Gender differences in the pharmacokinetics of propofol in elderly patients during and after continuous infusion.

Differences in the pharmacokinetics of propofol between male and female patients during and after continuous infusion have not been described in detail in patients aged 65 yr and older. To increase our insight into the pharmacokinetics of propofol in this patient population and to obtain pharmacokinetic parameters applicable in target controlled infusion (TCI), the pharmacokinetics of propofol during and after continuous infusion were studied in 31 ASA class 1 and 2 patients, aged 65-91 yr, scheduled for general surgery. Patients received propofol 1.5 mg kg(-1) i.v. in 1 min followed by 7 mg kg(-1) h(-1) until skin closure in the presence of a variable rate infusion of alfentanil during oxygen-air ventilation. On the basis of arterial blood samples that were taken up to 24 h post-infusion, the pharmacokinetics of propofol were evaluated in a two-stage manner. Multiple linear regression analysis was used to explore the effect of age, weight, gender and lean body mass as covariates. Gender significantly affected the pharmacokinetics of propofol. V3, Cl1 and Cl2 were significantly different between male and female patients, weight only affected Cl1. The pharmacokinetic parameters were: V1=4.88 litre, V2=24.50 litre, V3 (litre)=115+147 x gender (gender: male=1, female=2), Cl1 (litre min(-1))=-0.29+0.022 x weight+0.22 x gender, Cl2 (litre min(-1))=2.84-0.65 x gender (male=1, female=2), and Cl3=0.788 litre min(-1).

Target-controlled infusion of alfentanil for postoperative analgesia: contribution of plasma protein binding to intra-patient and inter-patient variability.

We have examined the influence of plasma protein binding on inter-individual and intra-individual variability in the effective postoperative analgesic concentration (EAC) of alfentanil and on the performance of the target-controlled infusion system used. Ten patients received standardized anaesthesia and target-controlled alfentanil for postoperative analgesia. Analgesia was assessed using a visual analogue scale (VAS). Plasma protein binding of alfentanil was assessed at four different times (on arrival in the recovery room, at 21:00 on the day of surgery and at 09:00 and 21:00 on the first postoperative day). Bias and inaccuracy were examined on the day of surgery and on the first postoperative day. Unbound fractions of alfentanil varied from 5 to 15% and varied in time. In general, the unbound fractions on the day of surgery were higher than those on the first postoperative day. Thirty-nine percent of inter-individual variability in the EAC of alfentanil (range 33-140 ng ml-1) at the onset of therapy could be explained by protein binding. At the other observation times, correlations between unbound fraction and EAC were only moderate. Bias on the day of surgery was -19% and 12% on the first postoperative day (ns). Inaccuracy was 23% and 18%, respectively (ns). We conclude that inter-individual variations in plasma protein binding can explain a significant portion of inter-individual variability in the EAC of alfentanil in the early postoperative phase.

Pharmacokinetics of prilocaine after intravenous administration in volunteers: enantioselectivity.

BACKGROUND: Prilocaine exists in two stereoisomeric configurations, the enantiomers S(+)- and R(-)-prilocaine. The drug is clinically used as the racemate. This study examined the pharmacokinetics of the enantiomers after intravenous administration of the racemate. METHODS: Ten healthy male volunteers received 200 mg racemic prilocaine as a 10-min intravenous infusion. Blood samples were collected for 8 h after the start of the infusion. Plasma concentrations were measured by stereoselective high-performance liquid chromatography (HPLC). Unbound fractions of the enantiomers in blank blood samples, spiked with racemic prilocaine, were determined using equilibrium dialysis. RESULTS: The unbound fraction of R(-)-prilocaine (mean +/- SD, 70%+/-8%) was smaller (P < 0.05) than that of S(+)-prilocaine (73%+/-5%). The total plasma clearance of R(-)-prilocaine (2.57+/-0.46 l/min) was larger (P < 0.0001) than that of S(+)-prilocaine (1.91+/-0.30 l/min). The steady-state volume of distribution of R(-)-prilocaine (279+/-94 l) did not differ from that of S(+)-prilocaine (291+/-93 l). The terminal half-life of R(-)-prilocaine (87+/-27 min) was shorter (P < 0.05) than that of S(+)-prilocaine (124+/-64 min), as was the mean residence time of R(-)-prilocaine (108+/-30 min) compared with S(+)-prilocaine (155+/-59 min; P < 0.005). CONCLUSIONS: The pharmacokinetics of prilocaine are enantioselective. The difference in clearance is most likely a result of a difference in intrinsic metabolic clearance. The difference in the pharmacokinetics of the enantiomers of prilocaine does not seem to be clinically relevant.

