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S L Shafer

Publications and source records attributed to S L Shafer.

At least 73 records · Page 4Linked to original sources
PubMed1994

The pharmacokinetics of propofol in children using three different data analysis approaches.

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

Child↗
PubMed1994

Pharmacokinetics and pharmacodynamics of intraspinal dexmedetomidine in sheep.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Adrenergic alpha-Agonists↗
PubMed1994

Pharmacokinetic parameters relevant to recovery from opioids.

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

Alfentanil↗
PubMed1993

Dexmedetomidine decreases cerebral blood flow velocity in humans.

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.

Adrenergic alpha-Agonists↗
PubMed1993

The pharmacokinetics and hemodynamic effects of intravenous and intramuscular dexmedetomidine hydrochloride in adult human volunteers.

BACKGROUND: Dexmedetomidine is an alpha 2 agonist with potential utility in clinical anesthesia for both its sedative and sympatholytic properties. METHODS: 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. RESULTS: 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%. CONCLUSIONS: The intramuscular administration of dexmedetomidine avoids the acute hemodynamic changes seen with intravenous administration, but results in similar hemodynamic alterations within 4 h.

Adrenergic alpha-Agonists↗
PubMed1993

Computer-controlled infusion of intravenous dexmedetomidine hydrochloride in adult human volunteers.

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

Adrenergic alpha-Agonists↗
PubMed1993

The pharmacokinetics of the new short-acting opioid remifentanil (GI87084B) in healthy adult male volunteers.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Remifentanil is a new, short-acting opioid with promising clinical potential in anesthesiology.

Adult↗
PubMed1993

Cardiopulmonary and behavioral responses to computer-driven infusion of detomidine in standing horses.

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)

Analgesics↗
PubMed1992

Application of semilinear canonical correlation to the measurement of opioid drug effect.

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.

Adult↗
PubMed1992

Algorithms to rapidly achieve and maintain stable drug concentrations at the site of drug effect with a computer-controlled infusion pump.

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.

Animals↗
PubMed1992

Measuring the predictive performance of computer-controlled infusion pumps.

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.

Adult↗
PubMed1992

Plasma concentration clamping in the rat using a computer-controlled infusion pump.

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)

Animals↗
PubMed1992

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

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

Adult↗
PubMed1992

Thiopental pharmacodynamics. II. Quantitation of clinical and electroencephalographic depth of anesthesia.

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)

Adult↗