Targeted Temperature Management for 48 vs 24 Hours and Neurologic Outcome After Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial

Abstract

Importance: 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.

Objective: To determine whether TTM at 33°C for 48 hours results in better neurologic outcomes compared with currently recommended, standard, 24-hour TTM.

Design, setting, and participants: 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.

Interventions: 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.

Main outcomes and measures: 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.

Results: 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; P = .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; P = .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; P = .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; P = .04). The median length of intensive care unit stay (151 vs 117 hours; P < .001), but not hospital stay (11 vs 12 days; P = .50), was longer in the 48-hour group than in the 24-hour group.

Conclusions and relevance: 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.

Trial registration: clinicaltrials.gov Identifier: NCT01689077.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Taccone reports receiving lecture fees from Bard. Dr Storm reports receiving remuneration for presentations, travel costs, and partial technical or material support from Philips, C. R. Bard, Zoll, Medivance, Covidien, and Nonin Medical and a grant from the German Heart Foundation. Dr Jeppesen reports receiving grants from Aarhus University Research Foundation, Research Center for Emergency Medicine, Danish Heart Foundation, Aase og Ejnar Danielsens Foundation, Dr Sofus Carl Emil Friis and Olga Doris Friis Foundation, Kathrine and Vigo Skovgaards Foundation, and "Fonden til lægevidenskabens fremme." Dr Grejs reports receiving grants from Central Denmark Region, Aarhus University Hospital, the Danish Society of Anaesthesiology and Intensive Care Medicine, the Scandinavian Society of Anaesthesiology and Intensive Care Medicine, Foundation of 1870, Aase and Ejnar Danielsen’s foundation, Lily Benthine Lund’s Foundation, Foundation of 1.6.1978, Raimond and Dagmar Ringgard-Bohn’s Foundation, the Danish Heart Association, and the Classenske Fideicommis Book and Software Scholarship. Dr Skrifvars reports receiving research funding from GE Healthcare and lecture fees from Covidien, Orion Pharma, Astellas, and Axis Shield Diagnostics.

Figures

Figure 1.. Screened, Excluded, and Included Patients in the Study of Targeted Temperature Management

OHCA indicates out-of-hospital cardiac arrest; ICU, intensive care unit; ROSC, return of spontaneous circulation. aReasons for not meeting inclusion (eligibility) criteria were as follows: not cardiac OHCA (n=75), age (n=53), Glasgow Coma Scale score >8 (n=49), and no stable ROSC (n=14). bExclusion criteria met were as follows: estimated time from collapse to ROSC >60 min (n=40), cardiac arrest with presumed noncardiac cause (eg, trauma, aorta dissection, intracerebral disease, massive bleeding, hanging, or hypoxemia) (n=63), in-hospital cardiac arrest (n=6), terminal disease or do-not-resuscitate order (n=15), severe coagulopathy (anticoagulant therapy, including thrombolysis, was not an exclusion criteria) (n=8), unwitnessed OHCA with asystole as first rhythm (n=21), time from cardiac arrest to initiation of cooling >240 min (n=19), neurologic disease with cognitive impairment (n=8), persistent cardiogenic shock, systolic blood pressure <80 mm Hg despite vasoactive treatment, or aortic balloon pump intervention (n=46), suspected or confirmed acute intracerebral bleeding (n=9), suspected or confirmed acute stroke (n=6), and acute coronary artery bypass surgery (n=1). cOther reasons for exclusion were as follows: patient died before enrollment (n=10), other interventional study precluding co-enrollment (n=5), patients transferred to other ICU because of bed availability (n=5), and patient not native to country of treatment, rendering follow-up difficult or impossible (n=3). dThe patient lost to follow-up was known to be alive and was included in the survival analyses, but could not be included in the primary analyses due to lack of primary outcome data.

Figure 2.. Core Temperature of the Intervention Groups

Temperatures in the study groups until 72 hours after achieving target temperature (≤34°C [dotted horizontal line]), with T0 defined as the time target temperature was reached. Temperature data were available for 347 of 352 patients and were recorded with variable frequency (median, 188; interquartile range, 61-798) during the depicted period, with no statistically significant difference in frequency between groups (P = .15). Values are presented as mean ±2 SDs.

Figure 3.. Probability of Death With Standard and Prolonged Targeted Temperature Management.

Kaplan-Meier probability of death from randomization to 6 months (200 days) in the study groups. Median follow-up time was 184 days (IQR, 33-196 days) in the 48-hour group and 181 days (IQR, 15-193 days) in the 24-hour group.