Recirculatory and compartmental pharmacokinetic modeling of alfentanil in pigs: the influence of cardiac output.

BACKGROUND: Cardiac output (CO) is likely to influence the pharmacokinetics of anesthetic drugs and should be accounted for in pharmacokinetic models. The influence of CO on the pharmacokinetic parameters of alfentanil in pigs was evaluated using compartmental and recirculatory models. METHODS: Twenty-four premedicated pigs were evaluated during halothane (0.6-2%) anesthesia. They were assigned randomly to one of three groups. One group served as control. In the other groups, the baseline CO was decreased or increased by 40% by pharmacologic intervention (propranolol or dobutamine). Boluses of alfentanil (2 mg) and indocyanine green (25 mg) were injected into the right atrium. Blood samples were taken for 150 min from the right atrium and aortic root. Arterial concentration-time curves of indocyanine green and alfentanil were analyzed using compartmental models (two-stage and mixed-effects approach) and a recirculatory model, which can describe lung uptake and early distribution. RESULTS: The CO of individual pigs varied from 1.33 to 6.44 l/min. Three-compartmental modeling showed that CO is a determinant of the central compartment volume (V1, r2 = 0.54), fast peripheral compartment volume (V2, r2 = 0.29), steady state distribution volume (Vss, r2 = 0.29), fast distribution clearance (Cl12, r2 = 0.39), and elimination clearance (Cl10, r2 = 0.51). Recirculatory modeling showed that CO is a determinant of total distribution volume (r2 = 0.48), elimination clearance (r2 = 0.54), and some distribution clearances. The pulmonary distribution volume was independent of CO. CONCLUSIONS: Cardiac output markedly influences the pharmacokinetics of alfentanil in pigs. Therefore, accounting for CO enhances the predictive value of pharmacokinetic models of alfentanil.

Alfentanil as an adjuvant to epidural bupivacaine in the management of postoperative pain after laparotomies: lack of evidence of spinal action.

UNLABELLED: In this double-blind study, we compared the efficacy of epidural versus i.v. administration of alfentanil in combination with small-dose bupivacaine for postoperative pain relief. Thirty-two patients were randomly allocated to one of two study groups. Patients from both groups received an epidural loading dose of 60 mg of bupivacaine (12 mL of 0.5%). Subsequently, patients in the epidural (EPI) group received an infusion (8 mL/h) of 0.125% bupivacaine (10 mg/h) plus alfentanil (0.36 mg/h) and an i.v. infusion (8 mL/h) of NaCl 0.9%. Patients in the i.v. group received an epidural infusion (8 mL/h) of 0.125% bupivacaine (10 mg/h) and an i.v. infusion (8 mL/h) of alfentanil (0.36 mg/h). Infusions were maintained for 24 h. These dose regimens were such that equivalent subanalgesic plasma concentrations of alfentanil were obtained. Patient-controlled analgesia with morphine was available to both groups. Time to onset of postoperative pain and morphine consumption were used as variables to compare the two regimens. Measured plasma concentrations of alfentanil during the postoperative observation period were similar (< 20 ng/mL) in both groups. Median times to onset of postoperative pain (EPI 600 min, i.v. 360 min) and total morphine consumption (EPI 11 mg, i.v. 10 mg) did not differ between the groups (P > 0.2). We conclude that, in combination with epidural bupivacaine 0.125%, an i.v. infusion of alfentanil is equally effective as an epidural infusion of alfentanil if the plasma concentrations are the same. The study did not demonstrate a spinal mechanism of action for alfentanil. IMPLICATIONS: This randomized, double-blind study showed that, when combined with small-dose bupivacaine (0.125%), epidurally administered alfentanil is not more effective than i.v. administered alfentanil for postoperative pain management when the regimens are such that equivalent subanalgesic plasma alfentanil concentrations are obtained. A spinal mechanism of action for alfentanil could therefore not be demonstrated.

