Steven Shafer

All Publications

• Calculating the probability of random sampling for continuous variables in submitted or published randomised controlled trials ANAESTHESIA Carlisle, J. B., Dexter, F., Pandit, J. J., Shafer, S. L., Yentis, S. M. 2015; 70 (7): 848-858

  View details for DOI 10.1111/anae.13126

  View details for Web of Science ID 000356090300012

• Publication Bias, Retrospective Bias, and Reproducibility of Significant Results in Observational Studies ANESTHESIA AND ANALGESIA Shafer, S. L., Dexter, F. 2012; 114 (5): 931-932

  View details for DOI 10.1213/ANE.0b013e31824a0b5b

  View details for Web of Science ID 000303231400005

  View details for PubMedID 22523409

• Shadow of Doubt ANESTHESIA AND ANALGESIA Shafer, S. L. 2011; 112 (3): 498-500

  View details for DOI 10.1213/ANE.0b013e31820ad3b7

  View details for Web of Science ID 000287698400004

  View details for PubMedID 21296856

• You Will Be Caught ANESTHESIA AND ANALGESIA Shafer, S. L. 2011; 112 (3): 491-493

  View details for DOI 10.1213/ANE.0b013e3182095c73

  View details for Web of Science ID 000287698400001

  View details for PubMedID 21350222

• The need for a journal policy on intrathecal, epidural, and perineural administration of non-approved drugs PAIN Eisenach, J. C., Shafer, S. L., Yaksh, T. 2010; 149 (3): 417-419

  View details for DOI 10.1016/j.pain.2010.02.028

  View details for Web of Science ID 000277804700002

  View details for PubMedID 20227830

• Consent Contraindicated? SCIENCE Yaksh, T. L., Eisenach, J. C., Shafer, S. L. 2010; 328 (5974): 45-45

  View details for Web of Science ID 000276202200019

  View details for PubMedID 20360092

• Mathematical Modeling of the Pain and Progress of the First Stage of Nulliparous Labor ANESTHESIOLOGY Debiec, J., Conell-Price, J., Evansmith, J., Shafer, S. L., Flood, P. 2009; 111 (5): 1093-1110

  Abstract

  Patient characteristics may contribute to the progress and pain of labor. Quantitative evaluation of the effects of patient characteristics requires robust mathematical models of labor progress and labor pain.The authors retrospectively studied 100 sequential deliveries from each of five self-reported ethnic groups (Asian, Black, Hispanic, Other, and White). Demographic variables, cervical dilation, and numerical rating scores for pain before analgesia and cervical dilation were abstracted from the automated medical record. Labor progress was modeled with a biexponential function describing the latent and active phases of labor. Labor pain was modeled as a sigmoid function of cervical dilation by using a previously validated mathematical model. The covariates, including self-described ethnicity, were analyzed with NONMEM.The biexponential function described the time course of labor progress better than several alternative functions, including the sigmoidal function introduced by Friedman. The sigmoidal function of labor pain described its dynamic nature well, with substantial intersubject variability. Asian women had slower active labor than other ethnicities (P < 0.01). Asian women also reported less pain during their labor compared to all other patients (P < 0.001). Slower labor progress was associated with less rapid progression of pain, but this did not obviate the effect of Asian ethnicity on pain. Neuraxial analgesia is strongly associated with slower labor (P < 0.0001). Greater maternal weight was associated with slower active labor (P < 0.0001).Mathematical models can be used to detect subtle effects of patient covariates on the progress and pain of the first stage of labor. Asian women and heavier women had slower labor and slower onset of labor pain than others. These effects were modest compared with the substantial remaining unexplained subject-to-subject variability in labor progress and labor pain.

  View details for Web of Science ID 000271172500021

  View details for PubMedID 19858874

• Additivity versus synergy: A theoretical analysis of implications for anesthetic mechanisms ANESTHESIA AND ANALGESIA Shafer, S. L., Hendrickx, J. F., Flood, P., Sonner, J., Eger, E. I. 2008; 107 (2): 507-524

  Abstract

  Inhaled anesthetics have been postulated to act at multiple receptors, with modest action at each site summing to produce immobility to noxious stimulation. Recent experimental results affirm prior findings that inhaled anesthetics interact additively. Synergy implies multiple sites of action by definition. In this essay, we explore the converse: does additivity imply a single site of action?The interaction of one versus two ligands competing for the same binding site at a receptor was explored using the law of mass action. Circuits were then constructed to investigate how the potency of drugs and the steepness of the concentration versus response relationship is amplified by the arrangement of suppressors into serial circuits, and enhancers into parallel circuits. Assemblies of suppressor and enhancer circuits into signal processing units were then explored to investigate the constraints signal processing units impose on additive interactions. Lastly, the relationship between synergy, additivity, and fractional receptor occupancy was explored to understand the constraints imposed by additivity.Drugs that compete for a single receptor, and that similarly affect the receptor, must be additive in their effects. Receptors that bind suppressors in serial circuits, or enhancers in parallel circuits, increase the apparent potency of the drugs and the steepness of the concentration versus response relationship. When assemblies of suppressor and enhancer circuits are arranged into signal processing units, the interactions may be additive or synergistic. The primary determinant is the relationship between the concentration of drug associated with the effect of interest and the concentration associated with 50% receptor occupancy, k(d). Effects mediated by very low concentrations are more likely to be additive. Similarly, inhaled anesthetics that act at separate sites are unlikely to exhibit additive interactions if anesthetic drug effect occurs at concentrations at or above 50% receptor occupancy. However, if anesthetic drug effect occurs at very low levels of receptor occupancy, then additivity is expected even among anesthetics acting on different receptors.Additivity among drugs acting on different receptors is only likely if the concentrations responsible for the drug effect of interest are well below the concentration associated with 50% receptor occupancy.

  View details for DOI 10.1213/ane.0b013e31817b7140

  View details for Web of Science ID 000258168300025

  View details for PubMedID 18633029

• Is synergy the rule? A review of anesthetic interactions a producing hypnosis and immobility ANESTHESIA AND ANALGESIA Hendrickx, J. F., Eger, E. I., Sonner, J. M., Shafer, S. L. 2008; 107 (2): 494-506

  Abstract

  Drug interactions may reveal mechanisms of drug action: additive interactions suggest a common site of action, and synergistic interactions suggest different sites of action. We applied this reasoning in a review of published data on anesthetic drug interactions for the end-points of hypnosis and immobility.We searched Medline for all manuscripts listing propofol, etomidate, methohexital, thiopental, midazolam, diazepam, ketamine, dexmedetomidine, clonidine, morphine, fentanyl, sufentanil, alfentanil, remifentanil, droperidol, metoclopramide, lidocaine, halothane, enflurane, isoflurane, sevoflurane, desflurane, N2O, and Xe that contained terms suggesting interaction: interaction, additive, additivity, synergy, synergism, synergistic, antagonism, antagonistic, isobologram, or isobolographic. When available, data were reanalyzed using fraction analysis or response surface analysis.Between drug classes, most interactions were synergistic. The major exception was ketamine, which typically interacted in either an additive or infra-additive (antagonistic) manner. Inhaled anesthetics typically showed synergy with IV anesthetics, but were additive or, in the case of nitrous oxide and isoflurane, possibly infra-additive, with each other.Except for ketamine, IV anesthetics acting at different sites usually demonstrated synergy. Inhaled anesthetics usually demonstrated synergy with IV anesthetics, but no pair of inhaled anesthetics interacted synergistically.

  View details for DOI 10.1213/ane.0b013e31817b859e

  View details for Web of Science ID 000258168300024

  View details for PubMedID 18633028

• In silico pharmacogenetics of warfarin metabolism NATURE BIOTECHNOLOGY Guo, Y. Y., Weller, P., Farrell, E., Cheung, P., Fitch, B., Clark, D., Wu, S. Y., Wang, J. M., Liao, G. C., Zhang, Z. M., Allard, J., Cheng, J., Nguyen, A., Jiang, S., Shafer, S., Usuka, J., Masjedizadeh, M., Peltz, G. 2006; 24 (5): 531-536

  Abstract

  Pharmacogenetic approaches can be instrumental for predicting individual differences in response to a therapeutic intervention. Here we used a recently developed murine haplotype-based computational method to identify a genetic factor regulating the metabolism of warfarin, a commonly prescribed anticoagulant with a narrow therapeutic index and a large variation in individual dosing. After quantification of warfarin and nine of its metabolites in plasma from 13 inbred mouse strains, we correlated strain-specific differences in 7-hydroxywarfarin accumulation with genetic variation within a chromosomal region encoding cytochrome P450 2C (Cyp2c) enzymes. This computational prediction was experimentally confirmed by showing that the rate-limiting step in biotransformation of warfarin to its 7-hydroxylated metabolite was inhibited by tolbutamide, a Cyp2c isoform-specific substrate, and that this transformation was mediated by expressed recombinant Cyp2c29. We show that genetic variants responsible for interindividual pharmacokinetic differences in drug metabolism can be identified by computational genetic analysis in mice.

  View details for DOI 10.1038/nbt1195

  View details for Web of Science ID 000237331300027

  View details for PubMedID 16680137

• In silico genetics: Identification of a functional element regulating H2-E alpha gene expression SCIENCE Liao, G. C., Wang, J. M., Guo, J. S., Allard, J., Cheng, J., Ng, A., Shafer, S., Puech, A., McPherson, J. D., Foernzler, D., Peltz, G., Usuka, J. 2004; 306 (5696): 690-695

  Abstract

  Computational tools can markedly accelerate the rate at which murine genetic models can be analyzed. We developed a computational method for mapping phenotypic traits that vary among inbred strains onto haplotypic blocks. This method correctly predicted the genetic basis for strain-specific differences in several biologically important traits. It was also used to identify an allele-specific functional genomic element regulating H2-Ealpha gene expression. This functional element, which contained the binding sites for YY1 and a second transcription factor that is probably serum response factor, is located within the first intron of the H2-Ealpha gene. This computational method will greatly improve our ability to identify the genetic basis for a variety of phenotypic traits, ranging from qualitative trait information to quantitative gene expression data, which vary among inbred mouse strains.

  View details for DOI 10.1126/science.1100636

  View details for Web of Science ID 000224756700053

  View details for PubMedID 15499019

• Pharmacodynamic interaction between propofol and remifentanil regarding hypnosis, tolerance of laryngoscopy, bispectral index, and electroencephalographic approximate entropy ANESTHESIOLOGY Bouillon, T. W., Bruhn, J., Radulescu, L., Andresen, C., Shafer, T. J., Cohane, C., Shafer, S. L. 2004; 100 (6): 1353-1372

  Abstract

  The purpose of this investigation was to describe the pharmacodynamic interaction between propofol and remifentanil for probability of no response to shaking and shouting, probability of no response to laryngoscopy, Bispectral Index (BIS), and electroencephalographic approximate entropy (AE).Twenty healthy volunteers received either propofol or remifentanil alone and then concurrently with a fixed concentration of remifentanil or propofol, respectively, via a target-controlled infusion. Responses to shaking and shouting and to laryngoscopy were assessed multiple times after allowing for plasma effect site equilibration. The raw electroencephalogram and BIS were recorded throughout the study, and AE was calculated off-line. Response surfaces were fit to the clinical response data using logistic regression or hierarchical response models. Response surfaces were also estimated for BIS and AE. Surfaces were visualized using three-dimensional rotations. Model parameters were estimated with NONMEM.Remifentanil alone had no appreciable effect on response to shaking and shouting or response to laryngoscopy. Propofol could ablate both responses. Modest remifentanil concentrations dramatically reduced the concentrations of propofol required to ablate both responses. The hierarchical response surface described the data better than empirical logistic regression. BIS and AE are more sensitive to propofol than to remifentanil.Remifentanil alone is ineffective at ablating response to stimuli but demonstrates potent synergy with propofol. BIS and AE values corresponding to 95% probability of ablating response are influenced by the combination of propofol and remifentanil to achieve this endpoint, with higher propofol concentrations producing lower values for BIS and AE.

  View details for Web of Science ID 000221551300005

  View details for PubMedID 15166553

• Mixed-effects modeling of the intrinsic ventilatory depressant potency of propofol in the non-steady state ANESTHESIOLOGY Bouillon, T., Bruhn, J., Radu-Radulescu, L., Andresen, C., Cohane, C., Shafer, S. L. 2004; 100 (2): 240-250

  Abstract

  Despite the ubiquitous use of propofol for anesthesia and conscious sedation and numerous publications about its effect, a pharmacodynamic model for propofol-induced ventilatory depression in the non-steady state has not been described. To investigate propofol-induced ventilatory depression in the clinically important range (at and below the metabolic hyperbola while carbon dioxide is accumulating because of drug-induced ventilatory depression), the authors applied indirect effect modeling to Paco2 data at a fraction of inspired carbon dioxide of 0 during and after administration of propofol.Ten volunteers underwent determination of their carbon dioxide responsiveness by a rebreathing design. The parameters of a power function were fitted to the end-expiratory carbon dioxide and minute ventilation data. The volunteers then received propofol in a stepwise ascending pattern with use of a target-controlled infusion pump until significant ventilatory depression occurred (end-tidal pressure of carbon dioxide > 65 mmHg and/or imminent apnea). Thereafter, the concentration was reduced to 1 microg/ml. Propofol pharmacokinetics and the Paco2 were determined from frequent arterial blood samples. An indirect response model with Bayesian estimates of the pharmacokinetics and carbon dioxide responsiveness in the absence of drug was used to describe the Paco2 time course. Because propofol reduces oxygen requirements and carbon dioxide production, a correction factor for propofol-induced decreasing of carbon dioxide production was included.The following pharmacodynamic parameters were found to describe the time course of hypercapnia after administration of propofol (population mean and interindividual variability expressed as coefficients of variation): F (gain of the carbon dioxide response), 4.37 +/- 36.7%; ke0, CO2, 0.95 min-1 +/- 59.8%; baseline Paco2, 40.9 mmHg +/- 12.8%; baseline minute ventilation, 6.45 l/min +/- 36.3%; kel, CO2, 0.11 min-1 +/- 34.2%; C50,propofol, 1.33 microg/ml +/- 49.6%; gamma, 1.68 +/- 21.3%.Propofol at common clinical concentrations is a potent ventilatory depressant. An indirect response model accurately described the magnitude and time course of propofol-induced ventilatory depression. The indirect response model can be used to optimize propofol administration to reduce the risk of significant ventilatory depression.

  View details for Web of Science ID 000188438500008

  View details for PubMedID 14739795

• A model of the ventilatory depressant potency of remifentanil in the non-steady state ANESTHESIOLOGY Bouillon, T., Bruhn, J., Radu-Radulescu, L., Andresen, C., Cohane, C., Shafer, S. L. 2003; 99 (4): 779-787

  Abstract

  The C50 of remifentanil for ventilatory depression has been previously determined using inspired carbon dioxide and stimulated ventilation, which may not describe the clinically relevant situation in which ventilatory depression occurs in the absence of inspired carbon dioxide. The authors applied indirect effect modeling to non-steady state Paco2 data in the absence of inspired carbon dioxide during and after administration of remifentanil.Ten volunteers underwent determination of carbon dioxide responsiveness using a rebreathing design, and a model was fit to the end-expiratory carbon dioxide and minute ventilation. Afterwards, the volunteers received remifentanil in a stepwise ascending pattern using a computer-controlled infusion pump until significant ventilatory depression occurred (end-tidal carbon dioxide [Peco2] > 65 mmHg and/or imminent apnea). Thereafter, the concentration was reduced to 1 ng/ml. Remifentanil pharmacokinetics and Paco2 were determined from frequent arterial blood samples. An indirect response model was used to describe the Paco2 time course as a function of remifentanil concentration.The time course of hypercarbia after administration of remifentanil was well described by the following pharmacodynamic parameters: F (gain of the carbon dioxide response), 4.30; ke0 carbon dioxide, 0.92 min-1; baseline Paco2, 42.4 mmHg; baseline minute ventilation, 7.06 l/min; kel,CO2, 0.08 min-1; C50 for ventilatory depression, 0.92 ng/ml; Hill coefficient, 1.25.Remifentanil is a potent ventilatory depressant. Simulations demonstrated that remifentanil concentrations well tolerated in the steady state will cause a clinically significant hypoventilation following bolus administration, confirming the acute risk of bolus administration of fast-acting opioids in spontaneously breathing patients.

  View details for Web of Science ID 000185573500005

  View details for PubMedID 14508307

• Using the time of maximum effect site concentration to combine pharmacokinetics and pharmacodynamics ANESTHESIOLOGY Minto, C. F., Schnider, T. W., Gregg, K. M., Henthorn, T. K., Shafer, S. L. 2003; 99 (2): 324-333

  Abstract

  To simulate the time course of drug effect, it is sometimes necessary to combine the pharmacodynamic parameters from an integrated pharmacodynamic-pharmacodynamic study (e.g., volumes, clearances, k(e0) [the effect site equilibration rate constant], C(50) [the steady state plasma concentration associated with 50% maximum effect], and the Hill coefficient) with pharmacokinetic parameters from a different study (e.g., a study examining a different age group or sampling over longer periods of time). Pharmacokinetic-pharmacodynamic parameters form an interlocked vector that describes the relationship between input (dose) and output (effect). Unintended consequences may result if individual elements of this vector (e.g., k(e0)) are combined with pharmacokinetic parameters from a different study. The authors propose an alternative methodology to rationally combine the results of separate pharmacokinetic and pharmacodynamic studies, based on t(peak), the time of peak effect after bolus injection.The naive approach to combining separate pharmacokinetic and pharmacodynamic studies is to simply take the k(e0) from the pharmacodynamic study and apply it naively to the pharmacokinetic study of interest. In the t(peak) approach, k(e0) is recalculated using the pharmacokinetics of interest to yield the correct time of peak effect. The authors proposed that the t(peak) method would yield better predictions of the time course of drug effect than the naive approach. They tested this hypothesis in three simulations: thiopental, remifentanil, and propofol.In each set of simulations, the t(peak) method better approximated the postulated "true" time course of drug effect than the naive method.T(peak) is a useful pharmacodynamic parameter and can be used to link separate pharmacokinetic and pharmacodynamic studies. This addresses a common difficulty in clinical pharmacology simulation and control problems, where there is usually a wide choice of pharmacokinetic models but only one or two published pharmacokinetic-pharmacodynamic models. The results will be immediately applicable to target-controlled anesthetic infusion systems, where linkage of separate pharmacokinetic and pharmacodynamic parameters into a single model is inherent in several target-controlled infusion designs.

  View details for Web of Science ID 000184352400013

  View details for PubMedID 12883405

• Cephalad movement of morphine and fentanyl in humans after intrathecal injection ANESTHESIOLOGY Eisenach, J. C., Hood, D. D., Curry, R., Shafer, S. L. 2003; 99 (1): 166-173

  Abstract

  Despite decades of use, controversy remains regarding the extent and time course of cephalad spread of opioids in cerebrospinal fluid (CSF) after intrathecal injection. The purpose of this study was to examine differences between two often used opioids, morphine and fentanyl, in distribution in the CSF after intrathecal injection.Eight healthy volunteers received intrathecal injection of morphine (50 microg) plus fentanyl (50 microg) at a lower lumbar interspace. CSF was sampled through a needle in an upper lumbar interspace for 60-120 min. At the end of this time, a sample was taken from the lower lumbar needle, and both needles were withdrawn. CSF volume was determined by magnetic resonance imaging. Pharmacokinetic modeling was performed with NONMEM.Morphine and fentanyl peaked in CSF at the cephalad needle at similar times (41 +/- 13 min for fentanyl, 57 +/- 12 min for morphine). The ratio of morphine to fentanyl in CSF at the cephalad needle increased with time, surpassing 2:1 by 36 min and 4:1 by 103 min. CSF concentrations did not correlate with weight, height, or lumbosacral CSF volume. The concentrations of morphine and fentanyl at both sampling sites were well described by a simple pharmacokinetic model. The individual model parameters did not correlate with the distance between the needles, CSF volume, patient height, or patient weight.Fentanyl is cleared more rapidly from CSF than morphine, although their initial distribution in the first hour after injection does not differ greatly. The pharmacokinetic model demonstrates that mixing is the primary determinant of early concentrations and is highly variable among individuals.

  View details for Web of Science ID 000183782100026

  View details for PubMedID 12826857

• Efficient trial design for eliciting a pharmacokinetic-pharmacodynamic model-based response surface describing the interaction between two intravenous anesthetic drugs ANESTHESIOLOGY Short, T. G., Ho, T. Y., Minto, C. F., Schnider, T. W., Shafer, S. L. 2002; 96 (2): 400-408

  Abstract

  The authors published a pharmacokinetic- pharmacodynamic model for two drugs based on response surface methodology. Because of the complexity of the model, they performed a simulation study to answer two questions about use of the model: (1) which study design would be most satisfactory; and (2) how many patients would need to be studied to adequately describe an entire response surface.Data were simulated using realistic variability for two hypothetical intravenous anesthetic drugs that interact synergistically and that could be given by computer-controlled infusion. Three trial designs were simulated, one that made a series of parallel slices of the response surface, one that crisscrossed the response surface, and one that made a series of radial slices across the surface. Series of 5, 10, 20, and 40 "subjects" were simulated. A pooled data approach was used to assess the ability of the various trial designs and numbers of subjects to adequately identify the interaction response surface and estimate the original response surface.The crisscross design was shown to be the most robust in terms of its ability to both discriminate the correct order of the interaction term and to discriminate the original response surface using the least number of patients. Twenty subjects would be required to adequately define a surface using the crisscross study design, and 40 subjects would be required using the other trial designs.The results showed that a number of trial designs would be viable, but a design that crossed the surface in a crisscross fashion would give the most robust result with the least patients.

  View details for Web of Science ID 000173606400023

  View details for PubMedID 11818774

• Propofol dosing regimens for ICU sedation based upon an integrated pharmacokinetic-pharmacodynamic model ANESTHESIOLOGY Barr, J., Egan, T. D., Sandoval, N. F., Zomorodi, K., Cohane, C., Gambus, P. L., Shafer, S. L. 2001; 95 (2): 324-333

  Abstract

  The pharmacology of propofol infusions administered for long-term sedation of intensive care unit (ICU) patients has not been fully characterized. The aim of the study was to develop propofol dosing guidelines for ICU sedation based on an integrated pharmacokinetic-pharmacodynamic model of propofol infusions in ICU patients.With Institutional Review Board approval, 30 adult male medical and surgical ICU patients were given target-controlled infusions of propofol for sedation, adjusted to maintain a Ramsay sedation scale score of 2-5. Propofol administration in the first 20 subjects was based on a previously derived pharmacokinetic model for propofol. The last 10 subjects were given propofol based on a pharmacokinetic model derived from the first 20 subjects. Plasma propofol concentrations were measured, together with sedation score. Population pharmacokinetic and pharmacodynamic parameters were estimated by means of nonlinear regression analysis in the first 20 subjects, then prospectively tested in the last 10 subjects. An integrated pharmacokinetic-pharmacodynamic model was used to construct dosing regimens for light and deep sedation with propofol in ICU patients.The pharmacokinetics of propofol were described by a three-compartment model with lean body mass and fat body mass as covariates. The pharmacodynamics of propofol were described by a sigmoid model, relating the probability of sedation to plasma propofol concentration. The pharmacodynamic model for propofol predicted light and deep levels of sedation with 73% accuracy. Plasma propofol concentrations corresponding to the probability modes for sedation scores of 2, 3, 4, and 5 were 0.25, 0.6, 1.0, and 2.0 microg/ml. Predicted emergence times in a typical subject after 24 h, 72 h, 7 days, and 14 days of light sedation (sedation score = 3 --> 2) with propofol were 13, 34, 198, and 203 min, respectively. Corresponding emergence times from deep sedation (sedation score = 5 --> 2) with propofol were 25, 59, 71, and 74 h.Emergence time from sedation with propofol in ICU patients varies with the depth of sedation, the duration of sedation, and the patient's body habitus. Maintaining a light level of sedation ensures a rapid emergence from sedation with long-term propofol administration.

  View details for Web of Science ID 000170237800007

  View details for PubMedID 11506101

• Response surface model for anesthetic drug interactions Minto, C. F., Schnider, T. W., Short, T. G., Gregg, K. M., Gentilini, A., Shafer, S. L. LIPPINCOTT WILLIAMS & WILKINS. 2000: 1603-1616

  Abstract

  Anesthetic drug interactions traditionally have been characterized using isobolographic analysis or multiple logistic regression. Both approaches have significant limitations. The authors propose a model based on response-surface methodology. This model can characterize the entire dose-response relation between combinations of anesthetic drugs and is mathematically consistent with models of the concentration-response relation of single drugs.The authors defined a parameter, theta, that describes the concentration ratio of two potentially interacting drugs. The classic sigmoid Emax model was extended by making the model parameters dependent on theta. A computer program was used to estimate response surfaces for the hypnotic interaction between midazolam, propofol, and alfentanil, based on previously published data. The predicted time course of effect was simulated after maximally synergistic bolus dose combinations.The parameters of the response surface were identifiable. With the test data, each of the paired combinations showed significant synergy. Computer simulations based on interactions at the effect site predicted that the maximally synergistic three-drug combination tripled the duration of effect compared with propofol alone.Response surfaces can describe anesthetic interactions, even those between agonists, partial agonists, competitive antagonists, and inverse agonists. Application of response-surface methodology permits characterization of the full concentration-response relation and therefore can be used to develop practical guidelines for optimal drug dosing.

  View details for Web of Science ID 000087389300013

  View details for PubMedID 10839909

• The influence of age on propofol pharmacodynamics ANESTHESIOLOGY Schnider, T. W., Minto, C. F., Shafer, S. L., Gambus, P. L., Andresen, C., Goodale, D. B., Youngs, E. J. 1999; 90 (6): 1502-1516

  Abstract

  The authors studied the influence of age on the pharmacodynamics of propofol, including characterization of the relation between plasma concentration and the time course of drug effect.The authors evaluated healthy volunteers aged 25-81 yr. A bolus dose (2 mg/kg or 1 mg/kg in persons older than 65 yr) and an infusion (25, 50, 100, or 200 microg x kg(-1) x min(-1)) of the older or the new (containing EDTA) formulation of propofol were given on each of two different study days. The propofol concentration was determined in frequent arterial samples. The electroencephalogram (EEG) was used to measure drug effect. A statistical technique called semilinear canonical correlation was used to select components of the EEG power spectrum that correlated optimally with the effect-site concentration. The effect-site concentration was related to drug effect with a biphasic pharmacodynamic model. The plasma effect-site equilibration rate constant was estimated parametrically. Estimates of this rate constant were validated by comparing the predicted time of peak effect with the time of peak EEG effect. The probability of being asleep, as a function of age, was determined from steady state concentrations after 60 min of propofol infusion.Twenty-four volunteers completed the study. Three parameters of the biphasic pharmacodynamic model were correlated linearly with age. The plasma effect-site equilibration rate constant was 0.456 min(-1). The predicted time to peak effect after bolus injection ranging was 1.7 min. The time to peak effect assessed visually was 1.6 min (range, 1-2.4 min). The steady state observations showed increasing sensitivity to propofol in elderly patients, with C50 values for loss of consciousness of 2.35, 1.8, and 1.25 microg/ml in volunteers who were 25, 50, and 75 yr old, respectively.Semilinear canonical correlation defined a new measure of propofol effect on the EEG, the canonical univariate parameter for propofol. Using this parameter, propofol plasma effect-site equilibration is faster than previously reported. This fast onset was confirmed by inspection of the EEG data. Elderly patients are more sensitive to the hypnotic and EEG effects of propofol than are younger persons.

