Pharmacokinetic parameter sets of alfentanil revisited: optimal parameters for use in target controlled infusion and anaesthesia display systems.

BACKGROUND: In open TCI and anaesthesia display systems, the choice of pharmacokinetic (PK) parameter sets of opioids is clinically relevant. Accuracy and bias of the PK models may be affected by administration mode and the co-administered hypnotic drug. We retrospectively evaluated the performance of eight PK parameter sets for alfentanil in two data sets (infusion and bolus application). METHODS: With the dosing history from two studies in orthopaedic patients anaesthetized with propofol or inhalation anaesthetics the alfentanil plasma concentration over time was calculated with eight PK parameter sets. Median absolute performance error (MDAPE), log accuracy, median performance error (MDPE), log bias, Wobble, and Divergence were computed. Mann-Whitney rank test with Bonferroni correction was used for comparison between bolus and infusion data, repeated measures analysis of variance on ranks was used for comparison among parameter sets. RESULTS: The parameters by Scott (original and weight adjusted) and Fragen had a MDAPE ≤30% and a median log accuracy <0.15 independent of the administration mode, while MDPE was within ±20% and log bias nearly within ±0.1, respectively. The sets by Maitre and Lemmens were within these limits only in the bolus data. All other parameter sets were outside these limits. CONCLUSIONS: In healthy orthopaedic patients, the PK parameters by Scott and by Maitre were equally valid when alfentanil was given as repeated boluses. When given as infusion, the Maitre parameters were less accurate and subject to a significant bias. We cannot exclude that the difference between bolus and infusion is partially because of the different hypnotics used.

Pharmacokinetics of intravenous dynorphin A(1-13) in opioid-naive and opioid-treated human volunteers.

BACKGROUND: Dynorphin A(1-13) is a fragment of the endogenous opioid neuropeptide dynorphin A. Previous research suggested that intravenously administered dynorphin A(1-13) has the ability to modulate morphine-induced analgesia. We designed this study to characterize the disposition of intravenous dynorphin immunoreactivity in humans and to determine whether concomitant long-term opioid therapy influenced the pharmacokinetics or side-effects profile of dynorphin A(1-13). METHODS: The study subjects comprised 20 volunteers divided into two groups of 10 each, stratified by dose (low dose, 250 micrograms/kg; high dose, 1000 micrograms/kg). There were four volunteers receiving long-term opioid therapy and six opioid-naive volunteers (nonopioid group) within each dosing group. Dynorphin A(1-13) was infused over 10 minutes, and arterial blood samples were drawn and assayed for dynorphin immunoreactivity. A population modeling approach was used to characterize the pharmacokinetics. Dynorphin effects on heart rate and arterial blood pressure were also studied. RESULTS: The pharmacokinetics of dynorphin immunoreactivity were linear over the dose range studied and were best described by a three-compartment mammillary model whose parameters were volume 1, 5.0 L; volume 2, 0.80 L; volume 3, 12 L; clearance 1, 6.0 L/min; clearance 2, 0.054 L/min; and clearance 3, 0.044 L/min. Concomitant opioid medication did not affect the disposition of dynorphin immunoreactivity. Tachycardia and flushing were commonly observed side effects. The incidence of side effects was dose dependent and was not influenced by long-term opioid use. CONCLUSIONS: Intravenously administered dynorphin A(1-13) is very rapidly metabolized, on the basis of the time course of immunoreactivity in the blood. Long-term opioid therapy did not influence either the pharmacokinetics or incidence of side effects.

A phase II/pharmacokinetic trial of high-dose progesterone in combination with paclitaxel.

