1.  Exemplary Care  Cutting-edge Research  World-class Education  UPMC Critical Care www.ccm.pitt.edu

2.  Exemplary Care  Cutting-edge Research  World-class Education  Therapeutic Hypothermia and Trauma Samuel A. Tisherman, MD, FACS, FCCM Departments of Critical Care Medicine and Surgery Safar Center for Resuscitation Research University of Pittsburgh

3.  Exemplary Care  Cutting-edge Research  World-class Education  Disclosure Co-author of patent “Emergency Preservation and Resuscitation Method”

4.  Exemplary Care  Cutting-edge Research  World-class Education 

7. I hope they cool me soon!

8.  Exemplary Care  Cutting-edge Research  World-class Education  Predisposition in Trauma Patients Exposure (field and trauma bay) Opening of body cavities Blood loss Infusion of cold fluids Limited heat production Shock Sedation, anesthesia, EtOH and drugs

9.  Exemplary Care  Cutting-edge Research  World-class Education  Triad of Death

10.  Exemplary Care  Cutting-edge Research  World-class Education  Damage Control

12.  Exemplary Care  Cutting-edge Research  World-class Education  Retrospective studies Increased injury severity Decreased temperature Increased mortality

13.  Exemplary Care  Cutting-edge Research  World-class Education  PA Trauma Outcome Study Statewide trauma registry 38,520 trauma patients (2000-2002) 1,921 (5%) hypothermic on admission (<35 o C) Adjusted for everything possible Age Injury severity Mechanism of injury Route of temp measurement Odds ratio for death 3.03 (2.62-3.5) CCM, 2005.

14.  Exemplary Care  Cutting-edge Research  World-class Education  Hypothermia and TBI Konstantinidis et l. J Trauma, 2011.

15. Hypothermia will add 10 years to your life

16.  Exemplary Care  Cutting-edge Research  World-class Education  TBI

17.  Exemplary Care  Cutting-edge Research  World-class Education  Marion, et al. NEJM, 1997. TBI and Hypothermia: Pittsburgh

18.  Exemplary Care  Cutting-edge Research  World-class Education  Clifton, et al. NEJM, 2001. National Acute Brain Injury Study: Hypothermia

19.  Exemplary Care  Cutting-edge Research  World-class Education  Subset analysis Hypothermia detrimental for >45 yo Under 45 and hypothermic on admission % with poor outcome Hypothermia 52% Normothermia 76% Intercenter differences in quality of care Clifton, et al. NEJM, 2001.

20.  Exemplary Care  Cutting-edge Research  World-class Education  NABIS:H II Clifton et al. Lancet Neurology, 2011.

21.  Exemplary Care  Cutting-edge Research  World-class Education  NABIS:H II Clifton et al. Lancet Neurology, 2011.

22.  Exemplary Care  Cutting-edge Research  World-class Education  TBI and Hypothermia Questions Early vs late (high ICP) Different types of TBI Depth Duration

23.  Exemplary Care  Cutting-edge Research  World-class Education  Spinal cord injury

24.  Exemplary Care  Cutting-edge Research  World-class Education  Dying Patterns from Hemorrhage Uncontrolled Hemorrhage Exsanguinating Hemorrhage Hypothermic Emergency Preservation And Resuscitation (EPR) Allow arrest “ Buy time ” Limited fluid resuscitation Mild hypothermia Pharmacologic hibernation Maintain pulse Transport Delayed Resuscitation Resuscitative Surgery Lose pulse

25.  Exemplary Care  Cutting-edge Research  World-class Education  Dying Patterns from Hemorrhage Uncontrolled Hemorrhage Exsanguinating Hemorrhage Hypothermic Emergency Preservation And Resuscitation (EPR) Allow arrest “ Buy time ” Limited fluid resuscitation Mild hypothermia Pharmacologic hibernation Maintain pulse Transport Delayed Resuscitation Resuscitative Surgery Lose pulse

27.  Exemplary Care  Cutting-edge Research  World-class Education  Temperature Levels Mild Moderate Deep Profound Ultra-profound

