Plasma Alfentanil Concentrations Research Articles

Alfentanil during rapid sequence induction with thiopental 4mg/kg and rocuronium 0.6mg/kg: tracheal intubation conditions.

Opioids have become an integral part of anaesthesia induction. We aimed to determine the dose of alfentanil needed to obtain perfect tracheal intubation conditions during rapid sequence induction with standard doses of thiopental and rocuronium, where laryngoscopy was initiated 55s after commencement of drug administration. The influence of covariates (sex, body weight, age, alfentanil plasma concentration at laryngoscopy) was tested. Eighty-four healthy individuals were randomly assigned to receive one of the seven assessor-blinded alfentanil doses (0, 10, 20, 30, 40, 50 and 60μg/kg) in conjunction with thiopental 4mg/kg and rocuronium 0.6mg/kg. For drug administration, 15s was allowed. Laryngoscopy was initiated 40s after rocuronium and tracheal intubation concluded within 70s after commencement of drug administration. Alfentanil doses associated with 50%, 90% and 95% probability of perfect intubation conditions were determined with logistic regression. Multiple logistic regressions were used to test the influence of covariates. The relationship between alfentanil dose and concentration at laryngoscopy was analysed with linear regression. The effects of covariates on plasma concentrations of alfentanil were tested with multiple linear regressions. Perfect intubation conditions of 95% probability was obtained with 56μg/kg (confidence intervals 44-68). None of the covariates were significant predictors of perfect intubation conditions. Alfentanil plasma concentration correlated with dose and increased with increasing body weight (1.7ng/ml/kg). Perfect intubation conditions during rapid sequence induction can be obtained with clinically relevant doses of alfentanil in most healthy patients anaesthetized with thiopental 4mg/kg and rocuronium 0.6mg/kg.

Pharmacokinetic parameter sets of alfentanil revisited: optimal parameters for use in target controlled infusion and anaesthesia display systems

BackgroundIn open TCI and anaesthesia display systems, the choice of pharmacokinetic (PK) parameter sets of opioids is clinically relevant. Accuracy and bias of the PK models may be affected by administration mode and the co-administered hypnotic drug. We retrospectively evaluated the performance of eight PK parameter sets for alfentanil in two data sets (infusion and bolus application). MethodsWith the dosing history from two studies in orthopaedic patients anaesthetized with propofol or inhalation anaesthetics the alfentanil plasma concentration over time was calculated with eight PK parameter sets. Median absolute performance error (MDAPE), log accuracy, median performance error (MDPE), log bias, Wobble, and Divergence were computed. Mann–Whitney rank test with Bonferroni correction was used for comparison between bolus and infusion data, repeated measures analysis of variance on ranks was used for comparison among parameter sets. ResultsThe parameters by Scott (original and weight adjusted) and Fragen had a MDAPE ≤30% and a median log accuracy <0.15 independent of the administration mode, while MDPE was within ±20% and log bias nearly within ±0.1, respectively. The sets by Maitre and Lemmens were within these limits only in the bolus data. All other parameter sets were outside these limits. ConclusionsIn healthy orthopaedic patients, the PK parameters by Scott and by Maitre were equally valid when alfentanil was given as repeated boluses. When given as infusion, the Maitre parameters were less accurate and subject to a significant bias. We cannot exclude that the difference between bolus and infusion is partially because of the different hypnotics used.

Concurrent Assessment of Hepatic and Intestinal Cytochrome P450 3A Activities Using Deuterated Alfentanil

Alfentanil (ALF) is a validated probe for hepatic, first-pass, and intestinal cytochrome P450 (CYP) 3A activity, using plasma clearances, single-point concentrations, and noninvasive pupil diameter change (miosis). Assessing intravenous (i.v.) and oral drug disposition typically requires separate dosing. This investigation evaluated concurrent administration of oral deuterated and i.v. unlabeled ALF to assess both intestinal and hepatic CYP3A, and compare sequential and simultaneous dosing. ALF disposition was evaluated after strong hepatic and/or intestinal CYP3A induction and inhibition by rifampin, ketoconazole, and grapefruit juice. Using plasma ALF concentrations and area under the curve (AUC), clearance, or single-point concentrations, both simultaneous and sequential dosing provided equivalent results and detected hepatic and intestinal CYP3A induction and inhibition. Miosis better detected CYP3A modulation with sequential vs. simultaneous dosing. These results show that concurrent administration of oral deuterated and i.v. ALF, either sequentially or simultaneously, is an efficient and effective approach to assessing hepatic and intestinal CYP3A activity.

