Dexmedetomidine decreases thiopental dose requirement and alters distribution pharmacokinetics.

BACKGROUND: alpha 2-Adrenergic agonists such as dexmedetomidine can be used to reduce the dose requirement of intravenous and volatile anesthetics. Whereas dexmedetomidine and volatile anesthetics interact pharmacodynamically (reduction of MAC), the mechanism of interaction between dexmedetomidine and intravenous anesthetics is not known. METHODS: Fourteen male ASA physical status 1 patients were randomly assigned to serve as control subjects (n = 7) or to be treated with dexmedetomidine (n = 7; 100, 30, and 6 ng.kg-1.min-1 for 10 min, 15 min, and thereafter, respectively). After 35 min, in all patients, thiopental (100 mg/min) was infused until burst suppression appeared in the raw tracing of the electroencephalogram. By using concentrations of thiopental in plasma and the electroencephalogram as a continuous pharmacologic effect measure, the apparent effect site concentrations for thiopental were estimated in both groups. Three-compartment pharmacokinetics were calculated for thiopental. RESULTS: Dexmedetomidine reduced the thiopental dose requirement for electroencephalographic burst suppression by 30%. There was no difference in estimated thiopental effect site concentrations between dexmedetomidine and control patients, suggesting the absence of a major pharmacodynamic interaction. Dexmedetomidine significantly decreased distribution volumes (V2, V3, and Vdss) and distribution clearances (Cl12 and Cl13) of thiopental. CONCLUSIONS: The thiopental dose-sparing effect of dexmedetomidine on the electroencephalogram is not the result of a pharmacodynamic interaction but rather can be explained by a dexmedetomidine-induced decrease in thiopental distribution volume and distribution clearances. Dexmedetomidine reduces thiopental distribution, most probably by decreasing cardiac output and regional blood flow.

[Diprivan: efficient concentrations in relation to physiological parameters and associated drugs]. / Diprivan: concentrations efficaces en fonction des variables physiologiques et des médicaments associés.

According to the literature there is a large inter-individual variability, with blood concentrations often ranging from 1 to 3-fold. These variations between patients reduce the value of recommended concentrations. In practice it is more important to titrate the dose according to the clinical response (or lack of response), rather than to blindly follow the various dosage regimens proposed and, with which it is theoretically possible to rapidly reach and then maintain the desired propofol concentration. In practice, what is the point of carefully maintaining a propofol concentration of 3.5 micrograms.mL-1 (theoretical maintenance level for an average patient), if the latter (failing to comply with the usual range of concentrations) needs a propofol level of 6 micrograms.mL? In practice, we must titrate!

Thiopental pharmacodynamics. I. Defining the pseudo-steady-state serum concentration-EEG effect relationship.

To assess depth of anesthesia for intravenous anesthetics using clinical stimuli and observed responses, it is necessary to achieve constant serum concentrations of drug that result in constant biophase or central nervous system concentrations. The goal of this investigation was to use a computer-controlled infusion pump (CCIP) to obtain constant serum thiopental concentrations and use the electroencephalogram (EEG) as a measure of thiopental's central nervous system drug effect. The number of waves per second obtained from aperiodic waveform analysis was used as the EEG measure. A CCIP was used in six male volunteers to attain rapidly and then maintain for 6-min time periods the following pseudo-steady-state constant serum thiopental target concentrations: 10, 20, 30, and 40 micrograms/ml. The median performance error (bias) of the CCIP using 149 measurements of thiopental serum concentrations in six subjects was +5%, and the median absolute performance error (accuracy) was 16%. Following the step change in serum thiopental concentration, the EEG number of waves per second stabilized within 2-3 min and the remained constant until the target serum thiopental concentration was changed. When the constant serum thiopental concentration was plotted against the number of waves per second for each subject, a biphasic serum concentration versus EEG effect relationship was seen. This biphasic concentration:response relationship was characterized with a nonparametric pharmacodynamic model. The awake, baseline EEG was 10.6 waves/s; at peak activation the EEG was 19.1 waves/s and occurred at a serum thiopental concentration of 13.3 micrograms/ml. At a serum thiopental concentration of 31.2 micrograms/ml the EEG had slowed to 10.6 waves/s (back to baseline) and at 41.2 micrograms/ml was 50% below the baseline, awake value. Zero waves per second occurred at serum thiopental concentrations greater than 50 micrograms/ml. Using a CCIP it is possible to establish constant serum thiopental concentration rapidly and characterize the concentration versus EEG drug effect relationship.

