Pharmacodynamic modeling of propofol-induced tidal volume depression in children
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This investigation aimed to develop a pediatric pharmacodynamic model of propofol-induced tidal volume depression towards an ultimate goal of developing a dosing schedule that would preserve spontaneous breathing following a loading dose of propofol.
Fifty two ASA 1 and 2 children aged 6–15 year presenting for gastrointestinal endoscopy were enrolled. Subjects were administered a loading dose of 4 mg/kg of propofol intravenously at a constant infusion rate determined by a randomization schedule. Respiratory parameters including tidal volume, respiratory rate, minute volume, and end-tidal CO2 were recorded at 5 s intervals. Using the predicted plasma concentration, based on the Paedfusor pharmacokinetic model, propofol-induced tidal volume depression was modeled by 3 different approaches (2-stage, pooled, and mixed effects) and results were compared using prediction residual, median percentage errors, median absolute percentage errors, and root-mean-squared normalized errors. The effects of age and body weight as covariates were examined.
Respiratory rate and end-tidal CO2 did not show clear dependence on the predicted plasma concentration. The pharmacodynamic models for tidal volume derived from different modeling approaches were highly consistent. The 2-stage, pooled, and mixed effects approaches yielded ke0 of 1.06, 1.24, and 0.72 min−1; γ of 1.10, 0.83, and 0.93; EC50 of 3.18, 3.44, and 3.00 mcg/ml. Including age and body weight as covariates did not significantly improve the predictive performance of the models.
A pediatric pharmacodynamic model of propofol-induced tidal volume depression was developed. Models derived from 3 different approaches were shown to be consistent with each other; however, the individual pharmacodynamic parameters exhibited significant inter-individual variability without strong dependence on age and body weight. This would suggest the desirability of adapting the pharmacodynamic model to each subject in real time.
Keywordspharmacodynamics pediatrics propofol tidal volume respiratory depression anesthesia
Conflict of interest
Conflict of interest: None.