  View details for Web of Science ID 000080553400003

  View details for PubMedID 10360845

• Population pharmacokinetics of midazolam administered by target controlled infusion for sedation following coronary artery bypass grafting ANESTHESIOLOGY Zomorodi, K., Donner, A., Somma, J., Barr, J., Sladen, R., Ramsay, J., Geller, E., Shafer, S. L. 1998; 89 (6): 1418-1429

  Abstract

  Midazolam is commonly used for short-term postoperative sedation of patients undergoing cardiac surgery. The purpose of this multicenter study was to characterize the pharmacokinetics and intersubject variability of midazolam in patients undergoing coronary artery bypass grafting.With institutional review board approval, 90 consenting patients undergoing coronary artery bypass grafting were enrolled at three study centers. All subjects received sufentanil and midazolam via target-controlled infusions. After operation, midazolam was titrated to maintain deep sedation for at least 2 h. It was then titrated downward to decrease sedation for a minimum of 4 h more and was discontinued before tracheal extubation. Arterial blood samples were taken throughout the study and were assayed for midazolam and 1-hydroxymidazolam. Midazolam population pharmacokinetic parameters were estimated using NONMEM. Cross-validation was used to estimate the performance of the model.The pharmacokinetics of midazolam were best described by a simple three-compartment mammillary model. Typical pharmacokinetic parameters were V1 = 32.2 l, V2 = 53 l, V3 = 245 l, Cl1 = 0.43 l/min, Cl2 = 0.56 l/min, and Cl3 = 0.39 l/min. The calculated elimination half-life was 15 h. The median absolute prediction error was 25%, with a bias of 1.4%. The performance in the cross-validation was similar. Midazolam metabolites were clinically insignificant in all patients.The intersubject variability and predictability of the three-compartment pharmacokinetic model are similar to those of other intravenous anesthetic drugs. This multicenter study did not confirm previous studies of exceptionally large variability of midazolam pharmacokinetics when used for sedation in intensive care settings.

  View details for Web of Science ID 000077376100019

  View details for PubMedID 9856717

• Population pharmacodynamics of midazolam administered by target controlled infusion in SICU patients after CABG surgery ANESTHESIOLOGY Somma, J., Donner, A., Zomorodi, K., Sladen, R., Ramsay, J., Geller, E., Shafer, S. L. 1998; 89 (6): 1430-1443

  Abstract

  Midazolam is used commonly for sedation in the surgical intensive care unit. A suboptimal dosing regimen may lead to relative overdosing, which could result in delayed extubation and increased cost. This multicenter trial characterized midazolam pharmacodynamics in patients recovering from coronary artery bypass grafting.Three centers enrolled 90 patients undergoing coronary artery bypass grafting. All patients received sufentanil and midazolam via target-controlled infusion. After surgery, midazolam was titrated to a Ramsay sedation score of 5 for 2 h and then decreased to maintain a sedation score of 3 or 4 for at least another 4 h. Pharmacodynamic parameters were derived using NONMEM. The model was cross-validated to test performance.The probability of a given level of sedation was related to the midazolam concentration by this equation: P(Sedation > or = ss) = Cn/(Cn + C(50,ss)n), where ss is the sedation score, C is the sum of the midazolam concentration and a term reflecting the dissipating effect of anesthesia: C = [midazolam] + theta x e(-Kt), where theta = 256 ng/ml and K = 0.19 h(-1). C(50,ss) values for Ramsay scores of 2 to 6 were 5.7, 71, 171, 260, and 659 ng/ml, respectively. The model predicted 57% of the data points correctly and 88% within one sedation score.Despite previous reports of high interindividual variability in midazolam pharmacodynamics in patients in the surgical intensive care unit, these cross-validation results suggest that, when midazolam is administered using a target-controlled infusion device, the level of sedation can be predicted within 1 sedation score in 88% of patients based on the target midazolam concentration and the time since the conclusion of the anesthetic.

  View details for Web of Science ID 000077376100020

  View details for PubMedID 9856718

• Cerebrospinal fluid pharmacokinetics and pharmacodynamics of intrathecal neostigmine methylsulfate in humans ANESTHESIOLOGY Shafer, S. L., Eisenach, J. C., Hood, D. D., Tong, C. Y. 1998; 89 (5): 1074-1088

  Abstract

  This study defines the cerebrospinal fluid (CSF) pharmacokinetics of neostigmine after intrathecal injection in humans and its effect on CSF acetylcholine, and it correlates physiologic effects with neostigmine dose and CSF acetylcholine concentrations.The CSF was sampled via an indwelling spinal catheter in 12 volunteers receiving intrathecal neostigmine (50-750 microg) and analyzed for neostigmine and acetylcholine. Pharmacokinetic and pharmacodynamic analyses were performed with NONMEM. Effect-site models linked the time course of the neostigmine concentration with the time course of analgesia.Acetylcholine concentrations increased from <20 pmol/ml at baseline to >100 pmol/ml within 15 min of neostigmine injection. The pharmacokinetics of intrathecal neostigmine were best described by a triexponential function with an absorption phase. Individual predicted concentrations varied 100-fold. Post hoc Bayesian estimates described the observed neostigmine concentrations with a median error of 22% and did not show systematic model misspecification. Individual estimates of effect site concentration producing a 50% maximal effect for foot visual analog scale analgesia correlated with the magnitude of individual CSF neostigmine concentrations.Intrathecal neostigmine concentrations can be well described by a triexponential disposition function, but the intersubject variability is large. The correlation between intersubject variability in concentration and intersubject variability in 50% maximal effect for foot analgesia suggests that both are offset by a common scalar, possibly the distance from the site of injection to the sampling and effect sites. These data provide the basis for the hypothesis of "observation at a distance" to describe the pharmacodynamics of intrathecally administered drugs.

  View details for Web of Science ID 000076891400006

  View details for PubMedID 9821995

• The influence of method of administration and covariates on the pharmacokinetics of propofol in adult volunteers ANESTHESIOLOGY Schnider, T. W., Minto, C. F., Gambus, P. L., Andresen, C., Goodale, D. B., Shafer, S. L., Youngs, E. J. 1998; 88 (5): 1170-1182

  Abstract

  Unresolved issues with propofol include whether the pharmacokinetics are linear with dose, are influenced by method of administration (bolus vs. infusion), or are influenced by age. Recently, a new formulation of propofol emulsion, containing disodium edetate (EDTA), was introduced in the United States. Addition of EDTA was found by the manufacturer to significantly reduce bacterial growth. This study investigated the influences of method of administration, infusion rate, patient covariates, and EDTA on the pharmacokinetics of propofol.Twenty-four healthy volunteers aged 26-81 yr were given a bolus dose of propofol, followed 1 h later by a 60-min infusion. Each volunteer was randomly assigned to an infusion rate of 25, 50, 100, or 200 microg x kg(-1) x min(-1). Each volunteer was studied twice under otherwise identical circumstances: once receiving propofol without EDTA and once receiving propofol with EDTA. The influence of the method of administration and of the volunteer covariates was explored by fitting a three-compartment mamillary model to the data. The influence of EDTA was investigated by direct comparison of the measured concentrations in both sessions.The concentrations of propofol with and without EDTA were not significantly different. The concentration measurements after the bolus dose were significantly underpredicted by the parameters obtained just from the infusion data. The kinetics of propofol were linear within the infusion range of 25-200 microg x kg(-1) x min(-1). Age was a significant covariate for Volume2 and Clearance2, as were weight, height, and lean body mass for the metabolic clearance.These results demonstrate that method of administration (bolus vs. infusion), but not EDTA, influences the pharmacokinetics of propofol. Within the clinically relevant range, the kinetics of propofol during infusions are linear regarding infusion rate.

  View details for Web of Science ID 000073536800006

  View details for PubMedID 9605675

• Pharmacokinetics and pharmacodynamics of remifentanil .2. Model application ANESTHESIOLOGY Minto, C. F., Schnider, T. W., Shafer, S. L. 1997; 86 (1): 24-33

  Abstract

  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.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.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.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.

  View details for Web of Science ID A1997WB86800005

  View details for PubMedID 9009936

• A comparison of spectral edge, delta power, and bispectral index as EEG measures of alfentanil, propofol, and midazolam drug effect CLINICAL PHARMACOLOGY & THERAPEUTICS Billard, V., Gambus, P. L., Chamoun, N., Stanski, D. R., Shafer, S. L. 1997; 61 (1): 45-58

  Abstract

  The effects of anesthetic drugs on electroencephalograms (EEG) have been studied to develop the EEG as a measure of anesthetic depth. Bispectral analysis is a new quantitative technique that measures the consistency of the phase and power relationships and returns a single measure, the bispectral index. The purpose of this study was to compare the performance of the bispectral index, version 1.1, with other spectral analysis EEG measures of drug effect for three commonly used anesthetic drugs.The EEG waveforms from 31 adults receiving infusions of alfentanil, propofol, or midazolam were analyzed. The time course of spectral edge (SE95), relative power in delta band, and bispectral index were related to the estimated effect-site concentration with use of a sigmoidal Emax model to estimate the potency (IC50) and the plasma effect-site equilibration rate constant (Ke0) for each measure. The performance of the fitting was assessed by the coefficient of correlation between predicted and observed effect.Alfentanil induced a high-amplitude low-frequency EEG response. Propofol induced a biphasic response. At low concentrations, both frequency and amplitude increased. When the concentration increased, the EEG slowed and the amplitude decreased. High concentration produced burst suppression. Midazolam increased EEG frequency and amplitude. Bispectral index, SE95, and delta power yield similar estimates of IC50 and ke0. Except for alfentanil, the performance of the modeling with the bispectral index was as good that with SE95 or delta power.Bispectral analysis can be used as a measure of the EEG effects of anesthetic drugs.

  View details for Web of Science ID A1997WF29100006

  View details for PubMedID 9024173

• Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil .1. Model development ANESTHESIOLOGY Minto, C. F., Schnider, T. W., Egan, T. D., Youngs, E., Lemmens, H. J., Gambus, P. L., Billard, V., Hoke, J. F., Moore, K. H., Hermann, D. J., Muir, K. T., Mandema, J. W., Shafer, S. L. 1997; 86 (1): 10-23

  Abstract

  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.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.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.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.

  View details for Web of Science ID A1997WB86800004

  View details for PubMedID 9009935

• Remifentanil versus alfentanil - Comparative pharmacokinetics and pharmacodynamics in healthy adult male volunteers ANESTHESIOLOGY Egan, T. D., Minto, C. F., Hermann, D. J., Barr, J., Muir, K. T., Shafer, S. L. 1996; 84 (4): 821-833

  Abstract

  Remifentanil is an esterase-metabolized opioid with a rapid clearance. The aim of this study was to contrast the pharmacokinetics and pharmacodynamics of remifentanil and alfentanil in healthy, adult male volunteers.Ten volunteers received infusions of remifentanil and alfentanil on separate study sessions using a randomized, open-label crossover design. Arterial blood samples were analyzed to determine drug blood concentrations. The electroencephalogram was employed as the measure of drug effect. The pharmacokinetics were characterized using a moment analysis, a nonlinear mixed effects model (NONMEM) population analysis, and context-sensitive half-time computer simulations. After processing the raw electroencephalogram to obtain the spectral edge parameter, the pharmacodynamics were characterized using an effect compartment, inhibitory maximum effect model.Pharmacokinetically, the two drugs are similar in terms of steady-state distribution volume (VD(SS)), but remifentanil's central clearance (CLc)) is substantially greater. The NONMEM analysis population pharmacokinetic parameters for remifentanil include a CLc of 2.9 l x min(-1), a VDss of 21.81, and a terminal half-life of 35.1 min. Corresponding NONMEM parameters for alfentanil are 0.36 l x min(-1), 34.11, and 94.5 min. Pharmacodynamically, the drugs are similar in terms of the time required for equilibration between blood and the effect-site concentrations, as evidenced by a T(12)k(e0) for remifentanil of 0.75 min [corrected] and 0.96 min for alfentanil. However, remifentanil is 19 times more potent than alfentanil, with an effective concentration for 50% maximal effect of 19.9 ng x ml(-1) versus 375.9 ng x ml(-1) for alfentanil.Compared to alfentanil, the high clearance of remifentanil, combined with its small steady-state distribution volume, results in a rapid decline in blood concentration after termination of an infusion. With the exception of remifentanil's nearly 20-times greater potency (30-times if alfentanil partitioning between whole blood and plasma is considered), the drugs are pharmacodynamically similar.

  View details for Web of Science ID A1996UD61400009

  View details for PubMedID 8638836

• THE PHARMACOKINETICS OF THE NEW SHORT-ACTING OPIOID REMIFENTANIL (GI87084B) IN HEALTHY ADULT MALE-VOLUNTEERS ANESTHESIOLOGY Egan, T. D., Lemmens, H. J., Fiset, P., Hermann, D. J., Muir, K. T., Stanski, D. R., Shafer, S. L. 1993; 79 (5): 881-892

  Abstract

  Remifentanil (GI87084B) is a new short-acting opioid with a unique ester structure. Metabolism of remifentanil by ester hydrolysis results in very rapid elimination. The aim of this study was to characterize in detail the pharmacokinetic profile of remifentanil in healthy male volunteers.Ten healthy adult male volunteers received a zero-order infusion of remifentanil at doses ranging from 1 to 8 micrograms.kg-1.min-1 for 20 min. Frequent arterial blood samples were drawn and analyzed by gas chromatographic mass spectroscopy to determine the remifentanil blood concentrations. The raw pharmacokinetic data were analyzed using three different parametric compartmental modeling methods (traditional two-stage, naive pooled data, and NONMEM). The raw pharmacokinetic data also were analyzed using numeric deconvolution and a nonparametric moment technique. A computer simulation using hte pharmacokinetic parameters of the NONMEM compartmental model was performed to provide a more intuitively meaningful and clinically relevant description of the pharmacokinetics. The simulation estimated the time necessary to achieve a 50% decrease in remifentanil concentration after a variable-length infusion.For each parametric method, a three-compartment mamillary model that accurately describes remifentanil's concentration decay curve was constructed. The NONMEM analysis population pharmacokinetic parameters included a central clearance of 2.8 l/min, a volume of distribution at steady state of 32.8 l, and a terminal half-life of 48 min. The mean results of the nonparametric moment analysis included a clearance of 2.9 l/min, a volume of distribution at steady state of 31.8 l, and a mean residence time of 10.9 min. The computer simulation revealed the strikingly unique pharmacokinetic profile of remifentanil compared to that of the currently available fentanyl family of opioids.Remifentanil is a new, short-acting opioid with promising clinical potential in anesthesiology.

  View details for Web of Science ID A1993MF83500003

  View details for PubMedID 7902032

• COMPUTER-CONTROLLED INFUSION OF INTRAVENOUS DEXMEDETOMIDINE HYDROCHLORIDE IN ADULT HUMAN VOLUNTEERS ANESTHESIOLOGY Dyck, J. B., Maze, M., Haack, C., Azarnoff, D. L., Vuorilehto, L., Shafer, S. L. 1993; 78 (5): 821-828

  Abstract

  This investigation extended the pharmacokinetic analysis of our previous study, of intravenous dexmedetomidine in 10 healthy male volunteers, and prospectively tested the resulting compartmental pharmacokinetics in an additional six subjects using a computer-controlled infusion pump (CCIP) to target four different plasma concentrations of dexmedetomidine for 30 min at each concentration.A three-compartment mamillary pharmacokinetic model best described the intravenous dexmedetomidine concentration versus time profile following the 5 min intravenous infusion of 2 micrograms/kg in our previous study. Nonlinear regression was performed using both two-stage and pooled data techniques to determine the population pharmacokinetics. The pooled technique allowed covariates, such as weight, age, and height of the subjects, to be incorporated into the nonlinear regression to test the hypothesis that these additional covariates would reduce the residual error between the measured concentrations and the predicted values.The addition of age, weight, lean body mass, and body surface area as covariates of the pharmacokinetic parameters did not improve the predictive value of the model. However, the model was improved when subject height was a covariate of the volume in the central compartment. The residual error in the pharmacokinetic model was markedly lower with the pooled versus the two-stage approach. The following pharmacokinetic values were obtained from the pooled analysis of the zero-order dexmedetomidine infusion: V1 = 8.05, V2 = 12.4, V3 = 175 (L), Cl1 = (0.0101*height [cm]) -1.33, Cl2 = 2.05, and Cl3 = 2.0 (L/min). Prospective evaluation of the pooled pharmacokinetic parameters using a computer-controlled infusion in six healthy volunteers showed the precision (average [(absolute error)/measured concentration]) of the CCIP to be 31.5% and the bias (average [error/measured concentration]) to be -22.4%. A pooled regression of the combined CCIP and zero-order data confirmed that the covariate, height (cm), was related in linear fashion to Cl1. A striking nonlinearity of dexmedetomidine pharmacokinetics related to concentration was observed during the CCIP infusion. The final pharmacokinetic values for the entire data set were: V1 = 7.99, V2 = 13.8, V3 = 187 (L), Cl1 = (0.00791*height [cm]) -0.927, Cl2 = 2.26, and Cl3 = 1.99 (L/min).Pharmacokinetics of dexmedetomidine are best described by a three-compartment model. Addition of age, weight, lean body mass, and body surface area do not improve the predictive value of the model. Additional improvement in CCIP accuracy for dexmedetomidine infusions would require magnification modification of the model based on the targeted concentration.

  View details for Web of Science ID A1993LA77700002

  View details for PubMedID 8098191

• APPLICATION OF SEMILINEAR CANONICAL CORRELATION TO THE MEASUREMENT OF OPIOID DRUG EFFECT JOURNAL OF PHARMACOKINETICS AND BIOPHARMACEUTICS Gregg, K. M., VARVEL, J. R., Shafer, S. L. 1992; 20 (6): 611-635

  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 R2s ranging from 0.37 to 0.83 for five commonly used ad hoc EEG components. The new components also had less variability in R2 between subjects.

  View details for Web of Science ID A1992KX56600003

  View details for PubMedID 1302765

• ALGORITHMS TO RAPIDLY ACHIEVE AND MAINTAIN STABLE DRUG CONCENTRATIONS AT THE SITE OF DRUG EFFECT WITH A COMPUTER-CONTROLLED INFUSION PUMP JOURNAL OF PHARMACOKINETICS AND BIOPHARMACEUTICS Shafer, S. L., Gregg, K. M. 1992; 20 (2): 147-169

  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.

  View details for Web of Science ID A1992JA55400002

  View details for PubMedID 1629794

• MEASURING THE PREDICTIVE PERFORMANCE OF COMPUTER-CONTROLLED INFUSION PUMPS JOURNAL OF PHARMACOKINETICS AND BIOPHARMACEUTICS VARVEL, J. R., Donoho, D. L., Shafer, S. L. 1992; 20 (1): 63-94

  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.

  View details for Web of Science ID A1992HL07400003

  View details for PubMedID 1588504

• A SIMPLE ANALYTICAL SOLUTION TO THE 3-COMPARTMENT PHARMACOKINETIC MODEL SUITABLE FOR COMPUTER-CONTROLLED INFUSION PUMPS IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING Bailey, J. M., Shafer, S. L. 1991; 38 (6): 522-525

  Abstract

  The disposition of many drugs following an intravenous bolus injection can be described by a biexponential or triexponential equation. Computer-controlled infusion pumps have been developed which dose intravenous drugs based on models of drug disposition. These pumps can maintain steady plasma drug concentrations and facilitate controlled increases and decreases in drug concentration, enhancing titration of intravenous drugs. Several investigators have proposed analytical solutions to the biexponential and triexponential disposition functions for use in computer-controlled infusion pumps. Because of the complexity of these analytical solutions, other investigators have used numerical techniques to approximate the analytical solution. We have derived an extremely simple analytical solution to polyexponential disposition functions. This solution simplifies both the prediction of the plasma drug concentration by a computer-controlled infusion pump and the stepwise calculation of the infusion rate required to maintain constant plasma drug concentrations.

  View details for Web of Science ID A1991FT33200002

  View details for PubMedID 1879840

• PHARMACOKINETICS, PHARMACODYNAMICS, AND RATIONAL OPIOID SELECTION Shafer, S. L., VARVEL, J. R. LIPPINCOTT-RAVEN PUBL. 1991: 53-63

  Abstract

  Fentanyl, alfentanil, and sufentanil have important pharmacokinetic and pharmacodynamic differences. Selecting one of these opioid analgesics as an adjunct to general anesthesia requires appreciation of the relationship between the pharmacokinetic and pharmacodynamic characteristics of these drugs and the onset of and recovery from drug effect. Using a pharmacokinetic-pharmacodynamic model, the authors simulated the decrease in plasma fentanyl, alfentanil, and sufentanil concentration after intravenous administration by either bolus injection, brief infusion, or prolonged infusion. The percentage change in concentration, rather than absolute concentration, was simulated to permit comparison of the relative opioid concentration independently of drug potency. These computer simulations quantified the relationship between infusion duration and the time required for recovery after termination of the infusion. The analysis suggests that alfentanil is best used for operations longer than 6-8 h when a rapid decrease in effect site (i.e., biophase) opioid concentration is desired after discontinuation of the infusion. Alfentanil may also be the most appropriate drug to provide a transient peak effect after a single bolus. Although sufentanil has longer distribution and elimination half-lives than alfentanil, recovery from sufentanil infusions may be more rapid than recovery from alfentanil infusions for operations shorter than 6-8 h. These computer simulations demonstrate that simply comparing pharmacokinetic parameters (e.g., half-lives) of different drugs will not predict the relative rates of decrease in effect site concentrations after either an intravenous bolus or a continuous infusion.

  View details for Web of Science ID A1991ET50400010

  View details for PubMedID 1824743

• ABSORPTION CHARACTERISTICS OF TRANSDERMALLY ADMINISTERED FENTANYL ANESTHESIOLOGY VARVEL, J. R., Shafer, S. L., Hwang, S. S., COEN, P. A., Stanski, D. R. 1989; 70 (6): 928-934

  Abstract

  Fentanyl was administered intravenously and transdermally to eight surgical patients to determine the systemic bioavailability and rate of absorption of the transdermally administered drug. Serum fentanyl concentrations reached a plateau approximately 14 h after placement of the transdermal fentanyl delivery system. This plateau was maintained until removal of the system at 24 h. The decline in serum fentanyl concentrations after removal of the transdermal system had a terminal half-life of 17.0 +/- 2.3 h (mean +/- SD), considerably longer than the terminal elimination half-life seen after intravenous administration of fentanyl in the same patients (6.1 +/- 2.0 h). The rate of fentanyl absorption, predicted to be 100 micrograms/h from in vitro data, appeared to be relatively constant during a period starting 4-8 h after placement of the transdermal system until removal of the system at 24 h. The rate of absorption during this period was 91.7 +/- 25.7 micrograms/h. After removal of the transdermal fentanyl delivery system, absorption continued at a declining rate. This indicates that the long terminal half-life of serum fentanyl concentrations after transdermal system removal is due to continued slow absorption of fentanyl, probably from a cutaneous depot of drug at the site of prior transdermal system placement. At the time of removal of the transdermal fentanyl system, 1.07 +/- 0.43 mg of drug remained in this depot. Systemic fentanyl bioavailability was found to be 0.92 +/- 0.33, with no evidence of significant cutaneous metabolism or degradation by the skin's bacterial flora. The transdermal administration of fentanyl produces relatively constant serum fentanyl concentrations for significant periods of time in the postsurgical patient requiring analgesic therapy.

  View details for Web of Science ID A1989U898800008

  View details for PubMedID 2729633

• TESTING COMPUTER-CONTROLLED INFUSION PUMPS BY SIMULATION ANESTHESIOLOGY Shafer, S. L., Siegel, L. C., Cooke, J. E., Scott, J. C. 1988; 68 (2): 261-266

  Abstract

  The pharmacokinetic behavior of intravenous anesthetic drugs can be described by two- or three-compartment models. Rapid achievement and maintenance of steady plasma concentrations of these drugs requires a complicated delivery scheme, perhaps best controlled by a computer. The authors developed a method of simulating the performance of a computer-controlled infusion pump from the differential equations describing drug transfer between compartments. They also derived a mathematically simple and flexible approximate solution to these equations using Euler's numerical method. They incorporated this approximate solution into a computer-controlled infusion pump for intravenous drugs. They tested their pump by simulating the administration of fentanyl to a hypothetical patient whose fentanyl pharmacokinetics were described by a three-compartment model. The exact analytical solution served as the standard of comparison. The approximation technique, using a 15-s interval between model updates, had a maximum error of 0.35 ng.ml-1, and rapidly converged on the exact solution. The simulations revealed oscillations in the system. The authors suggest that such simulations be used to evaluate computer-controlled infusion pumps prior to clinical trials of these devices.

  View details for Web of Science ID A1988L961800013

  View details for PubMedID 3341578

• Experience = Education: Time for the Next Step. A & A case reports Schwartz, A. J., Nussmeier, N. A., Shafer, S. 2015; 5 (2): 15-16

  View details for DOI 10.1213/XAA.0000000000000199

  View details for PubMedID 26171735

• A & a case reports: a progress report and an update on requirements for patient consent. A & A case reports Nussmeier, N., Saidman, L. J., Shafer, S. 2014; 3 (11): 141-?

  View details for DOI 10.1213/XAA.0000000000000117

  View details for PubMedID 25612098

• Impact of Cervical Effacement and Fetal Station on Progress during the First Stage of Labor: A Biexponential Model AMERICAN JOURNAL OF PERINATOLOGY Quincy, M. M., Weng, C., Shafer, S. L., Smiley, R. M., Flood, P. D., Mirza, F. G. 2014; 31 (9): 745-751

  Abstract

  To develop a model that uses cervical effacement, fetal station, and parity to predict progress during the first stage of labor.This was a secondary analysis of a cohort of 1,128 parturients delivering after 34 weeks. Timed cervical exams from each patient were fit with a biexponential model. Methods for consideration of fetal station, cervical effacement and parity were developed and validated.The biexponential model fit the data in an unbiased manner with a median absolute prediction error of 1.1 cm. Although nulliparous women had slower active labor, they did not differ from multiparous women in their rate of latent labor or the cervical dilation at which they transitioned to active labor. In addition, nulliparous women began laboring with a more effaced cervix (45 vs. 31%) and lower fetal station (-2.8 vs. -3.2).We validated a biexponential model for labor progress using a large mixed parity cohort. We demonstrated that parity and initial fetal station add important clinical information that can be used to make a labor model more accurate. As such, parity and fetal station can be utilized in such structural models to predict normal labor progress and potentially identify abnormalities in labor progress.

  View details for DOI 10.1055/s-0033-1359721

  View details for Web of Science ID 000340901000005

  View details for PubMedID 24338118

• Anesthesia & Analgesia Case Reports ANESTHESIA AND ANALGESIA Shafer, S. L. 2013; 116 (3): 513-514

  View details for DOI 10.1213/ANE.0b013e3182825fdd

  View details for Web of Science ID 000315540400001

  View details for PubMedID 23439810

• Bispectral Index Dynamics During Propofol Hypnosis Is Similar in Red-Haired and Dark-Haired Subjects ANESTHESIA AND ANALGESIA Doufas, A. G., Orhan-Sungur, M., Komatsu, R., Lauber, R., Akca, O., Shafer, S. L., Sessler, D. I. 2013; 116 (2): 319-326

  Abstract

  We have previously shown that red hair is associated with increased desflurane requirement for immobility, compared with dark hair. The effect of red hair on IV anesthetic requirement remains unknown. We tested the hypothesis that the propofol concentration in the effect site associated with half maximal electroencephalogram response, Ce50, is at least 50% higher in subjects with red hair.We modeled the propofol concentration versus electroencephalogram response relationship using a 2-step approach in 29 healthy dark- and red-haired volunteers receiving a propofol infusion to produce loss of consciousness. Bispectral Index (BIS) was the measure of drug effect. The parameters of a 3-compartment pharmacokinetic model were fit to measured arterial propofol concentrations. The relationship between effect-site propofol concentration (Ce) and BIS was characterized using a sigmoid Emax model. Model performance and accuracy of the estimated parameters were evaluated using accepted metrics and bootstrap resampling. The effect of hair color on the Ce50 for BIS response in the final model was assessed using a threshold of 6.63 (P<0.01) in reduction of -2 log likelihood. The influence of body weight on the model was also assessed.The inclusion of hair color as a model covariate did not improve either the pharmacokinetic or the pharmacodynamic model. A separate analysis for the dark- and red-haired subjects estimated a median (95% confidence interval) Ce50 BIS of 2.71 μg/mL (2.28-3.36 μg/mL) and 2.57 μg/mL (1.68-3.60 μg/mL), respectively. Body weight was a significant covariate for the CL1 and V1.Red hair phenotype does not affect the pharmacokinetics or pharmacodynamics of propofol.

