Pharmacokinetics and Pharmacodynamics of Remifentanil in Volunteer Subjects with Severe Liver Disease

Background: Remifentanil, a new micro-opioid agonist with an extremely short duration of action, is metabolized by circulating and tissue esterases; therefore, its clearance should be relatively unaffected by changes in hepatic or renal function. This study was designed to determine whether severe hepatic disease affects the pharmacokinetics or pharmacodynamics of remifentanil.

Methods: Ten volunteers with chronic, stable, severe hepatic disease and awaiting liver transplantation and ten matched controls were enrolled. Each subject was given a 4-h infusion of remifentanil. The first five pairs received 0.0125 micro gram *symbol* kg sup -1 *symbol* min sup -1 for 1 h followed by 0.025 micro gram *symbol* kg sup -1 *symbol* min sup -1 for 3 h; the second five pairs received double these infusion rates. During and after the infusion, arterial blood was obtained for pharmacokinetic analyses, and the ventilatory response to a hypercarbic challenge was assessed. Simultaneous pharmacokinetic and pharmacodynamic analyses were performed. The pharmacokinetics were described using a one-compartment intravenous infusion model, and ventilatory depression was modelled using the inhibitory Emax model. The pharmacokinetics of the metabolite GR90291 were determined using noncompartmental methods.

Results: There were no differences in any of the pharmacokinetic parameters for remifentanil or GR90291 between the two groups. The subjects with liver disease were more sensitive to the ventilatory depressant effects of remifentanil. The EC50 values (the remifentanil concentrations determined from simultaneous pharmacokinetic/pharmacodynamic analyses to depress carbon dioxide-stimulated minute ventilation by 50%) in the control and hepatic disease groups were 2.52 ng/ml (95% confidence interval 2.07-2.97 ng/ml) and 1.56 ng/ml (95% confidence interval 1.37-1.76 ng/ml), respectively.     

Anesthetic Potency of Remifentanil in Dogs

Background: Remifentanil is an opioid that is rapidly inactivated by esterases in blood and tissues. This study examined the anesthetic potency and efficacy of remifentanil in terms of its reduction of enflurane minimum alveolar concentration (MAC) in dogs.

Methods: Twenty-five dogs were anesthetized with enflurane. One group received incremental infusion rates of remifentanil from 0.055 to 5.5 micro gram *symbol* kg sup -1 *symbol* min sup -1. A second group received constant rate infusions of remifentanil of 1.0 micro gram *symbol* kg sup -1 *symbol* min sup -1 for 6-8 h. Enflurane MAC was measured before, hourly during remifentanil infusion, and at the end of the experiment after naloxone administration. A third group received alternating infusions of 0.5 and 1.0 micro gram *symbol* kg sup -1 *symbol* min sup -1 with MAC determinations made 30 min after each change in the infusion rate. Heart rate, mean arterial pressure, and remifentanil blood concentrations were measured during MAC determinations.

Results: Enflurane MAC was reduced up to a maximum of 63.0+/- 10.4% (mean+/-SD) in a dose-dependent manner by remifentanil infusion. The dose producing a 50% reduction in the enflurane MAC was calculated as 0.72 micro gram *symbol* kg sup -1 *symbol* min sup -1 and the corresponding blood concentration was calculated as 9.2 ng/ml. Enflurane MAC reduction remained stable during continuous, constant rate infusions for periods of 6-8 h without any signs of tolerance. Recovery of enflurane MAC to baseline occurred in 30 min (earliest measurement) after stopping the remifentanil infusion.     

Influence of Age and Gender on the Pharmacokinetics and Pharmacodynamics of Remifentanil: I. Model Development

Background: Previous studies have reported conflicting results concerning the influence of age and gender on the pharmacokinetics and pharmacodynamics of fentanyl, alfentanil, and sufentanil. The aim of this study was to determine the influence of age and gender on the pharmacokinetics and pharmacodynamics of the new short-acting opioid remifentanil.

Methods: Sixty-five healthy adults (38 men and 27 women) ages 20 to 85 y received remifentanil by constant-rate infusion of 1 to 8 micro gram [centered dot] kg sup -1 [centered dot] min sup -1 for 4 to 20 min. Frequent arterial blood samples were drawn and assayed for remifentanil concentration. The electroencephalogram was used as a measure of drug effect. Population pharmacokinetic and pharmacodynamic modeling was performed using the software package NONMEM. The influence of volunteer covariates were analyzed using a generalized additive model. The performances of the simple (without covariates) and complex (with covariates) models were evaluated prospectively in an additional 15 healthy participants ages 41 to 84 y.

