IMPORTANCE: Therapeutic hypothermia is widely used for neuroprotection following cardiac arrest, but clinical trials have not consistently demonstrated improved neurological outcomes, and the optimal duration of cooling remains uncertain.
OBJECTIVE: To determine the duration of therapeutic hypothermia that maximizes neurological recovery in comatose survivors of out-of-hospital cardiac arrest.
DESIGN, SETTING, AND PARTICIPANTS: Multicenter, randomized, adaptive-allocation clinical trial conducted at 71 hospitals in the US. Adults with out-of-hospital cardiac arrest who remained unconscious, achieved a target temperature less than 34 °C within 4 hours of cardiac arrest, and had a definitive temperature control device started were eligible. Patients were enrolled between June 2020 and June 2025.
INTERVENTIONS: Therapeutic hypothermia at 33 °C with adaptive randomized allocation to cooling durations of 6, 12, 18, 24, 30, 36, 42, 48, 60, and 72 hours. The first 200 patients were randomized to 12-, 24-, and 48-hour durations in a 1:1:1 ratio. Subsequently, a response-adaptive randomization algorithm allocated preferentially to the groups most likely to be optimal and to best inform the duration-response curve separately within each rhythm type.
MAIN OUTCOMES AND MEASURES: The primary outcome was neurological function at 90 days, measured using a weighted modified Rankin Scale score, analyzed using a bayesian duration-response model. The primary analysis estimated the posterior probability that each duration was optimal, wherein optimal indicates the shortest duration consistent with the best outcome observed at any duration.
RESULTS: A total of 1158 patients were randomized (883 with nonshockable rhythms and 275 with shockable rhythms). Participants had a median age of 61 (IQR, 50-70) years and 39.6% were female. The trial met a prespecified stopping rule at the interim analysis. For the nonshockable rhythm cohort, the posterior probability that 6 hours was the shortest duration achieving the maximal mean weighted modified Rankin Scale score was 0.51. Results were similar in the shockable rhythm cohort. No differences were observed in secondary outcomes or mortality across cooling durations.
CONCLUSIONS AND RELEVANCE: Among comatose survivors of out-of-hospital cardiac arrest treated with therapeutic hypothermia at 33 °C, increasing cooling duration did not improve neurological outcomes.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04217551.
| Discipline Area | Score |
|---|---|
| Neurology |  |
| Intensivist/Critical Care |  |
| Emergency Medicine | |
| Cardiology | Coming Soon... |
1,158 comatose patients after out-of-hospital cardiac arrest were randomized to different durations of therapeutic hypothermia at 33°C. The study does not prove that 6 hours is superior; it shows that longer hypothermia did not provide additional benefit on neurological outcomes or mortality.
Like other trials, the length of TTM/therapeutic hypothermia (TH) did not seem to make a difference in outcomes. As the authors stated, this may raise questions about which subgroup of patients may benefit, and future TH research should focus on that.
Hypothermia is an effective procedure for neurological recovery in OHCA. The problem remains: what is the best hypothermic duration and temperature in a clinical setting? This RCT examined the duration of hypothermic therapy at less than 34 C and had a reasonable and fairly reduced recovery rate with prolonged duration. We may seek another procedure combined with or in addition to hypothermic therapy.
Large trial adding evidence that cooling nonselected comatose survivors of cardiac arrest might be of little benefit.