  View details for DOI 10.1213/ANE.0b013e31827533b4

  View details for Web of Science ID 000314078300011

• Caveat Lector ANESTHESIA AND ANALGESIA Eldawlatly, A., Shafer, S. L. 2012; 114 (6): 1160-1162

  View details for DOI 10.1213/ANE.0b013e318254a2d5

  View details for Web of Science ID 000304504000006

  View details for PubMedID 22615444

• Caveat lector. Saudi journal of anaesthesia Eldawlatly, A., Shafer, S. L. 2012; 6 (2): 99-101

  View details for DOI 10.4103/1658-354X.97017

  View details for PubMedID 22754430

• Validation of Statistical Methods to Compare Cancellation Rates on the Day of Surgery (vol 101, pg 465, 2005) ANESTHESIA AND ANALGESIA Dexter, F., Shafer, S. L. 2012; 114 (3): 693-693

  View details for DOI 10.1213/ANE.0b013e31824e8a98

  View details for Web of Science ID 000300707300030

• Happy 25th Anniversary, FAER! ANESTHESIA AND ANALGESIA Shafer, S. L. 2011; 113 (4): 675-676

  View details for DOI 10.1213/ANE.0b013e31822ddc69

  View details for Web of Science ID 000295215100001

• From d-tubocurarine to sugammadex: the contributions of T. Cecil Gray to modern anaesthetic practice BRITISH JOURNAL OF ANAESTHESIA Shafer, S. L. 2011; 107 (1): 97-102

  Abstract

  One hundred years after Morton's demonstration of the anaesthetic effects of ether, T. Cecil Gray revolutionized anaesthesia with his introduction of balanced general anaesthesia. Gray's technique involved i.v. induction, administration of a neuromuscular blocking agent (curare), tracheal intubation, controlled ventilation, maintenance of unconsciousness with a light inhaled anaesthetic (supplemented with opioids if necessary), and reversal of neuromuscular blocking agent at the conclusion of the anaesthetic. In the 65 yr since his seminal papers, our drugs have changed, and i.v. anaesthetics suitable for maintenance of anaesthesia have been introduced, but the basic principles of general anaesthesia today are those set forward by Gray 65 yr ago.

  View details for DOI 10.1093/bja/aer117

  View details for Web of Science ID 000291746000014

  View details for PubMedID 21613280

• beta 2-Adrenergic Receptor Genotype and Other Variables that Contribute to Labor Pain and Progress ANESTHESIOLOGY Reitman, E., Conell-Price, J., Evansmith, J., Olson, L., Drosinos, S., Jasper, N., Randolph, P., Smiley, R. M., Shafer, S., Flood, P. 2011; 114 (4): 927-939

  Abstract

  β2-Adrenergic receptor (β2AR) activity influences labor. Its genotype affects the incidence of preterm delivery. We determined the effect of β2AR genotype on term labor progress and maternal pain.We prospectively enrolled 150 nulliparous parturients in the third trimester and obtained sensory thresholds, demographic information, and DNA. Cervical dilation, pain scores, and labor management data were extracted with associated times. The association of genetic and demographic factors with labor was tested using mixed effects models.Parturients who express Gln at the 27 position of the β2AR had slower labor (P < 0.03). They progressed from 1-10 cm dilation in approximately 21 h compared with 14 h among other patients. Asian ethnicity, previously associated with slower labor, is highly associated with this polymorphism (P < 0.0001). Heavier and black patients had slower latent labor (P < 0.01, 0.01). Neuraxial analgesia was associated with slower labor progress (P < 0.0001). It could take up to 36 h for parturients who were black and/or more than median weight (165 lb) to transition from 1 cm cervical dilation to active labor. However, after this active phase began, labor rates among these patients were similar to that of other parturients.We detected a strong association between β2AR genotype and slower labor. Asian ethnicity may be a proxy for β2AR genotype. Black women and those of higher than average weight have slower latent labor. These results confirm many of the associations found when this mathematical model was applied to a large retrospective cohort, further validating this approach to description and analysis of labor progress.

  View details for Web of Science ID 000288694400024

  View details for PubMedID 21394004

• Anesthesia & Analgesia Policy on Institutional Review Board Approval and Informed Consent for Research ANESTHESIA AND ANALGESIA Shafer, S. L. 2011; 112 (3): 494-495

  View details for DOI 10.1213/ANE.0b013e3182095c5d

  View details for Web of Science ID 000287698400002

  View details for PubMedID 21350223

• The Scott Reuben Saga: One Last Retraction ANESTHESIA AND ANALGESIA White, P. F., Rosow, C. E., Shafer, S. L. 2011; 112 (3): 512-515

  View details for DOI 10.1213/ANE.0b013e318209736f

  View details for Web of Science ID 000287698400008

  View details for PubMedID 21350225

• Pitfalls in Chronobiology: A Suggested Analysis Using Intrathecal Bupivacaine Analgesia as an Example ANESTHESIA AND ANALGESIA Shafer, S. L., Lemmer, B., Boselli, E., Boiste, F., Bouvet, L., Allaouchiche, B., Chassard, D. 2010; 111 (4): 980-985

  Abstract

  The duration of analgesia from epidural administration of local anesthetics to parturients has been shown to follow a rhythmic pattern according to the time of drug administration. We studied whether there was a similar pattern after intrathecal administration of bupivacaine in parturients. In the course of the analysis, we came to believe that some data points coincident with provider shift changes were influenced by nonbiological, health care system factors, thus incorrectly suggesting a periodic signal in duration of labor analgesia. We developed graphical and analytical tools to help assess the influence of individual points on the chronobiological analysis.Women with singleton term pregnancies in vertex presentation, cervical dilation 3 to 5 cm, pain score >50 mm (of 100 mm), and requesting labor analgesia were enrolled in this study. Patients received 2.5 mg of intrathecal bupivacaine in 2 mL using a combined spinal-epidural technique. Analgesia duration was the time from intrathecal injection until the first request for additional analgesia. The duration of analgesia was analyzed by visual inspection of the data, application of smoothing functions (Supersmoother; LOWESS and LOESS [locally weighted scatterplot smoothing functions]), analysis of variance, Cosinor (Chronos-Fit), Excel, and NONMEM (nonlinear mixed effect modeling). Confidence intervals (CIs) were determined by bootstrap analysis (1000 replications with replacement) using PLT Tools.Eighty-two women were included in the study. Examination of the raw data using 3 smoothing functions revealed a bimodal pattern, with a peak at approximately 0630 and a subsequent peak in the afternoon or evening, depending on the smoother. Analysis of variance did not identify any statistically significant difference between the duration of analgesia when intrathecal injection was given from midnight to 0600 compared with the duration of analgesia after intrathecal injection at other times. Chronos-Fit, Excel, and NONMEM produced identical results, with a mean duration of analgesia of 38.4 minutes (95% CI: 35.4-41.6 minutes), an 8-hour periodic waveform with an amplitude of 5.8 minutes (95% CI: 2.1-10.7 minutes), and a phase offset of 6.5 hours (95% CI: 5.4-8.0 hours) relative to midnight. The 8-hour periodic model did not reach statistical significance in 40% of bootstrap analyses, implying that statistical significance of the 8-hour periodic model was dependent on a subset of the data. Two data points before the change of shift at 0700 contributed most strongly to the statistical significance of the periodic waveform. Without these data points, there was no evidence of an 8-hour periodic waveform for intrathecal bupivacaine analgesia.Chronobiology includes the influence of external daily rhythms in the environment (e.g., nursing shifts) as well as human biological rhythms. We were able to distinguish the influence of an external rhythm by combining several novel analyses: (1) graphical presentation superimposing the raw data, external rhythms (e.g., nursing and anesthesia provider shifts), and smoothing functions; (2) graphical display of the contribution of each data point to the statistical significance; and (3) bootstrap analysis to identify whether the statistical significance was highly dependent on a data subset. These approaches suggested that 2 data points were likely artifacts of the change in nursing and anesthesia shifts. When these points were removed, there was no suggestion of biological rhythm in the duration of intrathecal bupivacaine analgesia.

  View details for DOI 10.1213/ANE.0b013e3181dd22d4

  View details for Web of Science ID 000282310200026

  View details for PubMedID 20442259

• Walk a Mile in My Shoes ANESTHESIA AND ANALGESIA Fisher, D. M., Shafer, S. L. 2010; 111 (2): 264-265

  View details for DOI 10.1213/ANE.0b013e3181cd6e76

  View details for Web of Science ID 000280478400006

  View details for PubMedID 20664088

• Computational Genetic Mapping in Mice: The Ship Has Sailed SCIENCE TRANSLATIONAL MEDICINE Zheng, M., Shafer, S., Liao, G., Liu, H., Peltz, G. 2009; 1 (3)

  Abstract

  Computational haplotype-based genetic mapping can be used to discover new biological mechanisms, disease-related pathways, and unexpected uses for existing drugs. Here we discuss the benefits and limitations of this methodology, its impact on translational medicine, and its future course.

  View details for DOI 10.1126/scitranslmed.3000377

  View details for Web of Science ID 000277196700004

  View details for PubMedID 20368166

• Neuromuscular Block Differentially Affects Immobility and Cortical Activation at Near-Minimum Alveolar Concentration Anesthesia ANESTHESIA AND ANALGESIA Doufas, A. G., Komatsu, R., Orhan-Sungur, M., Sengupta, P., Wadhwa, A., Mascha, E., Shafer, S. L., Sessler, D. I. 2009; 109 (4): 1097-1104

  Abstract

  Anesthesia-induced immobility and cortical suppression are governed by anatomically separate, but interacting, areas of the central nervous system. Consequently, larger volatile anesthetic concentrations are required to suppress cortical activation than to abolish movement in response to noxious stimulation. We examined the effect of decreased afferent input, as produced by neuromuscular block (NMB), on immobility and cortical activation, as measured by bispectral index (BIS) of the electrocardiogram, in the presence of noxious stimulation during approximately minimum alveolar concentrations (MACs) of desflurane anesthesia.The effect of NMB on the median effective end-tidal concentration of desflurane (EtDes(50), or MAC(tetanus)) for immobility was estimated using the up-and-down method and isolated forearm technique in 24 healthy volunteers. Each volunteer sequentially received saline, mivacurium, and succinylcholine in a randomized order, while EtDes concentration during each of the treatments was determined based on the movement response of the previous volunteer on the same treatment. Nonlinear mixed-effects modeling was used to evaluate the effect of NMB on BIS versus EtDes concentration relationship at baseline and after noxious stimulation, while the frontal electromyogram (EMG(BIS)) effect on BIS was also modeled as a covariate. Cardiovascular responses to noxious stimulation were compared across treatments.Succinylcholine and mivacurium significantly reduced MAC(tetanus) (95% confidence interval) from 5.00% (4.85%-5.13%), during saline, to 4.05% (3.81%-4.29%) and 3.84% (3.60%-4.08%), respectively. Noxious stimulation significantly, although minimally, increased BIS response during all treatments. Succinylcholine increased BIS independently of an effect on EMG(BIS). Succinylcholine administration increased cardiovascular activity. Interestingly, although cardiovascular reaction to the noxious event was ablated by mivacurium, cortical response, as determined by BIS, was retained.Both succinylcholine and mivacurium enhanced immobility during near-MAC anesthesia. All treatments were associated with a small, although significant, BIS increase in response to noxious stimulation, whereas succinylcholine increased BIS independently of noxious stimulation or EMG(BIS). Mivacurium suppressed autonomic response to a noxious event.

  View details for DOI 10.1213/ANE.0b013e3181af631a

  View details for Web of Science ID 000270209100019

  View details for PubMedID 19762737

• Automated Responsiveness Monitor to Titrate Propofol Sedation ANESTHESIA AND ANALGESIA Doufas, A. G., Morioka, N., Mahgoub, A. N., Bjorksten, A. R., Shafer, S. L., Sessler, D. I. 2009; 109 (3): 778-786

  Abstract

  In previous studies, we showed that failure to respond to automated responsiveness monitor (ARM) precedes potentially serious sedation-related adversities associated with loss of responsiveness, and that the ARM was not susceptible to false-positive responses. It remains unknown, however, whether loss and return of response to the ARM occur at similar sedation levels. We hypothesized that loss and return of response to the ARM occur at similar sedation levels in individual subjects, independent of the propofol effect titration scheme.Twenty-one healthy volunteers aged 20-45 yr underwent propofol sedation using an effect-site target-controlled infusion system and two different dosing protocol schemes. In all, we increased propofol effect-site concentration (Ce) until loss of response to the ARM occurred. Subsequently, the propofol Ce was decreased either by a fixed percentage (20%, 30%, 40%, 50%, 60%, and 70%; fixed percentage protocol, n = 10) or by a linear deramping (0.1, 0.2, and 0.3 microg x mL(-1) x min(-1); deramping protocol, n = 11) until the ARM response returned. Consequently, the propofol Ce was maintained at the new target for a 6-min interval (Ce plateau) during which arterial samples for propofol determination were obtained, and a clinical assessment of sedation (Observer's Assessment of Alertness/Sedation [OAA/S] score) performed. Each participant in the two protocols experienced each percentage or deramping rate of Ce decrease in random order. The assumption of steady state was tested by plotting the limits of agreement between the starting and ending plasma concentration (Cp) at each Ce plateau. The probability of response to the ARM as a function of propofol Ce, Bispectral Index (BIS) of the electroencephalogram, and OAA/S score was estimated, whereas the effect of the protocol type on these estimates was evaluated using the nested model approach (NONMEM). The combined effect of propofol Ce and BIS on the probability for ARM response was also evaluated using a fractional probability model (P(BIS/Ce)).The measured propofol Cp at the beginning and the end of the Ce plateau was almost identical. The Ce50 of propofol for responding to the ARM was 1.73 (95% confidence interval: 1.55-2.10) microg/mL, whereas the corresponding BIS50 was 75 (71.3-77). The OAA/S50 probability for ARM response was 12.5/20 (12-13.4). A fractional probability (P(BIS/Ce)) model for the combined effect of BIS and Ce fitted the data best, with an estimated contribution for BIS of 63%. Loss and return of ARM response occurred at similar sedation levels in individual subjects.Reproducible ARM dynamics in individual subjects compares favorably with clinical and electroencephalogram sedation end points and suggests that the ARM could be used as an independent instrumental guide of drug effect during propofol-only sedation.

  View details for DOI 10.1213/ane.0b013e3181b0fd0f

  View details for Web of Science ID 000269330800015

  View details for PubMedID 19690246

• 2009 Anesthesia & Analgesia Guide for Authors ANESTHESIA AND ANALGESIA Brull, S. J., Capdevila, X., Chan, V. W., Cohen, N., Csete, M. E., Davis, P. J., Dexter, F., Donati, F., Durieux, M. E., Fukuda, K., Gal, T. J., Gan, T. J., Gelb, A. W., Gin, T., Glass, P. S., Gregg, K. M., Gross, J. B., Hall, G. M., Hogan, Q. H., Hogue, C. W., Horlocker, T. T., Johansson, J. S., Kissin, I., Levy, J. H., Liu, S. S., London, M. J., Nemergut, E. C., Nussmeier, N. A., Pagel, P. S., Prielipp, R. C., Rosow, C. E., Saidman, L. J., Sear, J., Shafer, S. L., Sherwood, E. R., Slinger, P. D., Strichartz, G. R., Takala, J., Westenskow, D. R., White, P. F., Wong, C. A., Yaksh, T. L., Zornow, M. H. 2009; 109 (1): 217-231

  View details for DOI 10.1213/ane.0b013e3181a977c0

  View details for Web of Science ID 000267275100037

• No evidence for the development of acute tolerance to analgesic, respiratory depressant and sedative opioid effects in humans PAIN Angst, M. S., Chu, L. F., Tingle, M. S., Shafer, S. L., Clark, J. D., Drover, D. R. 2009; 142 (1-2): 17-26

  Abstract

  It is widely accepted that chronic opioid therapy is associated with the development of pharmacological tolerance. More controversial is the question as to whether acute opioid administration can result in "acute tolerance." The aim of this double-blind, placebo-controlled study in thirty-six healthy human volunteers was to examine whether a 3-h intravenous infusion delivering two different but clinically relevant doses of the mu-opioid receptor agonist remifentanil would result in tolerance to analgesic, respiratory depressant and/or sedative opioid effects. The blood remifentanil concentration versus opioid effect relationship was determined before and after the 3-h infusion. Tolerance was inferred if the potency of remifentanil was significantly lower after the 3-h infusion. Opioid analgesia was assessed with the aid of the cold pressor test and models of electrical and heat pain. Respiratory depression was assessed by measuring arterial pCO2 and minute ventilation. Subjective sedation scores were assessed on a visual analogue scale. Mixed effects modeling was used to relate the steady-state blood remifentanil concentration to each pharmacodynamic assessment. Neither dose of remifentanil produced detectable tolerance to any of the measured opioid effects following a 3-h infusion. The study was adequately powered to detect a decrease in potency of 5-24% for analgesia, 20-48% for respiratory depression, and 32% for sedative effects. These results suggest that short-term administration of clinically useful doses of remifentanil is not associated with the development of significant tolerance to analgesic, respiratory depressant, or sedative opioid effects.

  View details for DOI 10.1016/j.pain.2008.11.001

  View details for Web of Science ID 000264275800008

  View details for PubMedID 19135798

• Is a new paradigm needed to explain how inhaled anesthetics produce immobility? ANESTHESIA AND ANALGESIA Eger, E. I., Raines, D. E., Shafer, S. L., Hemmings, H. C., Sonner, J. M. 2008; 107 (3): 832-848

  Abstract

  A paradox arises from present information concerning the mechanism(s) by which inhaled anesthetics produce immobility in the face of noxious stimulation. Several findings, such as additivity, suggest a common site at which inhaled anesthetics act to produce immobility. However, two decades of focused investigation have not identified a ligand- or voltage-gated channel that alone is sufficient to mediate immobility. Indeed, most putative targets provide minimal or no mediation. For example, opioid, 5-HT3, gamma-aminobutyric acid type A and glutamate receptors, and potassium and calcium channels appear to be irrelevant or play only minor roles. Furthermore, no combination of actions on ligand- or voltage-gated channels seems sufficient. A few plausible targets (e.g., sodium channels) merit further study, but there remains the possibility that immobilization results from a nonspecific mechanism.

  View details for DOI 10.1213/ane.0b013e318182aedb

  View details for Web of Science ID 000258702500020

  View details for PubMedID 18713892

• Inhaled anesthetics do not combine to produce synergistic effects regarding minimum alveolar anesthetic concentration in rats ANESTHESIA AND ANALGESIA Eger, E. J., Tang, M., Liao, M., Laster, M. J., Solt, K., Flood, P., Jenkins, A., Raines, D., Hendrickx, J. F., Shafer, S. L., Yasumasa, T., Sonner, J. M. 2008; 107 (2): 479-485

  Abstract

  We hypothesized that pairs of inhaled anesthetics having divergent potencies [one acting weakly at minimum alveolar anesthetic concentration (MAC); one acting strongly at MAC] on specific receptors/channels might act synergistically, and that such deviations from additivity would support the notion that anesthetics act on multiple sites to produce anesthesia.Accordingly, we studied the additivity of MAC for 11 anesthetic pairs divergently (one weakly, one strongly) affecting a specific receptor/channel at MAC. By "divergently," we usually meant that at MAC the more strongly acting anesthetic enhanced or blocked the in vitro receptor or channel at least twice (and usually more) as much as did the weakly acting anesthetic. The receptors/channels included: TREK-1 and TASK-3 potassium channels; and gamma-aminobutyric acid type A, glycine, N-methyl-D-aspartic acid, and acetylcholine receptors. We also studied the additivity of cyclopropane-benzene because the N-methyl-D-aspartic acid blocker MK-801 had divergent effects on the MACs of these anesthetics. We also studied four pairs that included nitrous oxide because nitrous oxide had been reported to produce infraadditivity (antagonism) when combined with isoflurane.All combinations produced a result within 10% of that which would be predicted by additivity except for the combination of isoflurane with nitrous oxide where infraadditivity was found.Such results are consistent with the notion that inhaled anesthetics act on a single site to produce immobility in the face of noxious stimulation.

  View details for DOI 10.1213/01.ane.0000295805.70887.65

  View details for Web of Science ID 000258168300022

  View details for PubMedID 18633026

• The development and validation of a dynamic model to account for the progress of labor in the assessment of pain ANESTHESIA AND ANALGESIA Conell-Price, J., Evans, J. B., Hong, D., Shafer, S., Flood, P. 2008; 106 (5): 1509-1515

  Abstract

  Labor pain is often described as the worst pain in a woman's life, but the experience is highly variable. Although many factors have been linked to labor pain, it has been difficult to assess the individual effects of these factors because labor is a dynamic process and pain intensity changes over the course of labor. Previous studies have used average pain scores. The aim of this study was to develop and validate a model that would allow for the statistical analysis of factors that affect pain throughout labor.We conducted this study with a retrospective database drawn from the medical records of 200 consecutive nulliparous parturients who delivered at New York Presbyterian Hospital between October 2006 and January 2007. Numerical rating scale scores for pain with contractions (0-10 scale), cervical dilation, and oxytocin use before analgesia request were recorded. Nonlinear effects modeling with a sigmoid equation was used to describe the relationship between reported pain and cervical dilation. The modeling technique was developed with data from 91 parturients and validated with an independent set of 95 parturients (all parturients with pain scores more than zero). The resulting model was used to analyze the effect of a sample covariate, oxytocin administration, on reported pain in the entire data set.The model derived from our training set was predictive of the data from our validation set (P < 0.001). Predicted pain scores were on average two numerical rating scale points above or below measured pain scores. Analyzing oxytocin as a covariant showed that women treated with oxytocin reported 48% more pain at the start of labor but did not have a significantly more rapid increase in pain or higher maximal pain when compared with women not treated with oxytocin. Women treated with oxytocin had slower early labor and more rapid late labor.We have developed and validated a model for describing pain over the course of labor. Our model is suited to the statistical analysis of covariance and could potentially be used to compare the effects of covariants on labor pain and the rate of change of pain.

  View details for DOI 10.1213/ane.0b013e31816d14f3

  View details for Web of Science ID 000255222700031

  View details for PubMedID 18420869

• Defining depth of anesthesia. Handbook of experimental pharmacology Shafer, S. L., Stanski, D. R. 2008: 409-423

  Abstract

  In this chapter, drawn largely from the synthesis of material that we first presented in the sixth edition of Miller's Anesthesia, Chap 31 (Stanski and Shafer 2005; used by permission of the publisher), we have defined anesthetic depth as the probability of non-response to stimulation, calibrated against the strength of the stimulus, the difficulty of suppressing the response, and the drug-induced probability of non-responsiveness at defined effect site concentrations. This definition requires measurement of multiple different stimuli and responses at well-defined drug concentrations. There is no one stimulus and response measurement that will capture depth of anesthesia in a clinically or scientifically meaningful manner. The "clinical art" of anesthesia requires calibration of these observations of stimuli and responses (verbal responses, movement, tachycardia) against the dose and concentration of anesthetic drugs used to reduce the probability of response, constantly adjusting the administered dose to achieve the desired anesthetic depth. In our definition of "depth of anesthesia" we define the need for two components to create the anesthetic state: hypnosis created with drugs such as propofol or the inhalational anesthetics and analgesia created with the opioids or nitrous oxide. We demonstrate the scientific evidence that profound degrees of hypnosis in the absence of analgesia will not prevent the hemodynamic responses to profoundly noxious stimuli. Also, profound degrees of analgesia do not guarantee unconsciousness. However, the combination of hypnosis and analgesia suppresses hemodynamic response to noxious stimuli and guarantees unconsciousness.

  View details for DOI 10.1007/978-3-540-74806-9_19

  View details for PubMedID 18175102

• Estimation of optimal modeling weights for a Bayesian-based closed-loop system for propofol administration using the bispectral index as a controlled variable: A simulation study ANESTHESIA AND ANALGESIA De Smet, T., Struys, M. M., Greenwald, S., Mortier, E. P., Shafer, S. L. 2007; 105 (6): 1629-1638

  Abstract

  Implementing Bayesian methods in a model-based closed-loop system requires the integration of a standard response model with a patient-specific response model. This process makes use of specific modeling weights, called Bayesian variances, which determine how the specific model can deviate from the standard model. In this study we applied simulations to select the Bayesian variances yielding the optimal controller for a Bayesian-based closed-loop system for propofol administration using the Bispectral Index (BIS) as a controlled variable.The relevant Bayesian variances determining the modeling process were identified. Each set of such Bayesian variances represents a potential controller. The set, which will result in optimal control, was estimated using calculations on a simulated population. We selected 625 candidate sets. Similar to our previous closed-loop performance study, we applied a simulation protocol to evaluate controller performance. Our population consisted of 416 virtual patients, generated using population characteristics from previous work. A BIS offset trajectory similar to a surgical case was used.We were able to develop, describe, and optimize the parameter setting for a patient-individualized model-based closed-loop controller using Bayesian optimization. Selection of the optimal set yields a controller performing with the following median absolute prediction errors at BIS targets 30, 50, and 70: 12.9 +/- 2.87, 7.59 +/- 0.74, and 5.76 +/- 1.03 respectively.We believe this system can be introduced safely into clinical testing for both induction and maintenance of anesthesia under direct observation of an anesthesiologist.

  View details for DOI 10.1213/01.ane.0000287269.06170.Of

  View details for Web of Science ID 000251274400021

  View details for PubMedID 18042860

• In silico and in vitro pharmacogenetic analysis in mice PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Guo, Y., Lu, P., Farrell, E., Zhang, X., Weller, P., Monshouwer, M., Wang, J., Liao, G., Zhang, Z., Hu, S., Allard, J., Shafer, S., Usuka, J., Peltz, G. 2007; 104 (45): 17735-17740

  Abstract

  Combining the experimental efficiency of a murine hepatic in vitro drug biotransformation system with in silico genetic analysis produces a model system that can rapidly analyze interindividual differences in drug metabolism. This model system was tested by using two clinically important drugs, testosterone and irinotecan, whose metabolism was previously well characterized. The metabolites produced after these drugs were incubated with hepatic in vitro biotransformation systems prepared from the 15 inbred mouse strains were measured. Strain-specific differences in the rate of 16 alpha-hydroxytestosterone generation and irinotecan glucuronidation correlated with the pattern of genetic variation within Cyp2b9 and Ugt1a loci, respectively. These computational predictions were experimentally confirmed using expressed recombinant enzymes. The genetic changes affecting irinotecan metabolism in mice mirrored those in humans that are known to affect the pharmacokinetics and incidence of adverse responses to this medication.

