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)     

Remifentanil Versus Alfentanil: Comparative Pharmacokinetics and Pharmacodynamics in Healthy Adult Male Volunteers

Background: Remifentanil is an esterase-metabolized opioid with a rapid clearance. The aim of this study was to contrast the pharmacokinetics and pharmacodynamics of remifentanil and alfentanil in healthy, adult male volunteers.

Methods: Ten volunteers received infusions of remifentanil and alfentanil on separate study sessions using a randomized, open-label crossover design. Arterial blood samples were analyzed to determine drug blood concentrations. The electroencephalogram was employed as the measure of drug effect. The pharmacokinetics were characterized using a moment analysis, a nonlinear mixed effects model (NONMEM) population analysis, and context-sensitive half-time computer simulations. After processing the raw electroencephalogram to obtain the spectral edge parameter, the pharmacodynamics were characterized using an effect compartment, inhibitory maximum effect model.

Results: Pharmacokinetically, the two drugs are similar in terms of steady-state distribution volume (VDss), but remifentanil's central clearance (CLc) is substantially greater. The NONMEM analysis population pharmacokinetic parameters for remifentanil include a CLc of 2.9 l *symbol* min sup -1, a VDss of 21.81, and a terminal half-life of 35.1 min. Corresponding NONMEM parameters for alfentanil are 0.36 l *symbol* min sup -1, 34.11, and 94.5 min. Pharmacodynamically, the drugs are similar in terms of the time required for equilibration between blood and the effect-site concentrations, as evidenced by a T12 Ke0 for remifentanil of 1.6 min and 0.96 min for alfentanil. However, remifentanil is 19 times more potent than alfentanil, with an effective concentration for 50% maximal effect of 19.9 ng *symbol* ml sup -1 versus 375.9 ng *symbol* ml sup -1 for alfentanil.     

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.     

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)     

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.     

Closed-loop control of mean arterial blood pressure during surgery with alfentanil: clinical evaluation of a novel model-based predictive controller

BACKGROUND: In contrast to hypnosis, there is no surrogate parameter for analgesia in anesthetized patients. Opioids are titrated to suppress blood pressure response to noxious stimulation. The authors evaluated a novel model predictive controller for closed-loop administration of alfentanil using mean arterial blood pressure and predicted plasma alfentanil concentration (Cp Alf) as input parameters. METHODS: The authors studied 13 healthy patients scheduled to undergo minor lumbar and cervical spine surgery. After induction with propofol, alfentanil, and mivacurium and tracheal intubation, isoflurane was titrated to maintain the Bispectral Index at 55 (+/- 5), and the alfentanil administration was switched from manual to closed-loop control. The controller adjusted the alfentanil infusion rate to maintain the mean arterial blood pressure near the set-point (70 mmHg) while minimizing the Cp Alf toward the set-point plasma alfentanil concentration (Cp Alfref) (100 ng/ml). RESULTS: Two patients were excluded because of loss of arterial pressure signal and protocol violation. The alfentanil infusion was closed-loop controlled for a mean (SD) of 98.9 (1.5)% of presurgery time and 95.5 (4.3)% of surgery time. The mean (SD) end-tidal isoflurane concentrations were 0.78 (0.1) and 0.86 (0.1) vol%, the Cp Alf values were 122 (35) and 181 (58) ng/ml, and the Bispectral Index values were 51 (9) and 52 (4) before surgery and during surgery, respectively. The mean (SD) absolute deviations of mean arterial blood pressure were 7.6 (2.6) and 10.0 (4.2) mmHg (P = 0.262), and the median performance error, median absolute performance error, and wobble were 4.2 (6.2) and 8.8 (9.4)% (P = 0.002), 7.9 (3.8) and 11.8 (6.3)% (P = 0.129), and 14.5 (8.4) and 5.7 (1.2)% (P = 0.002) before surgery and during surgery, respectively. A post hoc simulation showed that the Cp Alfref decreased the predicted Cp Alf compared with mean arterial blood pressure alone. CONCLUSION: The authors' controller has a similar set-point precision as previous hypnotic controllers and provides adequate alfentanil dosing during surgery. It may help to standardize opioid dosing in research and may be a further step toward a multiple input-multiple output controller.     

