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D R Stanski

Publications and source records attributed to D R Stanski.

At least 73 records · Page 4Linked to original sources
PubMed1988

Simultaneous determination of fentanyl and alfentanil in rat tissues by capillary column gas chromatography.

Fentanyl and alfentanil were determined in blood and in thirteen tissues from rats by gas chromatography, with splitless injections on a fused-silica capillary column and nitrogen-selective detection. Sufentanil was used as the internal standard for both drugs and the acetyl analogue of sufentanil was used as an external standard to quantitate extraction recoveries. The extraction solvent was isopentanol-pentane (1:49) and a back-extraction into 0.1 M hydrochloric acid was used for sample clean-up. The extraction recoveries from tissue homogenates averaged 88% for fentanyl, 72% for alfentanil and 87% for sufentanil. The standard curves were linear over a range of 0.5-800 ng per sample for both drugs and the coefficients of variation for eight determinations of the drugs in tissue homogenates were 2-9% at 0.8-32 ng per sample. Assays of tissues from rats treated with simultaneous intravenous infusions of fentanyl and alfentanil confirmed the high precision and sensitivity of the method, which should therefore prove feasible for studies of the tissue distribution of these opioids.

Alfentanil↗
PubMed1988

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

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

Adult↗
PubMed1988

Comparison of a computer-assisted infusion versus intermittent bolus administration of alfentanil as a supplement to nitrous oxide for lower abdominal surgery.

The anesthesiologist attempts to balance the dose or concentration of an anesthetic against the intensity of noxious stimulation so as to: 1) maintain a satisfactory anesthetic state, 2) minimize side effects and toxicity of the anesthetic, and 3) allow for a rapid recovery from anesthesia. The development of infusion pumps controlled by computers programmed according to pharmacokinetic principles should facilitate the achievement of these objectives for intravenous drugs. To test this hypothesis, the authors compared anesthetic conditions achieved with a computer-controlled infusion to those produced by the traditional method of intermittent intravenous injections. In both cases, the intravenous opiate, alfentanil, was used to supplement nitrous oxide anesthesia, and the dose/dose-rate of alfentanil after the induction dose was guided by the use of precisely defined clinical signs of inadequate anesthesia. One group of ten patients received 10 mg of alfentanil and 66% N2O to induce anesthesia, and was subsequently given 1 or 2 mg iv doses of alfentanil whenever the depth of anesthesia was inadequate. A second group of ten patients had a target alfentanil concentration of 475 ng/ml of plasma established by the computer-controlled infusion, which subsequently raised or lowered the concentration by 50 or 100 ng/ml according to the presence or absence of clinical signs of inadequate anesthesia. Regular measurements of alfentanil concentrations in plasma showed that the computer-assisted infusion produced relatively stable concentrations that closely paralleled those predicted (prediction error of -64 +/- 40 ng/ml [+/- SD] in the range of 150-600 ng/ml). The traditional method of intermittent injections resulted in continuous, rapid fluctuations in alfentanil concentrations. Both methods were successful in controlling the patients' responses to noxious stimuli, but the infusion group had: 1) a lower incidence of responsiveness, 2) greater hemodynamic stability, 3) no patients requiring naloxone for satisfactory ventilation postoperatively, and 4) an incidence of side effects that tended to be lower. The previously reported alfentanil concentration versus anesthetic effect relationships were confirmed.

Adjuvants, Anesthesia↗
PubMed1988

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

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

Alfentanil↗
PubMed1987

Pharmacodynamic modeling of the EEG effects of ketamine and its enantiomers in man.

