- Investigators sought to determine whether the duration of therapeutic hypothermia had an effect on outcomes for comatose survivors of out-of-hospital cardiac arrest (OHCA).
- No improvement in neurological outcomes was found with more hours of therapeutic hypothermia at 33°C.
- An effective strategy of hypothermic neuroprotection after OHCA continues to evade researchers.
Extra hours of therapeutic hypothermia after out-of-hospital cardiac arrest (OHCA) conferred no better neuroprotection, a randomized trial found.
The ICECAP trialists intended to test a range of durations of therapeutic hypothermia, from 6 to 72 hours, and found it evident after the first 200 patients that there was no point cooling people for more than 48 hours in terms of neurologic outcomes at 90 days.
In the end, there was no improvement in modified Rankin Scale (mRS) scores beyond the minimal 6 hours of cooling to 33°C (91.4°F): The posterior probability of 6 hours being the shortest duration that achieves the maximal mean weighted mRS score was 0.51 in the nonshockable rhythm cohort, and 0.49 in the shockable rhythm cohort, according to Robert Silbergleit, MD, of the University of Michigan in Ann Arbor, and colleagues reporting in JAMA.
“The results of the current study demonstrate that increasing cooling duration, as performed and evaluated in this trial in broadly representative and inclusive cohorts of patients after OHCA, does not improve outcomes,” study authors concluded.
Their trial marks another setback in the search for an effective strategy of hypothermic neuroprotection after OHCA. In 2021, two major trials showed no improvement in clinical outcomes from targeting cooling to 33°C or the more aggressive 31°C (87.8°F).
Without the evidence for therapeutic hypothermia, practice is shifting toward fever prevention alone after OHCA.
“It may be that large trials with broad inclusion criteria cannot resolve the question of therapeutic hypothermia translation without exploring differential effects of heterogeneous injury phenotypes, clinical practice variability, or even underlying social and genetic determinants of health,” wrote Silbergleit’s team. “We may instead need to answer the questions of in whom is it important to control temperature, and how and when is it best to deliver such care?”
Substudies are ongoing using electroencephalography, MRI, and biomarkers to identify better responders to therapeutic cooling, the authors noted.
In any case, the larger picture of OHCA recovery is still bleak. In the ICECAP trial, 90-day mortality was still high at 81.3% in the nonshockable rhythm cohort and 52% in the shockable rhythm cohort; weighted mRS scores averaged 0.8 in the nonshockable rhythm cohort and 3.5 in the shockable rhythm cohort.
ICECAP was conducted at 71 U.S. centers within the Strategies to Innovate Emergency Care Clinical Trials Network. Therapeutic hypothermia was a routine clinical practice across participating sites.
Patients were comatose survivors of OHCA who achieved a target temperature
The study plan was to randomize individuals to therapeutic hypothermia at 33°C across cooling durations of 6, 12, 18, 24, 30, 36, 42, 48, 60, and 72 hours. After the first 200 patients were randomized to 12-, 24-, and 48-hour durations, however, the allocation shifted to shorter durations on account of a response-adaptive randomization algorithm.
Across participants, median age was 61 years and 39.6% were women. Cardiac arrest was most commonly attributed to respiratory (29.4%), overdose/poisoning (28.1%), and cardiac (22.5%) issues. Median time from cardiac arrest to definitive temperature control device initiation was 151 minutes. A surface cooling device was used in 55% of patients and an endovascular device in 45%.
Shivering and sedation were managed according to local practice. Controlled rewarming to 36.5°C was initiated at the end of the allocated cooling duration, according to Silbergleit and colleagues.
Ultimately, the trial met a prespecified stopping rule at the interim analysis.
No differences in secondary outcomes or mortality could be identified across cooling durations.
Limitations of the trial include its relatively high proportion of OHCA patients with nonshockable presenting rhythms, who have lower odds of survival in the first place, and possible inclusion of patients with more severe injury already in hypothermia or easier to cool because of impaired thermoregulation.
There was also some degree of local variability about decisions to withdraw life-sustaining therapy.