Results: The parameters for the simple three-compartment pharmacokinetic model were V1 = 4.98 l, V2 = 9.01 l, V3 = 6.54 l, Cl1 = 2.46 l/min, Cl2 = 1.69 l/min, and Cl3 = 0.065 l/min. Age and lean body mass were significant covariates. From the ages of 20 to 85 y, V1 and Cl1 decreased by approximately 25% and 33%, respectively. The parameters for the simple sigmoid Emax pharmacodynamic model were ke0 = 0.516 min sup -1, E0 = 20 Hz, Emax = 5.62 Hz, EC50 = 11.2 ng/ml, and gamma = 2.51. Age was a significant covariate of EC50 and ke0, with both decreasing by approximately 50% for the age range studied. The complex pharmacokinetic-pharmacodynamic model performed better than did the simple model when applied prospectively.     

Population Pharmacodynamics and Pharmacokinetics of Remifentanil as a Supplement to Nitrous Oxide Anesthesia for Elective Abdominal Surgery

Background: Remifentanil blood concentrations necessary for adequate intraoperative anesthesia have not been defined. The goal of this study was to determine the blood concentrations of remifentanil needed for anesthesia with 66% nitrous oxide during intraabdominal surgery. In addition, the pharmacokinetics of remifentanil and the effects of covariates on both the pharmacodynamics and the pharmacokinetics were determined.

Methods: Anesthesia was induced and maintained with 66% nitrous oxide in oxygen and remifentanil. Remifentanil was administered by a computer-controlled infusion pump that rapidly attained, and then maintained, constant remifentanil blood concentrations. If the patient showed signs of inadequate anesthesia (autonomic or somatic response), the target concentration was increased by 1 or 2 ng/ml. If no response occurred during a 15-min period, the concentration was decreased by 1 or 2 ng/ml. Remifentanil pharmacodynamics and pharmacokinetics were estimated using NONMEM.

Results: The remifentanil blood concentration for which there is a 50% probability of adequate anesthesia during abdominal surgery (Cb50) with 66% nitrous oxide was 4.1 ng/ml in men and 7.5 ng/ml in women. The Cb50 values for prostatectomy, nephrectomy, and other abdominal procedures were 3.8, 5.6, and 7.5 ng/ml, respectively. Remifentanil pharmacokinetics were best described by a two-compartment model with lean body mass as a significant covariate, where V1 = 0.129(lean body mass-50) + 3.79 l, V (2) = 6.87 l, CL1 = 0.0389(lean body mass-50) + 2.34 l/min and CL2 = 1.14 l/min.     

Pharmacokinetics Anesthesiologists, and Pharmacodynamics of Remifentanil in Persons with Renal Failure Compared with Healthy Volunteers

Background: Remifentanil is an opioid analgesic for use in anesthesia. An ester linkage renders it susceptible to rapid metabolism by blood and tissue esterases. Thus it was hypothesized that remifentanil elimination would be independent of renal function. Because its principal metabolite (GR90291) is eliminated renally, it would depend on renal function. This study was designed to evaluate the pharmacokinetics and pharmacodynamics of remifentanil and its metabolite in persons with and without renal failure.

Methods: Two groups of volunteers received two-stage infusions of remifentanil: low dose with 0.0125 micro gram [center dot] kg sup -1 [center dot] min sup -1 for 1 h followed by 0.025 micro gram kg sup -1 [center dot] min sup -1 for 3 h; and high dose with 0.025 micro gram [center dot] kg sup -1 [center dot] min sup -1 for 1 h followed by 0.05 micro gram [center dot] kg sup -1 [center dot] min sup -1 for 3 h. Blood samples were collected for analysis of remifentanil and GR90291 concentrations. The pharmacokinetics of remifentanil were fit using a one-compartment pharmacokinetic model. Remifentanil's effect was determined intermittently using minute ventilation during a hypercapnic (7.5% CO2) challenge.

Results: Fifteen patients with renal failure and eight control participants were enrolled. The clearance and volume of distribution of remifentanil were not different between those with renal failure and the controls. Patients with renal failure showed a marked reduction in the elimination of GR90291; the half-life of the metabolite increased from 1.5 h in the controls to more than 26 h in patients with renal failure. The steady-state concentration of GR90291 is likely to be more than 25 times higher in persons with renal failure. There were no obvious differences in opioid effects on minute ventilation in the controls and in patients with renal failure.     

Pharmacokinetics of Propofol after a Single Dose in Children Aged 1-3 Years with Minor Burns: Comparison of Three Data Analysis Approaches

Background: No complete pharmacokinetic profile of propofol is yet available in children younger than 3 yr, whereas clinical studies have demonstrated that both induction and maintenance doses of propofol are increased with respect to body weight in this age group compared to older children and adults. This study was therefore undertaken to determine the pharmacokinetics of propofol after administration of a single dose in aged children 1-3 yr requiring anesthesia for dressing change.

