1. Brian O’Neil, MD Hypothermic Resuscitation in Patients with CNS Injury Due to Cardiac Arrest

2. Brian O’Neil, MD FERNE Brain Illness and Injury Course

3. Brian O’Neil, MD 4 th Mediterranean Emergency Medicine Congress Sorrento, Italy September 17, 2007 4 th Mediterranean Emergency Medicine Congress Sorrento, Italy September 17, 2007

4. Brian O’Neil, MD Brian J. O’Neil, MD Professor Department of Emergency Medicine Wayne State University, Research Director, William Beaumont Hospital Royal Oak, MI

5. Brian O’Neil, MD Disclosures Advisory Boards: Heartscape, BMSAdvisory Boards: Heartscape, BMS Speakers’ Bureau: GSK, Sanofi-Aventis, BMS, Schering PloughSpeakers’ Bureau: GSK, Sanofi-Aventis, BMS, Schering Plough Site PI: Artic Sun-RESCUE trialSite PI: Artic Sun-RESCUE trial ACEP Research CommitteeACEP Research Committee Co-Chair ACEP Research ForumCo-Chair ACEP Research Forum Board Member: FERNEBoard Member: FERNE

6. Brian O’Neil, MD Learning Objectives and Key Clinical Questions

7. Brian O’Neil, MD Session Objectives Discuss Hypothermia and Ischemia: Discuss Hypothermia and Ischemia: Physiology, mechanisms Physiology, mechanisms Review: Review: Current evidence, clinical trials Current evidence, clinical trials Examine: Examine: Future Therapies Future Therapies Pratical Recommendations: Pratical Recommendations: You can use today You can use today

8. Brian O’Neil, MD Post-Ischemic Cerebral Reperfusion CPR restores ROSC in about 100,000 patients a year in the US 60% of these die from neurologic complications Only 3-20% of resuscitated patients are able to resume their former lifestyles Krause GS, Kumar K, White BC, Aust SD, Wiegenstein JG. Ischemia, resuscitation, and reperfusion: Mechanisms of tissue injury and prospects for protection. Am Heart J 1986; 111:768-80.

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

10. Brian O’Neil, MD phospholipase activation Free Arachidonate ER Ca 2+ Depletion REPERFUSION Epinephrine ATP PKA activation PP2A I 1 activation PP1 inhibited eIF2  kinase activation eIF2  (P) Inhibited Protein Synthesis Apoptosis. O 2 - Fe 2+ Lipid Peroxidation Membrane Damage Inhibited Growth Factor Signaling CHOP Bad dephosphorylation, Bax, mitochondria release cytochrome c & caspase 9 to APAF1 active caspase 3 Cytosolic Ca 2+ ATPDepolarization ISCHEMIA eIF4G & spectrin degradation  -calpain activation calcineurin activation NOS activation peroxynitrite cAMP AND REPERFUSION THAT LEAD TO NEURONAL DEATH DEATH MODEL OF MOLECULAR EVENTS DURING BRAIN ISCHEMIA

11. Brian O’Neil, MD

12. Historical Observations Not Dead till Warm and Dead Not Dead till Warm and Dead Cold patients would awaken in the Morgue Cold patients would awaken in the Morgue Kids / Hockey Players- fall through ice, long rescue times, but good recovery Kids / Hockey Players- fall through ice, long rescue times, but good recovery Hibernation: state of low oxygen, acidosis, low energy supply Hibernation: state of low oxygen, acidosis, low energy supply Basic science animal research showed promising results Basic science animal research showed promising results

13. Brian O’Neil, MD Hypothermia: Potential Mechanisms 6%  in metabolic rate per 1  C reduction in brain temperature CMR declined to 50% after brain cooling to 32 degrees C (CBF & CMR coupled) blocks release of excitatory amino acid reduces early calcium rise reduces calpain specific and cytoskeletal damage

14. Brian O’Neil, MD Clinical Hypothermia Bernard et al (77 pts) external cooling, ice bags, initiated by EMS at ROSC 33.5 C within two hours ROSC cooled for 12 hours Good outcome = 49% v 26%

15. Brian O’Neil, MD Clinical Hypothermia The European group, 136 pts, VF arrest, comatose, stable hemodynamics external cooling device, 8 hrs = median time to target Temp (33 C) 14.4% did not reach target T° Cooling for a mean of 24 hours Good outcome = 55% v 39%

