A simulation study of common propofol and propofol-opioid dosing regimens for upper endoscopy: implications on the time course of recovery.

BACKGROUND: Using models of respiratory compromise, loss of response to esophageal instrumentation, and loss of responsiveness, the authors explored through simulation published dosing schemes for endoscopy using propofol alone and in combination with selected opioids. They hypothesized that models would predict adequate conditions for esophageal instrumentation and once drug administration is terminated, rapid return of responsiveness and minimal respiratory compromise. METHODS: Four published dosing regimens of propofol alone or in combination with opioids were used to predict the probability of loss of response to esophageal instrumentation for a 10-min procedure and the probability of respiratory compromise and return of responsiveness once the procedure had ended. RESULTS: Propofol alone provided a low probability (9-20%) and propofol-opioid techniques provided a moderate probability (15-58%) of loss of response to esophageal instrumentation. Once the procedure ended, all techniques provided a high likelihood of rapid return of responsiveness (less than 3 min). Propofol-opioid techniques required more time than propofol alone to achieve a high probability of no respiratory compromise (7 vs. 4 min). CONCLUSIONS: Propofol alone would likely lead to inadequate conditions for esophageal instrumentation but would provide a rapid return to responsiveness and low probability of respiratory compromise once the procedure ended. The addition of remifentanil or fentanyl improved conditions for esophageal instrumentation and had an equally rapid return to responsiveness. The time required to achieve a low probability of respiratory compromise was briefly prolonged; this is likely inconsequential given that patients are responsive and can be prompted to breathe.

An exploration of remifentanil-propofol combinations that lead to a loss of response to esophageal instrumentation, a loss of responsiveness, and/or onset of intolerable ventilatory depression.

BACKGROUND: Remifentanil and propofol are increasingly used for short-duration procedures in spontaneously breathing patients. In this setting, it is preferable to block the response to moderate stimuli while avoiding loss of responsiveness (LOR) and intolerable ventilatory depression (IVD). In this study, we explored selected effects of combinations of remifentanil-propofol effect-site concentrations (Ces) that lead to a loss of response to esophageal instrumentation (EI), LOR, and/or onset of IVD. A secondary aim was to use these observations to create response surface models for each effect measure. We hypothesized that (1) in a large percentage of volunteers, selected remifentanil and propofol Ces would allow EI but avoid LOR and IVD, and (2) the drug interaction for these effects would be synergistic. METHODS: Twenty-four volunteers received escalating target-controlled remifentanil and propofol infusions over ranges of 0 to 6.4 ng · mL(-1) and 0 to 4.3 µg · mL(-1), respectively. At each set of target concentrations, responses to insertion of a blunt end bougie into the midesophagus (40 cm), level of responsiveness, and respiratory rate were recorded. From these data, response surface models of loss of response to EI and IVD were built and characterized as synergistic, additive, or antagonistic. A previously published model of LOR was used. RESULTS: Of the possible 384 assessments, volunteers were unresponsive to EI at 105 predicted remifentanil-propofol Ces; in 30 of these, volunteers had no IVD; in 30, volunteers had no LOR; and in 9, volunteers had no IVD or LOR. Many other assessments over the same concentration ranges, however, did have LOR and/or IVD. The combinations that allowed EI and avoided IVD and/or LOR primarily clustered around remifentanil-propofol Ces ranging from 0.8 to 1.6 ng · mL(-1) and 1.5 to 2.7 µg · mL(-1), respectively, and to a lesser extent approximately 3.0 to 4.0 ng · mL(-1) and 0.0 to 1.1 µg · mL(-1), respectively. Models of loss of response to EI and IVD both demonstrated a synergistic interaction between remifentanil and propofol. CONCLUSION: Selected remifentanil-propofol concentration pairs, especially higher propofol-lower remifentanil concentration pairs, can block the response to EI while avoiding IVD in spontaneously breathing volunteers. It is, however, difficult to block the response to EI and avoid both LOR and IVD. It may be necessary to accept some discomfort and blunt rather than block the response to EI to consistently avoid LOR and IVD.

An evaluation of remifentanil-sevoflurane response surface models in patients emerging from anesthesia: model improvement using effect-site sevoflurane concentrations.

INTRODUCTION: We previously reported models that characterized the synergistic interaction between remifentanil and sevoflurane in blunting responses to verbal and painful stimuli. This preliminary study evaluated the ability of these models to predict a return of responsiveness during emergence from anesthesia and a response to tibial pressure when patients required analgesics in the recovery room. We hypothesized that model predictions would be consistent with observed responses. We also hypothesized that under non-steady-state conditions, accounting for the lag time between sevoflurane effect-site concentration (Ce) and end-tidal (ET) concentration would improve predictions. METHODS: Twenty patients received a sevoflurane, remifentanil, and fentanyl anesthetic. Two model predictions of responsiveness were recorded at emergence: an ET-based and a Ce-based prediction. Similarly, 2 predictions of a response to noxious stimuli were recorded when patients first required analgesics in the recovery room. Model predictions were compared with observations with graphical and temporal analyses. RESULTS: While patients were anesthetized, model predictions indicated a high likelihood that patients would be unresponsive (> or = 99%). However, after termination of the anesthetic, models exhibited a wide range of predictions at emergence (1%-97%). Although wide, the Ce-based predictions of responsiveness were better distributed over a percentage ranking of observations than the ET-based predictions. For the ET-based model, 45% of the patients awoke within 2 min of the 50% model predicted probability of unresponsiveness and 65% awoke within 4 min. For the Ce-based model, 45% of the patients awoke within 1 min of the 50% model predicted probability of unresponsiveness and 85% awoke within 3.2 min. Predictions of a response to a painful stimulus in the recovery room were similar for the Ce- and ET-based models. DISCUSSION: Results confirmed, in part, our study hypothesis; accounting for the lag time between Ce and ET sevoflurane concentrations improved model predictions of responsiveness but had no effect on predicting a response to a noxious stimulus in the recovery room. These models may be useful in predicting events of clinical interest but large-scale evaluations with numerous patients are needed to better characterize model performance.