A three-step approach combining Bayesian regression and NONMEM population analysis: application to midazolam.

NONMEM, the only available supported program for population pharmacokinetic analysis, does not provide the analyst with individual subject parameter estimates. As a result, the relationship between pharmacokinetic parameters and demographic factors such as age, gender, and body weight cannot be sought by plotting demographic factors vs. kinetic parameters. To overcome this problem, we devised a three-step approach. In step 1, an initial NONMEM analysis provides the population pharmacokinetic parameters without taking into account the demographic factors. Step 2 consists of individual bayesian regressions using the measured drug concentrations for each subject and the population pharmacokinetic parameters obtained in step 1. The bayesian parameter estimates of the individual subject can be plotted against the demographic factors of interest. From the scatter plots, it can be seen which are the demographic factors that appear to affect the pharmacokinetic parameters. In step 3, the NONMEM analysis is resumed, and the demographic factors found in step 2 are entered into the NONMEM regression model in a stepwise manner. This method was used to analyze the pharmacokinetics of midazolam in 64 subjects from 714 plasma concentrations and 11 demographic factors. CL (elimination clearance) and V1 were found to be a function of body weight. Age and liver disease were found to decrease CL. Of the 11 demographic factors recorded for each patient, none was found to influence VSS or intercompartmental clearance.

Electroencephalographic effects of benzodiazepines. I. Choosing an electroencephalographic parameter to measure the effect of midazolam on the central nervous system.

The goal of this investigation was to determine a numerical electroencephalographic parameter that best indicated the degree of the effect of midazolam, administered in hypnotic doses, on the central nervous system. This electroencephalographic parameter could then be used to relate midazolam plasma concentrations and electroencephalographic drug effect (pharmacodynamic modeling). Intravenous doses of midazolam (3.75 to 25 mg) were given to five men at an infusion rate of 5 mg/min. A cortical electroencephalogram was continuously recorded. Two waveform analysis approaches were examined: fast Fourier transformation and aperiodic analysis. From fast Fourier transformation and aperiodic analysis a set of parameters were examined as measures of drug effect. We conclude that the voltage per second from aperiodic analysis provided the electroencephalographic parameter that optimally measured the effect of midazolam on the central nervous system.

Electroencephalographic effects of benzodiazepines. II. Pharmacodynamic modeling of the electroencephalographic effects of midazolam and diazepam.

The comparative pharmacodynamics of midazolam and diazepam were examined by use of the electroencephalogram as a measure of drug effect on the central nervous system. Intravenous doses of 7.5, 15, and 25 mg midazolam and 15, 30, and 50 mg diazepam were given on repeated occasions to three volunteers. Arterial plasma concentration and electroencephalogram voltage were related with nonparameteric and parametric pharmacodynamic models. The peak increases in voltage (maximal effect) and the slopes of the plasma concentration versus effect curve were similar for both drugs. The half-time of blood:brain equilibration was significantly longer for midazolam than diazepam (4.8 minutes versus 1.6 minutes). Midazolam was found to have an intrinsic steady-state potency that was approximately five times greater than that of diazepam (152 ng/ml versus 958 ng/ml).

A simple pocket calculator approach to predict anesthetic drug concentrations from pharmacokinetic data.

Use of pharmacokinetic concepts to predict anesthetic drug concentrations has not had extensive use in clinical anesthetic practice to date. The multiple exponent equations needed to describe iv drug disposition have required computer capability not practical for the operating room. An algorithm is presented that allows the clinician to use information from the pharmacokinetic literature to improve accuracy of drug dosing in the operating room. Implemented on a pocket calculator, this approach does not involve complex mathematics or lengthy computations and allows the clinician to obtain a continuous prediction of the plasma anesthetic concentration during the course of the anesthetic from iv bolus or continuous infusion of anesthetic drugs.

Estimating the rate of thiopental blood-brain equilibration using pseudo steady state serum concentrations.

