Noon Conf: Therapeutic hypothermia


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Noon Conf: Therapeutic hypothermia

  1. 1. therapeutic hypothermia in survivors of cardiac arrest Sherry Goldyn, MD, MPH Pulmonary/Critical Care July 13, 2011
  2. 2. Therapeutic hypothermia (TH) <ul><li>The use of mild induced hypothermia (32-34 ° C) as a way to protect the brain after anoxic injury from cardiac arrest </li></ul><ul><li>overview: </li></ul><ul><ul><li>Incidence of cardiac arrest </li></ul></ul><ul><ul><li>Pathophysiology post-arrest </li></ul></ul><ul><ul><li>Historical context, recent supportive data for therapeutic hypothermia </li></ul></ul><ul><ul><li>Physiologic changes during cooling </li></ul></ul><ul><ul><li>Kaiser’s TH protocol </li></ul></ul>
  3. 3. Incidence <ul><li>Out-of-hospital cardiac arrest </li></ul><ul><ul><li>350,000-450,000 cases in US per year </li></ul></ul><ul><ul><li>80% occur at home </li></ul></ul><ul><ul><ul><li>death rate ~90% </li></ul></ul></ul><ul><ul><li>Resuscitation attempted in ~100,000 </li></ul></ul><ul><ul><li>40,000 survive to hospital admission </li></ul></ul><ul><ul><li>10,000-15,000 survive to hospital discharge </li></ul></ul>
  4. 4. Incidence <ul><li>In-hospital cardiac arrest </li></ul><ul><ul><li>36,902 cases January 2000-March 2004 </li></ul></ul><ul><ul><ul><li>Voluntary reporting by 253 hospitals to the National Registry of Cardiopulmonary Resuscitation (AHA) </li></ul></ul></ul><ul><ul><li>ROSC in 44% </li></ul></ul><ul><ul><li>Survival to discharge ~17% </li></ul></ul><ul><ul><ul><li>Good neuro function in 60% of survivors </li></ul></ul></ul><ul><li>NEJM 2009;361:605-11 </li></ul>
  5. 5. Post cardiac arrest syndrome <ul><li>Anoxic brain injury </li></ul><ul><li>Arrest-related myocardial dysfunction </li></ul><ul><ul><ul><li>Global hypokinesis, elevated LVEDP </li></ul></ul></ul><ul><li>Systemic ischemic/reperfusion response </li></ul><ul><ul><ul><li>Systemic inflammation, clotting cascade activation, disturbed vasoregulation, infection risk </li></ul></ul></ul><ul><li>Persistent underlying pathology </li></ul><ul><ul><ul><li>ACS </li></ul></ul></ul><ul><ul><ul><li>PE </li></ul></ul></ul><ul><ul><ul><li>Cardiomyopathy </li></ul></ul></ul><ul><ul><li>Circulation. 2011;123:1428-1435 </li></ul></ul>
  6. 6. Post cardiac arrest syndrome <ul><li>Anoxic brain injury </li></ul><ul><li>Arrest-related myocardial dysfunction </li></ul><ul><ul><ul><li>Global hypokinesis, elevated LVEDP </li></ul></ul></ul><ul><li>Systemic ischemic/reperfusion response </li></ul><ul><ul><ul><li>Systemic inflammation, clotting cascade activation, disturbed vasoregulation, infection risk </li></ul></ul></ul><ul><li>Persistent underlying pathology </li></ul><ul><ul><ul><li>ACS </li></ul></ul></ul><ul><ul><ul><li>PE </li></ul></ul></ul><ul><ul><ul><li>Cardiomyopathy </li></ul></ul></ul><ul><ul><li>Circulation. 2011;123:1428-1435 </li></ul></ul>
  7. 7. Post-cardiac arrest <ul><li>Neurologic outcome </li></ul><ul><ul><li>~80% of post-arrest patients remain comatose for >1h post-resuscitation </li></ul></ul><ul><ul><li><50% of these have “good neurologic recovery” </li></ul></ul><ul><ul><ul><li>Clinical Performance Category 1 or 2 </li></ul></ul></ul>
