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  • 1
    Electronic Resource
    Electronic Resource
    Bispectral Index (BIS) and Burst Suppression: Revealing a Part of the BIS Algorithm (2000)
    Springer
    Journal of clinical monitoring and computing 16 (2000), S. 593-596 
    Details
    ISSN: 1573-2614
    Keywords: EEG ; monitoring
    Source: Springer Online Journal Archives 1860-2000
    Topics: Computer Science , Medicine
    Notes: Abstract Objective. The bispectral index (BIS) is a complex EEG parameter which integrates several disparate descriptors of the EEG into a single variable. One of the subparameters incorporated in the BIS is the suppression ratio, quantifying the percentage of suppression during burst suppression pattern. The exact algorithm used to synthetize the information to the BIS value is unpublished and still unknown. This study provides insight into the integration of the suppression ratio into the BIS algorithm. Methods. EEG data of 10 healthy volunteers during propofol infusion were analyzed. Propofol concentrations were ramped up to 4 predetermined concentrations (1, 2, 3, 4, 6, 8, 9, or 12 µg/ml) using a computer controlled infusion pump (STANPUMP). EEG recordings were performed with an Aspect A-1000 EEG monitor (Version 3.22). The relationship of the processed EEG variables bispectral index and suppression ratio, calculated by the Aspect A-1000 monitor, was analyzed. Results. Up to 40% suppression ratio the average BIS values remained constant regardless of suppression ratios (r= 0.13). Beyond a suppression ratio of 40%, BIS and suppression ratio were invariably linearly correlated (r= −1). At a suppression ratio ≥ 40% the BIS value could be calculated as BIS = 50 – suppression ratio/2. Conclusions. Suppression ratio values 〉 40% are linearly correlated with BIS values from 30 to 0. An increasing anesthetic drug effect resulting in an increase of the duration of suppression to a suppression ratio up to 40% is not adequately reflected by the BIS value.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1012216600170
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  • 2
    Electronic Resource
    Electronic Resource
    An efficient control strategy for dosage regimens (1994)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 22 (1994), S. 73-94 
    Details
    ISSN: 1573-8744
    Keywords: Bayesian ; compartment model ; discrete prior ; dose regimen design ; pharmacokinetics ; stochastic control
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract In medical drug therapy, efficient dosage strategies are needed to maintain target drug concentrations. The relationship between the concentration of a drug and the dosages is often described by compartment models in which the parameters are unknown, although prior knowledge may be available and can be updated after blood samples are taken during the therapy. Currently MAP (maximum a posteriori) Bayesian is the most often used control strategy in this setting. We show by simulation in a one-compartment context that the performance of the MAP Bayesian strategy depends on the assumptions in prior distribution of the parameters as well as the cost function. We propose an alternative control strategy, VU, that outperforms and is more robust than the MAP Bayesian strategy in a variety of problem settings.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02353411
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  • 3
    Electronic Resource
    Electronic Resource
    A comparison of parametric with semiparametric analysis of the concentration versus effect relationship of metocurine in dogs and pigs (1989)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 17 (1989), S. 291-304 
    Details
    ISSN: 1573-8744
    Keywords: Pharmacokinetics ; pharmacodynamics ; compartmental and effect compartment modeling ; semiparametric modeling ; neuromuscular relaxants ; metocurine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract We investigated the ability of two pharmacokinetic modeling techniques to estimate the equilibration delay (i.e., hysteresis) between plasma drug concentration and observed drug effect. The data were from 20 animals (15 dogs, 5 pigs) receiving an infusion of metocurine, a neuromuscular blocking drug. An effect compartment model was used to model the hysteresis and characterize the relationship between drug concentration and effect. The effect compartment model requires identification of ke0, the rate constant of drug elimination from the effect compartment. Two methods were used to estimate ke0. The first technique was to fit the plasma metocurine concentration-time curve to a two-compartment pharmacokinetic model and then to use this pharmacokinetic model, along with the neuromuscular blockade vs. time curve to estimate ke0 and the parameters of a pharmacodynamic model (the Hill equation). The second technique was to directly estimate ke0 by a recently described semiparametric technique that does not require either a pharmacokinetic or pharmacodynamic model, although it does assume that drug flux to and front the effect compartment is a first-order process. This semiparametric technique only estimates a single parameter, ke0. The results from the new semiparametric analysis technique were similar to the results from the parametric analysis. In the few animals where the results differed, the semi-parametric analysis produced a better description of the data.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01061898
