Julia L. White

A Response Surface Analysis of Propofol–Remifentanil Pharmacodynamic Interaction in Volunteers

Background: Characterizing drug interactions using a response surface allows for the determination of the interaction over a complete range of clinically relevant concentrations. Gathering the data necessary to create this surface is difficult to do in a clinical setting and requires the use of volunteer experiments with surrogate noxious stimuli to adequately control the process for data collection. The pharmacodynamic synergy of opioids and hypnotics was investigated using a volunteer study paradigm. Methods: Twenty-four volunteer subjects (12 male, 12 female) were studied using computer-controlled infusions of propofol and remifentanil to create an increasing staircase drug concentration profile in each subject. Three different drug delivery profiles were administered to subjects, one with a single agent and two with combinations of propofol and remifentanil. At each plateau of the staircase profile, drug effect was assessed using four surrogate measures: Observer Assessment of Alertness/Sedation score, tibial pressure algometry, electrical tetany, and response to laryngoscopy. Response surfaces were developed that mapped the interaction of propofol and remifentanil to these surrogate effect measures in all subjects. An interaction parameter was used to assess whether these two drugs behave synergistically to blunt response to noxious stimuli. Results: The response surfaces showed considerable synergy between remifentanil and propofol for blunting response to the noxious stimuli. The interaction index, a measure of synergy, was 8.2 and 14.7 for response to algometry and tetany, respectively (P < 0.001), and 5.1 and 33.2 for sedation and laryngoscopy, respectively (P < 0.001), using the Greco interaction model. The surrogate stimuli mapped to clinically relevant concentrations for these agents in combination. Conclusions: The response surface models reveal the tremendous synergy between remifentanil and propofol. The surface morphologic features give some indication of the relative contribution of sedation and analgesia to blunting subject response. Further, the results of this investigation validate the volunteer study paradigm and use of surrogate effect measures for its clinical relevance.

Effects of intrathecal morphine on the ventilatory response to hypoxia.

BACKGROUND Intrathecal administration of morphine produces intense analgesia, but it depresses respiration, an effect that can be life-threatening. Whether intrathecal morphine affects the ventilatory response to hypoxia, however, is not known. METHODS We randomly assigned 30 men to receive one of three study treatments in a double-blind fashion: intravenous morphine (0.14 mg per kilogram of body weight) with intrathecal placebo; intrathecal morphine (0.3 mg) with intravenous placebo; or intravenous and intrathecal placebo. The selected doses of intravenous and intrathecal morphine produce similar degrees of analgesia. The ventilatory response to hypercapnia, the subsequent response to acute hypoxia during hypercapnic breathing (targeted end-tidal partial pressures of expired oxygen and carbon dioxide, 45 mm Hg), and the plasma levels of morphine and morphine metabolites were measured at base line (before drug administration) and 1, 2, 4, 6, 8, 10, and 12 hours after drug administration. RESULTS At base line, the mean (+/-SD) values for the ventilatory response to hypoxia (calculated as the difference between the minute ventilation during the second full minute of hypoxia and the fifth minute of hypercapnic ventilation) were similar in the three groups: 38.3+/-23.2 liters per minute in the placebo group, 33.5+/-16.4 liters per minute in the intravenous-morphine group, and 30.2+/-11.6 liters per minute in the intrathecal-morphine group (P=0.61). The overall ventilatory response to hypoxia (the area under the curve) was significantly lower after either intravenous morphine (20.2+/-10.8 liters per minute) or intrathecal morphine (14.5+/-6.4 liters per minute) than after placebo (36.8+/-19.2 liters per minute) (P=O.003). Twelve hours after treatment, the ventilatory response to hypoxia in the intrathecal-morphine group (19.9+/-8.9 liters per minute), but not in the intravenous-morphine group (30+/-15.8 liters per minute), remained significantly depressed as compared with the response in the placebo group (40.9+/-19.0 liters per minute) (P= 0.02 for intrathecal morphine vs. placebo). Plasma concentrations of morphine and morphine metabolites either were not detectable after intrathecal morphine or were much lower after intrathecal morphine than after intravenous morphine. CONCLUSIONS Depression of the ventilatory response to hypoxia after the administration of intrathecal morphine is similar in magnitude to, but longer-lasting than, that after the administration of an equianalgesic dose of intravenous morphine.

