Extending therapeutic hypothermia beyond six hours at 33°C does not improve neurological outcomes for comatose survivors of out-of-hospital cardiac arrest. The findings from a large 71-hospital U.S. clinical trial published in JAMA challenge the assumption that longer cooling provides additional neuroprotection.
Medical researchers have long sought to optimize targeted temperature management for cardiac arrest patients. When cardiac arrest deprives the brain of oxygen and glucose within seconds, a cascade of cellular damage continues even after circulation is restored. The sudden return of oxygen triggers harmful molecules, inflammation, mitochondrial damage, and blood-brain barrier disruption. Because lowering body temperature reduces metabolic demand and slows these damaging processes, targeted temperature management has become an important component of post-cardiac-arrest care. Yet, determining the ideal duration of cooling has remained an open question in modern resuscitation medicine.
The ICECAP Trial Findings on Cooling Duration
To resolve whether longer durations of cooling offer better protection, researchers conducted the Influence of Cooling duration on Efficacy in Cardiac Arrest Patient trial, known as ICECAP. Led by investigators at the University of Michigan and conducted across 71 U.S. hospitals between June 2020 and June 2025, the trial enrolled 1,158 adults who survived out-of-hospital cardiac arrest. Patients were cooled to 33°C using a response-adaptive allocation algorithm targeting cooling durations ranging from 6 to 72 hours. However, a prespecified interim analysis led investigators to stop enrollment before any patients were assigned to the 60- or 72-hour groups.
The trial evaluated patients based on presenting heart rhythms, analyzing nonshockable rhythms (n = 883) and shockable rhythms (n = 275) separately to account for differences in injury severity. The primary outcome relied on a weighted modified Rankin Scale score at 90 days, measuring both survival and neurological recovery. Secondary neuropsychological testing using the National Institutes of Health Toolbox Cognition Battery revealed no meaningful differences across the tested cooling durations.
“No clinical strategy has implemented therapeutic hypothermia in comatose survivors of OHCA in a manner that consistently demonstrates efficacy despite extensive preclinical research identifying the mechanisms underlying hypothermic neuroprotection in global cerebral ischemia. 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.”
Researchers, Strategies to Innovate Emergency Care Clinical Trials Network
Balancing Clinical Benefits Against Patient Risks
While laboratory experiments previously suggested that longer cooling periods were more beneficial, translating those findings to clinical environments has proven challenging. According to Robert Silbergleit, M.D., professor of emergency medicine at the University of Michigan, investigators understood that cooling reduces brain injury but lacked clarity on how to scale that effect successfully in practice, noting that most of the previous trials used limited durations of cooling, but longer durations were better in laboratory experiments
.
Prolonged hypothermia is not without physiological drawbacks. Extended cooling can provoke shivering, which drives up metabolic demand, while sedation and neuromuscular blockade complicate neurological evaluations. Furthermore, prolonged temperature management increases infection risks, alters drug metabolism, and triggers disturbances in potassium, magnesium, and glucose levels. By demonstrating that cooling beyond six hours yields no added neurological advantage, the trial suggests clinicians can avoid unnecessary treatment exposure, thereby simplifying care and mitigating potential complications.
Survival Realities in Shockable and Nonshockable Rhythms
The trial’s patient population highlighted the wide divide in clinical presentation between sudden cardiac arrests caused by heart attacks and instances where patient bodies slowed down over time. William Meurer, M.D., professor of emergency medicine and neurology at the University of Michigan, noted that the two situations created a lot of uncertainty in previous studies because those who have a sudden arrest are usually less sick and their hearts can be quickly restarted with defibrillators
.
Funding and Future Research Directions
Following these results, investigators plan to explore whether cooling duration holds greater significance for specific patient subgroups.
Keep reading