Evidence Based Medicine Induced Hypothermia After Cardiac Arrest October 5, 2010

1. Evidence Based MedicineInduced Hypothermia After Cardiac ArrestOctober 5, 2010 Maria Victoria Peralta, MD Department of Medicine

3. Objectives Discuss research and current evidence regarding use of induced hypothermia after cardiac arrest Discuss current AHA recommendations Review how to order induced hypothermia at Harbor-UCLA Medical Center

4. Introduction Sudden cardiac death causes 300,000 to 400,000 deaths a year (5.6% annual mortality) Cardiac arrest: sudden ineffective cardiac forward flow due to asystole or PEA or VT/VF Survival rate out-of-hospital cardiac arrest: 5% to 18% Asystole or PEA survival 0.9% VT/VF survival 9.5% to 41%

5. Introduction Lack of cerebral perfusion after 5 minutes generates free radicals Subsequent reperfusion cerebral injury 1950: Induction of moderate hypothermia (28°C to 32°C) before cardiac arrest prior to open-heart surgery was neuroprotective. Also some successful use of post-cardiac arrest therapeutic hypothermia. 1980: Induced systemic hypothermia after return of spontaneous circulation (ROSC) in dogs improved neurologic outcomes Proposed mechanisms: reduction in cerebral oxygen consumption and other multifactorial chemical and physical mechanisms during and after ischemia ? retardation of destructive enzymatic reactions, suppression of free radical reactions, protection of fluidity of lipoprotein membranes, reduction of oxygen demand in low-flow regions, reduction of intracellular acidosis, and inhibition of biosynthesis, release, and uptake of excitatory neurotransmittersProposed mechanisms: reduction in cerebral oxygen consumption and other multifactorial chemical and physical mechanisms during and after ischemia ? retardation of destructive enzymatic reactions, suppression of free radical reactions, protection of fluidity of lipoprotein membranes, reduction of oxygen demand in low-flow regions, reduction of intracellular acidosis, and inhibition of biosynthesis, release, and uptake of excitatory neurotransmitters

6. The New England Journal of MedicineMild therapeutic hypothermia to improve the neurologic outcome after cardiac arrestHypothermia after Cardiac Arrest Study Group(HACA)February 21, 2002

7. HACA, NEJM 2002 Population: patients who had cardiac arrest due to VF Intervention: mild hypothermia (34°C) Comparison: standard normothermia Outcome: favorable neurologic outcome within 6mo after cardiac arrest, mortality at 6mo, and complications within 7d

8. HACA, NEJM 2002 Study design: prospective, randomized, controlled trial with blinded assessment of the outcome Patients who had ROSC after a witnessed cardiac arrest of cardiac origin (Vfib or nonperfusing Vtach). 5-15 minutes from time of collapse to first attempt at out-of-hospital resuscitation. Interval of no more than 60 minutes from collapse to ROSC. 275 patients enrolled 137 to the hypothermia group and 138 to the normothermia group, assignments randomly generated by computer in blocks of 10

9. HACA, NEJM 2002 All patients IV midazolam and fentanyl for sedation as needed for mechanical ventilation IV pancuronium for paralysis to prevent shivering monitored temp with IR tympanic thermometer or bladder temp probe

10. HACA, NEJM 2002 Normothermia group: conventional hospital bed and kept normothermic Hypothermic group: cooled to target 32°C to 34°C with external cooling devices with goal to reach target bladder temp in 8hrs after return of spontaneous circulation and maintained for 24hrs, followed by passive rewarming over 8hrs

11. HACA, NEJM 2002

12. HACA, NEJM 2002 The T bars indicate the 75th percentile in the normothermia group and the 25th percentile in the hypothermia group. The target temperature in the hypothermia group was 32°C to 34°C, and the duration of cooling was 24 hours. Only patients with recorded temperatures were included in the analysis.The T bars indicate the 75th percentile in the normothermia group and the 25th percentile in the hypothermia group. The target temperature in the hypothermia group was 32°C to 34°C, and the duration of cooling was 24 hours. Only patients with recorded temperatures were included in the analysis.

