A Direct Dynamic Dose-Response Model of Propofol for Individualized Anesthesia Care

Abstract

In an effort to open up new opportunities in individualized anesthesia care, this paper presents a dynamic dose-response model of propofol that relates propofol dose (i.e., infusion rate) directly to a clinical effect. The proposed model consists of a first-order equilibration dynamics plus a nonlinear Hill equation model, each representing the transient distribution of propofol dose from the plasma to the effect site and the steady-state dose-effect relationship. Compared to traditional pharmacokinetic-pharmacodynamic (PKPD) models, the proposed model has structural parsimony and comparable predictive capability, making it more attractive than its PKPD counterpart for identifying an individualized dose-response model in real-time. The efficacy of the direct dynamic dose-response model over a traditional PKPD model was assessed using a mixed effects modeling analysis of the electroencephalogram (EEG)-based state entropty (SE) response to intravenous propofol administration in 34 pediatric subjects. An improvement in the mean-squared error and r(2) value of individual prediction, as well as the Akaike's information criterion (AIC) was seen with the direct dynamic dose-response model.