Target-controlled infusion of alfentanil for postoperative analgesia: a feasibility study and pharmacodynamic evaluation in the early postoperative period.

We have examined the feasibility of target-controlled infusion of alfentanil (TCIA) and the pharmacodynamics of alfentanil in the early postoperative period. Patients were allocated randomly to one of the three groups to receive balanced anaesthesia with bolus injections of fentanyl (group F), sufentanil (group S) or alfentanil (group A). In the recovery room all patients received the same analgesic regimen, comprising TCIA. To evaluate the efficacy of postoperative analgesia, pain scores were measured on a visual analogue scale (VAS) and patients indicated a need for additional analgesia. EC50, the concentration at which, with a 50% probability, patients reported adequate analgesia, was estimated using logistic regression. Six patients did not complain of pain. The time from the last intraoperative bolus injection of opioid until patients complained of postoperative pain was shorter (P < 0.05) in group A (mean 68 min) than in group F (101 min) and group S (136 min). The time to onset of satisfactory analgesia was comparable in the three groups (median 18 min in group F, 15 min in group S and 14 min in group A). EC50 of alfentanil was determined in 28 patients; mean values were 26 ng ml-1 (group F), 39 ng ml-1 (group S) and 52 ng ml-1 (group A). We conclude that TCIA, under the conditions studied, resulted in a fast onset of adequate analgesia, irrespective of the opioid administered during operation. Also, there was no effect of opioids administered during operation on postoperative pharmacodynamics of alfentanil.

Pharmacokinetics of the enantiomers of mepivacaine after intravenous administration of the racemate in volunteers.

The pharmacokinetics of R(-)-mepivacaine and S(+)-mepivacaine were investigated in 10 healthy volunteers. The volunteers received racemic mepivacaine, hydrochloride (dose 60 mg) via a 10-min intravenous infusion. Blood samples were collected at gradually increasing intervals until 8 h after the start of the infusion. Plasma concentrations of the enantiomers were determined with a stereoselective high-performance liquid chromatographic (HPLC) method. Unbound fractions of the enantiomers were determined using equilibrium dialysis. The unbound fraction of R(-)-mepivacaine (mean +/- SD: 35.6% +/- 4.5%) was larger (P < 0.0001) than that of S(+)-mepivacaine (25.1% +/- 4.6%). The total plasma clearance and steady-state volume of distribution of R(-)-mepivacaine, based on total plasma concentrations (total plasma clearance [CL] = 0.79 +/- 0.12 L/min; volume of distribution at steady state [VSS] = 103 +/- 14 L) as well as on unbound plasma concentrations (plasma clearance of unbound drug [CLu] = 2.24 +/- 0.30 L/min; volume of distribution of unbound drug at steady state [Vuss] = 290 +/- 32 L), were larger (P < 0.0001) than those of S(+)-mepivacaine (CL = 0.35 +/- 0.06 L/min; Vss = 57 +/- 7 L; CLu = 1.43 +/- 0.24 L/ min; Vuss = 232 +/- 30 L). The terminal half-life (t1/2,Z) and mean residence time (MRT) of R(-)-mepivacaine (t1/2,Z = 113 +/- 17 min; MRT = 131 +/- 15 min) were shorter than those of S(+)-mepivacaine (t1/2,Z = 123 +/- 20 min, P < 0.02; MRT = 165 +/- 24 min, P < 0.0001). This study demonstrated a marked difference in the pharmacokinetics of the enantiomers of mepivacaine. The stereoselectivity can be partially explained by a difference in the plasma protein binding of the enantiomers.

Epidural vs. intravenous infusion of alfentanil in the management of postoperative pain following laparotomies.

