Response surface model for anesthetic drug interactions

Background: Anesthetic drug interactions traditionally have been characteri zed using isobolographic analysis or multiple logistic regression, Both app roaches have significant limitations. The authors propose a model based on response-surface methodology. This model can characterize the entire dose-r esponse relation between combinations of anesthetic drugs and is mathematic ally consistent with models of the concentration-response relation of singl e drugs. Methods: The authors defined a parameter, theta, that describes the concent ration ratio of two potentially interacting drugs. The classic sigmoid E-ma x model was extended by making the model parameters dependent on theta, A c omputer program was used to estimate response surfaces for the hypnotic int eraction between midazolam, propofol, and alfentanil, based on previously p ublished data, The predicted time course of effect was simulated after maxi mally synergistic bolus dose combinations. Results: The parameters of the response surface were identifiable. With the test data, each of the paired combinations showed significant synergy. Com puter simulations based on interactions at the effect site predicted that t he maximally synergistic three-drug combination tripled the duration of eff ect compared with propofol alone. Conclusions: Response surfaces can describe anesthetic interactions, even t hose between agonists, partial agonists, competitive antagonists, and inver se agonists. Application of response-surface methodology permits characteri zation of the full concentration-response relation and therefore can be use d to develop practical guidelines for optimal drug dosing.