1. POST-RESUCITATIVE CARE: HYPOTHERMIA ++ Brian J. O’Neil, MD, FACEP Edward S. Thomas Endowed Professor, Interim Chair Specialist in Chief Director of Basic Science Research, Department of Emergency Medicine Wayne State University Detroit, Michigan

2. DISCLOSURES Much to confess, less to Disclose ACLS Chair Steering Committee ICECAP Previous funding/ Speakers from Medivance Much to confess, less to Disclose ACLS Chair Steering Committee ICECAP Previous funding/ Speakers from Medivance

3. OOHCA Data: ROC EMS treated – 22.9% VF – 7.9% survival to D/C Initial VF rhythm – 21% D/C from hospital Range 7.7% to 39.9% Non VF rhythm – 4% D/C from hospital EMS treated – 22.9% VF – 7.9% survival to D/C Initial VF rhythm – 21% D/C from hospital Range 7.7% to 39.9% Non VF rhythm – 4% D/C from hospital Nichol G et al. JAMA. 2008;300:1423-31.

4. CARES Registry

7. Neuroprotection 1955-2000 Neuroprotective Agents Tested 49 RCTs Performed 114 Patients Enrolled 21,445 Trials with Positive Results 0 Kidwell CS et al. Stroke. 2001;32(6):1349-59. Trials of Neuroprotection Agents in Stroke

8. EVENTS LEADING TO NEURONAL DEATH DURING POST-ISCHEMIC BRAIN REPERFUSION ATPDepolarization Cytosol Ca++activated P’lipases Ischemia Proteolysis of eIF4G by Calpain I Free Arachidonate.O2-.O2- Fe 2+ Lipid Peroxidation Membrane Damage Apoptosis Inhibited Growth Factor Signaling Bad, Bax, Mito caspase 9 & cyt c release to APAF1 CHOP caspase 3 Cells unable to respond to injury and DIE ATP PP1 inhibited REPERFUSION Epinephrine cAMP PKA activation PP2A I1 Activation Depletion ER Ca++ PERK Autophosphorylation eIF-2  (P) Inhibition of Prot Synthesis

9. Post-Cardiac Arrest Care Change: Change: New 5 th link in the chain of survival New 5 th link in the chain of survival Includes: Includes: Optimizing vital organ perfusion Optimizing vital organ perfusion Titration of FiO 2 to maintain O 2 sat ≥ 94% Titration of FiO 2 to maintain O 2 sat ≥ 94% Transport to comprehensive post-arrest system of care Transport to comprehensive post-arrest system of care Emergent coronary reperfusion for STEMI or high suspicion of AMI. Emergent coronary reperfusion for STEMI or high suspicion of AMI. Temperature control Temperature control Anticipation, treatment, and prevention of multiple organ dysfunction Anticipation, treatment, and prevention of multiple organ dysfunction © 2010 American Heart Association. All rights reserved.

10. Neuroprotection Beyond Hypothermia, Goal Directed Therapy the ACLS updates Reanimation: Keeping Your Eye on the Prize

11. Case: DW OOHCA* Cardiac Arrest Initial rhythm: VF Age: 54 Est. Downtime: Call to ACLS-7 minutes Witnessed: yes Co-morbid conditions: IDDM, CAD What are DW’s chances for a good neurologic outcome?? *Out-of-hospital cardiac arrest

12. DW: Things Get Sticky Within 2 mins of ACLS Defib to NSR with palpable pulse 27 mins later lost his pulse 13 more mins – ROSC NE and dopamine with SBP of 90 What are his chances now?? What else can we do for DW?

14. Hypothermia: Potential Mechanisms 6%  in metabolic rate per 1  C reduction in brain temperature CMR declined to 50% after brain cooling to 32 °C (CBF & CMR coupled) Blocks release of excitatory amino acid Reduces early calcium rise Think Hibernation:

15. NEJM Volume 346:549-556 February 21, 2002 Number 8 NEJM Volume 346:557-563 February 21, 2002 Number 8

16. The HACA group, 136 pts, The HACA group, 136 pts, VF arrest, comatose, stable hemodynamics, external cooling device, VF arrest, comatose, stable hemodynamics, external cooling device, 8 hours = median time to target Temp (32-34 C) 8 hours = median time to target Temp (32-34 C) Cooling continued for a mean of 24 hours Cooling continued for a mean of 24 hours Bernard et al (77 pts), VF arrest Bernard et al (77 pts), VF arrest external cooling, ice bags, initiated by EMS at ROSC external cooling, ice bags, initiated by EMS at ROSC 33.5 C within two hours ROSC cooled for 12 hours 33.5 C within two hours ROSC cooled for 12 hours Bernard, S.A., Clinical trial of Induced Hypothermia in Comatose Survivors of Out-of-Hospital Cardiac Arrest. Journal of Emergency Medicine, 1997 Bernard, S.A., Clinical trial of Induced Hypothermia in Comatose Survivors of Out-of-Hospital Cardiac Arrest. Journal of Emergency Medicine, 1997

17. HACA and Bernard et al. HACA: CPC 1or 2 75 /136 pts (55%) hypothermia 54/137 (39%) in the normothermia group Risk ratio 1.40 (95% CI 1.08 - 1.81) NNT to improve neuro outcome= 6 pts NNT to prevent 1 death = 7 patients NNT to Harm = 14 1 Bernard et al. (77 pts) Good outcome = 49% v 26% 2 2 Bernard SA et al. N Engl J Med. 2002 Feb 21;346(8):557-63. 1 Hypothermia After Cardiac Arrest Study Group. N Engl J Med. 2002 Feb 21;346(8):549-56.