  8. 8. Clinical Performance Category Lancet 1975. 1(7905):480-4 CPC 5. Brain death: apnea, areflexia, EEG silence, etc. CPC 4 . Coma or vegetative state: any degree of coma without the presence of all brain death criteria. Unawareness, even if appears awake (vegetative state) without interaction with environment; may have spontaneous eye opening and sleep/awake cycles. Cerebral unresponsiveness. CPC 3. Severe cerebral disability: conscious, dependent on others for daily support because of impaired brain function. Ranges from ambulatory state to severe dementia or paralysis CPC 2. Moderate cerebral disability: conscious, sufficient cerebral function for independent activities of daily life. Able to work in sheltered environment CPC 1. Good cerebral performance: conscious, alert, able to work, might have mild neurologic or psychologic deficit
  9. 9. Pathophysiology of anoxic injury <ul><li>Vasomotor paralysis  Initial hyperemia </li></ul><ul><li>Prolonged hypoperfusion during arrest/CPR </li></ul><ul><li>After ROSC  reperfusion and reoxygenation injury </li></ul><ul><ul><li>Stores of O2 in the brain lost in seconds </li></ul></ul><ul><ul><li>Stores of glucose/ATP lost within 5 minutes </li></ul></ul><ul><ul><li>Inflammatory response, endothelial activation, leukocyte infiltration </li></ul></ul><ul><ul><li>NEJM 2010. 363;23:1256-1264 </li></ul></ul>
  10. 11. <ul><li>Free radical formation, oxidative damage </li></ul><ul><ul><li>Loss of blood-brain barrier </li></ul></ul><ul><ul><li>Loss of transmembrane chemical gradients </li></ul></ul><ul><ul><li>Glutamate release  increase intracellular Ca++  excitotoxic cell death </li></ul></ul><ul><li>Further exacerbated by brain edema, loss of cerebral autoregulation, hypotension, hypoxia </li></ul>Pathophysiology of anoxic injury
  11. 12. Rationale for cooling <ul><li>Reduces the cerebral metabolic rate for oxygen (CMRO2) </li></ul><ul><ul><ul><li>↓ 6% for every 1°C reduction in brain temperature >28° </li></ul></ul></ul><ul><li>Suppresses chemical reactions associated with reperfusion injury </li></ul><ul><ul><ul><li>Inhibits excitatory amino acid release (eg glutamate) </li></ul></ul></ul><ul><ul><ul><li>Decreases free radical production </li></ul></ul></ul><ul><ul><ul><li>Limits calcium shifts that cause mitochondrial damage and apoptosis </li></ul></ul></ul><ul><li>Decreases intracranial pressure </li></ul>
  12. 13. Historical context <ul><li>Hypothermia used in various scenarios </li></ul><ul><ul><li>Described by ancient Greeks and Romans </li></ul></ul><ul><ul><li>Treatment of tetanus in 4 th century BC </li></ul></ul><ul><ul><li>Treatment of trauma, Hippocrates </li></ul></ul><ul><ul><li>Treatment of typhoid fever, Osler 19 th century </li></ul></ul>
  13. 14. Historical context <ul><li>Neurosurgeon Temple Fay advocated local and generalized refrigeration in 1930s-1950s </li></ul><ul><ul><ul><li>intractable headache pain </li></ul></ul></ul><ul><ul><ul><li>traumatic brain injury </li></ul></ul></ul><ul><ul><ul><li>abscess </li></ul></ul></ul><ul><ul><ul><li>cerebritis, seizures </li></ul></ul></ul><ul><ul><ul><li>malignancy </li></ul></ul></ul>
  14. 15. Fay T, Early experiences with local and generalized refrigeration of the human brain, Journal of Neurosurgery, May, 1959, number 3; 16:239-260, 
