title: Pharmacodynamic modeling of propofol-induced tidal volume depression in children.
abstract: 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.
authors.affiliation: Department of Mechanical Engineering, University of Alberta, Edmonton, AB, Canada. jinoh.hahn@alum.mit.edu
authors.forename: Jin-Oh
authors.initials: JO
authors.lastname: Hahn
authors.forename: Sara
authors.initials: S
authors.lastname: Khosravi
authors.forename: Maryam
authors.initials: M
authors.lastname: Dosani
authors.forename: Guy A
authors.initials: GA
authors.lastname: Dumont
authors.forename: J
authors.initials: J
authors.lastname: Mark Ansermino
mesh_terms: D000293:Adolescent; D018686:Anesthetics, Intravenous / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D002245:Carbon Dioxide / Q000502:physiology; D002648:Child; D003864:Depression, Chemical; D006801:Humans; D007262:Infusions, Intravenous; D008954:Models, Biological; D015742:Propofol / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D056152:Respiratory Rate / Q000187:drug effects; D013990:Tidal Volume / Q000187:drug effects* / Q000502:physiology
chemical_list: D018686:Anesthetics, Intravenous; D002245:Carbon Dioxide; D015742:Propofol