Pharmacokinetics and pharmacodynamics of alfentanil infusions during general anesthesia

The pharmacokinetic and pharmacodynamic properties of alfentanil were studied in 64 surgical patients. Alfentanil was administered as a loading infusion (25-130 micrograms/kg) followed by a maintenance infusion (0.25-1.3 micrograms X kg-1 X min-1) as part of a nitrous oxide-narcotic-muscle relaxant technique. Although alfentanil doses of at least 50 micrograms/kg (in combination with thiopental, 2 mg/kg) were required to prevent hemodynamic changes during intubation, apnea or chest wall rigidity frequently occurred with alfentanil loading infusions exceeding 75 micrograms/kg. The alfentanil clearance rate was significantly lower in patients with liver dysfunction (2.3 +/- 1.3 vs 4.2 +/- 2.0 ml X kg-1 X min-1, mean +/- SD). In addition, the patients who required opioid antagonists to reverse postoperative respiratory depression had lower clearance rates (1.5 +/- 0.7 vs 4.1 +/- 1.9 ml X kg-1 X min-1) and longer elimination half-life values (406 +/- 304 vs 87 +/- 53 min). For maintenance of hemodynamic stability during superficial and intraabdominal operations, alfentanil serum concentration-response curves revealed ED95 values exceeding 300 ng/ml and 400 ng/ml, respectively. Our study also demonstrated a wide range of clinical responses to fixed doses of alfentanil. At equivalent doses, some patients required supplemental anesthetics, whereas others required an opioid antagonist. Careful titration of the alfentanil maintenance infusion is recommended to minimize the possibility of postoperative respiratory depression.     

The enflurane-sparing effect of alfentanil in dogs

Some investigators believe that the dog is less sensitive than are humans to the anesthetic/analgesic actions of opioids. The alfentanil plasma concentration [ALF] vs anesthetic effect relationship has been determined for humans undergoing surgery. This study was designed to determine the [ALF] vs anesthetic relationship for alfentanil in the enflurane-anesthetized dog and thereby to provide data by which the [ALF] vs anesthetic effect relationships in the dog and in humans could be compared. Mongrel dogs (n = 10) were anesthetized with enflurane, and enflurane MAC (EMAC) was determined in each dog. After this, each dog received at least three incremental infusions of alfentanil using infusion rates of 0.625, 1.6, 8, 32, or 80 micrograms.kg-1.min-1. EMAC and [ALF] were determined during each infusion rate. There was a linear increase in [ALF] produced by incremental infusions of alfentanil (r = 0.999). Administration of alfentanil produced a dose-dependent reduction of EMAC up to a maximum of 72.5 +/- 3.7% (mean +/- SEM) at 32 micrograms.kg-1.min-1 ([ALF] = 960 +/- 86 ng/ml); a ceiling effect was evident. The degree of EMAC reduction (69%) produced by an infusion rate of 8 micrograms.kg-1.min-1 ([ALF] = 223 +/- 13 ng/ml) was not statistically different from the EMAC reductions produced by infusion rates of 32 (73% reduction at [ALF] = 960 +/- 86 ng/ml) or 80 micrograms.kg-1.min-1 (70% reduction at [ALF] = 2613 +/- 247 ng/ml) (P greater than 0.05). The relative potency of alfentanil was one-seventh to one-tenth that of fentanyl studied under identical conditions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiovascular effects of and interaction between calcium blocking drugs and anesthetics in chronically instrumented dogs. I. Verapamil and halothane

In order to assess the interaction between halothane and verapamil on the cardiovascular system, mongrel dogs were instrumented so that the following measurements could be made awake and under the influence of the drugs: aortic, left ventricular, and left atrial blood pressures; myocardial segment length shortening; heart rate and rhythm; and coronary, carotid, and renal blood flows. The effect of two infusion doses of verapamil (3 micrograms X kg-1 X min-1 and 6 micrograms X kg-1 X min-1 after 200 micrograms X kg-1 bolus) were examined awake. On a different day in the same dogs, two concentrations of halothane (1.2-low and 2.4-high % end-tidal) and the effect of the two infusion doses of verapamil during low and high halothane were studied. Thirty minutes of either infusion dose of verapamil produced only heart rate and electrocardiographic P-R interval increases in conscious dogs. Halothane produced dose-related decreases in mean aortic pressure, left ventricular maximum rate of tension development (dP/dt), and segment length shortening and increases in heart rate and left atrial pressure. Carotid blood flow was increased by low halothane concentrations and returned to control with high halothane concentrations. There were no significant changes in coronary or renal blood flow produced by halothane. Verapamil infusion during low halothane concentration produced minimal effects. However, both the 3 and 6 micrograms X kg-1 X min-1 verapamil doses further depressed hearts already depressed by the high concentrations of halothane and decreased renal and carotid blood flows.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Dose-independent pharmacokinetics of fentanyl