BACKGROUND: This study was designed to compare the efficacy of epidural vs. intravenous administration of alfentanil for treatment of postoperative pain. METHODS: Twenty patients were randomly allocated to one of the two study groups to receive either an epidural bolus dose (0.75 mg) followed by an epidural infusion (0.36 mg/h) (EPI group) or an intravenous infusion (0.36 mg/h) of alfentanil (IV group) for 24 h. These dose regimens were chosen such that equivalent and subanalgesic plasma concentrations of alfentanil were obtained. PCA-morphine was available to both groups. Morphine consumption, pain scores measured on a Visual Analogue Scale (VAS) and the number of demands were used as variables to evaluate the efficacy of the postoperative analgesic therapy. In addition, plasma concentrations of alfentanil were measured. RESULTS: The mean plasma concentrations of alfentanil were similar and < 20 ng/ml in both groups. Total morphine consumption (EPI: 40 mg, i.v.: 43 mg), pain scores (time when the VAS-score > 3.0: EPI: median 215 min; i.v.: median 215 min) and number of valid demands (EPI: median 25; i.v.: median 34) did not differ between the groups. CONCLUSION: Compared to intravenous infusion of alfentanil epidural infusion resulting in the same plasma concentrations is not more effective in relieving postoperative pain. In view of this observation we were not able to demonstrate a spinal mechanism of alfentanil.

High-performance liquid chromatographic assay of mepivacaine enantiomers in human plasma in the nanogram per milliliter range.

A method enabling quantification of R-(-)- and S-(+)-mepivacaine in human plasma in the low nanogram per milliliter range is described. The procedure involves extraction from plasma with diethyl ether, centrifugation, back-extraction into an acidified aqueous solution, washing with a mixture of pentane and isoamylalcohol, alkalinisation, followed by extraction with a mixture of n-pentane and isoamylalcohol. After evaporation of the organic phase, the residue is redissolved in the mobile phase used for the HPLC analysis, which consists of a 6.8:93.2 (v/v) isopropanol-sodium hydrogenphosphate buffer solution with the pH adjusted to 6.8 using phosphoric acid. The HPLC method has been described previously. Separation of the enantiomers is achieved with an alpha 1-AGP column and the UV detection wavelength is 210 nm. The minimal detectable concentration is ca. 3 ng/ml and the lower limit of quantification is 5 ng/ml for each enantiomer. For both enantiomers r is > 0.9995 over the plasma enantiomeric concentration range of 10.5-1053 ng/ml.

Pharmacodynamic interaction between propofol and alfentanil when given for induction of anesthesia.

BACKGROUND: Propofol and alfentanil often are combined during induction of anesthesia. However, the interaction between these agents during induction has not been studied in detail. The influence of alfentanil on the propofol concentration-effect relationships was studied for loss of eyelash reflex, loss of consciousness, and hemodynamic function in 20 unpremedicated ASA physical status 1 patients aged 20-55 yr. METHODS: Patients were randomly divided into four groups to receive a computer- controlled infusion of alfentanil with target concentrations of 0, 50, 200, or 400 ng/ml (groups A, B, C, and D, respectively). While the target concentration of alfentanil was maintained constant, patients received a computer- controlled infusion of propofol, with an initial target concentration of 0.5-1 microgram/ml, that was increased every 12 min by 0.5-1 microgram/ml. Every 3 min, the eyelash reflex and state of consciousness were tested an an arterial blood sample was taken for blood propofol and plasma alfentanil determination. The propofol-alfentanil concentration-response relationships for loss of eyelash reflex and loss of consciousness were determined by nonlinear regression, and for the percentage of change in systolic blood pressure and heart rate by logistic regression. RESULTS: The patient characteristics did not differ significantly among the four groups. The patients in groups A and B continued to breathe adequately, whereas all patients in groups C and D required assisted ventilation. End-tidal carbon dioxide partial pressure remained less than 46 mmHg in all patients. With plasma alfentanil concentrations increasing from 0 to 500 ng/ml, the EC(50) of propofol decreased from 2.07 to 0.83 microgram/ml for loss of eyelash reflex and from 3.62 to 1.55 microgram/ml for loss of consciousness. With plasma alfentanil concentrations increasing from 0 to 500 ng/ml, the blood propofol concentrations associated with a 10% decrease in systolic blood pressure and heart rate decreased from 1.68 to 0.17 microgram/ml and from 2.36 to 0.04 microgram/ml, respectively. CONCLUSIONS: Alfentanil significantly reduces blood propofol concentrations required for loss of eyelash reflex and loss of consciousness. In addition, alfentanil enhances the depressant effects of propofol on systolic blood pressure and heart rate. Hemodynamic stability, therefore, does not increase in patients receiving propofol in combination with alfentanil compared to those receiving propofol as the sole agent for induction of anesthesia.