PURPOSE: The purpose of this study was to investigate the effect of high-dose progesterone, an inhibitor of P glycoprotein, on the pharmacokinetics and toxicity of paclitaxel. PATIENTS AND METHODS: A total of 29 patients with various tumors were treated with single-agent paclitaxel (125 mg/m2 administered over 3 h once every 3 weeks) until progression of disease, at which point high-dose progesterone (3 g administered i.v. over 24 h) was added to the paclitaxel treatment program in 20 patients (13 women, 7 men). Pharmacokinetic studies of paclitaxel administered alone and with progesterone were performed in eight patients. RESULTS: The pharmacokinetic parameters of paclitaxel were highly variable. High-dose progesterone increased the peak plasma levels (3.00 +/- 0.94 vs. 4.15 +/- 1.63 microM; P = 0.029; mean +/- SD) and the area under the curve (AUC; 14.3 +/- 4.75 vs. 17.3 +/- 5.59 microM x h; P = 0.006) of paclitaxel. The absolute neutrophil and platelet nadir counts did not differ significantly between the paclitaxel and the combined treatment cycles. Three of the 20 patients documented to have progressive disease on paclitaxel alone had partial responses when high-dose progesterone was added to the paclitaxel regimen. CONCLUSION: Progesterone had a statistically significant impact on the pharmacokinetics of paclitaxel. The addition of high-dose progesterone to paclitaxel is feasible, but the small number of patients prevents conclusions being drawn about the clinical efficacy of combined progesterone and paclitaxel.

Identification and targeting policies for computer-controlled infusion pumps.

In this article a series of useful techniques is presented to improve the adaptation capabilities of computer-controlled infusion pumps: an identification algorithm for the time constant of the effect compartment, a smoothing technique for estimation based on noisy data, and an infusion policy to target any effect site concentration with no overshoot.

Modeling and closed-loop control of hypnosis by means of bispectral index (BIS) with isoflurane.

A model-based closed-loop control system is presented to regulate hypnosis with the volatile anesthetic isoflurane. Hypnosis is assessed by means of the bispectral index (BIS), a processed parameter derived from the electroencephalogram. Isoflurane is administered through a closed-circuit respiratory system. The model for control was identified on a population of 20 healthy volunteers. It consists of three parts: a model for the respiratory system, a pharmacokinetic model and a pharmacodynamic model to predict BIS at the effect compartment. A cascaded internal model controller is employed. The master controller compares the actual BIS and the reference value set by the anesthesiologist and provides expired isoflurane concentration references to the slave controller. The slave controller maneuvers the fresh gas anesthetic concentration entering the respiratory system. The controller is designed to adapt to different respiratory conditions. Anti-windup measures protect against performance degradation in the event of saturation of the input signal. Fault detection schemes in the controller cope with BIS and expired concentration measurement artifacts. The results of clinical studies on humans are presented.

[Characterization of dose profile of remifentanil with computer simulation: comparative study with fentanyl and alfentanyl]. / Caracterización del perfil de dosificación del remifentanilo mediante simulación con ordenador: estudio comparativo con fentanilo y alfentanilo.

