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THERAPEUTIC HYPOTHERMIA AFTER CARDIAC ARREST

THERAPEUTIC HYPOTHERMIA AFTER CARDIAC ARREST. Adam Oster R3 Resident Oral Presentation November 13, 2003. Therapeutic Hypothermia Post Cardiac Arrest. Guiding questions Supporting science Preliminary studies Clinical trials Cooling technology Who to cool When to cool How long to cool.

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THERAPEUTIC HYPOTHERMIA AFTER CARDIAC ARREST

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  1. THERAPEUTIC HYPOTHERMIA AFTER CARDIAC ARREST Adam Oster R3 Resident Oral Presentation November 13, 2003

  2. Therapeutic Hypothermia Post Cardiac Arrest • Guiding questions • Supporting science • Preliminary studies • Clinical trials • Cooling technology • Who to cool • When to cool • How long to cool

  3. Therapeutic Hypothermia Post Cardiac Arrest • Baseline cardiac arrest data • Physiology of CA • Preliminary studies of induced HT • Recent clinical trials • Cooling Technology • The Future…

  4. Promising Therapies? • Thiopental • Steroids • Calcium channel antagonists • Glutamate channel antagonists • Nimodipine • Lidoflazine • PEG-SOD • Mg +/-ativan

  5. OPALS Data1991-1997 • 9273 out-of-hospital CA • 38.6% VF/pVT • 27% ROSC • 21% admitted to hospital • 9% survival to discharge • 15% poor neurologic outcome * • *not OPALS data • 7% of all pre-hospital CA return home to independent living • Eisenberg, M. Annals of Emergency Medicine, 1990.

  6. VF/VTCognitive Sequelae • Outcome of patients surviving to hospital post-VF/VT with GCS =/<9 • Best estimates (based on control group in two large trials) • Mortality at 6 mo 55%-68% • Neurologic outcome at 6 mo • 26-40% poor outcome [CPC 3/4]

  7. Cardiac Arrest:Cognitive Sequelae • Graves, J. Resuscitation 1997 • Sweden 1980-1993 • N=3754 • 9% survived to discharge • 21% mortality at 1yr • 56% by 5yrs • 82% by 10yrs • Cerebral Performance Category on discharge, N=320 • 1 53% • 2 21% • 3 24% • 4 2%

  8. Cardiac Arrest:Cognitive Sequelae • Bur, A. Intensive Care Medicine, 2001. • Patients admitted post-VF CA, N=276 (out of 1254) • 50% mortality at 6mo • 87% good neurologic outcome • Age, duration of ROSC, time to EMS, time to 1st defib, and amount of epi all significantly related to CPC category.

  9. Cardiac Arrest:Cognitive Sequelae and QOL • Granja, C. Resuscitation, 2002. • Compared CPC and QOL post-CA • QOR survey administered at 6mo, N=24/97 • N=97 admitted after CA • 36 (37%) discharged from hospital • 12 more died before 6mo • 5 LTFU • Questionnaire administered to 19 • No significant differences compared to other non-CA ICU survivors

  10. Cardiac Arrest Physiology • 4 stages • Pre-arrest • Arrest • Resuscitation • Post-resuscitation

  11. How Effective is CPR? • CPR cardiac output • optimally carried-out up to 60% • realistically 20-30% • CO inversely proportional to duration of CA preceding initiation of CPR • animal models; • 50% pre-arrest CBF if <2mins • 0% if >10mins

  12. Cardiac Arrest Physiology • Arrest and Resuscitative Phases • No to low-flow state tolerated for approx 5mins • Brain O2 stores lost in 20secs • ATP and glucose in 5 mins • cells revert to anaerobic metabolism • Major mechanism of injury is Ca influx • multiple biochemical pathways are initiated • loss of normal cellular ionic gradients • tissues most susceptible -- • brain (esp. hippocampus, cerebral cortex and cerebellum) Ross. Journal of Cerebral Blood Flow and Metabolism, 1993.

