Targeted Temperature Management for 48 vs 24 Hours and Neurologic Outcome After Out-of-Hospital Cardiac Arrest
Authors: Hans Kirkegaard, Eldar Søreide, Inge de Haas, Ville Pettilä, Fabio Silvio Taccone, Urmet Arus, Christian Storm, Christian Hassager, Jørgen Feldbæk Nielsen, Christina Ankjær Sørensen, Susanne Ilkjær, Anni Nørgaard Jeppesen, Anders Morten Grejs, Christophe Henri Valdemar Duez, Jakob Hjort, Alf Inge Larsen, Valdo Toome, Marjaana Tiainen, Johanna Hästbacka, Timo Laitio, Markus B. Skrifvars
Journal: JAMA (2017)

<h3>Importance</h3> International resuscitation guidelines recommend targeted temperature management (TTM) at 33°C to 36°C in unconscious patients with out-of-hospital cardiac arrest for at least 24 hours, but the optimal duration of TTM is uncertain. <h3>Objective</h3> To determine whether TTM at 33°C for 48 hours results in better neurologic outcomes compared with currently recommended, standard, 24-hour TTM. <h3>Design, Setting, and Participants</h3> This was an international, investigator-initiated, blinded-outcome-assessor, parallel, pragmatic, multicenter, randomized clinical superiority trial in 10 intensive care units (ICUs) at 10 university hospitals in 6 European countries. Three hundred fifty-five adult, unconscious patients with out-of-hospital cardiac arrest were enrolled from February 16, 2013, to June 1, 2016, with final follow-up on December 27, 2016. <h3>Interventions</h3> Patients were randomized to TTM (33 ± 1°C) for 48 hours (n = 176) or 24 hours (n = 179), followed by gradual rewarming of 0.5°C per hour until reaching 37°C. <h3>Main Outcomes and Measures</h3> The primary outcome was 6-month neurologic outcome, with a Cerebral Performance Categories (CPC) score of 1 or 2 used to define favorable outcome. Secondary outcomes included 6-month mortality, including time to death, the occurrence of adverse events, and intensive care unit resource use. <h3>Results</h3> In 355 patients who were randomized (mean age, 60 years; 295 [83%] men), 351 (99%) completed the trial. Of these patients, 69% (120/175) in the 48-hour group had a favorable outcome at 6 months compared with 64% (112/176) in the 24-hour group (difference, 4.9%; 95% CI, −5% to 14.8%; relative risk [RR], 1.08; 95% CI, 0.93-1.25;<i>P</i> = .33). Six-month mortality was 27% (48/175) in the 48-hour group and 34% (60/177) in the 24-hour group (difference, −6.5%; 95% CI, −16.1% to 3.1%; RR, 0.81; 95% CI, 0.59-1.11;<i>P</i> = .19). There was no significant difference in the time to mortality between the 48-hour group and the 24-hour group (hazard ratio, 0.79; 95% CI, 0.54-1.15;<i>P</i> = .22). Adverse events were more common in the 48-hour group (97%) than in the 24-hour group (91%) (difference, 5.6%; 95% CI, 0.6%-10.6%; RR, 1.06; 95% CI, 1.01-1.12;<i>P</i> = .04). The median length of intensive care unit stay (151 vs 117 hours;<i>P</i> &lt; .001), but not hospital stay (11 vs 12 days;<i>P</i> = .50), was longer in the 48-hour group than in the 24-hour group. <h3>Conclusions and Relevance</h3> In unconscious survivors from out-of-hospital cardiac arrest admitted to the ICU, targeted temperature management at 33°C for 48 hours did not significantly improve 6-month neurologic outcome compared with targeted temperature management at 33°C for 24 hours. However, the study may have had limited power to detect clinically important differences, and further research may be warranted. <h3>Trial Registration</h3> clinicaltrials.gov Identifier:NCT01689077