Targeted temperature management after out-of-hospital cardiac arrest: certainties and uncertainties

Targeted temperature management was adopted as part of the treatment of unconscious survivors of out-ofhospital cardiac arrest following the publication of two landmark studies [1,2] which concluded that mild induced hypothermia (32°C to 34°C) improved survival and neurological outcome, substantiating the neuroprotective effect of mild hypothermia described in experimental animal data [3]. Subsequently, this therapy was recommended by international guidelines [4,5] and became a standard of care. Although both trials [1,2] had exclusion criteria limiting generalizability, mild induced hypothermia was applied to the wider cardiac arrest population. Until recently [6], despite uncertainties over what represents the optimal target population, temperature, duration of therapy, or rate of rewarming [5], no large randomized clinical trials (RCTs) had been conducted since 2003. A systematic review and meta-analysis performed by using the Grading of Recommendations Assessment, Development, and Evaluation system [7] and trial sequential analysis [8] concluded that the existing quality of evidence was low and that firm evidence in support of induced hypothermia was lacking [9]. To further investigate targeted temperature management, the Target Temperature Management (TTM) after out-of-hospital cardiac arrest trial group was established. As mild induced hypothermia had become ingrained in clinical practice, it was considered infeasible to compare 32°C to 34°C with no temperature control, as failing to control fever would have been unacceptable to many clinicians. The primary objective of the TTM trial [6] was to compare 33°C with 36°C in unconscious survivors of