Methods: This study was performed in 12 children admitted to the burn unit and in whom burn surface area was less than or equal to 12% of total body surface area. Exclusion criteria were: unstable hemodynamic condition, inappropriate fluid loading, associated pulmonary injury, or burn injury older than 2 days. Propofol (4 mg *symbol* kg sup -1) plus fentanyl (2.5 micro gram *symbol* kg sup -1) was administered while the children were bathed and the burn area cleaned during which the children breathed spontaneously a mixture of oxygen and nitrous oxide (50:50). Venous blood samples of 300 micro liter were obtained at 5, 15, 30, 60, 90, and 120 min, and 3, 4, 8, and 12 h after injection; an earlier sample was obtained from 8 of 12 children. The blood concentration curves obtained for individual children were analyzed by three different methods: noncompartmental analysis, mixed-effects population model, and standard two-stage analysis.

Results: Using noncompartmental analysis, total clearance of propofol (+/-SD) was 0.053+/-0.013 l *symbol* kg sup -1 *symbol* min sup -1, volume of distribution at steady state 9.5+/-3.7 l *symbol* kg sup -1, and mean residence time 188+/-85 min. Propofol pharmacokinetics were best described by a weight-proportional three-compartmental model in both population and two-stage analysis. Estimated and derived pharmacokinetic parameters were similar using these two pharmacokinetic approaches. Results of population versus two-stage analysis are as follow: systemic clearance 0.049 versus 0.048 l *symbol* kg sup -1 *symbol* min sup -1, volume of central compartment 1.03 versus 0.95 l *symbol* kg sup -1, volume of distribution at steady state 8.09 versus 8.17 l *symbol* kg sup -1.     

Pharmacokinetics of Rocuronium in Children Aged 4-11 Years

Background: Rocuronium is a new nondepolarizing muscle relaxant with a rapid onset and intermediate duration of action. Although the pharmacokinetics of rocuronium have been determined in adults and the elderly, similar data are lacking in children. Accordingly, rocuronium's pharmacokinetics were determined in children aged 4-11 yr.

Methods: Rocuronium (600 micro gram/kg) was administered to 20 children aged 4-11 yr anesthetized with nitrous oxide and less or equal to 1% halothane, and four plasma samples were obtained over 4 h to determine rocuronium concentrations. The pharmacokinetics of rocuronium were determined using two sparse-sampling population approaches, mixed- effects modeling, and naive pooled data analysis.

Results: With mixed-effects modeling, weight-normalized plasma clearance varied with weight (P < 0.01), being 79.4 ml *symbol* min sup -1 + 3.13 ml *symbol* kg sup -1 *symbol* min sup -1. Neither weight- normalized distributional clearance (2.67 ml *symbol* kg sup -1 *symbol* min sup -1), weight-normalized central compartment volume (106 ml/kg), nor weight-normalized volume of distribution at steady-state (224 ml/kg) varied with weight, height, or age. Similar results were obtained with the naive pooled data approach.     

Tourniquet-induced Exsanguination in Patients Requiring Lower Limb Surgery: An Ischemia-Reperfusion Model of Oxidant and Antioxidant Metabolism

Background: Surgically induced ischemia and reperfusion is frequently accompanied by local and remote organ injury. It was hypothesized that this procedure may produce injurious oxidants such as hydrogen peroxide (H2 O2), which, if unscavenged, will generate the highly toxic hydroxyl radical (*symbol* OH). Accordingly, it was proposed that tourniquet-induced exsanguination for limb surgery may be a useful ischemia-reperfusion model to investigate the presence of oxidants, particularly H2 O2.

Methods: In ten patients undergoing knee surgery, catheters were placed in the femoral vein of the limb operated on for collection of local blood and in a vein of the arm for sampling of systemic blood. Tourniquet-induced limb exsanguination was induced for about 2 h. After tourniquet release (reperfusion), blood samples were collected during a 2-h period for measurement of H2 O2, xanthine oxidase activity, xanthine, uric acid (UA), glutathione, and glutathione disulfide.

