肝功能不全重症患者伏立康唑谷浓度监测及其影响因素分析

Monitoring voriconazole trough concentrations and investigating the influencing factors in patients with liver dysfunction in ICU

目的:描述肝功能不全重症患者中伏立康唑血浆谷浓度(Cmin)的分布特点,并考察Cmin的影响因素。方法:回顾性收集重症监护病房中接受静脉用伏立康唑治疗的肝功能不全患者的Cmin数据和生理病理资料,采用Child-Pugh评分进行肝功能不全分级,伏立康唑Cmin通过高效液相色谱串联质谱法(HPLC-MS/MS)测定,SPSS软件用于统计分析。结果:44例肝功能不全患者(包括肝移植患者)共92个Cmin纳入最终分析。经验治疗方案下(维持剂量:200 mg bid iv),患者的平均Cmin超出治疗窗(2-6μg·mL^-1)上限且Cmin个体差异较大[中值±四分位距,(6.17±3.20)μg·mL^-1],仅43.5%的Cmin在治疗范围内。Child-Pugh C级患者的Cmin显著高于Child-Pugh AB级患者的Cmin[(7.98±3.60)vs.(5.28±3.16)μg·mL^-1,P<0.001],Child-Pugh分级是Cmin的独立影响因素。此外,肝移植患者的Cmin低于非肝移植患者,且两者的Cmin差异在Child-Pugh C级中较为显著[(7.35±2.95)vs.(8.99±4.21)μg·mL^-1,P=0.033]。结论:200 mg bid iv维持剂量下,伏立康唑在肝功能不全患者中的Cmin高,按Child-Pugh分级的肝功能是Cmin的主要影响因素。肝功能不全重症患者使用伏立康唑时,应基于Child-Pugh分级减少给药剂量和/或延长给药间隔,同时进行严密的血药浓度监测,以避免严重不良反应发生。

OBJECTIVE To describe the distribution characteristics of voriconazole plasma trough concentrations(Cmin) in patients with liver dysfunction in ICU, and to investigate the influencing factors of Cmin.METHODS The Cmin data and physiological and pathological data of patients with liver dysfunction treated with intravenous voriconazole in ICU were retrospectively collected. The Child-Pugh score was used to categorize the degree of liver dysfunction in patients. Cmin of voriconazole was determined by a validated high-performance liquid chromatography-tandem mass spectrometry method(HPLC-MS/MS). Statistical analysis was performed using SPSS software.RESULTS A total of 92 Cmin from 44 patients with liver dysfunction were included in the final analysis(including liver transplant recipients). Under the empirical treatment regimen(maintenance dose: 200 mg bid iv), the average Cmin of patients exceeded the upper limit of the therapeutic window(2-6 μg·mL^-1) and the individual variability of Cmin was significant [median±interquartile range,(6.17±3.20) μg·mL^-1], and only 43.5% of Cmin lied within the therapeutic range. The Cmin in patients with Child-Pugh class C was significantly higher than that in patients with Child-Pugh class A and B [(7.98±3.60) vs.(5.28±3.16) μg·mL^-1, P<0.001], and the Child-Pugh classification was an independent influencing factor for Cmin. In addition, Cmin of patients with liver transplantation was lower than that of non-liver transplant patients, especially in patients with Child-Pugh class C [(7.35±2.95) vs.(8.99±4.21) μg·mL^-1, P=0.033].CONCLUSION At a maintenance dose of 200 mg bid iv, the Cmin of voriconazole in patients with liver dysfunction is high. Child-Pugh classification is a main influencing factor for Cmin. In patients with liver dysfunction in ICU, reduction of the dose and/or prolongation of the administration interval of voriconazole should be performed based on Child-Pugh classification. Meanwhile, plasma concentrations should be closely monitored to avoid serious adverse events.