  13. Cerebral Blood Flow • Post-arrest CBF • Reperfusion injury • After initial increase, CBF reduced to 50% normal for 90mins to 24hrs in normotensive pts • Heterogenous CBF • Increase in cerebral O2 uptake Bottiger, et al., Resuscitation 1997. • Some evidence of raised ICP and cerebral edemapost-ROSC. Morimoto, et.al., Critical Care Medicine, 1993.

  14. Effects of Hyperthermia • Hickey, R. Critical Care Medicine. 2003. • Hyperthermia exacerbates histologic neuronal damage post-hypoxic arrest in rats.

  15. Hypothermia Physiology • How could hypothermia help? • 7% reduction in cerebral metabolic rate (CMRO2) for every 1 degree reduction in brain temp. • In part due to reduction in electric activity Critical Care Medicine, 1996 • Suppresses many chemical reactions • Reduction in oxidative damage • Reduces free calcium shifts • Maintains mitochondrial function • Reduces excitatory glutamate release Journal of Cerebral Blood Flow, 2000.

  16. Hypothermia Physiology • CNS effects of IH • Cerebral metabolic rate for O2 is the major determinant of CBF • May improve flow to selective ischemic areas of the brain • Decreases ICP • Likely due to global cerebral vasoconstriction and decreased IC blood volume • Critical Care Medicine, 1984. • Decreases amount of excitatory neurotransmitters • Anaesthesia, 1994.

  17. Hypothermia Physiology • CVS Effects of IH • With shivering mechanism blocked… • Decrease HR • Increases SVR • SV and MAP constant • Osbourne wave at 33 deg

  18. Hypothermia Physiology • Respiratory Effects of IH • ?increased risk of pneumonia • Does not appear to if <24hrs

  19. Hypothermia Physiology • Renal effects of IH • Decreased resorbtion of solute causes osmotic diuresis • K shifts into cells • Decreased phosphate

  20. Hypothermia Physiology • Acid-Base/ABG correction • When ABG corrected for temp, looks like a respiratory alkalosis • Controversial whether ABGs should be corrected for temp but currently they are not corrected • Some evidence for better outcome (animal studies) if you do correct for temp and manage pH  decreased cerebral infarct volume and amount of edema formed. • Anesthesiology, 2002.

  21. Hypothermia Physiology • GI effects of IH • Decreased motility • Decreased insulin release causes increase in glucose. All patients require insulin to avoid the complications of hyperglycemia.

  22. Induced Hypothermia Trials • Bigelow, 1950. • Benson et al., 1955. • Williams and Spencer, 1958. • Bernard et al. Annals of Emergency Medicine, 1997. • Yanagawa et al. Resuscitation, 1998. • Zeiner, et al. Stroke, 2000 • Holzer et al. NEJM, 2002. • Bernard et al. NEJM, 2002.

  23. Neurologic Outcome Measurements • Glasgow Outcome Score • Cerebral Performance Category • Physiatrist assessment of best discharge location

  24. Bernard et al., Annals of Emergency Medicine, 1997. • Prospective, consecutive case series compared to consecutive historic control group • ROSC post-CA (included non-VF/VT) • Exclusion • SBP <90 with pressors • Decreased LOC possibly due to trauma or CVA • Age <16, possibly pregnant • N=22

  25. Bernard et al., Annals of Emergency Medicine, 1997. • Intubation/paralysis and sedation • Surface cooling with ice packs to 33deg for 12hrs then actively rewarmed • Thrombolysis as indicated (no angioplasty) • Similar protocoled ICU management • Glasgow Outcome Scale estimated by unblinded chart review based on data at time of hospital discharge

  26. Bernard et al., Annals of Emergency Medicine, 1997. • Results • 2 groups comparable at entry • Similar incidences of witnessed collapse, time to CPR, ROSC, VF as presenting rhythm, brainstem reflexes • None in NT group received thrombolysis vs 4 in MH group • Mortality • MH 10 vs NT 17 (45% vs 77% ARR 32%  NNT 3), sig. • Good neurologic outcomes (GOS1/2) • MH 11 vs NT 3 (50% vs. 13.7, ARR 36%  NNT 2.7), sig. • Adverse Events • No difference between groups

