Pharmacokinetics of Propofol in Adult Patients Undergoing Coronary Revascularization

Abstract

Background Propofol is increasingly used for cardiac anesthesia and for perioperative sedation. Because pharmacokinetic parameters vary among distinct patient populations, rational drug dosing in the cardiac surgery patient is dependent on characterization of the drug's pharmacokinetic parameters in patients actually undergoing cardiac procedures and cardiopulmonary bypass (CPB). In this study, the pharmacokinetics of propofol was characterized in adult patients undergoing coronary revascularization. Methods Anesthesia was induced and maintained by computer-controlled infusions of propofol and alfentanil, or sufentanil, in 41 adult patients undergoing coronary artery bypass graft surgery. Blood samples for determination of plasma propofol concentrations were collected during the predefined study periods and assayed by high-pressure liquid chromatography. Three-compartment model pharmacokinetic parameters were determined by nonlinear extended least-squares regression of pooled data from patients receiving propofol throughout the perioperative period. The effect of CPB on propofol pharmacokinetics was modeled by allowing the parameters to change with the institution and completion of extracorporeal circulation and selecting the optimal model on the basis of the logarithm of the likelihood. Predicted propofol concentrations were calculated by convolving the infusion rates with unit disposition functions using the estimated parameters. The predictive accuracy of the parameters was evaluated by cross-validation and by a prospective comparison of predicted and measured levels in a subset of patients. Results Optimal pharmacokinetic parameters were: central compartment volume = 6.0 l; second compartment volume = 49.5 l; third compartment volume = 429.3 l; Cl1 (elimination clearance) = 0.68 l/min; Cl2 (distribution clearance) = 1.97 l/min1; and Cl3 (distribution clearance) = 0.70 l/min. The effects of CPB were optimally modeled by step changes in V1 and Cl1 to values of 15.9 and 1.95, respectively, with the institution of CPB. Median absolute prediction error was 18% in the cross-validation assessment and 19% in the prospective evaluation. There was no evidence for nonlinear kinetics. Previously published propofol pharmacokinetic parameter sets poorly predicted the observed concentrations in cardiac surgical patients. Conclusions The pharmacokinetics of propofol in adult patients undergoing cardiac surgery with CPB are dissimilar from those reported for other adult patient populations. The effect of CPB was best modeled by an increase in V1 and Cl1. Predictive accuracy of the derived pharmacokinetic parameters was excellent as measured by cross-validation and a prospective test.