Alfentanil pharmacokinetics in patients undergoing abdominal aortic surgery

The pharmacokinetics of alfentanil, 300 micrograms.kg-1 IV, were determined in patients undergoing elective abdominal aortic reconstruction. The mean age (+/- SD) of the patients was 64.3 +/- 7.4 yr; their mean weight was 74.7 +/- 13.8 kg. Five patients underwent aneurysm repair and six had aortobifemoral grafting. Serum alfentanil concentrations were measured by gas-liquid chromatography in samples drawn at increasing intervals over a 24-hr period. A three-compartment model was fitted to the concentration versus time data. The volume of the central compartment and the volume of distribution at steady state (Vdss) were 0.44 +/- 0.022 and 0.63 +/- 0.32 L.kg-1, respectively. Total drug clearance was 6.4 = 1.9 ml.min-1.kg-1. The elimination half-time was 3.7 +/- 2.6 hr. Patient age was positively correlated with both Vdss and elimination half-time. There were no significant correlations between the pharmacokinetic variables and the duration of aortic cross-clamping, the duration of surgery, or the rate or total volume of IV fluids infused intraoperatively. In general surgical patients, the elimination half-time of alfentanil has been reported to be 1.2-2.0 hr. Although the elimination half-time of alfentanil was longer in patients undergoing abdominal aortic surgery, alfentanil was eliminated much faster than either fentanyl or sufentanil in this patient population.     

A comparison of enflurane with alfentanil anaesthesia for gynaecological surgery

Forty patients undergoing gynaecological surgery were randomly assigned to receive either alfentanil and thiopentone for induction of anaesthesia, followed by alfentanil-N2O/O2 (60%/40%) for maintenance of anaesthesia, or low-dose fentanyl and thiopentone, followed by enflurane-N2O/O2 (60%/40%). More patients given enflurane developed a tachycardia (P less than 0.03) and 20% decreases in systolic and diastolic blood pressure. Times to recovery were significantly shorter after alfentanil than after enflurane. Plasma concentrations of alfentanil during induction suggested that haemodynamic and catecholamine responses were either less than, or did not differ from, baseline levels when the plasma concentration of the drug exceeded 150 ng ml-1. At extubation and the beginning of spontaneous breathing, the plasma concentration was 278 +/- 129 ng ml-1. Values for pharmacokinetic parameters of alfentanil were as follows: clearance, 5.2 +/- 2.0 ml kg-1 min-1; volume of distribution, 0.63 +/- 0.20 1 kg-1; and elimination half-life, 96.9 +/- 52.5 min. Two patients who had extended surgery had significantly lower plasma clearance of alfentanil and increased half-life. The authors conclude that the alfentanil technique was preferable to maintenance with enflurane.     

Closed-loop Control of Mean Arterial Blood Pressure during Surgery with Alfentanil: Clinical Evaluation of a Novel Model-based Predictive Controller

Background: In contrast to hypnosis, there is no surrogate parameter for analgesia in anesthetized patients. Opioids are titrated to suppress blood pressure response to noxious stimulation. The authors evaluated a novel model predictive controller for closed-loop administration of alfentanil using mean arterial blood pressure and predicted plasma alfentanil concentration (Cp Alf) as input parameters.

Methods: The authors studied 13 healthy patients scheduled to undergo minor lumbar and cervical spine surgery. After induction with propofol, alfentanil, and mivacurium and tracheal intubation, isoflurane was titrated to maintain the Bispectral Index at 55 (+/- 5), and the alfentanil administration was switched from manual to closed-loop control. The controller adjusted the alfentanil infusion rate to maintain the mean arterial blood pressure near the set-point (70 mmHg) while minimizing the Cp Alf toward the set-point plasma alfentanil concentration (Cp Alfref) (100 ng/ml).

Results: Two patients were excluded because of loss of arterial pressure signal and protocol violation. The alfentanil infusion was closed-loop controlled for a mean (SD) of 98.9 (1.5)% of presurgery time and 95.5 (4.3)% of surgery time. The mean (SD) end-tidal isoflurane concentrations were 0.78 (0.1) and 0.86 (0.1) vol%, the Cp Alf values were 122 (35) and 181 (58) ng/ml, and the Bispectral Index values were 51 (9) and 52 (4) before surgery and during surgery, respectively. The mean (SD) absolute deviations of mean arterial blood pressure were 7.6 (2.6) and 10.0 (4.2) mmHg (P = 0.262), and the median performance error, median absolute performance error, and wobble were 4.2 (6.2) and 8.8 (9.4)% (P = 0.002), 7.9 (3.8) and 11.8 (6.3)% (P = 0.129), and 14.5 (8.4) and 5.7 (1.2)% (P = 0.002) before surgery and during surgery, respectively. A post hoc simulation showed that the Cp Alfref decreased the predicted Cp Alf compared with mean arterial blood pressure alone.     

