BACKGROUND The choice of drugs for patients with status epilepticus that is refractory to treatment with benzodiazepines has not been thoroughly studied. METHODS In a randomized, blinded, adaptive trial, we compared the efficacy and safety of three intravenous anticonvulsive agents - levetiracetam, fosphenytoin, and valproate - in children and adults with convulsive status epilepticus that was unresponsive to treatment with benzodiazepines. The primary outcome was absence of clinically evident seizures and improvement in the level of consciousness by 60 minutes after the start of drug infusion, without additional anticonvulsant medication. The posterior probabilities that each drug was the most or least effective were calculated. Safety outcomes included life-threatening hypotension or cardiac arrhythmia, endotracheal intubation, seizure recurrence, and death. RESULTS A total of 384 patients were enrolled and randomly assigned to receive levetiracetam (145 patients), fosphenytoin (118), or valproate (121). Reenrollment of patients with a second episode of status epilepticus accounted for 16 additional instances of randomization. In accordance with a prespecified stopping rule for futility of finding one drug to be superior or inferior, a planned interim analysis led to the trial being stopped. Of the enrolled patients, 10% were determined to have had psychogenic seizures. The primary outcome of cessation of status epilepticus and improvement in the level of consciousness at 60 minutes occurred in 68 patients assigned to levetiracetam (47%; 95% credible interval, 39 to 55), 53 patients assigned to fosphenytoin (45%; 95% credible interval, 36 to 54), and 56 patients assigned to valproate (46%; 95% credible interval, 38 to 55). The posterior probability that each drug was the most effective was 0.41, 0.24, and 0.35, respectively. Numerically more episodes of hypotension and intubation occurred in the fosphenytoin group and more deaths occurred in the levetiracetam group than in the other groups, but these differences were not significant. CONCLUSIONS In the context of benzodiazepine-refractory convulsive status epilepticus, the anticonvulsant drugs levetiracetam, fosphenytoin, and valproate each led to seizure cessation and improved alertness by 60 minutes in approximately half the patients, and the three drugs were associated with similar incidences of adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ESETT ClinicalTrials.gov number, NCT01960075.).

中文翻译：

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三种抗惊厥药物治疗癫痫持续状态的随机试验。

背景技术对于苯二氮卓类药物难以治疗的癫痫持续状态患者的药物选择尚未进行彻底研究。方法在一项随机，双盲，适应性试验中，我们比较了三种静脉抗惊厥药（左乙拉西坦，磷苯乙妥英和丙戊酸盐）在癫痫持续状态对苯并二氮杂treatment治疗无反应的儿童和成人中的疗效和安全性。主要结果是在开始输注药物后60分钟内没有临床上明显的癫痫发作和意识水平的改善，而没有额外的抗惊厥药物。计算每种药物最有效或最不有效的后验概率。安全性结果包括危及生命的低血压或心律不齐，气管插管，癫痫发作复发，并死亡。结果总共入选384例患者，并随机分配接受左乙拉西坦（145例），磷苯妥英钠（118）或丙戊酸盐（121）。患有第二次癫痫持续状态的患者重新入组是另外16例随机病例。根据预先确定的停药规则，即发现一种药的优劣是徒劳的，计划中的中期分析导致了该试验的停止。在所有入组患者中，有10％被确定患有精神病性癫痫发作。左乙拉西坦组68例患者（47％; 95％可信区间为39至55），60例苯乙妥英（45％; 95％）出现癫痫持续状态和60分钟意识水平改善的主要结局。可信区间36到54），56名患者被分配为丙戊酸盐（46％；可信区间为95％，38至55）。每种药物最有效的后验概率分别为0.41、0.24和0.35。磷苯妥英钠治疗组发生低血压和插管的次数更多，而左乙拉西坦组死亡的发生率高于其他两组，但这些差异并不显着。结论在苯二氮卓难治性惊厥性癫痫持续状态下，抗惊厥药左乙拉西坦，磷苯乙妥英和丙戊酸盐分别导致约半数患者发作停止和警觉性提高了60分钟，并且这三种药物的不良事件发生率相似。（由国家神经疾病和中风研究所资助； ESETT ClinicalTrials.gov编号，NCT01960075。）。