Post-Stroke Fever Prevention Still Lacking in Clinical Benefit

A dedicated temperature management machine dampened the risk of fever for stroke patients in the intensive care unit (ICU), though this did not translate into better functional outcomes months later in the INTREPID randomized trial.

In this international study of neurocritical care patients with a vascular brain injury, randomization to fever prevention successfully reduced daily mean fever burden over usual care (0.37 °C-hour vs 0.73 °C-hour over the cutoff of 37.9 °C [or 100.2 °F], P<0.001). This was supported by mean total fever durations of 9.0 vs 21.6 hours between treatment and control groups.

Scores on the modified Rankin Scale (mRS), however, suggested no difference in functional recovery by 3 months. The two study arms scored the same median mRS of 4.0; the odds of a good outcome (mRS 0-3) were also not statistically different (39.2% vs 42.8%, RR 0.92, 95% CI 0.76-1.12), according to researchers led by David Greer, MD, MA, of Boston University School of Medicine.

They suggested several reasons why these results — in line with various trials of hypothermia in various neurologic injuries showing neither clear benefit nor harm — might have come out neutral in their INTREPID trial, published in JAMA.

“Although INTREPID demonstrated efficacy in preventing and controlling fever, 8% could not tolerate therapy due to shivering or discomfort. The greatest separation of temperatures between the groups occurred during the first 5 days,” they wrote. “Several factors may explain this, including that some patients may not require prolonged ICU-level care, patients with severe stroke may succumb to care limitations, and discontinuation of fever prevention therapy.”

Additionally, investigators stopped enrollment for futility after reaching 686 out of the 1,176 planned patients.

Greer’s group had aimed to enroll patients with severe strokes — including ischemic stroke, subarachnoid hemorrhage, and intracerebral hemorrhage — requiring at least 72 hours in intensive care who were likely to have a fever and experience harms from the fever.

The authors noted that one in four control patients never developed a fever, and this probably meant a similar proportion of people in the fever prevention group wouldn’t either. “Preventing fever may not impact outcome in these patients. Whether fever prevention improves outcomes in only patients with fever burden or with very high likelihood of developing fever requires further investigation.”

“Given that there is now understanding that fever prevention does not benefit everyone, there is still the open question of whether it will benefit anyone,” agreed Teresa May, DO, of Maine Medical Center, Portland, and Lori Shutter, MD, of University of Pittsburgh School of Medicine, in an accompanying editorial.

“Due to the heterogeneous nature of cerebrovascular disease and variability in management options, it is rare for any single intervention to achieve a 10% change in functional outcome. After decades of nonpositive pragmatic clinical trials in broad populations, focus needs to shift to studies determining which more granular patient types would benefit most from the treatment approaches and incorporating adaptive designs in clinical research,” the duo urged.

INTREPID was an open-label trial conducted in seven countries from 2017 to 2021. Participants were randomized to fever prevention or standard care.

Fever prevention targeted 37.0 °C for 14 days or until ICU discharge using the Arctic Sun, an automated surface temperature management device hooked up to disposable gel pads, and a continuous core temperature probe.

Standard care comprised tiered fever treatment with various therapies once temperatures hit 38 °C or higher.

Ultimately, the enrolled cohort was roughly split between sexes with a median age of 62 years. Over 80% of patients were from Korea.

The INTREPID authors acknowledged that the study did not blind clinicians to the assigned treatment groups, which may have affected care decisions in the study.