Results: At 30 s of reperfusion, H2 O2 concentrations increased ([nearly equal] 90%) from 133+/-5 to 248+/-8 nmol *symbol* ml sup -1 (P < 0.05) in local blood samples, but no change was evident in systemic blood. However, in both local and systemic blood, xanthine oxidase activity increased [nearly equal] 90% (1.91+/- 0.07 to 3.93+/-0.41 and 2.19+/-0.07 to 3.57+/- 0.12 nmol UA *symbol* ml sup -1 *symbol* min sup -1, respectively) as did glutathione concentrations (1.27+/-0.04 to 2.69+/-0.14 and 1.27+/-0.03 to 2.43+/-0.13 micro mol *symbol* ml sup -1, respectively). At 5 min reperfusion, in local blood, H2 O2 concentrations and xanthine oxidase activity peaked at 796+/-38 nmol *symbol* ml sup -1 ([nearly equal] 500%) and 11.69+/-1.46 nmol UA *symbol* ml sup -1 *symbol* min sup -1 ([nearly equal] 520%), respectively. In local blood, xanthine and UA increased from 1.49 +/-0.07 to 8.36+/-0.33 nmol *symbol* ml sup -1 and 2.69 +/-0.16 to 3.90+/-0.18 micro mol *symbol* ml sup -1, respectively, whereas glutathione and glutathione disulfide increased to 5.13+/-0.36 micro mol *symbol* ml sup -1 and 0.514+/- 0.092 nmol *symbol* ml sup -1, respectively. In systemic blood, xanthine oxidase activity peaked at 4.75+/-0.20 UA nmol *symbol* ml sup -1 *symbol* min sup -1. At 10 min reperfusion, local blood glutathione and UA peaked at 7.08+/-0.46 micro mol *symbol* ml sup -1 and 4.67 +/-0.26 micro mol *symbol* ml sup -1, respectively, while the other metabolites decreased significantly toward pretourniquet levels. From 20 to 120 min, most metabolites returned to pretourniquet levels; however, local and systemic blood xanthine oxidase activity remained increased 3.76+/-0.29 and 3.57+/-0.37 nmol UA *symbol* ml sup -1 *symbol* min sup -1, respectively. Systemic blood H2 O2 was never increased during the study. During the burst period ([nearly equal] 5-10 min), local blood H2 O2 concentrations and xanthine oxidase activities were highly correlated (r = 0.999).     

Mixed-effects Modeling of the Influence of Alfentanil on Propofol Pharmacokinetics

Background: The influence of alfentanil on the pharmacokinetics of propofol is poorly understood. Therefore, the authors studied the effect of a pseudo-steady state concentration of alfentanil on the pharmacokinetics of propofol.

Methods: The pharmacokinetics of propofol were studied on two occasions in eight male volunteers in a randomized crossover manner with a 3-week interval. While volunteers breathed 30% O2 in air, 1 mg/kg intravenous propofol was given in 1 min, followed by 3 mg [middle dot] kg-1 [middle dot] h-1 for 59 min (sessions A and B). During session B, a target-controlled infusion of alfentanil (target concentration, 80 ng/ml) was given from 10 min before the start until 6 h after termination of the propofol infusion. Blood pressure, cardiac output, electrocardiogram, respiratory rate, oxygen saturation, and end-tidal carbon dioxide were monitored. Venous blood samples for determination of the blood propofol and plasma alfentanil concentration were collected until 6 h after termination of the propofol infusion. Nonlinear mixed-effects population pharmacokinetic models examining the influence of alfentanil and hemodynamic parameters on propofol pharmacokinetics were constructed.

Results: A two-compartment model, including a lag time accounting for the venous blood sampling, adequately described the concentration-time curves of propofol. Alfentanil decreased the elimination clearance of propofol from 2.1 l/min to 1.9 l/min, the distribution clearance from 2.7 l/min to 2.0 l/min, and the peripheral volume of distribution from 179 l to 141 l. Scaling the pharmacokinetic parameters to cardiac output, heart rate, and plasma alfentanil concentration significantly improved the model.     

Effects of Thiopental on Regional Blood Flows in the Rat

Background: The goal of this investigation was to characterize the effects of thiopental on cardiac output and regional blood flows in the rat. Blood flows influence thiopental pharmacokinetics. Acquisition of these data may ultimately permit evaluation of the contribution of thiopental-induced alterations in regional blood flows to the disposition and hypnotic effect of this drug.

Methods: Chronically instrumented unrestrained Wistar rats (n = 20) aged 3-4 months received either a dose of thiopental sufficient to induce a brief period of unconsciousness (20 mg *symbol* kg sup -1) or a larger dose achieving electroencephalographic burst suppression (45 mg *symbol* kg sup -1). Cardiac output and blood flows to 14 tissues were determined at 4 times in each rat for a period of 420 min using injections of radioactive microspheres (expressed as mean+/-SD). Mean arterial pressure, heart rate, and blood gas tensions were determined at all measurement times. Arterial plasma concentrations we sampled at postinfusion times.

Results: No important changes in systemic cardiovascular measurements were detected after the smaller dose of thiopental. One minute after the larger dose, cardiac output decreased from baseline (123+/-14 to 84+/-11 ml *symbol* min sup -1, P < 0.01), flow to muscle and fat decreased, and muscle and fat resistance increased. At 5 min, compared to baseline, no difference in cardiac output was detected (123+/-14 vs. 119+/-11 ml *symbol* min sup -1), intestinal flows increased, and intestinal resistances decreased. Cardiac output was again depressed at 30, 90, and 180 min. Brain blood flow decreased 25+/-19% (P < 0.01) from baseline for the duration of the study.     

