Response Surface Modeling of Remifentanil-Propofol Interaction on Cardiorespiratory Control and Bispectral

Background: Since propofol and remifentanil are frequently combined for monitored anesthesia care, we examined the influ- ence of the separate and combined administration of these agents on cardiorespiratory control and bispectral index in humans. Methods: The effect of steady-state concentrations of remifen- tanil and propofol was assessed in 22 healthy male volunteer subjects. For each subject, measurements were obtained from experiments using remifentanil alone, propofol alone, and remifentanil plus propofol (measured arterial blood concentra- tion range: propofol studies, 0 -2.6 g/ml; remifentanil studies, 0 -2.0 ng/ml). Respiratory experiments consisted of ventilatory responses to three to eight increases in end-tidal PCO2 (PETCO2). Invasive blood pressure, heart rate, and bispectral index were monitored concurrently. The nature of interaction was assessed by response surface modeling using a population approach with NONMEM. Values are population estimate plus or minus standard error. Results: A total of 94 responses were obtained at various drug combinations. When given separately, remifentanil and propo- fol depressed cardiorespiratory variables in a dose-dependent fashion (resting Vi: 12.6 3.3% and 27.7 3.5% depression at 1 g/ml propofol and 1 ng/ml remifentanil, respectively; Vi at fixed PETCO2 of 55 mmHg: 44.3 3.9% and 57.7 3.5% depres- sion at 1 g/ml propofol and 1 ng/ml remifentanil, respec- tively; blood pressure: 9.9 1.8% and 3.7 1.1% depression at 1 g/ml propofol and 1 ng/ml remifentanil, respectively). When given in combination, their effect on respiration was synergistic (greatest synergy observed for resting Vi). The ef- fects of both drugs on heart rate and blood pressure were modest, with additive interactions when combined. Over the dose range studied, remifentanil had no effect on bispectral index even when combined with propofol (inert interaction). Conclusions: These data show dose-dependent effects on respi- ration at relatively low concentrations of propofol and remifen- tanil. When combined, their effect on respiration is strikingly synergistic, resulting in severe respiratory depression. THE COMBINED administration of opioids and anesthetics for induction and maintenance of anesthesia is common practice. The anesthetic is given to lose consciousness, prevent awareness, and reduce movement responses in the patient; the opioid is given to suppress somatic, stress, and adrenergic responses to surgical stimulation. An important advantage of combining an opioid and an anesthetic is the synergistic increase in these desired effects, with conse- quently the need for less drugs to attain the goal of ade- quate anesthesia relative to the amount of drug needed when only a single agent (i.e., an anesthetic) is given. 1 Since this is not only true for patients who are ventilated but also for patients who maintain their own breathing (for example, during minimal, moderate, and deep sedation), it is of interest to address the issue of the effect of drug combinations on respiration. While it is known that anes- thesia induces many side effects, it is acknowledged that respiratory depression is potentially life-threatening. 2 Therefore, we studied the effect of the opioid remifentanil and intravenous anesthetic propofol on the cardiorespira- tory control. This combination of drugs is frequently used in patients receiving monitored anesthesia care for minor (without additional regional anesthesia) and major (with additional regional anesthesia) surgery. Knowledge on the quantitative and qualitative (additive vs. synergistic) nature of their interaction is clinically important and may lead to specific dosing regimens aimed at the titration of sedation/ analgesia versus respiratory effect. To study the remifentanil-propofol interaction, we used the technique of response surface modeling. 3-7 This technique allows the observation of the concentra- tion-effect relation among infinite combinations of remifentanil and propofol over the whole surface area in three-dimensional space. We previously made successful use of this technique to quantify the interactive effects of sevoflurane and alfentanil on cardiorespiratory control. 6