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  • 4
    Electronic Resource
    Electronic Resource
    Estimating the rate of thiopental blood-brain equilibration using pseudo steady state serum concentrations (1990)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 18 (1990), S. 175-187 
    Details
    ISSN: 1573-8744
    Keywords: pharmacodynamic modeling ; pharmacokinetic modeling ; thiopental ; effect compartment ; pseudo steady state ; computer-driven infusion scheme
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract 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 (k eo ) 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 k eo was estimated by means of a semipammetric 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 k eo 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 k eo in the nonlinear portion of the thiopental concentration vs. response curve, i.e., at the peak of the biphasic concentration-effect relationship.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01062198
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  • 5
    Electronic Resource
    Electronic Resource
    Comparison of some control strategies for three-compartment PK/PD models (1994)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 22 (1994), S. 525-550 
    Details
    ISSN: 1573-8744
    Keywords: Bayesian ; compartment model ; dose regimen design ; pharmacokinetics ; pharmacodynamics ; stochastic control ; effect site
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract In drug therapy, effective dosage strategies are needed to maintain target drug effects. The relationship between drug dose and drug effect is often described by pharmacokinetic/pharmacodynamic (PK/PD) models where typically the PK model has a multicompartment form and the PD model is the sigmoidal Emax model. The parameters in the PK/PD model are generally unknown in the individual patient, although prior knowledge may be available and can be updated after measurements of drug effect are taken during the therapy. This fact, together with the complexity of the PK/PD model, makes the control problem complex. This paper investigates several control strategies in the framework of a three-compartment PK model plus an effect site with a PD model. Using computer simulations under different assumptions, we show that a MAP (maximum a posteriori) Bayesian type of strategy is effective, nevertheless in high-risk situations a stochastic control strategy hedging against estimation errors provides better performance at computational cost.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02353793
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  • 6
    Electronic Resource
    Electronic Resource
    Measuring the predictive performance of computer-controlled infusion pumps (1992)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 20 (1992), S. 63-94 
    Details
    ISSN: 1573-8744
    Keywords: anesthesia ; computer-assisted equipment ; infusion pump ; performance pharmacokinetics ; predictive performance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Current measures of the performance of computer-controlled infusion pumps (CCIPs) are poorly defined, of little use to the clinician using the CCIP, and pharmacostatistically incorrect. We propose four measures be used to quantitate the performance of CCIPs: median absolute performance error (MDAPE), median performance error (MDPE), divergence, and wobble. These measures offer several significant advantages over previous measures. First, their definitions are based on the performance error as a fraction of the predicted (rather than measured) drug concentration, making the measures much more useful to the clinician. Second, the measures are defined in a way that addresses the pharmacostatistical issue of appropriate estimation of population parameters. Finally, the measure of inaccuracy, MDAPE, is defined in a way that is consistent with iteratively reweighted least squares nonlinear regression, a commonly used method of estimating pharmacokinetic parameters. These measures make it possible to quantitate the overall performance of a CCIP or to compare the predictive performance of CCIPs which differ in either general approach (e.g., compartmental model driven vs. plasma efflux approach), pump mechanics, software algorithms, or pharmacokinetic parameter sets.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01143186
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  • 7
    Electronic Resource
    Electronic Resource
    Algorithms to rapidly achieve and maintain stable drug concentrations at the site of drug effect with a computer-controlled infusion pump (1992)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 20 (1992), S. 147-169 
    Details
    ISSN: 1573-8744
    Keywords: computers ; pharmacokinetics ; pharmacodynamics ; infusions ; drug delivery ; computer driven ; effect site
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Computer-controlled infusion pumps incorporating an internal model of drug pharmacokinetics can rapidly achieve and maintain constant drug concentrations in the plasma. Although these pumps offer more accurate titration of intravenous drugs than is possible with simple boluses or constant rate infusions, the choice of the plasma as the target site is arbitrary. The plasma is not the site of drug effect for most drugs. This manuscript describes two algorithms for calculation of the infusion rates necessary for a computer-controlled infusion pump to rapidly achieve, and then maintain, the desired target concentration at the site of drug effect rather than in the plasma.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01070999