Mu-opioid receptor (A118G) single-nucleotide polymorphism affects alfentanil requirements for extracorporeal shock wave lithotripsy: A pharmacokinetic–pharmacodynamic study

Background There are diverse reports concerning the single-nucleotide polymorphism (SNP) A118G in the gene coding for the mu-opioid receptor. This study assessed pharmacokinetic–pharmacodynamic relationships in patients with acute pain (water-immersed extracorporeal shock wave lithotripsy). Methods Ninety-nine patients (ASA I–II, age 18–70) were assessed in this prospective observational study. Blinding was achieved by determining genotype only after the procedure. I.V. alfentanil was administered by patient-controlled administration (loading dose, 10 µg kg −1 ; continuous infusion, 20 µg kg −1 h −1 ; bolus, 3 µg kg −1 ; lockout time, 1 min); no other analgesic or sedating medication was used. Results The allelic frequency was 15.2% in our population. The G118 SNP (AG/GG) was associated with a 27% increase in plasma alfentanil concentration ( P =0.034), a 54% increase in alfentanil dose ( P =0.009), a 47% increase in dose per kg body weight ( P =0.004), a 55% increase in dose per kg corrected for stimulus intensity ( P =0.002), a 112% increase in the numbers of attempted boluses ( P =0.015), a 79% increase in the numbers of successful boluses ( P =0.013), and a 153% increase in the numbers of failed boluses ( P =0.042). Despite the increased alfentanil self-administration, the G118 SNP was associated with a 52% increase in verbal analogue pain scores over the same period of time ( P =0.047). Conclusions We demonstrated increased opioid requirement for alfentanil in patients with the G118 SNP, who self-administered a higher dose, achieved higher plasma concentration, and yet complained of more severe pain. This observation suggests that G118 SNP impairs the analgesic response to opioids.

Mu-opioid receptor (A118G) single-nucleotide polymorphism affects alfentanil requirements for extracorporeal shock wave lithotripsy: a pharmacokinetic–pharmacodynamic study

There are diverse reports concerning the single-nucleotide polymorphism (SNP) A118G in the gene coding for the mu-opioid receptor. This study assessed pharmacokinetic-pharmacodynamic relationships in patients with acute pain (water-immersed extracorporeal shock wave lithotripsy). Ninety-nine patients (ASA I-II, age 18-70) were assessed in this prospective observational study. Blinding was achieved by determining genotype only after the procedure. I.V. alfentanil was administered by patient-controlled administration (loading dose, 10 microg kg(-1); continuous infusion, 20 microg kg(-1) h(-1); bolus, 3 microg kg(-1); lockout time, 1 min); no other analgesic or sedating medication was used. The allelic frequency was 15.2% in our population. The G118 SNP (AG/GG) was associated with a 27% increase in plasma alfentanil concentration (P=0.034), a 54% increase in alfentanil dose (P=0.009), a 47% increase in dose per kg body weight (P=0.004), a 55% increase in dose per kg corrected for stimulus intensity (P=0.002), a 112% increase in the numbers of attempted boluses (P=0.015), a 79% increase in the numbers of successful boluses (P=0.013), and a 153% increase in the numbers of failed boluses (P=0.042). Despite the increased alfentanil self-administration, the G118 SNP was associated with a 52% increase in verbal analogue pain scores over the same period of time (P=0.047). We demonstrated increased opioid requirement for alfentanil in patients with the G118 SNP, who self-administered a higher dose, achieved higher plasma concentration, and yet complained of more severe pain. This observation suggests that G118 SNP impairs the analgesic response to opioids.

