伏立康唑致神经系统不良反应的临床特征及低血钾和低血钠发生情况

Clinical Characteristics of Voriconazole-induced Neurological ADR and the Occurrence of Hypokalemia and Hyponatremia

目的:探讨伏立康唑致神经系统不良反应的临床特征及不良反应发生前的低血钾和低血钠发生情况。方法:回顾性分析2018年1月-2020年11月我院收治的411例使用伏立康唑治疗的患者资料,包括基本资料(性别、年龄、体质量、感染类型、基础疾病、致病真菌类型以及伏立康唑的给药方式、维持剂量、血药浓度等),发生神经系统不良反应患者的基本情况(性别、年龄、感染类型、基础疾病、联合用药情况、发生时间、临床表现等)及其发生神经系统不良反应前3天内的血钾、血钠和肝功能指标[谷丙转氨酶(ALT)、谷草转氨酶(AST)、γ-谷氨酰转肽酶(γ-GT)、碱性磷酸酶(ALP)、总胆红素、直接胆红素]水平,并分析神经系统不良反应与伏立康唑谷浓度、血钾、血钠水平的关系。结果:411例患者中,有31例患者(7.54%)出现了神经系统不良反应,男性患者占比(64.52%)高于女性(35.48%),以50岁及以上人群(74.20%)为主,肺部感染(96.77%)为主要感染类型。在31例发生神经系统不良反应的患者中,有26例患者(83.87%)为给药1~7 d后出现神经系统不良反应;30例患者(96.77%)为静脉滴注给药。伏立康唑谷浓度>5.0μg/mL患者(8.99%)的神经系统不良反应发生率显著高于谷浓度≤5.0μg/mL患者(3.42%,χ^(2)=4.91,P=0.027)。临床表现主要为幻觉(32.35%)、烦躁(32.35%)、睡眠差(17.65%)等。在30例检测相关指标的患者发生神经系统不良反应的前3天内,有16例患者(53.33%)出现低血钾,12例患者(40.00%)出现低血钠,均显著高于未发生神经系统不良反应患者的低血钾发生率(24.74%,P=0.001)和低血钠发生率(12.89%,P<0.001);分别有8、10、7、13、7、10例患者出现ALT、AST、ALP、γ-GT、总胆红素和直接胆红素升高。31例发生神经系统不良反应的患者经减少剂量或停用伏立康唑后,其相关症状均减轻或消失。结论:伏立康唑致神经系统不良反应多发生在给药后1~7 d,以静脉滴注给药为主,多发生于男性和50岁及以上人群:神经系统不良反应的发生可能与伏立康唑谷浓度有关,且神经系统不良反应发生前大多数患者出现了低血钾或低血钠。

OBJECTIVE:To explore the clinical characteristics of voriconazole-induced neurological ADR and the occurrence of hypokalemia and hyponatremia before ADR.METHODS:The medical records of 411 patients receiving voriconazole therapy,who admitted to our hospital from January 2018 to November 2020,were retrospectively analyzed.The general information of all patients,including sex,age,body weight,type of infection,underlying disease,type of pathogenic fungal infection and administration route of voriconazole,maintenance dose,blood drug concentration,were collected.The basic information of patients with neurological ADR,including sex,age,types of infection,underlying disease,drug combination,occurrence time and clinical manifestations,were collected.The levels of blood potassium,blood sodium and liver function indexes(ALT,AST,γ-GT,ALP,total bilirubin,direct bilirubin)within 3 days before the neurological ADR were also collected.The relationship of neurological ADR with voriconazole trough concentration,blood potassium and blood sodium levels was analyzed.RESULTS:Among 411 patients,31(7.54%)patients suffered from neurological ADR,which were higher in male(64.52%)than in female(35.48%),mainly in patients aged 50 and over(74.20%).The major infection type was lung infection(96.77%).Among 31 patients with neurological ADR,26 patients suffered from neurological ADR after 1-7 days after voriconazole administration,accounting for 83.87%.Thirty patients received intravenous drip,accounting for 96.77%.The incidence of neurological ADR in patients with voriconazole trough concentration>5.0μg/mL(8.99%)was significantly higher than that in patients with trough concentration≤5.0μg/mL(3.42%,χ^(2)=4.91,P=0.027).The clinical manifestations of the patients were mainly hallucinations(32.35%),irritability(32.35%)and poor sleep(17.65%),etc.Within 3 days before 30 patients,receiving related indexes test,suffered from neurological ADR,16 patients(53.33%)had hypokalemia and 12 patients(40.00%)had hyponatremia,which were significantly higher than the incidence of hypokalemia(24.74%,P=0.001)and hyponatremia(12.89%,P<0.001)in those without neurological ADR.There were 8,10,7,13,7 and 10 patients with ALT,AST,ALP,γ-GT,total bilirubin and direct bilirubin increased.In 31 patients with neurological ADR,the neurological ADR were relieved or disappeared after reducing the dosage or discontinuing voriconazole.CONCLUSIONS:The neurological ADR of voriconazole mostly occurs 1-7 days after voriconazole administration,mainly by intravenous drip,mostly in male and people aged 50 and over.The occurrence of neurological ADR may be related to trough concentration of voriconazole,and most patients suffer from hypokalemia or hyponatremia before the occurrence of ADR.