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

Hong Su; Jeroen V Koomen; Douglas J Eleveld; Michel M R F Struys; Pieter J Colin

doi:10.1016/j.bja.2023.04.043

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

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

Authors

Hong Su¹, Jeroen V Koomen², Douglas J Eleveld¹, Michel M R F Struys³, Pieter J Colin⁴

Affiliations

¹ Department of Anesthesiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
² 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.
³ Department of Anesthesiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Department of Basic and Applied Medical Sciences, Ghent University, Ghent, Belgium.
⁴ Department of Anesthesiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. Electronic address: p.j.colin@umcg.nl.

PMID: 37355412
DOI: 10.1016/j.bja.2023.04.043

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^-1. Additionally, the dissipation rates of HR and stroke volume were attenuated by 4.8% and 4.9% per 1 ng ml^-1 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^-1. 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.

Keywords: haemodynamic; healthy volunteers; interaction; mechanism-based pharmacodynamic modelling; propofol; remifentanil.

Publication types

Clinical Trial

MeSH terms

Anesthetics, Intravenous / pharmacology
Healthy Volunteers
Hemodynamics
Humans
Piperidines / pharmacology
Propofol* / pharmacology
Remifentanil / pharmacology

Substances

Anesthetics, Intravenous
Piperidines
Propofol
Remifentanil

Associated data

ClinicalTrials.gov/NCT03143972
ClinicalTrials.gov/NCT02043938