Differential Opioid Action on Sensory and Affective Cerebral Pain Processing

Low doses of morphine, the most commonly used opioid analgesic, have been shown to significantly reduce the affective but not the sensory intensive dimension of pain. This suggests differential dose-response relationships of opioid analgesia on the sensory and affective components of pain. We investigated the effects of different alfentanil plasma concentration levels (0, 19.6+/-2.7, 47.2+/-7.6, and 76.6+/-11.3 ng/ml) on pain-related brain activation achieved by short pulses of gaseous CO(2) delivered to the nasal mucosa, using functional magnetic resonance imaging (fMRI) on a 3.0 T MRI scanner in 16 non-carriers and 9 homozygous carriers of the mu-opioid receptor gene variant OPRM1 118A>G. Increasing opioid concentrations had differential effects in brain regions processing the sensory and affective dimensions of pain. In brain regions associated with the processing of the sensory intensity of pain (primary and secondary somatosensory cortices, posterior insular cortex), activation decreased linearly in relation to alfentanil concentrations, which was significantly less pronounced in OPRM1 118G carriers. In contrast, in brain regions known to process the affective dimension of pain (parahippocampal gyrus, amygdala, anterior insula), pain-related activation disappeared at the lowest alfentanil dose, without genotype differences.

Alfentanil-Induced Miosis as a Surrogate Measure of Alfentanil Pharmacokinetics in Patients with Mild and Moderate Liver Cirrhosis

(i) To evaluate the pupillary response to alfentanil as a surrogate measure of alfentanil pharmacokinetics in cirrhotic patients and to compare the data observed in cirrhotic patients with those found in healthy volunteers (historical control group); and (ii) to compare this test with other liver function tests in cirrhotic patients. Six patients with mild cirrhosis (Child-Pugh grade A) and six patients with moderate cirrhosis (Child-Pugh grade B) were studied after a single 15 microg/kg bolus of alfentanil. Alfentanil plasma concentrations were measured by liquid chromatography-tandem mass spectrometry, and pupillary responses were measured with a Pupilscan II pupillometer. Alfentanil pharmacokinetics (plasma concentration, area under the plasma concentration-time curve from time zero to infinity [AUC(infinity(p))] and from time zero to 2 hours [AUC(2(p))], apparent volume of distribution at steady state, clearance and terminal elimination half-life [t((1/2)(p))]) and miosis pseudo-kinetic parameters [AUC(infinity)((miosis)), AUC(2)((miosis)), t((1/2))((miosis))] were determined using a noncompartmental analysis method. In six patients (three Child-Pugh grade A and three Child-Pugh grade B), antipyrine (measure of liver intrinsic activity) and D-sorbitol (measure of liver blood flow) tests were performed. A significant correlation was found between the alfentanil AUC(infinity(p)) and AUC(infinity)((miosis)) (r = 0.6, p < 0.05) in cirrhotic patients. This correlation was even more significant if AUC determinations were limited to the first 2 hours after alfentanil administration (r = 0.9, p < 0.01). Statistically significant differences in pharmacokinetics and miosis pseudo-kinetic parameters were observed between cirrhotic patients and healthy volunteers from our previous experiment (historical control group). The correlations were significant between alfentanil clearance and antipyrine clearance (n = 6, r = 0.9, p < 0.05), alfentanil clearance and steady-state hepatic blood clearance [CL(H(b))] measured by the D-sorbitol test (n = 6, r = 0.9, p < 0.05). Alfentanil pharmacokinetic parameters were correlated with miosis pseudo-kinetic parameters in cirrhotic patients. There was a significant decrease in pharmacokinetics and miosis pseudo-kinetics in cirrhotic patients compared with volunteers from the historical control group. Alfentanil-induced miosis has the advantage of being noninvasive and can be limited to miosis measurements during the first 2 hours after alfentanil administration in cirrhotic patients. We thus propose to substitute the AUC(2(miosis)) for alfentanil pharmacokinetics in cirrhosis.