Patient-controlled alfentanil

We have compared the opioid effects of a patient-demand, target-controlled infusion of alfentanil (n = 10), with patient-controlled bolus administration of morphine (n = 10) following major spinal surgery in Chinese patients aged from 11 to 67 years. The same general anaesthesia regimen was used in all patients. One group of patients were given intra-operative morphine analgesia followed by postoperative intravenous morphine patient-controlled analgesia, while the other group received an intra-operative target-controlled infusion of alfentanil. Following surgery, the alfentanil group were given control of a handset and were able to increase the target alfentanil plasma level in 5ng.ml^-1 increments with a 2-min lockout interval. If analgesia was not demanded within a 15-min period, the computer reduced the target concentration by 5ng.ml^-1. All patients had continuous pulse oximetry monitoring and hourly recording of pain, sedation, nausea scores and respiratory rate. Patients receiving alfentanil had the target concentration noted hourly and four blood samples taken during the first 24 h for measurement of plasma alfentanil concentrations by high performance liquid chromatography. The alfentanil infusion system was equally effective as an analgesic technique when compared with morphine patient-controlled analgesia. There were no hypoxaemic episodes (oxygen saturation <94%), no difference in sedation scores and the incidence of nausea (30%) was the same in both groups. There was a significantly (p < 0.001) lower respiratory rate in the alfentanil group compared with patients receiving morphine at, clinically assessed, equianalgesia. The predicted plasma alfentanil concentrations increased rapidly from about 30ng.ml^-1 during the first 4 h to around 100ng.ml^-1 at the end of the 24-h study period. The precision of the target-controlled infusion system was 75.4% and the mean prediction error (bias) 58.1%, suggesting an underestimation of the measured alfentanil concentrations by the alfentanil infusion system in these Chinese patients.     

AN EVALUATION OF THE ACCURACY OF PHARMACOKINETIC DATA FOR THE COMPUTER ASSISTED INFUSION OF ALFENTANIL

The accuracy of using average alfentanil pharmacokinetic datain a computer assisted infusion pump (TIAC) to predict alfentanilplasma concentrations was tested in 35 patients {divided intothree groups) receiving alfentanil and nitrous oxide in oxygenanaesthesia for lower and upper abdominal surgery. By frequentlymeasuring the arterial plasma concentration, it was possibleto determine the average prediction error for individual patientsand for groups of patients. For the groups, there were no significantsystematic over- or underpredictions of the alfentanil plasmaconcentrations (bias). However, there existed a moderate degreeof variability (imprecision) within the groups, caused by deviationsof measured and predicted plasma concentrations in the individualpatients within each group. As a result, prediction errors of22.2-32.5% can be expected with the average pharmacokineticdata used in this study to drive TIAC. It was concluded that,as a result of the moderate degree of imprecision, it is unwiseto rely totally on the absolute values of alfentanil plasmaconcentrations predicted by a computer-regulated infusion pumpsuch as TIAC. However, such devices can be used to attain rapidlya relatively stable plasma concentration that can be adjusted(titrated) to the requirements of an individual patient duringanaesthesia. Overhovenerstr. 12, 6131 B2 Sittard, The Netherlands ^*Department of Anesthesia and Medicine (Clinical Pharmacology),Stanford University Medical Center, Stanford, California 94305,U.S.A. Department of Anesthesiology and Pharmacology, Emory UniversitySchool of Medicine, Atlanta, Georgia 30322, U.S.A.     

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)     

Influence of dexmedetomidine and clonidine on human liver microsomal alfentanil metabolism.

