布美他尼治疗新生儿惊厥的一项随机、对照、双盲试验。
A Pilot Randomized, Controlled, Double-Blind Trial of Bumetanide to Treat Neonatal Seizures.
机构信息
Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
出版信息
Ann Neurol. 2021 Feb;89(2):327-340. doi: 10.1002/ana.25959. Epub 2020 Dec 3.
OBJECTIVE
In the absence of controlled trials, treatment of neonatal seizures has changed minimally despite poor drug efficacy. We tested bumetanide added to phenobarbital to treat neonatal seizures in the first trial to include a standard-therapy control group.
METHODS
A randomized, double-blind, dose-escalation design was employed. Neonates with postmenstrual age 33 to 44 weeks at risk of or with seizures were eligible. Subjects with electroencephalography (EEG)-confirmed seizures after ≥20 and <40mg/kg phenobarbital were randomized to receive additional phenobarbital with either placebo (control) or 0.1, 0.2, or 0.3mg/kg bumetanide (treatment). Continuous EEG monitoring data from ≥2 hours before to ≥48 hours after study drug administration (SDA) were analyzed for seizures.
RESULTS
Subjects were randomized to treatment (n = 27) and control (n = 16) groups. Pharmacokinetics were highly variable among subjects and altered by hypothermia. The only statistically significant adverse event was diuresis in treated subjects (48% vs 13%, p = 0.02). One treated (4%) and 3 control subjects died (19%, p = 0.14). Among survivors, 2 of 26 treated subjects (8%) and 0 of 13 control subjects had hearing impairment, as did 1 nonrandomized subject. Total seizure burden varied widely, with much higher seizure burden in treatment versus control groups (median = 3.1 vs 1.2 min/h, p = 0.006). There was significantly greater reduction in seizure burden 0 to 4 hours and 2 to 4 hours post-SDA (both p < 0.01) compared with 2-hour baseline in treatment versus control groups with adjustment for seizure burden.
INTERPRETATION
Although definitive proof of efficacy awaits an appropriately powered phase 3 trial, this randomized, controlled, multicenter trial demonstrated an additional reduction in seizure burden attributable to bumetanide over phenobarbital without increased serious adverse effects. Future trials of bumetanide and other drugs should include a control group and balance seizure severity. ANN NEUROL 2021;89:327-340.
目的
尽管药物疗效不佳，但由于缺乏对照试验，新生儿惊厥的治疗方法基本没有改变。我们首次进行了一项包括标准治疗对照组的试验，测试了呋塞米联合苯巴比妥治疗新生儿惊厥。
方法
采用随机、双盲、剂量递增设计。胎龄 33 至 44 周、有或有癫痫发作风险的新生儿符合条件。在接受≥20 至<40mg/kg 苯巴比妥后，经脑电图（EEG）证实有癫痫发作的受试者，被随机分为接受额外的苯巴比妥联合安慰剂（对照组）或 0.1、0.2 或 0.3mg/kg 呋塞米（治疗组）。分析给药前≥2 小时至给药后≥48 小时的连续 EEG 监测数据，以评估癫痫发作情况。
结果
受试者被随机分配至治疗组（n=27）和对照组（n=16）。受试者的药代动力学差异很大，且受体温过低的影响。唯一具有统计学意义的不良事件是治疗组的利尿作用（48% vs 13%，p=0.02）。1 例治疗组（4%）和 3 例对照组（19%）的受试者死亡（p=0.14）。在幸存者中，26 例治疗组中有 2 例（8%）和 13 例对照组中有 0 例（0%）发生听力损伤，且 1 例非随机化的受试者也发生了听力损伤。总的癫痫发作负担差异很大，治疗组的癫痫发作负担明显高于对照组（中位数=3.1 与 1.2 分钟/小时，p=0.006）。治疗组与对照组相比，在 SDA 后 0 至 4 小时和 2 至 4 小时时，癫痫发作负担显著降低（均 p<0.01），与 SDA 前 2 小时的基线相比有调整。
结论
尽管需要进行适当的、有更大样本量的 III 期试验来提供确切的疗效证据，但这项随机、对照、多中心试验表明，与苯巴比妥相比，呋塞米可进一步降低癫痫发作负担，且无不良反应增加。未来的呋塞米和其他药物的试验应包括对照组，并平衡癫痫发作的严重程度。
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