Voriconazole, but not terbinafine, markedly reduces alfentanil clearance and prolongs its half-life

Alfentanil is a short-acting synthetic opioid analgesic, which is extensively metabolized, mainly by hepatic cytochrome P450 (CYP) 3A enzymes. Concomitant administration of alfentanil and CYP3A inhibitors may lead to clinically important drug interactions. We investigated the possible interactions between alfentanil and orally administered voriconazole and terbinafine. A randomized crossover study design in 3 phases was used. Twelve healthy volunteers were given 20 microg/kg intravenous alfentanil without pretreatment (control), after oral voriconazole administration (400 mg twice on the first day and 200 mg twice on the second day), or after oral terbinafine administration (250 mg once daily for 3 days). Plasma concentrations of alfentanil were measured for 10 hours, and the pharmacokinetic parameters were calculated by use of noncompartmental methods. Voriconazole decreased the mean plasma clearance of intravenous alfentanil by 85%, from the control value of 4.4+/-2.4 mL.min-1.kg-1 to 0.67+/-0.27 mL.min-1.kg-1 (P<.001), and prolonged its elimination half-life from 1.5+/-0.49 hours to 6.6+/-1.8 hours (P<.001). The area under the alfentanil plasma concentration-time curve was increased by 6-fold by voriconazole (P<.001). Terbinafine had no statistically significant effect on the pharmacokinetics of alfentanil. Alfentanil administration caused nausea in 5 volunteers and vomiting in 2. These side effects all occurred in volunteers in the voriconazole phase. Oral voriconazole, but not terbinafine, markedly inhibited the metabolism of alfentanil. Caution should be exercised when alfentanil is given to patients receiving voriconazole. It is reasonable to assume that patients receiving voriconazole require 70% to 90% less alfentanil for the maintenance of analgesia than patients who are not receiving concomitant CYP3A inhibitors.

Closed-loop Control of Mean Arterial Blood Pressure during Surgery with Alfentanil

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. 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). 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. 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.

Le xénon ne réduit pas les besoins d’opioïdes en chirurgie orthopédique

Is to test the hypothesis that 70% xenon has a relevant opioid sparing effect compared to a minimum alveolar concentration (MAC)-equivalent combination of N(2)O and desflurane. In this randomized, controlled study of 30 patients undergoing major orthopedic surgery, we determined the plasma alfentanil concentration required to suppress response to skin incision in 50% of patients (Cp(50)) anesthetized with xenon (70%) or a combination of N(2)O (70%) and desflurane (2%). A response was defined as movement, pressor response > 15 mmHg, heart rate > 90 beats x min(-1), autonomic reactions or a combination of these. At skin incision, alfentanil was administered at a randomly selected target plasma concentration thereafter the concentration was increased or decreased according to the patient's response. After skin incision, desflurane was adjusted to maintain the bispectral index below 60 and prevent responsiveness in both groups. The Cp(50) (+/- standard error) of alfentanil was 83 +/- 48ng x mL(-1) with xenon and 49 +/- 26 ng x mL(-1) with N(2)O/desflurane (P =0.451). During surgery five xenon and 15 N(2)O/desflurane patients were given desflurane at 1.0 +/- 0.5 volume % and 2.5 +/- 0.7 volume %. The total age adjusted MAC was 0.97 +/- 0.07 and 0.94 +/- 0.07 respectively (P = 0.217). The intraoperative plasma alfentanil concentrations were 95 +/- 80 and 93 +/- 60 ng x mL(-1) respectively (mean +/- SD; P = 0.451). Patients given xenon were slightly more bradycardic, whereas blood pressure was similar. Xenon compared to a MAC-equivalent combination of N(2)O and desflurane does not substantially reduce opioid requirement for orthopedic surgery. A small but clinically irrelevant difference cannot be excluded, however.