The equilibration between drug serum concentration and drug effect under non-steady state concentrations has been classically modeled using an effect compartment where the transfer from the serum to the effect compartment is considered to be a first-order process. The purpose of the present study was to examine whether an effect compartment with first-order transfer was adequate for describing thiopental serum concentration-EEG pharmacodynamics. The study has two facets: (i) Successive pseudo steady state serum concentrations of thiopental having a square wave shape were produced and maintained in six human subjects by means of a computer-driven infusion pump. An aperiodic wave form transformation of the electroencephalogram (EEG) was used as a continuous measure of thiopental EEG drug effect. The time course of the EEG effect following each thiopental serum concentration square wave showed an exponential pattern. The first-order rate constant for equilibration of the effect site concentration with the drug serum concentration (keo) was estimated by fitting a monoexponential model to the effect vs. time data resulting from the pseudo steady state thiopental serum concentration profile. (ii) In a second experiment, data were obtained from a classical design, i.e., a zero-order intravenous infusion of thiopental. The same subjects were studied. The keo was estimated by means of a semiparametric iterative method using convolution (effect compartment, transfer of drug from serum to site of action is assumed to be a first-order process). The mean pseudo steady state value for keo of 0.51 min-1 was not different from the mean value of 0.46 min-1 from the semi parametric approach when data from a linear portion of the drug concentration vs. effect curve were examined. The pseudo steady state technique gave inaccurate estimates of keo in the nonlinear portion of the thiopental concentration vs. response curve, i.e., at the peak of the biphasic concentration-effect relationship.

Evaluation of population (NONMEM) pharmacokinetic parameter estimates.

The application of population pharmacokinetic analysis has received increasing attention in the last few years. The main goal of this report is to make investigators aware of the necessity of independent evaluation of the results obtained from a population analysis based on observational studies. We also describe with the help of a specific example (a new synthetic opiate Alfentanil) how such evaluation can be performed for parameter estimates obtained with the software system NONMEM. The method differs depending on the type of serum concentration data that are used for the evaluation. A general method is described, based on the regression model used in NONMEM, that can test for bias in the estimates of fixed and random effects independent of the number of observations per patient and dosing. Since the procedure for testing for statistically significant bias in the prediction of the average concentration and its variability can be relatively complex, we propose that generally available program packages performing estimation of the pharmacokinetic parameters from observational data should contain the necessary software to evaluate the reliability of the parameter estimates on a second data set.

Population pharmacokinetics and pharmacodynamics of thiopental: the effect of age revisited.

The authors have previously attributed the mechanism for the 50-67% decrease in the required dose of thiopental for induction of anesthesia in aged human patients to a decrease in the initial distribution volume for thiopental. Using a larger group of patients and volunteers studied in the laboratory, the authors have re-examined thiopental pharmacokinetics and EEG pharmacodynamics relative to age. A population data analysis approach (NONMEM), using a three-compartment model, was used to analyze bolus and rapid iv infusion thiopental serum concentration versus time data from 64 subjects. A one-compartment model was also used on the first 10 min of serum concentration data to focus only on the initial distribution phase. The population pharmacokinetic analysis demonstrated that when thiopental is administered via an iv bolus injection, traditional pharmacokinetic models limit the accurate characterization of thiopental distribution phenomena. Using the rapid iv infusion data, the pharmacokinetic mechanism for the decreased thiopental dose requirement in the elderly was a decreased rapid intercompartment clearance. Thiopental distribution from the central compartment of the three-compartment model to the rapidly equilibrating compartment (rapid intercompartment clearance) decreased 27% between the ages of 35-80 yr and decreased 34% in the one-compartment analysis. EEG spectral edge versus time data from 37 subjects was analyzed with a semiparametric modelling approach to remove the disequilibrium between thiopental serum concentration and the spectral edge. A population data analysis (NONMEM) was performed with several pharmacodynamic models. There was no age-related change in brain responsiveness or pharmacodynamics when the spectral edge is used as a measure of drug effect.

Chronic alcohol intake does not change thiopental anesthetic requirement, pharmacokinetics, or pharmacodynamics.

The anesthetic requirements of chronic alcoholics for induction of anesthesia with thiopental were investigated using an electroencephalographic (EEG) measure of thiopental's CNS drug effect and pharmacodynamic modeling to relate thiopental serum concentrations to drug effect. Eleven patients with a history of excessive alcohol intake were studied from an inpatient alcohol rehabilitation program and compared with nine control patients or volunteers who were social drinkers. The alcoholic population had consumed ethanol 9-17 days prior to the study. They had no evidence of acute intoxication or acute withdrawal at the time of the study. Five of the 11 alcoholic patients were restudied after 1 month of abstinence from alcohol consumption. Each study consisted of a thiopental infusion until EEG burst suppression (1-3 s of isoelectric signal) was achieved. Timed arterial and then venous blood samples were obtained for measurement of thiopental serum concentrations for up to 36 h. Pharmacokinetic differences between groups were analyzed using a three-compartment model. Power spectral analysis of the EEG allowed determination of spectral edge frequency. An inhibitory sigmoid Emax pharmacodynamic model combined with an effect compartment was used to analyze concentration-response relationships and to provide an estimate of brain sensitivity to thiopental in the study populations. The thiopental anesthetic dose requirement using the EEG was not different between alcoholics and nonalcoholics. The mean dose requirement (+/- SD) of alcoholics was 823 +/- 246 mg and the mean dose requirement of nonalcoholics was 733 +/- 218 mg. There were no differences in thiopental pharmacokinetic and pharmacodynamic parameters between alcoholics and nonalcoholics.(ABSTRACT TRUNCATED AT 250 WORDS)

