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S L Shafer

Publications and source records attributed to S L Shafer.

88 records · Page 5Linked to original sources
PubMed1991

Pharmacokinetics, pharmacodynamics, and rational opioid selection.

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.

Alfentanil↗
PubMed1991

A simple analytical solution to the three-compartment pharmacokinetic model suitable for computer-controlled infusion pumps.

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.

Infusion Pumps↗
PubMed1990

Two equally valid interpretations of the linear multicompartment mammillary pharmacokinetic model.

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.

Infusions, Intravenous↗
PubMed1990

Estimating the rate of thiopental blood-brain equilibration using pseudo steady state serum concentrations.

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.

Adult↗
PubMed1990

The prospective use of population pharmacokinetics in a computer-driven infusion system for alfentanil.

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)

Adult↗
PubMed1990

A simple pocket calculator approach to predict anesthetic drug concentrations from pharmacokinetic data.

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.

Adult↗
PubMed1990

Pharmacokinetics of fentanyl administered by computer-controlled infusion pump.

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.

Adult↗
PubMed1989

A comparison of parametric with semiparametric analysis of the concentration versus effect relationship of metocurine in dogs and pigs.

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.

Animals↗
PubMed1989

The longitudinal distribution of pulmonary vascular resistance during unilateral hypoxia.

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.

Animals↗
PubMed1989

Absorption characteristics of transdermally administered fentanyl.

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.

Administration, Cutaneous↗
PubMed1989

Exercise produces sensitivity to metocurine.

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.

Animals↗
PubMed1988

Simultaneous measurements of cardiac output by thermodilution, esophageal Doppler, and electrical impedance in anesthetized patients.

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.

Cardiac Output↗
PubMed1988

Testing computer-controlled infusion pumps by simulation.

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.

Anesthetics↗
PubMed1988

Pharmacokinetics and pharmacodynamics of propofol infusions during general anesthesia.

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.

Adult↗