Evaluation of First‐Pass Cytochrome P4503A (CYP3A) and P‐Glycoprotein Activities Using Alfentanil and Fexofenadine in Combination

Cytochrome P4503A (CYP3A) and P-glycoprotein (P-gp) are major determinants of oral bioavailability. Development of in vivo probe(s), for both CYP3A and P-gp, which could be administered in combination, is a current goal. Nevertheless, there is considerable overlap in CYP3A and P-gp substrate selectivities; there are few discrete probes. Alfentanil is a selective CYP3A probe but not a P-gp substrate. Fexofenadine is a P-gp probe but not a CYP3A substrate. This investigation tested the hypothesis that alfentanil and fexofenadine could be administered in combination to probe first-pass CYP3A and P-gp activities in humans. Two 3-way crossover studies were conducted in healthy volunteers. In the first protocol, subjects received oral alfentanil alone, fexofenadine alone, or fexofenadine 1 hour after alfentanil. In the second protocol, subjects abstained from citrus and apple products for 5 days and received fexofenadine alone, fexofenadine 1 hour after alfentanil, or alfentanil 4 hours after fexofenadine. An assay using solid-phase extraction and electrospray liquid chromatography/mass spectrometry was developed for the simultaneous quantification of plasma alfentanil and fexofenadine. In both protocols, alfentanil plasma concentrations and area under the concentration versus time curve (AUC) were unaffected by fexofenadine or meal composition. Fexofenadine given 1 hour after alfentanil and followed 1 hour later by a meal containing orange or apple juice had a somewhat lower AUC compared with fexofenadine alone (geometric mean ratio with and without the interacting drug = 0.73, 90% confidence interval [CI] = 0.59-1.04). Fexofenadine given 1 hour after alfentanil and followed 2 hours later by a meal not containing citrus or apple products had an AUC that was unchanged compared with fexofenadine alone (ratio = 0.91, 90% CI = 0.70-1.35). These results show that alfentanil disposition was not affected by fexofenadine. A dosing regimen was identified in which fexofenadine disposition was not affected by alfentanil. The timing and content of meals after fexofenadine had a significant effect on fexofenadine disposition. Alfentanil and fexofenadine in combination appear to be a useful probe for evaluating both first-pass CYP3A and P-gp activities in humans.

Elimination of alfentanil delivered by infusion is not altered by the chronic administration of atorvastatin

Background and objective: Statins are prescribed for patients with hypercholesterolemia. Atorvastatin is metabolized by cytochrome P4503A4 and inhibits P4503A4 activity in vitro. Alfentanil is a potent opioid used in clinical anaesthetic practice and is also metabolized by P4503A4. This study tested the hypothesis that chronic atorvastatin administration inhibits the metabolism of alfentanil. Methods: Sixteen patients undergoing elective surgery were studied as matched pairs. One member of each pair was maintained on standard doses of atorvastatin for at least 4 months. Each patient received an alfentanil bolus (80 μg kg−1) intravenously (i.v.), followed by an alfentanil infusion (0.67 μg kg−1 min−1) for 90 min. Serial plasma alfentanil concentrations were measured using gas chromatography-nitrogen phosphorous detection. Pharmacokinetic parameters were calculated using two-compartment linear modelling. Results: One patient and the corresponding match were excluded from the analysis. The elimination half-life of alfentanil was similar in the control and atorvastatin groups (98.8 ± 12.4 versus 98.3 ± 11.3 min, respectively). The clearance (Cl), volume of distribution at steady-state (Vdss) and area under the curve (AUC) were similar in the two groups (Cl = 0.20 (±0.06) and 0.22 (±0.04) L min−1, Vdss = 0.38 (±0.07) and 0.39 (±0.07) L kg−1, AUC = 0.05 (±0.02) and 0.04 (±0.01) mg min mL−1). Conclusions: Concurrent atorvastatin administration does not alter the pharmacokinetics of alfentanil in patients undergoing elective surgery.

Disposition and miotic effects of oral alfentanil: a potential noninvasive probe for first-pass cytochrome P4503A activity.