Mixed-effects modeling of the influence of alfentanil on propofol pharmacokinetics

BACKGROUND: The influence of alfentanil on the pharmacokinetics of propofol is poorly understood. Therefore, the authors studied the effect of a pseudo-steady state concentration of alfentanil on the pharmacokinetics of propofol. METHODS: The pharmacokinetics of propofol were studied on two occasions in eight male volunteers in a randomized crossover manner with a 3-week interval. While volunteers breathed 30% O2 in air, 1 mg/kg intravenous propofol was given in 1 min, followed by 3 mg.kg(-1).h(-1) for 59 min (sessions A and B). During session B, a target-controlled infusion of alfentanil (target concentration, 80 ng/ml) was given from 10 min before the start until 6 h after termination of the propofol infusion. Blood pressure, cardiac output, electrocardiogram, respiratory rate, oxygen saturation, and end-tidal carbon dioxide were monitored. Venous blood samples for determination of the blood propofol and plasma alfentanil concentration were collected until 6 h after termination of the propofol infusion. Nonlinear mixed-effects population pharmacokinetic models examining the influence of alfentanil and hemodynamic parameters on propofol pharmacokinetics were constructed. RESULTS: A two-compartment model, including a lag time accounting for the venous blood sampling, adequately described the concentration-time curves of propofol. Alfentanil decreased the elimination clearance of propofol from 2.1 l/min to 1.9 l/min, the distribution clearance from 2.7 l/min to 2.0 l/min, and the peripheral volume of distribution from 179 l to 141 l. Scaling the pharmacokinetic parameters to cardiac output, heart rate, and plasma alfentanil concentration significantly improved the model. CONCLUSIONS: Alfentanil alters the pharmacokinetics of propofol. Cardiac output and heart rate have an important influence on the pharmacokinetics of propofol.     

Repeated Doses of Rocuronium Bromide Administered to Cirrhotic and Control Patients Receiving Isoflurane: A Clinical and Pharmacokinetic Study

Background: Steroid muscle relaxants often display pharmacodynamic changes in patients with cirrhosis because of alterations in elimination processes. Rocuronium is a new steroid muscle relaxant possibly eliminated through the liver. This study was designed to compare rocuronium pharmacodynamics and pharmacokinetics in cirrhotic and healthy patients.

Methods: Rocuronium was administered to 26 cirrhotic patients and 24 control subjects anesthetized with isoflurane for an elective procedure. Patients were randomly allocated to receive an initial dose of rocuronium: 120, 180, 250, or 300 micro gram *symbol* kg sup -1. Dose-response curves were established, and ED50 was calculated. Preselected maintenance doses (75, 150, or 225 micro gram *symbol* kg sup -1) were administered at 25% recovery of twitch height to compare clinical duration of action. At the end of the procedure, relaxation was reversed in half of the patients, and the time course of recovery was compared in the two groups. Blood samples drawn during the procedure and after the last maintenance dose allowed pharmacokinetic analysis in six cirrhotic patients and six control subjects.

Results: ED50 of the initial dose was 144 micro gram *symbol* kg sup -1 in cirrhotic patients and 60 micro gram *symbol* kg sup -1 in control subjects, related to a higher initial volume of distribution (cirrhotic 78.5+/-31.7 ml *symbol* kg sup -1, control 29.8 +/-17.3 ml *symbol* kg sup -1). Time from complementary dose to 25% recovery was longer in cirrhotic patients (41.0+/-20.7 min vs. 30.2+/-9.7 min), but time course of action during maintenance was not statistically different in the two groups. In cirrhotic patients receiving five maintenance doses or more, prolongation of the duration of action with successive maintenance doses could be statistically demonstrated. Spontaneous recovery was delayed in cirrhotic patients, because of impaired elimination processes: greater volume of distribution at steady-state (264+/-92 vs. 151+/-59 ml *symbol* kg sup -1); trend toward a lower clearance (189+/-60 vs. 296 +/-169 ml *symbol* min sup -1).     

Dose Comparison of Remifentanil and Alfentanil for Loss of Consciousness

Background: This study evaluated the efficacy and safety of remifentanil, a potent mu agonist opioid with a rapid onset and offset of effect, as a sole induction agent for loss of consciousness (LOC) and compared it with alfentanil.

