1. Hypothermia for Hemorrhagic Shock: It’s Cool to be Cool!! Samuel A. Tisherman, MD Associate Professor Surgery and Critical Care Medicine Safar Center for Resuscitation Research University of Pittsburgh

3. Mechanisms of Benefit Energy failure Energy failure Oxidant injury Oxidant injury Delayed neuronal death Delayed neuronal death Excitotoxicity Excitotoxicity ICP ICP Edema formation Edema formation Cytoskeletal protein degradation Cytoskeletal protein degradation BBB permeability BBB permeability IL-1  production IL-1  production Neutrophil accumulation Neutrophil accumulation Who cares?

4. Predisposition in Trauma Patients Exposure (field and trauma bay) Exposure (field and trauma bay) –Opening of body cavities Blood loss Blood loss Infusion of cold fluids Infusion of cold fluids Limited heat production Limited heat production –Shock –Sedation, anesthesia, EtOH and drugs

5. Hypothermia Therapeutic/controlled Exposure/uncontrolled 

6. Temperature Levels Mild32-36 o C Mild32-36 o C Moderate28-32 o C Moderate28-32 o C Deep10-20 o C Deep10-20 o C Profound5-10 o C Profound5-10 o C Ultraprofound<5 o C Ultraprofound<5 o C

7. Dying Patterns from Hemorrhage Uncontrolled HS Limited FR Hypothermia Pharmacologic hibernation Maintain pulse Transport Delayed Resuscitation Resuscitative Surgery Exsanguinating Hemorrhage Hypothermic Pharmacologic Preservation “Suspended Animation” Allow circulatory arrest Lose pulse

8. Moderate hypothermia and HS Meyer and Horton, Curr Surg, 1988.

10. Time (min) 050100200150250300 % surviving 0 20 40 60 80 100 Hth Group 2 O2-Hth Group 4 O2 Group 3 Control Group 1 Kim, et al. J Trauma, 1998.

11. Number of rats alive Time Prolonged Hypothermia Group 3 Brief Hypothermia Group 2 Normothermia Group 1 (9/10) (7/10) (3/10) p = 0.02 vs. Group 3; p = 0.18 vs. Group 2 Survival from Pressure-controlled HS Prueckner, J Trauma, 2001.

12. Hemorrhagic shockResuscitation to 4 h MAP Temp. (rectal) 40 mmHg to 30% uptake G. I: 37.5 °C to 12 h G. II: 34 °C to 12 h 35 °C Observation to 72 h G. III 2 h 34 C Rewarming vs. Continued Hypothermia after HS SCRR. 2001 Wu, et al. 2002

13. Temp. under control for 12 h 0255075 0 2 4 6 8 Resuscitation Time (h) Rewarmed Hypo-12 h Hypo-2 h SCRR. 2001 Rewarming vs. Continued Hypothermia after HS Survivors

14. Hemorrhagic shockResuscitation to 4 h MAP Temperature (rectal) 40 mmHg Group I: 37.5 °C to 12 h Group II: 34 °C to 12 h 35 °C Observation to 72 h 50% uptake of shed blood 3ml/100g over 15 min SCRR. 2002 Rewarming vs. Continued Hypothermia after HS

15. 01020304050 0 2 4 6 8 Survivors Resuscitation Time (h) Cooling Group Rewarming Group P = 0.0029 Temp Controlled Rewarming vs. Continued Hypothermia after HS

16. Very Prolonged HS (6 h) Hypothermia 0 RT 0 RT 24 hRT 48 h RT 72 h 0 2 6 12 14 # Survivors Hypo-10 min (p=0.005 vs normothermia, Log Rank [Peto]) Hypo-1 h (p=0.01 vs normothermia, Log Rank [Peto]) Normothermia HS Temp. Controlled Observation 10 8 4 HS: Hemorrhagic shock; RT: Resuscitation time (hours)

17. Hypothermia is a double-edged sword.

18. Hypothermia and Trauma High ISS High ISS –Hypothermia –Decreased shivering, thermoregulation, heat production Coagulopathy and acidosis Coagulopathy and acidosis –"Damage control laparotomy"

19. Hypothermia - complications Coagulopathy Coagulopathy –Platelets - number and function, TxB2 –Elevated PT and PTT –?Increased fibrinolysis Dysrhythmias and hypotension Dysrhythmias and hypotension Metabolic acidosis Metabolic acidosis Infections Infections

20. Preclinical Pig Study Pressure-controlled HS Pressure-controlled HS Hemodilution Hemodilution Normothermia vs hypothermia (34 o C) Normothermia vs hypothermia (34 o C) Laparotomy Laparotomy –Excise edge of liver –Measure blood loss Coags, platelets, TEG, ACT Coags, platelets, TEG, ACT Wu, in preparation.

21. 0 200 400 600 800 1000 1200 1400 1600 1800 2000 050100150200250300350 Hypothermia Normothermia Heparin 200 u/kg Resuscitation time (min) Cumulative blood loss (ml) † † † † † † † † † † † † HYPOTHERMIA AND HEMORRHAGIC SHOCK IN PIGS BLEEDING FROM THE INJURED LIVER Wu, et al. SCCM 2002

22. PRECLINICAL STUDY OF HYPOTHERMIA DURING HS-PIGS Wu, et al. SCCM 2002 Coagulation Tests in Pigs at 3 h after HS and Liver Injury Thromboelastograph (TEG) PT (sec) PTT (sec) Platelets (/  l) R (min)K (min)MA (mm) Alpha (  ) Normothermia 11.2  22.9  280    3.5  62.4  69  Hypothermia 12.1  19.6  236   10.2  3.7  53.3  61  ACT (sec) 127.7  21.1 140.0 

23. Hypothermia and Trauma Luna, et al (U of Washington) Luna, et al (U of Washington) –T>36 o C (n=32): ISS 28, survival 78% –T=34-36 o C (n=41): ISS 29, survival 59% –T<34 o C (n=21): ISS 36, survival 41% Jurkovich, et al (U of South Alabama) Jurkovich, et al (U of South Alabama) –ISS 25-29 >33 o C: survival 97% >33 o C: survival 97% <33 o C: survival 50% <33 o C: survival 50% J Trauma, 1987.

24. Hypothermia and TRISS UCSD UCSD 173 with ISS >9 and known core temp 173 with ISS >9 and known core temp Hypothermic pt: n=37 Hypothermic pt: n=37 –More hypotensive –Survival as predicted by TRISS –No difference in ICU days for survivors Steinemann, J Trauma, 1990.

25. Prospective Hypothermia Study Harborview Medical Center, Seattle Harborview Medical Center, Seattle Core temp <34.5 o C and PAC needed Core temp <34.5 o C and PAC needed Standard Tx Standard Tx –Warm fluids, gases, air blanket, hat Treatment Treatment –Continuous arteriovenous rewarming Gentilello, et al. Ann Surg, 1997.

26. Continuous arteriovenous rewarming technique. Gentilello, et al Ann Surg, 1997.

27. Prospective Hypothermia Study Survival to discharge Survival to discharge –SR = 14 (50%) –CAVR = 19 (66%) CAVR CAVR –More late deaths - ?SR weeded out sick No significant difference in coags No significant difference in coags Gentilello, et al. Ann Surg, 1997.

29. Clinical Trials 1.Mild hypothermia for HS 2.Suspended animation for exsanguination arrest Financial: Funding Ethical: Consent Medical: ProtocolsPolitical: Centers

30. Snowbird, Utah, SHOCK Society annual meeting, June, 2000