Fentanyl is used as an analgesic in small doses (1-2 micrograms X kg-1) and as an anesthetic in very large doses (greater than 150 micrograms X kg-1). It has been demonstrated that the effects of fentanyl correlate with its concentrations in plasma. It is important, therefore, to know whether or not the pharmacokinetics of fentanyl vary with dose size in order to predict the plasma concentrations and effects produced by various dosage regiments. The authors studied the pharmacokinetics of fentanyl in dogs. 3H-fentanyl (2.5-640 micrograms X kg-1) was injected intravenously in dogs anesthetized at a stable level with enflurane-O2. Arterial plasma and urine were analyzed for unchanged 3H-fentanyl. Kinetic indices were derived by nonlinear least-squares analysis of log concentration of fentanyl in plasma (ng X ml-1) versus time after a bolus injection. The terminal elimination half-time (t 1/2 beta = 211 min), the apparent volume of distribution (9.5 l X kg-1), the volume of the central compartment (1.14 l X kg-1), and the clearance (37 ml X kg-1 X min-1) of fentanyl were independent of dose over the 6.4-640 micrograms X kg-1 dose range. The distribution volume and distribution half-times were lower for the 2.5 micrograms X kg-1 than for some of the larger doses; this was attributed to differences in experimental conditions. The authors conclude that the pharmacokinetics of fentanyl are dose independent certainly over the 6.4-640 micrograms X kg-1 dose range. There is no evidence of saturation of biotransformation or tissue uptake mechanisms for doses in the range of 2.5 to 640 micrograms X kg-1.     

Cardiovascular effects of and interaction between calcium blocking drugs and anesthetics in chronically instrumented dogs. V. Role of pharmacokinetics and the autonomic nervous system in the interactions between verapamil and inhalational anesthetics

To assess the role of both pharmacokinetics and the autonomic nervous system in the interaction between inhalational anesthetics and verapamil, dogs were chronically instrumented to measure heart rate, PR interval, dP/dt, cardiac output, and aortic blood pressure. In a first group of seven dogs, studied awake and during halothane (1.2%), enflurane (2.5%), and isoflurane anesthesia (1.6%), verapamil was infused for 30 min in doses calculated to obtain similar plasma concentrations (83 +/- 10, 82 +/- 6, 81 +/- 10, and 77 +/- 9 ng.ml-1, respectively). For the latter purpose, the infusion dose was 3 and 2 micrograms.kg-1.min-1 awake and during anesthesia, respectively, preceded by a loading dose of 200, 150, and 100 micrograms.kg-1, awake, during isoflurane, and halothane and enflurane, respectively. In awake dogs, verapamil induced an increase in heart rate (24 +/- 5 bpm) and PR interval (35 +/- 9 msec) and a decrease in mean arterial pressure (-5 +/- 2 mmHg) and dP/dt (-494 +/- 116 mmHg/s). Although plasma concentrations were similar in awake and in anesthetized dogs, the only statistically significant changes induced by verapamil were an increase in heart rate and a decrease in dP/dt during halothane and enflurane, while left atrial pressure increased only with enflurane. In a second group of six dogs, verapamil pharmacokinetics were determined in the presence and absence of a ganglionic blocking drug (chlorisondamine, 2 mg.kg-1 iv). Blockade of ganglionic transmission resulted in a decrease in both initial volume of distribution and total clearance of verapamil--changes similar to those previously reported with inhalational anesthetics.(ABSTRACT TRUNCATED AT 250 WORDS)     

Alfentanil infusion for postoperative pain: a comparison of epidural and intravenous routes