Performance of computer-controlled infusion of propofol: an evaluation of five pharmacokinetic parameter sets.

Computer-controlled infusion of propofol is used with increasing frequency for the induction and maintenance of anesthesia. The performance of computer-controlled infusion devices is highly dependent on how well the implemented pharmacokinetic parameter set matches the pharmacokinetics of the patient. This study examined the performance of a computer-controlled infusion device when provided with five different pharmacokinetic parameter sets of propofol in female patients. The infusion rate-time data that had been stored on a disk from 19 female patients who had been given propofol by computer-controlled infusion, using the pharmacokinetic parameter set from Gepts et al. (Anesth Analg 1987;66:1256-63), were entered into a computer simulation program to recalculate predicted propofol concentrations that would have been obtained with four other pharmacokinetic parameter (Shafer et al., Anesthesiology 1988;69:348-56; Kirkpatrick et al., Br J Anesth 1988;60:146-50; Cockshott et al., Br J Anesth 1987;59:941P; Tackley et al., Br J Anesth, 1989;62:46-53) sets of propofol, had these been implemented. The performance error (PE) was determined for each measured blood propofol concentration, on the basis of each of the five pharmacokinetic parameter sets. Then, for each of the five pharmacokinetic parameter sets, the performance in the population was determined by the median absolute performance error (MDAPE), the median performance error (MDPE), the wobble (the median absolute deviation of each PE from the MDPE), and the divergence (the percentage change of the absolute PE with time). The MDPE and MDAPE were compared between the parameter sets by the multisample median test. The initially used pharmacokinetic parameter set from Gepts et al. resulted in a MDPE of 24% and MDAPE of 26%.(ABSTRACT TRUNCATED AT 250 WORDS)

Computer-controlled infusion of alfentanil versus patient-controlled administration of morphine for postoperative analgesia: a double-blind randomized trial.

This study compared the efficacy of computer-controlled infusion of alfentanil (CCiA) with patient-controlled administration of morphine (PCAM) for postoperative analgesia. Twenty patients were randomly allocated to one of the two study groups to receive either an intravenous CCiA or PCAM regimen. Pain scores measured on a visual analog scale (VAS) and the number of valid demands were used as variables to evaluate the efficacy of the postoperative analgesic therapy. In addition, the bias and inaccuracy of the pharmacokinetic data set of alfentanil used in the CCiA program were examined by determining the median performance error (MDPE), and the median absolute performance error (MDAPE). The onset of satisfactory analgesia was faster (P < 0.05) in the CCiA group (median: 20 min) than in the PCAM group (median: 50 min). The total number of demands was lower (21 vs 34, P < 0.05) and the time when the VAS score was > 3.0 was shorter (P < 0.05, 12% of the time) in the CCiA group than in the PCAM group (21% of the time). The MDPE and MDAPE were 8% and 22%, respectively. The maximum alfentanil concentrations associated with pain and the minimum effective analgesic concentrations of alfentanil varied considerably both inter- and intraindividually. In conclusion, compared to a standard intravenous PCAM regimen, a CCiA is faster in onset of analgesia and is as effective in providing postoperative analgesia.

The pharmacodynamic interaction of propofol and alfentanil during lower abdominal surgery in women.