Opioid-volatile anesthetic synergy : A response surface model with remifentanil and sevoflurane as prototypes

Background:Combining a hypnotic and an analgesic to produce sedation, analgesia, and surgical immobility required for clinical anesthesia is more common than administration of a volatile anesthetic alone. The aim of this study was to apply response surface methods to characterize the interactions between remifentanil and sevoflurane. Methods:Sixteen adult volunteers received a target-controlled infusion of remifentanil (0–15 ng/ml) and inhaled sevoflurane (0–6 vol%) at various target concentration pairs. After reaching pseudo–steady state drug levels, the Observers Assessment of Alertness/Sedation score and response to a series of randomly applied experimental pain stimuli (pressure algometry, electrical tetany, and thermal stimulation) were observed for each target concentration pair. Response surface pharmacodynamic interaction models were built using the pooled data for sedation and analgesic endpoints. Using computer simulation, the pharmacodynamic interaction models were combined with previously reported pharmacokinetic models to identify the combination of remifentanil and sevoflurane that yielded the fastest recovery (Observers Assessment of Alertness/Sedation score ≥ 4) for anesthetics lasting 30–900 min. Results:Remifentanil synergistically decreased the amount of sevoflurane necessary to produce sedation and analgesia. Simulations revealed that as the duration of the procedure increased, faster recovery was produced by concentration target pairs containing higher amounts of remifentanil. This trend plateaued at a combination of 0.75 vol% sevoflurane and 6.2 ng/ml remifentanil. Conclusion:Response surface analyses demonstrate a synergistic interaction between remifentanil and sevoflurane for sedation and all analgesic endpoints.

The influence of hemorrhagic shock on propofol: a pharmacokinetic and pharmacodynamic analysis.

Background Propofol is a common sedative hypnotic for the induction and maintenance of anesthesia. Clinicians typically moderate the dose of propofol or choose a different sedative hypnotic in the setting of severe intravascular volume depletion. Previous work has established that hemorrhagic shock influences both the pharmacokinetics and pharmacodynamics of propofol in the rat. To investigate this further, the authors studied the influence of hemorrhagic shock on the pharmacology of propofol in a swine isobaric hemorrhage model. Methods After approval from the Animal Care Committee, 16 swine were randomly assigned to control and shock groups. The shock group was bled to a mean arterial blood pressure of 50 mmHg over a 20-min period and held there by further blood removal until 30 ml/kg of blood was removed. Propofol 200 &mgr;g · kg−1 · min−1 was infused for 10 min to both groups. Arterial samples (15 from each animal) were collected at frequent intervals until 180 min after the infusion began and analyzed to determine drug concentration. Pharmacokinetic parameters for each group were estimated using a three-compartment model. The electroencephalogram Bispectral Index Scale was used as a measure of drug effect. The pharmacodynamics were characterized using a sigmoid inhibitory maximal effect model. Results The raw data demonstrated higher plasma propofol levels in the shock group. The pharmacokinetic analysis revealed slower intercompartmental clearances in the shock group. Hemorrhagic shock shifted the concentration effect relationship to the left, demonstrating a 2.7-fold decrease in the effect site concentration required to achieve 50% of the maximal effect in the Bispectral Index Scale. Conclusions Hemorrhagic shock altered the pharmacokinetics and pharmacodynamics of propofol. Changes in intercompartmental clearances and an increase in the potency of propofol suggest that less propofol would be required to achieve a desired drug effect during hemorrhagic shock.

When is a bispectral index of 60 too low?: Rational processed electroencephalographic targets are dependent on the sedative-opioid ratio.

Background: Opioids are commonly used in conjunction with sedative drugs to provide anesthesia. Previous studies have shown that opioids reduce the clinical requirements of sedatives needed to provide adequate anesthesia. Processed electroencephalographic parameters, such as the Bispectral Index (BIS; Aspect Medical Systems, Newton, MA) and Auditory Evoked Potential Index (AAI; Alaris Medical Systems, San Diego, CA), can be used intraoperatively to assess the depth of sedation. The aim of this study was to characterize how the addition of opioids sufficient to change the clinical level of sedation influenced the BIS and AAI. Methods: Twenty-four adult volunteers received a target-controlled infusion of remifentanil (0–15 ng/ml) and inhaled sevoflurane (0–6 vol%) at various target concentration pairs. After reaching pseudo–steady state drug levels, the modified Observer’s Assessment of Alertness/Sedation score, BIS, and AAI were measured at each target concentration pair. Response surface pharmacodynamic interaction models were built using the pooled data for each pharmacodynamic endpoint. Results: Response surface models adequately characterized all pharmacodynamic endpoints. Despite the fact that sevoflurane–remifentanil interactions were strongly synergistic for clinical sedation, BIS and AAI were minimally affected by the addition of remifentanil to sevoflurane anesthetics. Conclusion: Although clinical sedation increases significantly even with the addition of a small to moderate dose of remifentanil to a sevoflurane anesthetic, the BIS and AAI are insensitive to this change in clinical state. Therefore, during “opioid-heavy” sevoflurane–remifentanil anesthetics, targeting a BIS less than 60 or an AAI less than 30 may result in an unnecessarily deep anesthetic state.

