Development of acute tolerance to the EEG effect of propofol in rats

Background. A previous study in rats with propofol suggested the development of acute tolerance to the EEG effect. The aim of this study was to evaluate acute tolerance by means of EEG-controlled closed-loop anaesthesia as this approach allows precise determination of drug requirement to maintain a defined drug effect. Methods. Ten male Sprague-Dawley rats [weight 402 (40) g, mean (SD) were included in the study. The EEG was recorded with occipito-occipital needle electrodes and a modified median frequency (mMEF) of the EEG power spectrum was used as a pharmacodynamic control parameter. The propofol infusion rate was controlled by a model-based adaptive algorithm to maintain a set point of mMEF=3 (0.5) Hz for 90 min. The performance of the closed-loop system was characterized by the prediction error PE=(mMEF-set point)/set point. Plasma propofol concentrations were determined from arterial samples by HPLC. Results. The chosen set point was successfully maintained in all rats. The median (SE) and absolute median values of PE were -5.0 (0.3) and 11.3 (0.2)% respectively. Propofol concentration increased significantly from 2.9 (2.2) μg ml^-1 at the beginning to 5.8 (3.8) μg ml^-1 at 90 min [mean(SD), P<0.05]. The cumulative dose increased linearly, with a mean infusion rate of 0.60 (0.16) mg kg^-1 min^-1. The minimum value of the mean arterial pressure during closed-loop administration of propofol was 130 (24) mm Hg, compared with a baseline value of 141 (12) mm Hg. Conclusions. The increase in propofol concentration at constant EEG effect indicates development of acute tolerance to the hypnotic effect of propofol.