1. Therapeutic hypothermia after cardiac arrest April 19,2013 Khartoum-Sudan Ashraf Altarifi,MD,FCCP Consultant Intensivist and Pulmonologist King Faisal Specialist Hospital and Research Center Riyadh, Saudi Arabia

2. Case presentation  65 year old male patient with hx of DM,HTN was found unresponsive at home  Patient taken to ER, found to be in asystole.  Patient intubated, CPR done for 25 minutes with return of pulse and blood pressure. Pt in sinus rhythm but requiring inotropes.

3. Neuro exam  Pt unresponsive, pupils non reactive.  No spontaneous movements in arms or legs.  2 hours later,Pt develops myoclonic jerks.EEG negative for seizures.  Patient started on sedation

4. Common Scenario!  Three weeks later patient remained comatosed in a persistent vegetative state.GCS 4/15.Tracheostomy done.  Patient develops ventilator associated pneumonia.  Patient develops respiratory failure, septic shock, and renal failure.  Patient dies 27 days after the initial cardiac arrest.

5. Magnitude of Sudden Cardiac Arrest in the US AIDS Breast Cancer Lung Cancer Stroke Sudden Cardiac Arrests Sudden cardiac arrest claims more lives each year than these other diseases combined 450,000 167,366 157,400 40,600 42,156 #1 Killer in the U.S.

6. Cardiopulmonary resuscitation on TV  97 episodes of ER, Chicago Hope and Rescue 911 reviewed  60 incidents of Cardiac arrest observed  Etiology of cardiac arrest 55% trauma,28% cardiac  75% of patients survived the immediate arrest  68% survived to hospital discharge  10 cases had miraculous recovery when physicians gave up hope.  Almost all patients surviving had normal neurolgic and functional outcome. NEJM 1996 :334 (1578-82)

7. Epidemiology of Out of Hospital cardiac arrests Cardiac arrest is common –295,000 per year in US 23% VF 31% Bystander CPR –Median survival all rhythms 7.9%, VF 21% –Prior to hypothermia –Best EMS systems: ie: Seattle 1998-2001 (resuscitated) 17.5% survival to hospital discharge 34% VT/VF subgroup –Since hypothermia (2006-2011 data) –MMC 6 month survival with GNO –Overall 30.6% (includes 55% PEA & Asystole) –58% VT/VF subgroup –IHCA adults: 19% (despite 95% witnessed or monitored) Circulation 2010;Jan 26:e12-13

8. Real life outcome of cardiac arrests  Survival usually defined as survival to hospital discharge.  Varies greatly between different EMS systems.  Varies according to downtime prior to resuscitation.  Varies according to initial rhythm.

9. Epidemiology of Out of Hospital cardiac arrests Cardiac arrest is common –295,000 per year in US 23% VF 31% Bystander CPR –Median survival all rhythms 7.9%, VF 21% –Prior to hypothermia –Best EMS systems: ie: Seattle 1998-2001 (resuscitated) 17.5% survival to hospital discharge 34% VT/VF subgroup Circulation 2010;Jan 26:e12-13

10. EMS systems have improved outcome of cardiac arrests

11. 3 Critical Interventions Save Lives in Cardiac Arrest  Bystander CPR –Chest compressions only  Minimally interrupted CPR by EMS –“Cardiocerebral resuscitation”  Modern post-resuscitation care –Therapeutic hypothermia –Cardiac and hemodynamic support

12. From what do they die…? Laver. Intensive Care Med 2004;30:2126 68% 9% 23% 51% 26% 23%

13. Critical care medicine 1999 Survival according to initial rhythm

14. Outcome of out of hospital cardiac arrests  46% survival in 1467 pts admitted after out of hospital arrest-BMJ 1996.  17% survival out of hospital arrest-Resuscitation Jan 2006.  Outcome of arrests in Finnish ICU 1986-1999: –In 1986 survival to hospital discharge was 39 % of patients (604 patients). –In 1999 survival to hospital discharge was 41% of patients (1036 patients). –However mortality improved for patients < 57 yr and for males Acta Anesthesiologica,Aug 2006

