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A689
October 19, 2008 2:00 PM - 4:00 PM Room Hall E2-Area M, |
| Rationale Volatile Anesthetic Opioid Selection Based on Pharmacokinetic-Pharmacodynamic Optimization |
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Dhanesh K. Gupta, M.D., Sandeep C. Manyam, Ph.D., Kenward B. Johnson, M.D., Dwyane R. Westenskow, Ph.D., Talmage D. Egan, M.D. Anesthesiology & Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois |
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INTRODUCTION: Although a wide variety of volatile anesthetic-opioid concentration pairs can produce adequate anesthesia, only a small subset of these combinations take advantage of the pharmacokinetics of the drugs to produce a quick recovery. We previously identified the combinations of sevoflurane and remifentanil that produce adequate anesthesia and result in the shortest time to awakening. Here we extend this technique to determine the optimum target concentration pairs of sevoflurane, desflurane, or isoflurane with remifentanil or fentanyl. METHODS: Response surface models describing the interaction between sevoflurane-remifentanil in preventing hemodynamic response to tetanic stimulation and in producing clinical sedation (modified Observer's Assessment of Alertness/Sedation scale) based on volunteer data were previously reported. These response surfaces were scaled to describe other volatile anesthetic-opioid interactions by using a fentanyl-remifentanil potency ratio of 2.4:1 and MAC ratios of sevoflurane:desflurane:isoflurane of 2:6:1.2. Published pharmacokinetic models were used to simulate dosing regimens that would maintain a constant effect site opioid concentrations and a constant alveolar end-tidal concentration of volatile anesthetic throughout the duration of the simulated anesthetic. A search algorithm that identified the concentration pairs that produced adequate anesthesia (95% probability of no response hemodynamic response to tetanic stimulation and OAA/S ≤ 1) and also produced the fastest recovery (OAA/S ≥ 4) was employed. These simulations were performed for anesthetics lasting 0.5—15 hours. RESULTS: The target concentration pairs that provided a 95% probability of no movement and no hemodynamic response to titanic stimulation and an OAA/S < 1 while producing the quickest return to an OAA/S > 4 are shown on the graph. (Multiple I or S = concentration changes with time).[figure1]DISCUSSION: With these generalized response surface models and pharmacokinetic-pharmacodynamic simulations, the optimum concentration pairs of a variety of volatile anesthetic and opioids can be determined. With the pharmacokinetic advantage of remifentanil, anesthetic combinations tended to have a high opioid-volatile anesthetic ratio, approaching the value of MAC-AWAKE for the very soluble volatile anesthetic, isoflurane. In contrast, with the longer context sensitive decrement-times of fentanyl, the anesthetic combinations tended to have a higher volatile anesthetic component. In general, the simulations show that the optimal target concentration pairs were biased toward the pharmacokinetically shorter acting drug. For short anesthetics this is not as evident as there is little accumulation of the drug. However, with increasing duration, there was a large bias toward the drugs with a shorter context sensitive decrement time. Therefore, rational choice of the anesthetics should take into account the complex interplay between pharmacodynamic interactions of the volatile anesthetics and opioids and pharmacokinetics of each of the drugs. Anesthesiology 2008; 109 A689 |
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