Methods: Remifentanil and alfentanil were administered intravenously over 2 min in ascending doses (remifentanil 2, 3, 4, 5, 6, 8, 10, 15, 20 micro gram/kg; alfentanil 40, 60, 80, 100, 120, 160, 200 micro gram/kg) to unpremedicated healthy patients. Patients were observed for rigidity and LOC for 30 s after the end of infusion. If patients had not lost consciousness, 2 mg [center dot] kg sup -1 [center dot] min sup -1 thiopental was administered until LOC was achieved. Arterial blood samples, obtained at specified time intervals, were analyzed for remifentanil and alfentanil whole-blood concentration. Blood pressure and heart rate were also recorded at preset time intervals.

Results: Neither drug could reliably produce LOC. With both drugs, there was a dose-dependent decrease in thiopental requirements and a dose-dependent increase in the incidence and severity of rigidity (P <0.05). The median effective dose (ED50) for LOC with remifentanil was 12 micro gram/kg, and for alfentanil it was 176 micro gram/kg. The median effective concentration (EC50; whole-blood concentration) of remifentanil was 53.8 ng/ml and for alfentanil it was 1,012 ng/ml. Minimal hemodynamic changes were observed after either drug was given.     

Pharmacodynamics and Pharmacokinetics of Cisatracurium in Geriatric Surgical Patients

Background: Cisatracurium, one of ten stereoisomers that comprise atracurium, is more potent than atracurium and has less propensity to release histamine. This study compares the pharmacokinetics and pharmacodynamics of cisatracurium in elderly and young patients.

Methods: Twelve elderly (aged 65-82 yr) and 12 younger patients (aged 30-49 yr) were anesthetized with nitrous oxide, fentanyl, and isoflurane (0.7%, end-tidal). The mechanomyographic response to train-of-four stimulation was assessed every 15 s after the administration of cisatracurium (0.1 mg/kg). Arterial samples were obtained over 6 h. Plasma cisatracurium concentration versus time data were fit to compartmental models. Pharmacokinetic parameters were determined assuming that elimination occurred from the central compartment only. This provides accurate clearance and half-life estimates but underestimates Vss (reported herein as Vss '). The pharmacodynamic response was described by the neuromuscular blocking profile.

Results: Onset to 90% paralysis (mean+/-SD) was delayed in the elderly (3.4+/-1.0 vs. 2.5+/-0.6 min). Recovery profiles were the same for both groups. Elimination half-life was minimally prolonged in the elderly (25.5+/-3.7 vs. 21.5 +/-2.4 min). The Vss ' was larger in the elderly (126 +/-16 vs. 108+/-13 ml/kg), although the clearances were the same for the two groups (5.0+/-0.9 vs. 4.6+/-0.8 ml *symbol* kg sup -1 *symbol* min sup -1).     

Propofol alters the pharmacokinetics of alfentanil in healthy male volunteers

BACKGROUND: The influence of propofol on the pharmacokinetics of alfentanil is poorly understood. The authors therefore studied the effect of a pseudo-steady state concentration of propofol on the pharmacokinetics of alfentanil. METHODS: The pharmacokinetics of alfentanil was studied on two occasions in eight male volunteers in a randomized crossover manner with a 3-week interval. While breathing 30% O2 in air, 12.5 microg/kg intravenous alfentanil was given in 2 min, followed by 25 microg.kg(-1).h(-1) for 58 min (sessions A and B). During session B, a target controlled infusion of propofol (target concentration, 1.5 microg/ml) was given from 10 min before the start until 6 h after termination of the alfentanil infusion. Blood pressure, cardiac output, electrocardiogram, respiratory rate, oxygen saturation, and end-tidal carbon dioxide were monitored. Venous blood samples for determination of the plasma alfentanil concentration were collected until 6 h after termination of the alfentanil infusion. Nonlinear mixed-effects population pharmacokinetic models examining the influence of propofol and mean arterial pressure were constructed. RESULTS: A three-compartment model, including a lag time accounting for the venous blood sampling, adequately described the concentration-time curves of alfentanil Propofol decreased the elimination clearance of alfentanil by 15%, rapid distribution clearance by 68%, slow distribution clearance by 51%, and lag time by 62%. Mean arterial pressure and systemic vascular resistance were significantly lower in the presence of propofol. Scaling the pharmacokinetic parameters to the mean arterial pressure instead of propofol improved the model. CONCLUSIONS: Propofol alters the pharmacokinetics of alfentanil. Hemodynamic changes induced by propofol may have an important influence on the pharmacokinetics of alfentanil.     

Pharmacokinetics of Cisatracurium in Patients Receiving Nitrous Oxide/Opioid/Barbiturate Anesthesia

Background: Cisatracurium, one of the ten isomers in atracurium, is a nondepolarizing muscle relaxant with an intermediate duration of action. It is more potent and less likely to release histamine than atracurium. As one of the isomers composing atracurium, it presumably undergoes Hofmann elimination. This study was conducted to describe the pharmacokinetics of cisatracurium and its metabolites and to determine the dose proportionality of cisatracurium after administration of 2 or 4 times the ED95.

