1. Post-Event Hypothermia Julie Swain M.D. Cardiovascular Surgeon Consultant to the FDA Circ System Devices Advisory Panel Sept 2004 DRAFT slides

2. Swain2 Outline of Presentation 1.Post-event hypothermia in MI 2.Post-event hypothermia in head trauma 3.Post-event hypothermia in resuscitation 4.ILCOR recommendations 5.Questions for panel

3. Swain3 Post-Event Hypothermia in Myocardial Infarction (Cool-MI Study ) Data presented at TCT 2003 (www.radiantmedical.com/download/TCT-ONeill.pdf) Prospective, randomized ( cooling with IVC catheter vs normothermia during PCI) MI < 6 hrs, cool to 33°C for 3 hrs Quantitative Endpoint – infarct size at 30 days

4. Swain4 COOL-MI Study Results % LV Infarct Size N = 180N = 177 p = N.S. Data presented at TCT 2003 (www.radiantmedical.com/download/TCT-ONeill.pdf

5. Swain5 COOL-MI Results ComplicationControl (n=180) Hypo T (33°) (n=177) Death 2.2% 3.4% Vascular/bleeding 15.6% 19.2% DVT 0 1.7% Shock 6.1% 12.4% Pulm Edema 1.7% 3.4% P = n.s. for all complications, not powered to assess MACE Data presented at TCT 2003 (www.radiantmedical.com/download/TCT-ONeill.pdf

6. Swain6 Post-Event Hypothermia in Brain Injury (Clifton GL, et al. Lack of Effect of Induction of Hypothermia after Acute Brain Injury. N Engl J Med 2001; 344: 556-63) Prospective, randomized, surface and GI cooling vs normothermia Injury < 6 hrs, cool to 33°C for 48 hrs Endpoint – Glasgow Outcome Score at 6 months (functional independence with mild or moderate disability) Secondary endpoints of psychometric tests

7. Swain7 Secondary Endpoints in Brain Injury Trial (at 6 mos) Neurobehavioral Rating Scale – Revised Disability Rating Scale Galveston Orientation and Amnesia test Selective Reminding Test Rey-Osterrieth Complex Figure Test Symbol Digit Modalities Test Trail Making Test B Controlled Oral Word Association Test Grooved Pegboard Test

8. Swain8 Brain Injury Outcome % of Patients Poor Outcome N = 193N = 199 p = N.S. p = N.S. for all secondary endpoints 57%

9. Swain9 Brain Injury Study Results ComplicationControl (n=193) HypoT (n=199) Critical Hypotension 3% 10% Bradycardia w hypotension 4% 16% p =.04 % of hosp. days with complications 70% 78% p =.01 p =.005

10. Swain10 Post-Event Hypothermia Cardiac Arrest Bernard SA, et al. Treatment of Comatose Survivors of Out-of-Hospital Cardiac Arrest with Induced Hypothermia. N Engl J Med 2002; 346:557-63 [Australia] The Hypothermia After Cardiac Arrest Study Group. Mild Therapeutic Hypothermia to Improve the Neurologic Outcome after Cardiac Arrest. N Engl J Med 2002; 346:549- 56 [Europe]

11. Swain11 Comparison of Cardiac Arrest Studies LocationAustraliaEurope # hypoT pts 43 136 Inclusion Criteria VF, return Spon Circ, coma, men>18 yrs, women >50 yrs Witnessed arrest, VF, VT, cardiac origin, 18-75 yrs, 5-15 min to resuscitation by medical personnel, <60 min from arrest to restore circ *** ***91% of screened pts not eligible

12. Swain12 Comparison of Cardiac Arrest Studies AustraliaEurope When cooling started In fieldHospital admission Cooling methodCold packs then ice packs Air-cooled mattress, ice packs Target Duration hypoT 12 hrs 24 hrs Target Temp 33° 32-34°

13. Swain13 Comparison of Cardiac Arrest Studies AustraliaEurope Rewarming ActivePassive Adjunctive medsMidazolam Vercuronium Midazolam Fentanyl pancuronium

14. Swain14 Comparison of Cardiac Arrest Studies AustraliaEurope Primary Endpoint survival to hospital discharge with neuro function allowing home or rehabilitation CPC good or moderate disability at 6 mos

15. Swain15 Comparison of Cardiac Arrest Studies % success endpoint {Australia} {Europe} p =.046 (***risk ratio 1.40, CI 1.08 – 1.81) ***

16. Swain16 Comparison of Cardiac Arrest Studies % mortality {Australia} {Europe} *** (***risk ratio 0.74, CI.58 -.95) p = N.S.

17. Swain17 ILCOR Recommendations (ILCOR Advisory Statement. Therapeutic Hypothermia after Cardiac Arrest. Circulation 2003;108:18-21) Unconscious adult patients with spontaneous circulation after out-of-hospital cardiac arrest should be cooled to 32°C to 34°C for 12 to 24 hours when the initial rhythm was ventricular fibrillation (VF). Such cooling may also be beneficial for other rhythms or in-hospital cardiac arrest.

18. Swain18 Safety Profile of Cooling Methods Surface –Cool air –Water cooling –Head and neck cooling GI lavage Endovascular –Extracorporeal Circulation Cardiopulmonary Bypass Veno-venous Arterial venous –IVC catheters

19. Swain19 Summary Is post-event hypothermia the standard for treating out-of-hospital arrest patients in the U.S.? Is surface-induced hypothermia comparable to endovascular hypothermia in safety and efficacy?