18. Table 1: Baseline Characteristics HYPOTHERMIA PATIENTS NORMOTHERMIA PATIENTS DATES5/05-9/061/97-2/06 TOTAL PTS 2380 AGE AVG 65.867.9 Bystand CPR 13 (56%) 45 (56%) Mean time till ROSC 2114

20. P = 0.033 52% 33% 52% 28% 48% 72% 0% 10% 20% 30% 40% 50% 60% 70% 80% Discharged AliveCPC 1 or 2CPC 3 or Greater Mortality and Neurological Outcomes HypothermiaNormothermia Data on file, William Beaumont Hospital. Unpublished.

22. Time to Target Group Median (25-75 th ) Arctic Sun 193 min (136 to 255 min) P < 0.001 Control 244 min (180 to 360 min) Heard K et al. RESCUE Study Group. Abstract 2411. Circulation. Oct 2007;116:II_529.

24. CPC Category 1 or 2: 6 Months Presenting Rhythm GroupVF or VT PEA or Asystole Arctic Sun 61.0% (38.6 to 80.3%) P = 0.76 11.1% (.3 to 48.3%) P = 1.0 Control 55.5% (30.7to 78.5%) 9.0% (.2 to 41.3%) Heard K et al. RESCUE Study Group. Abstract 2411. Circulation. Oct 2007;116:II_529.

25. Adult Immediate Post-Cardiac Arrest Care Peberdy et al, Circulation 2010;122:S768-786.

26. COOL-MI 357 patients randomized 357 patients randomized majority were inferior AMI majority were inferior AMI 88% achieved target temp prior to PCI; mean to cool < 35º C was 31 mins. 88% achieved target temp prior to PCI; mean to cool < 35º C was 31 mins. 94% tolerated the procedure 94% tolerated the procedure Similar 30 day MACE rates and incidence of death, reinfarction, or target vessel revascularization Similar 30 day MACE rates and incidence of death, reinfarction, or target vessel revascularization

27. COOL-MI anterior MIs achieving hypothermia before PCI(n = 16) anterior MIs achieving hypothermia before PCI(n = 16) significantly smaller infarcts significantly smaller infarcts 9.3% vs 21.9% of the of at risk LV, P =.05 9.3% vs 21.9% of the of at risk LV, P =.05 trend toward lower CK-MB levels and higher LVEF trend toward lower CK-MB levels and higher LVEF No benefits were noted in hypothermia patients with inferior MIs No benefits were noted in hypothermia patients with inferior MIs

28. ICE-IT ICE-IT* AMI 6 h; randomized to PCI with mild hypothermia or PCI alone ICE-IT* AMI 6 h; randomized to PCI with mild hypothermia or PCI alone 228 enrolled 228 enrolled Infarct size by SPECT imaging Infarct size by SPECT imaging Overall, no difference in primary endpoint, but reduction of infarct size in anterior MI group Overall, no difference in primary endpoint, but reduction of infarct size in anterior MI group

29. Nephrons No large trials to date No large trials to date Plenty of clinical events Plenty of clinical events IT MAKES PEOPLE PEE IT MAKES PEOPLE PEE

30. Galocyanin-stained Autoradiographs Immunostained eIF2  (P) Control 10I- 90R 10I- 90R + Insulin 20 U/kg 25  m  m High-Dose Insulin Restores Protein Synthesis

31. As an Adjunct to Hypothermia

33. The Facts There is a 500% difference in outcomes from cardiac arrest that cannot be explained by demographics There is a 500% difference in outcomes from cardiac arrest that cannot be explained by demographics The treatment of cardiac arrest patients with ROSC is: The treatment of cardiac arrest patients with ROSC is: COMPLEX COMPLEX is time sensitive, is time sensitive, Requires well coordinated interactions with a myriad of healthcare Requires well coordinated interactions with a myriad of healthcare Requires a communitywide plan to optimize treatment Requires a communitywide plan to optimize treatment

34. Lessons from Literature Lessons from Literature

35. Impact of Resuscitation Center on Site 3 Not a Resuscitation Center: 3a,3b,3c,3e: 1/76 with normal neuro function (1.3%) Resuscitation Center Hospital 3d: 7/55 with normal neuro function (12%)

36. Back to DW (Phenylephrine) (Norepinephrine)

37. 1 Year Outcome for DW CPC 1: fully to pre-arrest levels – – DW states he is smarter than he was DW states was life-changing event – – Also changed him spiritually DW beat all the odds: Stated he is now gambling, because if he can beat death he can beat anything!!

