Relationship between etomidate plasma concentration and EEG effect in the rat

Purpose. The effect-plasma concentration relationship of etomidate was stud ied in the rat using electroencephalographic changes as a pharmacodynamic p arameter. Methods. Etomidate was infused (50 mg/kg/h) in chronically instrumented rat s (n = 6) until isoelectric periods of 5 s or longer were observed in the e lectroencephalogram (EEG). The EEG was continuously recorded during the exp eriment and frequent arterial blood samples were taken for determination of etomidate plasma concentrations. The changes observed in the raw EEG signa l were quantified using aperiodic analysis in the 2.5-7.5 Hz frequency band . The return of the righting reflex was used as another parameter of anesth esia. Results. A mean dose of 8.58 +/- 0.41 mg/kg needed to be infused to reach t he end point of 5 s isoelectric EEG. The plasma concentration time profiles were most adequately fitted using a three-exponential model. Systemic clea rance, volume of distribution at steady-state and elimination half-life ave raged 93 +/- 6 ml/min/kg, 4.03 +/- 0.24 l/kg and 59.4 +/- 10.7 min respecti vely. The EEG effect-plasma concentration relationship was biphasic exhibit ing profound hysteresis. Semi-parametric minimization of this hysteresis re vealed an equilibration half-life of 2.65 +/- 0.15 min, and the biphasic ef fect-concentration relationship was characterized nonparametrically by desc riptors. The effect-site concentration at the return of the righting reflex was 0.44 +/- 0.03 mu g/ml. Conclusions. The results of the present study show that the concentration-e ffect relationship of etomidate can be characterized in individual rats usi ng aperiodic analysis in the 2.5-7.5 Hz frequency band of the EEG. This cha racterization can be very useful for studying the influence of diseases on the pharmacodynamics of etomidate in vivo.