OBJECTIVES: To estimate the optimum dosing regimen and delivery system for remifentanil, a new opioid, using computer simulations based on information from pharmacokinetic and pharmacodynamic models available for fentanyl, alfentanil and remifentanil, as well as from clinical trials of fentanyl and alfentanil. PATIENTS AND METHODS: We estimated the site concentration ranges likely to be needed to blunt response to anesthetic or surgical stimuli and to recover from spontaneous ventilation. Dosing guidelines for remifentanil, fentanyl and alfentanil were estimated for three methods of administration (bolus, bolus + variable continuous infusion or constant continuous infusion). To that end, the time course of opioid concentration was simulated for hypothetical balanced anesthesia lasting 60 min. We then studied the number of boluses, the number of infusion rate steps, time taken to reach the terapeutic threshold, and time from turning off the infusion until reaching a concentration compatible with spontaneous ventilation. RESULTS: The estimated "effect site" concentration ranges for remifentanil were 6 to 10 ng.ml-1 during intubation; 4 to 6 ng.ml-1 during cutaneous incision; 4 to 7 ng.ml-1 for maintenance; and less than 2.5 ng.ml-1 for recovery of spontaneous ventilation. Simulated bolus administration indicated that 21 boluses of remifentanil, 4 boluses of fentanyl and 7 boluses of alfentanil were needed during one hour. The therapeutic threshold was reached within the first minute with remifentanil, within 2 minutes with fentanyl and within 1 min with alfentanil. Time until recovery of spontaneous ventilation was 7 min with remifentanil, 22 min with fentanyl and 14 min with alfentanil. In the simulation of bolus plus variable infusion, the initial bolus of remifentanil was 100 micrograms, the infusion rate for induction and maintenance was 25 micrograms.min-1 and the maintenance rate was 15 micrograms.min-1. The initial bolus of fentanyl was 300 micrograms, the infusion rate for induction and maintenance was 5 micrograms.min-1. The initial bolus of alfentanil was 2,000 micrograms, the infusion rate for induction was 200 micrograms.min-1 and the maintenance rates were 75 and 25 micrograms.min-1. The therapeutic threshold was reached in 1 min with remifentanil, in 2 min with fentanyl and within 1 min with alfentanil. Spontaneous ventilation was recovered 4 min after turning off the infusion of remifentanil, 4 min afterwards with fentanyl and 6 min afterwards with alfentanil. The simulated constant infusion rate for remifentanil of 15 micrograms.min1 (8 micrograms.min-1 for fentanyl and 75 micrograms.min-1 for alfentanil) allowed the therapeutic threshold to be reached in 10 min with remifentanil, in 22 min with fentanyl and in 17 min with alfentanil. Recovery of spontaneous ventilation occurred 5 min after closure of the infusion pump with remifentanil (24 min with fentanyl and 17 min with alfentanil). CONCLUSIONS: Information from pharmacokinetic and pharmacodynamic models allows us to establish the effect site concentration ranges for remifentanil and determine the ideal administration technique for this drug. The simulation also allows us to compare the properties of remifentanil to those of other common opioids such as fentanyl and alfentanil. The results are fairly consistent with clinical evidence, demonstrating the power of pharmacokinetic and pharmacodynamic models for rationally establishing opioid dosing guidelines.

Contributions of PK/PD modeling to intravenous anesthesia.

Pharmacokinetic (PK)/pharmacodynamic (PD) modeling has made an enormous contribution to intravenous anesthesia. PK/PD models have provided us with insight into the factors affecting the onset and offset of drug effect. For example, we are now able to describe the influence of cardiac output on the disposition of intravenous drugs within the first few minutes after administration of the drug. We are able to calculate intravenous loading doses that allow for the delay between the concentration of the drug in the plasma and the rising concentration at the site of drug effect. We are able to achieve and maintain a stable level of anesthetic effect using computerized infusion pumps that target the site of drug effect rather than the plasma. Importantly, on the basis of models of drug interaction and an understanding of how drug offset varies with duration of administration, we are now able to rationally combine hypnotics and opioids.

Comparision of etomidate and propofol for fibreoptic intubation as part of an airway management algorithm:a prospective, randomizes, double-blind study.

BACKGROUND AND OBJECTIVE: In our algorithm for management of the anticipated difficult airway the induction agent (etomidate) is administered after the tip of the fibreoptic is placed in the trachea but before the tube is advanced over it. In a previous investigation we demonstrated the safety of this method. Due to its popularity as an induction agent, some would like to replace etomidate with propofol. However, because rapid recovery of spontaneous breathing is crucial with this technique, substitution might not be advisable. We compared the speed of recovery of spontaneous breathing after fibreoptic intubation between etomidate and propofol. METHODS: In this prospective, randomized, double-blind study we used either 0.2 mg kg[-1] etomidate or 2 mg kg[-1] propofol for induction. Our technique of nasotracheal fibreoptic intubation consists of using fentanyl, cocaine instillation into the lower nasal canals, cricothyroid injection of lidocaine, performing bronchoscopy, administration of etomidate and advancing the tube after loss of consciousness. We measured time to loss of consciousness, time to recovery of spontaneous breathing, lowest bi-spectral index value and time to lowest value. RESULTS: Time to loss of consciousness did not differ. The time to recovery of spontaneous breathing differed significantly: the median time (interquartile range [range]) for etomidate was 81 s (62--102 [0--166]), and for propofol 146 s (95--260 [65--315]); P=0.001. The lowest bi-spectral index values were not different. The time of the lowest bi-spectral index values differed significantly: for etomidate 58 s (51--68 [38--100]), and for propofol 90 s (52--125 [38--172]); P=0.015. CONCLUSION: For nasotracheal fibreoptic intubation, where the tube is advanced after induction of anaesthesia, we still recommend etomidate because spontaneous breathing recovers faster than with propofol.

