静脉应用负荷剂量抗癫痫药物的安全性

目的探讨静脉给予负荷剂量抗癫痫药物(AED)治疗成人全面惊厥性癫痫持续状态(GCSE)的安全性。方法采用合并数据的方法收集首都医科大学宣武医院2007年1月至2010年1月和2011年6月至2012年5月进行的2项前瞻性随机对照试验(RCT)的结果,分析比较地西泮组、地西泮后续丙戊酸组和地西泮后续苯巴比妥组患者的临床数据。3组患者一线AED治疗均为静脉注射负荷剂量地西泮(0.2 mg/kg,5 mg/min)。二线AED治疗方案:地西泮组为静脉注射负荷剂量地西泮(0.2 mg/kg,5 mg/min)后继续静脉泵注维持量地西泮(4 mg/h,每3分钟增加1μg/kg),地西泮后续丙戊酸组为静脉注射负荷剂量丙戊酸30 mg/kg,6 mg/(kg·min)]后继续静脉泵注维持量丙戊酸1～2 mg/(kg·h)],地西泮后续苯巴比妥组为静脉注射负荷剂量苯巴比妥(20 mg/kg,50 mg/min)后继续静脉注射维持量苯巴比妥(100 mg/6 h,50 mg/min),治疗持续至癫痫发作终止后24 h,以后逐渐减量。严密监测患者用药后反应。结果 101例患者纳入研究,男性53例,女性48例;平均年龄(42±16)岁。地西泮组男性20例,女性18例,平均年龄(41±19)岁;地西泮后续丙戊酸组男性22例,女性18例,平均年龄(45±15)岁;地西泮后续苯巴比妥组男性11例,女性12例,平均年龄(41±14)岁。3组患者基线资料差异无统计学意义。地西泮组、地西泮后续丙戊酸组和地西泮后续苯巴比妥组GCSE终止率分别为63.2%(24/38)、57.5%(23/40)和60.9%(14/23),差异无统计学意义(P=0.902)。地西泮组6例(15.8%)出现不良反应,其中呼吸抑制、循环抑制和骨髓抑制分别为2、3和1例;地西泮后续丙戊酸组11例(27.5%)出现不良反应,其中不伴高血氨脑病的轻度血氨升高、轻度肝功能异常和骨髓抑制分别为8、2和1例;地西泮后续苯巴比妥组11例(47.8%)出现不良反应,其中呼吸抑制、循环抑制、轻度肝功能异常和骨髓抑制分别为3、2、5和1例。地西泮组不良反应发生率明显低于地西泮后续苯巴比妥组(P=0.033)。上述不良反应经停药与对症治疗后均可消除。结论静脉给予负荷剂量地西泮或丙戊酸或苯巴比妥治疗成人GCSE均安全有效。用药过程中应密切监测患者的不良反应,特别是对地西泮与苯巴比妥联用的患者。一旦出现不良反应,应及时停药并予以对症治疗。

The safety of a loading dose of intravenous antiepileptic drugs

Objective To investigate the safety of a loading dose of Ⅳ antiepileptic drugs （AED）in the treatment of adult patients with generalized convulsive status epilepticus （GCSE）.Methods A method for the analysis of pooled data was adopted.The results from the two prospective randomized controlled trials （RCTs） performed by Xuanwu Hospital from January 2007 to January 2010 and from June 2010 to May 2012 were collected.The clinical data were analyzed and compared among the patients in the diazepam group,the diazepam and subsequent valproate group,and the diazepam and subsequent phenobarbital group.A loading dose of Ⅳ diazepam （0.2 mg/kg,5 mg/min） was as first-line AED treatment for all patients in the 3 groups.Second-line AED treatment were as follows：in the diazepam group,a loading dose of Ⅳ diazepam （0.2 mg/kg,5mg/min） was given,then a maintenance dose of Ⅳ diazepam （4.0 mg/h,increase by 1.0 μg/kg every 3 minutes） was given via a pump.In the diazepam subsequent valproate group,a loading dose of Ⅳ diazepam 30 mg/kg,6 mg/（kg · min）] was given,then a maintenance dose of Ⅳ valproate 1-2 mg/（kg · h） was given via a pump.In the diazepam subsequent phenobarbital group,a loading dose of Ⅳ phenobarbital （20 mg/kg,50 mg/min） was given,then a maintenance dose of Ⅳ phenobarbital （100 mg/6 h,50 mg/min） was given.The second-line AED treatment should be continued until 24 hours after epileptic seizure stopped,then the dosage was gradually reduced.The patients should be closely monitored for reactions after drug administration.Results A total of 101 patients were enrolled in the study.They comprised 53 male and 48 female with mean age of （42 ±16） years.The diazepam group comprised 20 male and 18 female with mean age of （41 ± 19）years.The diazepam and subsequent valproate group comprised 22 male and 18 female with mean age of （45 ± 15）years.The diazepam and subsequent phenobarbital group comprised 11 male and 12 female with mean age of （41 ± 14）years.There was no statistically significant difference among the baseline data of patients in the three groups.The termination rate of GCSE in the diazepam,diazepam and subsequent valproate,and diazepam and subsequent phenobarbital groups were 63.2% （24/38）,57.5% （23/40）and 60.9% （14/23）,respectively.The difference was not statistically significant （P =0.902）.There were 6 cases （15.8%） of adverse reactions in the diazepam group.The number of cases of respiratory depression,circulatory depression,and bone marrow depression were 2,3,and 1,respectively.There were 11 cases （27.5%） of adverse reactions in the diazepam and subsequent valproate group.The number of cases of slight hyperammonemia without hyperammonemia encephalopathy,mild abnormal liver function,and bone marrow depression were 8,2,and 1,respectively.There were 11 cases （47.8%） of adverse reactions in the diazepam and subsequent phenobarbital group.The number of cases of respiratory depression,circulation depression,mild abnormal liver function,and bone marrow depression were 3,2,5,and 1,respectively.The incidence of adverse reactions in the diazepam group was markedly lower than that in the diazepam and subsequent phenobarbital group （P =0.033）.The above-mentioned adverse symptoms could resolve after drug withdrawal and symptomatic treatment.Conclusions A loading dose of Ⅳ diazepam or Ⅳ valproate or Ⅳ phenobarbital are effective and safe in the treatment of adult patients with GCSE.The patient should be closely monitored for adverse reactions during the antiepileptic treatment,especially in the patients receiving diazepam combined with phenobarbital.Once adverse reactions developed,the drug should be stopped and symptomatic treatment should be given.