Anesthésie et recherche clinique
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Prediction Variability of Combined Pharmacokinetic Pharmacodynamic Models: A Simulation Study of Propofol in Combination with Remifentanil and Fentanyl

Carl Tams and Ken Johnson

Introduction: The aims of this study were to estimate model prediction variability for drug concentrations and effects during a simulated propofol-remifentanil-fentanyl anesthetic and identify the change in propofol infusion rates or fentanyl bolus doses necessary to detect changes in the duration of selected drug effects. We hypothesized that drug effect variability is large when drug concentrations are within the dynamic range of concentration effect curves (i.e. during emergence from anesthesia), but when drug concentrations are above or below the dynamic range variability is small.

Methods: 1000 parameter sets were randomly generated from published pharmacokinetic model parameters and their metrics of variability and published pharmacodynamic remifentanil-propofol interaction model parameters and their metrics of variability for loss of response to laryngoscopy, loss of responsiveness, analgesia, and intolerable ventilatory depression. 1000 simulated patients were administered 90-minute combined remifentanil (0.20 mcg/kg/ min) and propofol (100 mcg/kg/min) infusions, and two fentanyl boluses at 0 and 75 minutes of 2 mcg/kg.

Results: The drug effect site concentration variability was larger for remifentanil than for propofol. The drug effect variability was minimal during the anesthetic but large during emergence. Moderate changes in infusion rates and bolus sizes caused minimal changes in the duration of drug effect following termination of the anesthetic.

Conclusion: Simulations in part confirmed our hypotheses; during the anesthetic, despite considerable concentration variability, drug effect variability is small at points of clinical interest. The combined low dose propofol and high dose remifentanil infusions provide a high probability of unresponsiveness and analgesia throughout the anesthetic. During emergence, however, drug effect variability is large and substantial dose changes are required to detect a difference in duration of selected effects.