The efficacy of intravenous (iv) and epidural infusions of alfentanil for postoperative pain relief was investigated in 24 patients (ASA physical status 1-2) who were scheduled for abdominal hysterectomy. The patients were allocated randomly to receive either epidural or iv alfentanil. In both groups, a loading dose of 15 micrograms.kg-1 was administered, followed by a constant rate infusion of 18 micrograms.kg-1.h-1 alfentanil for 20 h. Both routes provided similar degrees of analgesia; however, analgesia occurred earlier in the intravenously treated group (P less than 0.03). Mean plasma alfentanil concentrations (Cps) varied between 42 and 82 ng.ml-1 in the iv group and 23 and 68 ng.ml-1 in the epidural group, with higher concentrations in the iv group for the first 60 min only (P less than 0.01). Cps increased with infusion time, suggesting accumulation of alfentanil. After infusion ended, pain recurred at the same time in both groups, whereas the alfentanil Cps still were greater than 45 ng/ml. Postoperative epinephrine concentrations decreased after 60 min of infusion (P less than 0.02), whereas, after 6 h, cortisol levels decreased to preoperative values. Norepinephrine concentrations decreased only slightly. The only clinically meaningful effect on vital signs that occurred was an abrupt reduction of respiratory rate after the iv loading dose. PaCO2 increased to the same extent in both groups during the first 15 min only. The incidence of opioid-related side effects was similar in both groups. These results suggest that the iv and epidural routes were equally effective for providing postoperative pain control and controlling the postoperative response to surgical stress.     

Enhancement by propofol of epinephrine-induced arrhythmias in dogs.

Although propofol is a widely used intravenous anesthetic, its effect on epinephrine-induced arrhythmias remains unknown. This study examined the possible interaction between propofol and epinephrine that might affect the induction of ventricular arrhythmias in dogs. The arrhythmogenic threshold of epinephrine was determined during anesthesia with halothane alone, propofol alone, etomidate alone, or etomidate plus varying doses of propofol. The arrhythmogenic dose and the corresponding plasma concentration of epinephrine during propofol anesthesia (blood propofol concentration 18.0 +/- 0.98 micrograms/ml) were 2.52 +/- 0.43 micrograms.kg-1.min-1 and 23.6 +/- 8.5 ng/ml, respectively. During halothane anesthesia (end-tidal 1.3 MAC), they were 2.66 +/- 0.21 micrograms.kg-1.min-1 and 35.7 +/- 1.9 ng/ml, respectively. During etomidate anesthesia, they were 9.67 +/- 1.06 micrograms.kg-1.min-1 and 205 +/- 27.5 ng/ml, respectively. The dose-effect relationship for propofol was examined during etomidate plus propofol anesthesia. Propofol reduced the arrhythmogenic plasma concentration of epinephrine in a concentration-dependent manner: at blood propofol concentrations of 2.33 +/- 0.46, 5.46 +/- 0.71, and 11.2 +/- 0.81 micrograms/ml, the corresponding plasma epinephrine concentrations were 182.6 +/- 52.5, 89.0 +/- 28.8, and 26.6 +/- 6.9 ng/ml, respectively. These results suggest that propofol enhances epinephrine-induced arrhythmias in a dose-dependent manner in dogs.     

Ventilatory effects of clonidine alone and in the presence of alfentanil, in human volunteers.

Clonidine, an alpha 2-adrenergic agonist, can potentiate opioid-induced analgesia. In a double-blind placebo-controlled study in human volunteers, we sought to determine whether clonidine also potentiates opioid-induced respiratory depression. Hypercapnic ventilatory responses (minute ventilation, mean inspiratory flow rate, and mouth occlusion pressure) were measured in five healthy male volunteers on two separate occasions (with or without clonidine, approximately 3.5 micrograms.kg-1 orally) under the following conditions: baseline, 2 h after clonidine/placebo (alfentanil concentration of 0), and during computer-controlled alfentanil infusions to approximate plasma concentrations of 5, 10, 20, 40, and 80 ng.ml-1. Plasma alfentanil concentrations were measured before and after each rebreathing test, and clonidine concentrations were measured after each rebreathing test. The end-tidal CO2 (PET(CO2)) was measured continuously. Data were analyzed by repeated-measures analysis of variance. The PET(CO2) and measured concentrations of alfentanil were included as covariates, and a compound symmetry error analysis was assumed. Statistical significance was achieved when P less than 0.05. For minute ventilation, mean inspiratory flow rate, and mouth occlusion pressure there was a statistically significant relationship to the covariates of PET(CO2) and plasma alfentanil concentration. Clonidine, when compared to placebo, caused a small but significant depression of mean inspiratory flow rate. There was similarly a small, but statistically insignificant, depression of minute ventilation by clonidine. The mouth occlusion pressure was not affected by clonidine treatment. Clonidine treatment did not potentiate alfentanil-induced respiratory depression. Although the combination of an opioid and an alpha 2-adrenergic agonist may act synergistically for the analgesic response, there is no synergistic effect by this drug combination on respiratory depression.     

