Characterization of the temporal profile of the antinociceptive effects of an intravenous bolus of ketamine using the analgesia nociception index in no-anesthetized adult patients.

An effect-site target-controlled infusion (TCI) would allow a more precise titration of intravenous analgesics effect. The analgesia nociception index (ANI) continuously monitors the analgesia/nociception balance during general anesthesia. This study aims to derive a PKPD model of ketamine antinociceptive effect using the Domino PK parameter set and the ANI response data in awake patients without other drugs affecting the ANI response. Twenty awake adult patients were prospectively studied before general anesthesia. Patients received a single intravenous bolus of ketamine 0.1 mg·kg, and the subsequent ANI values were recorded. An effect compartment model incorporating the Domino PK parameter set was used to characterize the time lag between ketamine plasma concentrations and the ANI response. The model was parameterized with a single parameter Ke0. An Emax pharmacodynamic model was used to fit the ANI response data. Model parameters were estimated with NONMEM 7.5. The minimum objective function value guided the model construction. After the ketamine administration, basal ANI values increased from 38.5 ± 4.95 to a maximum of 53.5 ± 4.95 with an observed time-to-peak effect of 1.83 ± 0.74 min. Modeling analysis revealed hysteresis between predicted plasma concentrations from the Domino model and observed ANI data. Hysteresis was characterized, incorporating an estimated Keo of 0.238 (CI95% 0.20-0.28) min-1 to the described PK parameters set. The developed PKPD model, using Domino's PK parameters and the ANI response data, adequately characterized the temporal profile of ketamine's antinociceptive effect. The current estimated model parameters can be used to perform an effect-site TCI of ketamine for analgesic purposes.