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  • 8
    Electronic Resource
    Electronic Resource
    Application of semilinear canonical correlation to the measurement of opioid drug effect (1992)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 20 (1992), S. 611-635 
    Details
    ISSN: 1573-8744
    Keywords: pharmacokinetics ; pharmacodynamics ; plasma concentration-effect relation-ship ; anesthesia ; analgesic ; narcotic ; opioids ; alfentanil ; brain ; electroencephalograph ; spectral edge ; semilinear canonical correlation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract To examine the relationship between the electroencephalograph (EEG) and plasma opioid concentration, one would like to collapse the high-dimensional EEG signal into a univariate quantity. Such a simplification of the EEG is desirable because a univariate quantity can be modeled using standard nonlinear regression techniques, and because most of the information in the EEG is redundant or unrelated to drug concentration. In previous studies of the EEG response to opioids, the manner in which a univariate component was extracted from the EEG was ad hoc.In this paper, this extraction was performed optimally using a new statistical technique, semilinear canonical correlation. Data from 15 patients who received an intravenous infusion of the semisynthetic opioid alfentanil were analyzed. The components of the EEG that were nearly maximally correlated with plasma drug concentration were found, based on a standard pharmacokinetic-pharmacodynamic model. Two new EEG components were produced from the powers in the frequency spectrum of the EEG: a weighted sum of the logarithms of the powers, and a weighted sum of the powers expressed as percentages of the total power. These components both had a median R2 of 0.84, compared to median R2sranging from 0.37 to 0.83 for five commonly used ad hocEEG components. The new components also had less variability in R2 between subjects.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01064422
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  • 9
    Electronic Resource
    Electronic Resource
    Plasma Concentration Clamping in the Rat Using a Computer-Controlled Infusion Pump (1992)
    Springer
    Pharmaceutical research 9 (1992), S. 800-807 
    Details
    ISSN: 1573-904X
    Keywords: computers ; infusion pumps ; infusions, intravenous ; pharmacokinetics ; thiopental ; rats ; computer-controlled drug delivery ; nonlinear regression
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract We have developed a computer-controlled infusion pump to achieve rapidly and then maintain stable plasma thiopental concentrations in rats. Initially we derived the parameters of a triexponential pharma-cokinetic model for thiopental, administered as a brief infusion to 10 rats, using nonlinear regression and standard pharmacokinetic equations. These parameters were incorporated into the pharmacokinetic model of a computer-controlled infusion pump. In a second group of animals this device was used to maintain three consecutive target thiopental concentrations ranging from 5 to 100 µg/ml in a stepwise fashion. Arterial blood gases were kept normal through controlled ventilation when necessary. The plasma thiopental concentrations in this second group of animals were generally higher than the target concentrations. The bias in pump performance (median prediction error) was +25%, and the inaccuracy (median absolute prediction error) was 26%. We fit the parameters of a three-compartment model to the plasma thiopental concentrations observed in the second group of animals. This produced a second set of thiopental pharmacokinetic parameters with the unique characteristic of having been derived from a computer controlled infusion study. These parameters were tested prospectively with a computer-controlled infusion pump in a third group of animals. This second set of thiopental pharmacokinetic parameters performed better, with a median prediction error of 0% and a median absolute prediction error of 15%. This study shows that it is possible to achieve rapidly and maintain steady plasma thiopental concentrations in the rat. Our results suggest that it is feasible to derive robust pharmacokinetic parameters from unusual drug dosing approaches, such as employed by a computer-controlled infusion pump. The ability rapidly to clamp plasma drug concentrations at desired targets in small laboratory animals will facilitate research into the relationship of plasma and tissue concentration to drug effect.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015863824277
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  • 10
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    Pharmacokinetic-pharmacodynamic modeling in drug development: Application to the investigational opioid trefentanil (1994)
    Wiley
    Details
    Publication Date: 1994-09-01
    Print ISSN: 0009-9236
    Electronic ISSN: 1532-6535
    Topics: Chemistry and Pharmacology , Medicine
    Published by Wiley
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