Predictors of onset and offset of drug effect.

Anaesthesiologists administer a wide variety of drugs, including benzodiazepines, opioids, intravenous anaesthetic agents, volatile anaesthetic agents, muscle relaxants, local anaesthetics, and other drugs, especially those influencing the cardiovascular system. Sometimes a drug is chosen because of its better effect and/or side-effect profile. However, many of the drugs within each group have similar effect and/or side-effect profiles and differ mainly in their pharmacokinetics. The choice of one drug over another may then need to be based on differences in their pharmacokinetic profiles. Traditional predictors of onset of drug effect, such as time to a specified effect, are dose-dependent. Traditional predictors of offset of drug effect, such as 'terminal half-life', often have little clinical relevance. Newer descriptors offer significant advantages. The time to peak effect-site concentration is an informative dose-independent descriptor of the onset of drug effect following an intravenous bolus dose. The relevant decrement time (for continuous measures of drug effect) and mean effect time (for binary measures of drug effect) build upon the context-sensitive half-time concept, by considering the time required for the concentrations to decrease from one clinically relevant level of drug effect to another.

[Modern concepts in pharmacokinetics of intravenous anesthetics]. / Moderne Konzepte der Pharmakokinetik intravenöser Anästhetika.

From a pharmacological perspective, anesthesia is concerned with controlling the time course of drug effect. Mathematical models are commonly used to relate the administered drug dose to the measured drug concentration (a pharmacokinetic model) and to relate the measured drug concentrations to the measured drug effects (a pharmacodynamic model). With such models, the time course of the drug effect for different drug regimens can be predicted. Although the conventional pharmacokinetic parameters such as the volume of distribution, clearance, distribution and elimination half-lives can be used to accurately describe the time course of the plasma concentration, the plasma is usually not the site of drug effect. An understanding of the "effect compartment concept" and the "time of the peak effect site concentration," together with the concepts of" context sensitive"half-time and "relevant decrement time,' contribute substantially to the anesthetist's understanding of the principles governing the onset and offset of drug effect. As part of a computer-controlled infusion system, the pharmacokinetic model facilitates optimized and rational dosing. These systems, also called target-controlled infusion systems (TCI), calculate the infusion rates for rapidly achieving and then maintaining a target concentration.

Pharmacokinetics and pharmacodynamics of remifentanil. II. Model application.

BACKGROUND: The pharmacokinetics and pharmacodynamics of remifentanil were studied in 65 healthy volunteers using the electroencephalogram (EEG) to measure the opioid effect. In a companion article, the authors developed complex population pharmacokinetic and pharmacodynamic models that incorporated age and lean body mass (LBM) as significant covariates and characterized intersubject pharmacokinetic and pharmacodynamic variability. In the present article, the authors determined whether remifentanil dosing should be adjusted according to age and LBM, or whether these covariate effects were overshadowed by the interindividual variability present in the pharmacokinetics and pharmacodynamics. METHODS: Based on the typical pharmacokinetic and pharmacodynamic parameters, nomograms for bolus dose and infusion rates at each age and LBM were derived. Three populations of 500 individuals each, ages 20, 50, and 80 yr, were simulated base on the interindividual variances in model parameters as estimated by the NONMEM software package. The peak EEG effect in response to a bolus, the steady-state EEG effect in response to an infusion, and the time course of drug effect were examined in each of the three populations. Simulations were performed to examine the time necessary to achieve a 20%, 50%, and 80% decrease in remifentanil effect site concentration after a variable-length infusion. The variability in the time for a 50% decrease in effect site concentrations was examined in each of the three simulated populations. Titratability using a constant-rate infusion was also examined. RESULTS: After a bolus dose, the age-related changes in V1 and Ke0 nearly offset each other. The peak effect site concentration reached after a bolus dose does not depend on age. However, the peak effect site concentration occurs later in elderly individuals. Because the EEG shows increased brain sensitivity to opioids with increasing age, an 80-yr old person required approximately one half the bolus dose of a 20-yr old of similar LBM to reach the same peak EEG effect. Failure to adjust the bolus dose for age resulted in a more rapid onset of EEG effect and prolonged duration of EEG effect in the simulated elderly population. The infusion rate required to maintain 50% EEG effect in a typical 80-yr old is approximately one third that required in a typical 20-yr old. Failure to adjust the infusion rate for age resulted in a more rapid onset of EEG effect and more profound steady-state EEG effect in the simulated elderly population. The typical times required for remifentanil effect site concentrations to decrease by 20%, 50%, and 80% after prolonged administration are rapid and little affected by age or duration of infusion. These simulations suggest that the time required for a decrease in effect site concentrations will be more variable in the elderly. As a result, elderly patients may occasionally have a slower emergence from anesthesia than expected. A step change in the remifentanil infusion rate resulted in a rapid and predictable change of EEG effect in both the young and the elderly. CONCLUSIONS: Based on the EEG model, age and LBM are significant demographic factors that must be considered when determining a dosage regimen for remifentanil. This remains true even when interindividual pharmacokinetic and pharmacodynamic variability are incorporated in the analysis.