  View details for DOI 10.1073/pnas.0700724104

  View details for Web of Science ID 000250897600036

  View details for PubMedID 17978195

• Influence of administration rate on propofol plasma - Effect site equilibration ANESTHESIOLOGY Struys, M. M., Coppens, M. J., De Neve, N., Mortier, E. P., Doufas, A. G., Van Bocxlaer, J. F., Shafer, S. L. 2007; 107 (3): 386-396

  Abstract

  The authors hypothesized a difference in plasma-effect site equilibration, depicted by a first-order constant k(e0), depending on the injection rate of propofol.Sixty-one patients received 2.5 mg/kg propofol given as a bolus or as a 1-, 2-, or 3-min infusion. The Bispectral Index was used to monitor drug effect. Propofol predicted plasma concentration was calculated using a three-compartment model and the effect site concentration over time as the convolution between the predicted plasma concentration and the disposition function of the effect site concentration. The authors evaluated the influence of the infusion rate on the k(e0) by comparing the model with one k(e0) for all groups with models estimating different k(e0) values for each group. The authors also assessed the accuracy of two pharmacokinetic models after bolus injection.The best model based was a fixed (Bispectral Index > or = 90) plus sigmoidal model (Bispectral Index < 90) with two values of k(e0), one for the bolus (t(1/2) k(e0) = 1.2 min) and one for the infusions (t(1/2) k(e0) = 2.2 min). However, the tested pharmacokinetic models poorly predicted the arterial concentrations in the first minutes after bolus injection. Simulations showed the requirement for two k(e0) values for bolus and infusion was mostly a compensation for the inaccurate prediction of arterial concentrations after a bolus.Propofol plasma-effect site equilibration occurs more rapidly after a bolus than after rapid infusion, based on the electroencephalogram as a drug effect measure, mostly because of misspecification of the pharmacokinetic model in the first minutes after bolus.

  View details for Web of Science ID 000249297200006

  View details for PubMedID 17721240

• The pharmacokinetics of the conopeptide Contulakin-G (CGX-1160) after intrathecal administration: An analysis of data from studies in beagles ANESTHESIA AND ANALGESIA Kern, S. E., Allen, J., Wagstaff, J., Shafer, S. L., Yaksh, T. 2007; 104 (6): 1514-1520

  Abstract

  The synthetic peptide agent Contulakin-G (CGX-1160), isolated from the toxin of the snail Conus geographus, produces significant analgesia in animals. Its peptide structure requires intrathecal administration for effectiveness, therefore we determined the intrathecal pharmacokinetics of CGX-1160 after bolus dose and multiple day infusions to beagles.For the bolus dose study, eight animals received a dose ranging from 16.7 to 1000 nmol under isoflurane anesthesia. Cerebral spinal fluid sampling for drug assay occurred up to 24 h. For the multiple day infusion study, three animals received infusions of 10, 40, and 160 microg/h respectively for 24 h at each rate. Cerebral spinal fluid sampling occurred during the infusion rate and the washout period after the 72 h of cumulative drug delivery. Data from the two study designs were modeled separately using NONMEM.The results showed a biexponential disposition profile for both experiments with a rapid rate constant that was an order of magnitude greater than the slow rate constant. The bolus results showed a nonlinear dependence of the slow rate constant on administered dose due to the large bolus range used in the study.These data, coupled with clinical pharmacology results, provide a basis for determining appropriate dosing strategies to achieve therapeutic intrathecal concentrations of Contulakin-G.

  View details for DOI 10.1213/01.ane.0000262038.58546.e6

  View details for Web of Science ID 000246791000035

  View details for PubMedID 17513651

• Untying the Gordian knot - In response ANESTHESIA AND ANALGESIA Tobin, J. R., Shafer, S. L., Davis, P. J. 2007; 104 (4): 993-994

  View details for DOI 10.1213/01.ane.000025600.96235.1d

  View details for Web of Science ID 000245371900055

• A phase I two-center study of the pharmacokinetics and pharmacodynamics of dexmedetomidine in children ANESTHESIOLOGY Petroz, G. C., Sikich, N., James, M., van Dyk, H., Shafer, S. L., Schily, M., Lerman, J. 2006; 105 (6): 1098-1110

  Abstract

  To investigate dexmedetomidine in children, the authors performed an open-label study of the pharmacokinetics and pharmacodynamics of dexmedetomidine.Thirty-six children were assigned to three groups; 24 received dexmedetomidine and 12 received no drug. Three doses of dexmedetomidine, 2, 4, and 6 microg x kg x h, were infused for 10 min. Cardiorespiratory responses and sedation were recorded for 24 h. Plasma concentrations of dexmedetomidine were collected for 24 h and analyzed. Pharmacokinetic variables were determined using nonlinear mixed effects modeling (NONMEM program). Cardiorespiratory responses were analyzed.Thirty-six children completed the study. There was an apparent difference in the pharmacokinetics between Canadian and South African children. The derived volumes and clearances in the Canadian children were V1 = 0.81 l/kg, V2 = 1.0 l/kg, Cl1 (systemic clearance) = 0.013 l x kg x min, Cl2 = 0.030 l x kg x min. The intersubject variabilities for V1, V2, and Cl1 were 45%, 38%, and 22%, respectively. Plasma concentrations in South African children were 29% less than in Canadian children. The volumes and clearances in the South African children were 29% larger. The terminal half-life was 110 min (1.8 h). Median absolute prediction error for the two-compartment mammillary model was 18%. Heart rate and systolic blood pressure decreased with time and with increasing doses of dexmedetomidine. Respiratory rate and oxygen saturation (in air) were maintained. Sedation was transient.The pharmacokinetics of dexmedetomidine in children are predictable with a terminal half-life of 1.8 h. Hemodynamic responses decreased with increasing doses of dexmedetomidine. Respiratory responses were maintained, whereas sedation was transient.

  View details for Web of Science ID 000242470800008

  View details for PubMedID 17122572

• Understanding our drugs and our diseases. Proceedings of the American Thoracic Society Guo, Y., Weller, P., Allard, J., Usuka, J., Masjedizadeh, M., Wu, S., Fitch, B., Clark, D., Clark, J. D., Shafer, S., Wang, J., Liao, G., Peltz, G. 2006; 3 (5): 409-412

  Abstract

  Analysis of mouse genetic models of human disease-associated traits has provided important insight into the pathogenesis of human disease. As one example, analysis of a murine genetic model of osteoporosis demonstrated that genetic variation within the 15-lipoxygenase (Alox15) gene affected peak bone mass, and that treatment with inhibitors of this enzyme improved bone mass and quality in rodent models. However, the method that has been used to analyze mouse genetic models is very time consuming, inefficient, and costly. To overcome these limitations, a computational method for analysis of mouse genetic models was developed that markedly accelerates the pace of genetic discovery. It was used to identify a genetic factor affecting the rate of metabolism of warfarin, an anticoagulant that is commonly used to treat clotting disorders. Computational analysis of a murine genetic model of narcotic drug withdrawal suggested a potential new approach for treatment of narcotic drug addiction. Thus, the results derived from computational mouse genetic analysis can suggest new treatment strategies, and can provide new information about currently available medicines.

  View details for PubMedID 16799083

• Do distribution volumes and clearances relate to tissue volumes and blood flows? A computer simulation. BMC anesthesiology Hendrickx, J. F., Lemmens, H. J., Shafer, S. L. 2006; 6: 7-?

  Abstract

  Kinetics of inhaled agents are often described by physiological models. However, many pharmacokinetic concepts, such as context-sensitive half-times, have been developed for drugs described by classical compartmental models. We derived classical compartmental models that describe the course of the alveolar concentrations (FA) generated by the physiological uptake and distribution models used by the Gas Man program, and describe how distribution volumes and clearances relate to tissue volumes and blood flows.Gas Man was used to generate FA vs. time curves during the wash-in and wash-out period of 115 min each with a high fresh gas flow (8 L x min(-1)), a constant alveolar minute ventilation (4 L x min(-1)), and a constant inspired concentration (FI) of halothane (0.75%), isoflurane (1.15%), sevoflurane (2%), or desflurane (6%). With each of these FI, simulations were ran for a 70 kg patient with 5 different cardiac outputs (CO) (2, 3, 5, 8 and 10 L x min(-1)) and for 5 patients with different weights (40, 55, 70, 85, and 100 kg) but the same CO (5 L x min(-1)). Two and three compartmental models were fitted to FA of the individual 9 runs using NONMEM. After testing for parsimony, goodness of fit was evaluated using median prediction error (MDPE) and median absolute prediction error (MDAPE). The model was tested prospectively for a virtual 62 kg patient with a cardiac output of 4.5 L x min(-1) for three different durations (wash-in and wash-out period of 10, 60, and 180 min each) with an FI of 1.5% halothane, 1.5% isoflurane, sevoflurane 4%, or desflurane 12%.A three-compartment model fitted the data best (MDPE = 0% and MDAPE < or = 0.074%) and performed equally well when tested prospectively (MDPE < or = 0.51% and MDAPE < or = 1.51%). The relationship between CO and body weight and the distribution volumes and clearances is complex.The kinetics of anesthetic gases can be adequately described e by a mammilary compartmental model. Therefore, concepts that are traditionally thought of as being applicable to the kinetics of intravenous agents can be equally well applied to anesthetic gases. Distribution volumes and clearances cannot be equated to tissue volumes and blood flows respectively.

  View details for PubMedID 16772041

• Pharmacogenomics and drug development PHARMACOGENOMICS Guo, Y. Y., Shafer, S., Weller, P., Usuka, J., Peltz, G. 2005; 6 (8): 857-864

  Abstract

  It is generally anticipated that pharmacogenomic information will have a large impact on drug development and will facilitate individualized drug treatment. However, there has been relatively little quantitative modeling to assess how pharmacogenomic information could be best utilized in clinical practice. Using a quantitative model, this review demonstrates that efficacy is increased and toxicity is reduced when a genetically-guided dose adjustment strategy is utilized in a clinical trial. However, there is limited information available regarding the genetic variables affecting the disposition or mechanism of action of most commonly used medications. These genetic factors must be identified to enable pharmacogenomic testing to be routinely used in the clinic. A recently described murine haplotype-based computational genetic analysis method provides one strategy for identifying genetic factors regulating the pharmacokinetics and pharmacodynamics of commonly used medications.

  View details for DOI 10.2217/14622416.6.8.857

  View details for Web of Science ID 000233692000010

  View details for PubMedID 16296948

• Arterial and venous pharmacokinetics of ropivacaine with and without epinephrine after thoracic paravertebral block ANESTHESIOLOGY Karmakar, M. K., Ho, A. M., Law, B. K., Wong, A. S., Shafer, S. L., Gin, T. 2005; 103 (4): 704-711

  Abstract

  Animal and volunteer studies indicate that ropivacaine is associated with less neurologic and cardiac toxicity than bupivacaine. Ropivacaine may offer advantages when used for thoracic paravertebral block. This study was designed to describe the pharmacokinetics of ropivacaine after thoracic paravertebral block.Twenty female patients undergoing elective unilateral breast surgery were randomly assigned to receive a single bolus thoracic paravertebral injection of 2 mg/kg ropivacaine, with or without 5 mug/ml epinephrine. Simultaneous arterial and venous blood samples were obtained for plasma ropivacaine assay. Data were analyzed with NONMEM, using two possible absorption models: conventional first-order absorption and absorption following the inverse gaussian density function.Epinephrine reduced the peak plasma concentrations and delayed the time of peak concentration of ropivacaine in both the arterial and venous blood. The time course of drug input into the systemic circulation was best described by two inverse gaussian density functions. The median bioavailability of the rapid component was approximately 20% higher when epinephrine was not used. The mean absorption times were 7.8 min for the rapid absorption phase and 697 min for the slow absorption phase, with wide dispersion of the absorption function for the acute phase. The half-time of arterial-venous equilibration was 1.5 min.The absorption of ropivacaine after thoracic paravertebral block is described by rapid and slow absorption phases. The rapid phase approximates the speed of intravenous administration and accounts for nearly half of ropivacaine absorption. The addition of 5 mug/ml epinephrine to ropivacaine significantly delays its systemic absorption and reduces the peak plasma concentration.

  View details for Web of Science ID 000232322300007

  View details for PubMedID 16192762

• Tutorial: Context-sensitive decrement times for inhaled anesthetics ANESTHESIA AND ANALGESIA Eger, E. I., Shafer, S. L. 2005; 101 (3): 688-696

  Abstract

  Context-sensitive decrement times for inhaled anesthetics connect two values: a) the duration of anesthesia (nominally at a constant alveolar concentration)-the "context" and b) the time to decrease the alveolar or vital tissue (e.g., brain, heart, kidney, and liver, collectively called the vessel-rich group of tissues) concentration by some fractional "decrement" of the starting concentration. Increasing duration of anesthesia increases the time to a given decrement in a nonlinear manner that may considerably delay recovery. In the present report we use a commercially available simulation program (Gas Man) to confirm and enlarge on these concepts. In this simulation, increasing duration of anesthesia can markedly delay complete awakening for isoflurane. Increasing anesthesia duration imposes considerably less delay in awakening from sevoflurane compared with isoflurane. For desflurane, only prolonged anesthesia or decrements of 95% and more should delay awakening from anesthesia. These changes are shown to be the result of the relative solubility of each anesthetic in blood and tissue. An increase in cardiac output is also shown to delay awakening.

  View details for DOI 10.1213/01.ANE.0000158611.15820.3D

  View details for Web of Science ID 000231434500017

  View details for PubMedID 16115976

• Differential activation of trigeminal C or A delta nociceptors by infrared diode laser in rats: Behavioral evidence BRAIN RESEARCH Tzabazis, A., Klyukinov, M., Manering, N., Nemenov, M. I., Shafer, S. L., Yeomans, D. C. 2005; 1037 (1-2): 148-156

  Abstract

  Radiant heat is often used for studying thermal nociception, although inherent characteristics such as the broad spectrum of applied wavelengths of typical light sources limit control over and repeatability of stimuli. To overcome these problems, we used a diode infrared laser-based stimulator (wavelength: 980 nm) for selectively stimulating trigeminal Adelta or C thermonociceptors in rats. To provide indirect evidence for nociceptor-selective stimulation, we tested the effects of capsaicin, dimethylsulfoxide (DMSO), and morphine on withdrawal latencies for long pulses with a low current (hypothesized to selectively stimulate C nociceptors) and for threshold currents of short pulses with high current (hypothesized to selectively stimulate Adelta nociceptors) in lightly anesthetized rats. Nonmem analysis was used to perform pharmacodynamic modeling. The measured baseline withdrawal latency for long pulses was 12.5 +/- 0.3 s which was changed significantly to 6.7 +/- 0.4 s after applying topical capsaicin which selectively sensitizes C nociceptors and to 16.5 +/- 1.3 s after 1.0 mg/kg morphine which preferentially attenuates C fiber nociception. Topical DMSO which appears to selectively sensitize Adelta afferents did not significantly alter withdrawal latencies to the long pulses. Fitted threshold currents for short pulses after DMSO were however significantly lower (974 +/- 53 mA vs. 1113 +/- 12 mA for baseline) indicating Adelta sensitization. Capsaicin and morphine did not significantly change threshold currents. Best Nonmem fits for the long pulse were obtained using a model assuming no DMSO effect, but a different inter-individual variability after applying this substance. For the short pulse, a model assuming no capsaicin or morphine effect, but again allowing different inter-individual variabilities after applying these drugs, best described the data. We conclude that different settings of the stimulator used in this study were capable of selectively activating trigeminal Adelta or C thermonociceptors.

  View details for DOI 10.1016/j.brainres.2005.01.019

  View details for Web of Science ID 000228251400018

  View details for PubMedID 15777763

• Variability of target-controlted infusion is less than the variability after bolus injection ANESTHESIOLOGY Hu, C. P., Horstman, D. J., Shafer, S. L. 2005; 102 (3): 639-645

  Abstract

  Target-controlled infusion (TCI) drug delivery systems deliver intravenous drugs based on pharmacokinetic models. TCI devices administer a bolus, followed by exponentially declining infusions, to rapidly achieve and maintain pseudo-steady state drug concentrations in the plasma or at the site of drug effect. Many studies have documented the prediction accuracy of TCI devices. The authors' goal was to apply linear systems theory to characterize the relation between the variability in concentrations achieved with TCI devices and the variability in concentrations after intravenous bolus injection.The authors developed a mathematical model of the variability of any arbitrary method of drug delivery, based on the variability with intravenous bolus injection or the variability with an arbitrary infusion regimen. They tested the model in a simulation of 1,000 patients receiving propofol by simple bolus injection, conventional infusion, or a TCI device. The authors then examined an experimental data set for the same behavior.The variability of any arbitrary infusion regimen, including TCI, is bounded by the variability after bolus injection. This is observed in the simulation and experimental data sets as well.TCI devices neither create nor eliminate biologic variability. For any drug described by linear pharmacokinetic models, no infusion regimen, including TCI, can have higher variability than that observed after bolus injection. The median performance of TCI devices should be reasonably close to the prediction of the device. However, the overall spread of the observations is an intrinsic property of the drug, not the TCI delivery system.

  View details for Web of Science ID 000227277200023

  View details for PubMedID 15731604

• Picking safe combinations ANESTHESIOLOGY Shafer, S. L. 2004; 101 (6): 1260-1261

  View details for Web of Science ID 000225380200002

  View details for PubMedID 15564930

• Induction speed is not a determinant of propofol pharmacodynamics ANESTHESIOLOGY Doufas, A. G., Bakhshandeh, M., Bjorksten, A. R., Shafer, S. L., Sessler, D. I. 2004; 101 (5): 1112-1121

  Abstract

  Evidence suggests that the rate at which intravenous anesthetics are infused may influence their plasma-effect site equilibration. The authors used five different rates of propofol administration to test the hypothesis that different sedation endpoints occur at the same effect site propofol concentration, independent of the infusion rate. The authors concurrently evaluated the automated responsiveness monitor (ARM) against other sedation measures and the propofol effect site concentration.With Human Studies Committee approval, 18 healthy volunteers received five consecutive target-controlled propofol infusions. During each infusion, the effect site concentration was increased by a rate of 0.1, 0.3, 0.5, 0.7, or 0.9 microg . ml . min. The Bispectral Index and ARM were recorded at frequent intervals. The times of syringe drop and loss and recovery of responsiveness were noted. Pharmacokinetic and pharmacodynamic modeling was performed using NONMEM.When the correct rate of plasma-effect site equilibration was determined for each individual (plasma-effect site equilibration = 0.17 min, time to peak effect = 2.7 min), the effect site concentrations associated with each clinical measure were not affected by the rate of increase of effect site propofol concentration. ARM correlated with all clinical measures of drug effect. Subjects invariably stopped responding to ARM at lower effect site propofol concentrations than those associated with loss of responsiveness.: Population-based pharmacokinetics, combined with real-time electroencephalographic measures of drug effect, may provide a means to individualize pharmacodynamic modeling during target-controlled drug delivery. ARM seems useful as an automated measure of sedation and may provide the basis for automated monitoring and titration of sedation for a propofol delivery system.

  View details for Web of Science ID 000224738600009

  View details for PubMedID 15505446

• Target controlled infusions: Targeting the effect site while limiting peak plasma concentration IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING Van Poucke, G. E., Bravo, L. J., Shafer, S. L. 2004; 51 (11): 1869-1875

  Abstract

  Target controlled infusion (TCI) systems are available commercially worldwide, except in North America. Existing systems target the plasma drug concentration, which may be less than ideal because the plasma is not the site of drug effect. The commonly accepted existing algorithm to target the site of drug effect results in high plasma concentrations, which may increase the acute hemodynamic effects of intravenous anesthetic drugs.A novel mathematical algorithm is proposed for controlling the effect site concentration using a TCI device. The algorithm limits the peak plasma concentration, thereby slowing the onset of anesthetic drug effect but potentially ameliorating side effects. Simulations are used to examine the delay in time to peak effect for fentanyl, alfentanil, sufentanil, remifentanil, and propofol when the peak plasma concentration is limited by the algorithm.The plasma overshoot required of the previously proposed algorithm to control the site of drug effect can be reduced by 60% with only about a 20% delay in the onset of drug effect.Concerns about the high plasma concentrations that result from targeting the effect site with a TCI device can be addressed by reducing the peak plasma concentration by as much as 60% with only a very modest increase in time to peak effect.

  View details for DOI 10.1109/TBME.2004.827935

  View details for Web of Science ID 000224657100001

  View details for PubMedID 15536889

• Application of Bispectral Index((R)) and Narcotrend((R)) index to the measurement of the electroencephalographic effects of isoflurane with and without burst suppression ANESTHESIOLOGY Kreuer, S., Bruhn, J., Larsen, R., Grundmann, U., Shafer, S. L., Wilhelm, W. 2004; 101 (4): 847-854

  Abstract

  The Narcotrend monitor (MonitorTechnik, Bad Bramstedt, Germany) has recently been introduced as an intraoperative monitor of anesthetic state, based on a classification scheme originally developed for visual assessment of the electroencephalogram. The authors compared the performance of the Narcotrend index (software version 4.0) to the Bispectral Index (BIS, version XP; Aspect Medical Systems, Natick, MA) as electroencephalographic measures of isoflurane drug effect during general anesthesia.The authors observed 15 adult patients scheduled to undergo radical prostatectomy with a combined epidural-isoflurane general anesthesia technique. At least 45 min after induction of general anesthesia, during a phase of constant surgical stimulation, end-tidal isoflurane concentrations were varied between 0.5 and 2.0 multiples of minimum alveolar concentration, and the BIS and the Narcotrend index were recorded. The prediction probability (PK) was calculated for the BIS and the Narcotrend index to predict isoflurane effect compartment concentration for each measure. The correlation analysis of the BIS and the Narcotrend index with the isoflurane effect compartment concentration was obtained by pharmacodynamic modeling based on two sigmoidal curves to account for the discontinuity in both indices with the onset of burst suppression.The prediction probabilities were indistinguishable (BIS PK = 0.72 +/- 0.07 (mean +/- SD); range, 0.61-0.84; Narcotrend index PK = 0.72 +/- 0.10; range, 0.51-0.87), as were the correlations between the electroencephalographic measures and isoflurane effect compartment concentrations (BIS R = 0.82 +/- 0.12; Narcotrend index R = 0.85 +/- 0.09). The pharmacodynamic models for the BIS and the Narcotrend index yielded nearly identical results.The BIS and the Narcotrend index detected the electroencephalographic effects of isoflurane equally. Combining two fractional sigmoid Emax models adequately described the data before and after the onset of burst suppression.

  View details for Web of Science ID 000224218400007

  View details for PubMedID 15448516

• Shock values ANESTHESIOLOGY Shafer, S. L. 2004; 101 (3): 567-568

  View details for Web of Science ID 000223605100001

  View details for PubMedID 15329579

• Spectral entropy as an electroennopbalograpbic measure of anesthetic drug effect - A comparison with bispectral index and precessed midlatency auditory evoked response ANESTHESIOLOGY Vanluchene, A. L., Vereecke, H., Thas, O., Mortier, E. P., Shafer, S. L., Struys, M. M. 2004; 101 (1): 34-42

  Abstract

  The authors compared the behavior of two calculations of electroencephalographic spectral entropy, state entropy (SE) and response entropy (RE), with the A-Line ARX Index (AAI) and the Bispectral Index (BIS) and as measures of anesthetic drug effect. They compared the measures for baseline variability, burst suppression, and prediction probability. They also developed pharmacodynamic models relating SE, RE, AAI, and BIS to the calculated propofol effect-site concentration (Ceprop).With institutional review board approval, the authors studied 10 patients. All patients received 50 mg/min propofol until either burst suppression greater than 80% or mean arterial pressure less than 50 mmHg was observed. SE, RE, AAI, and BIS were continuously recorded. Ceprop was calculated from the propofol infusion profile. Baseline variability, prediction of burst suppression, prediction probability, and Spearman rank correlation were calculated for SE, RE, AAI, and BIS. The relations between Ceprop and the electroencephalographic measures of drug effect were estimated using nonlinear mixed effect modeling.Baseline variability was lowest when using SE and RE. Burst suppression was most accurately detected by spectral entropy. Prediction probability and individualized Spearman rank correlation were highest for BIS and lowest for SE. Nonlinear mixed effect modeling generated reasonable models relating all four measures to Ceprop.Compared with BIS and AAI, both SE and RE seem to be useful electroencephalographic measures of anesthetic drug effect, with low baseline variability and accurate burst suppression prediction. The ability of the measures to predict Ceprop was best for BIS.

  View details for Web of Science ID 000222281200007

  View details for PubMedID 15220769

• Determination of the pharmacodynamic interaction of propofol and remifentanil during esophagogastroduodenoscopy in children ANESTHESIOLOGY Drover, D. R., Litalien, C., Wellis, V., Shafer, S. L., Hammer, G. B. 2004; 100 (6): 1382-1386

  Abstract

  Propofol is commonly used to anesthetize children undergoing esophagogastroduodenoscopy. Opioids are often used in combination with propofol to provide total intravenous anesthesia. Because both propofol and remifentanil are associated with rapid onset and offset, the combination of these two drugs may be particularly useful for procedures of short duration, including esophagogastroduodenoscopy. The authors previously demonstrated that the median effective concentration (C50) of propofol during esophagogastroduodenoscopy in children is 3.55 microg/ml. The purpose of this study was to describe the pharmacodynamic interaction of remifentanil and propofol when used in combination for esophagogastroduodenoscopy in pediatric patients.The authors studied 32 children aged between 3 and 10 yr who were scheduled to undergo esophagogastroduodenoscopy. Propofol was administered via a target-controlled infusion system using the STANPUMP software based on a pediatric pharmacokinetic model. Remifentanil was administered as a constant rate infusion of 25, 50, and 100 ng.kg(-1).min(-1) to each of three study groups, respectively. A sigmoid Emax model was developed to describe the interaction of remifentanil and propofol.There was a positive interaction between remifentanil and propofol when used in combination. The concentration of propofol alone associated with 50% probability of no response was 3.7 microg/ml (SE, 0.4 microg/ml), and this was decreased to 2.8 microg/ml (SE, 0.1 microg/ml) when used in combination with remifentanil.A remifentanil infusion of 25 ng.kg(-1).min(-1) reduces the concentration of propofol required for adequate anesthesia for esophagogastroduodenoscopy from 3.7 to 2.8 microg/ml. Increasing the remifentanil infusion yields minimal additional decrease in propofol concentration and may increase the risk of side effects.

  View details for Web of Science ID 000221551300007

  View details for PubMedID 15166555

• Use of population modeling to define rational monitoring of amiodarone hepatic effects CLINICAL PHARMACOLOGY & THERAPEUTICS Pollak, P. T., Shafer, S. L. 2004; 75 (4): 342-351

  Abstract

  Amiodarone causes hepatotoxicity in experimental models, but in humans, the relationships between drug administration, serum concentrations, markers of liver function, and how to monitor for hepatotoxicity have not been well characterized.An open-dose, prospective study collected serum amiodarone, desethylamiodarone, ALT, AST, lactate dehydrogenase (LDH), alkaline phosphatase, total bilirubin, and albumin concentrations over a 5-year period from 125 patients. Nonlinear mixed-effects modeling (NONMEM) was used to explore the relationship between markers of hepatotoxicity and concentrations of amiodarone and desethylamiodarone.No patients had clinical symptoms of hepatotoxicity during follow-up. The natural history of changes in hepatic makers showed ALT to have the strongest independent relationship to changes in serum amiodarone (r = 0.32, P <.001). An ALT greater than 3 times the upper limit of normal developed in only 8 patients (7%), with the earliest occurrence at 55 days of therapy. A mixed-effects model relating ALT elevation to serum amiodarone was improved by the addition of an effect compartment having an equilibration half-time of 87 days (r = 0.81, P <.001). The model predicts that 6% of patients will have an ALT greater than 3 times the upper limit of normal if amiodarone concentrations are maintained at less than 2.5 mg/L, and virtually no patients will have such ALT elevations if amiodarone concentrations are maintained at less than 1.5 mg/L.Concentrations of amiodarone below a threshold of 1.5 mg/L are associated with a minimal risk of hepatotoxicity, whereas concentrations greater than 2.5 mg/L are associated with a greater than 6% risk of hepatotoxicity. There is significant hysteresis between changes in amiodarone concentration and the resulting change in ALT. The model suggests that monitoring ALT at baseline, 1, 3, and 6 months, and then semiannually would be an efficient strategy to detect amiodarone-induced hepatotoxicity.