Cardiovascular response of a continuous variable rate alfentanil infusion for abdominal aortic surgery

A prospective study was undertaken to determine the cardiovascular response of a continuous alfentanil infusion during abdominal aortic surgery (AAS). Each subject (n = 20) received a beta-blocking drug preoperatively, and was premedicated with oral lorazepam. Anaesthesia was induced with alfentanil 50 micrograms.kg-1 and thiopentone 3 mg.kg-1, and was maintained with a variable rate infusion of alfentanil and 66 per cent nitrous oxide in oxygen. During the infusion, boluses of alfentanil, 7.5 micrograms.kg-1, were administered to maintain heart rate and blood pressure within 20 per cent of awake baseline values. Haemodynamic stability during surgery was achieved with infusion rates varying between 0.5 and 2.5 micrograms.kg-1, which resulted in mean alfentanil serum concentrations ranging from 186 +/- 53 to 315 +/- 98 ng.ml-1. The mean cumulative alfentanil dose was 15.4 +/- 6.2 mg.patient-1 for surgery which lasted an average of 141 +/- 41 min. Throughout surgery, no patient required inhalational anaesthetic agents or vasoactive drugs. Fifteen of the 20 patients had perioperative Holter monitoring. No myocardial ischaemia was detected during the intraoperative period. However, there was a 33 per cent incidence of myocardial ischaemia on the first postoperative day. There were no myocardial infarcts and no deaths. We conclude that in beta-blocked patients undergoing aortic reconstructive surgery, a variable rate alfentanil infusion administered with 66 per cent nitrous oxide provides anaesthesia characterized by good haemodynamic control without the need for supplemental agents or vasoactive drugs.     

The concentration-effect relationship of the respiratory depressant effects of alfentanil and fentanyl

The relative potencies of fentanyl and alfentanil for respiratory depression were determined in eight healthy male volunteers in a double-blinded, randomized study with a cross-over design. The drugs were delivered by computer-driven infusion with logarithmically ascending plasma concentrations until the respiratory rate reached 2/min and/or oxygen saturation decreased below 85% with subjects breathing room air. Ventilation was measured with respiratory inductive plethysmography, indirect calorimetry, and arterial blood gas analysis, and plasma drug concentrations were determined. Pharmacodynamic modeling was performed using a fractional E(max) model for minute volume and respiratory rate and the concentrations producing 50% depression (i.e., apparent 50% effective concentration [EC(50)] values) were determined. Both drugs decreased ventilation in a similar manner, and drug infusions were terminated at mean +/- SD measured plasma concentrations of 254 +/- 88 ng/mL and 5.1 +/- 1.7 ng/mL for alfentanil and fentanyl, respectively. Alfentanil decreased minute volume from baseline by 54% +/- 19% and respiratory rate by 40% +/- 11% with EC(50) values of 234 +/- 57 ng/mL and 195 +/- 101 ng/mL. The respective decreases for fentanyl were 50% +/- 11%, 41% +/- 15%, and the estimated EC(50) values were 6.1 +/- 1.4 ng/mL and 3.5 +/- 1.4 ng/mL, respectively. Using the apparent EC(50) values, the calculated potency ratio for alfentanil:fentanyl was (mean and 95% confidence interval) 1:39 (1:31-1:46) for minute volume and 1:51 (1:34-1:68) for respiratory rate. This is analogous to the analgesic effect studied earlier. The findings support the notion of parallel analgesic and respiratory depressant effects of alfentanil and fentanyl. Therefore equianalgesic concentrations of both drugs will lead to equally pronounced respiratory depression. IMPLICATIONS: This double-blinded, randomized study evaluated the potency ratio of alfentanil and fentanyl-induced respiratory depression. The findings support the notion of parallel analgesic and respiratory depressant effects of alfentanil and fentanyl. Therefore equianalgesic concentrations of both drugs will lead to equally pronounced respiratory depression.     