13. HACA, NEJM 2002 Primary outcome: favorable neurologic outcome within six months based on Pittsburgh cerebral-performance categories 1: good recovery 2: moderate disability 3: severe disability 4: vegetative state 5: death

14. HACA, NEJM 2002

15. HACA, NEJM 2002 Hypothermia 75 of 136 to normothermia 54 of 137 with favorable neurologic outcome (NNT 6 to prevent unfavorable neurologic outcome) with death rate 14% lower in hypothermia group (NNT 7 to prevent death)

16. HACA, NEJM 2002 Censored data are indicated by tick marks.Censored data are indicated by tick marks.

17. HACA, NEJM 2002 Secondary outcomes: overall mortality at six months and rate of complications during the first seven days after cardiac arrest Bleeding of any severity *Pneumonia *Sepsis Pancreatits Renal failure Pulmonary edema Seizures Arrhythmias Pressure sores * more likely to develop with hypothermia than normothermia, but not statistically significant

18. HACA, NEJM 2002

19. The New England Journal of MedicineTreatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermiaBernard SA, Gray TW, et al.February 21, 2002

20. Bernard et al., NEJM 2002 Population: comatose survivors who had out-of-hospital cardiac arrest due to VF Intervention: moderate hypothermia (33°C) Comparison: standard normothermia (37°C) Outcome: discharge home or to a rehabilitation facility (good outcome) vs. death in the hospital or discharge to a long-term nursing facility (poor outcome)

21. Bernard et al., NEJM 2002 Study design: prospective, randomized, controlled trial, with blinded assessment of the outcome Patients who had initial cardiac rhythm of Vfib at time of arrival of EMS with persistent coma after ROSC 77 patients enrolled 43 to the hypothermia group and 34 to the normothermia group, randomly assigned to a particular group according to the day of the month (odd-numbered days go to hypothermia group)

22. Bernard et al., NEJM 2002 Upon arrival to ED and evaluation of neurologic status, all patients IV midazolam for sedation IV vecuronium for paralysis to prevent shivering IV lidocaine to prevent recurrent ventricular tachyarrhythmias IV potassium to maintain serum levels above 4.0 mmol/L SQ insulin for blood glucose below 180 mg/dL Aspirin MAP maintained between 90 and 100 by infusion of epi or NTG Thrombolytic therapy for suspected AMI, unless contraindicated. Monitored tympanic or bladder temp until PA catheter placed.

23. Bernard et al., NEJM 2002 Normothermic patients: maintained target core temp of 37°C with passive rewarming if mild spontaneous hypothermia on arrival. Hypothermia patients: basic cooling measures with ice packs in the field by paramedics, then vigorous cooling in ED/ICU until core temp 33°C, then maintained this temp for 12 hours. Patients actively rewarmed with heated-air blanket after 12 hours.

24. Bernard et al., NEJM 2002 After 24hrs, patients who regained consciousness were extubated. After 72hrs, patients who remained deeply comatose had active life support withdrawn. Patients with uncertain prognosis underwent tracheostomy and discharged from ICU

25. Bernard et al., NEJM 2002

26. Bernard et al., NEJM 2002 Hypothermia no association with adverse affects Although decreased pulse and increased SVR, no clinically significant cardiac arrhythmias in hypothermia group

27. Bernard et al., NEJM 2002

28. Bernard et al., NEJM 2002 Increase in serum potassium a result of rewarming and, though statistically significant, not clinically important Increase in glucose, previously described in patients undergoing therapeutic hypothermia Total CK and CKMB no significant difference, indicating hypothermia does not increase extent of myocardial damage

29. Bernard et al., NEJM 2002

30. Bernard et al., NEJM 2002 Although other studies have shown adverse effects on platelet and WBC counts when hypothermia used for extended periods, no statistically significant difference between groups for hypothermia used for 12hrs Also, no clinically significant infections in either group

31. Bernard et al., NEJM 2002

32. Bernard et al., NEJM 2002 49% patient in hypothermia group considered to have good outcome vs. 26% patient in normothermia group (P=0.046) Therefore, OR for good outcome in hypothermia group 5.25 Difference in mortality: hypothermia 51% vs. normothermia 68% not significant

33. Bernard et al., NEJM 2002 Every two-year age increase, 9% decrease likelihood of good outcome (OR 0.91) Each additional 1.5min from collapse to ROSC 14% decrease likelihood of good outcome (OR 0.86) CPR by bystander showed nonsignificant improvement in outcome (OR 1.4)

34. Bernard et al., NEJM 2002

35. ResuscitationInduced hypothermia using large volume, ice-cold intravenous fluid in comatose survivors of out-of-hospital cardiac arrest: a preliminary reportBernard S, Buist M, et al.2003

36. Bernard et al., Resus 2003 Population: patients who had cardiac arrest, then received rapid infusion of large volume (30mL/kg) ice-cold (4°C) IVF Intervention: post fluid infusion vital signs and laboratory investigations Comparison: pre fluid infusion vital signs and laboratory investigations Outcome: significant improvements in mean arterial blood pressure, renal function and acid/base analysis Ice packs decrease core temperature by 0.9°C/h, and forced cold air cooling by 0.4°C/h. Animal studies show improved outcome if cooling initiation during resuscitation or immediately after ROSCIce packs decrease core temperature by 0.9°C/h, and forced cold air cooling by 0.4°C/h. Animal studies show improved outcome if cooling initiation during resuscitation or immediately after ROSC