  View details for DOI 10.1016/j.clpt.2003.12.008

  View details for Web of Science ID 000220724800009

  View details for PubMedID 15060512

• Teaching application of clinical pharmacology skills using unusual observations from clozapine overdoses JOURNAL OF CLINICAL PHARMACOLOGY Pollak, P. T., Shafer, S. L. 2004; 44 (2): 141-149

  Abstract

  Massive drug overdoses provide a unique opportunity to observe human pharmacokinetic data not otherwise ethically available. They can also provide practical examples for teaching thoughtful application of the principles of clinical pharmacology. Following a case of clozapine overdose in which onset of toxicity was delayed by 72 hours, a probable explanation was found in an exploration of three cases with unusual concentration-time profiles and revealed unexpected implications for the management of clozapine overdoses. The authors systematically addressed the possible mechanisms proposed in the literature for an unusual plateau in concentrations observed in three clozapine overdoses. The effects that the most commonly suggested explanations (i.e., delayed absorption and saturated or impaired metabolism) would have on both clozapine and norclozapine concentrations were then modeled using the data available from those three cases to provide an objective illustration for comparison. This exercise was then used as a teaching seminar, leading students through the steps required to reach a logical explanation for the observed delayed toxicity and to consider the implications for therapy. Delayed absorption best predicted the sustained serum clozapine and norclozapine concentrations observed in three cases, and modeling suggests that much of the drug remains in the gut, available for absorption for days following an overdose. As a seminar, the exercise provides students with a practical example of the value of systematically ruling out possible explanations by considering what effects various pharmacokinetic alterations would have on observed data. Absorption following massive clozapine overdose appears fundamentally different from that with conventional dosing. This suggests a potential for delayed or prolonged toxicity, extending well beyond the time frame predicted by its half-life, unless aggressive and sustained efforts are applied to remove clozapine from the gut. Data from drug overdoses provide opportunities to explore unusual aspects of pharmacokinetics, better understand future overdoses of the same agent, and present excellent material for teaching. A seminar illustrating the role that thoughtful application of pharmacologic principles had in addressing this case is now used to introduce the clinical aspects of pharmacology to students at our institutions.

  View details for DOI 10.1177/0091270003262106

  View details for Web of Science ID 000188369900004

  View details for PubMedID 14747422

• The in vivo activity of THRX-918661, a novel, pharmacokinetically responsive sedative/hypnotic agent Beattie, D., Jenkins, T., McCullough, J., Thibodeaux, H., Renner, T., Bolton, J., Cook, D., Steffensen, S., Egan, T., Shafer, S. BLACKWELL PUBLISHING. 2004: 101-101

  View details for Web of Science ID 000187343100041

• THRX-918661, a novel, pharmacokinetically responsive sedative/hypnotic agent Jenkins, T., Beattie, D., Jaw-Tsai, S., Amagasu, S., Halladay, J., Vanapalli, S., Kern, R., Shaw, J. P., Egan, T., Shafer, S. BLACKWELL PUBLISHING. 2004: 100-100

  View details for Web of Science ID 000187343100040

• MAC attack? ANESTHESIOLOGY Sani, O., Shafer, S. L. 2003; 99 (6): 1249-1250

  View details for Web of Science ID 000186848600001

  View details for PubMedID 14639133

• Target-controlled infusions for intravenous anesthetics - Surfing USA not! ANESTHESIOLOGY Egan, T. D., Shafer, S. L. 2003; 99 (5): 1039-1041

  View details for Web of Science ID 000186239800002

  View details for PubMedID 14576533

• Piritramide and Alfentanil display similar respiratory depressant potency ACTA ANAESTHESIOLOGICA SCANDINAVICA Bouillon, T., Garstka, G., Stafforst, D., Shafer, S., Schwilden, H., Hoeft, A. 2003; 47 (10): 1231-1241

  Abstract

  The question whether some opioids exert less respiratory depression than others has not been answered conclusively. We applied pharmacokinetic/pharmacodynamic (PKPD) modeling to obtain an estimate of the C50 for the depression of CO2 elimination as a measure of the respiratory depressant potency of alfentanil and piritramide, two opioids with vastly different pharmacokinetics and apparent respiratory depressant action.Twenty-three patients received either alfentanil (2.3 microg x kg(-1) x min-1, 14 patients, as published previously) or piritramide (17.9 microg x kg(-1) x min(-1), nine patients) until significant respiratory depression occurred. Opioid pharmacokinetics and the arterial PCO2 (PaCO2) were determined from frequent arterial blood samples. An indirect response model accounting for the respiratory stimulation due to increasing PaCO2 was used to describe the PaCO2 data.The following pharmacodynamic parameters were estimated with NONMEM [population means and interindividual variability (CV)]: k(elCO2) (elimination rate constant of CO2) 0.144 (-) min(-1), F (gain of the CO2 response) 4.0 (fixed according to literature values) (28%), C50 (both drugs) 61.3 microg l-1 (41%), k(eo alfentanil) 0.654 (-) min(-1) and k(eo piritramide) 0.023 (-) min(-1). Assigning separate C50 values for alfentanil and piritramide did not improve the fit compared with a model with the same C50.Since the C50 values did not differ, both drugs are equally potent respiratory depressants. The apparently lower respiratory depressant effect of piritramide when compared with alfentanil is caused by slower equilibration between the plasma and the effect site. Generalizing our results and based on simulations we conclude that slowly equilibrating opioids like piritramide are intrinsically safer with regard to respiratory depression than rapidly equilibrating opioids like alfentanil.

  View details for Web of Science ID 000186385900009

  View details for PubMedID 14616320

• Isoflurane antagonizes the capacity of flurothyl or 1,2-dichlorohexafluorocyclobutane to impair fear conditioning to context and tone ANESTHESIA AND ANALGESIA Eger, E. I., Xing, Y. L., Pearce, R., Shafer, S., Laster, M. J., Zhang, Y., Fanselow, M. S., Sonner, J. M. 2003; 96 (4): 1010-1018

  Abstract

  In animals, the conventional inhaled anesthetic, isoflurane, impairs learning fear to context and fear to tone, doing so at concentrations that produce amnesia in humans. Nonimmobilizers are inhaled compounds that do not produce immobility in response to noxious stimulation, nor do they decrease the requirement for conventional inhaled anesthetics. Like isoflurane, the nonimmobilizer 1,2-dichlorohexafluorocyclobutane (2N) impairs learning at concentrations less than those predicted from its lipophilicity to produce anesthesia. The capacity of the nonimmobilizer di-(2,2,2,-trifluoroethyl) ether (flurothyl) to affect learning and memory has not been studied. Both nonimmobilizers can cause convulsions. We hypothesized that if isoflurane, 2N, and flurothyl act by the same mechanism to impair learning and memory, their effects should be additive. We found that isoflurane, 2N, and flurothyl (each, alone) impaired learning fear to context and fear to tone in rats, with the nonimmobilizers doing so at concentrations less than those that cause convulsions. (Fear was defined by freezing [volitional immobility] in the presence of the conditioned stimulus [context or tone].) However, the combination of isoflurane and 2N or flurothyl produced an antagonistic rather than an additive effect on learning, a finding in conflict with our hypothesis. And flurothyl was no less potent than 2N (at least no less potent relative to the concentration of each that produced convulsions) in its capacity to impair learning. We conclude that conventional inhaled anesthetics and nonimmobilizers impair learning and memory by different mechanisms. The basis for this impairment remains unknown.Conventional inhaled anesthetics and nonimmobilizers are antagonistic in their effects on learning and memory, and this finding suggests that they impair learning and memory, at least in part, by different mechanisms.

  View details for DOI 10.1213/01.ANE.0000055360.30078.FF

  View details for Web of Science ID 000181808300019

  View details for PubMedID 12651651

• Correlation of approximate entropy, bispectral index, and spectral edge frequency 95 (SEF95) with clinical signs of "anesthetic depth" during coadministration of propofol and remifentanil ANESTHESIOLOGY Bruhn, J., Bouillon, T. W., Radulescu, L., Hoeft, A., Bertaccini, E., Shafer, S. L. 2003; 98 (3): 621-627

  Abstract

  Several studies relating electroencephalogram parameter values to clinical endpoints using a single (mostly hypnotic) drug at relatively low levels of central nervous system depression (sedation) have been published. However, the usefulness of a parameter derived from the electroencephalogram for clinical anesthesia largely depends on its ability to predict the response to stimuli of different intensity or painfulness under a combination of a hypnotic and an (opioid) analgesic. This study was designed to evaluate the predictive performance of spectral edge frequency 95 (SEF95), BIS, and approximate entropy for the response to increasingly intense stimuli under different concentrations of both propofol and remifentanil in the therapeutic range.Ten healthy male and ten healthy female volunteers were studied during coadministration of propofol and remifentanil. After having maintained a specific target concentration for 10 min, the depth of sedation-anesthesia was assessed using the responsiveness component of the Observer's Assessment of Alertness/Sedation (OAA/S) rating scale, which was modified by adding insertion of a laryngeal mask and laryngoscopy. The electroencephalogram derived parameters approximate entropy, bispectral index, and SEF95 were recorded just before sedation level was assessed.The prediction probability values for approximate entropy were slightly, but not significantly, better than those for bispectral index, SEF95, and the combination of drug concentrations. A much lower prediction ability was observed for tolerance of airway manipulation than for hypnotic endpoints.Approximate entropy revealed informations on hypnotic and analgesic endpoints using coadministration of propofol and remifentanil comparable to bispectral index, SEF95, and the combination of drug concentrations.

  View details for Web of Science ID 000181290800007

  View details for PubMedID 12606904

• Mathematical analysis of a pharmacodynamic model without plasma concentrations to extend its applicability MEDICAL HYPOTHESES Nava-Ocampo, A. A., Shafer, S. L., Velaquez-Armenta, Y., Ruiz-Velazco, S., Toni, B. 2003; 60 (3): 453-457

  Abstract

  Using a mathematical approach, we analyzed the behavior of the PD model originally described by Bragg et al. The effect was dose-dependent modified until a maximum value (E(max)) was reached. Further increments in dose prolonged the E(max), but the recovery phase did not increase beyond a calculable asymptope. In the absence of plasma concentrations, it was impossible to distinguish the rate of plasma equilibration with the effect compartment (k(e0)) from the rate of drug elimination (k(e1)). Variations on the sigmoidicity affected both the onset and offset of drug effect. Sigmoidicity and the slowest rate constant had identical effects on the spontaneous reversion of the effect, as judged by the recovery index. The IR(50), the index of potency, merely shifted the dose-response relationship to the left or right. Changes in IR(50) were compensated for by making the same proportional changes in dose.

  View details for DOI 10.1016/S0306-9877(02)00449-8

  View details for Web of Science ID 000181152100029

  View details for PubMedID 12581628

• Non-steady state analysis of the pharmacokinetic interaction between propofol and remifentanil ANESTHESIOLOGY Bouillon, T., Bruhn, J., Radu-Radulescu, L., Bertaccini, E., Park, S., Shafer, S. 2002; 97 (6): 1350-1362

  Abstract

  The pharmacokinetics of both propofol and remifentanil have been described extensively. Although they are commonly administered together for clinical anesthesia, their pharmacokinetic interaction has not been investigated so far. The purpose of the current investigation was to elucidate the nature and extent of pharmacokinetic interactions between propofol and remifentanil.Twenty healthy volunteers aged 20-43 yr initially received either propofol or remifentanil alone in a stepwise incremental and decremental fashion a target controlled infusion. Thereafter, the respective second drug was infused to a fixed target concentration in the clinical range (0-4 microg/ml and 0-4 ng/ml for propofol and remifentanil, respectively) and the stepwise incremental pattern repeated. Frequent blood samples were drawn for up to 6 h for propofol and 40 min for remifentanil after the end of administration and assayed for the respective drug concentrations with gas chromatography-mass spectrometry. The time courses of the measured concentrations were fitted to standard compartmental models. Calculations were performed with NONMEM. After having established the individual population models for both drugs and an exploratory analysis for hypothesis generation, pharmacokinetic interaction was identified by including an interaction term into the population model and comparing the value of the objective function in the presence and absence of the respective term.The concentration-time courses of propofol and remifentanil were described best by a three- and two-compartment model, respectively. In the concentration range examined, remifentanil does not alter propofol pharmacokinetics. Coadministration of propofol decreases the central volume of distribution and distributional clearance of remifentanil by 41% and elimination clearance by 15%. This effect was not concentration-dependent in the examined concentration range of propofol.Coadministration of propofol decreases the bolus dose of remifentanil needed to achieve a certain plasma-effect compartment concentration but does not alter the respective maintenance infusion rates and recovery times to a clinically significant degree.

  View details for Web of Science ID 000179590500004

  View details for PubMedID 12459659

• Pharmacokinetic study of FFP photochemically treated with amotosalen (S-59) and UV light compared to FFP in healthy volunteers anticoagulated with warfarin TRANSFUSION Hambleton, J., Wages, D., Radu-Radulescu, L., Adams, M., MacKenzie, M., Shafer, S., Lee, M., Smyers, J., Wiesehahn, G., Corash, L. 2002; 42 (10): 1302-1307

  Abstract

  To date, no clinical trials have characterized FFP infusion efficacy, and infusion still carries infectious risk. This single-blinded crossover study compared postinfusion kinetics of FVII in photochemically treated FFP to standard FFP.Subjects donated plasma by apheresis. Half of the collected plasma was treated with the psoralen amotosalen hydrochloride (S-59) and UVA light, and half were prepared as standard plasma. Subjects received warfarin over 4 days to lower FVII levels. On Day 4, subjects received 1 L of either treated or standard FFP. After 2 weeks, subjects underwent a regimen identical to that with the other type of FFP.After warfarin ingestion, the mean FVII concentration was 0.33 IU per mL. Both types of FFP exhibited comparable FVII kinetics, with a mean peak increment of 0.10 to 0.12 IU per mL occurring at the end of infusion. The effect disappeared after 8 hours.Study data of warfarin-treated healthy volunteers demonstrate that psoralen plus UV-treated FFP provides an equivalent in vivo coagulation response to control plasma. A 1-L dose of FFP in adults may provide an initial increment of 0.10 IU per mL of FVII. In the absence of bleeding, FVII levels return to baseline after 8 hours.

  View details for Web of Science ID 000178465200011

  View details for PubMedID 12423514

• Artifact robustness, inter- and intraindividual baseline stability, and rational EEG parameter selection Bruhn, J., Bouillon, T. W., Hoeft, A., Shafer, S. L. LIPPINCOTT WILLIAMS & WILKINS. 2002: 54-59

  Abstract

  Artifact robustness (i.e., size of deviation of an electroencephalographic parameter value from baseline caused by artifacts) and baseline stability (i.e., consistency of median baseline values) of electroencephalographic parameters profoundly influence electroencephalography-based pharmacodynamic parameter estimation and the usefulness of the processed electroencephalogram as measure of the arousal state of the central nervous system (depth of anesthesia). In this study, the authors compared the artifact robustness and the interindividual and intraindividual baseline stability of several univariate descriptors of the electroencephalogram (Shannon entropy, approximate entropy, spectral edge frequency 95, delta ratio, and canonical univariate parameter).Electroencephalographic data of 16 healthy volunteers before and after administration of an intravenous bolus of propofol (2 mg/kg body weight) were analyzed. Each volunteer was studied twice. The baseline electroencephalogram was recorded for a median of 18 min before drug administration. For each electroencephalographic descriptor, the authors calculated the following: (1) baseline variability (= (median baseline - median effect) [i.e., signal]/SD baseline [i.e., noise]) without artifact rejection; (2) baseline variability with artifact rejection; and (3) baseline stability within and between individuals (= (median baseline - median effect) averaged over all volunteers/SD of all median baselines).Without artifact rejection, Shannon entropy and canonical univariate parameter displayed the highest signal-to-noise ratio. After artifact rejection, approximate entropy, Shannon entropy, and the canonical univariate parameter displayed the highest signal-to-noise ratio. Baseline stability within and between individuals was highest for approximate entropy.With regard to robustness against artifacts, the electroencephalographic entropy parameters and the canonical univariate parameter were superior to spectral edge frequency 95 and delta ratio. Electroencephalographic approximate entropy displayed the best interindividual and intraindividual baseline stability.

  View details for Web of Science ID 000173086000011

  View details for PubMedID 11753002

• Onset of propofol-induced burst suppression may be correctly detected as deepening of anaesthesia by approximate entropy but not by bispectral index BRITISH JOURNAL OF ANAESTHESIA Bruhn, J., Bouillon, T. W., Shafer, S. L. 2001; 87 (3): 505-507

  Abstract

  The bispectral index (BIS) is a complex EEG variable that combines several disparate descriptors of the EEG into a single value. Approximate entropy is a novel EEG measure that quantifies the regularity of a data time series such as EEG. We report two patients in which the EEG effect of propofol was quantified very similarly by BIS and approximate entropy. However, at the beginning of burst suppression of the EEG, BIS did not indicate an increased anaesthetic drug effect, while approximate entropy did.

  View details for Web of Science ID 000171452400023

  View details for PubMedID 11517141

• A double-blind, randomized comparison of IV lorazepam versus midazolam for sedation of ICU patients via a pharmacologic model Barr, J., Zomorodi, K., Bertaccini, E. J., Shafer, S. L., Geller, E. LIPPINCOTT WILLIAMS & WILKINS. 2001: 286-298

  Abstract

  Benzodiazepines, such as lorazepam and midazolam, are frequently administered to surgical intensive care unit (ICU) patients for postoperative sedation. To date, the pharmacology of lorazepam in critically ill patients has not been described. The aim of the current study was to characterize and compare the pharmacokinetics and pharmacodynamics of lorazepam and midazolam administered as continuous intravenous infusions for postoperative sedation of surgical ICU patients.With Institutional Review Board approval, 24 consenting adult surgical patients were given either lorazepam or midazolam in a double-blind fashion (together with either intravenous fentanyl or epidural morphine for analgesia) through target-controlled intravenous infusions titrated to maintain a moderate level of sedation for 12-72 h postoperatively. Moderate sedation was defined as a Ramsay Sedation Scale score of 3 or 4. Sedation scores were measured, together with benzodiazepine plasma concentrations. Population pharmacokinetic and pharmacodynamic parameters were estimated using nonlinear mixed-effects modeling.A two-compartment model best described the pharmacokinetics of both lorazepam and midazolam. The pharmacodynamic model predicted depth of sedation for both midazolam and lorazepam with 76% accuracy. The estimated sedative potency of lorazepam was twice that of midazolam. The predicted C50,ss (plasma benzodiazepine concentrations where P(Sedation > or = ss) = 50%) values for midazolam (sedation score [SS] > or = n, where n = a Ramsay Sedation Score of 2, 3, ... 6) were 68, 101, 208, 304, and 375 ng/ml. The corresponding predicted C50,ss values for lorazepam were 34, 51, 104, 152, and 188 ng/ml, respectively. Age, fentanyl administration, and the resolving effects of surgery and anesthesia were significant covariates of benzodiazepine sedation. The relative amnestic potency of lorazepam to midazolam was 4 (observed). The predicted emergence times from sedation after a 72-h benzodiazepine infusion for light (SS = 3) and deep (SS = 5) sedation in a typical patient were 3.6 and 14.9 h for midazolam infusions and 11.9 and 31.1 h for lorazepam infusions, respectively.The pharmacology of intravenous infusions of lorazepam differs significantly from that of midazolam in critically ill patients. This results in significant delays in emergence from sedation with lorazepam as compared with midazolam when administered for ICU sedation.

  View details for Web of Science ID 000170237800003

  View details for PubMedID 11506097

• Pharmacokinetics and pharmacodynamics of inhaled versus intravenous morphine in healthy volunteers Dershwitz, M., Walsh, J. L., Morishige, R. J., Conners, P. M., Rubsamen, R. M., Shafer, S. L., Rosow, C. E. LIPPINCOTT WILLIAMS & WILKINS. 2000: 619-628

  Abstract

  A new pulmonary drug delivery system produces aerosols from disposable packets of medication. This study compared the pharmacokinetics and pharmacodynamics of morphine delivered by an AERx prototype with intravenous morphine.Fifteen healthy volunteers were enrolled. Two subjects were administered four inhalations of 2.2 mg morphine each at 1-min intervals or 4.4 mg over 3 min by intravenous infusion. Thirteen subjects were given twice the above doses, i.e., eight inhalations or 8.8 mg intravenously over 7 min. Arterial blood sampling was performed every minute during administration and at 2, 5, 7, 10, 15, 20, 45, 60, 90, 120, 150, 180, and 240 min after administration. The effect of morphine was assessed by measuring pupil diameter and ventilatory response to a hypercapnic challenge. Pharmacokinetic and pharmacodynamic analyses were performed simultaneously using mixed-effect models.The pharmacokinetic data after intravenous administration were described by a three-exponent decay model preceded by a lag time. The pharmacokinetic model for administration by inhalation consisted of the three-exponent intravenous pharmacokinetic model preceded by a two-exponent absorption model. The authors found that, with administration by inhalation, the total bioavailability was 59%, of which 43% was absorbed almost instantaneously and 57% was absorbed with a half-life of 18 min. The median times to the half-maximal miotic effects of morphine were 10 and 5.5 min after inhalation and intravenous administration, respectively (P < 0.01). The pharmacodynamic parameter ke0 was approximately 0.003 min-1.The onset and duration of the effects of morphine are similar after intravenous administration or inhalation via this new pulmonary drug delivery system. Morphine bioavailability after such administration is 59% of the dose loaded into the dosage form.

  View details for Web of Science ID 000089133100005

  View details for PubMedID 10969293

• Characterization of benzodiazepine receptors in the cerebellum PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY Lameh, J. V., Wang, P., Meredith, D., Shafer, S. L., Loew, G. H. 2000; 24 (6): 979-991

  Abstract

  1. The goals of the work reported here were to further characterize benzodiazepine/GABA(A) (BDZR) receptor heterogeneity in the cerebellum and to measure the affinities and selectivities of structurally diverse benzodiazepines at each site identified. 2. Five chemical families were included in these studies. These were 1,4-benzodiazepines (flunitrazepam), imidazobenzodiazepines (RO15-1788 and RO15-4513 and RO16-6028), beta-carbolines (Abecarnil) and pyrazoloquinolines (CGS 8216, CGS 9895 and CGS 9896). 3. Saturation and competition binding assays were combined with powerful data analysis software developed in our laboratory. Among the capabilities of this software is the identification of multiple binding sites for a cold ligand using a non-selective labeled ligand that binds with equal, but high, affinity to all the binding sites 4. Saturation binding assays using either [3H]-RO15-1788 or [3H]-RO15-4513 revealed only one apparent binding site, with a higher affinity for RO15-4513 than for RO15-1788. However, using [3H]-RO15-4513 for the competition binding studies in the cerebellum, together with our data analysis software, led to the identification of two distinct binding sites with equal densities for the diverse benzodiazepines studied. 5. In rat cerebellum one of the sites identified corresponds to GABA(A) receptors exhibiting alpha1 subunit pharmacology and the other to GABA(A) receptors exhibiting alpha6 subunit pharmacology. In general, the diverse families of BDZR ligands studied had much lower affinities for the alpha6 containing receptors.

  View details for Web of Science ID 000088966400008

  View details for PubMedID 11041538

• Unraveling the identity of benzodiazepine binding sites in rat hipppocampus and olfactory bulb EUROPEAN JOURNAL OF PHARMACOLOGY Lameh, J., Wang, P., Elgart, D., Meredith, D., Shafer, S. L., Loew, G. H. 2000; 400 (2-3): 167-176

  Abstract

  The goals of the work reported here were (i) to identify distinct GABA(A)/benzodiazepine receptors in the rat hippocampus and olfactory bulb using receptor binding assays, and (ii) to determine the affinities and selectivities of benzodiazepine receptor ligands from structurally diverse chemical families at each site identified. These studies were aided by the use of software AFFINITY ANALYSIS SYSTEM, developed in our laboratory for analysis of receptor binding data that allows the determination of receptor heterogeneity using non-selective radioligands. Saturation binding assays using [3H]RO15-4513 (ethyl 8-azido-6-dihydro-5-methyl-6-oxo-4H-imidazo[1, 5-a]-[1,4]benzodiazepine-3-carboxylate) revealed two binding sites in each of these two tissues. The higher affinity site corresponds to alpha(5) subunit-containing GABA(A) receptor and the lower affinity site to a combination of alpha(1), alpha(2), and alpha(3) subunit-containing receptors. These results should be useful in the challenging task of identifying the various functional GABA(A) receptors in the central nervous system, and in providing a link between receptor affinities and in vivo activities of the GABA(A)/benzodiazepine receptor ligands studied.

  View details for Web of Science ID 000088350200003

  View details for PubMedID 10988330

• Enantioselective relief of neuropathic pain by systemic mexiletine in the rat JOURNAL OF PAIN Sinnott, C. J., Garfield, J. M., Zeitlin, A., Teo, S., Wu, M. D., Chen, J. H., Shafer, S. L., Strichartz, G. R. 2000; 1 (2): 128-137

  View details for Web of Science ID 000089481200009

• Population pharmacokinetics of long-term oral amiodarone therapy CLINICAL PHARMACOLOGY & THERAPEUTICS Pollak, P. T., Bouillon, T., Shafer, S. L. 2000; 67 (6): 642-652

  Abstract

  Amiodarone is an increasingly popular and uniquely effective antiarrhythmic agent for which population pharmacokinetic parameters in patients receiving long-term oral therapy have not been defined previously.We collected 605 observations of serum amiodarone and desethylamiodarone metabolite concentrations from 77 patients (mean follow-up, 2 years). Mixed-effects modeling (NONMEM) was used to determine the typical population pharmacokinetic parameters, their respective variabilities, and a simple oral dosing regimen to rapidly achieve and maintain a target concentration of 1.5 mg/L. Individual serum concentration versus time curves were simulated for the study population based on regimens outlined in the product monograph and were compared with those for the proposed dosing regimen. The relationship between the duration of amiodarone therapy and the rate of decrement in serum concentration after discontinuation was explored.Amiodarone concentrations were best described by a two-compartment model with the typical parameters +/- interindividual coefficients of variation (where applicable) as follows: volumes of distribution/bioavailability (V1/F = 882 L; V2/F = 12,700 L +/- 58%) and clearances/bioavailability (CL1/F = 229 L/day +/- 31%; and CL2/F = 599 L/day +/- 56%). Rapid distribution half-life was 17 hours, and terminal half-life was 55 days. A practical dosing regimen of 1600 mg/d for 2 days, 1,200 mg/d for 5 days, 1,000 mg/d for 7 days, 800 mg/d for 7 days, 600 mg/d for 7 days, and 400 mg/d for 62 days followed by a maintenance dose of 343 mg/d (400 mg/d for 6 of 7 days) is proposed. After steady state is reached, cessation of dosing produces a 25% serum concentration decrement in 3 days and 50% in 36 days.Population pharmacokinetics confirm that amiodarone has an extraordinarily long half-life. The slow elimination rate makes anticipating the timing of adjustments in amiodarone therapy to avoid toxicity unusually perplexing. However, based on the estimated variability, the proposed dosing regimen would produce steady-state concentrations within the therapeutic window for 90% of patients.