The pharmacodynamics of a racemic mixture of ketamine R,S(+/-)-ketamine and of each enantiomer, S(+)-ketamine and R(-)-ketamine, were studied in five volunteers. The median frequency of the electroencephalogram (EEG) power spectrum, a continuous noninvasive measure of the degree of central nervous system (CNS) depression (pharmacodynamics), was related to measured serum concentrations of drug (pharmacokinetics). The concentration-effect relationship was described by an inhibitory sigmoid Emax pharmacodynamic model, yielding estimates of both maximal effect (Emax) and sensitivity (IC50) to the racemic and enantiomeric forms of ketamine. R(-)-ketamine was not as effective as R,S(+/-)-ketamine or S(+)-ketamine in causing EEG slowing. The maximal decrease (mean +/- SD) of the median frequency (Emax) for R(-)-ketamine was 4.4 +/- 0.5 Hz and was significantly different from R,S(+/-)-ketamine (7.6 +/- 1.7 Hz) and S(+)-ketamine (8.3 +/- 1.9 Hz). The ketamine serum concentration that caused one-half of the maximal median frequency decrease (IC50) was 1.8 +/- 0.5 micrograms/mL for R(-)-ketamine; 2.0 +/- 0.5 micrograms/mL for R,S(+/-)-ketamine; and 0.8 +/- 0.4 microgram/mL for S(+)-ketamine. Because the maximal effect (Emax) of the R(-)-ketamine was different from that of S(+)-ketamine and R,S(+/-)-ketamine, it was not possible to directly compare the potency (i.e., IC50) of these compounds. Accordingly, a classical agonist/partial-agonist interaction model was examined, using the separate enantiomer results to predict racemate results. Although the model did not predict racemate results well, its failure was not so great as to provide clear evidence of synergism (or excess antagonism) of the enantiomers.

Adult↗
PubMed1987

Assay methods for fentanyl in serum: gas-liquid chromatography versus radioimmunoassay.

In this study, two independent laboratories assessed the validity of the fentanyl radioimmunoassay (RIA) by measuring a series of spiked control serum samples and 429 serum samples from 20 patients receiving fentanyl for their anesthesia. Additionally, a gas-liquid chromatographic (GLC) method specific for the parent drug was also applied to the same serum samples. The RIA measurement of fentanyl by the two laboratories resulted in comparable values for both control samples and samples from patients in a range of 0.5-50 ng/ml. The GLC method agreed with both RIA measurements in the spiked control and patient samples. The authors' results demonstrate the validity of the RIA as a measurement technique for fentanyl in human serum samples.

Calibration↗
PubMed1987

The role of pharmacokinetics in anaesthesia: application to intravenous infusions.

Pharmacokinetic concepts describe the relationship between drug dose and resulting plasma concentration. A drug's pharmacokinetic profile can be described by distribution and elimination half-lives, initial volume of distribution, steady-state distribution volume, and metabolic and distributional clearance. After initiating a fixed rate of drug infusion, four to five terminal elimination half-lives are required to reach a steady state of constant plasma concentration. If a loading dose is given, a steady state can be achieved more rapidly. The most rapid method of achieving a constant plasma concentration involves using a variable rate of drug infusion that adjusts for the metabolic clearance and distribution of the drug. Computer-driven infusion pumps can be used to rapidly achieve, then maintain, constant plasma concentrations of a drug.

Anesthesia, Intravenous↗
PubMed1987

Narcotic pharmacokinetics and dynamics: the basis of infusion applications.

Morphine, pethidine and fentanyl have similar pharmacokinetic profiles with moderately long elimination half-lives (3 to 4 hours), large steady-state volumes of distribution (2 to 4 l/kg), and high hepatic clearances (10 to 20 ml/kg/min). Alfentanil has a shorter terminal elimination half-life (1 1/2 hours) because of a decreased steady-state volume of distribution (0.5 to 1 l/kg). Physicochemical properties and blood:brain tissue solubility can explain the clinical differences in the rate of onset and dissipation of narcotic effect for these four narcotics. Morphine's low lipid solubility and limited rate of blood:brain barrier penetration results in the slow onset and dissipation of narcotic effect relative to pethidine or fentanyl. Alfentanil's lower blood:brain solubility results in the very rapid onset of narcotic effect when compared to fentanyl. All of the narcotics have a very steep blood concentration:narcotic effect curves. Thus, small changes of narcotic blood concentrations can have profound changes of narcotic effect. Finally, different degrees of perioperative stimuli result in different narcotic blood concentration requirements. Thus, narcotic infusion rates need be varied during surgical procedures to adjust for the varying opiate requirement.

