Background Sevoflurane may prolong the corrected QT (QTc) interval in healthy humans when administered for induction and maintenance of anesthesia. Little information is available about the dose-response relationship of sevoflurane on the QTc interval. We performed a pharmacodynamic analysis of the relationship between end-tidal sevoflurane concentration (CET) and the QTc. Methods Twenty-one patients aged 20-50 yr were enrolled in this study. Sevoflurane concentrations were progressively increased and then decreased over 15 min at the start of anesthesia; CET and automated QT interval were recorded continuously. Pharmacodynamic analysis using a sigmoid Emax model was performed to assess the concentration-effect relationship. Results Maximal CET was 4.30 ± 0.33%. Measured baseline and maximally prolonged QTc interval values were 351.7 ± 15.4 ms and 397.8 ± 17.5 ms, respectively. During sevoflurane anesthesia, increased concentrations were correlated with prolonged QTc interval. Hysteresis between the CET and QTc interval were observed and accounted for in the model. Ce50 and ke0 were 2.5 ± 1.4 and 2.0 ± 1.0, respectively. The median prediction error, median absolute prediction error, and the coefficient of determination (R) were 0.02%, 0.75%, and 0.95, respectively. The effect-site concentration (Ce50) and QTc interval data fit to a sigmoid Emax model. Conclusions Among patients receiving sevoflurane for anesthesia, QTc interval changes correlate to anesthetic level. The Ce50 for significant QTc change is at clinically relevant levels of sevoflurane anesthesia.

Background The aim of this trial was to evaluate the induction and recovery characteristics of microemulsion propofol (Aquafol; Daewon Pharmaceutical Co., Ltd., Seoul, Korea). Pharmacokinetics, pharmacodynamics, and safety profile were investigated. Lipid emulsion propofol (Diprivan; AstraZeneca, London, United Kingdom) was used as a comparator. Methods Thirty-one healthy volunteers aged 20-79 yr were given an intravenous bolus of propofol 2 mg/kg, followed by variable rate infusion for 60 min. Each volunteer was studied twice with different formulations at an interval of 1 week. Arterial concentrations of propofol were measured, and Bispectral Index was used as a surrogate measure of propofol effect. The induction and recovery characteristics including bioequivalence were evaluated by noncompartmental analysis. The pharmacokinetics and pharmacodynamics were investigated using a population approach with mixed effects modeling. The rate, severity, and causal relation of adverse events were analyzed. Results Both formulations were bioequivalent. The observed time to peak effect after a bolus of both formulations was 1.5 min. Plasma concentration of propofol at loss of consciousness, time to loss of consciousness after a bolus, and time to recovery of consciousness after discontinuation of infusion did not show significant differences. The population pharmacokinetics and pharmacodynamics revealed a variety of differences between two formulations. Aquafol showed similar safety profile to Diprivan. Conclusions The efficacy and safety of Aquafol were not different from those of Diprivan within the dose range in this study.

Background Minto et al. (Anesthesiology 2000) described a mathematical approach based on response surface methods for characterizing drug-drug interactions between several intravenous anesthetic drugs. To extend this effort, the authors developed a flexible interaction model based on the general Hill dose-response relation that includes a set of parameters that can be statistically assessed for interaction significance. Methods This new model was developed to identify pharmacologically meaningful interaction-related parameters and address mathematical limitations in previous models. The flexible interaction model and the model of Minto et al. were compared in their assessment of additivity using simulated sample data sets. The flexible interaction model was also compared with the Minto model in describing drug interactions using data from several other clinical studies of propofol, opioids, and benzodiazepines from Short et al. (Anesthesiology 2002) and Kern et al. (Anesthesiology 2004). Results The flexible interaction model was able to accurately classify an additive interaction based on the classic definition proposed by Loewe, with at most an 8% difference between the two surfaces. Also, the proposed model fit the clinical interaction data as well or slightly better than that of Minto et al. Conclusions The new model can accurately classify additive and synergistic drug interactions. It also can classify antagonistic interactions with biologically rational surfaces. This has been a problem for other interaction models in the past. The statistically assessable interaction parameters provide a quantitative manner to assess the interaction significance.