Pharmacokinetics of alfentanil and clinical responses during cardiac surgery

This study assessed the pharmacokinetic and pharmacodynamic behaviour of alfentanil during and after coronary artery bypass grafting (CABG). Twenty-eight patients with good ventricular function having CABG were divided into three groups and premedicated with morphine 0.1 mg.kg-1 IM, scopolamine 0.005 mg.kg-1 IM and diazepam 0.1 mg.kg-1 PO. Group I patients received an infusion of 250 micrograms.kg-1 of alfentanil over one hour coincidental with a second infusion at 2.5 micrograms.kg-1.min-1 which was continued to the end of surgery. Patients in group II received 300 micrograms.kg-1 and 3.0 micrograms.kg-1.min-1 and patients in group III 350 micrograms.kg-1 and 3.5 micrograms.kg-1.min-1. The tracheas of all patients were intubated after receiving alfentanil 96 micrograms.kg-1 and pancuronium 0.15 micrograms.kg-1. Haemodynamic responses to intubation and surgical stimuli (greater than or equal to 20 per cent increase in heart rate and/or systolic blood pressure from control) were treated with isoflurane, one to two per cent inspired, until abolished. Blood samples were taken during and after surgery for plasma alfentanil concentrations which were determined by radioimmunoassay. After surgery the times to awakening and extubation, and alfentanil elimination half-life (t1/2B = 0.693/-k) were determined for each patient. Haemodynamic responses occurred in 20 patients. There were no significant differences in any variable among the groups. The times to awakening and extubation for all patients were 3.2 +/- 0.6 and 8.8 +/- 1.2 hr (mean +/- SEM) respectively. The elimination half-life for all patients was 5.1 +/- 1.0 hr (mean +/- SEM).(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of the effects of 15 and 60 micrograms/kg fentanyl used for induction of anesthesia in patients with coronary artery disease

We compared the effects of 15 and 60 micrograms/kg fentanyl used for induction in 40 patients, 50-72 yr old, with coronary artery disease and mildly impaired ventricular contractility. Morphine (0.1 mg/kg) and scopolamine (0.4 mg) were used for premedication. Crystalloid (500 ml) was administered before induction, and nitroglycerin (0.3 micrograms X kg-1 X min-1) was infused during the study. Fentanyl, 15 or 60 micrograms/kg, was administered at a rate of 1.2 micrograms X kg-1 X sec-1. Pancuronium (0.04 mg/kg) and metocurine (0.16 mg/kg) were used for muscle relaxation. Data were collected 2 min before induction (baseline), before intubation (3 min), at 6 min, and at 13 min. Responses to 15 and 60 micrograms/kg were similar. At 3 min the heart rate (HR) in patients given 15 micrograms/kg increased by 6; whereas the HR in those given 60 micrograms/kg increased by 14 (P less than 0.01). Subsequent differences in HR were not significant. There were no dose-related differences in mean arterial pressure, cardiac index, central venous pressure, or pulmonary capillary wedge pressure. The EEG showed high-voltage low-frequency activity within 2 min in all patients. Arterial plasma fentanyl concentrations at 3 min averaged 25.9 +/- 3.8 ng/ml with 15 micrograms/kg and 89.9 +/- 15.2 ng/ml with 60 micrograms/kg. At 4 hr, plasma concentrations averaged 0.4 +/- 0.2 ng/ml and 3.6 +/- 0.7 ng/ml, respectively. We conclude that anesthesia for induction and intubation is achieved by the rapid administration of 15 micrograms/kg fentanyl and that 60 micrograms/kg has no substantially different effect on cardiovascular responses.     

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 enflurane sparing effect of sufentanil in dogs

There is a ceiling to the reduction of enflurane MAC by fentanyl in the dog. Sufentanil (SUF), a more potent narcotic, may be more efficacious in reducing enflurane MAC. To test this hypothesis, 25 mongrel dogs were studied in three groups. Group 1 (n = 8) received SUF in progressively increasing infusion rates from 0.005 micrograms . kg-1 . min-1 to a maximum of 1.215 micrograms . kg-1 . min-1. MAC was determined at stable SUF concentrations in plasma [SUF] during each infusion rate. Group 2 (n = 10) received SUF at a dose rate (0.007 micrograms . kg-1 . min-1) designed to produce approximately 35% MAC reduction, and MAC determinations were made at regular intervals over a mean infusion time of 7.6 +/- 0.43 h (mean +/- SEM). Group 3 (n = 7) received 1.215 micrograms . kg-1 . min-1 and were studied as in group 2 over an infusion time of 6.7 +/- 0.42 h. In group 1, the highest infusion rate (1.215 micrograms . kg-1 . min-1) produced [SUF] = 48 ng/ml and reduced MAC by 71 +/- 6%. This was not statistically different from the reduction which occurred at [SUF] = 0.92 ng/ml (57 +/- 7%; infusion rate 0.015 micrograms . kg-1 . min-1; P = 0.21). In group 2, the degree of MAC reduction achieved by stable [SUF] (0.54 +/- 0.08 ng/ml) declined over time (MAC reduction at start = 34 +/- 2% versus 18 +/- 4.0% at the end of the infusion; P = 0.001), suggesting the development of tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of Alfentanil and Fentanyl as Supplements to Induction of Anaesthesia with Thiopentone