39. In a Nutshell 2 liters of 4 ◦ C NS (Drops temp 1 ◦ C) 2 liters of 4 ◦ C NS (Drops temp 1 ◦ C) Start induction in the ED Start induction in the ED Feedback control Temp systems are best Feedback control Temp systems are best Watch for the slippery slope Watch for the slippery slope Esophageal>foley> rectal temp Esophageal>foley> rectal temp Paralyze for shivering: only Paralyze for shivering: only Ativan for sedation: rarely needed Ativan for sedation: rarely needed

40. Other Therapeutic Applications

41. Demographics Cardiac Arrest = 3 rd leading cause of death Cardiac Arrest = 3 rd leading cause of death Up to 71% with Cardiac Arrest (CA) have CAD Up to 71% with Cardiac Arrest (CA) have CAD 97% Patients catheterized after resuscitated from OOHCA have CAD 97% Patients catheterized after resuscitated from OOHCA have CAD 50% of these have occlusion 50% of these have occlusion Autopsy study showed coronary occlusion Autopsy study showed coronary occlusion Symptoms C/W ischemia- 93% Symptoms C/W ischemia- 93% Controls – 4% Controls – 4%

42. Adult Immediate Post-Cardiac Arrest Care Peberdy et al, Circulation 2010;122:S768-786.

43. PROCAT Circ Cardiovasc Interv. 2010;3:200-207

44. PROCAT

45. PROCAT

46. Cardiac catheterization is underutilized after in-hospital cardiac arrest Raina M. Merchanta,b,c, ∗, Benjamin S. Abellab, Monica Khand, Kuang-Ning Huangd, David G. Beiserd, Robert W. Neumarc, Brendan G. Carra,b,c, Lance B. Beckerb, Terry L. Vanden Hoek

47. Successful PCI was associated with survival: 76% vs. 58%, p < 0.05% Cardiac catheterization is underutilized after in-hospital cardiac arrest Raina M. Merchanta, Benjamin S. Abella, Monica Khan, Kuang-Ning Huang, David G. Beiser, Robert W. Neumar, Brendan G. Carra, Lance B. Becker, Terry L. Vanden Hoek

48. AHA policy statement the AHA policy statement strongly supports a mechanism to report PCI outcomes for out- of-hospital cardiac arrest separate from PCI outcomes following STEMI, as this will remove potential barriers for interventional cardiologists to actively participate in the care of this population the AHA policy statement strongly supports a mechanism to report PCI outcomes for out- of-hospital cardiac arrest separate from PCI outcomes following STEMI, as this will remove potential barriers for interventional cardiologists to actively participate in the care of this population I Recommend Cath for: I Recommend Cath for: STEMI STEMI VF arrest VF arrest Hypotension Hypotension

49. HYPOTHERMIA: What We Still Need to Know IS FASTER BETTER ? IS FASTER BETTER ? HOW LONG TO COOL ? HOW LONG TO COOL ? WHO NOT TO COOL ? WHO NOT TO COOL ? WHO NOT TO CATH ? WHO NOT TO CATH ? WHAT IS THE EFFECTS OF TEMPERATURE FLUCUATIONS ? WHAT IS THE EFFECTS OF TEMPERATURE FLUCUATIONS ? VENTILATORY MANAGEMENT VENTILATORY MANAGEMENT EFFECT OF ADJUNCTS EFFECT OF ADJUNCTS

50. Conclusions Post-ROSC neurologic resuscitation: – – Needs to improve – – We have the tools Therapeutic Hypothermia: – Currently only proven therapy – Cheap – Easy – Risk / benefit ratio is huge – NNT to benefit = 6 – NNT to harm = 14

51. Conclusions Cool everyone post arrest: Cool everyone post arrest: Except those that push you away Except those that push you away Push for Cath on patients with: Push for Cath on patients with: STEMI STEMI VF arrest VF arrest Hypotension Hypotension Stress Dose steroids Hydrocortisone 100 mg

52. BURNING QUESTIONS Epinephrine in CA: Epinephrine in CA: Effective Effective Rhythm dependent Rhythm dependent Timing and Dosing Timing and Dosing Pre-Hospital cooling Pre-Hospital cooling EMS standardization EMS standardization Cardiac Arrest Centers of Excellence Cardiac Arrest Centers of Excellence Neurologic Prognostication During Hypothermia Neurologic Prognostication During Hypothermia

53. The Future: Building on the Foundation THERAPEUTIC HYPOTHERMIA Radical Scavengers Growth Factors Calcium Other AGGRESSIVE REPERFUSION Antag

54. Therapeutic Hypothermia Just Do IT!!