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.

Flow-through versus sidestream capnometry for detection of end tidal carbon dioxide in the sedated patient.

BACKGROUND: End tidal carbon dioxide (ETCO(2)) in non-intubated patients can be monitored using either sidestream or flow-through capnometry [Yamamori et al., J Clin Monit Comput 22(3):209-220, 2008]. The hypothesis of this validation study is that, flow-through capnometry will yield a more accurate estimate of ETCO(2) than sidestream capnometry when evaluated in a bench study during low tidal volumes and high oxygen administration via nasal cannula. Secondarily, when ETCO(2) from each is compared to arterial CO(2) (PaCO(2)) during a study in which healthy, non-intubated volunteers are tested under normocapnic, hypocapnic and hypercapnic conditions, the flow-through capnometer will resemble PaCO(2) more closely than the sidestream capnometer. This will be especially true during periods of lower minute ventilation and high oxygen flow rates via mask in non-intubated, remifentanil sedated, healthy volunteers whose physiologic deadspace is small. METHODS: The performance of a flow-through (cap-ONE, Nihon Kohden, Tokyo, Japan) and a sidestream (Microcap Smart CapnoLine Plus, Oridion Inc., Needham, MA) capnometer were compared in a bench study and a volunteer trial. A bench study evaluated ETCO(2) accuracy using waveforms generated via mechanical lungs during low tidal volumes and high oxygen flow rates. A volunteer study compared the ETCO(2) for each capnometer against PaCO(2) during sedation in which 8 l O(2) was delivered via mask rather than the nasal cannula. RESULTS: In the bench study, the flow-through capnometer gave slightly higher values of ETCO(2) during high-flow oxygen and no discernable differences during variable tidal volumes. Bland and Altman plots comparing ETCO(2) to PaCO(2) showed essentially equal performance between the two capnometers in the volunteers. CONCLUSIONS: Within a wide limit of agreement between the volunteer and bench study, flow-through and sidestream capnometry performed equally well during bench testing and in non-intubated, sedated patients.

Part Task and variable priority training in first-year anesthesia resident education: a combined didactic and simulation-based approach to improve management of adverse airway and respiratory events.

BACKGROUND: Part task training (PTT) focuses on dividing complex tasks into components followed by intensive concentrated training on individual components. Variable priority training (VPT) focuses on optimal distribution of attention when performing multiple tasks simultaneously with the goal of flexible allocation of attention. This study explored how principles of PTT and VPT adapted to anesthesia training would improve first-year anesthesiology residents' management of simulated adverse airway and respiratory events. The authors hypothesized that participants with PTT and VPT would perform better than those with standard training. METHODS: Twenty-two first-year anesthesia residents were randomly divided into two groups and trained over 12 months. The control group received standard didactic and simulation-based training. The experimental group received similar training but with emphasis on PTT and VPT techniques. Participant ability to manage seven adverse airway and respiratory events were assessed before and after the training period. Performance was measured by the number of correct tasks, making a correct diagnosis, assessment of perceived workload, and an assessment of scenario comprehension. RESULTS: Participants in both groups exhibited significant improvement in all metrics after a year of training. Participants in the experimental group were able to complete more tasks and answered more comprehension questions correctly. There was no difference in perceived workload or the number of correct diagnoses between groups. CONCLUSION: This study in part confirmed the study hypotheses. The results suggest that VPT and PTT are promising adjuncts to didactic and simulation-based training for management of adverse airway and respiratory events.

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.

Rapid recovery from sevoflurane and desflurane with hypercapnia and hyperventilation.

BACKGROUND: Hypercapnia with hyperventilation shortens the time between turning off the vaporizer (1 MAC) and when patients open their eyes after isoflurane anesthesia by 62%. METHODS: In the present study we tested whether a proportional shortening occurs with sevoflurane and desflurane. RESULTS: Consistent with a proportional shortening, we found that hypercapnia with hyperventilation decreased recovery times by 52% for sevoflurane and 64% for desflurane (when compared with normal ventilation with normocapnia). CONCLUSION: Concurrent hyperventilation to rapidly remove the anesthetic from the lungs and rebreathing to induce hypercapnia can significantly shorten recovery times and produce the same proportionate decrease for anesthetics that differ in solubility.

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.

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.

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 Observer's 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 (Observer's Assessment of Alertness/Sedation score > or = 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.

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.

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 microg. 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.

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

UNLABELLED: 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 micro g x kg(-1) x 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. IMPLICATIONS: Hemorrhagic shock produced minimal changes in the pharmacokinetics and no change in the pharmacodynamics of etomidate in swine. These results suggest that, unlike other sedative hypnotics and opioids, minimal adjustment in the dose of etomidate is required to achieve the same drug effect during hemorrhagic shock.