Postoperative sedation with midazolam in heart surgery patients: pharmacokinetic considerations.

Midazolam remains one of the few drugs that can safely be used for the sedation of intubated patients in an intensive care unit. Midazolam pharmacokinetics in patients recovering from cardiac surgery were recently reported and found to be different from the drug's kinetics in young and healthy patients or volunteers. In particular, the elimination half-life was prolonged (10.6 h) and the metabolic clearance was reduced. For the clinician, pharmacokinetics parameters do not have a straightforward meaning. The purpose of the present paper is to review the pharmacokinetics of midazolam in this category of patients, and to examine what kind of practical information and dosing recommendation can be derived.

Pharmacokinetics of midazolam in patients recovering from cardiac surgery.

The pharmacokinetics of midazolam has been studied in patients recovering from cardiac surgery, who required sedation for postoperative mechanical ventilation. Twelve males (mean age 64.5 years) with severe heart disease received an infusion of midazolam 15 mg.h-1 for 4 h, starting 1 to 3 h post surgery. Multiple blood samples were collected from each patient during the infusion and up to 48-93 h after it. The pharmacokinetic parameters of midazolam were determined using both moment analysis and the program NONMEM. The average terminal half-life was 10.6 h. The prolonged elimination was mainly due to a decrease in its metabolic clearance (0.25 l.min-1). The maintenance infusion dose of midazolam in such patients should be reduced. The time to recovery after stopping an infusion depends upon the amount of drug in the body at that time and a simulation of the plasma concentrations after various infusion regimens suggests that recovery will be delayed after prolonged (greater than 48 h) administration of midazolam to these patients. However, after shorter infusions (less than 12 h), redistribution of the drug away from the site of action was still occurring and recovery would be expected to be relatively rapid.

Bayesian forecasting improves the prediction of intraoperative plasma concentrations of alfentanil.

To achieve therapeutic plasma concentrations of the opioid alfentanil, one must administer the drug as a variable rate continuous infusion. For most patients, using population pharmacokinetic parameters of alfentanil for dosing regimen allows accurate prediction of the plasma concentration of the drug over time. However, for some patients, using such parameters results in systematic over- or underprediction of the concentration. Retrospectively studying a data set (dosage history and measured concentrations) for 34 patients, the authors examined how Bayesian forecasting could improve the precision of prediction. For each patient, a Bayesian regression was performed to estimate "individualized" pharmacokinetic parameters, using population pharmacokinetic values for alfentanil and the measurement of alfentanil in one or more plasma samples from each patient. These individualized parameters were then used to predict the subsequent plasma concentrations of alfentanil over time. By comparing the value of each measured point with its corresponding predicted value, the authors calculated the prediction error as a percentage of the measured value. The precision of the prediction was assessed by the percent mean absolute prediction error. After Bayesian forecasting using a single point sampled at 80 min after start of anesthesia, the average precision of the prediction was 13.8 +/- 6.1% (SD). Using no Bayesian forecasting and only population values of the pharmacokinetic parameters for the prediction of the concentration, the precision was 24.3 +/- 16.9%. The improvement in precision brought by Bayesian forecasting was especially noticeable for those patients whose prediction of alfentanil was poor using population pharmacokinetic values (i.e., "outlier" patients).(ABSTRACT TRUNCATED AT 250 WORDS)

Midazolam in plasma from hospitalized patients as measured by gas-liquid chromatography with electron-capture detection.

