基于血药浓度监测的儿童癫痫患者使用丙戊酸钠的疗效和药品不良反应研究

目的:基于丙戊酸钠的体内代谢过程具有显著的年龄发育特征,本研究旨在考察不同年龄段儿童癫痫患者使用丙戊酸钠后的稳态血药浓度特征及其与癫痫控制情况、药品不良反应(ADR)之间的关联,以此获得丙戊酸钠在儿科使用的安全性和有效性数据。方法:纳入2017年1月至2020年6月该院神经科确诊为癫痫并使用丙戊酸钠的患儿748例,采集其口服给药3 d后的清晨空腹静脉血,检测血浆中丙戊酸钠浓度并记录其癫痫发作频率,神经系统、胃肠道和皮肤方面的ADR发生情况。结果:丙戊酸钠的稳态血药浓度随年龄呈现显著的阶梯式升高特征,<1岁癫痫患儿的丙戊酸钠平均血药浓度为(50.06±28.18)mg/L;1~2岁患儿为(51.08±18.71)mg/L;>2~6岁患儿为(59.87±22.07)mg/L,显著高于1~2岁患儿,差异有统计学意义(P<0.05);>6~14岁患儿为(63.23±26.67)mg/L,高于>2~6岁患儿,但差异无统计学意义(P>0.05),明显高于1~2岁患儿(P<0.001)和<1岁患儿(P<0.01),差异均有统计学意义。丙戊酸钠低剂量组患儿<20 mg/(kg·d)]的稳态血药浓度低于中剂量组20~30 mg/(kg·d)]、高剂量组>30 mg/(kg·d)],但是中、高剂量组患儿中丙戊酸钠血药浓度并不呈现剂量相关性。丙戊酸钠中、高血药浓度组患儿的癫痫控制率分别为90.0%(387/430)和91.1%(41/45),显著高于低血药浓度组的70.0%(191/273),差异均有统计学意义(P<0.05)。共收集39例ADR,发生率较高的ADR为神经系统反应(14例)、肝功能受损(11例)和消化系统反应(9例)。ADR发生率随丙戊酸钠血药浓度升高而有升高趋势,且呈年龄相关性,≤2岁的低年龄段癫痫患儿使用丙戊酸钠的ADR发生率显著高于其他年龄段(>2~14岁)癫痫患儿。结论:(1)儿童的丙戊酸钠血药浓度和ADR有年龄段特异性分布特征,婴幼儿(≤2岁)的丙戊酸钠血药浓度易低于最低治疗浓度,但更易发生ADR,在临床用药过程中应注意密切监测;(2)儿童群体血药浓度控制在50~100 mg/L范围内时,丙戊酸钠的安全性和有效性均较为理想;(3)相对于成人,儿童的肝损伤发生率较高,使用丙戊酸钠过程中应加强肝功能指标的监测。

Efficacy and Adverse Drug Reactions of Sodium Valproate in Children with Epilepsy Based on Blood Concentration Monitoring

OBJECTIVE:To investigate the characteristics of steady-state blood concentration of sodium valproate in children with epilepsy of different ages and its correlation with epileptic control and adverse drug reactions(ADR)based on the significantly age-dependent developmental characteristic of the metabolic process of valproate,so as to obtain the safety and efficacy data of sodium valproate in pediatrics.METHODS:A total of 748 children diagnosed with epilepsy and treated with sodium valproate in the department of neurology in this hospital from Jan.2017 to Jun.2020 were included.The early morning fasting venous blood was collected 3 d after the oral administration,the concentration of sodium valproate in the plasma was measured,and the frequency of epilepsy,nervous system reaction,gastrointestinal reaction and ADR of skin were recorded.RESULTS:The steady-state blood concentration of valproate showed a significant stepwise increase with age,and the mean blood concentration of valproate was(50.06±28.18)mg/L in epilepsy children<1 year old,(51.08±18.71)mg/L in children aged from 1 to 2 years,and(59.87±22.07)mg/L in children aged from>2 to 6 years,which was significantly higher than that in the group of children aged from 1 to 2 years,the difference was statistically significant(P<0.05).The mean blood concentration of valproate was(63.23±26.67)mg/L in children aged from>6 to 14 years old,higher than that of children aged from>2 to 6 years old,but the difference was not statistically significant(P>0.05),and significantly higher than that of children aged from 1 to 2 years old(P<0.001)and<1 years old(P<0.01),the differences were statistically significant.Steady-state blood concentration of sodium valproate were lower in the low-dose group<20 mg/(kg·d)]than in the medium-dosefrom 20 mg/(kg·d)to 30 mg/(kg·d)]and high-dose group>30 mg/(kg·d)],but the blood concentration of sodium valproate in patients in the medium-dose and high-dose group did not show the dose correlation.The control rates of epilepsy in sodium valproate medium and high blood concentration group were respectively 90.0%(387/430)and 91.1%(41/45),significantly higher than those in low blood concentration group 70.0%(191/273),with statistically significant difference(P<0.05).A total of 39 ADR cases were collected,and the most common ADR cases were neurological reactions(14 cases),impaired liver function(11 cases)and digestive reactions(9 cases).The incidence of ADR tended to increase with increasing blood concentration of sodium valproate and showed an age correlation,and the incidence of ADR was significantly higher in children with epilepsy in the younger age group≤2 years old than in children with epilepsy in other age groups(from>2 to 14 years old).CONCLUSIONS:(1)The blood concentration and ADR of sodium valproate in children have age-specific distribution characteristics,and the blood concentration of infants and children(≤2 years old)is easily lower than the minimum therapeutic concentration,but more likely to have adverse drug reactions,which should be closely monitored in clinic.(2)The safety and efficacy of sodium valproate are satisfactory when the blood concentration of sodium valproate in children is controlled within the range from 50 mg/L to 100 mg/L.(3)Compared with adults,the incidence of liver damage in children is higher,and the monitoring of corresponding indicators of liver function should be strengthened during the administration of valproate sodium.