BACKGROUND: Propofol and alfentanil are frequently combined to provide general anesthesia. The purpose of this study was to characterize the pharmacodynamic interaction between propofol and alfentanil for several clinically relevant end points. METHODS: Twenty-one women, aged 20-55 yr, scheduled for lower abdominal surgery, were randomly assigned in a double-blind manner to one of three groups to receive a computer-controlled infusion of propofol with target concentrations of 2, 4, or 6 micrograms/ml. In addition, all patients received computer-controlled infusion of alfentanil (initial target concentration 50 ng/ml). While the target concentration of propofol was maintained constant, the target concentration of alfentanil was varied in steps of 10-50 ng/ml according to the presence or absence of patient responses to perioperative stimuli. Arterial blood samples for alfentanil and propofol determination were taken at clinically relevant stimuli. Alfentanil-propofol interactions for laryngoscopy, intubation, skin incision, the opening of the peritoneum, and awakening were determined by logistic regression over the three groups (n = 21). The alfentanil concentrations associated with a 50% probability (EC50s) of suppression of responses to intraabdominal surgical stimuli, as determined by logistic regression in the individual patients, were related to corresponding mean blood propofol concentrations by nonlinear regression analysis. RESULTS: With blood propofol concentrations increasing from 2 to 10 micrograms/ml, the EC50 of alfentanil decreased from 170 to 25 ng/ml for laryngoscopy, from 280 to 23 ng/ml for intubation, from 259 to 9 ng/ml for the opening of the peritoneum, and from 209 to 16 ng/ml for the intraabdominal surgical stimuli. With plasma alfentanil concentrations increasing from 10 to 150 ng/ml, the EC50 of propofol for the regaining of consciousness decreased from 3.8 to 0.8 microgram/ml. DISCUSSION: We defined the pharmacodynamic interaction between propofol and alfentanil for suppression of responses to perioperative stimuli during lower abdominal surgery. We conclude that propofol reduces alfentanil requirements for all studied clinical end points. In addition, alfentanil decreases propofol concentrations at which patients regain consciousness.

The effect of epidural administration of alfentanil on intra-operative intravenous alfentanil requirements during nitrous oxide-oxygen-alfentanil anaesthesia for lower abdominal surgery.

The effects of epidural administration of alfentanil on the intravenous alfentanil dose requirements and the plasma concentrations required to suppress responses to surgical stimulation during nitrous oxide-oxygen-alfentanil anaesthesia in 20 patients undergoing lower abdominal surgery were studied. Before induction of anaesthesia, patients in one group (E) received an epidural injection of 1 mg alfentanil, followed by an epidural infusion of alfentanil 0.2 mg.h-1 until skin closure, whilst patients in the other group (C, control) received a continuous infusion of sodium chloride via a sham catheter in order to blind the main investigator to the treatment. Anaesthesia was induced and maintained with nitrous oxide (66%) in oxygen and a 'target'-controlled intravenous infusion of alfentanil. During surgery, the 'target' alfentanil concentration was increased or decreased according to patients' responses. The number of responses to surgical stimulation was smaller in patients from group E (median 1, range 0-3) than in patients from group C (median 4, range 1-15; p < 0.005), even though the alfentanil intravenous infusion rates were smaller in group E [mean (SD): 1.6(0.5) micrograms.kg-1 min-1] than in group C [2.9(1.2) micrograms.kg-1 min-1, p < 0.02]. Both the lowest concentrations associated with no response [133(40) ng.ml-1] and the highest concentrations associated with a response [155(65) ng.ml-1] in group E were lower than those in group C [238(100) ng.ml-1, p < 0.01 and 334(163) ng.ml-1, p < 0.05, respectively]. We concluded that epidural administration of alfentanil reduces intravenous alfentanil requirements during nitrous oxide-oxygen-alfentanil anaesthesia for lower abdominal surgery. The results indicate a spinal mechanism of action of epidural alfentanil.

Plasma concentrations of alfentanil following epidural administration.

The plasma concentration-time profile of alfentanil following epidural administration was determined in eight patients undergoing lower abdominal surgery under nitrous oxide (66%)-oxygen (33%)-halothane (0.3%) anaesthesia, supplemented with intravenous sufentanil. Alfentanil (1 mg) was administered epidurally before induction of general anaesthesia. Blood samples for the determination of plasma alfentanil concentrations by capillary gas chromatography were collected at intervals until 12 h after the epidural injection. Peak plasma concentrations [mean (SD)] were 9.7 (2.3)ng.ml-1, and were attained in a median (range) time of 90 (30-120) min. The results suggest that alfentanil is slowly absorbed from the epidural space into the general circulation.

Pharmacokinetics of alfentanil after epidural administration. Investigation of systemic absorption kinetics with a stable isotope method.