  15. 16. Historical context <ul><li>Nazis confiscated Dr. Fay’s data and used hypothermia without anesthesia during medical experiments in Dachau </li></ul><ul><li>Abandoned as a therapy for several decades because of uncertain benefit and difficulties with its implementation </li></ul><ul><li>Hypothermia introduced as a protective strategy during cardiac surgery in the 1950s </li></ul>
  16. 18. Ann Surg. 1958 September; 148(3): 462–466
  17. 19. <ul><li>Fast forward 45 years… </li></ul>
  18. 21. Hypothermia after Cardiac Arrest Group <ul><li>European multicenter RCT, blinded assessment of outcome </li></ul><ul><li>Inclusion criteria: </li></ul><ul><ul><li>ROSC after witnessed VF or pulseless VT arrest Presumed cardiac origin of arrest </li></ul></ul><ul><ul><li>18-75 years old </li></ul></ul><ul><ul><li>5-15 minute interval to 1 st attempt at resuscitation </li></ul></ul><ul><ul><li><60 minutes to ROSC </li></ul></ul><ul><li>275 patients enrolled </li></ul><ul><ul><ul><li>137 hypothermia </li></ul></ul></ul><ul><ul><ul><li>138 normothermia </li></ul></ul></ul>
  19. 22. Hypothermia after Cardiac Arrest Group <ul><li>Goal temperature 32-34 ° C with external cooling device within 4 hours, started in ICU </li></ul><ul><li>Cooled for 24 hours </li></ul><ul><li>Passively rewarmed over 8 hours </li></ul><ul><li>Primary endpoint: </li></ul><ul><ul><li>cerebral performance category of 1 (good recovery) or 2 (moderate disability) </li></ul></ul><ul><li>Secondary endpoints: </li></ul><ul><ul><li>6 month mortality </li></ul></ul><ul><ul><li>Complications within 1 st week </li></ul></ul>
  20. 23. The Hypothermia after Cardiac Arrest Study Group. N Engl J Med 2002;346:549-556
  21. 24. The Hypothermia after Cardiac Arrest Study Group. N Engl J Med 2002;346:549-556
  22. 25. Cumulative Survival The Hypothermia after Cardiac Arrest Study Group. N Engl J Med 2002;346:549-556
  23. 27. Induced hypothermia after out-of-hospital cardiac arrest <ul><li>Australian multicenter, RCT </li></ul><ul><li>Inclusion criteria: </li></ul><ul><ul><li>VF as initial rhythm </li></ul></ul><ul><ul><li>Successful ROSC </li></ul></ul><ul><ul><li>Persistent coma after ROSC </li></ul></ul><ul><li>Exclusion criteria: </li></ul><ul><ul><li>Male<18yo or F<50yo </li></ul></ul><ul><ul><li>Cardiogenic shock (SBP<90 despite epi gtt) </li></ul></ul><ul><li>77 included in study </li></ul><ul><ul><li>43 hypothermia </li></ul></ul><ul><ul><li>34 normothermia </li></ul></ul>
  24. 28. Bernard, S. et al. N Engl J Med 2002;346:557-563
  25. 29. Induced hypothermia after out-of-hospital cardiac arrest <ul><li>Randomization in the field </li></ul><ul><ul><li>Cooling measures (ice packs) instituted in ambulance </li></ul></ul><ul><li>Cooled to 33 °C , maintained for 12 hours </li></ul><ul><li>At 18 hours, active rewarming for 6 hours with heated-air blanket </li></ul><ul><li>Primary endpoint: </li></ul><ul><ul><li>survival to hospital discharge with sufficiently good neuro function to go home or to rehab </li></ul></ul><ul><li>Secondary endpoints: </li></ul><ul><ul><li>hemodynamic, biochemical, hematologic effects </li></ul></ul>
  26. 30. Crit Care Med 2009; 37(7):S223-S226.
