In Reply:
We would like to thank Dr. Kempen for his particular interest regarding our article investigating pharmacokinetic- pharmacodynamic modeling of propofol in children.1In response to his comments, we would like to precise that, as real data, the average total dose of propofol administrated for induction was specified in our article in table 3. However, unfortunately rates of propofol infusion were not detailed in extenso in our article, despite that these data were continuously recorded during the study. Indeed, the aim of our study was to investigate pharmacokinetic-pharmacodynamic modeling of propofol and not to validate an extrapolated propofol infusion regimen. This kind of schema using real data, such as milligram per kilogram per minute and derived from a classic pediatric pharmacokinetic model, has been demonstrated to be associated with prolonged delay of recovery.2In addition, taking into account that the pediatric population is characterized by a wide physiologic interindividual variability, a single pharmacokinetic approach may lead to inaccurate dosing, exposing patients to the risk of over- or underdosing and their deleterious clinical consequences, such as perioperative hypotension or awareness. In agreement with the comments of Dr. Kempen, real data such as measured propofol concentrations were used in our study to test pharmacokinetic models. We demonstrated that measured propofol concentrations were poorly predicted whatever the pharmacokinetic model tested, even for those that showed the best prediction of the hypnotic effect, as assessed by the bispectral index. The bispectral index is an electroencephalography-based device that assesses the cerebral cortical inhibition attributable to, for instance, GABAergic hypnotic agents. In anesthetized children, bispectral index values were highly correlated with measured and estimated propofol concentrations, despite the discrepancies between both concentrations.3The pharmacokinetic and pharmacodynamic approaches seem inseparable whatever the mode of propofol administration. Pharmacokinetic-pharmacodynamic modeling allows automatic adjustment of drug-dosing profiles to achieve a constant pharmacodynamic target, on that may require a nonconstant time course of drug concentration or rate infusion.
Indeed, during continuous propofol administration, the degree of cortical inhibition might be considered the real electroencephalography endpoint or pharmacodynamic target for the clinical scientist, especially in children in whom this clinical feedback may blunt the interindividual variability of requirements and thus improve anesthetic management.
* Hopital d'Enfants Armand Trousseau, Assistance Publique- Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France. isabelle.constant@trs.aphp.fr
