ImportanceA third of children who survive malaria with neurological involvement (central nervous system [CNS] malaria) develop sequelae. A higher maximum temperature (Tmax) and seizures are risk factors for sequelae.ObjectiveTo compare aggressive antipyretic therapy using scheduled acetaminophen and ibuprofen vs usual care with acetaminophen alone given only for a temperature of 38.5 °C or higher.Design, Setting, and ParticipantsThis randomized clinical trial was conducted at inpatient pediatric services of 1 tertiary care and 1 district hospital in Zambia and a tertiary care center in Malawi. Included were children aged 2 to 11 years with CNS malaria (excluding those with creatinine >1.2 mg/dL), who were enrolled from 2019 to 2022. Data analysis took place from December 2022 to April 2023.InterventionThe aggressive antipyretic group received acetaminophen (30 mg/kg load, then 15 mg/kg) plus ibuprofen, 10 mg/kg, every 6 hours, regardless of clinical temperature for 72 hours. The usual care group received 15 mg/kg of acetaminophen as needed every 6 hours for a temperature of 38.5 °C or higher.Main Outcomes and MeasuresThe primary outcome variable was Tmax over 72 hours, the total duration of follow-up. Secondary outcomes included seizures and parasite clearance.ResultsFive hundred fifty-three patients were screened, 226 (40.9%) were ineligible, and 57 (10.3%) declined. A total 256 participants (n = 128/group) had a mean (SD) age of 4.3 (2.1) years; 115 (45%) were female, and 141 (55%) were male. The aggressive antipyretic group had a lower Tmax, 38.6 vs 39.2 °C (difference, −0.62 °C; 95% CI, −0.82 to −0.42; P < .001) and lower odds of experiencing multiple or prolonged seizures, 10 (8%) vs 34 children (27%) in the usual care group (odds ratio [OR], 0.26; 95% CI, 0.12 to 0.56). No group difference in parasite clearance time was detected. Severe adverse events occurred in 40 children (15%), 25 (20%) in the usual care group and 15 (12%) in the aggressive antipyretic group, including 13 deaths (10 [8%] and 3 [2%], respectively). Increased creatinine resulted in study drug discontinuation in 8 children (6%) in the usual care group and 13 children (10%) in the aggressive antipyretic group (OR, 1.74; 95% CI, 0.63 to 5.07).Conclusions and RelevanceThis study found that aggressive antipyretic therapy reduced mean Tmax to temperature levels comparable with the Tmax among children without neurological impairments in prior observational studies and improved acute seizure outcomes with no prolongation of parasitemia.Trial RegistrationClinicalTrials.gov Identifier: NCT03399318

中文翻译：

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对乙酰氨基酚和布洛芬治疗小儿中枢神经系统疟疾


重要性 三分之一患有神经系统疾病（中枢神经系统 [CNS] 疟疾）的疟疾幸存者会出现后遗症。较高的最高温度 (Tmax) 和癫痫发作是后遗症的危险因素。目的比较使用预定的对乙酰氨基酚和布洛芬的积极退热治疗与仅在体温达到 38.5 °C 或更高时单独给予对乙酰氨基酚的常规治疗。设计、设置和参与者临床试验在赞比亚的 1 个三级护理机构和 1 个地区医院以及马拉维的一个三级护理中心的住院儿科服务机构进行。其中包括 2 至 11 岁患有中枢神经系统疟疾的儿童（不包括肌酐大于 1.2 mg/dL 的儿童），这些儿童于 2019 年至 2022 年入组。数据分析于 2022 年 12 月至 2023 年 4 月进行。 30 mg/kg 负荷，然后 15 mg/kg）加布洛芬 10 mg/kg，每 6 小时一次，无论临床体温如何，持续 72 小时。当体温达到 38.5 °C 或更高时，常规护理组根据需要每 6 小时接受 15 mg/kg 对乙酰氨基酚。 主要结果和措施 主要结果变量是 72 小时内的 Tmax，即随访的总持续时间。次要结局包括癫痫发作和寄生虫清除。结果对 553 名患者进行了筛查，其中 226 名 (40.9%) 不符合资格，57 名 (10.3%) 拒绝。共有 256 名参与者（n = 128/组），平均 (SD) 年龄为 4.3 (2.1) 岁； 115 名（45%）为女性，141 名（55%）为男性。积极退热组的 Tmax 较低，分别为 38.6 与 39.2 °C（差异，-0.62 °C；95% CI，-0.82 至 -0.42；磷< 。001），并且经历多次或长期癫痫发作的几率较低，常规护理组中有 10 名儿童（8%）与 34 名儿童（27%）相比（比值比 [OR]，0.26；95% CI，0.12 至 0.56）。没有检测到寄生虫清除时间的组间差异。 40 名儿童 (15%) 发生严重不良事件，其中常规护理组有 25 名儿童 (20%)，积极退烧组有 15 名儿童 (12%)，其中 13 人死亡（10 人 [8%] 和 3 人 [2%]，分别）。肌酐升高导致常规护理组的 8 名儿童 (6%) 和积极退热组的 13 名儿童 (10%) 停止研究药物（OR，1.74；95% CI，0.63 至 5.07）。结论和相关性本研究发现积极的退热治疗将平均 Tmax 降低至与先前观察研究中无神经损伤儿童的 Tmax 相当的温度水平，并改善急性癫痫发作结果，且不延长寄生虫血症。试验注册临床试验。政府标识符： NCT03399318