The influence of age on propofol pharmacodynamics

Background: The authors studied the influence of age on the pharmacodynamic s of propofol, including characterization of the relation between plasma co ncentration and the time course of drug effect., Methods: The authors evaluated healthy volunteers aged 25-81 yr. A bolus do se (2 mg/kg or 1 mg/kg in persons older than 65 yr) and an infusion (25, 50 100, or 200 mu g kg(-1) min(-1) of the older or the new (containing EDTA) formulation of propofol were given on each of two different study days. The propofol concentration was determined in frequent arterial samples. The el ectroencephalogram (EEG) was used to measure drug effect. A statistical tec hnique called semilinear canonical correlation was used to select component s of the EEG power spectrum that correlated optimally with the effect-site concentration. The effect-site concentration was related to drug effect wit h a biphasic pharmacodynamic model. The plasma effect- site equilibration r ate constant was estimated pammetrically. Estimates of this rate constant w ere validated by comp:comparing the predicted time of peak effect with the time of peak EEG effect. The probability of being asleep, as a function of age, was determined from steady state concentrations after 60 min of propof ol infusion. Results: Twenty-four volunteers completed the study. Three parameters of th e biphasic pharmacodynamic model were correlated linearly with age. The pla sma effect-site equilibration rate constant was 0.456 min(-1). The predicte d time to peak effect after bolus injection ranging was 1.7 min, The time t o peak effect assessed visually was 1.6, min (range, 1-2.4,ri min). The ste ady state observations showed increasing sensitivity to propofol In elderly patients, with C-50,, values for loss of con sciousness of 2,35, 1,8, and 1.25 mu g/ml in volunteers who were 25, 50, and 75)yr old, respectively. Conclusions: Semilinear canonical correlation defined a new measure of prop ofol effect on the EEG, the canonical univariate parameter for propofol, Us ing this parameter, propofol plasma effect-site equilibration is faster tha n previously reported. This fast onset was confirmed by inspection of the E EG data. Elderly patients are more sensitive to the hypnotic and EEG effect s of propofol than are younger persons.