  27. 31. Cooling techniques <ul><li>Ice packs </li></ul><ul><li>Iced saline infusion </li></ul><ul><li>Iced nasogastric or bladder lavage </li></ul><ul><li>Cooling blankets </li></ul><ul><li>Fans </li></ul><ul><li>ECMO </li></ul><ul><li>Cooling devices </li></ul>
  28. 32. Cool Gard with Icy Femoral Catheter
  29. 33. Arctic Sun
  30. 34. Physiologic effects of cooling
  31. 35. Physiologic effects of cooling <ul><li>3 stages of therapeutic hypothermia </li></ul><ul><ul><li>Induction phase </li></ul></ul><ul><ul><ul><ul><li>Goal <34 ° C ?as quickly as possible </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Highest risk of acute instability (electrolytes, hemodynamics) </li></ul></ul></ul></ul><ul><ul><li>Maintenance phase </li></ul></ul><ul><ul><ul><ul><li>24h tight core temp control </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Highest risk of long-term complications (infections, skin breakdown) </li></ul></ul></ul></ul><ul><ul><li>Rewarming phase </li></ul></ul><ul><ul><ul><ul><li>Slow, controlled </li></ul></ul></ul></ul><ul><ul><ul><ul><li>0.2-0.5 degree/hour </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Some acute instability but more easily managed </li></ul></ul></ul></ul>
  32. 36. Physiologic effects of cooling <ul><li>Cardiovascular </li></ul><ul><ul><li>Initially: cold vasoconstriction  ↑ venous return  reflex tachycardia </li></ul></ul><ul><ul><ul><li>↑ SVR, ↑BP, ↑CVP </li></ul></ul></ul><ul><ul><li><35 degrees: bradycardia, ↓ CO 25-40% </li></ul></ul><ul><ul><ul><li>MVO2 ~same ( ↓ O2 consumption) </li></ul></ul></ul><ul><ul><li>Hypovolemia due to “cold diuresis” </li></ul></ul><ul><ul><ul><li>Vasoconstriction, hyperglycemia, ↓ renal tubular absorption, increased ADH </li></ul></ul></ul><ul><ul><li>Lactate levels elevated (but stable) </li></ul></ul>
  33. 37. Physiologic effects of cooling <ul><li>Cardiovascular </li></ul><ul><ul><li>HR 40-60 </li></ul></ul><ul><ul><li>↑ PR, ↑ QTc, widened QRS </li></ul></ul><ul><ul><li>Osborne waves </li></ul></ul>
  34. 38. Physiologic effects of cooling <ul><li>Cardiovascular </li></ul><ul><ul><li>Arrhythmias: </li></ul></ul><ul><ul><ul><li>Sinus brady </li></ul></ul></ul><ul><ul><ul><li>Afib  VT  VF (particularly <28C) </li></ul></ul></ul><ul><ul><ul><li>Myocardium less sensitive to anti-arrhythmics </li></ul></ul></ul><ul><ul><li>Ischemia prevented/mitigated? </li></ul></ul>
  35. 39. Physiologic effects of cooling <ul><li>Hepatic </li></ul><ul><ul><li>↓ drug metabolism </li></ul></ul><ul><ul><ul><li>Paralytics </li></ul></ul></ul><ul><ul><ul><li>Opioids </li></ul></ul></ul><ul><ul><ul><li>Benzodiazepines </li></ul></ul></ul><ul><ul><ul><li>AEDs </li></ul></ul></ul><ul><ul><ul><li>propofol </li></ul></ul></ul><ul><ul><ul><li>cephalosporins </li></ul></ul></ul>
  36. 40. Physiologic effects of cooling <ul><li>Metabolic derangements </li></ul><ul><ul><li>intracellular shift (K+, magnesium) and ↑ renal excretion </li></ul></ul><ul><ul><li>Hyperglycemia </li></ul></ul><ul><ul><ul><li>↓ insulin sensitivity in tissues </li></ul></ul></ul><ul><ul><ul><li>↓ insulin secretion by islet cells </li></ul></ul></ul><ul><ul><li>Metabolic acidosis </li></ul></ul><ul><ul><ul><li>↑ FFA, ketones, lactate </li></ul></ul></ul><ul><ul><ul><li>Intracellular pH is actually higher </li></ul></ul></ul><ul><ul><li>↓ O2 consumption/CO2 production </li></ul></ul>
  37. 41. Physiologic effects of cooling <ul><li>Hematologic </li></ul><ul><ul><li>↑ bleeding time </li></ul></ul><ul><ul><li>platelet dysfunction, mild thrombocytopenia </li></ul></ul><ul><ul><li>clotting factor dysfunction </li></ul></ul><ul><ul><li>activation of fibrinolysis cascade </li></ul></ul><ul><li>no significant increase in bleeding risk unless already bleeding (eg trauma) </li></ul>
