基于药效动力学机制的瑞芬太尼和丙泊酚在健康志愿者中血液动力学效应的相互作用模型。

Pharmacodynamic mechanism-based interaction model for the haemodynamic effects of remifentanil and propofol in healthy volunteers.

机构信息

Department of Anesthesiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Department of Anesthesiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Department of Pharmacology, Toxicology and Kinetics, Dutch Medicines Evaluation Board, Utrecht, the Netherlands.

出版信息

Br J Anaesth. 2023 Aug;131(2):222-233. doi: 10.1016/j.bja.2023.04.043. Epub 2023 Jun 22.

DOI:10.1016/j.bja.2023.04.043

PMID:37355412

Abstract

BACKGROUND

Propofol and remifentanil are frequently combined for the induction and maintenance of general anaesthesia. Both propofol and remifentanil cause vasodilation and potentially reduce arterial BP. We aimed to develop a mechanism-based model that characterises the haemodynamic interactions between remifentanil and propofol.

METHODS

Data from two clinical trials in healthy volunteers were analysed using remifentanil-alone, propofol-alone, and combination groups. We evaluated remifentanil effects on haemodynamics using a previously developed mechanism-based haemodynamic model of propofol. The interaction between propofol and remifentanil was explored using the principles of the general pharmacodynamic interaction (GPDI) model.

RESULTS

Remifentanil alone increased the dissipation rate of total peripheral resistance by 50% at 3.0 ng ml. Additionally, the dissipation rates of HR and stroke volume were attenuated by 4.8% and 4.9% per 1 ng ml increase in remifentanil concentration, respectively. The maximal effect of propofol alone in decreasing the production rate of total peripheral resistance was 78%, which decreased to 32% when combined with remifentanil 4 ng ml. The effects of remifentanil on HR and stroke volume were attenuated by propofol with maximum decreases of 11.9% and 21.2%, respectively. Goodness-of-fit plots and prediction-corrected visual predictive check plots showed good predictive performance of the models.

CONCLUSIONS

The structure of the previous mechanism-based haemodynamic model for propofol was able to describe the effects of remifentanil alone on haemodynamic variables. The GPDI model provided a good framework for characterising the pharmacodynamic interaction between remifentanil and propofol on haemodynamic properties.

CLINICAL TRIAL REGISTRATION

NCT02043938; NCT03143972.

摘要

背景

丙泊酚和瑞芬太尼常联合用于全身麻醉的诱导和维持。丙泊酚和瑞芬太尼均引起血管扩张，并可能降低动脉血压。我们旨在开发一种基于机制的模型，以描述瑞芬太尼和丙泊酚之间的血流动力学相互作用。

方法

使用瑞芬太尼单药、丙泊酚单药和联合组分析两项健康志愿者临床试验的数据。我们使用先前开发的丙泊酚基于机制的血流动力学模型评估瑞芬太尼对血流动力学的影响。使用一般药效学相互作用（GPDI）模型的原理探索丙泊酚和瑞芬太尼之间的相互作用。

结果

瑞芬太尼单药可使总外周阻力的耗散率增加 50%，达到 3.0ng/ml。此外，瑞芬太尼浓度每增加 1ng/ml，心率和每搏量的耗散率分别降低 4.8%和 4.9%。丙泊酚单药降低总外周阻力产生率的最大效应为 78%，当与瑞芬太尼 4ng/ml 联合使用时，降低至 32%。瑞芬太尼对心率和每搏量的影响被丙泊酚减弱，最大降低分别为 11.9%和 21.2%。拟合优度图和预测校正可视化预测检查图表明模型具有良好的预测性能。