are experimental (eg. Other strategies are experimental (eg. cold RL bolus, frigicap) and may be helpful cold RL bolus, frigicap) and may be helpful for inductionfor induction

The Near FutureThe Near Future►Formalized relationship with Critical Formalized relationship with Critical

Care Medicine (ICU and CCU) with a Care Medicine (ICU and CCU) with a shared protocol and QA strategy.shared protocol and QA strategy. Initiated cooling of appropriate patients in Initiated cooling of appropriate patients in

the EDthe ED Transfer to the receiving service with Transfer to the receiving service with

minimal delayminimal delay

The Not-So-Near FutureThe Not-So-Near Future►Further studies to define optimal Further studies to define optimal

implementation of induced implementation of induced hypothermiahypothermia

►Study whether benefit in other arrest Study whether benefit in other arrest rhythmsrhythms

►Pediatric population applicationPediatric population application

THERAPEUTIC HYPOTHERMIA AFTER CARDIAC ARREST

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