Methods: Twenty ASA physical status 1 or 2 patients undergoing elective surgery under nitrous oxide/opioid/barbiturate anesthesia were studied. Patients received a single rapid intravenous bolus dose of 0.1 or 0.2 mg *symbol* kg sup -1 (2 or 4 times the ED95, respectively) cisatracurium. All patients were allowed to recover spontaneously to a train-of-four ratio greater or equal to 0.70 after cisatracurium-induced neuromuscular block. Plasma was extracted, acidified, and stored frozen before analysis for cisatracurium, laudanosine, the monoquaternary acid, and the monoquaternary alcohol metabolite.

Results: The clearances (5.28+/-1.23 vs. 4.66+/- 0.67 ml *symbol* min sup -1 *symbol* kg sup -1) and terminal elimination half-lives (22.4+/-2.7 vs. 25.5+/-4.1 min) were not statistically different between patients receiving 0.1 mg *symbol* kg sup -1 and 0.2 mg *symbol* kg sup -1, respectively. Maximum concentration values for laudanosine averaged 38+/-21 and 103+/-34 ng *symbol* ml sup -1 for patients receiving the 0.1 and 0.2 mg *symbol* kg sup -1 doses, respectively. Maximum concentration values for monoquaternary alcohol averaged 101+/-27 and 253+/-51 ng *symbol* ml sup -1, respectively. Monoquaternary acid was not quantified in any plasma sample.     

Pharmacokinetics of Dichloroacetate in Patients Undergoing Liver Transplantation

Background: Dichloroacetate (DCA) is an effective alternative to bicarbonate to treat lactic acidosis and stabilize acid-base homeostasis during liver transplantation. Although DCA presumably is metabolized by the liver, the impact of end-stage liver disease and liver transplantation on DCA distribution and elimination is unknown. Therefore, the pharmacokinetics of DCA were determined in patients with end-stage liver disease undergoing orthotopic liver transplantation.

Methods: Thirty-three patients undergoing liver transplantation were given DCA as two 40-mg/kg infusions over 60 min, the first after induction of anesthesia, the second 4 h later. Plasma DCA concentrations were determined by gas chromatography-mass spectroscopy. One- and two-compartment pharmacokinetic models were fitted to DCA concentrations versus time data using a mixed-effects population approach. Various models permitted changes in central compartment volume and/or plasma clearance to account for changes in hepatic mass and function and circulatory status during the paleohepatic, anhepatic, and neohepatic periods.

Results: The optimal model had two compartments. DCA clearance was 0.997, 0.0, and 1.69 ml *symbol* kg sup -1 *symbol* min sup -1 during the paleohepatic, anhepatic, and neohepatic periods, respectively (P < 0.05). Interindividual variability in central compartment volume differed during the paleohepatic and neohepatic periods. There was no apparent influence of blood or fluid requirements during surgery on DCA clearance or volume of distribution.     

Determination of the potency of remifentanil compared with alfentanil using ventilatory depression as the measure of opioid effect.

BACKGROUND: Remifentanil is a new opioid with properties similar to other mu-specific agonists. To establish its pharmacologic profile relative to other known opioids, it is important to determine its potency. This study investigated the relative potency of remifentanil compared with alfentanil. METHODS: Thirty young healthy males were administered double-blind remifentanil or alfentanil intravenously for 180 min using a computer-assisted continuous infusion device. Depression of ventilation was assessed by the minute ventilatory response to 7.5% CO2 administered via a "bag in the box" system. The target concentration of the study drug was adjusted to obtain 40-70% depression of baseline minute ventilation. Multiple blood samples were obtained during and following the infusion. The concentration-effect relationship of each drug was modeled, and the concentration needed to provide a 50% depression of ventilation (EC50) was determined. RESULTS: Only 11 subjects in each drug group completed the study; however, there were sufficient data in 28 volunteers to model their EC50 values. The EC50 (mean and 95% confidence interval) for depression of minute ventilation with remifentanil was 1.17 (0.85-1.49) ng/ml and the EC50 for alfentanil was 49.4 (32.4-66.5) ng/ml. CONCLUSION: Based on depression of the minute ventilatory response to 7.5% CO2, remifentanil is approximately 40 (26-65) times more potent than alfentanil when remifentanil and alfentanil whole-blood concentrations are compared. As alfentanil is usually measured as a plasma concentration, remifentanil is approximately 70 (41-104) times more potent than alfentanil when remifentanil whole-blood concentration is compared with alfentanil plasma concentration. This information should be used when performing comparative studies between remifentanil and other opioids.     