  27. Bernard et al., Annals of Emergency Medicine, 1997. • Study limitations • Small numbers • Historic controls • Some pre-hospital data unavailable (eg EMS to ROSC • Unclear if post-resuscitation protocols similar • Non-blinded assessment of outcome  classification bias • Underpowered to find difference in adverse events • Strengths • MH feasible and likely safe • May have effect on mortality and neurologic outcome

  28. Yanagawa, et al. Resuscitation, 1998 • Consecutive, patients with ROSC post-CA, N=13 • Compared to historic normothermic control group. • Similar exclusion criteria • Intubated/paralyzed/sedated as per protocol • MH cooled to 33 deg for 48hrs using cooling blankets and EtOH on skin • Passively rewarmed over 3-4 days • GOS at 6 mo (not blinded to treatment)

  29. Yanagawa, et al. Resuscitation, 1998 • Results • Groups had different incidences of cardiac (vs pulmonary) etiology of arrest • Stat sig difference in witnessed collapse (10 vs 3, in MH group) • No difference in mortality • 3 vs 1 with GOS 1/2 • Stat sig. increase in pulmonary complications in MH group

  30. Zeiner, A. et al., Stroke, 2000. • Prospective, multicentered. • Historic controls • Included only post-VF • Exclusion • CA <5 or >15 mins or 60 mins without ROSC • Post-resuscitation SBP<60 or SaO2<85 • Pts having subsequent CA within 6mo • Cooled to 33deg via external head and body for 24hrs then passively rewarmed • CPC at 6mo

  31. Zeiner, A. et al., Stroke, 2000 • Results • 31 pts MH • 4 excluded from analysis • 11 died (mortality 41%) • CPC 1/2 14 (52%) • CPC 3/4 2 (7%) • No formal comparison with historic controls

  32. Bernard et al. and Holzer et al., NEJM, 2002. • Two (European and Australian) prospective, randomised controlled trials of MH post VF/VT CA. • Similar inclusion and exclusion criteria • Primary outcome was neurologic function at 6 mo or discharge from hospital • Differences: cooling methodology, initiation of IH, total duration of cooling and blinding of evaluators.

  33. Bernard et al., NEJM, 2002. • Australian Trial • Only included VF-resuscitated out-of-hospital pts who remained unresponsive • Did not specify duration of CA • Exclusion criteria… • Odd-even day randomization • Pre-hospital initiation of cooling • Thrombolysis as indicated

  34. Bernard et al., NEJM, 2002. • Ice packs to head, neck, torso and limbs • MH for 12hrs with sedation and paralysis • Actively re-warmed with heating blanket at 18hrs • After 24hrs patient care followed usual ICU protocols • Blinded assessment by Physiatrist when pt ready for d/c from hospital (good vs poor outcome)

  35. Bernard et al., NEJM, 2002. • 84 pts eligible over 33mo • 7 excluded from analysis • 77 pts  43 (MH), 34 (NT) • Groups statistically different in rates of bystander CPR (NT>MH) • 72 treated correctly • Intention-to-treat analysis • Median time to target temp from ROSC, 120min

  36. Bernard et al., NEJM, 2002. • Results • Good neuro outcome at discharge (MH vs NT) • 49% vs 26%, p=0.045 (n=21 vs 9) • ARR 23%  NNT 4 • OR for good outcome with MH was 5.25 (1.47-18.5), p=0.01 • Mortality (MH vs NT) • 51% vs 68% (95% CI crosses 1) • Complication rate • Not stated

  37. Bernard et al., NEJM, 2002. • Take home • Small study • Randomization method • Neurologic benefit • Mortality benefit not statistically sig • ?underpowered • Unblinded treating physicians may have introduced treatment bias • Unable to confirm that outcome assessors were blinded to treatment assignment • Did not publish complication rate