Perioperative administration of the alpha 2 agonist clonidine has been shown to increase plasma alfentanil concentrations; however, the mechanism for this pharmacokinetic drug interaction is unknown. Because alfentanil undergoes extensive hepatic biotransformation, clonidine inhibition of alfentanil metabolism may alter alfentanil disposition. The first purpose of this investigation was to test the hypothesis that clonidine impairs human liver alfentanil metabolism. The new highly selective alpha 2 agonist dexmedetomidine (D-medetomidine) is a substituted imidazole and thus may inhibit hepatic drug biotransformation. The second purpose of this study, therefore, was to assess the effect of D-medetomidine and its levo (L) isomer on alfentanil biotransformation. Human liver microsomal alfentanil metabolism was assessed in vitro using a gas chromatography--mass spectrometry assay. Clonidine, at concentrations as great as 10 microM (far exceeding therapeutic levels), had no significant effect on alfentanil oxidation. In contrast, D-medetomidine and its optical isomer L-medetomidine were potent inhibitors of human liver microsomal alfentanil metabolism. The concentration producing 50% inhibition (IC50) of alfentanil (10 microM) oxidation was 0.7-1.0 and 2.8-4.0 microM for D-medetomidine and L-medetomidine, respectively. Preincubation of D-medetomidine with microsomes did not enhance the inhibition of alfentanil metabolism. These results suggest that the increased alfentanil plasma concentrations and potentiation of alfentanil anesthesia associated with clonidine do not result from clonidine inhibition of alfentanil metabolism. D-medetomidine impairment of alfentanil metabolism, however,if present at therapeutic concentrations, may influence alfentanil disposition.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Derivation and Cross-validation of Pharmacokinetic Parameters for Computer-controlled Infusion of Lidocaine in Pain Therapy

Background: Lidocaine administered intravenously is efficacious in treating neuropathic pain at doses that do not cause sedation or other side effects. Using a computer-controlled infusion pump (CCIP), it is possible to maintain the plasma lidocaine concentration to allow drug equilibration between the plasma and the site of drug effect. Pharmacokinetic parameters were derived for CCIP administration of lidocaine in patients with chronic pain.

Methods: Thirteen patients (mean age 45 yr, mean weight 66 kg) were studied. Eight subjects received a computer-controlled infusion, targeting four increasing lidocaine concentrations (1-7 micro gram *symbol* ml sup -1) for 30 min each, based on published kinetic parameters in which venous samples were obtained infrequently after bolus administration. From the observations in these eight patients, new lidocaine pharmacokinetic parameters were estimated. These were prospectively tested in five additional patients. From the complete data set (13 patients), final structural parameters were estimated using a pooled analysis approach. The interindividual variability was determined with a mixed-effects model, with the structural model parameters fixed at the values obtained from the pooled analysis. Internal cross-validation was used to estimate the residual error in the final pharmacokinetic model.

Results: The lidocaine administration based on the published parameters consistently produced higher concentrations than desired, resulting in acute lidocaine toxicity in most of the first eight patients. The highest measured plasma concentration was 15.3 micro gram *symbol* ml sup -1. The pharmacokinetic parameters estimated from these eight patients differed from the initial estimates and included a central volume one-sixth of the initial estimate. In the subsequent prospective test in five subjects, the new parameters resulted in concentrations evenly distributed around the target concentration. None of the second group of subjects had evidence of acute lidocaine toxicity. The final parameters (+/-population variability expressed as %CV) were estimated as follows: V1 0.101+/-53% 1 *symbol* kg sup -1, V2 0.452 +/-33% l *symbol* kg sup -1, Cl1 0.0215+/-25% l *symbol* kg sup -1 *symbol* min sup -1, and Cl2 0.0589+/-35% l *symbol* kg sup -1 *symbol* min sup -1. The median error measured by internal cross-validation was +1.9%, and the median absolute error was 14%.     

Prädiktivität und Präzision einer „target-controlled infusion” (TCI) von Propofol mit dem System „Disoprifusor TCI®”