BACKGROUND: The effects of epidurally administered alfentanil may be due in part to its uptake into the systemic circulation. Therefore we examined the systemic absorption kinetics after epidural injection of alfentanil. METHODS: Pharmacokinetics were determined using a stable isotope method in ten patients, undergoing lower abdominal surgery under general anesthesia. After epidural injection of 0.68 mg deuterium-labeled alfentanil (alfentanil-d5), 1 mg unlabeled alfentanil was administered over 1 h by an intravenous infusion. Blood samples were collected for 12 h. Concentrations of alfentanil and alfentanil-d5 were measured by a combination of gas chromatography and mass fragmentography. The systemic absorption profiles of alfentanil-d5 were determined by deconvolution of the plasma alfentanil-d5 concentrations with the biexponential unit disposition functions, derived from the intravenous data. In addition, data were analyzed by moment analysis. RESULTS: The mean (+/- SD) steady-state volume of distribution, total plasma clearance, elimination half-life and mean residence time, derived from the unlabeled alfentanil concentration-time data, were 43.2 +/- 19.5 1,418 +/- 129 ml/min, 119 +/- 34 min, and 103 +/- 26 min, respectively. The absorption of alfentanil-d5 was monophasic in most patients. The mean systemic availability and mean absorption time derived from the deconvolution data were 100 +/- 17% and 114 +/- 24 min. The values determined by moment analysis were 107 +/- 18% and 112 +/- 36 min, respectively. CONCLUSIONS: After epidural administration alfentanil is slowly absorbed into the general circulation. Resulting plasma concentrations are very low and do not contribute appreciably to the systemic opioid effect.

Influence of Crohn's disease on the pharmacokinetics and pharmacodynamics of alfentanil.

We have compared the dose requirements, pharmacokinetics and pharmacodynamics of alfentanil in 12 patients with Crohn's disease and 10 control patients undergoing abdominal surgery. Plasma concentrations of alpha 1-acid glycoprotein (AAG) and alfentanil protein binding were also measured. Anaesthesia was induced with alfentanil 100 micrograms kg-1 and thiopentone, and maintained with nitrous oxide in oxygen and alfentanil 25-200 micrograms kg-1 h-1. Arterial blood samples were obtained before and after each change in the alfentanil infusion rate and for 6 h after stopping the infusion. Pharmacokinetic data were derived using non-compartmental methods. Alfentanil concentration-effect data were evaluated by non-linear regression, where effect was either response or no response to surgical stimulation. Mean intraoperative alfentanil requirement was greater in patients with Crohn's disease (2.48 micrograms kg-1 min-1) than in control patients (1.35 micrograms kg-1 min-1) (P < 0.01). Mean elimination half-life, total plasma clearance and steady state distribution volume in patients with Crohn's disease were comparable to those in control patients (80 vs 81 min, 5.7 vs 6.4 ml kg-1 min-1 and 0.70 vs 0.68 litre kg-1, respectively). Mean plasma concentration at which the probability of no response was 50% for the intra-abdominal period of surgery was greater in the Crohn group (359 ng ml-1) than in the control group (199 ng ml-1) (P < 0.02). Plasma AAG concentrations were greater in the Crohn group, but the free fraction of alfentanil was similar in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Computer-controlled infusion of alfentanil for postoperative analgesia. A pharmacokinetic and pharmacodynamic evaluation.

BACKGROUND: Although computer-controlled infusion (CCI) of alfentanil has been shown to be effective intraoperatively, this technique has not been validated for postoperative use. Therefore, the authors examined the efficacy of this technique in providing postoperative pain relief. The study comprised both a validation of published pharmacokinetic data sets and the definition of the minimum effective analgesic concentrations after major orthopedic surgery. METHODS: The bias and inaccuracy of the implemented pharmacokinetic data set were examined, in 20 patients who had undergone major orthopedic surgery, by determination of the median performance error (MDPE) and median absolute performance error (MDAPE). The performance of two other published pharmacokinetic data sets was also examined by simulating the plasma concentrations that would have been predicted, had these data sets been implemented. The minimum effective analgesic concentrations (MEAC) were determined at the following time points: at the onset of pain, at 9:00 PM on the day of surgery, and at 9:00 AM and 9:00 PM on the first postoperative day. RESULTS: Measured plasma concentration-time profiles generally were parallel to the target concentration-time profiles. The MDPE and MDAPE obtained were 12% and 28%, respectively. The MEACs ranged from < 1 to 175 ng/ml and showed substantial interindividual variability. The median MEACs at the four study times were 59, 52, 65, and 43 ng/ml. The MEAC at 9:00 PM on the first postoperative day was significantly lower than those at the other study times (P < 0.05). CONCLUSION: Computer-controlled infusion of alfentanil provides adequate postoperative analgesia. The study demonstrated that pharmacokinetic data sets that are useful for intraoperative CCI of alfentanil are equally valid in the postoperative phase. Although required plasma concentrations of alfentanil are reasonably stable in time, interindividual variations are large, necessitating individual titration.

