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T W Schnider

Publications and source records attributed to T W Schnider.

28 records · Page 2Linked to original sources
PubMed1997

Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I. Model development.

BACKGROUND: Previous studies have reported conflicting results concerning the influence of age and gender on the pharmacokinetics and pharmacodynamics of fentanyl, alfentanil, and sufentanil. The aim of this study was to determine the influence of age and gender on the pharmacokinetics and pharmacodynamics of the new short-acting opioid remifentanil. METHODS: Sixty-five healthy adults (38 men and 27 women) ages 20 to 85 y received remifentanil by constant-rate infusion of 1 to 8 micrograms.kg-1.min-1 for 4 to 20 min. Frequent arterial blood samples were drawn and assayed for remifentanil concentration. The electroencephalogram was used as a measure of drug effect. Population pharmacokinetic and pharmacodynamic modeling was performed using the software package NONMEM. The influence of volunteer covariates were analyzed using a generalized additive model. The performances of the simple (without covariates) and complex (with covariates) models were evaluated prospectively in an additional 15 healthy participants ages 41 to 84 y. RESULTS: The parameters for the simple three-compartment pharmacokinetic model were V1 = 4.98 l, V2 = 9.01 l, V3 = 6.54 l, Cl1 = 2.46 l/min, Cl2 = 1.69 l/min, and Cl3 = 0.065 l/min. Age and lean body mass were significant covariates. From the ages of 20 to 85 y, V1 and Cl1 decreased by approximately 25% and 33%, respectively. The parameters for the simple sigmoid Emax pharmacodynamic model were Ke0 = 0.516 min-1, E0 = 20 Hz, Emax = 5.62 Hz, EC50 = 11.2 ng/ml, and gamma = 2.51. Age was a significant covariate of EC50 and Ke0, with both decreasing by approximately 50% for the age range studied. The complex pharmacokinetic-pharmacodynamic model performed better than did the simple model when applied prospectively. CONCLUSIONS: This study identified (1) an effect of age on the pharmacokinetics and pharmacodynamics of remifentanil; (2) an effect of lean body mass on the pharmacokinetic parameters; and (3) no influence of gender on any pharmacokinetic or pharmacodynamic parameter.

Adult↗
PubMed1997

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.

Adult↗
PubMed1997

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.

Accidents↗
PubMed1996

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.

Adult↗
PubMed1996

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.

Adult↗
PubMed1996

Derivation and cross-validation of pharmacokinetic parameters for computer-controlled infusion of lidocaine in pain therapy.

BACKGROUND: Lidocaine administered intravenously is efficacious in treating neuropathic pain at doses that do not cause sedation or other side effects. Using a computer-controlled infusion pump (CCIP), it is possible to maintain the plasma lidocaine concentration to allow drug equilibration between the plasma and the site of the drug effect. Pharmacokinetic parameters were derived for CCIP administration of lidocaine in patients with chronic pain. METHODS: Thirteen patients (mean age 45 yr, mean weight 66 kg) were studied. Eight subjects received a computer-controlled infusion, targeting four increasing lidocaine concentrations (1-7 micrograms.ml-1) for 30 min each, based on published kinetic parameters in which venous samples were obtained infrequently after bolus administration. From the observations in these eight patients, new lidocaine pharmacokinetic parameters were estimated. These were prospectively tested in five additional patients. From the complete data set (13 patients), final structural parameters were estimated using a pooled analysis approach. The interindividual variability was determined with a mixed-effects model, with the structural model parameters fixed at the values obtained from the pooled analysis. Internal cross-validation was used to estimate the residual error in the final pharmacokinetic model. RESULTS: The lidocaine administration based on the published parameters consistently produced higher concentrations than desired, resulting in acute lidocaine toxicity in most of the first eight patients. The highest measured plasma concentration was 15.3 micrograms.ml-1. The pharmacokinetic parameters estimated from these eight patients differed from the initial estimates and included a central volume one-sixth of the initial estimate. In the subsequent prospective test in five subjects, the new parameters resulted in concentrations evenly distributed around the target concentration. None of the second group of subjects had evidence of acute lidocaine toxicity. The final parameters ( +/- population variability expressed as %CV) were estimated as follows: V1 0.101 +/- 53% 1.kg-1, V2 0.452 +/- 33% 1.kg-1, Cl1 0.0215 +/- 25% 1.kg-1.min-1, and Cl2 0.0589 +/- 35% 1.kg-1.min-1. The median error measured by internal cross-validation was +1.9%, and the median absolute error was 14%. CONCLUSIONS: Pharmacokinetic parameters for lidocaine were derived and administration was prospectively tested via computer-controlled infusion pumps for patients with chronic neuropathic pain. The estimated parameters performed well when tested prospectively. A second estimation step further refined the parameters and improved performance, as measured using internal cross-validation.

Adult↗
PubMed1996

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...

Adolescent↗
PubMed1993

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.

Aged↗