Pharmacokinetics of propofol in adult patients undergoing coronary revascularization

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. Threecomparrment model pharmacokinetic parameters were determined by nonlinear extended least-squares regression of posied data from patients receiving propofol throughout the peiioperatlve 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 convolvlng 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 1; second compartment volume = 49.5 1; third compartment volume = 429.3 1; C1, (elimination clearance) = 0.68 l/min; Cl-2 (distribution clearance) = 1.971/min(1); and Cl-3 (dstribution clearance) = 0.701/min. The effects of CPB were optimally modeled by step changes In V-1 and Cl-1 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 a-as 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 In increase In V-1 and Cl-1. Predictive accuracy of the derived pharmacskinetic parameters was excellent as measured by cross-validation and a prospective test.