An evaluation of remifentanil propofol response surfaces for loss of responsiveness, loss of response to surrogates of painful stimuli and laryngoscopy in patients undergoing elective surgery.

INTRODUCTION:In this study, we explored how a set of remifentanil-propofol response surface interaction models developed from data collected in volunteers would predict responses to events in patients undergoing elective surgery. Our hypotheses were that these models would predict a patient population’s loss and return of responsiveness and the presence or absence of a response to laryngoscopy and the response to pain after surgery. METHODS:Twenty-one patients were enrolled. Anesthesia consisted of remifentanil and propofol infusions and fentanyl boluses. Loss and return of responsiveness, responses to laryngoscopy, and responses to postoperative pain were assessed in each patient. Model predictions were compared with observed responses. RESULTS:The loss of responsiveness model predicted that patients would become unresponsive 2.4 ± 2.6 min earlier than observed. At the time of laryngoscopy, the laryngoscopy model predicted an 89% probability of no response to laryngoscopy and 81% did not respond. During emergence, the loss of responsiveness model predicted return of responsiveness 0.6 ± 5.1 min before responsiveness was observed. The mean probability of no response to pressure algometry was 23% ± 35% when patients required fentanyl for pain control. DISCUSSION:This preliminary assessment of a series of remifentanil-propofol interaction models demonstrated that these models predicted responses to selected pertinent events during elective surgery. However, significant model error was evident during rapid changes in predicted effect-site propofol-remifentanil concentration pairs.

The Influence of Hemorrhagic Shock on Etomidate: A Pharmacokinetic and Pharmacodynamic Analysis

We studied the influence of hemorrhagic shock on the pharmacology of etomidate in swine. Sixteen swine were randomly assigned to control and shock groups. The shock group was bled to a mean arterial blood pressure of 50 mm Hg and held there until 30 mL/kg blood was removed. Etomidate 300 &mgr;g · kg−1 · min−1 was infused for 10 min to both groups. Fifteen arterial samples were collected until 180 min after the infusion began to determine drug concentration. Pharmacokinetic variables for each group were estimated by using a three-compartment model. The bispectral index scale was used as a measure of drug effect. The pharmacodynamics were characterized by using a sigmoid inhibitory maximal effect model. The raw data revealed a 25% increase in the plasma etomidate concentration at the end of the 10-min infusion which resolved after termination of the infusion in the shock group. The pharmacokinetic analysis revealed subtle changes in the variable estimates between groups. The etomidate infusion produced a similar Bispectral Index Scale change in both groups. These results demonstrated that, unlike the influence of hemorrhagic shock on other sedative hypnotics and opioids, moderate hemorrhagic shock produced minimal changes in the pharmacokinetics and no change in the pharmacodynamics of etomidate.

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 &mgr;g · 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 &mgr;g · mL−1, respectively, and to a lesser extent approximately 3.0 to 4.0 ng · mL−1 and 0.0 to 1.1 &mgr;g · 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 (≥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.

Hypercapnic hyperventilation shortens emergence time from isoflurane anesthesia

BACKGROUND:To shorten emergence time after a procedure using volatile anesthesia, 78% of anesthesiologists recently surveyed used hyperventilation to rapidly clear the anesthetic from the lungs. Hyperventilation has not been universally adapted into clinical practice because it also decreases the Paco2, which decreases cerebral bloodflow and depresses respiratory drive. Adding deadspace to the patient’s airway may be a simple and safe method of maintaining a normal or slightly increased Paco2 during hyperventilation. METHODS:We evaluated the differences in emergence time in 20 surgical patients undergoing 1 MAC of isoflurane under mild hypocapnia (ETco2 approximately 28 mmHg) and mild hypercapnia (ETco2 approximately 55 mmHg). The minute ventilation in half the patients was doubled during emergence, and hypercapnia was maintained by insertion of additional airway deadspace to keep the ETco2 close to 55 mmHg during hyperventilation. A charcoal canister adsorbed the volatile anesthetic from the deadspace. Fresh gas flows were increased to 10 L/min during emergence in all patients. RESULTS:The time between turning off the vaporizer and the time when the patients opened their eyes and mouths, the time of tracheal extubation, and the time for normalized bispectral index to increase to 0.95 were faster whenever hypercapnic hyperventilation was maintained using rebreathing and anesthetic adsorption (P < 0.001). The time to tracheal extubation was shortened by an average of 59%. CONCLUSIONS:The emergence time after isoflurane anesthesia can be shortened significantly by using hyperventilation to rapidly clear the anesthetic from the lungs and CO2 rebreathing to induce hypercapnia during hyperventilation. The device should be considered when it is important to provide a rapid emergence, especially after surgical procedures where a high concentration of the volatile anesthetic was maintained right up to the end of the procedure, or where surgery ends abruptly and without warning.