Prediction of Movement during Propofol/Nitrous Oxide Anesthesia: Performance of Concentration, Electroencephalographic, Pupillary, and Hemodynamic Indicators

Background: Movement in response to painful stimulation is the end point classically used to assess the potency of anesthetic agents. In this study, the ability of modeled propofol effect-site concentration to predict movement in volunteers during propofol/nitrous oxide anesthesia was tested, then it was compared with the predictive abilities of the Bispectral Index and 95% spectral edge frequency of the electroencephalogram, pupillary reflex amplitude, and systolic arterial blood pressure. In addition, the relationships between simple end points of loss and recovery of consciousness, and pupillary, hemodynamic, and propofol concentration indicators were studied.

Methods: Ten healthy volunteers were anesthetized with an infusion of propofol, which was increased in three equal steps to 21 mg *symbol* kg lean body mass sup -1 *symbol* h sup -1. After loss of the ability to hold a syringe and of the eyelash reflex, 60% nitrous oxide was introduced and the trachea was intubated without the use of muscle relaxants. The propofol infusion rate then was decreased to 15.4 mg *symbol* kg lean body mass sup -1 *symbol* h sup -1. Ten minutes later, tetanic electrical stimulation was administered to the thigh via needle electrodes: if movement was observed within 1 min, the propofol infusion rate was increased by 1.75 mg *symbol* kg lean body mass sup -1 *symbol* h sup -1 5 min after the stimulus; if not, it was similarly decreased. This 15-min sequence was repeated until volunteers "crossed over" from movement to no movement (or vice versa) four times. The propofol infusion rate then was increased to 21 mg *symbol* kg lean body mass sup -1 *symbol* h sup -1, nitrous oxide was discontinued, the trachea was extubated, and the infusion rate was decreased in five equal steps over 50 min. The times at which the eyelash reflex returned and the birth date was recalled were recorded. The electroencephalogram was monitored continuously (FP1, FP2, ref: nasion, ground: mastoid). Measurements of the pupillary response, arterial blood pressure, and heart rate were recorded during induction and awakening, just before and for 5 min after each stimulation. Arterial blood samples were obtained for propofol assay, and propofol effect-site concentrations were calculated at each time. The predictive value of indicators was compared using a new statistic, the prediction probability (PK).

Results: Loss and return of the eyelash reflex occurred at greater propofol effect-site concentrations than either dropping the syringe or recall of the birthday. The propofol effect-site concentration (in the presence of 60% nitrous oxide) predicted to prevent movement after a supramaximal stimulus in 50% of volunteers was 1.80 micro gram/ml (95% confidence limits: 1.40-2.34 micro gram/ml). The Bispectral Index (PK = 0.86), 95% spectral edge frequency (PK = 0.81), pupillary reflex amplitude (PK = 0.74), and systolic arterial blood pressure (PK = 0.78) did not differ significantly from modeled propofol effect-site concentration (PK = 0.76) in their ability to predict movement.     

Propofol Fails to Attenuate the Cardiovascular Response to Rapid Increases in Desflurane Concentration

Background: A rapid increase in desflurane concentration to greater than 1 MAC transiently increases heart rate, arterial blood pressure, and circulating catecholamine concentration. Because propofol decreases sympathetic outflow, it was hypothesized that propofol would blunt these responses.

Methods: To test this hypothesis, five healthy male volunteers were studied three times. After induction of anesthesia with 2 mg *symbol* kg sup -1 propofol, anesthesia was maintained with 4% end-tidal desflurane in oxygen (0.55 MAC) via an endotracheal tube for 32 min. On separate occasions, in random order, either no propofol or 2 mg *symbol* kg sup -1 propofol was administered either 2 or 5 min before increasing end-tidal desflurane concentration from 4% to 8%.

Results: Without propofol pretreatment, the increase to 8% desflurane transiently increased heart rate (from 63+/-3 beats/min to 108 +/-5 beats/min, mean+/-SEM; P < 0.01), mean arterial pressure (from 73+/-1 mmHg to 118+/-6 mmHg; P < 0.01), and epinephrine concentration (from 14+/-1 pg *symbol* ml sup -1 to 279+/-51 pg *symbol* ml sup -1; P < 0.05). There was no significant change in norepinephrine concentration (from 198+/-37 pg *symbol* ml sup -1 to 277+/-46 pg *symbol* ml sup -1). The peak plasma epinephrine concentration was attenuated by each propofol pretreatment (158+/-35 pg *symbol* ml sup -1, propofol given 2 min before, and 146 + 41 pg *symbol* ml sup -1, propofol given 5 min before; P < 0.05), but neither propofol pretreatment modified the cardiovascular or norepinephrine responses.