Fever Prevention in Patients With Acute Vascular Brain Injury: The INTREPID Randomized Clinical Trial

IMPORTANCE: Fever is associated with worse outcomes in patients with stroke, but whether preventing fever improves outcomes is unclear. OBJECTIVE: To determine whether fever prevention after acute vascular brain injury is achievable and impacts functional outcome. DESIGN, SETTING, AND PARTICIPANTS: Open-label randomized clinical trial with blinded outcome assessment that enrolled 686 of 1176 planned critically ill patients with stroke at 43 intensive care units in 7 countries from March 2017 to April 2021 (last date of follow-up was May 12, 2022). INTERVENTION: Patients randomized to fever prevention (n = 339) were targeted to 37.0 °C for 14 days or intensive care unit discharge using an automated surface temperature management device. Standard care patients (n = 338) received standardized tiered fever treatment on occurrence of temperature of 38 °C or greater. MAIN OUTCOMES AND MEASURES: Primary outcome was daily mean fever burden: the area under the temperature curve above 37.9 °C (total fever burden) divided by the total number of hours in the acute phase, multiplied by 24 hours (°C-hour). The principal secondary outcome was 3-month functional recovery by shift analysis of the 6-category modified Rankin Scale, which is scored from 0 (no symptoms) to 6 (death). Major adverse events included death, pneumonia, sepsis, and malignant cerebral edema. RESULTS: Enrollment was stopped after a planned interim analysis demonstrated futility of the principal secondary end point. In total, 686 patients were enrolled, and 9 were consented but not randomized, leaving a primary analysis population of 677 patients (254 ischemic stroke, 223 intracerebral hemorrhage, 200 subarachnoid hemorrhage; 345 were female [51%]; median age, 62 years) with 433 (64%) completing the study through 12 months. Daily mean (SD) fever burden was significantly lower in the fever prevention group (0.37 [1.0] °C-hour; range, 0.0-8.0 °C-hour) compared with the standard care group (0.73 [1.1] °C-hour; range, 0.0-10.3 °C-hour) (difference, −0.35 [95% CI, −0.51 to −0.20]; P