  38. 42. Physiologic effects of cooling <ul><li>Study of 31 comatose patients post-cardiac arrest due to AMI treated with hypothermia 2005-2006 </li></ul><ul><ul><ul><li>Historical matched controls </li></ul></ul></ul><ul><ul><ul><li>Goal temp 33 ° C </li></ul></ul></ul><ul><ul><ul><li>11 pts received thrombolysis in the field </li></ul></ul></ul><ul><ul><ul><li>25 pts underwent PCI and stenting </li></ul></ul></ul><ul><ul><ul><li>All pts got clopidogrel 600mg load/75mg daily, heparin gtt </li></ul></ul></ul><ul><ul><ul><li>16 PCI pts received IIb/IIIa inhibitor </li></ul></ul></ul><ul><ul><li>Int J Cardiology.132;2009:387-391. </li></ul></ul>
  39. 43. Physiologic effects of cooling <ul><li>Study of 31 comatose patients post-cardiac arrest due to AMI treated with hypothermia 2005-2006 </li></ul><ul><ul><ul><li>Favorable neuro outcome in TH (19/31 had CPC 1 or 2 vs control 6/31) </li></ul></ul></ul><ul><ul><ul><li>No difference in ICU mortality (10/31 in both groups) </li></ul></ul></ul><ul><ul><ul><li>No difference in incidence of clinically overt blood loss (6/31 in both groups) </li></ul></ul></ul><ul><ul><ul><ul><li>Trend towards increase in # units transfused in TH </li></ul></ul></ul></ul><ul><ul><li>Int J Cardiology.132;2009:387-391. </li></ul></ul>
  40. 44. Physiologic effects of cooling <ul><li>Immunologic </li></ul><ul><ul><li>Inhibits leukocyte migration, function </li></ul></ul><ul><ul><li>Inhibits secretion of inflammatory cytokines </li></ul></ul><ul><ul><li>Increased risk of wound infection </li></ul></ul><ul><ul><ul><li>Related to vasoconstriction to skin, hyperglycemia </li></ul></ul></ul><ul><ul><li>Already at-risk population (higher rates of aspiration, more ventilator days, higher rates of VAP, sepsis in post-cardiac arrest patients) </li></ul></ul><ul><ul><li>Resuscitation 2004;60:65-69. </li></ul></ul><ul><ul><li>Intensive Care Med 2005;31:621-626 </li></ul></ul>
  41. 45. <ul><li>Retrospective review of prospective ICU database from single center in France </li></ul><ul><li>421 post-arrest patients 2004-2008 </li></ul><ul><li>67% of patients had 373 infectious complications </li></ul><ul><ul><ul><li>Pneumonia, bloodstream infections </li></ul></ul></ul><ul><ul><ul><li>GNR 64% </li></ul></ul></ul><ul><ul><ul><ul><li>?related to gut hypoperfusion? </li></ul></ul></ul></ul><ul><ul><ul><li>Staph, e coli, h flu, strept pneumo </li></ul></ul></ul><ul><li>Crit Care Med 2011;39(6):1359-1364 </li></ul>
  42. 46. <ul><li>Use of and duration of TH associated with ↑ infection, ↑ ventilator days, ↑ ICU LOS </li></ul><ul><li>No difference in ICU mortality or neurologic outcome </li></ul><ul><li>Challenge of recognizing infection </li></ul><ul><ul><ul><li>Wbc count, temperature not reliable indicators </li></ul></ul></ul><ul><ul><ul><li>This group suggests surveillance cultures during hypothermia phase </li></ul></ul></ul><ul><li>Crit Care Med 2011;39(6):1359-1364 </li></ul>
  43. 47. <ul><li>Limits: </li></ul><ul><ul><li>Single institution, retrospective review without historical comparison </li></ul></ul><ul><ul><li>No control for premorbid factors </li></ul></ul><ul><ul><li>Excluded deaths within 1 st 24 hrs </li></ul></ul><ul><li>Crit Care Med 2011;39(6):1359-1364 </li></ul>
  44. 48. Physiologic effects of cooling <ul><li>Counter-regulatory response to hypothermia </li></ul><ul><ul><li><36.5 ° C vasoconstriction of skin </li></ul></ul><ul><ul><li><35.5 ° C shivering </li></ul></ul><ul><ul><ul><li>Increases heat production </li></ul></ul></ul><ul><ul><ul><li>Increases O2 consumption up to 40% </li></ul></ul></ul><ul><li>Avoidance of shivering </li></ul><ul><ul><li>Medications (narcotics, benzos, paralytics , magnesium, acetaminophen) </li></ul></ul><ul><ul><li>Skin counterwarming? </li></ul></ul>
