How to target temperature after cardiac arrest: insights from a randomized clinical trial.

Implementation of treatments able to improve survival and neurological recovery of cardiac arrest (CA) survivors is a major clinical challenge. More than ten years ago, two pivotal trials showed that application of therapeutic hypothermia (TH, 32-34 °C) to patients resuscitated from an out-of-hospital CA (OHCA) with an initial shockable rhythm significantly ameliorated their outcome. Since then, TH has been used also for non-shockable rhythms and for in-hospital CA to some extent, even if the quality of evidence supporting TH in such situations remained very low. The objective of this randomized, controlled, multicenter study (named "Targeted Temperature Management" TTM study) was to compare two different strategies of temperature control after CA; patients were randomized to be treated either at 33 °C or at 36 °C for 24 hours, while fever was accurately avoided for the first 3 days since randomization. Inclusion criteria were: Glasgow Coma Score <8, presumed cardiac origin of arrest, randomization occurring within the first 4 hours from the return of spontaneous circulation. Patients were excluded if they had an unwitnessed arrest with asystole as the initial rhythm, suspected or known acute intracranial hemorrhage or stroke, and a body temperature of less than 30 °C. A specific algorithm was used to decide for withdrawal of care in patients remaining comatose after 72 hours since normothermia was achieved. The primary outcome was 6-month mortality. After the enrollment of 939 patients, the authors did not find any significant difference between groups in primary outcome (235/473 [50%] and 225/466 [48%] of patients died in 33 °C and 36 °C group, respectively; HR for death if in the 33 °C group, 1.06 [95% CI 0.89 to 1.28; P=0.51]). Similarly, the analysis of the composite outcome of death or poor neurologic function yielded similar results between the two groups. This is the largest study evaluating the effects of two different strategies of temperature management after CA. Some important concerns have been raised on the real benefit of keeping CA patients at 33 °C and major changes in clinical practice are expected. We discussed herein the main differences with previous randomized trials and tried to identify possible explanations for these findings.