The INTREPID randomized trial reveals that while dedicated temperature management can reduce fever in stroke patients within the intensive care unit (ICU), this intervention does not translate into improved functional outcomes several months post-stroke.
Study Details
The international study focused on neurocritical care patients with vascular brain injuries. Participants were randomized to either fever prevention using the Arctic Sun temperature management device or standard care. Fever prevention significantly reduced the daily mean fever burden (0.37 °C-hour vs 0.73 °C-hour above 37.9 °C, P < 0.001) and mean total fever duration (9.0 hours vs 21.6 hours) compared to standard care.
However, the primary outcome, measured by the modified Rankin Scale (mRS) at 3 months, showed no significant difference between the two groups. The median mRS was 4.0 in both arms, and the odds of a good outcome (mRS 0-3) were not statistically different (39.2% vs 42.8%, RR 0.92, 95% CI 0.76-1.12).
Possible Explanations for Neutral Outcomes
David Greer, MD, MA, of Boston University School of Medicine, and colleagues suggested several reasons for the neutral results, aligning with previous trials of hypothermia in neurologic injuries. They noted that 8% of patients could not tolerate the fever prevention therapy due to shivering or discomfort. The most significant temperature differences between the groups occurred within the first 5 days. The authors also stated that some patients might not require prolonged ICU care, while others with severe strokes may face care limitations, leading to discontinuation of fever prevention therapy.
The study was terminated early for futility after enrolling 686 of the planned 1,176 patients. Researchers aimed to include patients with severe strokes—ischemic stroke, subarachnoid hemorrhage, and intracerebral hemorrhage—requiring at least 72 hours in intensive care and likely to develop fever.
The authors also pointed out that one in four control patients never developed a fever, suggesting that fever prevention may not impact outcomes in patients unlikely to develop fever. Further research is needed to determine if fever prevention benefits only patients with a high fever burden or a high likelihood of developing fever.
Expert Commentary
Teresa May, DO, of Maine Medical Center, and Lori Shutter, MD, of the University of Pittsburgh School of Medicine, commented in an accompanying editorial that the open question remains whether fever prevention will benefit anyone, given the understanding that it does not benefit everyone.
They emphasized the heterogeneous nature of cerebrovascular disease and the variability in management options, making it rare for a single intervention to achieve a 10% change in functional outcome. They advocate for studies that focus on identifying granular patient types who would benefit most from specific treatment approaches and incorporating adaptive designs in clinical research.
Trial Design and Patient Population
INTREPID was an open-label trial conducted across seven countries from 2017 to 2021. Patients were randomized to fever prevention or standard care. Fever prevention targeted a temperature of 37.0 °C for 14 days or until ICU discharge, using the Arctic Sun device and a continuous core temperature probe. Standard care involved tiered fever treatment with various therapies once temperatures reached 38 °C or higher.
The study cohort was approximately evenly split between sexes, with a median age of 62 years. Over 80% of patients were from Korea. The authors acknowledged that the lack of blinding may have influenced care decisions.