  45. 49. Kaiser NCAL Therapeutic Hypothermia protocol
  46. 50. Kaiser NCAL hypothermia protocol <ul><li>Inclusion Criteria </li></ul><ul><ul><li>Age>18 </li></ul></ul><ul><ul><li>Negative pregnancy test </li></ul></ul><ul><ul><li>Witnessed cardiac arrest or known down time <15 min to initiation of ACLS </li></ul></ul><ul><ul><li>ROSC within 30 min of cardiac arrest </li></ul></ul><ul><ul><ul><li>VF, pulseless VT, PEA, asystole </li></ul></ul></ul><ul><ul><li>Unresponsive post-resuscitation (GCS<8) </li></ul></ul><ul><ul><li>No eye opening to pain </li></ul></ul><ul><ul><li>SBP>90 (IVF, 1 pressor ok) </li></ul></ul><ul><ul><li>Intubated with set RR </li></ul></ul><ul><li>Exclusion Criteria </li></ul><ul><ul><li>Pregnant </li></ul></ul><ul><ul><li>AMS due to other etiology </li></ul></ul><ul><ul><li>Major surgery within 14d </li></ul></ul><ul><ul><li>Pre-existing sepsis or systemic infection </li></ul></ul><ul><ul><li>Resuscitation efforts >30m before ROSC (relative) </li></ul></ul><ul><ul><li>GCS>/=8 </li></ul></ul><ul><ul><li>Pre-existing coagulopathy or bleeding diathesis (INR>2, PTT>40, plt<50) </li></ul></ul><ul><ul><ul><li>Relative, eg if on warfarin </li></ul></ul></ul><ul><ul><li>T<30 ° C post-resuscitation </li></ul></ul><ul><ul><li>Known terminal illness or DNR </li></ul></ul>
  47. 52. Maintenance cooling
  48. 53. Re-warming phase
  49. 59. Post-warming <ul><li>Prolonged coma </li></ul><ul><ul><li>Delayed and unpredictable clearance of opiates, benzos, propofol and paralytics </li></ul></ul><ul><li>Seizure incidence up to 50% post-cardiac arrest, increased risk with TH </li></ul><ul><li>Poor prognostic sign if no neurologic recovery within 72 hours of normothermia </li></ul>
  50. 60. <ul><li>From the 8 th New York Symposium on Neurocritical Care, 2011 </li></ul>
  51. 61. Current recommendations <ul><li>“ Comatose adult patients (not responding in a meaningful way to verbal commands) with spontaneous circulation after out-of-hospital VF cardiac arrest should be cooled to 32 to 34°C for 12 to 24 hours. Induced hypothermia might also benefit comatose adult patients with spontaneous circulation after out-of-hospital cardiac arrest from a nonshockable rhythm, or cardiac arrest in hospital.” </li></ul><ul><li>American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science, 2010 </li></ul>
  52. 62. Current recommendations <ul><li>Do not delay TH for CT scan, cardiac catheterization, central line placement </li></ul><ul><ul><ul><li>Initiate cooling en route? </li></ul></ul></ul><ul><li>Faster time to cooling may not matter </li></ul><ul><li>Initiate within 10 hours of ROSC </li></ul><ul><li>“ Bundle” therapy to be used along with other ICU bundles </li></ul><ul><ul><li>Continue all other usual supportive measures </li></ul></ul>
  53. 63. Further research <ul><li>What about other rhythms besides VT/VF? </li></ul><ul><ul><li>Theoretical benefit is the same </li></ul></ul><ul><ul><li>Benefit>risk? </li></ul></ul><ul><ul><li>Registry study of >1000 European survivors of cardiac arrest at 6 months </li></ul></ul><ul><ul><ul><li>56% VT/VF had good neurologic outcome </li></ul></ul></ul><ul><ul><ul><li>23% PEA </li></ul></ul></ul><ul><ul><ul><li>21% asystole </li></ul></ul></ul><ul><li>Acta Anaesthesiol Scand. 2009;53:926–934. </li></ul>
  54. 64. Further research <ul><li>Continuous eeg monitoring? </li></ul><ul><li>Prophylactic anti-seizure medication? </li></ul><ul><ul><li>Up to 40% seizure incidence post-ROSC </li></ul></ul><ul><li>Prophylactic antibiotics? </li></ul><ul><li>Optimal duration of cooling? </li></ul><ul><li>Optimal temperature goal? </li></ul>