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Pharmacodynamic modeling of propofol-induced tidal volume depression in children
Jin-Oh Hahn1, Sara Khosravi, Maryam Dosani
1Department of Mechanical Engineering, University of Alberta, Edmonton, AB, Canada. jinoh.hahn@alum.mit.edu
Insights
A pediatric pharmacodynamic model for propofol-induced tidal volume depression was developed in children. This model, crucial for safe anesthesia, showed significant inter-individual variability, suggesting real-time adaptation for personalized dosing.
Area of Science:
- Anesthesiology
- Pharmacodynamics
- Pediatric Medicine
Background:
- Propofol is a common anesthetic agent used in pediatric procedures.
- Understanding its effects on respiratory function, specifically tidal volume, is critical for patient safety.
- Developing predictive models can aid in optimizing anesthetic delivery and preserving spontaneous breathing.
Purpose of the Study:
- To develop a pediatric pharmacodynamic model for propofol-induced tidal volume depression.
- To establish a dosing schedule that preserves spontaneous breathing after a propofol loading dose.
- To compare different modeling approaches for accuracy and consistency.
Main Methods:
- Fifty-two pediatric patients (6-15 years) received a propofol loading dose.
- Respiratory parameters (tidal volume, respiratory rate, end-tidal CO2) were continuously monitored.
- Propofol plasma concentrations were used with pharmacokinetic models to develop pharmacodynamic models for tidal volume depression using 2-stage, pooled, and mixed-effects approaches.
Main Results:
- Pharmacodynamic models for tidal volume depression were consistent across the 2-stage, pooled, and mixed-effects approaches.
- Key parameters (k(e0), γ, EC50) were estimated, showing consistency between models.
- Age and body weight did not significantly improve the predictive performance of the models.
Conclusions:
- A consistent pediatric pharmacodynamic model for propofol-induced tidal volume depression was successfully developed.
- Significant inter-individual variability in pharmacodynamic parameters was observed.
- Real-time adaptation of the pharmacodynamic model for each patient is recommended for personalized dosing.
Objective:
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.
Methods:
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 CO(2) 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.
Results:
Respiratory rate and end-tidal CO(2) 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 k(e0) 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.
Conclusions:
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.
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