Systemic clearance of the opioid alfentanil after intravenous administration is an excellent in vivo probe for hepatic cytochrome P4503A (CYP3A) activity and drug interactions. Alfentanil effect (miosis) is a surrogate for plasma alfentanil concentrations, and alfentanil effect kinetics may be a suitable noninvasive probe for hepatic CYP3A. Oral alfentanil might be a probe for first-pass CYP3A activity; however, it is not used clinically, and oral alfentanil disposition is unknown. This investigation evaluated the disposition and miotic effects of oral alfentanil. Ten healthy volunteers were studied in a dose-escalation fashion, receiving 23, 30, 43, and 75 microg/kg oral alfentanil on different days. Dark-adapted pupil diameter was measured at the time of venous blood sampling. Alfentanil was quantified by liquid chromatography-mass spectrometry. Plasma concentrations of alfentanil and pupil diameter change versus time data were analyzed by noncompartmental modeling. Alfentanil was rapidly absorbed (time to maximum concentration [T(max)], 0.7 +/- 0.5 hour). Mean values for area under the plasma concentration-time curve extrapolated to infinity (AUC( infinity )) (27 +/- 14, 38 +/- 22, 57 +/- 31, and 105 +/- 59 ng x h x mL(-1)) and maximum concentration (16 +/- 8, 23 +/- 16, 31 +/- 18, and 50 +/- 22 ng/mL) were linear with dose, although there was considerable interindividual variability. T(max), elimination half-life (1.0 +/- 0.2 hours), total body clearance after oral administration (20 +/- 18 mL x kg(-1) x min(-1)), and dose-normalized AUC(infinity ) were independent of dose. Dose-dependent alfentanil disposition was mirrored by commensurate changes in clinical effect, although miosis was variable and not detectable in all subjects at the lowest dose. Mean miosis AUC (AUEC) and peak miosis were log-dose linear. Effect half-life (1.3 +/- 0.9 hours) was similar to plasma half-life. Oral alfentanil is rapidly absorbed, exhibits linear and dose-independent kinetics, and undergoes substantial first-pass metabolism. Oral alfentanil may be a suitable probe for first-pass CYP3A activity. Alfentanil effect (miosis) may be an acceptable surrogate for plasma alfentanil concentrations. Oral alfentanil effect may be a noninvasive surrogate for conventional pharmacokinetics. Further studies are warranted to determine whether oral alfentanil and alfentanil effect kinetics may be a suitable noninvasive in vivo probe for first-pass CYP3A activity.

Alfentanil potentiates anaesthetic and electroencephalographic responses to ketamine in the rat

The interactions between μ-opioid and N-methyl- d-aspartate (NMDA) receptors have important implications for clinical pain management. We recently examined the pharmacokinetics of ketamine in rats following i.v. infusion of ketamine (racemate, 50 mg/kg/5 min) and found increased central nervous system distribution of ketamine in the presence of low constant plasma alfentanil concentrations (∼50 ng/ml). We now report on the effects of low plasma alfentanil concentrations on the duration of anaesthetic and electroencephalographic (EEG) responses to i.v. infusion of ketamine. Compared to ketamine alone, alfentanil significantly increased both the duration of anaesthesia (by 130%, P=0.00022) and the processed EEG power (μV 2/s) (by 48%, P=0.0040). The plasma ketamine concentration producing half-maximal EEG effect was significantly reduced (by 60%, P<0.0001) in the presence of alfentanil. The results indicate that low plasma alfentanil concentrations potentiate the anaesthetic and EEG effects produced by ketamine.

Prediction of the haemodynamic response to tracheal intubation: comparison of laser-Doppler skin vasomotor reflex and pulse wave reflex