37. Bernard et al., Resus 2003 Study design: prospective, nonrandomized trial Patients, who arrived unconscious in ED after cardiac arrest due to Vfib, asystole, or PEA, received IV infusion of 30mL/kg of 4°C Lactated Ringers (LR) solution over 30min using pressurized bag Exclusion of spontaneous hypothermia (<34°C at initial measurement)

38. Bernard et al., Resus 2003 All patients: Mechanical ventilation MAP maintained between 90 and 100 by infusion of epi or glyceryl tri-nitrate infusions IV midazolam for sedation IV vecuronium for paralysis to prevent shivering Monitored continuous ECG and invasive BP. Bladder catheter for temp.

39. Bernard et al., Resus 2003 Initial assessment confirmed coma and involved routine ECG, CXR, BMP, CBC, cardiac enzymes, and ABG Immediately following infusion, vitals recorded and blood sent for BMP, CBC, and ABG Ice packs then used to further decrease temperature to goal of 33°C and maintain for 12hrs, then active rewarming over 6hrs Bernard Bernard

40. Bernard et al., Resus 2003 Bernard et al., NEJM 2002, hypothermia group core temperature decrease from mean 34.9°C at 30min after ROSC to mean 33.5°C at 120min after ROSC (decrease of 0.9°C/hr) In this study, time from ROSC to infusion, when median 35.5°C, was median 73.0min. After 30min infusion, median 33.8°C.

41. Bernard et al., Resus 2003 Total collapse to ROSC comparable to other studiesTotal collapse to ROSC comparable to other studies

42. Bernard et al., Resus 2003 AHA report from 2010, median survival to hospital discharge following out-of-hospital cardiac arrest was 7.9% with median survival of Vfib 21%. Significantly lower if first recorded rhythm not Vfib or pulseless Vtach (~0 to 2% survival rate). In this study, overall survival 45.4% Survival of patients who had cardiac arrest due to Vfib 57.1% vs. survival of patients who had cardiac arrest due to non-Vfib 25% Rate of survival to discharge after in-hospital cardiac arrest 19%Rate of survival to discharge after in-hospital cardiac arrest 19%

43. Bernard et al., Resus 2003 Total collapse to ROSC comparable to other studiesTotal collapse to ROSC comparable to other studies

44. Bernard et al., Resus 2003 In addition to a quickly lowering the core temperature after 30min infusion, there were significant improvements in MAP, CVP, pH, pCO2, bicarbonate, and creatinine Bernard Bernard

45. Bernard et al., Resus 2003

46. ResuscitationMild hypothermia induced by a helmet device: a clinical feasibility studyHachimi-Idrissi S, Corne L, et al.2001

47. Hachimi-Idrissi et al., Resus 2001 Population: patients with asystole or PEA arrest Intervention: mild hypothermia (34°C) using Frigicap® Comparison: standard normothermia (37°C) Outcome: improved hemodynamics, electrolytes, lactate, arterial pH, CaO2, CvO2 and O2 extraction ratio

48. Hachimi-Idrissi et al., Resus 2001 Study design: prospective, blindly randomized, controlled trial Only patients with asystole or PEA out-of-hospital cardiac arrest with ROSC Age>18 y/o Tympanic temperature >30°C on admission to ED GCS<7 No history of CNS depressant medication prior to event SBP>100 mmHg MAP> 60 mmHg

49. Hachimi-Idrissi et al., Resus 2001 30 consecutive patients included 16 patients to hypothermic group and 14 to normothermic group

50. Hachimi-Idrissi et al., Resus 2001 All patients: received standard post resuscitation care protocol IV midazolam and fentanyl for sedation and analgesia IV pancurorium for 4 hours to prevent shivering Vent management to maintain O2 sat>95% with 100>PaO2>150 and 40>PaCO2>45, PEEP 5, MAP>60 Pressors prn

51. Hachimi-Idrissi et al., Resus 2001 Normothermia group: Initial hypothermic patient passively rewarmed Hypothermia group: Frigicap ® at -4°C placed around head and neck and changed Q1h until core temp 34°C or for 4hrs. Helmet/scalp temp monitored with double disposable contact thermometer, while core temp monitored with bladder temperature. Passive rewarming over 8hrs.