Deep accidental hypothermia and cardiac arrest--rewarming with forced air.

BACKGROUND: During the last two cold winters we have treated 5 severely hypothermic patients (temperature below 30 degrees C) with active external rewarming rather than with extracorporal circulation and heat exchanger. PATIENTS: Two patients were found in cardiac arrest, and 3 victims of mountain accidents suffered deep hypothermia without arrest. In one of them, ventricular fibrillation (VF) was converted successfully to a sinus rhythm at a core temperature of 25.9 degrees C. Both arrested patients developed an adequate hemodynamic state during resuscitation although they were at very low temperature. All the patients were warmed with a convective cover inflated with warm air of about 38 degrees C (Bair Hugger). The core temperature increased by approximately 1 degree C/h in all patients. During rewarming we observed neither an initial drop of the core temperature (afterdrop) nor cardiac arrhythmias. The outcome of all 5 patients was good without neurological sequelae. CONCLUSION: We conclude that external rewarming with forced air is a feasible alternative to cardiopulmonary bypass in severely hypothermic patients with electrical activity. This method can be used even in patients with VF because defibrillation can be successfully performed in deep hypothermia. Although after-drop during external rewarming is feared, we did not observe this phenomenon. Rewarming with forced air is inexpensive, easy to perform and direct access to the patient is possible at any time. It does not require heparinisation and can be used in hospitals where they do not have cardiopulmonary bypass facilities. Thus, this method is particularly useful in situations when the hypothermic patient cannot be transferred to a major medical center.

Different benefit of bispectal index (BIS) in desflurane and propofol anesthesia.

BACKGROUND: Bispectal index (BIS) monitoring may reduce drug usage and hasten recovery in propofol and inhalation anesthesia. The faster emergence profile of desflurane may reduce the effect of BIS monitoring on recovery from desflurane compared with propofol. This study compared hypnotic drug usage, recovery, patient satisfaction and incidence of inadequate sedation in BIS monitored and nonmonitored women anesthetized with desflurane or propofol. METHODS: One hundred and sixty patients scheduled for elective gynecological surgery were randomly assigned to desflurane or propofol anesthesia with and without BIS monitoring. Fentanyl, vecuronium and remifentanil were administered according to clinical criteria. The BIS monitor was used in all patients, but the monitor screen was covered in the controls. A BIS level between 45 and 55 was targeted in the BIS monitored patients whereas depth of anesthesia was assessed by clinical criteria in the controls. RESULTS: The mean (SD) desflurane MAC-hours administered with and without BIS were 0.70 (0.15) and 0.76 (0.12), respectively, resulting in extubation times of 6.5 (4.1) and 8.3 (6.1) min. (NS). Bispectal index monitoring was associated with improved patient satisfaction, reduced postoperative nausea and antiemetic drug requirement, and fewer episodes with sustained BIS levels > 60. The mean (SD) propofol infusion rates were 6.0 (1.4) and 6.6 (0.9) mg kg(-1)h(-1) with and without the BIS monitor (P = 0.023), resulting in mean (SD) extubation times of 6.8 (4.6) and 10.5 min (5.9), respectively (P < 0.05). CONCLUSION: Bispectal index monitoring reduced propofol usage and hastened recovery after propofol anesthesia, whereas in desflurane anesthesia it was associated with improved patient satisfaction, probably because of decreased postoperative nausea and fewer episodes of inadequate hypnosis.

