Boston University Chobanian and Avedisian School of Medicine and Boston Medical Center, Boston, Massachusetts.
Department of Neurology, Kepler University Hospital, Johannes Kepler University Linz, Linz, Austria.
JAMA. 2024 Nov 12;332(18):1525-1534. doi: 10.1001/jama.2024.14745.
Fever is associated with worse outcomes in patients with stroke, but whether preventing fever improves outcomes is unclear.
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).
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.
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.
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 < .001). Between-group differences for the primary outcome by stroke subtype were -0.10 (95% CI, -0.35 to 0.15) for ischemic stroke, -0.50 (95% CI, -0.78 to -0.22) for intracerebral hemorrhage, and -0.52 (95% CI, -0.81 to -0.23) for subarachnoid hemorrhage (all P < .001 by Wilcoxon rank-sum test). There was no significant difference in functional recovery at 3 months (median modified Rankin Scale score, 4.0 vs 4.0, respectively; odds ratio for a favorable shift in functional outcome, 1.09 [95% CI, 0.81 to 1.46]; P = .54). Major adverse events occurred in 82.2% of participants in the fever prevention group vs 75.9% in the standard care group, including 33.8% vs 34.5% for infections, 14.5% vs 14.0% for cardiac disorders, and 24.5% vs 20.5% for respiratory disorders.
In patients with acute vascular brain injury, preventive normothermia using an automated surface temperature management device effectively reduced fever burden but did not improve functional outcomes.
ClinicalTrials.gov Identifier: NCT02996266.
发热与中风患者的预后较差相关，但预防发热是否能改善预后尚不清楚。
确定急性血管性脑损伤后预防发热是否可行，并影响功能结局。
设计、设置和参与者：这是一项在 7 个国家的 43 个重症监护病房进行的、计划纳入 1176 例重症中风患者的开放性随机临床试验，其中 686 例患者完成了入组（最后随访日期为 2022 年 5 月 12 日）。该研究采用盲法结局评估。
接受发热预防的患者（n=339）接受目标体温管理，设定为 37.0°C，持续 14 天或直至重症监护病房出院。采用自动体表温度管理设备。标准治疗组（n=338）在体温达到 38°C 或更高时，采用标准化分级发热治疗。
主要结局是每日平均发热负担：体温高于 37.9°C 的曲线下面积（总发热负担）除以急性期总小时数，再乘以 24 小时（°C 小时）。主要次要结局是 3 个月时的功能恢复，采用 6 级改良 Rankin 量表的移位分析，评分为 0（无症状）至 6（死亡）。主要不良事件包括死亡、肺炎、脓毒症和恶性脑肿胀。
在一项计划的中期分析显示主要次要终点无效后，研究停止了入组。共纳入 686 例患者，其中 9 例患者同意但未随机分组，因此主要分析人群为 677 例患者（254 例缺血性中风、223 例脑出血、200 例蛛网膜下腔出血；345 例女性[51%]；中位年龄 62 岁），其中 433 例（64%）在 12 个月时完成了研究。与标准治疗组（0.73°C-hour；范围，0.0-10.3°C-hour）相比，发热预防组的每日平均发热负担（0.37°C-hour；范围，0.0-8.0°C-hour）显著降低（差异，-0.35°C-hour；95%CI，-0.51 至 -0.20；P<0.001）。按中风亚型进行的主要结局组间差异为：缺血性中风为-0.10（95%CI，-0.35 至 0.15），脑出血为-0.50（95%CI，-0.78 至 -0.22），蛛网膜下腔出血为-0.52（95%CI，-0.81 至 -0.23）（所有 P 值均<0.001，采用 Wilcoxon 秩和检验）。3 个月时的功能恢复无显著差异（中位数改良 Rankin 量表评分分别为 4.0 分和 4.0 分；功能结局改善的优势比为 1.09；95%CI，0.81 至 1.46；P=0.54）。在发热预防组中，82.2%的患者发生了主要不良事件，而标准治疗组中为 75.9%，包括 33.8%的感染、14.5%的心脏疾病和 24.5%的呼吸系统疾病。
在急性血管性脑损伤患者中，使用自动体表温度管理设备进行预防性体温正常化可有效降低发热负担，但不能改善功能结局。
ClinicalTrials.gov 标识符：NCT02996266。