The laser-Doppler skin vasomotor reflex (SVmR) caused by tetanic stimulation of the ulnar nerve may be a test that can predict the haemodynamic response to tracheal intubation. A decrease in pulse wave amplitude (pulse wave reflex, PWR) may be an alternative index of this response. We compared the abilities of PWR and SVmR to predict the haemodynamic response to tracheal intubation and studied how alfentanil, muscle relaxation, stimulation site and stimulation pattern affected the two reflexes. Anaesthesia was induced and maintained with 2% sevoflurane and 50% nitrous oxide in two groups of 10 ASA status 1 patients. Tetanic stimuli were applied to the flexor muscles of the forearm and the ulnar nerve before and after administration of vecuronium. The change in skin blood flow (laser-Doppler) and pulse wave amplitude (pulse oximetry) after a 5 and 10 s stimulation was measured on the opposite hand. If skin blood flow (laser-Doppler) decreased by more than 10%, a computer-controlled infusion of alfentanil was started and the target plasma concentration was increased in steps until this response was suppressed (< 10%). The trachea was intubated and arterial pressure and heart rate responses were recorded. Plasma alfentanil concentration was measured. When PWR and SVmR were suppressed, the haemodynamic response to tracheal intubation was reduced in 100 and 53% of patients respectively. PWR and SVmR responses decreased with increasing plasma alfentanil concentration. The SVmR response to muscle stimulation was reduced by muscle relaxants. The pulse wave response to both muscle and neural stimulation was reduced by relaxants. The responses to 5 and 10 s stimulations were similar. An absent SVmR does not predict a blunted arterial pressure or heart rate response to tracheal intubation. The PWR may be a better predictor.

Target-Controlled Infusion of Alfentanil and Propofol for Total Abdominal Hysterectomy

Background: Alfentanil has been shown to act synergistically if combined with propofol, with or without nitrous oxide, or if combined with potent inhalation anesthetics. The goal of this study was to determine the dosing rate and target plasma concentration of propofol to supplement nitrous oxide in the presence of varying concentrations of alfentanil and to determine the optimal combination of propofol and alfentanil. Methods: Sixty patients undergoing a total abdominal hysterectomy (TAH) were anesthetized with nitrous oxide, and given a target-controlled infusion (TCI) of alfentanil [target plasma concentrations of 0 (A0 group), 50 ng/ml (A50 group), and 100 ng/ml (A100 group)], and propofol at rates varied up and down depending on the bispectal index (BIS). The mean target concentration (Tc) and infusion rate of propofol according to changes of concentrations of alfentanil were determined. Recovery time (from infusion stop to eye opening) and side effects were compared. Results: Induction time and recovery time were shortened in the A50 group and A100 group compared with the A0 group (P 0.05). The infusion rate and mean target concentration of propofol were significantly lower in the A100 group (7.5 mg/kg/h, 3.4g/ml) than the A0 (12.6 mg/kg/h, 4.5g/ml) and A50 (10.2 mg/kg/h, 4.0g/ml) groups (P 0.01). Side effects did not differ among the three groups. Conclusions: The optimal blood propofol and plasma alfentanil concentration, with respect to satisfactory intraoperative anesthetic conditions and speed of recovery, are 4.0g/ml and 50 ng/ml or 3.4g/ ml and 100 ng/ml in TAH patients.

Concurrent ketamine and alfentanil administration: pharmacokinetic considerations

A ketamine-alfentanil combination has been suggested for total i.v. anaesthesia. We determined the pharmacokinetics of ketamine and alfentanil, alone and together, in three groups of adult male rats, to assess any pharmacokinetic interaction. Group 1 animals were infused with i.v. ketamine for 5 min; in group 2, constant low plasma concentrations of alfentanil were maintained by computer-controlled infusion; in group 3, the treatments were combined. Serial plasma and terminal tissue concentrations were measured by high performance liquid chromatography or gas chromatography-mass spectrometry. In the presence of alfentanil, the mean plasma ketamine concentration-time area under the curve (AUC) value was significantly lower (by 13%, P<0.05), while clearance (CIT) and volume of distribution (Vss) were significantly higher (by 16 and 28%, respectively, both P<0.05). Tissue:plasma distribution coefficients for ketamine in the presence of alfentanil were significantly higher in forebrain (by 128%, P<0.005), hindbrain (by 207%, P<0.01), gut (by 254%, P<0.005), and fat (by 344%, P<0.0001). Mean AUC values for alfentanil did not differ significantly in the presence of ketamine, but alfentanil tissue concentrations were significantly lower in forebrain (by 77%, P<0.0001), hindbrain (by 28%, P<0.01), heart (by 33%, P<0.01), lung (30%, P<0.05), and gut (by 21%, P<0.05). Corresponding tissue:plasma distribution coefficients were significantly lower for forebrain (by 69%, P<0.0001) alone. The finding that the distribution of ketamine into the brain was increased by low plasma concentrations of alfentanil could have important clinical applications for pain management.

