Influence of administration rate on propofol plasma - Effect site equilibration

Background: The authors hypothesized a difference in plasma-effect site equilibration, depicted by a first-order constant k(e0), depending on the injection rate of propofol. Methods: Sixty-one patients received 2.5 mg/kg propofol given as a bolus or as a 1-, 2-, or 3-min infusion. The Bispectral index was used to monitor drug effect. Propofol predicted plasma concentration was calculated using a three-compartment model and the effect site concentration over time as the convolution between the predicted plasma concentration and the disposition function of the effect site concentration. The authors evaluated the influence of the infusion rate on the k(e0) by comparing the model with one k(e0) for all groups with models estimating different k(e0) values for each group. The authors also assessed the accuracy of two pharmacokinetic models after bolus injection. Results: The best model based was a fixed (Bispectral Index t 90) plus sigmoidal model (Bispectral Index < 90) with two values of k(e0), one for the bolus (t, k(e0) = 1.2 min) and one for the infusions (t(1/2) k(e0) = 2.2 min). However, the tested pharmacokinetic models poorly predicted the arterial concentrations in the first minutes after bolus injection. Simulations showed the requirement for two k(e0) values for bolus and infusion was mostly a compensation for the inaccurate prediction of arterial concentrations after a bolus. Conclusion: Propofol plasma-effect site equilibration occurs more rapidly after a bolus than after rapid infusion, based on the electroencephalogram as a drug effect measure, mostly because of misspecification of the pharmacokinetic model in the first minutes after bolus.