  View details for Web of Science ID 000087779400006

  View details for PubMedID 10872646

• Electromyographic activity falsely elevates the bispectral index ANESTHESIOLOGY Bruhn, J., Bouillon, T. W., Shafer, S. L. 2000; 92 (5): 1485-1487

  View details for Web of Science ID 000086867100038

  View details for PubMedID 10781298

• Hot air or full steam ahead? An empirical pharmacokinetic model of potent inhalational agents. British journal of anaesthesia Bouillon, T., Shafer, S. L. 2000; 84 (4): 429-431

  View details for PubMedID 10823089

• Location, location, location ANESTHESIOLOGY Shafer, S. L., Eisenach, J. C. 2000; 92 (3): 641-643

  View details for Web of Science ID 000085628800003

  View details for PubMedID 10719940

• The pharmacology of anesthetic drugs in elderly patients. Anesthesiology clinics of North America Shafer, S. L. 2000; 18 (1): 1-?

  Abstract

  Elderly patients are more sensitive to anesthetic drugs than younger patients. This increased sensitivity has a pharmacokinetic basis if the dose produces a higher drug concentration in an elderly patient than in a younger patient. The increased sensitivity has a pharmacodynamic basis if the same concentration produces a more profound drug effect in elderly patients. This article reviews the mechanisms of increased sensitivity of elderly patients to opioids, hypnotics, amnestica, and muscle relaxants.

  View details for PubMedID 10934997

• Comparison of plasma compartment versus two methods for effect compartment-controlled target-controlled infusion for propofol Struys, M. M., De Smet, T., Depoorter, B., Versichelen, L. F., Mortier, E. P., Dumortier, F. J., Shafer, S. L., Rolly, G. LIPPINCOTT WILLIAMS & WILKINS. 2000: 399-406

  Abstract

  Target-controlled infusion (TCI) systems can control the concentration in the plasma or at the site of drug effect. A TCI system that targets the effect site should be able to accurately predict the time course of drug effect. The authors tested this by comparing the performance of three control algorithms: plasmacontrol TCI versus two algorithms for effect-site control TCI.One-hundred twenty healthy women patients received propofol via TCI for 12-min at a target concentration of 5.4 microg/ml. In all three groups, the plasma concentrations were computed using pharmacokinetics previously reported. In group I, the TCI device controlled the plasma concentration. In groups II and III, the TCI device controlled the effect-site concentration. In group II, the effect site was computed using a half-life for plasma effect-site equilibration (t1/2k(eo)) of 3.5 min. In group III, plasma effect-site equilibration rate constant (k(eo)) was computed to yield a time to peak effect of 1.6 min after bolus injection, yielding a t1/2keo of 34 s. the time course of propofol was measured using the bispectral index. Blood pressure, ventilation, and time of loss of consciousness were measured.The time course of propofol drug effect, as measured by the bispectral index, was best predicted in group III. Targeting the effect-site concentration shortened the time to loss of consciousness compared with the targeting plasma concentration without causing hypotension. The incidence of apnea was less in group III than in group II.Effect compartment-controlled TCI can be safely applied in clinical practice. A biophase model combining the Marsh kinetics and a time to peak effect of 1.6 min accurately predicted the time course of propofol drug effect.

  View details for Web of Science ID 000085078600017

  View details for PubMedID 10691226

• Bispectral index (BIS) and burst suppression: revealing a part of the BIS algorithm. Journal of clinical monitoring and computing Bruhn, J., Bouillon, T. W., Shafer, S. L. 2000; 16 (8): 593-596

  Abstract

  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.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 microg/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.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 > or = 40% the BIS value could be calculated as BIS = 50 - suppression ratio/2.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.

  View details for PubMedID 12580235

• Drug interactions. Applications in fast-track anesthesia. Acta anaesthesiologica Belgica Shafer, S. L. 1999; 50 (4): 153-160

  View details for PubMedID 10603988

• Pharmacokinetics, cortisol release, and hemodynamics after intravenous and subcutaneous injection of human corticotropin-releasing factor in humans CLINICAL PHARMACOLOGY & THERAPEUTICS Angst, M. S., Dyck, J. B., Azarnoff, D. L., Goldblum, R., Ho, B., Gfroerer, T., Linton, E. A., Glynn, B. P., Shafer, S. L. 1998; 64 (5): 499-510

  Abstract

  Two clinical trials investigated the pharmacokinetics of human corticotropin-releasing factor (hCRF), resulting cortisol release, and associated hemodynamic changes.In a 3 x 3 Latin square design, subjects were randomized to receive a single dose of 5 microg x kg(-1) hCRF as a 10-minute intravenous infusion, a 180-minute infusion, and a subcutaneous injection in separate study sessions 7 days apart. Twelve additional subjects obtained a subcutaneous dose of either 300, 600, or 1200 microg hCRF on 3 consecutive days. Noncompartmental and compartmental pharmacokinetic analysis was performed. Hemodynamic response was characterized with use of pharmacodynamic models.The volume of distribution at steady state was 9.81 +/- 3.0 and 15.61 +/- 2.9, and the clearance was 256 +/- 40 mL x min(-1) and 345 +/- 90 mL x min(-1) for the 10-minute and 180-minute intravenous infusion, respectively (P < .05). Corresponding elimination half-life was 45 +/- 7 minutes and 37 +/- 10 minutes. Two-compartment and 1-compartment models adequately described the 10-minute and 180-minute infusions, respectively. The bioavailability of hCRF after subcutaneous administration was 67% +/- 17%. Apparent clearance remained unchanged for different subcutaneous doses. Peak plasma cortisol concentrations were similar after subcutaneous and intravenous administration of hCRF. Repetitive administration of hCRF did not result in accumulation but produced a reduced plasma cortisol response. A sigmoidal model related plasma hCRF concentrations to increase in heart rate (maximum, 39 beats x min(-1)). The relationship between the modest decrease in diastolic blood pressure and plasma hCRF concentrations was linear.The pharmacokinetics of intravenously administered hCRF were nonlinear, but apparent clearance was constant for various subcutaneous doses. An excellent bioavailability and preserved bioactivity make the subcutaneous route an attractive choice. Repetitive administration of hCRF probably caused tolerance of the cortisol response.

  View details for Web of Science ID 000077167800005

  View details for PubMedID 9834042

• Does size matter? ANESTHESIOLOGY Bouillon, T., Shafer, S. L. 1998; 89 (3): 557-560

  View details for Web of Science ID 000075828400001

  View details for PubMedID 9743389

• Pharmacokinetics of intravenous dynorphin A(1-13) in opioid-naive and opioid-treated human volunteers CLINICAL PHARMACOLOGY & THERAPEUTICS Gambus, P. L., Schnider, T. W., Minto, C. F., Youngs, E. J., Billard, V., Brose, W. G., Hochhaus, G., Shafer, S. L. 1998; 64 (1): 27-38

  Abstract

  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).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.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.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.

  View details for Web of Science ID 000075103400004

  View details for PubMedID 9695716

• Writing successful research proposals for medical science ANESTHESIOLOGY Schwinn, D. A., DeLong, E. R., Shafer, S. L. 1998; 88 (6): 1660-1666

  View details for Web of Science ID 000074153400030

  View details for PubMedID 9637661

• Pharmacokinetics and pharmacodynamics in anesthetic drug development. Acta anaesthesiologica Belgica Shafer, S. L. 1998; 49 (2): 65-78

  View details for PubMedID 9675375

• Nomenclature for computer-assisted infusion devices ANESTHESIOLOGY Glass, P. S., Glen, J. B., Kenny, G. N., Schuttler, J., Shafer, S. L. 1997; 86 (6): 1430-1431

  View details for Web of Science ID A1997XE80600033

  View details for PubMedID 9197319

• Urine and plasma catecholamine and cortisol concentrations after myocardial revascularization - Modulation by continuous sedation ANESTHESIOLOGY PLUNKETT, J. J., Reeves, J. D., Ngo, L., Bellows, W., Shafer, S. L., Roach, G., Howse, J., Herskowitz, A., Mangano, D. T. 1997; 86 (4): 785-796

  Abstract

  Cardiopulmonary bypass is associated with substantial release of catecholamines and cortisol for 12 or more h. A technique was assessed that may mitigate the responses with continuous 12-h postoperative sedation using propofol.One hundred twenty-one patients having primary elective cardiopulmonary bypass graft (CABG) surgery were enrolled in a double-blind, randomized trial and anesthetized using a standardized sufentanil-midazolam regimen. When arriving at the intensive care unit (ICU), patients were randomly assigned to either group SC (standard care), in which intermittent bolus administration of midazolam and morphine were given as required to keep patients comfortable; or group CP (continuous propofol), in which 12 h of continuous postoperative infusion of propofol was titrated to keep patients deeply sedated. Serial perioperative measurements of plasma and urine cortisol, epinephrine, norepinephrine, and dopamine were obtained; heart rate and blood pressure were recorded continuously, and medication use, including requirements for opioids and vasoactive drugs, was recorded. Repeated-measures analysis was used to assess differences between study groups for plasma catecholamine and cortisol levels at each measurement time.In the control state-before the initiation of postoperative sedation in the ICU-no significant differences between study groups were observed for urine or plasma catecholamine or cortisol concentrations. During the ICU study period, for the first 6-8 h, significant differences were found between study groups SC and CP in plasma cortisol (SC = 28 +/- 15 mg/dl; CP = 19 +/- 12 mg/dl; estimated mean difference [EMD] = 9 mg/dl; P = 0.0004), plasma epinephrine (SC = 132 +/- 120 micrograms/ml; CP = 77 +/- 122 micrograms/ml; EMD = 69 micrograms/ml; P = 0.009), urine cortisol (SC = 216 +/- 313 micrograms/ml; CP = 93 +/- 129 micrograms/ml; EMD = 127 micrograms/ml; P = 0.007), urine dopamine (SC = 85 +/- 48 micrograms; CP = 52 +/- 43 micrograms; EMD = 32 micrograms; P = 0.002), urine epinephrine (SC = 7 +/- 8 micrograms; CP = 4 +/- 5 micrograms; EMD = 3 micrograms; P = 0.0009), and urine norepinephrine (SC = 24 +/- 14 mg; CP = 13 +/- 9 mg; EMD = 11 mg; P = 0.0004). Reductions in urine and plasma catecholamine and cortisol concentrations found for the CP group generally persisted during the 12-h propofol infusion period and then rapidly returned toward control (SC group) values after propofol was discontinued. Postoperative opioid use was reduced in the CP group (SC = 97%; CP = 49%; P = 0.001), as was the incidence of tachycardia (SC = 79%; CP = 60%; P = 0.04) and hypertension (SC = 58%; CP = 33%; P = 0.01), but the incidence of hypotension was increased (SC = 49%; CP = 81%; P = 0.001).Cardiopulmonary bypass graft surgery is associated with substantial increases in plasma and urine catecholamine and cortisol concentrations, which persist for 12 or more h. This hormonal response may be mitigated by a technique of intensive continuous 12-h postoperative sedation with propofol, which is associated with a decrease in tachycardia and hypertension and an increase in hypotension.

  View details for Web of Science ID A1997WT00800010

  View details for PubMedID 9105222

• Pharmacokinetic model-driven infusion of fentanyl in children ANESTHESIOLOGY Ginsberg, B., Howell, S., Glass, P. S., Margolis, J. O., Ross, A. K., Dear, G. D., Shafer, S. L. 1996; 85 (6): 1268-1275

  Abstract

  This study determined the accuracy of previously defined adult fentanyl pharmacokinetics in children having surgery; from this population, the pharmacokinetics of fentanyl were characterized in children when administered via a computerized assisted continuous-infusion device.Twenty children between the ages of 2.7 and 11 y scheduled to undergo elective noncardiac surgery were studied. After induction, anesthesia was maintained with 60% nitrous oxide in oxygen supplemented with fentanyl (n = 10) or fentanyl plus isoflurane (n = 10). Fentanyl was administered via computerized assisted continuous-infusion to target concentrations determined by clinical requirements. Plasma fentanyl concentrations were measured and used to evaluate the performance of the fentanyl pharmacokinetics and then to determine a new set of pharmacokinetic parameters and the variance in the context-sensitive half-times simulated for these patients.The original adult fentanyl pharmacokinetics resulted in a positive bias (10.4%), indicating that measured concentrations were mostly greater than predicted. A two-compartment model with age and weight as covariates provided the optimal pharmacokinetic parameters. These resulted in a residual performance error of -1.1% and a median absolute performance error of 17.4%. The context-sensitive times determined from this pediatric population were considerably shorter than the context-sensitive times previously published for adults.The pharmacokinetics of fentanyl administered by computerized assisted continuous-infusion differ between adults and children. The newly derived parameters are probably more suitable to determine infusion schemes of up to 4 h in children between the ages of 2 and 11 y.

  View details for Web of Science ID A1996VX62100008

  View details for PubMedID 8968173

• Trefentanil shows clinical benefit over alfentanil using respiratory pharmacodynamic measures. Minto, C. F., Schnider, T. W., Gambus, P. L., Cohane, C., Lemmens, H., Youngs, E., Shafer, S. L. LIPPINCOTT WILLIAMS & WILKINS. 1996: A338-A338

  View details for Web of Science ID A1996VM46600338

• Comparison of some suboptimal control policies in medical drug therapy OPERATIONS RESEARCH Hu, C. P., Lovejoy, W. S., Shafer, S. L. 1996; 44 (5): 696-709

  View details for Web of Science ID A1996VT59000004

• The EEG versus clinical measures of opioid potency: Defining the EEG-clinical potency fingerprint with application to remifentanil Egan, T. D., Muir, K. T., Stanski, D. R., Shafer, S. L. LIPPINCOTT WILLIAMS & WILKINS. 1996: A349-A349

  View details for Web of Science ID A1996VM46600349

• Pharmacokinetics of propofol in adult patients undergoing coronary revascularization ANESTHESIOLOGY Bailey, J. M., MORA, C. T., Shafer, S. L. 1996; 84 (6): 1288-1297

  Abstract

  Propofol is increasingly used for cardiac anesthesia and for perioperative sedation. Because pharmacokinetic parameters vary among distinct patient populations, rational drug dosing in the cardiac surgery patient is dependent on characterization of the drug's pharmacokinetic parameters in patients actually undergoing cardiac procedures and cardiopulmonary bypass (CPB). In this study, the pharmacokinetics of propofol was characterized in adult patients undergoing coronary revascularization.Anesthesia was induced and maintained by computer-controlled infusions of propofol and alfentanil, or sufentanil, in 41 adult patients undergoing coronary artery bypass graft surgery. Blood samples for determination of plasma propofol concentrations were collected during the predefined study periods and assayed by high-pressure liquid chromatography. Three-compartment model pharmacokinetic parameters were determined by nonlinear extended least-squares regression of pooled data from patients receiving propofol throughout the perioperative period. The effect of CPB on propofol pharmacokinetics was modeled by allowing the parameters to change with the institution and completion of extracorporeal circulation and selecting the optimal model on the basis of the logarithm of the likelihood. Predicted propofol concentrations were calculated by convolving the infusion rates with unit disposition functions using the estimated parameters. The predictive accuracy of the parameters was evaluated by cross-validation and by a prospective comparison of predicted and measured levels in a subset of patients.Optimal pharmacokinetic parameters were: central compartment volume = 6.0 l; second compartment volume = 49.5 l; third compartment volume = 429.3 l; Cl1 (elimination clearance) = 0.68 l/min; Cl2 (distribution clearance) = 1.97 l/min1; and Cl3 (distribution clearance) = 0.70 l/min. The effects of CPB were optimally modeled by step changes in V1 and Cl1 to values of 15.9 and 1.95, respectively, with the institution of CPB. Median absolute prediction error was 18% in the cross-validation assessment and 19% in the prospective evaluation. There was no evidence for nonlinear kinetics. Previously published propofol pharmacokinetic parameter sets poorly predicted the observed concentrations in cardiac surgical patients.The pharmacokinetics of propofol in adult patients undergoing cardiac surgery with CPB are dissimilar from those reported for other adult patient populations. The effect of CPB was best modeled by an increase in V1 and Cl1. Predictive accuracy of the derived pharmacokinetic parameters was excellent as measured by cross-validation and a prospective test.

  View details for Web of Science ID A1996UQ74400004

  View details for PubMedID 8669668

• Comparative absorption kinetics of intramuscular midazolam and diazepam CANADIAN JOURNAL OF ANAESTHESIA-JOURNAL CANADIEN D ANESTHESIE Hung, O. R., Dyck, J. B., VARVEL, J., Shafer, S. L., Stanski, D. R. 1996; 43 (5): 450-455

  Abstract

  This study investigates the rate and extent of absorption following intramuscular injection of midazolam and diazepam.Four healthy male volunteers were recruited in this randomized three-way cross-over study. On one occasion each subject received simultaneous im injections of 5 mg midazolam and 10 mg diazepam in separate deltoid muscles. On two other separate occasions each subject received an iv infusion of 7.5 mg midazolam and 30 mg diazepam over five minutes. Frequent arterial blood samples were collected for up to two hours and venous blood samples were collected for up to 24 hours for midazolam and ten days for diazepam. A gas chromatography assay was used to determine the plasma concentrations of midazolam and diazepam. The im absorption profiles were estimated using constrained least-squares deconvolution.There were substantial intersubject variabilities in the estimated pharmacokinetic parameters (volume and clearances) of intravenous midazolam and diazepam. The mean (+/-sd) time to peak plasma concentration (Cmax) was shorter for im midazolam (17.5 +/- 6.5 min) relative to diazepam (33.8 +/- 7.5 min). The mean (+sd) time to peak absorption rate was also shorter for midazolam (9 +/- 2 vs 13.8 +/- 7.5 min). The peak rate of absorption was identical (0.18 mg. min-1) and bioavailability was 1.0 for both drugs.We conclude that midazolam has more rapid absorption than diazepam following im administration.

  View details for Web of Science ID A1996UJ24300006

  View details for PubMedID 8723850

• Inhalation versus intravenous anesthesia: A fictitious debate between E.I. Eger II and P.F. White JOURNAL OF CLINICAL ANESTHESIA Shafer, S. L., Gambus, P. L. 1996; 8: S38-S41

  View details for Web of Science ID A1996UH60400008

• Inhalation versus intravenous anesthesia: a fictitious debate between E.I. Eger II and P.F. White. Journal of clinical anesthesia Shafer, S. L., Gambús, P. L. 1996; 8 (3): 38S-41S

  View details for PubMedID 8695113

• Derivation and cross-validation of pharmacokinetic parameters for computer-controlled infusion of lidocaine in pain therapy ANESTHESIOLOGY Schnider, T. W., Gaeta, R., BROSE, W., Minto, C. F., Gregg, K. M., Shafer, S. L. 1996; 84 (5): 1043-1050

  Abstract

  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.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.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%.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.

  View details for Web of Science ID A1996UJ07100006

  View details for PubMedID 8623997

• Semilinear canonical correlation applied to the measurement of the electroencephalographic effects of midazolam and flumazenil reversal ANESTHESIOLOGY Schnider, T. W., Minto, C. F., Fiset, P., Gregg, K. M., Shafer, S. L. 1996; 84 (3): 510-519

  Abstract

  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.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.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.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.

  View details for Web of Science ID A1996UA37700005

  View details for PubMedID 8659777

• Using the electroencephalographic (EEG) fingerprint to define the clinical pharmacodynamics (PD) of a novel opioid: Application to remifentanil (REMI) Egan, T. D., Muir, K. T., Stanski, D. R., Shafer, S. L. NATURE PUBLISHING GROUP. 1996: PI1-PI1

  View details for Web of Science ID A1996TX00100001

• LINEARITY OF PHARMACOKINETICS AND MODEL ESTIMATION OF SUFENTANIL ANESTHESIOLOGY Gepts, E., Shafer, S. L., Camu, F., Stanski, D. R., Woestenborghs, R., VANPEER, A., HEYKANTS, J. J. 1995; 83 (6): 1194-1204

  Abstract

  The pharmacokinetic profiles of sufentanil available in the literature are conflicting because of methodologic differences. Length of sampling and assay sensitivity are key factors involved in accurately estimating the volumes of distribution, clearances, and elimination phase. The unit disposition function of increasing doses of sufentanil were investigated and the influence of dose administered on the linearity of pharmacokinetics was assessed.The pharmacokinetics of sufentanil were investigated in 23 patients, aged 14-68 yr, scheduled for surgery with postoperative ventilation. After induction of anesthesia, sufentanil was administered as a short infusion (10-20 min) in doses ranging from 250 micrograms to 1,500 micrograms. Frequent arterial blood samples were gathered during and at the end of infusion, then at specific intervals up to 48 h after infusion. Plasma concentrations of sufentanil were measured by radioimmunoassay (limit of sensitivity 0.02 ng.ml-1). The data were analyzed with the standard two-stage, naive pooled-data and the mixed effect pharmacokinetic approaches.The pharmacokinetics of sufentanil were adequately described by a linear three-compartmental mamillary model with the following parameters, expressed as log mean values with 95% confidence intervals: the central volume of distribution = 14.3 l (13.1-15.41), the rapidly equilibrating volume = 63.1 l (61.9-64.3 l), the slowly equilibrating volume = 261.6 l (260.2-262.9 l), the steady-state distribution volume = 339 l (335-343 l), metabolic clearance = 0.92 l.min-1 (0.84-1.05 l.min-1), rapid distribution clearance = 1.55 l.min-1 (1.34-2.14 l.min-1), slow distribution clearance = 0.33 l.min-1 (0.27-0.49 l.min-1), and elimination half-life = 769 min (690-1011 min). No relation to age, weight, or lean body mass was found for any of the parameters.Sufentanil pharmacokinetics were linear within the dose range studied. Drug detection up to 24 h after dosing was necessary to define the terminal elimination phase. The metabolic clearance approached liver blood flow and a large volume of distribution was identified, consistent with the long terminal elimination half-life. Simulations predicted that plasma sufentanil steady-state concentrations would rapidly decline after termination of an infusion despite the long half-lives.

  View details for Web of Science ID A1995TJ32900010

  View details for PubMedID 8533912

• PHARMACODYNAMIC MODELING OF THE ELECTROENCEPHALOGRAPHIC EFFECTS OF FLUMAZENIL IN HEALTHY-VOLUNTEERS SEDATED WITH MIDAZOLAM CLINICAL PHARMACOLOGY & THERAPEUTICS Fiset, P., Lemmens, H. L., Egan, T. E., Shafer, S. L., Stanski, D. R. 1995; 58 (5): 567-582

  Abstract

  The purpose of this study was to model pharmacodynamically the reversal of midazolam sedation with flumazenil. Ten human volunteers underwent four different sessions. In session 1, individual midazolam pharmacokinetics and electroencephalographic pharmacodynamics were determined. In sessions 2 and 3, a computer-controlled infusion of midazolam with individual volunteer pharmacokinetic data was administered, targeting a plasma concentration corresponding to a light or deep level of sedation (20% or 80% of the maximal midazolam electroencephalographic effect) for a period of 210 minutes. After obtaining a stable electroencephalographic effect and constant midazolam plasma concentrations, a zero-order infusion of flumazenil was started until complete reversal of midazolam electroencephalographic effect was obtained. The flumazenil infusion was then stopped and the volunteer was allowed to resedate because of the constant midazolam drug effect. The electroencephalographic response was measured during a 180-minute period and analyzed by aperiodic analysis and fast-Fourier transforms. In session 4, a midazolam plasma concentration corresponding to a deep level of sedation was targeted for 210 minutes to examine for the possible development of acute tolerance. No flumazenil was given in session 4. For a light sedation level, with a mean midazolam plasma concentration of 160 +/- 64 ng/ml, the mean half-life of the equilibration rate constant of flumazenil reversal is 5.0 +/- 2.5 minutes, and the mean effect site concentration causing 50% of Emax is 13.7 +/- 5.8 ng/ml. For a deep level of sedation, with a mean midazolam plasma concentration of 551 +/- 196 ng/ml, the mean half-life of the equilibration rate constant is 3.9 +/- 1.5 minutes, and the mean effect site concentration causing 50% of Emax is 20.6 +/- 6.8 ng/ml. This study provides an estimate of the magnitude of the blood/central nervous system equilibration delay for flumazenil antagonism of midazolam sedation and further defines the usefulness of the electroencephalogram as a measure of midazolam pharmacodynamic effect.

  View details for Web of Science ID A1995TH58600011

  View details for PubMedID 7586951

• EVOLVING CLINICALLY USEFUL PREDICTORS OF RECOVERY FROM INTRAVENOUS ANESTHETICS ANESTHESIOLOGY Schnider, T. W. 1995; 83 (5): 902-905

  View details for Web of Science ID A1995TD72300003

  View details for PubMedID 7486175

• PHARMACOKINETICS OF COMPUTER-CONTROLLED ALFENTANIL ADMINISTRATION IN CHILDREN UNDERGOING CARDIAC-SURGERY ANESTHESIOLOGY Fiset, P., Mathers, L., Engstrom, R., Fitzgerald, D., Brand, S. C., Hsu, F., Shafer, S. L. 1995; 83 (5): 944-955

  Abstract

  Cardiopulmonary bypass (CPB) induces changes in the pharmacokinetics of drugs. The purpose of this study was to model the pharmacokinetics of alfentanil in children undergoing cardiac surgery to provide accurate dosage titration intraoperatively as well as in the postoperative period.Fourteen children (aged 3 months to 8 yr) undergoing cardiac surgery with CPB were administered alfentanil via a computer-controlled infusion pump. During surgery, the computer-controlled infusion pump was set to target plasma alfentanil concentrations of 500-2500 micrograms/ml. After surgery, the computer-controlled infusion pump was set to target plasma concentrations of 200-500 micrograms/ml. Parameters for children previously published by Goresky et al. were programmed into the device. Arterial blood samples were taken throughout the infusion. Plasma samples were assayed by radioimmunoassay. Alfentanil pharmacokinetics were estimated using a pooled-data approach with a simple weight-proportional, three-compartment mamillary model with parameters expressed in volumes and clearances as well as a CPB-adjusted, three-compartment model in which the parameters were allowed to change before, during, and after CPB. The accuracy of the three models was compared using cross-validation.Plasma alfentanil concentrations during computer-controlled infusion pump administration exceeded target concentrations for the first 10 min of drug administration, and from 300 min to the end of the study. The median absolute performance error was 33%. Pharmacokinetic modeling estimated a set of parameters for a simple three-compartment model with a median absolute weighted residual of 18.4%. A CPB-adjusted model nominally decreased the median absolute weighted residual to 17.0%. The performance of these models as measured by cross-validation performance was 18.9% median absolute performance error for the simple model and 18.4% median absolute performance error for the CPB-adjusted model. Parameters for the simple three-compartment model are: V1 = 19.2 ml.kg-1; V2 = 99 ml.kg-1; V3 = 2344 ml.kg-1; Cl1 = 2.5 ml.kg-1.min-1; Cl2 = 38 ml.kg-1.min-1; and Cl3 = 15 ml.kg-1.min-1. In the CPB-adjusted model V1, V2, and Cl2 changed with the onset of CPB. After CPB, V1 and Cl2 returned to the initial values, while V2 was described by a third value.The population pharmacokinetics of alfentanil in children undergoing cardiac surgery were well described by both a simple weight-proportional, three-compartment model and a weight-proportional, CPB-adjusted three-compartment model. Cross-validation estimated an expected median inaccuracy of approximately 18-20% with the estimated models in identical experimental circumstances. The flexible CPB-adjusted pharmacokinetic model could be used for modeling any drug with linear pharmacokinetics given in the context of CPB.