15. Outcome of in-hospital cardiac arrest  National Registry of Cardiopulmonary Resuscitation (NRCPR) of 14720 in-hospital arrests with 17% hospital discharge. –16% of patients had V Fib as initial rhythm with 34% hospital discharge  105 patients with in-hospital arrests reviewed.44% survived the arrest and 22% survived to discharge  Better prognosis –Cardiac etiology –V Tach or V Fib  The only predictor of hospital survival was absence for need of endotracheal intubations  76% of patients had good neurologic outcome (CPC 1) Internal Medicine Journal 34 ; 398 - July 2004

16. Cardiac arrest in the ICU  Causes of arrest –Metabolic disturbances 29% –Shock 26% –Hypoxemia 23% –Cardiac ischemia 11% –Brain death 7% –PE 2%  Initial rhythms –Asystole 47% –Brdycardia followed by asystole 29% –PEA 18% –V Fib/V Tach 6% Hospital survival is 11% Critical care, 2001

17. Resuscitation after cardiac arrest: A 3-phase time-sensitive model Weisfeldt ML. JAMA 2002 No FlowLow FlowPost-CPR ROSC Cardiac Arrest CPR Electrical phase Metabolic phase > 10 min. Circulatory phase 4 – 10 min. 0 – 4 min.

18. Mode of death after admission to ICU post cardiac arrest Intensive care medicine, 2004 0 10 20 30 40 50 60 70 80 MSOF Neurologic complications shock VF/VTPEA/asyst

19. Cerebral performance categories after cardiac arrest  CPC 1Goodawake alert, May have mild psycho-cognitive dysfunction  CPC 2Moderateawake, alert. May have weakness or dysarthria but able to do ADL.  CPC 3Severeconscious, dependent on others. May have dementia or minimal communication  CPC 4ComaUnconscious, Persistent Vegetative State  CPC 5Brain death Critical Care Medicine: Volume 24(2S) Supplement February 1996 pp 69S-80S

20. Overall performance after cardiac arrest  OPC 1GoodCPC 1,capable of normal life, no other organ disability  OPC 2ModerateCPC 2 or disability from another organ dysfunction.Can work under special conditions.  OPC 3SevereCPC 3 or severe disability from another organ. Dependent on others.  OPC 4VegetativePersistent Vegetative State  OPC 5Death Critical Care Medicine: Volume 24(2S) Supplement February 1996 pp 69S-80S

21. Can the outcome of cardiac arrest be improved?

22. Anesthesia and Analgesia 1959;38 (6): 423

23. Benson et al,Anesth Analg 1959; 38: 423-8.  Comatose survivors  Asystole or VF  31-32°C  Cooling until neurologic recovery (3 hours to 8 days)  Water-filled blanket The Use of Hypothermia After Cardiac Arrest

26. Mild Therapeutic Hypothermia to Improve the Neurologic Outcome After Cardiac Arrest (HACA)  Patients with witnessed cardiac arrest from VF or pulseless VT, 18-75 years of age, estimated 5-15 minutes to attempted resuscitation, and less than 60 minutes from collapse to restoration of spontaneous circulation (ROSC).  275 patients of 3,551 cardiac arrests screened were eligible for the study (8%)  137 patients randomized to receive hypothermia (32-34°c) for 24 hours Dr. Fritz Sterz, Vienna, Austria, and The Hypothermia After Cardiac Arrest Study Group, N Engl J Med 2002; 346:549-556

27. HACA Study Group  Randomized trial 2002 -Hypothermia vs Normothermia  Methods –Inclusion - OOHCA due to VF –Exclusion – Cardiogenic shock  Hypothermia group –32°C - 34°C –Cooled for 24 hrs –Rewarming over 8 hrs Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346:549-556. 3351 assessed 3246 ineligible 30 Not included 275 enrolled 137 hypothermia 138 normothermia

28. HACA Study Group  Neurologic outcome  Pittsburgh cerebral performance category scale Cerebral Performance Category (CPC) CPC 1Good cerebral performance CPC 2Moderate cerebral disability CPC 3Severe cerebral disability CPC 4Coma or vegetative state CPC 5Brain death Positive Outcomes Negative Outcomes

29. HACA study: results Bladder Temperature in the Normothermia and Hypothermia Groups.

30. Hypothermia for Coma After Cardiac Arrest Hypothermia Normothermia P 0.02 Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346:549-556.

31. Mild Therapeutic Hypothermia to Improve the Neurologic Outcome After Cardiac Arrest (HACA)  Mortality at 6 months was 41% in the hypothermia group and 55% in the normothermia group  55% of hypothermia group and 39% of normothermia group had a favorable neurologic outcome (good recovery or moderate disability) p value 0.009  Complication rate did not differ significantly between the two groups Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346:549-556.

