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 Data 1991-1997 ► 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/VT Cognitive 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 1 st 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 edema post-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 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 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 Trial FeatureHolzerBernard inclusion differenceswitnessed VF/VTwitnessed VF Exclusion>5 <15 mins to first BLSno restriction to time to BLS N=27577 Randomizationstratified according to centreeven-odd day Initiation of coolinghospitalpre-hospital Lytics?noyes cooling deviceMattress (TheraKool)ice-packs (CoolCare) Duration of cooling2412 Goal temp3333 =/-1 Rewarmingpassiveactively at 18hrs Primary end-pointfavourable outcome within 6moat hospital discharge Result55% vs 39%49% vs 26% NNT6.254 Mortality41% vs 55%51% vs 68% ComplicationsNSnot stated

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?

51. When should cooling be initiated? ► Kuboyama et al. Critical Care Medicine, 1993.  Prospective, randomised and controlled dog study  N=18 VF arrest 12.5min  CPB  defib <5min  randomised  standard ICU care for 96hrs  3 groups ► NT control ► Immediate IH to 24 deg for 60mins ► Delayed IH for 15mins then maintained for 60mins  better overall performance category in group 2 (NS) and improved brain histologic score.

52. Clinical Feasibility Studies How to cool ► External blankets ► Ice-packs ► Cranial cooling ► Cold fluid IV infusion

53. Clinical Feasibility Studies ► Felberg, et al. Circulation, 2001.  2 Cooling blankets (RK-2000, Thermia)  Initiation to goal temp took median time of 300min (goal 120mins).  Approximately 0.3C/hr

54. Clinical Feasibility Studies ► Callaway, et al., Resuscitation, 2002.  External cranial cooling ► Ice applied to head and necks of subjects with out- of-hospital arrests during CPR ► Rate of temp decrease 0.06 +/-0.06 C/min similar to control group without ice. ► Likely ineffective

55. Clinical Feasibility Studies ► Hachimi-Idrissi, et al. Resuscitation, 2001.  Helmet device (Frigicap®) containing aqueous glycerol placed around the head and neck. Kept in refrigerator prior to use. Changed Q1H.

56. Clinical Feasibility Studies ► Hachimi-Idrissi, et al. Resuscitation, 2001.  Mean starting temp 35.7  Target bladder temp reached at median time of 180min after ROSC.  (Target median tympanic temp reached at 60min)

57. Clinical Feasibility Studies ► Bernard, et al. Resuscitation, 2003.  30cc/kg 4 deg LR over 30min for induction followed by ice-packs  N=22 CA pts  No adverse events (including pulmonary edema)  Median decrease in core (bladder) temp 1.6 deg

58. ILCOR Advisory Statement ► Nolan, J. et al., Circulation, 2003.  Recommends MH in witnessed, out-of-hospital VF arrests with spontaneous ROSC who remain unconscious  Cool to 32-34 degrees for 12 to 24hrs

59. CCU (draft) Protocol Inclusion ► Witnessed ► VF or pVT ► 18-75 yrs ► <15min est to BLS ► <60mins to ROSC ► MAP>60 Exclusion ► Initial T<30 ► GCS>9 ► Coma prior to CA ► Pregnant ► Terminal illness ► SaO2 15min ► Shock (?)

60. CCU (draft) Protocol ► Minimum of 10 covered ice packs +/- cooling blankets prn ► Maintain for 24hrs ► Allow for passive re-warming ► Intubation/sedation/paralysis ► Document neurologic exam prior to initiation

61. Take Home ► Appropriate patients are a highly selected sub-group (approx 8% of all-comers with CA)  Arrest of primary cardiac origin  Witnessed  First attempt at resuscitation <15mins  ROSC<60mins  SBP>90 and SaO2>90%  Remain unresponsive  Reasonable pre-arrest quality of life and life expectancy  Insufficient evidence to support ped use

62. Take Home ► Timing of Cooling  As soon as possible after ROSC (animal studies) ► But, likely beneficial even if delayed upto 6hrs  ?No longer than 16hrs after ROSC ► Target Temperature  More research needed  33 deg +/- 1 deg ► Duration of Cooling  More research needed  No longer than 24hrs (may not be any benefit from >12hrs)

63. Take Home ► Cooling Technique  Unsure if any benefit from rapid induction of MH vs gradual onset  External cooling method (ie. Cooling blanket +/- ice packs) are the simplest and have been tested.  Other strategies are experimental (eg. cold RL bolus, frigicap) and may be helpful for induction

64. The Near Future ► Formalized relationship with Critical Care Medicine (ICU and CCU) with a shared protocol and QA strategy.  Initiated cooling of appropriate patients in the ED  Transfer to the receiving service with minimal delay

65. The Not-So-Near Future ► Further studies to define optimal implementation of induced hypothermia ► Study whether benefit in other arrest rhythms ► Pediatric population application