Background The aim of this study was to investigate the independent effect of remifentanil on the approximate entropy (ApEn) in frontoparietal montages. The authors investigated which montages were relevant to assess the remifentanil effect on the electroencephalogram. Spectral edge frequency and the canonical univariate parameter were used as comparators. Methods Twenty-eight healthy volunteers were enrolled. With recording of the electroencephalogram at the F3, F4, Cz, P3, and P4 montages, remifentanil was infused at the rate of 1-8 mug . kg . min for 15-20 min. The relation between remifentanil concentration and the electroencephalographic parameters were tested by Spearman correlation. Signal-to-noise ratio, artifact robustness, coefficient of variation of the median baseline and maximal electroencephalographic effects, and ratio of average maximal electroencephalographic effect to interindividual baseline variability were measured. The performance of ApEn as an index of remifentanil effect site concentrations was tested by prediction probability. Results Approximate entropy showed significant correlation (R = -0.6465, P < 0.0001) with remifentanil concentration. It provided comparable signal-to-noise ratio, artifact robustness, and ratio of average maximal electroencephalographic effect to interindividual baseline variability to 95% spectral edge frequency. The coefficients of variation of the median baseline and maximal electroencephalo graphic effects were smallest in ApEn. Parietal montages showed higher ratios of average maximal electroencephalographic effect to interindividual baseline variability for all electroencephalographic parameters and lower coefficients of variation of the baseline values for ApEn and 95% spectral edge frequency than frontal montages. The prediction probability of ApEn was 0.7730. Conclusions Approximate entropy derived from a parietal montage is appropriate for the assessment of the remifentanil effect on the electroencephalogram.

Background Previous work has demonstrated that ongoing hemorrhagic shock dramatically alters the distribution, clearance, and potency of propofol. Whether volume resuscitation after hemorrhagic shock restores drug behavior to baseline pharmacokinetics and pharmacodynamics remains unclear. This is particularly relevant because patients suffering from hemorrhagic shock are typically resuscitated before surgery. To investigate this, the authors studied the influence of an isobaric bleed followed by crystalloid resuscitation on the pharmacokinetics and pharmacodynamics of propofol in a swine model. The hypothesis was that hemorrhagic shock followed by resuscitation would not significantly alter the pharmacokinetics but would influence the pharmacodynamics of propofol. Methods After approval from the Animal Care Committee, 16 swine were randomly assigned to control and shock-resuscitation groups. Swine randomized to the shock-resuscitation group were bled to a mean arterial blood pressure of 40 mm Hg over a 20-min period and held there by further blood removal until 42 ml/kg of blood had been removed. Subsequently, animals were resuscitated with lactated Ringer's solution to maintain a mean arterial blood pressure of 70 mm Hg for 60 min. After resuscitation, propofol (750 microg x kg(-1) x min(-1)) was infused for 10 min. The control group underwent a sham hemorrhage and resuscitation and received propofol at the same dose and approximate time as the shock-resuscitation group. Arterial samples (20 from each animal) were collected at frequent intervals until 180 min after the infusion began and were analyzed to determine drug concentrations. 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. Pharmacodynamics were characterized using a sigmoid inhibitory maximal effect model. Results The raw data demonstrated minimal differences in the mean plasma propofol concentrations between groups. The compartment analysis revealed some subtle differences between groups in the central and slow equilibrating volumes, but the differences were not significant. Hemorrhagic shock followed by resuscitation shifted the concentration effect relationship to the left, demonstrating a 1.5-fold decrease in the effect-site concentration required to achieve 50% of the maximal effect in the Bispectral Index Scale. Conclusions Hemorrhagic shock followed by resuscitation with lactated Ringer's solution did not alter the pharmacokinetics but did increase the potency of propofol. These results demonstrate that alterations in propofol pharmacokinetics observed in moderate to severe blood loss can be reversed with resuscitation. These results suggest that a modest reduction in propofol is prudent to achieve a desired drug effect after resuscitation from severe hemorrhagic shock.

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.

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.

Background Hemorrhagic shock is known to alter significantly the pharmacokinetics of fentanyl, an opioid that requires delivery to the liver for metabolism. The authors hypothesized that the pharmacokinetics and pharmacodynamics of remifentanil, an esterase metabolized opioid that does not require delivery to a metabolic organ, would be altered less by hemorrhagic shock that those of fentanyl. Methods Sixteen pigs were assigned randomly to control and shock groups. The shock group was bled using an isobaric hemorrhage model. Remifentanil 10 microg x kg(-1) x min(-1) was infused for 10 min to both groups. Arterial samples were collected for remifentanil concentration assay. Pharmacokinetic parameters were estimated using a three-compartment model. The electroencephalogram spectral edge was used as a measure of drug effect. The pharmacodynamics were characterized using a sigmoid inhibitory maximal effect model. Results Remifentanil blood levels were higher in the shocked group. The central clearance was slower and the central compartment was smaller in shocked animals. No difference between groups was observed in the magnitude or time course of the remifentanil-induced decrease in spectral edge. Conclusions Hemorrhagic shock altered the pharmacokinetics of remifentanil, suggesting that less remifentanil would be required to maintain a target plasma concentration. However, because of its rapid metabolism, the impact of hemorrhagic shock on the concentration decline of remifentanil after termination of the infusion was minimal. Hemorrhagic shock did not alter the pharmacodynamics of remifentanil.