32. Treatment of Comatose Survivors of OOH Cardiac Arrest with Induced Hypothermia  77 patients with cardiac arrest due to VF, with ROSC but coma, randomized to hypothermia or normothermia  Patients excluded if the age of men was less than 18, and women less than 50, or cardiogenic shock  Hypothermia to 33 degrees begun within two hours and continued for 12 hours with cold packs. Bernard et al,N Engl J Med 2002; 346:557-563

33. Treatment of Comatose Survivors of OOH Cardiac Arrest with Induced Hypothermia  Survival was 21/43 of the hypothermia group (49%) vs. 9/34 treated with normothermia (25%) p = 0.01  Good outcome (normal or with minimal or moderate disability) was 49% in hypothermia group and 26% in the normothermia p = 0.046 Bernard et al. (Australia), N Engl J Med 2002; 346:557-563

34. Favorable Neuro Outcome :All three studies combined  Benson 1959 –50% with Hypo (12) –15% with Normo (7)  HACA 2002 –55% with Hypo (137) –39% with Normo (138)  Bernard 2002 –49% with Hypo (43) –25% with Normo (34) Total patients: Hypo = 192 Normo = 179

35. Combined Data (3 studies)  Favorable Neurologic outcome –Hypothermia = 53% (102/192) –Normothermia=35% (63/116) p < 0.0005

36. ILCOR Advisory Statement  Unconscious adult patients with ROSC after out-of-hospital VF cardiac arrest should be cooled to 32°C - 34°C for 12 - 24 hours  Possible benefit for other rhythms or in- hospital cardiac arrest

37. 2005 AHA guidelines for ACLS and post CPR care  In a select subset of patients who were initially comatose but hemodynamicaly stable after a witnessed VF arrest of presumed cardiac etiology, active induction of hypothermia was beneficial. Thus, unconscious adult patients with ROSC 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 VF (Class IIa). Similar therapy may be beneficial for patients with non-VF arrest out of hospital or for in-hospital arrest (Class IIb). 2005 AHA guidelines, Circulation, 2005

38. Possible mechanisms for clinical benefit

39. Interruption of Cerebral Blood Flow Hypoxia-Ischemia Resuscitation Reperfusion Injury Pathogenesis of Hypoxic-Ischemic Cerebral Injury

40. Mechanisms ischemia glutamate release oxygen-free radicals calcium shifts mitochondrial dysfunction reperfusion excitotoxicity inflam. cascades Cell Death blood brain barrier disruption & cerebral edema hypothermia lower metabolic rate less oxygen consumption Geocadin RG, Koenig MA, Jia X et al. Management of brain injury after resuscitation from cardiac arrest. Neurol Clin. 2008;22:487-506.

41. It is not that complicated!! How to apply hypothermia

42. Four Modes of Heat Transfer  Conduction –Cold water immersion  Radiation –Cold room  Convection –Fans (do not use for infection control purposes)  Evaporation –Sweating

43. Basics of Therapeutic Hypothermia: Three phases of treatment –Induction Rapidly bring the temperature to 32-34C Sedate with propofol or midazolam during TH Paralyze to suppress heat production –Maintenance maintain the goal temperature at 33C Standard 12-24 hours (optimal duration is unknown) Suppress shivering –Rewarming Most dangerous period: hypotension, brain swelling, Goal is to reach normal body temperature over 12- 24h Stop all sedation when normal body temperature is achieved

44. Induction: how to cool  Commercial cooling devices –External (surface cooling) systems Hydrogel heat exchange pads Cold water circulating through plastic “suit” Cold water immersion : ? safety data –Invasive (catheter based) systems Heat exchange catheter in SVC or IVC Plastic or metalic heat-exchange catheter

45. Devices

47. Medivance ARCTIC SUN

48. Cold IV Fluids  Polderman 2005 –110 patients, 2-3L over 50 min –36.9°C to 34.6°C, MAP increased by 15mmHg, no pulmonary edema Bernard 2003 - 22 patients 30cc/kg LR at 4°C over 30 min: 35.5°C to 33.8°C Improvements in MAP, renal function, no pulmonary edema Polderman. Crit Care Med 2005;33:2744 Bernard. Resuscitation 2003;56:9