Analgesics, Opioid↗
PubMed1987

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

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

Adult↗
PubMed1987

Decreased fentanyl and alfentanil dose requirements with age. A simultaneous pharmacokinetic and pharmacodynamic evaluation.

The effect of increasing age on the dose of fentanyl or alfentanil required to produce the same electroencephalographic (EEG) stage was studied in adult male patients. The pharmacokinetic and pharmacodynamic components of each patient's dose-response relationship were evaluated simultaneously. Frequent arterial blood samples drawn during and after an infusion of fentanyl or alfentanil were assayed by radioimmunoassay and permitted determination of each patient's pharmacokinetic profile. The EEG was analyzed by power spectral analysis and a parameter (spectral edge frequency) chosen to quantitate the narcotic-induced EEG slowing. An inhibitory sigmoid Emax pharmacodynamic model related spectral edge frequency to narcotic serum concentrations. The dose requirement of fentanyl or alfentanil decreased significantly with increasing age (a 50% decrease from age 20 to 89). No age-related changes in the pharmacokinetic parameters were found. Brain sensitivity (as determined by EEG changes) did decrease significantly with age. Thus, the decreased dose requirement in the elderly had a pharmacodynamic explanation, using the EEG as a measure of narcotic drug effect.

Adult↗
PubMed1987

The clinical pharmacology of alfentanil.

Alfentanil has a different pharmacokinetic and pharmacodynamic profile compared to fentanyl. Alfentanil is approximately five to eight times less potent than fentanyl when given as a single i.v. dose. The onset of alfentanil effect is five to six times more rapid than fentanyl because of a more rapid blood: brain equilibration. The rapid dissipation of alfentanil's effect occurs due to both redistribution from the brain to other tissues and rapid elimination from the body, secondary to the short elimination half-life. The short alfentanil elimination half-life arises from the marked reduction in steady-state distribution volume from a limited tissue distribution. Higher plasma concentrations are needed for endotracheal intubation and skin incision than skin closure and post-operative ventilation. Upper abdominal surgical procedures require higher plasma concentrations than lower abdominal or breast surgery. Optimal alfentanil anaesthesia occurs when plasma concentrations are maintained relatively constant at therapeutic values using infusion techniques. Age and hepatic disease alter alfentanil pharmacokinetics. Age and other CNS depressants can lower the alfentanil plasma concentrations needed for adequate clinical anaesthesia. In spite of adjusting for these factors that affect alfentanil pharmacokinetics and pharmacodynamics, unexplained pharmacokinetic variability of 30-50% exists. Alfentanil infusions must be titrated and adjusted in each patient, based upon the clinical response to circumvent this pharmacokinetic and pharmacodynamic variability.

Aging↗
PubMed1986

Increased sensitivity to etomidate in the elderly: initial distribution versus altered brain response.

To determine the effect of aging on the pharmacokinetics and pharmacodynamics of etomidate, we administered etomidate (5 to 10 mg/min) by intravenous infusion to 21 healthy surgical patients, age 22 to 82 yr. Etomidate produced progressive slowing of the EEG to an easily recognized pattern (stage 3) that determined the dosage endpoint. Subsequent power-spectrum analysis of the EEG gave the median frequency. Median frequency values and simultaneous measurements of blood etomidate concentration were incorporated into a sigmoid Emax pharmacodynamic model that permitted an estimate of IC50, the blood etomidate concentration which produced a 50% reduction in the median frequency. The dose of etomidate required to reach the uniform EEG endpoint decreased significantly with increasing age (r2 = .68) as did the dose needed to produce maximal median frequency depression (r2 = .69). None of the parameters of the pharmacodynamic effect model, including IC50, correlated with age, suggesting that increased brain sensitivity in the elderly does not cause the age-related change in dose requirement. The initial distribution volume for etomidate decreased significantly with increasing age (r = .56), implying that a higher initial blood concentration in the elderly following any given dose of etomidate is part of the cause of the lower dose requirement in the elderly patient. A contracted initial distribution volume in the elderly may result from well described physiologic changes of age. Etomidate clearance also decreased with age. Age-dependent changes in etomidate pharmacokinetics rather than altered brain responsiveness may be the basis for the decreased etomidate dose requirement in the elderly.

