Impact of therapeutic hypothermia onset and duration on survival, neurologic function, and neurodegeneration after cardiac arrest

Objective: Post-cardiac-arrest therapeutic hypothermia improves outcomes inComatoseCardiac arrest survivors. This study tests the hypothesis that the efficacy of post-cardiac-arrest therapeutic hypothermia is dependent on the onset and duration of therapy. Design: Prospective randomized laboratory investigation. Setting: University research laboratory. Subjects: A total of 268 male Long Evans rats. Interventions: Post-cardiac-arrest therapeutic hypothermia. Measurements and Main Results: Adult male Long Evans rats that achieved return of spontaneousCirculation after a 10-min asphyxialCardiac arrest were block randomized to normothermia (37 degrees C +/- 1 degrees C) or therapeutic hypothermia (33 degrees C +/- 1 degrees C) initiated 0, 1, 4, or 8 hrs after return of spontaneousCirculation and maintained for 24 or 48 hrs. Therapeutic hypothermia initiated 0, 1, 4, and 8 hrs after return of spontaneousCirculation resulted in 7-day survival rates of 45%*, 36%*, 36%*, and 14%, respectively,Compared to 17% for normothermicControls and survival with good neurologic function rates of 24%*, 24%*, 19%*, and 0%, respectively, compared to 2% for normothermicControls (* p <.05 vs. normothermia). These outcomes were not different when therapeutic hypothermia was maintained for 24 vs. 48 hrs. InContrast, hippocampalCA1 pyramidal neuronCounts were 53% +/- 27%*, 53% +/- 19%*, 51% +/- 24%*, and 65% +/- 16%* of normal, respectively, when therapeutic hypothermia was initiated 0, 1, 4, or 8 hrs after return of spontaneousCirculationCompared to 9% in normothermic controls (* p <.01 vs. normothermia). Furthermore, surviving neuronCounts were greater when therapeutic hypothermia was maintained for 48 hrsCompared to 24 hrs (68% +/- 15%* vs. 42% +/- 22%, * p <.0001). Conclusions: In this study, post-cardiac-arrest therapeutic hypothermia resulted inComparable improvement of survival and survival with good neurologic function when initiated within 4 hrs after return of spontaneousCirculation. However, histologic assessment of neuronal survival revealed a potentially broader therapeutic window and greater neuroprotection when therapeutic hypothermia was maintained for 48 vs. 24 hrs. (CritCare Med 2011; 39: 1423-1430)