James R. Jacobs

Measured Context-sensitive Half-times of Remifentanil and Alfentanil

BackgroundThe context-sensitive half-time, rather than the terminal elimination half-life, has been proposed as a more clinically relevant measure of decreasing drug concentration after a constant infusion of a given duration. The context-sensitive half-time is derived from computer modelling using

Pharmacokinetic model-driven infusion of fentanyl: assessment of accuracy.

Computer-assisted continuous infusion (CACI) is a pharmacokinetic model-driven infusion device that enables physicians to administer intravenous (iv) drugs in a quantitative fashion, specifying a theoretical blood or plasma concentration. This study evaluated the accuracy of CACI administration of fentanyl using a newly developed CACI device programmed with a well-known set of pharmacokinetic parameters for fentanyl. Patients received diazepam 1 or 2 h before surgery. Anesthesia was induced by a combination of 70% N2O and fentanyl administered by CACI to a predicted concentration of 15-25 ng.ml-1. After neuromuscular blockade and tracheal intubation, the desired plasma fentanyl concentration (setpoint) entered into CACI was 3-6 ng.ml-1, and then the setpoint fentanyl concentration was titrated according to strict criteria of adequate or inadequate anesthesia. Plasma samples for subsequent assay of fentanyl concentration then were taken: at predefined stimuli, when inadequate anesthesia occurred, or 5 min before an anticipated decrease in the fentanyl setpoint. The predictive accuracy of CACI was assessed by calculating for each patient the tenth, 50th, and 90th percentile of the performance error and absolute performance error from each measured and predicted plasma sample pair. Cumulative probability functions for each of these were then plotted. Precision was defined as the dispersion of the tenth to 90th percentile of the median percent performance error for the population and was found to be -31-26%. The median population performance error was -4%, and the median population absolute performance error was 21%.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging increases pharmacodynamic sensitivity to the hypnotic effects of midazolam.

The effect of aging on the pharmacodynamics of midazolam was investigated in a double-blinded study involving 39 consenting patients ranging in age from 39 to 77 yr. Midazolam was infused intravenously (IV) using a pharmacokinetic model-driven drug infusion device to achieve a plasma midazolam concentration that was held constant for the 10-min duration of the study. Blood samples were obtained from the radial artery at 5 and 10 min for subsequent measurement of the plasma midazolam concentrations. With the 10-min sample, the patients were also assessed for the presence or absence of responsiveness to verbal command. To ensure that the pharmacodynamic end-point was assessed under the condition of a relative steady-state effect-site midazolam concentration, only those patients (n = 33) in whom the plasma midazolam concentration at 10 min was within 30% of the measured concentration at 5 min were included in the subsequent data analyses. Logistic regression was used to fit the verbal command response/no response data to a mathematical model that included patient age and the plasma midazolam concentration measured at 10 min. Cp50, the steadystate plasma midazolam concentration at which 50% of patients would be expected not to respond to a specific stimulus (e.g., verbal command), was calculated as a function of age from the parameterized logistic model. The midazolam Cp50 for response to verbal command decreased significantly (P = 0.034) with increasing patient age, demonstrating that aging increases pharmacodynamic sensitivity to the hypnotic effects of midazolam independent of pharmacokinetic factors. (Anesth Analg 1995;80:143-8)

Midazolam and fentanyl continuous infusion anesthesia for cardiac surgery: comparison of computer-assisted versus manual infusion systems

