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THERAPEUTIC HYPOTHERMIA AFTER CARDIAC ARREST

THERAPEUTIC HYPOTHERMIA AFTER CARDIAC ARREST

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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?