Predictability of processed electroencephalography effects on the basis ofpharmacokinetic-pharmacodynamic modeling during repeated propofol infusions in patients with extradural analgesia

Background: Pharmacokinetic-pharmacodynamic (PKPD) modeling can be used to characterize the concentration-effect relation of drags. If the concentrati on-effect relation of a hypnotic drug is stable over time, an effect parame ter derived from the processed electroencephalographic signal may be used t o control the Infusion for hypnosis. Therefore, the stability of the propof ol concentration-electroencephalographic effect relation over time was inve stigated under non-steady state conditions. Methods: Three propofol infusions (25 mg (.) kg(-1) (.) h(-1) for 10 min, 2 2 mg (.) kg(-1) (.) h(-1) for 10 min, and 12.5 mg (.) kg(-1) (.) h(-1) for 20 min) were administered to 10 patients during extradural analgesia. Each successive infusion was started immediately after the patient had regained responsiveness after termination of the preceding infusion. Electroencephal ography was recorded from bilateral prefrontal to mastoid leads. Electroenc ephalographic amplitude in the 11- to 15-Hz band and the Bispectral Index w ere used as electroencephalographic effect variables. PKPD parameters were calculated with use of parametric and nonparametric models based on electro encephalographic data and arterial propofol concentrations derived during t he initial infusion, and these were used to predict electroencephalographic effect during the subsequent infusions. The predictability of the electroe ncephalographic effects was determined by the coefficient of determination (R-2) and of the - 2 log likelihood of the sequential infusions. Results. The direction of electroencephalographic changes in response to th e infusions was reproducible. Although PKPD parameters could be estimated w ell during the initial infusion (median [range] parametric R-2 = 0.74 [0.56 -0.95] for electroencephalographic amplitude and 0.90 [0.27-0-99] for Bispe ctral index), none of the modeling techniques could predict accurately the electroencephalographic effect during subsequent infusions (R-2 = 0.00 [-0. 31-0.46] for electroencephalographic amplitude and 0.15 [-0.46-0.57] for Bi spectral Index; P < 0.01). Conclusions. The relation between blood propofol concentrations and the ele ctroencephalographic effect under non-steady state conditions is not stable over time and is too complex to be modeled by any of the applied PKPD mode ls.