Incremental dosing versus single-dose spinal anesthesia and hemodynamic stability.

We compared the hemodynamic stability after spinal anesthesia with two different dosing regimens in the elderly. Fifty patients, all older than 60 yr and scheduled for elective knee or hip surgery were assigned to two groups. After administration of 10 mL/kg of lactated Ringer's solution (RL) intravenously (i.v.) in the first group, we performed a continuous spinal anesthesia (CSA) by means of a 28-gauge catheter through which repetitive injections of 2.5-5 mg of plain bupivacaine 0.5% were given. In the other group, a single-dose spinal anesthesia (SS) with 20 mg of the same local anesthetic (LA) was carried out. Noninvasive mean arterial pressure (MAP), heart rate, and levels of analgesia were measured. To maintain MAP within 25% of initial value, the patients received additional i.v. fluids (RL) as first measure. When MAP could not be maintained despite hydration, incremental doses of ephedrine were given i.v. Six patients in the CSA group and 17 in the SS group developed a level of anesthesia higher than T6 (P < 0.01). In the SS group more fluid was needed (792 vs 388 ml) than in the CSA group (P < 0.01). Moreover, more patients of the SS group (11 vs 4) required ephedrine (P < 0.05). We conclude that CSA produces reliable and predictable analgesia for lower limb surgery with less need for correction of hemodynamic changes compared to SS.

Population pharmacodynamic modeling and covariate detection for central neural blockade.

BACKGROUND: In spinal anesthesia, often a large interindividual variability in analgesic response is observed after administration of a certain fixed dose of anesthetic to a patient population. To improve therapeutic outcome it is important to characterize the variability in response by means of a population model (e.g., mixed-effects models or two-stage approaches). The purpose of this investigation is to derive a population model for spinal anesthesia with plain bupivacaine. Based on the population models, a description of a patient's time course of drug action is obtained, the influence of patient covariates on clinically important endpoints is examined, and the success of Bayesian forecasting of the offset of effect in a specific patient from the data obtained during onset is evaluated. METHODS: The level of central neural blockade after intrathecal injection of plain bupivacaine was assessed by testing analgesia to pinprick. A total of 714 measurements in 96 patients (4-10 per subject) were available for analysis. Two pharmacodynamic models, based on the understanding of the physiology of the spread of local anesthetic in the spinal fluid, were evaluated to characterize the time course of analgesia in a specific patient. The first model is a combination of a biexponential pharmacokinetic model, describing the onset and offset of effect and a linear pharmacodynamic model. The second model combines the biexponential pharmacokinetic model with an Emax type pharmacodynamic model. The interindividual variability in model parameters was modeled by an exponential variance model. An additional term characterized the residual error. The population mean parameters, interindividual variance, and residual variance were estimated using the first-order conditional estimate method in the NONMEM software package. Clinically important endpoints such as onset time, time to reach the maximal level, the maximal level, and the duration of analgesia were estimated from the Bayesian fit of each subject's data and correlated with patient-specific covariates. Using Bayesian forecasting, the offset of spinal analgesia was predicted for each patient based on the population model and measurements from the first 30 min and from the first 60 min, respectively. RESULTS: The Emax type pharmacodynamic model was superior based on the improvement in likelihood (P < 0.001) and on visual inspection of the fits. The estimates of the population mean parameters (coefficient of variation) were: (1) maximal effects: T4, which was coded for the purpose of the calculation as 18 (14%); (2) rate of offset of effect: 0.0118 (26%) min-1; (3) rate of onset of effect: 0.061 (45%) min-1. The standard deviation of the residual error was 1.4. Large interindividual differences were observed in the time course of analgesic response and clinically important endpoints. The mean onset time; that is, time to reach T10 (interindividual variability) was 4.2 min (90%), the mean time to maximal level was 35.5 min (29%), the mean duration of effect was 172 min (28%), and the mean maximal achieved level was T6 (12%). Significant correlations between onset time and height and weight, between time to maximal level and age, between maximal level and weight and height, and between duration and height were found. Bayesian regression using the population model and data from the first 30 min and from the first 60 min predicted the offset of effect in each patient reasonably well, with coefficients of determination (R2) of 0.71 and 0.72. This is a significant improvement over the population mean prediction. CONCLUSION: A population model was derived for the description of the time course of central neural blockade. Based on the population model, a continuous effect profile over time was obtained for each person...