52. Hachimi-Idrissi et al., Resus 2001

53. Hachimi-Idrissi et al., Resus 2001

54. Hachimi-Idrissi et al., Resus 2001 Median time elapsed from collapse to start of study 102min with <15s to place helmet in hypothermic group 99min in normothermic group

55. Hachimi-Idrissi et al., Resus 2001

56. Hachimi-Idrissi et al., Resus 2001 Hemodynamics, pH, electrolytes, CBC, and lactate showed no difference at start of study At end of study, comparing hypothermic to normothermic group (all statistically significant p<0.05): CvO2 higher Lactate lower O2 extraction ratio lower

57. Hachimi-Idrissi et al., Resus 2001 Hypothermic group lactate significantly lower from start of study to end of study Normothermic group CvO2 significantly lower and O2 extraction ratio significantly higher from start of study to end of study

58. Hachimi-Idrissi et al., Resus 2001

59. Hachimi-Idrissi et al., Resus 2001 13 of 16 patients died in hypothermia group (19% survival), and 13 of 14 died in normothermia group (7% survival) No patient died during study period No complications noted, not even device related complications, such as scalp freezing or tissue necrosis

60. CirculationTherapeutic hypothermia after cardiac arrest: An advisory statement by the Advanced Life Support Task Force of the International Liaison Committee on ResuscitationNolan JP, Morley PT, et al.2003

61. Nolan et al., Circ 2003 ILCOR Recommendations 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 Vfib Such cooling may also be beneficial for other rhythms or in-hospital cardiac arrest

62. Nolan et al., Circ 2003 Limited studies on the effectiveness of mild therapeutic hypothermia on patients who had non-VF cardiac arrest

63. Nolan et al., Circ 2003 Limited studies on the effectiveness of mild therapeutic hypothermia on patients who had in-hospital cardiac arrest.

64. Nolan et al., Circ 2003

65. Nolan et al., Circ 2003 Timing of cooling Cooling should start as soon as ROSC, but has shown benefit despite delay Reach target temperature of 32°C to 34°C within range of 4 to 16hrs Cooling techniques External cooling methods (cooling blankets, ice packs, wet towels and fanning, and cooling helmet) simple to use, but slow IV infusion of 30 mL/kg of crystalloid at 4°C over 30min Peritoneal and pleural lavage is effective, but invasive

66. Nolan et al., Circ 2003 Complications and monitoring Complications, such as arrhythmias, infection (pneumonia and sepsis), and coagulopathy may increase if core temp falls considerably below 32°C MONITOR, MONITOR, MONITOR frequently using bladder temperature probe or a pulmonary artery catheter, since intermittent tympanic temperature measurements less reliable Another complication of therapy hyperglycemia

67. CirculationAmerican Heart Association Guidelines for Cardiopulmonary Resiscitation and Emergency Cardiovascular Care2005 ECC committee, Subcommittees and Task Force of the American Heart Association. 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care “Part 7.5: Postresuscitation Support”. Circulation. 2005;112:IV-84-8. ECC committee, Subcommittees and Task Force of the American Heart Association. 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care “Part 7.5: Postresuscitation Support”. Circulation. 2005;112:IV-84-8.

68. AHA Recommendations Do not actively rewarm hemodynamically stable patients who spontaneously develop a mild degree of hypothermia (>33°C) after resuscitation from cardiac arrest Mild hypothermia, whether permissive hypothermia or active induction of hypothermia may be beneficial to neurologic outcome Cool to 32°C to 34°C for 12 to 24 hours when initial rhythm VF (Class IIa) Therapy may benefit patients with non-VF arrest out-of-hospital or for in-hospital arrest (Class IIb)

69. Harbor-UCLA Order Forms

70. Harbor-UCLA Order Forms

71. Harbor-UCLA Order Forms

72. References Ali B and Zafari AM. Narrative review: cardiopulmonary resuscitation and emergency cardiovascular care: review of the current guidelines. Ann Intern Med. 2007;147:171-9. 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. Bernard SA, Gray TW, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346:557-63. Bernard S, Buist M, et al. Induced hypothermia using large volume, ice-cold intravenous fluid in comatose survivors of out-of-hospital cardiac arrest: a preliminary report. Resuscitation. 2003;56:9-13. Lloyd-Jones D, Adams, RJ, et al. Heart Disease and Stroke Statistics—2010 Update: a report from the American Heart Association. Circulation. 2010;121:e46-215.

73. References Hachimi-Idrissi S, Corne L, et al. Mild hypothermia induced by a helmet device: a clinical feasibility study. Resuscitation. 2001;51:275-281. Nolan JP, Morley PT, et al. Therapeutic hypothermia after cardiac arrest: An advisory statement by the Advanced Life Support Task Force of the International Liaison Committee on Resuscitation. Circulation. 2003;108:118-21. ECC committee, Subcommittees and Task Force of the American Heart Association. 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care “Part 7.5: Postresuscitation Support”. Circulation. 2005;112:IV-84-8.