Adult↗
PubMed1986

Plasma concentrations of alfentanil required to supplement nitrous oxide anesthesia for general surgery.

To design an efficient infusion regimen from pharmacokinetic data, it is necessary to know the alfentanil plasma concentrations required for satisfactory anesthesia. In 37 patients about to undergo lower abdominal gynecologic, upper abdominal, or breast surgery, anesthesia was induced with alfentanil 150 micrograms/kg iv and 66% N2O in oxygen. Thereafter, N2O anesthesia was supplemented with a continuous infusion of alfentanil that was varied between 25 and 150 micrograms X kg-1 X h-1, as indicated by the patient's responses to surgical stimulation. Small bolus doses of alfentanil 7 or 14 micrograms/kg were administered and the infusion rate increased to suppress precisely defined somatic, autonomic, and hemodynamic responses. Arterial plasma concentrations of alfentanil were measured during the operation when the patient did and did not respond to noxious stimulation. Logistic regression was used to determine plasma concentration-effect curves for different stimuli. Plasma alfentanil concentrations required along with 66% N2O to obtain responses to single episodes of stimulation in 50% of the 37 patients (Cp50 +/- SE) were: 475 +/- 28 ng/ml for tracheal intubation, 279 +/- 20 ng/ml for skin incision, and 150 +/- 23 ng/ml for skin closure. Between skin incision and closure, multiple determinations of response/no response were made for each patient and an individual Cp50 was estimated. The Cp50 (mean +/- SD) for the three surgical procedures were: breast, 270 +/- 63 ng/ml (n = 12); lower abdominal, 309 +/- 44 ng/ml (n = 14); and upper abdominal, 412 +/- 135 ng/ml (n = 11). The Cp50 for satisfactory spontaneous ventilation after the discontinuation of N2O was 223 +/- 13 ng/ml. These data demonstrate that different perioperative stimuli require different alfentanil concentrations to suppress undesirable responses. Thus, the alfentanil infusion rate should be varied according to the patient's responsiveness to stimulation in order to maintain satisfactory anesthetic and operative conditions and to provide rapid recovery of consciousness and spontaneous ventilation.

Adult↗
PubMed1985

Factors affecting the measurement of lidocaine protein binding by equilibrium dialysis in human serum.

A systematic study was undertaken to assess in vitro factors that influence the value of the lidocaine free fraction obtained by equilibrium dialysis in human serum. These factors include pH readjustment to 7.40 after serum storage; choice of buffers for dialysis; the effect of phosphate buffer ionic strength; temperature of storage for serum samples; the use of untreated versus silanized glassware for storage; and age of serum. It was concluded that the pH of serum that contains lidocaine must be brought back to the original whole blood pH found in the patient before equilibrium dialysis because the protein binding of lidocaine is critically dependent on pH. It was also found that Krebs-Ringer bicarbonate buffer, when used with room air atmosphere in the dialysis cell, is not adequate to control pH even when serum pH is readjusted to the physiological pH of the patient. Isotonic phosphate buffer and 0.10 M phosphate buffer are effective for pH control and give identical values of lidocaine free fraction when the original serum sample is first pH-adjusted. If the pH of the serum is correct and the pH of the buffer remains constant, then freezing, the choice of container, or the age of serum are not important variables affecting the measurement of the lidocaine free fraction.

Blood Proteins↗
PubMed1985

An evaluation of the accuracy of pharmacokinetic data for the computer assisted infusion of alfentanil.