16. Brian O’Neil, MD Hypothermia: The Beaumont Experience INCLUSION Patients with witnessed out of hospital cardiac arrest of presumed cardiac origin any initial rhythm that had ACLS within 15 minutes restoration of spontaneous circulation, (ROSC) within 60 mins of collapse able to obtain informed consent by representative/family member were enrolled

17. Brian O’Neil, MD 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%) INITIAL RHYTHM RHYTHM vfib 14 (61%) 62 (78%) pea 4 (17%) 5 (6%) asystole 5 (22%) 13 (16%) Mean time till ROSC 2114

18. Brian O’Neil, MD p = 0.033

19. Brian O’Neil, MD Practical Hypothermia First thing you need are Champions First thing you need are Champions Next get Buy In: Next get Buy In: ED, CCU, ICU, Nursing and Administration ED, CCU, ICU, Nursing and Administration Sit down and hammer out a protocol Sit down and hammer out a protocol Educate Staff Educate Staff Facilitate the first few patients Facilitate the first few patients

20. Brian O’Neil, MD Practical Hypothermia Initiation: Sooner the Better: Pre-hospital or in- hospital Initiation: Sooner the Better: Pre-hospital or in- hospital Ice bags in Groin, Axilla and Neck Ice bags in Groin, Axilla and Neck Cold IV fluids Cold IV fluids Regular cooling blanket Regular cooling blanket Intravenous catheters / Gel Pads Intravenous catheters / Gel Pads More consistent temperature regulation More consistent temperature regulation Target 33.5  C: Target 33.5  C: Esophageal > bladder > rectal probes Esophageal > bladder > rectal probes Bladder probes need urine output Bladder probes need urine output Watch for rapid drop, cooling is non-linear Watch for rapid drop, cooling is non-linear

21. Brian O’Neil, MD Practical Hypothermia Paralyze / Sedate Paralyze / Sedate Ativan drip: added seizure control Ativan drip: added seizure control Watch for: Watch for: Low K+ and Mg ++ Low K+ and Mg ++ High Glucose High Glucose Stress dose insulin with boluses Stress dose insulin with boluses Bradycardia Bradycardia Prolonged QT Prolonged QT Bleeding Bleeding Pneumonia/ sepsis Pneumonia/ sepsis

22. Brian O’Neil, MD Practical Hypothermia Re-warming: Not truly active Not truly active Decreased rate of cooling Decreased rate of cooling Beware of temperature overshoot Beware of temperature overshoot Stop re-warming around 35  C Stop re-warming around 35  C Watch for: Watch for: Seizures Seizures Arrhythmias Arrhythmias Fevers Fevers

23. Brian O’Neil, MD What the Future Holds NMDA/ AMPA receptor antagonist and NMDA/ AMPA receptor antagonist and phase II trials have recently shown some efficacy in CHI phase II trials have recently shown some efficacy in CHI Estradiols and Progesterone Estradiols and Progesterone Hypothermia during resuscitation Hypothermia during resuscitation : Cannabinoids: most potent antioxidants known, (dexanabinol) most potent antioxidants known, (dexanabinol) Many receptor similarities to opioids Many receptor similarities to opioids Also induces hypothermia Also induces hypothermia Insulin and other growth factors Insulin and other growth factors

24. Brian O’Neil, MD What the Future Holds Opioid receptor antagonists:  -, DADLE,  opioid receptor, BRL-52537  -, DADLE,  opioid receptor, BRL-52537 proteins trigger hibernation proteins trigger hibernation -opiate antagonists reverse hibernation pre-conditioning protein pre-conditioning protein - myocytes and neurons mechanisms: ATP-K+ channels, PKC, free radicals mechanisms: ATP-K+ channels, PKC, free radicals -increases ERK and bcl-2

25. Brian O’Neil, MDConclusions Post-ROSC Neurologic resuscitation: needs to improve Injury Mechanisms: Complex, Multi-factoral Silver Bullet Trials have Failed The Future Looks Bright Therapeutic Hypothermia: Currently only proven therapy Cheap, Easy, risk / benefit ratio is huge

26. Brian O’Neil, MDRecommendations Therapeutic Hypothermia: √ √ JUST DO IT 

27. Brian O’Neil, MD Questions? www.FERNE.org bo’neil@beaumont.edu ferne_memc_2007_braincourse_oneil_hypothermic_091707_finalcd 8/8/2015 9:32 PM