Induction speed is not a determinant of propofol pharmacodynamics

Background: Evidence suggests that the rate at which intravenous anesthetics are infused may influence their plasma-effect site equilibration. The authors used five different rates of propofol administration to test the hypothesis that different sedation endpoints occur at the same effect site propofol concentration, independent of the infusion rate. The authors concurrently evaluated the automated responsiveness monitor (ARM) against other sedation measures and the propofol effect site concentration. Methods: With Human Studies Committee approval, 18 healthy volunteers received five consecutive target-controlled propofol infusions. During each infusion, the effect site concentration was increased by a rate of 0.1, 0.3, 0.5, 0.7, or 0.9 mug (.) ml(-1) (.) min(-1). The Bispectral Index and ARM were recorded at frequent intervals. The times of syringe drop and loss and recovery of responsiveness were noted. Pharmacokinetic and pharmacodynamic modeling was performed using NONMEM. Results: When the correct rate of plasma-effect site equilibration was determined for each individual (plasma-effect site equilibration = 0.17 min(-1), time to peak effect = 2.7 min), the effect site concentrations associated with each clinical measure were not affected by the rate of increase of effect site propofol concentration. ARM correlated with all clinical measures of drug effect. Subjects invariably stopped responding to ARM at lower effect site propofol concentrations than those associated with loss of responsiveness. Conclusions: Population-based pharmacokinetics, combined with real-time electroencephalographic measures of drug effect, may provide a means to individualize pharmacodynamic modeling during target-controlled drug delivery. ARM seems useful as an automated measure of sedation and may provide the basis for automated monitoring and titration of sedation for a propofol delivery system.