The accuracy of using average alfentanil pharmacokinetic data in a computer assisted infusion pump (TIAC) to predict alfentanil plasma concentrations was tested in 35 patients (divided into three groups) receiving alfentanil and nitrous oxide in oxygen anaesthesia for lower and upper abdominal surgery. By frequently measuring the arterial plasma concentration, it was possible to determine the average prediction error for individual patients and for groups of patients. For the groups, there were no significant systematic over- or underpredictions of the alfentanil plasma concentrations (bias). However, there existed a moderate degree of variability (imprecision) within the groups, caused by deviations of measured and predicted plasma concentrations in the individual patients within each group. As a result, prediction errors of 22.2-32.5% can be expected with the average pharmacokinetic data used in this study to drive TIAC. It was concluded that, as a result of the moderate degree of imprecision, it is unwise to rely totally on the absolute values of alfentanil plasma concentrations predicted by a computer-regulated infusion pump such as TIAC. However, such devices can be used to attain rapidly a relatively stable plasma concentration that can be adjusted (titrated) to the requirements of an individual patient during anaesthesia.

Adjuvants, Anesthesia↗
PubMed1985

Comparative pharmacology of the ketamine isomers. Studies in volunteers.

The clinical and electroencephalographic (EEG) effects of the individual ketamine isomers were compared with the racemic mixture in five volunteers who received each drug on a separate occasion. Racemic ketamine 275 +/- 25 mg, s(+) ketamine 140 +/- 21 mg or R(-) ketamine 429 +/- 37 mg produced an anaesthetic state lasting 6 +/- 2 min (mean +/- SD). However, the EEG evaluation of the R(-) isomer revealed less overall slowing, and an absence of the large slow wave complexes produced by the S(+) isomer and the racemic mixture. The pharmacokinetic profiles for the individual isomers of ketamine did not differ significantly from the racemic mixture. Even though the apparent anaesthetic state produced in these healthy volunteers did not differ qualitatively between the three drug groups, recovery times (assessed using a standardized battery of psychometric tests) were consistently shorter following the individual isomers compared with the racemic mixture. The serum ketamine concentrations associated with regaining consciousness and orientation were consistent with an S(+):R(-) isomer potency ratio of 4:1. In terms of their ability to impair psychomotor function, the S(+):R(-) potency ratio varied from 3:1 to 5:1. After comparable degrees of CNS depression, we conclude that the more potent S(+) isomer of ketamine was associated with a more rapid recovery of psychomotor skills than the currently used racemic mixture.

Adult↗
PubMed1985

EEG quantitation of narcotic effect: the comparative pharmacodynamics of fentanyl and alfentanil.

Fentanyl and alfentanil produce very similar electroencephalographic (EEG) changes in humans. With increasing serum concentrations of either narcotic, progressive slowing in frequency occurs. This narcotic effect on the brain was quantitated using off-line EEG power spectrum analysis. During EEG recording, six unpremedicated patients received a fentanyl infusion (150 micrograms/min), and six received alfentanil (1,500 micrograms/min) until a specific level of EEG depression (delta waves) occurred. Timed arterial blood samples were obtained for measurement of the narcotic serum concentrations. The narcotic-induced EEG changes were found to lag behind (in time) the serum narcotic concentration changes. To accurately relate EEG changes to serum narcotic concentrations, a pharmacodynamic model (inhibitory sigmoid Emax) was combined with a pharmacokinetic model that incorporated an "effect" compartment. (The effect compartment is the separate pharmacokinetic compartment where drug effect is directly proportional to drug concentration. It is the effect site.) The magnitude of the time lag was quantitated by the half-time of equilibration between serum narcotic concentrations and concentrations in the effect compartment. With fentanyl a significantly greater time lag was present (half-time = 6.4 +/- 1.3 min; mean +/- SD) than with alfentanil (half-time = 1.1 +/- 0.3 min). This difference in time lag between blood concentration and effect may be due to the larger brain-blood partition coefficient for fentanyl. The steady-state serum concentration that caused one-half of the maximal EEG slowing was 6.9 +/- 1.5 ng/ml for fentanyl, compared with 520 +/- 163 ng/ml for alfentanil.(ABSTRACT TRUNCATED AT 250 WORDS)

Alfentanil↗