49. Maintainance: how to cool  Monitor core temperature –Bladder, esophagus, or central venous/pulmonary arterial  Ice packs and cooling mats –Effective, but difficult to control rate of temperature change –Overcooling is dangerous  Endovascular cooling allows for gradual reduction in temp, maintainence at desired temp and prevents over cooling

50. Management of shivering  Neuromuscular blockade –Vecuronium bolus 0.1mg/kg prn BSAS>2 –Cisatricurium in renal failure  Propofol  Alpha blockade –Dexmedetomidine infusion or clonidine  Scheduled acetaminophen, buproprion  Meperidine or fentanyl  Focal counterwarming  Magnesium infusion (serum level 3mg/dl)

51. Re-warming  If using surface cooling: Use passive re-warming  Remove Ice packs  Stop cold IV fluids  If using endovascular cooling: set temperature rise at 0.3-0.5 degrees per hour  Avoid rapid re-warming

52. Re-warming  Vasodilation causes hypotension –May require several liters IVF  More shivering during this phase  Inflammation increases at higher temperature –“post-resuscitation” syndrome  Increased ICP  Watch for hyperkalemia –Primarily problematic in renal failure

53. Side Effects of hypothermia  Toxicity increases with increased duration & intensity of cooling  Four categories of toxicity: –Cardiovascular Arrhythmia –Hematologic Platelet dysfunction, coagulopathy –Immunologic Impaired neutrophil function leading to increased infection –Metabolic Hypokalemia, hyperglycemia, ileus, pancreatitis Re-warming: SIRS physiology?

54. Hypothermia Questions  How quickly? –ASAP, but at least within 6 hours of event –Longer the delay, the longer hypothermia must be continued to provide protection  How cold? –At least 35 o C core temperature but not lower than 32 o C –Temp < 30 degrees leads to more complications  How to cool? Use NSAID? –Blanket cooling not effective in adults; intravascular cooling with bolus of iced RL or NS is effective –Selective head cooling may benefit neonates

55. Hypothermia Questions  How long to cool? –At least 12 hours; 24 hours probably better  How to rewarm? –Worse outcome if rewarm rapidly –Management of shivering/stress response  Which patients should be cooled? –Only comatose adults after ROSC who are “hemodynamically stable” –Should cooling start in the field or at the referring hospital?

56. Hypothermia Questions  How to monitor cooling? –Bladder, rectal or blood temperature? Brain temperature?  How should we manage shivering? –If use NMB, need to monitor EEG –Sub-clinical seizures may be more common than clinically recognized – should we load with anticonvulsants?  How to adjust medications in the hypothermic patient  Are there useful biomarkers?

57. Use of Therapeutic Hypothermia survey

58. Critical Care (n=33) Cardiology (n=64) Emergency Medicine (n=109) All respondents (n=263) YesNo 5% 95% 11% 89% 29% 71% 13% 87% Use of Therapeutic Hypothermia by Clinical Specialty

59. Not enough data Haven’t considered it Not in ACLS guidelines Too technically difficult Current methods cool too slow Unsatisfactory initial attempts 0% 10% 20% 30% 40% 50% Reason for nonuse- Percentage of respondents 49% 32% 19% 9% 4% Reasons Against Use of Hypothermia as a Therapeutic Tool

60. Cooling Technique Cooling blankets Ice / cold liquid packing Ice / cold liquid gastric lavage IV cooling catheter Cooling mist Other method 0% 10% 20% 30% 40% 50% Cooling technique Percentage of respondents 50% 15% 13% 2% 17%

61. KFSH Hypothermia protocol

64. Different Scenario New patient March 12  55 year old male s/p gastric bypass surgery with hx of pyloric stenosis  Massive aspiration leading to respiratory then cardiac arrest.  CPR done for 14 minutes  Pt admitted to ICU. Hypothermia protocol applied  Within 48 hours, pt fully awake, follows commands  Extubated day 5.

65. Take home messages  Strong evidence that mild hypothermia is neuro-protective after return of spontaneous circulation.  Fever is detrimental post resuscitation (and for any neuro patient)  Hypothermia is underutilized so far but should be included in post resuscitaion care of cardiac arrest victims

66. Thank you

67. CHAIN OF SURVIVAL

68. What are the risks?  More infections –Lung  Trends toward more bleeding  Electrolyte shifts  Clinically insignificant bradycardia  Changes in drug metabolism HCASG. NEJM 2002;346:549-56