  View details for Web of Science ID A1995TD72300007

  View details for PubMedID 7486179

• THE PHARMACOKINETICS OF 8-METHOXYPSORALEN FOLLOWING IV ADMINISTRATION IN HUMANS BRITISH JOURNAL OF CLINICAL PHARMACOLOGY Billard, V., Gambus, P. L., Barr, J., Minto, C. F., Corash, L., TESSMAN, J. W., Stickney, J. L., Shafer, S. L. 1995; 40 (4): 347-360

  Abstract

  1. 8-methoxypsoralen (8-MOP) is a naturally occurring photoreactive substance which, in the presence of u.v. light, forms covalent adducts with pyrimidine bases in nucleic acids. For many years, 8-MOP has been used in PUVA therapy for treatment of psoriasis. Recently, the drug has been found to inactivate effectively bacteria spiked into platelet concentrates. The purpose of this study was to determine the pharmacokinetics and safety of 8-MOP administered intravenously in the bactericidal dosage range. 2. Eighteen volunteers were divided into three treatment groups to receive, respectively, 5, 10, and 15 mg 8-MOP infused over 60 min. Frequent arterial samples were gathered, and the blood and plasma were assayed for 8-MOP concentration. The pharmacokinetic parameters were determined by moment and compartmental population analysis, the latter performed with the program NONMEM. Haemodynamics, ventilatory pattern, and subjective effects were recorded throughout the study. 3. The intravenously administered 8-MOP was well tolerated in all individuals, and no acute toxicity was observed. 4. The pharmacokinetics of 8-MOP were best described by a three-compartment mammillary model in which the volumes and clearances were proportional to weight. The mean pharmacokinetic parameters for the plasma concentrations were: V1 = 0.045 1 kg-1, V2 = 0.57 1 kg-1, V3 = 0.15 1 kg-1, CL1 (systemic) = 0.010 1 kg-1 min-1, CL2 = 0.0067 1 kg-1 min-1, CL3 = 0.012 1 kg-1 min-1. The mean pharmacokinetic parameters for the blood concentrations were: V1 = 0.061 1 kg-1, V2 = 1.15 1 kg-1, V3 = 0.21 1 kg-1, CL1 (systemic) = 0.015 1 kg-1 min-1, CL2 = 0.011 1 kg-1 min-1 and CL3 = 0.015 1 kg-1 min-1. 5. The plasma pharmacokinetic model described the observations with a median absolute error of 17%, and the blood pharmacokinetic model described the observations with a median absolute error of 18%. Analysis of the relative concentration of 8-MOP between plasma and red blood cells suggested concentration-dependent partitioning. 6. The addition of 7.5 mg 8-MOP to 300 ml platelet concentrate would produce bactericidal concentrations of 25 micrograms ml-1. Simulations based upon our data show that intravenous administration of 7.5 mg over 60 min would result in systemic concentrations of 8-MOP similar to those observed with conventional PUVA therapy. We conclude that the extensive safety history established in PUVA therapy will be applicable to this new application of 8-MOP.

  View details for Web of Science ID A1995RY55800009

  View details for PubMedID 8554937

• PROLONGED ALLEVIATION OF TACTILE ALLODYNIA BY INTRAVENOUS LIDOCAINE IN NEUROPATHIC RATS ANESTHESIOLOGY Chaplan, S. R., Bach, F. W., Shafer, S. L., Yaksh, T. L. 1995; 83 (4): 775-785

  Abstract

  Lidocaine may be useful in the treatment of neuropathic pain states. The authors hypothesized that lidocaine would reduce tactile allodynia observed in a rat nerve injury model. In an effort to determine the site of drug action, effects after intravenous, intrathecal, and regional administration were compared.Rats underwent ligation of the left fifth and sixth lumbar spinal nerves. The 50% thresholds (g) for left hind paw withdrawal of awake rats to von Frey hairs were documented before, during, and after intravenous administration of lidocaine at programmed/documented pseudo-steady-state plasma concentrations, and correlated with measured plasma concentrations. Responses to lidocaine application intrathecally and regionally to the injured nerves were also recorded.In rats with tactile allodynia, intravenous lidocaine yielded 66 +/- 11% of the maximal possible effect on thresholds (100% = normal threshold), versus -1.3 +/- 2.7% for saline infusion. Twenty-one days after lidocaine infusion, 30-40% of the maximal possible effect persisted. Threshold increases depended on plasma concentration, rather than quantity of drug administered: rats receiving 15 mg/kg with higher plasma concentrations (1.2 +/- 0.1 micrograms/ml) showed significant allodynia suppression throughout 7 days of follow-up, whereas rats receiving 15 mg/kg at a slower rate with lower plasma concentrations (0.6 +/- 0.1 microgram/ml) did not. The EC50 for acute allodynia suppression was 0.75 microgram/ml. No such allodynia suppression was seen after intrathecal or regional administration of lidocaine despite transient neural blockade.Intravenous, but not intrathecal or regionally applied, lidocaine produces dose-dependent suppression of allodynia associated with nerve injury. The effects far outlast plasma concentrations of lidocaine. The mechanism of these prolonged effects is unknown.

  View details for Web of Science ID A1995RY95500019

  View details for PubMedID 7574057

• VALIDATION OF THE ALFENTANIL CANONICAL UNIVARIATE PARAMETERS AS A MEASURE OF OPIOID EFFECT ON THE ELECTROENCEPHALOGRAM ANESTHESIOLOGY Gambus, P. L., Gregg, K. M., Shafer, S. L. 1995; 83 (4): 747-756

  Abstract

  Several parameters derived from the multivariate electroencephalographic (EEG) signal have been used to characterize the effects of opioids on the central nervous system. These parameters were formulated on an empirical basis. A new statistical method, semilinear canonical correlation, has been used to construct a new EEG parameter (a certain combination of the powers in the EEG power spectrum) that correlates maximally with the concentration of alfentanil at the effect site. To date, this new canonical univariate parameter (CUP) has been tested only in a small sample of subjects receiving alfentanil.The CUP was tested on EEG data from prior studies of the effect of five opioids: alfentanil (n = 5), fentanyl (n = 15), sufentanil (n = 11), trefentanil (n = 5), and remifentanil (n = 8). We compared the CUP to the commonly used EEG parameter spectral edge, SE95%. The comparison was based on the signal to noise ratio, obtained by fitting a nonlinear pharmacodynamic model to both parameters. The pharmacodynamic parameter estimates obtained using both measurements were also compared.The values for signal-to-noise ratio were significantly greater for the CUP than for SE95% when considering all the opioids at once. The pharmacodynamic estimates were similar between the two EEG parameters and with previously published results. Semilinear canonical correlation coefficients estimated within each drug group showed patterns similar to each other and to the coefficients in the CUP, but different from coefficients for propofol and midazolam.Although the CUP was originally designed and tested using alfentanil, we have proven it to be a general measure of opioid effect on the EEG.

  View details for Web of Science ID A1995RY95500016

  View details for PubMedID 7574054

• BIOPHARMACEUTICS OF A NEW TRANSDERMAL FENTANYL DEVICE ANESTHESIOLOGY Fiset, P., Cohane, C., Browne, S., Brand, S. C., Shafer, S. L. 1995; 83 (3): 459-469

  Abstract

  Compared with conventional routes of delivering potent analgesics to postoperative patients, transdermal administration of fentanyl offers the advantages of simplicity and noninvasive delivery. The only available form of transdermal fentanyl, the Duragesic system, has been implicated in preventable patient deaths when used for postoperative analgesia and is contraindicated in the management of postoperative pain. We examined the biopharmaceutics of a new transdermal fentanyl device developed by Cygnus and intended for use as a postoperative analgesic to see whether the new formulation offers pharmacokinetic advantages that might permit safe use in postoperative patients.We studied 15 consenting male adult surgical patients. Patients received 650 or 750 micrograms intravenous fentanyl as part of the induction of anesthesia. Plasma fentanyl concentrations were measured over the following 24-h period. On the first postoperative day, 24 h after the intravenous dose of fentanyl, a transdermal fentanyl device was placed on the upper torso of the patient for 24 h and then removed. Plasma fentanyl concentrations were measured for 72 h after application of the transdermal fentanyl device. From the concentration versus time profile for the 24 h after intravenous fentanyl administration we determined each patient's clearance and unit disposition function by moment analysis and constrained numeric deconvolution, respectively. From the concentration versus time profile for the 72 h after application of the transdermal device we determined the amount of fentanyl absorbed and the rate of absorption, again by moment analysis and constrained numeric deconvolution. The residual fentanyl in the transdermal fentanyl device was measured, permitting calculation of the absolute bioavailability of transdermally administered fentanyl.Of the 14 subjects who received transdermal fentanyl, 3 had clinically significant fentanyl toxicity, mandating early removal of the device. The range during the plateau from 12 to 24 h in subjects still wearing the device was 0.34-6.75 ng/ml, a 20-fold range in concentration. In subjects wearing the device for 24 h, the terminal half-life of fentanyl after removal of the device was 16 h. The bioavailability of transdermally administered fentanyl was 63 +/- 35% coefficient of variation. The rate of fentanyl absorption from 12-24 h ranged from 10 to 230 micrograms/h in subjects still wearing the device. In two subjects, the rate within the first 6 h briefly exceeded 300 micrograms/h. Both of these subjects demonstrated fentanyl toxicity, requiring early removal of the device.The Cygnus transdermal fentanyl device shows great variability in the rate of fentanyl absorption, resulting in highly variable plasma fentanyl concentrations. Some persons may rapidly absorb fentanyl from the device in the first few hours after application, leading to fentanyl toxicity. The variability in effect of the Cygnus transdermal fentanyl device is appreciably greater than that reported for the currently available Duragesic transdermal fentanyl device, which is contraindicated for postoperative analgesia.

  View details for Web of Science ID A1995RT88900006

  View details for PubMedID 7661346

• THE PHARMACOKINETICS OF IV DYNORPHIN-A-(1-13) IN OPIOID NAIVE AND OPIOID TOLERANT HUMAN VOLUNTEERS Gambus, P. L., Minto, C. F., Schnider, T. W., Youngs, E., Shafer, S. L. LIPPINCOTT WILLIAMS & WILKINS. 1995: A369-A369

  View details for Web of Science ID A1995RX68500369

• PHARMACOKINETICS OF INHALED LIPOSOME-ENCAPSULATED FENTANYL ANESTHESIOLOGY Hung, O. R., WHYNOT, S. C., VARVEL, J. R., Shafer, S. L., MEZEI, M. 1995; 83 (2): 277-284

  Abstract

  Pulmonary administration of fentanyl solution can provide satisfactory but brief postoperative pain relief. Liposomes are microscopic phospholipid vesicles that can entrap drug molecules. Liposomal delivery of fentanyl has the potential to control the uptake of fentanyl by the lungs and thus provide sustained drug release. To demonstrate that inhalation of a mixture of free and liposome-encapsulated fentanyl can provide a rapid increase and sustained plasma fentanyl concentrations (CfenS), this study determined the pharmacokinetic profiles after the inhalation of free and liposome-encapsulated fentanyl in healthy volunteers.After obtaining institutional approval and informed consent, ten healthy volunteers (five men, five women) were studied. Each subject received 200 micrograms intravenous fentanyl and inhaled 2,000 micrograms of free (50%) and liposome-encapsulated fentanyl (50%) on separate occasions. Frequent venous blood samples were collected, and CfenS were determined by radioimmunoassay. The pharmacokinetics and absorption characteristics of the inhaled mixture of free and liposome-encapsulated fentanyl were determined using moment analysis and least-squares numeric deconvolution.The mean (+/- SD) volume of distribution at steady-state and clearance of fentanyl after the intravenous administration were comparable to previous studies: 435 +/- 1821 and 0.584 +/- 0.209 l.min-1, respectively. The mean (+/- SD) peak Cfen was significantly greater for the intravenous administration compared to the aerosol mixture of free and liposome-encapsulated fentanyl (4.67 +/- 1.87 vs. 1.15 +/- 0.36 ng.ml-1). However, CfenS at 8 and 24 h after aerosol administration were greater compared to intravenous (0.25 +/- 0.14 and 0.12 +/- 0.16 ng.ml-1 for aerosol versus 0.16 +/- 0.10 and 0.05 +/- 0.06 ng.ml-1 for intravenous). The peak absorption rate, time to peak absorption, and bioavailability after inhalation were 7.02 (+/- 2.34) micrograms.min, -1(16) (+/- 8.0) min, and 0.12 (+/- 0.11), respectively.The data suggest that this analgesic method offers a simple and noninvasive route of administration with a rapid increase of Cfen and a prolonged therapeutic fentanyl concentration. Future studies are required to determine the optimal liposome composition that would produce a sustained stable Cfen within analgesic therapeutic concentrations.

  View details for Web of Science ID A1995RM71100008

  View details for PubMedID 7631949

• COMPUTER-CONTROLLED EPIDURAL INFUSION TO TARGETED CEREBROSPINAL-FLUID CONCENTRATIONS IN HUMANS ANESTHESIOLOGY Eisenach, J. C., Hood, D. D., Tuttle, R., Shafer, S., Smith, T., Tong, C. Y. 1995; 83 (1): 33-47

  Abstract

  Pharmacokinetically designed infusions have been demonstrated to achieve rapidly and maintain desired concentrations of drug in plasma after intravenous administration. In this study we tested whether a similar approach, targeting concentrations in cerebrospinal fluid (CSF), could be used with epidural administration of the alpha 2-adrenergic analgesic clonidine.After institutional review board approval and informed consent had been obtained, seven healthy volunteers received a clonidine infusion through a lower lumbar epidural catheter. Infusion of clonidine (10 micrograms/ml) was controlled by the STANPUMP program for sequential 75-min periods to targeted CSF clonidine concentrations of 25, 50, 75, and 150 ng/ml. Before reprogramming to the next higher targeted concentration, mean arterial blood pressure and heart rate were measured; blood was obtained for clonidine and catecholamine assays; and visual analog score for sedation and pain to immersion of foot and hand in ice water were obtained. CSF was collected during infusion with an indwelling lumbar intrathecal catheter and was analyzed for clonidine, catecholamines, and acetylcholine.CSF clonidine concentrations rapidly increased and were maintained at steady values with the stepped infusion, although observed concentrations were consistently greater than targeted. The relation between CSF clonidine concentration and analgesia in the foot was similar to that previously observed after epidural bolus administration. Clonidine also was associated with concentration-dependent sedation; decreased mean arterial blood pressure, heart rate, and CSF norepinephrine concentration; and increased CSF acetylcholine concentration.This study suggests that pharmacokinetically designed infusions of drugs in the epidural space in humans can maintain steady concentrations of drug in CSF. In addition to providing a useful tool for investigation of mechanisms of action and drug interactions, this technique may improve analgesia and diminish side effects from epidurally administered analgesics.

  View details for Web of Science ID A1995RH99900005

  View details for PubMedID 7605017

• QUANTIFYING ANESTHETIC DRUG-INTERACTION - IMPLICATIONS FOR DRUG DOSING ANESTHESIOLOGY Stanski, D. R., Shafer, S. L. 1995; 83 (1): 1-5

  View details for Web of Science ID A1995RH99900001

  View details for PubMedID 7604988

• Clinical drug level predictions and practice INTERNATIONAL ANESTHESIOLOGY CLINICS Howell, S., Shafer, S. L., Reves, J. G., Sladen, R. 1995; 33 (3): 91-100

  View details for Web of Science ID A1995TM63200007

  View details for PubMedID 8838754

• ALLOMETRY OF PHARMACOKINETICS AND PHARMACODYNAMICS OF THE MUSCLE-RELAXANT METOCURINE IN MAMMALS AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY Gronert, G. A., Fung, D. L., Jones, J. H., Shafer, S. L., Hildebrand, S. V., Disbrow, E. A. 1995; 268 (1): R85-R91

  Abstract

  We investigated the effects of body size on the pharmacokinetics and pharmacodynamics of the renally cleared muscle relaxant metocurine. We hypothesized that pharmacokinetics of the drug would change allometrically in proportion to physiological time [infinity Mb0.25, where Mb is body mass] and that pharmacodynamics would be independent of size because of the highly conserved structure of the acetylcholine receptor. Metocurine effects during general anesthesia were examined in 17 rats, 8 cats, 6 dogs, 5 pigs, 7 sheep, and 12 horses. Allometric analysis demonstrated size dependence for pharmacokinetics, which were affected by physiological time (Mb0.25). Pharmacodynamics were size independent, except for the value for effect compartment concentration associated with 50% twitch paralysis (IC50). Data from individual species had a bimodal distribution that was significant: pigs and sheep were more sensitive than other large species, and their IC50 appeared size independent. IC50 was size dependent in more active species (horse, dog, cat, rat). Although the mechanism is unknown, we speculate that this trend might relate to receptor density within the end plate. Thus pharmacokinetics changed in proportion to physiological time, and pharmacodynamics were in part size independent.

  View details for Web of Science ID A1995QB49900013

  View details for PubMedID 7840343

• COMPARISON OF SAME CONTROL STRATEGIES FOR 3-COMPARTMENT PK/PD MODELS JOURNAL OF PHARMACOKINETICS AND BIOPHARMACEUTICS Hu, C. P., Lovejoy, W. S., Shafer, S. L. 1994; 22 (6): 525-550

  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.

  View details for Web of Science ID A1994RN34100005

  View details for PubMedID 7473080

• PHARMACOKINETIC PARAMETERS RELEVANT TO RECOVERY FROM OPIOIDS ANESTHESIOLOGY Youngs, E. J., Shafer, S. L. 1994; 81 (4): 833-842

  Abstract

  Several recent studies have suggested that the terminal half-lives of many drugs do not predict the rate of washout of drug after the relatively short durations of infusions used in anesthesia. Many anesthetic drugs fit a three-compartment mamillary model, with three volumes of distribution (central [V1] and peripheral [V2 and V3]) and three clearances (elimination or metabolic [Cl1] and distribution [Cl2 and Cl3]). It has been suggested that a large V3:Cl3 ratio contributes to rapid recovery after infusion. We investigated the role of each of these primary pharmacokinetic parameters to determine values of each that would contribute to rapid recovery after various dosing schemes.Three sets of computer simulations were performed based on a three-compartment mamillary model for fentanyl, alfentanil, and sufentanil. Set I predicted the change in plasma concentration of each drug after a bolus if each pharmacokinetic parameter were independently increased by 5%. Set II predicted the time for an 80%, 50%, or 20% decrease in plasma concentration after infusions of varying duration (the 80%, 50%, and 20% decrement time, respectively) if each pharmacokinetic parameter were independently increased by 5%. Set III calculated the percent change in each pharmacokinetic parameter alone that would give a 30% shorter decrement time after infusions of varying duration.Set I demonstrated that after a bolus dose to obtain identical initial plasma concentrations, the drug with a larger V1 had a higher plasma concentration than did the parent drug at all subsequent times. The drug with a larger Cl1 had a lower plasma concentration than did the parent drug at all times. A larger V2, V3, Cl2, or Cl3 led to a lower plasma concentration at times soon after the bolus and subsequently to a higher plasma concentration than did the parent drug. Set II demonstrated that after an infusion, increasing V1 led to a longer decrement time and increasing Cl1 led to a shorter decrement time for infusions of all durations. Increasing V2, V3, Cl2, or Cl3 led to a shorter decrement time when the infusion had been short and when a small decrease in plasma concentration was desired. Increasing each of these four parameters led to a longer decrement time when the infusion had been long and when a larger decrease in plasma concentration was desired. Set III demonstrated that a smaller V1 or a larger Cl1 always led to a shorter decrement time. For infusions of short duration and for a small decrease in plasma concentration, a larger V2, V3, Cl2, or Cl3 led to the desired decrease in decrement time. For infusions of longer duration and for larger decreases in plasma concentration, a smaller V2, V3, Cl2, or Cl3 was able to decrease the decrement time by 30%.This study proposes qualitative guidelines for pharmacokinetic properties desirable in anesthetic drugs. If a rapid decrease in plasma concentration is desired after an infusion, it is always beneficial to have a small V1 and a large Cl1. For infusions of short duration, after which only a small decrease in plasma concentration is required, it is beneficial to have a larger V2, V3, Cl2, and Cl3. For infusions of longer duration, after which a large decrease in plasma concentration is desired, it is beneficial to have a smaller V2, V3, Cl2, and Cl3. These proposals may be beneficial for planning clinical trials of new drugs.

  View details for Web of Science ID A1994PK61400011

  View details for PubMedID 7943834

• PHARMACOKINETIC-PHARMACODYNAMIC MODELING IN DRUG DEVELOPMENT - APPLICATION TO THE INVESTIGATIONAL OPIOID TREFENTANIL CLINICAL PHARMACOLOGY & THERAPEUTICS Lemmens, H. J., Dyck, J. B., Shafer, S. L., Stanski, D. R. 1994; 56 (3): 261-271

  Abstract

  We determined the possible benefits of a new opioid, trefentanil, relative to fentanyl and alfentanil using high-resolution pharmacokinetic-pharmacodynamic modeling and computer simulations of clinical dosing scenarios.First, we determined in nine volunteers the electroencephalographic (EEG) effects and the trefentanil infusion rate that gave maximal EEG changes in 3 to 10 minutes. Then, in a crossover fashion in five volunteers, we compared the pharmacokinetics and EEG pharmacodynamics of trefentanil with fentanyl and alfentanil. Finally, we used computer simulations to predict offset of opioid effects of trefentanil, fentanyl, and alfentanil when given in different dosing schemes.The pharmacokinetic-pharmacodynamic profile of trefentanil was similar to alfentanil, except for a higher elimination clearance. Trefentanil versus alfentanil pharmacokinetic parameters were as follows: Elimination clearance, 0.444 +/- 0.073 versus 0.184 +/- 0.031 L/min; steady-state distribution volume, 37 +/- 7 versus 23 +/- 3 L; and elimination half-life, 127 +/- 24 versus 114 +/- 19 minutes. Trefentanil versus alfentanil pharmacodynamics were as follows: the equilibration half-time between EEG effect and arterial drug concentration, 1.2 +/- 0.5 versus 0.6 +/- 0.4 minutes; and the concentration resulting in 50% of maximal EEG effect, 429 +/- 313 versus 577 +/- 273 ng/ml. The pharmacokinetic-pharmacodynamic profile of fentanyl was significantly different from trefentanil and alfentanil. Simulation of effect compartment concentration decay curves after variable-length infusions predicted more rapid recovery from trefentanil than from alfentanil or fentanyl.We suggest that high-resolution pharmacokinetic-pharmacodynamic studies and computer simulations of clinical dosing scenarios may have significant usefulness in appreciating differences between new and established drugs in early phase I studies.

  View details for Web of Science ID A1994PK65800007

  View details for PubMedID 7924121

• DERIVATION OF PHARMACOKINETIC PARAMETERS FOR COMPUTER-CONTROLLED INFUSION OF LIDOCAINE IN PAIN THERAPY Schnider, T. W., Minto, C. F., Gaeta, R., BROSE, W., Shafer, S. L. LIPPINCOTT WILLIAMS & WILKINS. 1994: A388-A388

  View details for Web of Science ID A1994PJ09100387

• THE ROLE OF COMPUTER-SIMULATION IN DESIGNING INDIVIDUALIZED METHADONE DOSING REGIMENS Minto, C. F., Schnider, T. W., Gregg, K. M., BROSE, W., Shafer, S. L. LIPPINCOTT WILLIAMS & WILKINS. 1994: A404-A404

  View details for Web of Science ID A1994PJ09100403

• PHARMACOKINETICS AND PHARMACODYNAMICS OF INTRASPINAL DEXMEDETOMIDINE IN SHEEP ANESTHESIOLOGY Eisenach, J. C., Shafer, S. L., Bucklin, B. A., Jackson, C., KALLIO, A. 1994; 80 (6): 1349-1359

  Abstract

  Epidural and spinal injection of alpha 2-adrenergic agonists causes analgesia and hypotension. For opioids, relative analgesic potency of epidural to intravenous administration decreases with increasing lipophilicity, but such pharmacodynamic studies have been performed with only one alpha 2-adrenergic agonist, clonidine, of moderate lipophilicity. This study examines antinociception, transfer to cerebrospinal fluid (CSF), and CSF pharmacokinetics in sheep of the selective alpha 2-adrenergic agonist dexmedetomidine, with lipophilicity 3.5 times greater than clonidine, and correlates CSF concentrations to hemodynamic effects.Six sheep with chronically implanted epidural, intrathecal, and vascular catheters received, on separate days, 100 micrograms dexmedetomidine intravenously, epidurally, or intrathecally. Cerebrospinal fluid and blood were sampled at specified intervals for dexmedetomidine assay. Pharmacokinetics of dexmedetomidine in CSF were determined using a NONMEM approach. Hemodynamic effects were measured and correlated to CSF concentrations. A second group of four sheep received intrathecal dexmedetomidine to define its time course for antinociception.Intrathecal dexmedetomidine decreased blood pressure within 1 min, with a maximum reduction of -22 +/- 3%. Epidural injection decreased blood pressure with a slower onset (11 min) and to a lesser degree (-14 +/- 4%), whereas intravenous injection did not affect blood pressure (-8 +/- 6%). Dexmedetomidine absorption in CSF after epidural injection was rapid (Tmax = 5-20 min), although pharmacokinetic modeling suggested a biphasic absorption process. Only 22% of the injected dose was identified in the CSF. There was a delay of at least 30 min between peak CSF concentrations and time of maximal reduction in blood pressure. At times of identical CSF dexmedetomidine concentrations, blood pressure decreased more after epidural than after intrathecal administration. Intrathecal dexmedetomidine injection produced maximum antinociception within 20-30 min of injection.These data support a primary spinal site of action for decreased blood pressure after intraspinal dexmedetomidine injection. Dexmedetomidine appears rapidly in CSF after epidural administration and decreases blood pressure. The relationship between CSF dexmedetomidine concentrations and drug effect may require more complex modeling tools than those used to relate plasma drug concentrations to effects of systemically administered opioids or neuromuscular blockers.

  View details for Web of Science ID A1994NR92600022

  View details for PubMedID 7912045

• EVALUATION OF BISPECTRAL INDEX OF EEG FOR MONITORING OF ANESTHETIC DRUG EFFECT Billard, V., Gambus, P. L., Shafer, S. L., Stanski, D. R. OXFORD UNIV PRESS. 1994: 67-67

  View details for Web of Science ID A1994MY17600128

• AN EFFICIENT CONTROL STRATEGY FOR DOSAGE REGIMENS JOURNAL OF PHARMACOKINETICS AND BIOPHARMACEUTICS Hu, C. P., Lovejoy, W. S., Shafer, S. L. 1994; 22 (1): 73-94

  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.