Effect of racemic mixture and the (S+)-isomer of ketamine on temporal and spatial summation of pain.

We have compared the analgesic efficacy of the racemic mixture and the stereoisomer (S+) of the NMDA antagonist ketamine. In a double-blind, three-way crossover, placebo-controlled study, we assessed the following: pain evoked by small/large area pressure stimuli, pain detection threshold and pain ratings to small/large area of heat stimuli, pain detection threshold and pain rating to heat stimuli of brief/long duration, summation pain threshold and pain ratings to repeated heat/electrical stimuli, side effects and reaction time. Plasma concentrations of 350 ng ml-1 for ketamine (racemic) and 180 ng ml-1 for ketamine (S+) were tried. We found that ketamine (racemic) prolonged the reaction time more than ketamine (S+). Both drugs affected pain caused by repeated stimuli or stimuli of long duration equally or more than a single stimulus of short duration. They also affected pain evoked from large areas equally or more than pain evoked from small areas. The (S+)-isomer was approximately twice as potent as the racemic mixture of ketamine in inhibiting central summation.

Semilinear canonical correlation applied to the measurement of the electroencephalographic effects of midazolam and flumazenil reversal.

BACKGROUND: The electroencephalographic (EEG) effect of benzodiazepines, and midazolam in particular, has been described using simple measures such as total power in the beta band, waves.s(-1) in the beta band and total power from aperiodic analysis. All these parameters failed to consistently describe the EEG effect of midazolam in a study in which large doses of midazolam were infused, and the effect subsequently reversed with flumazenil. Using a technique called semilinear correlation it is possible to extract a parameter from the EEG that is statistically optimally correlated with the apparent concentration of the benzodiazepine in the effect site. This method has been used to develop new univariate measures of the effects of opioids on the EEG but has not previously been applied to the EEG effects of benzodiazepines. METHODS: Data from ten subjects who received an infusion of midazolam were analyzed. The data were divided into "learning" and "test" sets. The learning set consisted of ten studies in which the volunteers received an infusion of 2.5 mg.min(-1) midazolam. Semilinear canonical correlation was used to extract an univariate descriptor of the EEG effect by weighting the different frequency bands of the EEG power spectrum. The test set comprised the same subjects on subsequent visits, in which the subjects received a continuous infusion of midazolam to maintain 20% or 80% of the peak drug effect for 3h. Twenty minutes after start of the midazolam infusion, the patient received an infusion of flumazenil to acutely reverse the benzodiazepine drug effect. The weights obtained from the learning set were tested prospectively in the test set, based on the coefficient of multiple determination, R(2), obtained by fitting the EEG effect to a sigmoid Emax model. RESULTS: The canonical univariate parameter of benzodiazepine drug effect on the EEG, when applied to the test set receiving the midazolam infusion with flumazenil reversal, yielded a median R(2) of 0.78. The median R(2) of six commonly used empirical EEG measures of drug effect ranged from 0.18 to 0.55. CONCLUSIONS: The canonical univariate parameter for benzodiazepine drug effect on the EEG correlates more accurately and consistently with the predicted EEG effects of midazolam and its reversal than previously reported EEG measures of benzodiazepine effect.