A pilot evaluation of alfentanil‐induced miosis as a noninvasive probe for hepatic cytochrome P450 3A4 (CYP3A4) activity in humans

ObjectiveThe opioid alfentanil is a CYP3A4 substrate whose plasma clearance depends exclusively on hepatic CYP3A4 activity. Alfentanil clearance is an excellent in vivo probe for hepatic CYP3A4 activity and drug interactions in humans. However, such pharmacokinetic studies are invasive and time‐consuming, and they require extensive analytical effort. This investigation tested the hypothesis that alfentanil‐induced miosis (drug effect) can be used as a surrogate measure for alfentanil plasma concentrations and that alfentanil effect clearance will reflect plasma clearance; thus alfentanil can serve as a noninvasive probe for hepatic CYP3A4.MethodsSix healthy volunteers were studied in a 3‐way randomized crossover design. Each volunteer received 1 mg intravenous midazolam, followed 1 hour later by 15 μg/kg intravenous alfentanil, after CYP3A4 induction (rifampin [INN, rifampicin]), CYP3A4 inhibition (troleandomycin), and control. Dark‐adapted pupil diameter and dynamic light response were measured coincident with venous blood sampling for up to 8 hours. Midazolam and alfentanil were quantified by gas chromatography‐mass spectrometry. Plasma concentrations of alfentanil and midazolam (an additional CYP3A4 probe) and pupil diameter versus time data were analyzed by use of noncompartmental modeling. Pupil diameter change was analyzed analogously to determine the area under the alfentanil effect (miosis)‐time curve (AUEC), effect clearance (CLmiosis), and effect half‐time.ResultsCompared with control, CYP3A4 induction and inhibition significantly altered the clearances of alfentanil (2.8 ±1.4, 5.3 ±1.0, and 0.42 ±0.1 ml/kg/min, respectively;P &lt; .05 versus control) and midazolam. Dark‐adapted resting diameter (in millimeters) was the best measure of alfentanil pupil effects. Alfentanil‐dependent miosis was significantly altered by CYP3A4 modulation, and log(diameter0 — diametert) versus time curves resembled alfentanil plasma disposition. AUEC∞ values after control, CYP3A4 induction, and inhibition were 280 ±150, 120 ±22, and 1030 ±240 mm · min, respectively (P &lt; .05 versus control). Effect clearances (CLmiosis) were 4.2 ±1.3, 8.8 ±2.4, and 1.2 ±0.8 μg/mm · min, respectively, and effect half‐times were 62 ±23, 34 ±27, and 211 ±35 minutes, respectively (P &lt; .05 versus control). CLmiosis was significantly correlated with plasma clearances of alfentanil (r = 0.77, P &lt; .001) and midazolam (r = 0.80; P &lt; .001).ConclusionsAlfentanil effect (miosis) may be a sensitive and reliable surrogate for plasma alfentanil concentrations. Alfentanil effect kinetics may be used as a noninvasive surrogate for conventional pharmacokinetics. CLmiosis appears to be a suitable noninvasive in vivo probe for hepatic CYP3A4 activity, and it merits further investigation.Clinical Pharmacology &amp; Therapeutics (2001) 70, 505–517; doi: 10.1016/S0009‐9236(01)23711‐4

This Month in ANESTHESIOLOGY

This Month in ANESTHESIOLOGY

Alfentanil as an Adjuvant to Epidural Bupivacaine in the Management of Postoperative Pain After Laparotomies

In this double-blind study, we compared the efficacy of epidural versus IV 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 IV infusion (8 mL/h) of NaCl 0.9%. Patients in the IV group received an epidural infusion (8 mL/h) of 0.125% bupivacaine (10 mg/h) and an IV 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, IV 360 min) and total morphine consumption (EPI 11 mg, IV 10 mg) did not differ between the groups (P > 0.2). We conclude that, in combination with epidural bupivacaine 0.125%, an IV 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 IV 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. (Anesth Analg 1998;86:574-8)