The present assay was developed for quantifying midazolam in plasma of patients hospitalized in intensive-care units or undergoing anesthesia and receiving many other drugs as well. Plasma samples are alkalinized with NaOH and midazolam is extracted into n-hexane. The organic phase is evaporated and reconstituted in n-butyl acetate, and the midazolam is quantified by gas-liquid chromatography with electron-capture detection. The calibration graph for midazolam was linear in the ranges 5-200 and 200-800 micrograms/L. The CVs for precision and reproducibility of the assay were less than 8%. The method was very specific for midazolam; most of the drugs commonly used in anesthesia and in the intensive-care unit did not interfere with the assay. The lowest detectable concentration was 1 microgram/L. The method is adaptable for use with an automated chromatographic system.

Evaluating the accuracy of using population pharmacokinetic data to predict plasma concentrations of alfentanil.

A major reason for quantitating the relationship of drug dose to plasma concentration is to design optimal drug administration schemes (i.e., those that can achieve desired target concentrations of a drug). Recently, the authors completed a population pharmacokinetic analysis of the new opioid alfentanil using the computer program NONMEM. This analysis quantified the effects of age, weight, and sex on disposition of alfentanil in 45 patients, and determined the average pharmacokinetic profile of the drug for the group. Using these population pharmacokinetic parameters, one can predict (estimate) the plasma concentration time course of alfentanil for any given dosage scheme. The present study evaluated the accuracy with which one could use these population data to predict plasma concentrations of alfentanil in a different group of surgical patients given iv boluses and a variable-rate infusion of alfentanil for induction and maintenance of anesthesia for abdominal and superficial surgery. A total of 597 plasma concentrations of alfentanil were measured for 19 patients. For each measured concentration, we used the population pharmacokinetic parameters obtained previously with NONMEM to calculate a predicted concentration. Accuracy and precision of the prediction were assessed by the mean bias of the prediction and by the mean absolute prediction error, respectively. The mean bias (+/- SE) (systematic over- or underprediction) was -7.9 +/- 5.2%. The mean absolute error (+/- SE), a measure of the precision, was 22.3 +/- 2.9%. Therefore, the authors' previously described population pharmacokinetic parameters for alfentanil appear to be "robust," and can be used to design computerized schemes for administration of alfentanil for general surgery.

Population pharmacokinetics of alfentanil: the average dose-plasma concentration relationship and interindividual variability in patients.

The population pharmacokinetic parameters describing the plasma concentration versus time profile of alfentanil in patients undergoing general anesthesia were determined from 614 plasma concentration measurements collected in four previously reported studies with a total of 45 patients. A nonlinear regression analysis evaluating the effect of six concomitant variables revealed a significant influence of body weight on the volume of the central compartment (Vc), and a decrease with age of total body clearance (CL) and of redistribution rate from the deep compartment (k31). A small but significant effect of sex on the Vc was also observed. The duration of anesthesia and the concomitant administration of inhalational anesthetics had no effect on alfentanil pharmacokinetic parameters. The mean CL and Vc for alfentanil in a 70-kg male, aged less than 40 yr, were estimated as 0.356 l/min and 7.77 l, respectively. After correction for age, body weight, and sex, the remaining interindividual variability of alfentanil kinetics (expressed as coefficient of variation) was 48% for CL and 33% for Vc. These population pharmacokinetic parameter estimates should increase the accuracy of predicting concentration-time profiles for intravenous alfentanil infusions. A computer program is presented that allows prediction of the alfentanil plasma concentration and the 68% interval limits of the prediction from the study data analysis.

The TUTOR, a software package for educational computing.

Computer Assisted Instruction (CAI) is an effective method of imparting factual knowledge relating to the practice of medicine. Unfortunately educational software remains scarse and expensive or lacks flexibility. This paper introduces a software package that permits continuing medical education and self assessment by Multiple Choice Question exercises. The questions are first written to a text file with an easy-to-use editor. The programs are written in BASIC and hardware prerequisite are a desk-top computer with 32K of CPU memory and a dual floppy disk drive.

[Intravenous sedation for gastroscopy: comparison between midazolam and diazepam]. / Sédation par voie intraveineuse pour gastroscopie: comparaison midazolam-diazépam.

Benzodiazepines are often used as premedication or intravenous sedative agents for endoscopies. The present study included 74 patients. It compared the sedative and amnestic properties of midazolam and diazepam, their relative potencies as well as the comfort of both the patient and the endoscopist during gastroscopy. The comparison has shown some statistically significant differences, allowing the following conclusions: amnesia was more frequent with midazolam; the dose requirement (in mg X kg-1) for adequate sedation was more important with diazepam, confirming the greater potency of midazolam; generally speaking, sedation was excellent with both drugs.