  38. Holzer et al. NEJM, 2002. • Consecutive pts, with witnessed VF/VT CA, >18yrs, CA duration>5 and <15mins, ROSC<60mins • Exclusion criteria… • No thrombolysis • Randomised to MH (33 deg) using a cooling blanket (TheraKool®) +/- ice packs if required • Cooling for 24hrs, followed by passive rewarming • Standard, protocoled intensive care

  39. Holzer et al. NEJM, 2002. • Primary Outcome • Blinded assessment of neurologic status within 6mo (Cerebral Performance Category) • Secondary Outcome • Mortality • Rate of complications • Intention-to-treat analysis for mortality outcome only

  40. Holzer et al. NEJM, 2002. • Results • 3551 pts eligible • 3426 did not meet inclusion criteria • 30 excluded for other reasons • 8% enrolled, 275  175 MH, 138 NT. • Groups different at baseline for DM/CAD and receipt of BLS (all higher in NT group), none stat sig. • Median time to cooling 105mins • Median time between ROSC and attainment of target temp, 8hrs • Target temp not reached in 19pts • Hypothermia discontinued early in 14 pts

  41. Holzer et al. NEJM, 2002. • Results • Favorable neurologic outcome CPC1/2 (MH vs NT) • 55% vs 39%, (RR 1.47, 95% CI 1.09-1.82) • ARR 16%  NNT 6.25 (4-25) • Mortality (MH vs NT) • 41% vs 55%, (RR 0.74, 0.58-0.95) • ARR 14%  NNT 7 (4-33) • Complication rates different between groups but not statistically significant (approx 70% of patients in both groups) • 22% more complications MH group (pneumonia NNH=12, sepsis NNH=14)

  42. Holzer et al. NEJM, 2002. • Take home • Larger study • Neurologic and mortality benefit • NNT 6-7 for each end-point • Establishes that there is a higher rate of complications • Unblinded treating physicians • Could not verify blinding of outcome assessments.

  43. Holzer and Bernard

  44. Lingering questions • Were groups randomised for all important prognostic features? • Ie brains stem reflexes, gluc • Blinding of outcome evaluators • How big a deal is not blinding the treating and outcome physicians? • Optimal time of initiation of cooling • Re-warming strategy • Cooling technique

  45. Were groups randomised for all important prognostic features? • Longstreth. NEJM, 1993. • 4 criterion model that predicts neurologic recovery (awakening) after out-of-hospital VF or asystolic CA • Retrospectively derived and tested • Predictor variables from ICU admission note • Median time 2.7days (longest 100days) • N=389 • 50% survived to discharge • 209 awakened

  46. Longstreth. NEJM, 1993. • Predictor variables • Motor response (0-4) • absent, extensor, flexor, non-posturing, withdraws or localizes. • Pupillary light response (3x) • Spontaneous eye movements • Glucose <20mmol/L

  47. Longstreth. NEJM, 1993. • Test Cohort • Cutoff of >/=4 maximized sensitivity (0.92) and specificity (0.65). • NPV 0.84 PPV .80 • 44 errors in classification • Majority were of predicted awakening in patients who never awakened • 16 patients predicted not to awaken who did awaken • 12 with severe neurologic defecits • 4 awakened within 36hrs and made a good recovery and returned to pre-arrest functioning.

  48. Non-blinding of treating physicians – introduction of bias? • Schulz, K. Empirical Evidence of Bias. JAMA, 1995. • Observational meta-analysis which assessed the methodological quality of 250 controlled studies on a specific topic • Determined the associations between those assessments and the published treatment effects.

  49. Schulz, K. Empirical Evidence of Bias. JAMA, 1995. • Controlling for allocation concealment • Trials that were not double-blinded had OR that were 17% higher than those trials that were double-blinded

  50. Timing of cooling. • When should cooling be initiated? • When is it too late for cooling to be beneficial?

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