28.  Exemplary Care  Cutting-edge Research  World-class Education  Isoflurane=0.5% 2.0% Time Isoflurane MAP Blood withdrawal 68.6 ml/kg/h 20 ml/kg/h 10 ml/kg/h Hemorrhagic Shock Stop isoflurane after splenectomy FR+intensive care HS 3 h RT 24h 40’ Splenectomy Spleen Cut RT12 h 35’95’ 0 Temperature Induction of Hypothermia + Limited Fluid Resuscitation Normothermia Group (Norm) (38°C) Hypothermia Groups (Hypo-Ice & -Rm) (34°C) Wu, et al. J Trauma, 2005. Pig HS Outcome Model ICU to 24 h

29.  Exemplary Care  Cutting-edge Research  World-class Education  Time (h) 0 48 12162024 0 8 # Survivors HS 3 h 7 6 5 4 3 2 1 Norm, n=8 Hypo-Ice, n=8 * Hypo-Rm, n=8 p<0.05 (Hypo-Rm vs Norm) Wu, et al. J Trauma, 2005. Pig Survival

30.  Exemplary Care  Cutting-edge Research  World-class Education  Why the dichotomy?

32.  Exemplary Care  Cutting-edge Research  World-class Education  PRECLINICAL STUDY OF HYPOTHERMIA DURING HS-PIGS 0 10 20 30 40 50 60 70 80 90 BL204060 (min)2h4h6h Mean arterial pressure (mm Hg) 31 32 33 34 35 36 37 38 39 40 PA temperature (C) Wu, et al. SCCM 2002 Normothermia Group Tpa Hypothermia Group Tpa MAP HSResuscitation Start coolingLiver injury Hemodilution

33.  Exemplary Care  Cutting-edge Research  World-class Education  Wu, et al. SCCM 2002 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  Clinical studies: No significant coagulation abnormalities at >34 o C! Coagulation Tests in Pigs at 3 h after HS and Liver Injury

34.  Exemplary Care  Cutting-edge Research  World-class Education  Resnick, et al. Neurosurgery, 1994. Hypothermia does not increase bleeding in traumatic brain injury!

35.  Exemplary Care  Cutting-edge Research  World-class Education  Dying Patterns from Hemorrhage Uncontrolled Hemorrhage Exsanguinating Hemorrhage Hypothermic Emergency Preservation And Resuscitation (EPR) Allow arrest “ Buy time ” Limited fluid resuscitation Mild hypothermia Pharmacologic hibernation Maintain pulse Transport Delayed Resuscitation Resuscitative Surgery Lose pulse

36.  Exemplary Care  Cutting-edge Research  World-class Education  Trauma case 23 yo male Multiple gunshot wounds HR 140, BP 80/p

37.  Exemplary Care  Cutting-edge Research  World-class Education  Clinical problem: Cardiac arrest from trauma Survival (%) Rhee, JACS, 2000

38.  Exemplary Care  Cutting-edge Research  World-class Education  Dr. Peter SafarCol. Ron Bellamy Time to Death in Combat Casualties

39.  Exemplary Care  Cutting-edge Research  World-class Education  Emergency Preservation and Resuscitation “Protection and preservation of the organism during circulatory arrest of 2 h or longer for transportation and control of bleeding during pulselessness followed by delayed resuscitation.” Could allow survival from otherwise lethal insults

41.  Exemplary Care  Cutting-edge Research  World-class Education  EPR Animal Model Custom-bred hunting dogs Anesthesia - light N 2 O-halothane Physiologic monitoring: ECG, MAP, PAP, PCW, CVP, ETCO2 ABG, Hct, lytes, glucose Temps: tympanic, PA, esoph, rectal 24 h/day ICU care

42.  Exemplary Care  Cutting-edge Research  World-class Education  Cardiopulmonary Bypass System

44.  Exemplary Care  Cutting-edge Research  World-class Education  Exsanguination Cardiac Arrest Model Exsanguination Cardiac Arrest 15-180 min Bleed Flush CPB Tty MAP VF

