Plasma Drug Efflux-A New Approach to Optimization of Drug Infusion for Constant Blood Concentration of Thiopental and Methohexital

Abstract

Plasma Drug Efflux is a time-varying measure of the rate of loss of drug from the plasma during conditions of constant plasma concentration. Its practical use is to define the parameters required for a programmed infusion to maintain a desired plasma concentration. The method of deriving the Efflux function, which does not depend on conventional pharmacokinetic models, was developed and tested using thiopental and methonhexital in a total of 51 unselected surgical patients free of hepatic or renal disease. Throughout a predetermined, known, but arbitrary computer-controlled drug infusion, the rate of which was modified according to patient lean body mass (LBM) and the desired concentration, blood samples were taken and the plasma assayed for either drug by an HPLC method. By dividing the known variable infusion rate at the time of each sampling by the arterial plasma concentration at each time, an estimate of the rate of loss of drug the plasma at each point, the Plasma Drug Efflux, was obtained. An error correcting iterative process was used with successive groups of patients until the optimum infusion profile was achieved. Only three iteration steps were required to optimize the infusion profile for each drug. The optimized infusion profile for thiopental was 25.35e-.145t + 4.85e-.0148t + 8.8 ml .cntdot. min-.1 .cntdot. kgLBM-1, and, for methohexital, 22.21e-.092t + 5.09e-.0121t + 15 ml .cntdot. min-1 .cntdot. kgLBM-1. It was concluded that the process of optimization under clinical conditions resulted in infusion profiles suitable for establishing and maintaining a designated arterial plasma concentration in adult surgical patients for periods up to 3 h.