接受体外膜肺氧合治疗的危重症患者静脉注射舒芬太尼的群体药代动力学。

Population pharmacokinetics of intravenous sufentanil in critically ill patients supported with extracorporeal membrane oxygenation therapy.

作者信息

Hahn Jongsung, Yang Seungwon, Min Kyoung Lok, Kim Dasohm, Jin Byung Hak, Park Changhun, Park Min Soo, Wi Jin, Chang Min Jung

机构信息

Department of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon, 21983, Republic of Korea.

Department of Pharmaceutical Medicine and Regulatory Sciences, Colleges of Medicine and Pharmacy, Yonsei University, Incheon, 21983, Republic of Korea.

出版信息

Crit Care. 2019 Jul 9;23(1):248. doi: 10.1186/s13054-019-2508-4.

DOI:10.1186/s13054-019-2508-4

PMID:31288863

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6615282/

Abstract

BACKGROUND

Sufentanil is commonly used for analgesia and sedation during extracorporeal membrane oxygenation (ECMO). Both ECMO and the pathophysiological changes derived from critical illness have significant effects on the pharmacokinetics (PK) of drugs, yet reports of ECMO and sufentanil PK are scarce. Here, we aimed to develop a population PK model of sufentanil in ECMO patients and to suggest dosing recommendations.

METHODS

This prospective cohort PK study included 20 patients who received sufentanil during venoarterial ECMO (VA-ECMO). Blood samples were collected for 96 h during infusion and 72 h after cessation of sufentanil. A population PK model was developed using nonlinear mixed effects modelling. Monte Carlo simulations were performed using the final PK parameters with two typical doses.

RESULTS

A two-compartment model best described the PK of sufentanil. In our final model, increased volume of distribution and decreased values for clearance were reported compared with previous PK data from non-ECMO patients. Covariate analysis showed that body temperature and total plasma protein level correlated positively with systemic clearance (CL) and peripheral volume of distribution (V2), respectively, and improved the model. The parameter estimates of the final model were as follows: CL = 37.8 × EXP (0.207 × (temperature - 36.9)) L h, central volume of distribution (V1) = 229 L, V2 = 1640 × (total plasma protein/4.5) L, and intercompartmental clearance (Q) = 41 L h. Based on Monte Carlo simulation results, an infusion of 17.5 μg h seems to reach target sufentanil concentration (0.3-0.6 μg L) in most ECMO patients except hypothermic patients (33 °C). In hypothermic patients, over-sedation, which could induce respiratory depression, needs to be monitored especially when their total plasma protein level is low.

CONCLUSIONS

This is the first report on a population PK model of sufentanil in ECMO patients. Our results suggest that close monitoring of the body temperature and total plasma protein level is crucial in ECMO patients who receive sufentanil to provide effective analgesia and sedation and promote recovery.

TRIAL REGISTRATION

Clinicaltrials.gov NCT02581280 , December 1st, 2014.

摘要

背景

舒芬太尼常用于体外膜肺氧合（ECMO）期间的镇痛和镇静。ECMO以及危重病引发的病理生理变化对药物的药代动力学（PK）均有显著影响，但关于ECMO与舒芬太尼PK的报道却很稀少。在此，我们旨在建立ECMO患者中舒芬太尼的群体PK模型并给出给药建议。

方法

这项前瞻性队列PK研究纳入了20例在静脉-动脉体外膜肺氧合（VA-ECMO）期间接受舒芬太尼治疗的患者。在舒芬太尼输注期间96小时以及停药后72小时采集血样。使用非线性混合效应建模建立群体PK模型。使用最终的PK参数和两种典型剂量进行蒙特卡洛模拟。

结果

二室模型能最好地描述舒芬太尼的PK。在我们的最终模型中，与非ECMO患者先前的PK数据相比，分布容积增加而清除率降低。协变量分析表明，体温和总血浆蛋白水平分别与全身清除率（CL）和外周分布容积（V2）呈正相关，并改善了模型。最终模型的参数估计如下：CL = 37.8 × EXP(0.207 × (体温 - 36.9)) L/h，中央分布容积（V1）= 229 L，V2 = 1640 ×（总血浆蛋白/4.5）L，以及隔室间清除率（Q）= 41 L/h。基于蒙特卡洛模拟结果，对于大多数ECMO患者（体温不低于33°C），输注17.5 μg/h似乎能达到目标舒芬太尼浓度（0.3 - 0.6 μg/L）。在体温过低的患者中，尤其当他们的总血浆蛋白水平较低时，需要监测可能诱发呼吸抑制的过度镇静情况。