In Germany a TCI-system for propofol (Disoprifusor-TCI®) has been commercially available since spring 1997. We investigated the prediction error and precision of this TCI system as part of a multicentre study. Bias, precision, blood concentrations and dosage of propofol were compared with patients receiving propofol via a manually controlled infusion device. Methods: After approval by the local Ethics Committee and written informed consent, 21 patients of ASA-classification I to III scheduled for major abdominal surgery received either a target controlled infusion (group T, Disoprifusor-TCI®) or a manually controlled infusion (group M) of propofol. The propofol plasma concentrations were measured by HPLC. The prediction error for each measurement, the median prediction error (MDPE) or bias, the median absolute prediction error (MDAPE) or precision and the divergence (change of the prediction error over infusion time) were calculated for both groups. Results: For all patients in group T (n?=?12) the bias of the TCI system was 6.7% and the precision 27.5%. For 70% of all measured plasma concentrations the absolute prediction error was ≤?37%. The divergence was ?5.4% per hour. For all patients in group M (n?=?9) the bias was 44.2% and the precision 50%. The mean amount of propofol infused per kilogramm body weight and hour was signifikant higher in T (9.0?±?1.2?mg/kg/h) than in M (6.6?±?1.2?mg/kg/h, p?Conclusions: With a precision of 27.5% the investigated TCI system (Diprifusor-TCI®) showed an acceptable inaccuracy, as for TCI-systems a median prediction error of ±?30% has to be expected due to the inherent variability of pharmacokinetic parameters. Further studies will be necessary to find out whether the investigated TCI system for propofol may offer substantial advantages.     

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 [mu]g/kg intravenous alfentanil was given in 2 min, followed by 25 [mu]g [middle dot] kg-1 [middle dot] h-1 for 58 min (sessions A and B). During session B, a target controlled infusion of propofol (target concentration, 1.5 [mu]g/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.     

Pharmacokinetics and placental transfer of intravenous and epidural alfentanil in parturient women

Alfentanil was administered as a 30 micrograms/kg single intravenous injection to five healthy women scheduled for elective cesarean section (group A). In five pregnant women normal vaginal delivery was supported by epidural analgesia with a 30 micrograms/kg loading dose followed by a 30 micrograms/kg-1/hr-1 infusion of alfentanil (group B). Five healthy nonpregnant women scheduled for minor general surgery received 120 micrograms/kg alfentanil intravenously as a bolus before surgical incision (group C). In groups A and B plasma alfentanil concentrations, alfentanil plasma protein binding, and alpha 1-acid glycoprotein (alpha 1-AGP) concentrations were measured in maternal and umbilical arterial or venous blood samples at delivery. Multiple arterial sampling in groups A and C for measurement of alfentanil plasma concentration decay analysis indicated three-compartmental characteristics in most patients. In the pregnant population terminal half-life (t1/2 beta), volume of distribution at steady state (Vdss), and total plasma clearance (Clp) amounted to 103 +/- 67 min, 541 +/- 155 ml/kg and 6.48 +/- 0.85 ml/kg-1/min-1, respectively (mean +/- SD), and did not differ significantly in nonpregnant patients. In groups A and B the fetal-maternal ratios indicated a concentration gradient for the total plasma alfentanil content (ratio of total alfentanil concentrations in umbilical venous and maternal blood (Uv/M), 0.31 +/- 0.08 and 0.28 +/- 0.06 (mean +/- SD) in groups A and B respectively) with a larger protein binding capacity in maternal plasma (group A, 85 +/- 3%; group B, 90 +/- 1%) (mean +/- SD).(ABSTRACT TRUNCATED AT 250 WORDS)     

The pharmacokinetics of alfentanil (R39209): a new opioid analgesic

The pharmacokinetics of alfentanil (R39209), a new short-acting opioid analgesic, have been studied in eleven patients. Six patients were given 50 micrograms/kg alfentanil and five patients 125 micrograms/kg as an intravenous bolus injection. Plasma concentrations were measured at intervals up to 6 h (50 micrograms/kg) or 8-10 h (125 micrograms/kg), using a specific radioimmunoassay technique. Plasma concentrations declined triexponentially in both groups. The initial elimination of alfentanil from the plasma was very rapid with 90% of the administered dose leaving the plasma within 30 min. The average half-lives for the three phases were similar for both groups. The combined mean (+/- SEM) half-lives for the 11 patients for the rapid and slow distribution phases were short (t 1/2 pi = 1.2 +/- 0.26 min, t 1/2 alpha = 11.6 +/- 1.63 min). The elimination half-life, t 1/2 beta was 94 +/- 5.87 min which is considerably shorter than that of other opioids. The mean (+/- SEM) total body clearance was 6.4 +/- 1.39 ml . kg-1 . min-1 and the volume of distribution (Vd) was 0.86 +/- 0.194 l/kg. The latter is considerably less than reported values for the chemically related drug, fentanyl, and suggests that alfentanil may have a lower tissue binding affinity than fentanyl. The rapid elimination and short duration of clinical action suggests the feasibility of repeated administration of alfentanil and its use by continuous intravenous infusion.     

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.