Continuous infusion of intravenous anesthetics can be achieved either by a manually controlled infusion (MCI) pump, or by a computer-assisted continuous infusion (CACI) pharmacokinetic model-driven infusion system. Randomized double-blind comparisons of the two infusion systems for general anesthesia were performed in 24 patients undergoing coronary artery bypass grafting. Patients were allocated to receive continuous infusions of midazolam and fentanyl by either a MCI device or CACI. Midazolam and fentanyl infusions were independently titrated to maintain hemodynamic stability, defined as mean arterial pressure (MAP) and heart rate (HR) within 20% of baseline values. As directed by the study design, comparable hemodynamic control was achieved in both groups. Mean plasma fentanyl concentrations measured at specific timepoints were similar between groups. The plasma midazolam level for induction was 196 +/- 139 ng/mL in the CACI group and 300 +/- 128 ng/mL in the MCI group, and the fentanyl level was similar in both groups, 6.7 +/- 1.9 ng/mL in CACI and 6.3 +/- 4.6 ng/mL in the MCI group. The drug levels were lower (P < or = .05) for midazolam during maintenance of anesthesia and similar for fentanyl during the maintenance of anesthesia. In the MCI group, the average duration of anesthesia was 246.5 +/- 35.0 minutes, with a mean total fentanyl dose of 30.27 +/- 11.14 micrograms/kg. In the CACI group, the average duration of anesthesia was 230.8 +/- 44.1 minutes, with a mean total fentanyl dose of 34.61 +/- 5.40 micrograms/kg (P > 0.05 for comparisons between groups for duration of anesthesia and total fentanyl dose).(ABSTRACT TRUNCATED AT 250 WORDS)

Algorithm for optimal linear model-based control with application to pharmacokinetic model-driven drug delivery

Computerized pharmacokinetic-model-driven administration of intravenous anesthetic agents has been implemented using a variety of algorithms to control the drug infusion regimen. All such algorithms are similar to the extent that they use a linear pharmacokinetic model of the drug being administered to determine drug infusion rates that theoretically achieve and maintain plasma drug concentrations (setpoints) specified by the physician. Since the behavior of the pharmacokinetic model can be computed for any input, it should be possible to achieve regulation of the drug infusion rates that is flexible (i.e. the physician can interactively adjust the setpoint), practical, and analytically optimized; these objectives are realized by the algorithm described.<<ETX>>

Plasma Concentration of Fentanyl, with 70% Nitrous Oxide, to Prevent Movement at Skin Incision

Background:The Cp50 (minimal steady state plasma concentration of an intravenous analgesic/anesthetic required to prevent a somatic response in 50% of patients following skin incision) and the Cp50-BAR (minimal plasma concentration of an analgesic/anesthetic required to prevent either a somatic, hemodynamic, or autonomic response in 50% of patients following skin incision) have been recently proposed as a measure, like minimum alveolar concentration (MAC; and MAC-BAR), to establish the relative potency of intravenous analgesics. This study was conducted to establish the Cp50 for fentanyl. Methods:Unpremedicated patients were administered fentanyl (in the presence of 70% N2O) via computer-assisted continuous infusion, a pharmacokinetic model-driven infusion device. After induction of anesthesia with fentanyl, the randomized target fentanyl concentration was entered into computer-assisted continuous infusion. This target fentanyl concentration was maintained until skin incision. Before induction, prior to skin incision, and immediately after skin incision, arterial blood samples were obtained for measurement of fentanyl and norepinephrine concentrations. At skin incision, patients were observed for a somatic, hemodynamic, or autonomic response. Only patients in whom the pre-and postincision fentanyl concentrations were within ±30% were included in the calculation of the Cp50. The Cp50 was calculated using logistic regression. Results:The Cp50 for fentanyl was 3.26 ng/ml, and the Cp50- BAR was 4.17 ng/ml. Conclusions:Comparing these results with the previously published Cp50 of alfentanil, the potency of fentanyl relative to alfentanil is 1:58. Establishing the Cp50, once effect site equilibration has occurred, will allow pharmacodynamic comparisons between the opioids at equipotent concentrations

Computerized continuous infusion of intravenous anesthetic drugs during pediatric cardiac surgery.

