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Steven L Shafer

Publications and source records attributed to Steven L Shafer.

17 recordsLinked to original sources
PubMed2004

Use of population modeling to define rational monitoring of amiodarone hepatic effects.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Aged↗
PubMed2004

Mixed-effects modeling of the intrinsic ventilatory depressant potency of propofol in the non-steady state.

BACKGROUND: 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. METHODS: 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. RESULTS: 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%. CONCLUSION: 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.

Adult↗
PubMed2004

Pharmacodynamic interaction between propofol and remifentanil regarding hypnosis, tolerance of laryngoscopy, bispectral index, and electroencephalographic approximate entropy.

BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Adult↗
PubMed2004

Determination of the pharmacodynamic interaction of propofol and remifentanil during esophagogastroduodenoscopy in children.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Child↗
PubMed2004

Spectral entropy as an electroencephalographic measure of anesthetic drug effect: a comparison with bispectral index and processed midlatency auditory evoked response.

BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Adolescent↗
PubMed2004

Shock values.

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Anesthetics, Intravenous↗
PubMed2004

Application of Bispectral Index and Narcotrend index to the measurement of the electroencephalographic effects of isoflurane with and without burst suppression.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Aged↗
PubMed2004

Teaching application of clinical pharmacology skills using unusual observations from clozapine overdoses.

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.

Adult↗
PubMed2003

Mathematical analysis of a pharmacodynamic model without plasma concentrations to extend its applicability.

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.

Blood↗
PubMed2003

Correlation of approximate entropy, bispectral index, and spectral edge frequency 95 (SEF95) with clinical signs of "anesthetic depth" during coadministration of propofol and remifentanil.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Adult↗
PubMed2003

Cephalad movement of morphine and fentanyl in humans after intrathecal injection.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Adolescent↗
PubMed2003

Using the time of maximum effect site concentration to combine pharmacokinetics and pharmacodynamics.

BACKGROUND: 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. METHODS: 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. RESULTS: In each set of simulations, the t(peak) method better approximated the postulated "true" time course of drug effect than the naive method. CONCLUSIONS: 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.

Aging↗
PubMed2003

A model of the ventilatory depressant potency of remifentanil in the non-steady state.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Adult↗
PubMed2003

MAC Attack?

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Anesthetics, Inhalation↗
PubMed2002

Artifact robustness, inter- and intraindividual baseline stability, and rational EEG parameter selection.

BACKGROUND: 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). METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

Adult↗
PubMed2002

Efficient trial design for eliciting a pharmacokinetic-pharmacodynamic model-based response surface describing the interaction between two intravenous anesthetic drugs.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Algorithms↗