45.  Exemplary Care  Cutting-edge Research  World-class Education  5 Brain death 4 Coma 3 Severe Disability 2 Moderate Disability 1 Normal 20 o C 15 o C 10 o C Final OPC Behringer, CCM, 2003. Effect of Aortic Flush Volume/Brain Temp (Tty) 60 min Exsanguination Arrest

46.  Exemplary Care  Cutting-edge Research  World-class Education  5 Brain Death 4 Coma 3 Severe Disability 2 Moderate Disability 1 Normal 90 min120 min Final OPC Behringer, CCM, 2003. Volume >500 ml/kg Whole body Exsanguination Cardiac Arrest (Tty 10 o C)

47.  Exemplary Care  Cutting-edge Research  World-class Education  Cold energy: 3 h EPR OPC Oxygen GlucoseOxygenGlucoseControl 5 Death 4 Coma 3 Severe disability 2 Moderate disability 1 Normal Wu, et al. JCBFM, 2008.

48.  Exemplary Care  Cutting-edge Research  World-class Education 

49. Prolonged HS->arrest, PHCA CPR group EPR group MAP Continuous bleedingCardiac arrestCPB Spleen transection HS time CPR:124±11 min SA: 128±17 min Bloodgas CPR EPR pH6.79±0.066.98±0.12 Potassium7.9 ±0.97.6±1.4 Lactate15.2±1.815.0±2.4 BE-16.9±2.2 -16.3±1.5 Splenectomy Wu et al. Circulation, 2006.

50.  Exemplary Care  Cutting-edge Research  World-class Education  Prolonged HS->arrest, PHCA Overall Performance CategoryCPR EPR-I (hypo-12h) EPR-II (hypo-36) 5 Dead    4 Coma  3 Severe disability  2 Moderate disability  1 Normal  Wu et al. Circulation, 2006. * * Seizures

51.  Exemplary Care  Cutting-edge Research  World-class Education  Rhee and Alam Cooling Rewarming

52. 0 20 40 60 80 100 Time 0 5 10 15 20 25 30 35 40 Temp (ºC) 5 min exsanguination 20 min EPR (including aortic flush) 1 min CA 60 min CPB (Temp N-EPR) (Temp H-EPR) MAP (mmHg)

53.  Exemplary Care  Cutting-edge Research  World-class Education 

54. Emergency Preservation Time Mean Arterial Pressure (MAP, mmHg) Tympanic Temperature (Tty, o C) Trauma Final gasp Lose pulse Open chest Transport to OR Hemostasis Delayed resuscitation Aortic flush Tty MAP

55.  Exemplary Care  Cutting-edge Research  World-class Education  Funding Telemedicine and Advanced Technology Research Center

56.  Exemplary Care  Cutting-edge Research  World-class Education  FDADSMBIRBCC/PDStart Regulatory process

57.  Exemplary Care  Cutting-edge Research  World-class Education  Team

58.  Exemplary Care  Cutting-edge Research  World-class Education  Trauma case 23 yo male Multiple gunshot wounds HR 140, BP 80/p Loses pulse in ED CPR-no response

59.  Exemplary Care  Cutting-edge Research  World-class Education  THE MEDIC OF THE FUTURE Fluids Smart catheter Cooling device Miniature pump Drugs

60.  Exemplary Care  Cutting-edge Research  World-class Education  For now? Maintain normothermia But…….

61.  Exemplary Care  Cutting-edge Research  World-class Education  Thanks EPR fellows Anthony Capone, MD Randy Woods, MD Stephan Prueckner, MD Wilhelm Behringer, MD Ala Nozari, MD Xianren Wu, MD Thomas Drabek, MD Bill Stezoski, Jason Stezoski Numerous technicians

62. Pat Kochanek, MD

63. Peter Safar, MD An inspiration to us all Snowbird, Utah, SHOCK Society annual meeting, June, 2000

64.  Exemplary Care  Cutting-edge Research  World-class Education  UPMC Critical Care www.ccm.pitt.edu