1. Francis Kim MD, Graham Nichol MD MPH, Charles Maynard PhD, Al Hallstrom PhD, Peter Kudenchuk MD, Thomas Rea MD, Michael Copass MD, David Carlbom MD Steven Deem MD, WT Longstreth Jr MD, Michele Olsufka RN, Leonard Cobb MD University of Washington Seattle, WA Randomized Clinical Trial of Pre- hospital Induction of Mild Hypothermia in Out-of-Hospital Cardiac Arrest Patients Using a Rapid Infusion of 4 o C Normal Saline

2. Background Hospital cooling (32-34 o C) improves neurologic outcome after out-of-hospital ventricular fibrillation (VF) Pre-hospital cooling may result in better outcomes compared to hospital alone Pre-hospital infusion of cold fluid to reduce temperature Determine whether prehospital cooling improves outcomes from cardiac arrest with VF or non-VF

3. Trial Setting/Design Emergency medical services (EMS) agencies in Seattle and surrounding King County Individual subjects randomized to –Intervention-Rapid infusion of 2 liters of 4 o C NS after ROSC, sedation, skeletal muscle relaxation –Control-standard care Randomization stratified by –Receipt of hospital cooling –First recorded rhythm

4. Eligibility Inclusion Criteria Adults Return of pulse Tracheal intubation Intravenous access Unconscious Esophageal temp probe Exclusion Criteria Traumatic cardiac arrest Age < 18 Following commands Temperature < 34ºC

5. Trial Flow Field Cardiac Arrest 1364 N=583 VF Intervention 292 Control 291 5696 Eligible Enrolled 2377 N=776 Non-VF Intervention 396 Control 380 Not Eligible (3319) Not Enrolled (1013) Outcomes: Survival at discharge/neurologic status

6. VFNON-VF Intervention (n=292) Control (n=291) Intervention (n=396) Control (n=380) Age 62.1 68.367.5 Men (78%) (75%) (54%) Witnessed cardiac arrest (78%) (74%) (53%) (52%) CPR before EMS arrival (68%)(64%) (50%) (53%) Time from call to randomization 32.932.534.435.2 Time from call to first responder arrival 5.35.25.45.2 Time from call to sustained ROSC 25242827 Baseline Characteristics

7. Temperature Effects VFNon-VF Intervention ControlP value Intervention ControlP value Temperature at randomization (95% CI) o C 36.1 (36.0-36.2) (n=292) 36.0 (35.9-36.1) (n=290) 0.16 36.0 (35.9-36.1) (n=396) 35.9 (35.8-36.0) (n=379) 0.09 Temperature at hospital arrival, o C 35.0 (34.8-35.2) (n= 260) 35.9 (35.8-36.0) (n=212) <0.0001 34.8 (34.6-35.0) (n=350) 35.7 (35.6-35.8) (n=248) <0.0001 Difference in temperature between randomization and arrival mean o C -1.2 (-1.33- -1.07) (n=260) -0.1 (-0.19- -0.02) (n=212) <0.0001 -1.3 (-1.4 - -1.2) (n=350) -0.1 (-0.19 --0.01) (n=248) <0.0001

8. Outcomes-Survival VF intervention n=292 control n=291 Non-VF intervention n=396 control n=380

9. Outcomes-neurologic status at discharge

10. Secondary Outcomes- Days to achieve awakening VF

11. InterventionControl P-value Re-arrest after randomization 176 (26%)138 (21%)0.008 Pressors after randomization 62 (9%)59 (9%)0.82 Deaths in field 9 (1.3%)11 (1.6%)0.61 Time from first dispatch to hospital arrival (min) 51+1349+140.006 Safety- prehospital

12. InterventionControlP-value Deaths in ED88 (12.8%)85 (12.7%) 0.95 Pressors in the first 12 hours of arrival 374 (56%)365 (56%) 0.93 Diuretics in the first 12 hours of arrival 119 (18%)81 (12%)0.009 Diuretics in 12-48 hours of arrival 151 (23%)109 (17%)0.011 pH 7.16+0.237.20+0.290.005 PaO2 (mmHg) 189+135218+144<0.0001 Pulmonary edema on 1 st chest x-ray 256 (41%)184 (30%)<0.0001 Pulmonary edema on 2 nd chest x-ray 133 (27%)123 (26%)0.95 Safety- ED and hospital

13. Summary of prehospital cooling

14. Conclusions Cold NS reduced core temperature by hospital arrival Use of cold NS associated with increased re-arrest during transport and increased transient pulmonary edema Lack of benefit of prehospital cooling consistent with previous smaller trial Prehospital cooling with cold NS did not improve survival or neurologic outcomes in patients with out-of-hospital VF or non-VF

15. Implications Cold fluid has associated risks Study findings do not support routine initiation of hypothermia using cold fluid in the prehospital setting

16. Paramedics in Seattle and King County Hospitals : Harborview Medical Center, Swedish Medical Center, Virginia Mason Hospital, UWMC, Northwest Hospital, Overlake Hospital, Valley Medical Center, Auburn General Hospital, St. Francis Hospital, Stevens Hospital. DSMB: Chair: Kyra Becker, MD. Members: Margaret Neff, MD, Tina Chang, MD, Karl B. Kern, MD, Nancy Temkin, PhD, Ralph D’Agostino, PhD, Chief Earl Sodeman, Seattle Fire Department, Thomas Hearne, Michele Plorde, King County Public Health, Emergency Medical Services Division. Study Nurses: Dianne K. Staloch, Karen Dong, Sue Scruggs, Alana C. Clark, Jane Edelson, Debi Solberg, Sally Ragsdale, Kathleen Fair, Barbara Ricker Funding: NIH/NHLBI Acknowledgements

17. F Kim and coauthors Effect of Prehospital Induction of Mild Hypothermia on Survival and Neurological Status Among Adults With Cardiac Arrest : A Randomized Clinical Trial Published online November 17, 2013 Available at www.jama.com and also at mobile.jamanetwork.com jamanetwork.com