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

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.