1. Therapeutic Hypothermia Fakhir Raza Haidri

2. Induced Hypothermia Post Cardiac Arrest With ROSC In 2002, the New England Journal published two well designed studies 1,2 showing dramatically improved outcomes when patients are actively cooled after resuscitation from V. Fib or Pulseless V. Tach. This led to an advisory statement by the ILCOR (International Liaison Committee on Resuscitation) that such patients should be cooled. 1. Bernard S. et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. NEJM 2002, Feb 21; 346(8): 557-563. 2. The Hypothermia After Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. NEJM 2002, Feb 21; 346(8): 549-556. 3. What does improved outcomes mean? Both studies showed improved neurologic outcomes, not just improved mortality. 4. A Meta analysis Meta-analysis including these two trials and another for patients resuscitated from PEA or asystole and cooled for 4 hours 2 . Neurologic recovery was improved and independent of method of cooling. Number needed to treat 4 13. 1. Holzer M, et al. Hypothermia for neuroprotection after cardiac arrest: Systemic review and individual patient data meta-analysis. Crit Care Med, 2005; 33(2): 414418. 5. ILCOR Advisory Statement Unconscious adult patients with spontaneous circulation after outof-hospital cardiac arrest should be cooled to 32 to 34C for 12 to 24 hours when the initial rhythm was ventricular fibrillation. Such cooling may also be beneficial for other rhythms or in-hospital cardiac arrest. International Liaison Committee on Resuscitation. 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: 118-121. 6. Theoretical Basis for Hypothermia Slow cerebral metabolism Reduce apoptosis (programmed cell death) Blunt excitatory neurotoxicity Modulate immune response 7. Why does it work? Theoretical Basis: Slowed cerebral metabolism decreased 5 to 7% for each degree Centigrade reduction in body temperature. Decrease core temperature 4C = 20-28% reduction in cerebral metabolism. Protective effects appear to be much greater than explained by this mechanism alone 1,2 .1. Milde LN. Clinical use of mild hypothermia for brain protection: a dream revisited. J. Neurosurg Anesth 1992; 4: 211-215. 2. Small DL, et al. Biology of ischemic cerebral cell death. Prog Cardiovasc Dis, 1999; 42: 185-207. 8. Why does it work? Theoretical Basis: Apoptosis: Apoptosis involves mitochondrial dysfunction and release of destructive intracellular enzymes. Hypothermia can prevent these two processes leading to apoptosis 9. Why does it work? Theoretical Basis: Excitatory neurotoxicity As neurons become ischemic, they cannot maintain membrane potential, depolarize and release glutamate. Energy-requiring mechanisms of re-uptake are impaired. Surrounding neurons are stimulated longer than normal in an ischemic state, causing more damage. Hypothermia is believed to stabilize cell membranes and has been shown in animals to slow excitatory neurotoxicity Glutamate release and free radical production following brain injury: effects of posttraumatic hypothermia. J Neurochem, 1995; 65: 1704-1711. 4. Busto R, et al 10. Why does it work? Theoretical Basis: Modulation of immune response and edema Hypothermia suppresses release of inflammatory cytokines (TNF- and IL-1) It also slows production of free radicals Reduces disruptions of the blood-brain barrier, decreasing edema. Moderate hypothermia delays proinflammatory cytokine production of human peripheral blood mononuclear cells. Crit Care Med, 2002; 30: 1499-1502. 2. Globus M, et al. 11. Inclusion CriteriaExclusion Criteria Non-Traumatic cardiac arrest with return of circulation TH initiated within 6 hours of arrest Systolic BP > 90 or MAP > 60 after fluid resuscitation with or without pressors > 12 years old GCS > 8 Greater than 6 hours since arrest DNR Non-mechanically ventilated patient Pregnancy Active bleeding Arrest secondary to sepsis 12. Internal Method 13. External Method 14. Complications of Cooling hypovolemia (hypothermia induced dieresis) coagulopathy (impaired coagulation cascade and thrombocytopenia electrolyte disorders (hypothermia induced dieresis, K+, Mg++, Ca++) insulin resistance changes in drugs effects and metabolism (altered clearance of fentanyl, midazolam, and atracurium) 15. Complications of Rewarming worsening cerebral edema further changes in electrolyte abnormalities (especially hyperkalemia) hyperthermia (induced fever) 16. Goal CPC 1 and CPC 2 17. Clinical Performance Category 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 Lancet 1975. 1(7905):480-4 18. Hypothermia in Comatose Survivors From Out-of-Hospital Cardiac Arrest: Pilot Trial Comparing 2 Levels of Target Temperature Circulation. published online November 6, 2012; 19. Methods and Results Patients were eligible if they had a witnessed out-of-hospital cardiac arrest from March 2008 to August 2011. Target temperature was randomly assigned to 32C or 34C. The primary outcome was survival free from severe dependence (Barthel Index score 60 points) at 6 months. Thirty-six patients were enrolled in the trial (26 shockable rhythm, 10 asystole), with 18 assigned to 34C and 18 to 32C. Eight of 18 patients in the 32C group (44.4%) met the primary end point compared with 2 of 18 in the 34C group (11.1%) (log-rank P0.12). 20. Conclusions The findings of this pilot trial suggest that a lower cooling level may be associated with a better outcome in patients surviving out-ofhospital cardiac arrest secondary to a shockable rhythm. The benefits observed here merit further investigation in a larger trial in out-of-hospital cardiac arrest patients with different presenting rhythms. 21. Original ArticleTargeted Temperature Management at 33C versus 36C after Cardiac Arrest N Engl J Med 2013; 369:2197-2206, December 5, 2013 22. Background Unconscious survivors of out-of-hospital cardiac arrest have a high risk of death or poor neurologic function. Therapeutic hypothermia is recommended by international guidelines, but the supporting evidence is limited, and the target temperature associated with the best outcome is unknown. Our objective was to compare two target temperatures, both intended to prevent fever. 23. Methods International trial randomly assigned 950 unconscious adults after out-of-hospital cardiac arrest of presumed cardiac cause to targeted temperature management at either 33C or 36C. The primary outcome was all-cause mortality through the end of the trial. Secondary outcomes included a composite of poor neurologic function or death at 180 days, as evaluated with the Cerebral Performance Category (CPC) scale and the modified Rankin scale. 24. Results 50% of the patients in the 33C group (235 of 473 patients) had died, as compared with 48% of the patients in the 36C group (225 of 466 patients) (P=0.51). At the 180-day follow-up, 54% of the patients in the 33C group had died or had poor neurologic function according to the CPC, as compared with 52% of patients in the 36C (P=0.78). In the analysis using the modified Rankin scale, the comparable rate was 52% in both groups (P=0.87). The results of analyses adjusted for known prognostic factors were similar. 25. Conclusions In unconscious survivors of out-of-hospital cardiac arrest of presumed cardiac cause, hypothermia at a targeted temperature of 33C did not confer a benefit as compared with a targeted temperature of 36C. 26. AnyQuestions