  View details for Web of Science ID A1994NG55000005

  View details for PubMedID 8027950

• THE PHARMACOKINETICS OF PROPOFOL IN CHILDREN USING 3 DIFFERENT DATA-ANALYSIS APPROACHES ANESTHESIOLOGY KATARIA, B. K., VED, S. A., NICODEMUS, H. F., Hoy, G. R., Lea, D., Dubois, M. Y., Mandema, J. W., Shafer, S. L. 1994; 80 (1): 104-122

  Abstract

  Accurate dosing of propofol in children requires accurate knowledge of propofol pharmacokinetics in this population. Improvement in pharmacokinetic accuracy may depend on the incorporation of individual patient factors into the pharmacokinetic model or the use of population approaches to estimating the pharmacokinetic parameters. We investigated whether incorporating individual subject covariates (e.g., age, weight, and gender) into the pharmacokinetic model improved the accuracy. We also investigated whether the use of a mixed-effects population model (e.g., the computer program NONMEM) improved the accuracy of the pharmacokinetic model beyond the accuracy obtained with models estimated using two simple approaches.We studied 53 healthy, unpremedicated children (28 boys and 25 girls) ranging from 3 to 11 yr of age. Twenty children only received an initial loading dose of 3 mg/kg intravenous propofol. In the remaining 33 children, an initial intravenous propofol dose of 3.5 mg/kg was followed by a propofol maintenance infusion. Six hundred fifty-eight venous plasma samples were gathered and assayed for propofol concentrations. Three different regression techniques were used to analyze the pharmacokinetics: the "standard two-stage" approach, the "naive pooled-data" approach, and the nonlinear mixed-effects modeling approach (as implemented in NONMEM). In both the pooled-data and mixed-effects approaches, individual covariates (age, weight, height, body surface area, and gender) were added to the model to examine whether they improved the quality of the fit. Accuracy of the model was measured by the ability of the model to describe the observed concentrations.The pharmacokinetics of propofol in children were best described by a three-compartment pharmacokinetic model. There were no appreciable differences among the pharmacokinetics estimated using the two-stage, pooled-data, and mixed-effects approaches. Weight was a significant covariate, and the weight-proportional model was supported by all three regression approaches. The pharmacokinetic parameters of the weight-proportional pharmacokinetic model (pooled-data approach) were: central compartment (V1) = 0.52 1 x kg-1; rapid-distribution compartment (V2) = 1.01 x kg-1; slow-distribution compartment (V3) = 8.2 1 x kg-1; metabolic clearance (Cl1) = 34 ml.kg-1 x min-1; rapid-distribution clearance (Cl2) = 58 ml.kg-1 x min-1; and slow-distribution clearance (Cl3) = 26 ml.kg-1 x min-1. The inclusion of age as an additional covariate of V2 statistically improved the model, but the actual improvement in the fit was small.The pharmacokinetics of propofol in children are well described by a standard three-compartment pharmacokinetic model. Weight-adjusting the volumes and clearances significantly improved the accuracy of the pharmacokinetics. Adjusting the pharmacokinetics for inclusion of additional patient covariates or using a mixed-effects model did not further improve the ability of the pharmacokinetic parameters to describe the observations.

  View details for Web of Science ID A1994MR30000018

  View details for PubMedID 8291699

• CARDIOPULMONARY AND BEHAVIORAL-RESPONSES TO COMPUTER-DRIVEN INFUSION OF DETOMIDINE IN STANDING HORSES AMERICAN JOURNAL OF VETERINARY RESEARCH Daunt, D. A., Dunlop, C. I., Chapman, P. L., Shafer, S. L., Ruskoaho, H., Vakkuri, O., Hodgson, D. S., TYLER, L. M., Maze, M. 1993; 54 (12): 2075-2082

  Abstract

  Cardiopulmonary and behavioral responses to detomidine, a potent alpha 2-adrenergic agonist, were determined at 4 plasma concentrations in standing horses. After instrumentation and baseline measurements in 7 horses (mean +/- SD for age and body weight, 6 +/- 2 years, and 531 +/- 48.5 kg, respectively), detomidine was infused to maintain 4 plasma concentrations: 2.1 +/- 0.5 (infusion 1), 7.2 +/- 3.5 (infusion 2), 19.1 +/- 5.1. (infusion 3), and 42.9 +/- 10 (infusion 4) ng/ml, by use of a computer-controlled infusion system. Detomidine caused concentration-dependent sedation and somnolence. These effects were profound during infusions 3 and 4, in which marked head ptosis developed and all horses leaned heavily on the bars of the restraining stocks. Heart rate and cardiac index decreased from baseline measurements (42 +/- 7 beats/min, 65 +/- 11 ml.kg of body weight-1.min-1) in linear relationship with the logarithm of plasma detomidine concentration (ie, heart rate = -4.7 [loge detomidine concentration] + 44.3, P < 0.01; cardiac index = -10.5 [loge detomidine concentration] + 73.6, P < 0.01). Second-degree atrioventricular block developed in 5 of 7 horses during infusion 3, and in 6 of 7 horses during infusion 4. Mean arterial blood pressure increased significantly from 118 +/- 11 mm of Hg at baseline to 146 +/- 27 mm of Hg at infusion 4. Similar responses were observed for mean pulmonary artery and right atrial pressures. Systemic vascular resistance (baseline, 182 +/- 28 mm of Hg.ml-1.min-1.kg-1) increased significantly during infusions 3 and 4 (to 294 +/- 79 and 380 +/- 58, respectively). (ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1993MK13800019

  View details for PubMedID 8116941

• A COMPARISON OF BISPECTRAL AND FFT WAVE-FORM ANALYSES FOR MIDAZOLAM, ALFENTANIL AND PROPOFOL Billard, V., Gambus, P. L., Shafer, S. L., Stanski, D. R. LIPPINCOTT WILLIAMS & WILKINS. 1993: A517-A517

  View details for Web of Science ID A1993LY10800517

• PHARMACOKINETIC-PHARMACODYNAMIC (PK-PD) MODELING OF MIDAZOLAM-FLUMAZENIL INTERACTIONS Fiset, P., Egan, T., Lemmens, H., Shafer, S., Stanski, D. LIPPINCOTT WILLIAMS & WILKINS. 1993: A362-A362

  View details for Web of Science ID A1993LY10800362

• THE PHARMACOKINETICS AND HEMODYNAMIC-EFFECTS OF INTRAVENOUS AND INTRAMUSCULAR DEXMEDETOMIDINE HYDROCHLORIDE IN ADULT HUMAN VOLUNTEERS ANESTHESIOLOGY Dyck, J. B., Maze, M., Haack, C., Vuorilehto, L., Shafer, S. L. 1993; 78 (5): 813-820

  Abstract

  Dexmedetomidine is an alpha 2 agonist with potential utility in clinical anesthesia for both its sedative and sympatholytic properties.The pharmacokinetics and hemodynamic changes that occurred in ten healthy male volunteers were determined after administration of dexmedetomidine 2 micrograms/kg by intravenous or intramuscular route in separate study sessions.The intramuscular absorption profile of dexmedetomidine, as determined by deconvolution of the observed concentrations against the unit disposition function derived from the intravenous data, was biphasic. The percentage bioavailability of dexmedetomidine administered intramuscularly compared with the same dose administered intravenously was 73 +/- 11% (mean +/- SD). After intramuscular administration, the mean time to peak concentration was 12 min (range 2-60 min) and the mean peak concentration was 0.81 +/- 0.27 ng/ml. After intravenous administration of dexmedetomidine, there were biphasic changes in blood pressure. During the 5-min intravenous infusion of 2 micrograms/kg dexmedetomidine, the mean arterial pressure (MAP) increased by 22% and heart rate (HR) declined by 27% from baseline values. Over the 4 h after the infusion, MAP declined by 20% from baseline and HR rose to 5% below baseline values. The hemodynamic profile did not show acute alterations after intramuscular administration. During the 4 h after intramuscular administration, MAP declined by 20% and HR declined by 10%.The intramuscular administration of dexmedetomidine avoids the acute hemodynamic changes seen with intravenous administration, but results in similar hemodynamic alterations within 4 h.

  View details for Web of Science ID A1993LA77700001

  View details for PubMedID 8098190

• CONSTANT VERSUS OPTIMAL PLASMA-CONCENTRATIONS ANESTHESIA AND ANALGESIA Shafer, S. L. 1993; 76 (3): 467-469

  View details for Web of Science ID A1993KY04000002

  View details for PubMedID 8452251

• DEXMEDETOMIDINE DECREASES CEREBRAL BLOOD-FLOW VELOCITY IN HUMANS JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM Zornow, M. H., Maze, M., Dyck, J. B., Shafer, S. L. 1993; 13 (2): 350-353

  Abstract

  This study was designed to determine the effects of dexmedetomidine on CBF velocity as measured by transcranial Doppler sonography in human volunteers. Dexmedetomidine, a potent alpha-2 adrenergic agonist, was administered by computer-driven infusion pump to six male volunteers. Serial measurements of middle cerebral artery blood flow velocity at four steady-state plasma concentrations of dexmedetomidine were made with a 2-MHz transcranial Doppler transducer via the temporal window. The targeted plasma concentrations were 0.49, 0.65, 0.81, and 0.97 ng/ml. These represent 60, 80, 100, and 120%, respectively, of the mean peak concentration following the intramuscular administration of 2 micrograms/kg of dexmedetomidine. Subjects experienced a significant degree of sedation at the highest infusion rates. Mean CBF velocity decreased with each increase in plasma concentration of dexmedetomidine and then began to return to basal levels after termination of the infusion. A trend toward an increase in the pulsatility index at the higher levels of dexmedetomidine suggests that the observed decrement in CBF velocity was due to an increase in cerebral vascular resistance. Upon initiation of the drug infusion, mean arterial pressure decreased from approximately 95 mm Hg to 78 mm Hg. There were no further decreases in arterial pressure with subsequent increases in plasma concentrations of dexmedetomidine. Arterial carbon dioxide tension increased to a maximum of 45 mm Hg during the drug infusion, but this increase from baseline was not statistically significant. These studies are in agreement with previous animal studies which demonstrate a decrease in CBF after administration of dexmedetomidine.

  View details for Web of Science ID A1993KM80800024

  View details for PubMedID 8094720

• EFFICIENT DRUG DEVELOPMENT - APPLYING HIGH-RESOLUTION PK PD MODELS TO RATIONAL DRUG DOSING Shafer, S. L., Lemmens, H. J., Stanski, D. R. NATURE PUBLISHING GROUP. 1993: 169-169

  View details for Web of Science ID A1993KP26900136

• PHASE I PHARMACODYNAMIC ASSESSMENT OF NEW OPIOIDS Lemmens, H. J., Egan, T. D., Fiset, P., Shafer, S. L., Stanski, D. R. NATURE PUBLISHING GROUP. 1993: 209-209

  View details for Web of Science ID A1993KP26900293

• THIOPENTAL PHARMACODYNAMICS .1. DEFINING THE PSEUDO STEADY-STATE SERUM CONCENTRATION EEG EFFECT RELATIONSHIP ANESTHESIOLOGY Buhrer, M., MAITRE, P. O., Hung, O. R., Ebling, W. F., Shafer, S. L., Stanski, D. R. 1992; 77 (2): 226-236

  Abstract

  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.

  View details for Web of Science ID A1992JG53300002

  View details for PubMedID 1642340

• THIOPENTAL PHARMACODYNAMICS .2. QUANTITATION OF CLINICAL AND ELECTROENCEPHALOGRAPHIC DEPTH OF ANESTHESIA ANESTHESIOLOGY Hung, O. R., VARVEL, J. R., Shafer, S. L., Stanski, D. R. 1992; 77 (2): 237-244

  Abstract

  This study examined the relationship among pseudo-steady-state (constant) serum thiopental concentrations, clinical anesthetic depth as assessed by several perioperative stimuli, and the electroencephalogram (EEG). Twenty-six ASA physical status 1 or 2 patients participated in the study. Two constant serum thiopental concentrations were maintained in each patient using a computer-controlled infusion pump. The first randomly assigned target serum concentration of 10-30 micrograms/ml was maintained for 5 min to allow serum:brain equilibration. Then the following stimuli were applied at 1-min intervals: verbal command, tetanic nerve stimulation, trapezius muscle squeeze, and laryngoscopy. A second, higher, randomly assigned target serum concentration of 40-90 micrograms/ml was then achieved and maintained by the computer-controlled infusion pump. The previously described stimuli were reapplied, after which laryngoscopy and intubation was performed. A positive response was recorded if purposeful extremity movement or coughing was observed. Using the quantal movement or cough response and the measured constant serum thiopental concentration, the probability of no movement to each stimulus was characterized using logistic regression. The serum thiopental concentrations that produced a 50% probability of no movement response for the clinical stimuli were as follows: 15.6 micrograms/ml for verbal command, 30.3 micrograms/ml for tetanic nerve stimulation, 39.8 micrograms/ml for trapezius muscle squeeze, 50.7 micrograms/ml for laryngoscopy, and 78.8 micrograms/ml for laryngoscopy followed by intubation. The EEG was analyzed using aperiodic waveform analysis to derive the number of waves per second. A biphasic relationship between constant serum thiopental concentration and the EEG number of waves per second was observed. Loss of responsiveness to verbal stimulation occurred when the EEG was activated at 15-18 waves/s.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1992JG53300003

  View details for PubMedID 1642341

• PLASMA-CONCENTRATION CLAMPING IN THE RAT USING A COMPUTER-CONTROLLED INFUSION PUMP PHARMACEUTICAL RESEARCH Gustafsson, L. L., Ebling, W. F., Osaki, E., HARAPAT, S., Stanski, D. R., Shafer, S. L. 1992; 9 (6): 800-807

  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 pharmacokinetic 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 micrograms/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.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1992HX88400016

  View details for PubMedID 1409364

• IMPROVING THE CLINICAL UTILITY OF ANESTHETIC DRUG PHARMACOKINETICS ANESTHESIOLOGY Shafer, S. L., Stanski, D. R. 1992; 76 (3): 327-330

  View details for Web of Science ID A1992HG47600001

  View details for PubMedID 1539841

• INTRAMUSCULAR (IM) ABSORPTION KINETICS OF MIDAZOLAM (M) AND DIAZEPAM (D) IN HEALTHY-VOLUNTEERS Hung, O. R., Dyck, B., VARVEL, J. R., Shafer, S. L., Stanski, D. R. NATURE PUBLISHING GROUP. 1992: 130-130

  View details for Web of Science ID A1992HE70300035

• COMPARATIVE BLOOD - BRAIN EQUILIBRATION OF MIDAZOLAM (M) VS DIAZEPAM (D) Hung, O. R., Dyck, B., VARVEL, J. R., Shafer, S. L., Stanski, D. R. NATURE PUBLISHING GROUP. 1992: 129-129

  View details for Web of Science ID A1992HE70300034

• PHARMACOKINETICS OF FENTANYL ADMINISTERED BY COMPUTER-CONTROLLED INFUSION PUMP ANESTHESIOLOGY Shafer, S. L., VARVEL, J. R., Aziz, N., Scott, J. C. 1990; 73 (6): 1091-1102

  Abstract

  Fentanyl was administered to 21 patients using a computer-controlled infusion pump (CCIP) based on a pharmacokinetic model. Eleven of the patients were dosed according to the pharmacokinetics described by McClain and Hug, and ten of the patients were dosed according to the pharmacokinetics described by Scott and Stanski. The authors measured the difference between the measured arterial fentanyl concentrations and the concentrations predicted by the CCIP for each pharmacokinetic parameter set. The median absolute performance error (MDAPE) in patients dosed according to McClain and Hug's parameters was 61%, and the MDAPE in patients dosed according to Scott and Stanski's parameters was 33%. The population pharmacokinetics in these 21 patients were analyzed using a pooled data technique. The pharmacokinetics of fentanyl in this population showed a smaller central compartment volume and a more rapid initial distribution half-life than previously estimated for fentanyl. The derived pharmacokinetic parameters described these patients well and also predicted the observed fentanyl concentrations from four previously published fentanyl studies with reasonable accuracy. Comparison of the parameters used by the authors with those of McClain and Hug demonstrated that dosing regimens designed from pharmacokinetic models can be fairly accurate at the times sampled in the original study but may not be accurate at time points not sampled in the original research. The authors concluded that although the pharmacokinetics of fentanyl administered by CCIP are the same as the pharmacokinetics of fentanyl administered by a bolus or constant rate infusion, a pharmacokinetic study using a CCIP may be particularly effective at characterizing the most rapid distribution pharmacokinetic parameters, and thus may provide parameters appropriate for subsequent use in a CCIP.

  View details for Web of Science ID A1990EM53800005

  View details for PubMedID 2248388

• A SIMPLE POCKET CALCULATOR APPROACH TO PREDICT ANESTHETIC DRUG CONCENTRATIONS FROM PHARMACOKINETIC DATA ANESTHESIOLOGY MAITRE, P. O., Shafer, S. L. 1990; 73 (2): 332-336

  Abstract

  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.

  View details for Web of Science ID A1990DV59100022

  View details for PubMedID 2382854

• A COMPUTER-CONTROLLED INFUSION PUMP RAPIDLY ACHIEVES AND MAINTAINS STABLE PLASMA THIOPENTAL CONCENTRATIONS AND EEG-EFFECTS IN THE RAT Gustafsson, L. L., Ebling, W. F., Shafer, S. L., Osaki, E., Stanski, D. R. ELSEVIER SCIENCE BV. 1990: 1597-1597

  View details for Web of Science ID A1990DU01300557

• THE PROSPECTIVE USE OF POPULATION PHARMACOKINETICS IN A COMPUTER-DRIVEN INFUSION SYSTEM FOR ALFENTANIL ANESTHESIOLOGY Raemer, D. B., BUSCHMAN, A., VARVEL, J. R., Philip, B. K., Johnson, M. D., Stein, D. A., Shafer, S. L. 1990; 73 (1): 66-72

  Abstract

  Maitre et al. recently evaluated the accuracy of a set of previously determined population pharmacokinetic parameters for the opioid alfentanil using data from an earlier study in which the drug had been administered using a computer-controlled infusion pump (CCIP). The present study evaluated the accuracy of these same parameters in a CCIP prospectively in two groups of clinically dissimilar patients: 29 healthy female day surgery patients and 11 relatively older and less healthy male inpatients. In addition, another set of pharmacokinetic parameters, previously determined by Scott et al. in the CCIP in 11 male inpatients was also evaluated. The bias and inaccuracy were assessed by the median performance error (MDPE) and the median absolute performance error (MDAPE) in which the performance error was determined as the difference between measured and target serum concentration as a fraction of the target serum concentration. Unlike Maitre et al., the current study found a consistent bias in both populations. The MDPE was +53% and the MDAPE was 53%, with no difference between patient groups. In the 11 patients studied using the Scott et al. pharmacokinetic parameters, the MDPE was +1% and the MDAPE was 17%. The parameters of Scott et al. were further tested by simulating the serum concentrations that would have been achieved had they been used in the CCIP in the first 40 patients; results indicated MDPE of +2% and an MDAPE of 18%. Therefore, reasonably reliable and accurate target serum concentrations of alfentanil can be achieved using the pharmacokinetic parameters of Scott et al. in a CCIP.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1990DK88500011

  View details for PubMedID 2360742

• ESTIMATING THE RATE OF THIOPENTAL BLOOD-BRAIN EQUILIBRATION USING PSEUDO STEADY-STATE SERUM CONCENTRATIONS JOURNAL OF PHARMACOKINETICS AND BIOPHARMACEUTICS MAITRE, P. O., Buhrer, M., Shafer, S. L., Stanski, D. R. 1990; 18 (3): 175-187

  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 (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.

  View details for Web of Science ID A1990DN62300001

  View details for PubMedID 2380918

• Quantitation of thiopental anesthetic depth with clinical stimuli. Canadian journal of anaesthesia = Journal canadien d'anesthésie Hung, O. R., VARVEL, J., Shafer, S., Stanski, D. R. 1990; 37 (4): S18-?

  View details for PubMedID 2361282

• 2 EQUALLY VALID INTERPRETATIONS OF THE LINEAR MULTICOMPARTMENT MAMMILLARY PHARMACOKINETIC MODEL JOURNAL OF PHARMACEUTICAL SCIENCES Jacobs, J. R., Shafer, S. L., Larsen, J. L., Hawkins, E. D. 1990; 79 (4): 331-333

  Abstract

  In pharmacokinetic modeling it is common to use compartmental structures to describe the disposition of a drug in the blood or plasma. Typically, a linear multicompartment mammillary model is equated with the multiexponential equation derived from observing the decay of the plasma drug concentration following an intravascular injection. Classically, the mammillary models are constructed so that the concentrations in each of the compartments are equal at steady state, the apparent volume of distribution at steady state is equal to the sum of the individual compartment volumes, and the apparent volume of each peripheral compartment is equal to the ratio of its intercompartmental rate constants times the central compartment volume. On the basis of what can be measured in the plasma, however, it is equally valid to assume that the sizes of the peripheral compartment volumes are equal to the central compartment volume and that the steady-state concentration in each peripheral compartment is equal to the ratio of its intercompartmental rate constants times the concentration in the central compartment. In fact, these are but two of an infinite number of interpretations of the peripheral compartment volumes.

  View details for Web of Science ID A1990CY51500011

  View details for PubMedID 2352145

• THE USE OF COMPUTER-CONTROLLED INFUSION PUMP TO STUDY ANESTHETIC PHARMACODYNAMICS Hung, O. R., VARVEL, J. R., Shafer, S., Stanski, D. R. NATURE PUBLISHING GROUP. 1990: 209-209

  View details for Web of Science ID A1990CP98700335

• A COMPARISON OF PARAMETRIC WITH SEMIPARAMETRIC ANALYSIS OF THE CONCENTRATION VERSUS EFFECT RELATIONSHIP OF METOCURINE IN DOGS AND PIGS JOURNAL OF PHARMACOKINETICS AND BIOPHARMACEUTICS Shafer, S. L., VARVEL, J. R., Gronert, G. A. 1989; 17 (3): 291-304

  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 from 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 semiparametric analysis produced a better description of the data.

  View details for Web of Science ID A1989AU86500001

  View details for PubMedID 2810069

• EXERCISE PRODUCES SENSITIVITY TO METOCURINE ANESTHESIOLOGY Gronert, G. A., White, D. A., Shafer, S. L., Matteo, R. S. 1989; 70 (6): 973-977

  Abstract

  Chronic muscle disuse decreases the sensitivity of skeletal muscle to nondepolarizing relaxants, such as metocurine (MTC). In this study, the authors determined whether chronic conditioning would produce the opposite effect and increase the sensitivity of skeletal muscle to MTC. Five dogs were exercised by daily running over a period of 5 weeks. At the conclusion of this training period, a pharmacokinetic and pharmacodynamic study of the MTC dose-response relationship was performed. The same analysis was performed on four dogs housed in the same kennel who did not undergo conditioning. Neuromuscular blockade was measured and recorded bilaterally in both gastrocnemius muscles while the animal was anesthetized with nitrous oxide and pentobarbital, 30 ml.kg-1. Plasma concentrations of MTC were measured by radioimmunoassay. The MTC concentration estimated in the effect compartment which produced 50% paralysis was 0.114 +/- 0.008 micrograms.ml-1 (mean +/- SD) in exercised dogs and 0.189 +/- 0.038 micrograms.ml-1 in nonexercised dogs, which was significant at P less than 0.005). The MTC concentration versus response curves were parallel. This supports the authors' hypothesis that exercise increases sensitivity to the nondepolarizing muscle relaxant metocurine.

  View details for Web of Science ID A1989U898800015

  View details for PubMedID 2729640

• THE LONGITUDINAL DISTRIBUTION OF PULMONARY VASCULAR-RESISTANCE DURING UNILATERAL HYPOXIA ANESTHESIOLOGY Siegel, L. C., Pearl, R. G., Shafer, S. L., REAM, A. K., Prielipp, R. C. 1989; 70 (3): 527-532

  Abstract

  Pulmonary capillary hydrostatic pressure and the longitudinal distribution of pulmonary vascular resistance (arterial and venous components) can be determined by analysis of pressure decay curves following pulmonary artery occlusion. To validate this technique in intact animals, pulmonary artery occlusion pressure decay curves were obtained from both lungs in six anesthetized sheep during control conditions (100% O2) and during unilateral hypoxic ventilation (100% O2 versus 100% N2). Analysis of pulmonary artery occlusion pressure curves indicated the following: 1) in the hypoxic lung, unilateral hypoxia increased the precapillary portion of pulmonary vascular resistance from 72% of the total resistance to 89% of the total resistance in that lung; 2) in the nonhypoxic lung, unilateral hypoxia did not significantly affect the distribution of pulmonary vascular resistance; and 3) unilateral hypoxia produced no significant change in pulmonary capillary pressure in the hypoxic lung compared with control; however, pulmonary capillary pressure was significantly greater in the nonhypoxic lung. These results are consistent with other evidence that hypoxic pulmonary vasoconstriction acts locally and primarily affects resistance at the arteriolar level. Pulmonary artery occlusion pressure decay curve analysis appears to be a valid technique for the measurement of pulmonary capillary pressure and the longitudinal distribution of pulmonary vascular resistance in intact anesthetized animals. These measurements pertain only to the vasculature distal to the site of pulmonary artery occlusion with the catheter, and, thus, caution must be used when applying this technique in a setting of nonhomogenous lung injury.

  View details for Web of Science ID A1989T501200025

  View details for PubMedID 2923299

• Simultaneous measurements of cardiac output by thermodilution, esophageal Doppler, and electrical impedance in anesthetized patients. Journal of cardiothoracic anesthesia Siegel, L. C., Shafer, S. L., Martinez, G. M., REAM, A. K., Scott, J. C. 1988; 2 (5): 590-595

  Abstract

  Simultaneous intraoperative measurements of cardiac output were obtained in nine patients with transesophageal Doppler, transthoracic impedance, and pulmonary artery thermodilution techniques to evaluate the utility of the noninvasive methods. Pairs of noninvasive and thermodilution measurements were obtained 25 times with transesophageal Doppler and 58 times with transthoracic impedance. Correlation of the noninvasive measurements with thermodilution was poor, with r = 0.43 for transthoracic impedance and r = .68 for transesophageal Doppler. The average difference between the noninvasive and the thermodilution values was -0.4 +/- 1.4 L/min (mean +/- SD) and -0.1 +/- 1.6 L/min for impedance and Doppler, respectively. Changes in cardiac output at sequential time points as measured by thermodilution were predicted with 95% confidence only when a change of >4 L/min was observed by transesophageal Doppler or >8 L/min was observed by transthoracic impedance. Therefore, it is concluded that neither noninvasive technique reliably estimated cardiac output as determined by thermodilution, and neither tracked trends.

  View details for PubMedID 17171947

• PHARMACOKINETICS AND PHARMACODYNAMICS OF PROPOFOL INFUSIONS DURING GENERAL-ANESTHESIA ANESTHESIOLOGY Shafer, A., Doze, V. A., Shafer, S. L., White, P. F. 1988; 69 (3): 348-356

  Abstract

  The pharmacokinetic and pharmacodynamic properties of propofol were studied in 50 surgical patients. Propofol was administered as a bolus dose, 2 mg/kg iv, followed by a variable-rate infusion, 0-20 mg/min, and intermittent supplemental boluses, 10-20 mg iv, as part of a general anesthetic technique that included nitrous oxide, meperidine, and muscle relaxants. For a majority of the patients (n = 30), the pharmacokinetics of propofol were best described by a two-compartment model. The propofol mean total body clearance rate was 2.09 +/- 0.65 1/min (mean +/- SD), the volume of distribution at steady state was 159 +/- 57 l, and the elimination half-life was 116 +/- 34 min. Elderly patients (patients older than 60 yr vs. those younger than 60 yr) had significantly decreased clearance rates (1.58 +/- 0.42 vs. 2.19 +/- 0.64 l/min), whereas women (vs. men) had greater clearance rates (33 +/- 8 vs. 26 +/- 7 l.kg-1.min-1) and volumes of distribution (2.50 +/- 0.81 vs. 2.05 +/- 0.65 l/kg). Patients undergoing major (intraabdominal) surgery had longer elimination half-life values (136 +/- 40 vs. 108 +/- 29 min). Patients required an average blood propofol concentration of 4.05 +/- 1.01 micrograms/ml for major surgery and 2.97 +/- 1.07 micrograms/ml for nonmajor surgery. Blood propofol concentrations at which 50% of patients (EC50) were awake and oriented after surgery were 1.07 and 0.95 microgram/ml, respectively. Psychomotor performance returned to baseline at blood propofol concentrations of 0.38-0.43 microgram/ml (EC50). This clinical study demonstrates the feasibility of performing pharmacokinetic and pharmacodynamic analyses when complex infusion and bolus regimens are used for administering iv anesthetics.

  View details for Web of Science ID A1988P966800011

  View details for PubMedID 3261954