Pharmacodynamics of alfentanil as a supplement to propofol or nitrous oxide for lower abdominal surgery in female patients.

BACKGROUND: Although propofol and alfentanil are given in combination in clinical practice, the pharmacodynamic interaction between these drugs has not been described. METHODS: The pharmacodynamics of alfentanil when given as a supplement to propofol were studied in 10 ASA physical status 1 female patients (group P) undergoing lower abdominal surgery and compared to the pharmacodynamics of alfentanil when given as a supplement to nitrous oxide (group N, n = 10). Anesthesia was induced by either computer-controlled infusion of propofol and alfentanil at target concentrations of 3 micrograms/ml and 100 ng/ml (group P) or computer-controlled infusion of 400 ng/ml alfentanil as a supplement to nitrous oxide and oxygen (ratio 2:1; group N). The target concentration of alfentanil was varied to patient responses, and the nitrous oxide and propofol concentrations were maintained constant. A sigmoid Emax model was fitted to response/no response data versus plasma alfentanil concentrations at intubation, skin incision, and the opening of the peritoneum in both groups and for the intraabdominal part of surgery in the individual patients. In addition, the speed of recovery in both groups was determined by a deletion-of-p's test. RESULTS: The EC50 (the concentration at which, with a 50% probability, the patients did not respond to the surgical stimuli) of alfentanil during propofol anesthesia was 92 ng/ml for intubation, 55 ng/ml for skin incision, 84 ng/ml for the opening of the peritoneum, and 66 +/- 38 ng/ml (mean +/- SD) for the intraabdominal part of surgery. The corresponding values during nitrous oxide anesthesia were significantly higher: 429 ng/ml for intubation, 101 ng/ml for skin incision, and 206 +/- 65 ng/ml for the intraabdominal part of surgery (P < 0.001). The speed of recovery was similar in both groups. CONCLUSIONS: The alfentanil requirements in ASA physical status 1 female patients undergoing lower abdominal surgery are less when given as a supplement to propofol (4 micrograms/ml) compared to 66% N2O.

Pharmacodynamics of propofol in female patients.

Although the clinical properties of propofol have been studied extensively, the pharmacodynamics have not yet been described fully. We studied the propofol concentration-effect relationships for loss of eyelash reflex, loss of consciousness, and hemodynamic changes in 18 female patients, ASA physical status 1, aged 20-49 yr. Propofol was given by computer-controlled infusion. The initial target concentration of 0.5-1 microgram/ml was increased every 12 min by 0.5-1 microgram/ml until the patients lost consciousness. Every 3 min, loss of eyelash reflex and loss of consciousness were tested and an arterial blood sample was taken for analysis of the blood propofol concentration. The concentration-response relationships for loss of eyelash reflex and loss of consciousness were defined by fitting a sigmoid Emax function (where Emax = the maximum effect that can be reached; i.e., 100% of the patients showing loss of eyelash reflex or loss of consciousness) to the response/no response data versus the propofol concentration, using nonlinear regression. The effect of propofol on hemodynamic parameters was analyzed by linear regression. The propofol concentrations at which 50% and 90% of the patients showed loss of eyelash reflex were 2.07 and 2.78 micrograms/ml, respectively. The corresponding values for loss of consciousness were 3.40 and 4.34 micrograms/ml. The systolic and diastolic blood pressure decreased with increasing blood propofol concentration. The correlation coefficients for the decrease in systolic and diastolic blood pressure versus the blood propofol concentration were r2 = -0.663 and r2 = -0.243, but heart rate did not change. In conclusion, propofol concentrations inducing loss of eyelash reflex are less than those inducing loss of consciousness.