Titration of the plasma effect site equilibrium rate constant of propofol; a link method of 'Concentration-Probability-Time'

BACKGROUND The plasma effect-site equilibrium rate constant (k(e0)) of propofol has been reported in various pharmacodynamic studies; however, it is not desirable to apply k(e0) for the link with pharmacokinetic models that were separately investigated. Thus, we titrated k(e0) for the pharmacokinetic model, which is known as the multiple covariates adjusted model of propofol. METHODS Ninety female patients scheduled for gynecologic surgery were randomly assigned to three groups targeting different plasma concentrations of 5.4, 8.1, and 10.8 microg/ml. Target-controlled infusions (TCI) were provided by a computer-assisted continuous infusion system. Time to loss of responsiveness (LOR) was measured by a blind investigator; effect-site concentrations (C(e)) for LOR were then calculated with simulation of TCI using different k(e0)s. We determined the k(e0) minimizing total discrepancy (TD) between the inputted and calculated k(e0) from the t(1/2)k(e0)s for a given probability of LOR of the C(e), and also obtained the k(e0) for the minimal TD between the median C(e), which were compared to the known k(e0). RESULTS K(e0)s from these two methods were 0.3692 and 0.3788/min. C(e)s for LOR with these k(e0)s were significantly different from those with Schnider's k(e0). CONCLUSIONS We proposed a method for titration of the k(e0) of propofol. The k(e0)s of propofol was lower than Schnider's k(e0). An adequate k(e0) for the specific pharmacokinetic model and a certain population would be useful for prediction of an accurate C(e), and could be used for calculation of accurate dosing during targeting of the effect site.