Propofol dosing regimens for ICU sedation based upon an integrated pharmacokinetic-pharmacodynamic model

Background: The pharmacology of propofol infusions administered for long-te rm sedation of intensive care unit (ICU) patients has not been fully charac terized. The aim of the study was to develop propofol dosing guidelines for ICU sedation based on an integrated pharmacokinetic-pharmacodynamic model of propofol infusions in ICU patients. Methods: With Institutional Review Board approval, 30 adult male medical an d surgical ICU patients were given target-controlled infusions of propofol for sedation, adjusted to maintain a Ramsay sedation scale score of 2-5. Pr opofol administration in the first 20 subjects was based on a previously de rived pharmacokinetic model for propofol. The last 10 subjects were given p ropofol based on a pharmacokinetic model derived from the first 20 subjects . Plasma propofol concentrations were measured, together with sedation scor e. Population pharmacokinetic and pharmacodynamic parameters were estimated by means of nonlinear regression analysis in the first 20 subjects, then p rospectively tested in the last 10 subjects. An integrated pharmacokinetic- pharmacodynamic model was used to construct dosing regimens for light and d eep sedation with propofol in ICU patients. Results: The pharmacokinetics of propofol were described by a three-compart ment model with lean body mass and fat body mass as covariates. The pharmac odynamics of propofol were described by a sigmoid model, relating the proba bility of sedation to plasma propofol concentration. The pharmacodynamic mo del for propofol predicted light and deep levels of sedation with 73% accur acy. Plasma propofol concentrations corresponding to the probability modes for sedation scores of 2, 3,4, and 5 were 0.25, 0.6, 1.0, and 2.0 mug/ml. P redicted emergence times in a typical subject after 24 h, 72 h, 7 days, and 14 days of light sedation (sedation score = 3 --> 2) with propofol were 13 , 34, 198, and 203 min, respectively. Corresponding emergence times from de ep sedation (sedation score = 5 --> 2) with propofol were 25, 59, 71, and 7 4 h. Conclusions: Emergence time from. sedation with propofol in ICU patients va ries with the depth of sedation, the duration of sedation, and the patient' s body habitus. Maintaining a light level of sedation ensures a rapid emerg ence from sedation with long-term propofol administration.