We evaluated the efficacy of a computer‐assisted continuous infusion device (CACI) using a two‐drug infusion of midazolam and sufentanil as an anesthetic technique during pediatric cardiac surgery. Seventeen pediatric patients were anesthetized with CACI using age‐appropriate pharmacokinetic models for administering sufentanil and midazolam. Predicted CACI plasma concentrations were correlated with assayed plasma drug concentrations at eight predefined intervals. The accuracy was assessed using median absolute prediction error. We found that plasma levels predicted by CACI provided a reasonable approximation of measured plasma concentrations for both drugs. The median absolute prediction error for sufentanil during cardiopulmonary bypass was compared with measurements made off of cardiopulmonary bypass (both pre and post cardiopulmonary bypass) and were 49% and 32%, respectively, and for midazolam 44% and 32%, respectively. We conclude that (a) current kinetic models provide a reasonable estimate of plasma drug concentrations, and (b) the ease of administration and targeted plasma level provided by the CACI system is an alternative to inhalation anesthesia using calibrated vaporizers.

Analytical solution to the three-compartment pharmacokinetic model

Simulations of pharmacokinetic models in software usually rely on discrete approximation of the continuous differential equations describing the system, but this need not be the case. Here, the analytical equations describing the temporal behavior of the three-compartment open pharmacokinetic model are derived, and an algorithm for their use in pharmacokinetic simulations is given.<<ETX>>

Effect of hypothermia and sampling site on blood esmolol concentrations

Esmolol hydrochloride was administered by constant‐rate continuous infusion to 10 patients undergoing hypothermic cardiopulmonary bypass for coronary artery revascularization surgery. After a suitable loading dose, the esmolol infusion was started approximately 30 minutes before bypass and was stopped 10 minutes after termination of bypass. Esmolol concentrations were measured in arterial and venous blood samples collected before and after bypass and in samples taken from the inflow and outflow ports of the membrane oxygenator during bypass. Blood esmolol concentrations increased during hypothermia in a manner that correlated significantly and inversely with temperature. All patients were separated from the extracorporeal circulation without difficulty, and the average arterial esmolol concentration was slightly below the prebypass concentration within minutes of discontinuing bypass. Esmolol disappeared from the blood rapidly on terminating the infusion. There was no difference between esmolol concentrations measured simultaneously from the inflow and outflow ports of the membrane oxygenator during bypass, but radial arterial esmolol concentrations before and after bypass were on average about sevenfold higher than forearm venous esmolol concentrations during the esmolol infusion! The results of this study lead to two important conclusions: (1) in vivo clearance of esmolol demonstrates acute temperature dependence and (2) esmolol is removed irreversibly as it passes through the microcirculation of the hand, making measurement of peripheral esmolol concentrations markedly dependent on sampling site (arterial versus venous).

Esmolol and Left Ventricular Function in the Awake Dog

Hypotension has been the most frequently reported adverse reaction associated with infusion of the β1-adrenergic receptor antagonist esmolol. In some patients, this hypotension has apparently occurred independent of reduction in heart rate or systemic vascular resistance, suggesting decreased stroke volume. In the present study, the preload recuitable stroke work area (PRSWA) model was used to evaluate the negative inotropic effects of esmolol in nine chronically instrumented awake dogs. Left ventricular (LV) transmural pressure and minor axis diameter were measured by micromanometers and sonomicrometry, respectively. Vena caval occlusions were performed so that an analog of stroke work (area within LV transmural pressure-diameter loop) could be measured over a range of preloading conditions during esmolol infusions of 0, 100, 300, 1000, and 3000 μg·kg−1·min−1 (n = 9), and at 15 and 30 min after termination of esmolol (n = 8). The linear relationship between stroke work and end-diastolic diameter was characterized for each caval occlusion by a slope and x-intercept. PRSWA was calculated for each caval occlusion as slope/two times the square of the difference between x-intercept and the largest end-diastolic diameter observed in the study of a particular dog. Heart rate was different from control (91 ± 4) only at the highest esmolol dose (127 ± 4). LV peak positive dP/dt, minor axis ejection shortening, stroke work, and PRSWA were depressed from control at esmolol doses ≥ 300 μg·kg−1·min−1. All parameters except dP/dt recovered within 30 min following termination of esmolol. Decline in PRSWA with esmolol occurred largely through an increase in x-intercept, which may indicate diastolic dysfunction. In the awake dog, moderate to large doses of esmolol impair LV function; the lack of any negative chronotropic effect by esmolol suggests that the negative inotropic effect of esmolol in this canine preparation is not by β1 blockade.