In 120 premedicated patients undergoing general surgery, anaesthesia was induced with thiopentone 3 mg kg-1, preceded by alfentanil 4.5, 9.0 or 13.5 micrograms kg-1 or fentanyl 1.5 micrograms kg-1. The largest alfentanil dose attenuated the arterial blood pressure response to laryngoscopy and intubation better than the smaller doses of alfentanil. Changes in frontal muscle electromyogram or plasma cortisol and prolactin levels were not dependent on the adjuvant used. After thiopentone, 30, 7 and 17% of the patients given alfentanil 9.0 and 13.5 micrograms kg-1 and fentanyl 1.5 micrograms kg-1, respectively, reacted to pinching of the lower abdomen. Patients given alfentanil 4.5 micrograms kg-1 did not tolerate the endotracheal tube after recovery from suxamethonium block and their heart rate was increased 12 min after alfentanil administration. We conclude that the antinociceptive effect of alfentanil is distinctly shorter than that of fentanyl. The analgesic potency of alfentanil is between one sixth and one ninth of that of fentanyl.     

The influence of hepatic plasma flow on alfentanil plasma concentration plateaus achieved with an infusion model in humans: measurement of alfentanil hepatic extraction coefficient

In a group of seven patients undergoing intracranial surgery under neurolept anesthesia, an alfentanil infusion was initiated with a loading dose of 235 micrograms/kg over 5 min, followed by a maintenance infusion rate of 1.8 microgram X kg-1 X min-1 in order to obtain a steady state plasma concentration (Css) of 400 ng/ml-1 according to an infusion model. The mean values of Css (446 +/- 209 ng/ml) were close to the predicted ones. Nevertheless, an important intersubject variability in Css values was observed. A positive linear correlation existed between alfentanil steady state clearance and indocyanine green clearance (r = 0.88) and between alfentanil steady state clearance and cardiac index (r = 0.93). In three patients, a catheter was inserted into an hepatic vein to determine the alfentanil hepatic extraction coefficient. Alfentanil plasma clearance did not differ from alfentanil hepatic clearance and alfentanil hepatic extraction coefficient values ranged from 0.32-0.53. We conclude that alfentanil is a drug with an intermediate hepatic extraction coefficient and that alfentanil plasma clearance depends on hepatic plasma flow, which is thus one of the factors accounting for individual variability in plasma concentration plateaus achieved with an infusion model.     

Isoflurane and total oxygen consumption in spontaneously breathing dogs in basal metabolic conditions

To study the metabolic effects of isoflurane, whole body oxygen consumption (VO2) was measured on 7 occasions in 7 dogs under standard conditions. The dogs were trained to lie unrestrained in the lateral position for the measurement of VO2 (STPD) in the unanaesthetized state. Blood gas tensions and pH of arterial blood, heart and respiratory rates, blood pressure, rectal temperature and CO2 production (VCO2) also were determined. The maximum VO2 (ml X kg-1 X min-1) of the alert and the minimum of the drowsy resting states averaged (+/- SE) 6.9 +/- 0.5 and 3.6 +/- 0.3 respectively. The calculated mean basal rate was 4.4 +/- 0.1 and VO2 during natural delta-sleep 2.8 +/- 0.3. With isoflurane and spontaneous ventilation VO2 averaged 4.1 +/- 0.2, 4.0 +/- 0.3 and 3.6 +/- 0.3 at 1, 1.5 and 2 Vol-% (inspired) respectively. During anaesthesia with isoflurane VO2 fluctuates between the calculated basal rate and that of natural sleep.     

Alcohol consumption alters the pharmacodynamics of alfentanil

Two groups of women, ASA physical status 1, undergoing surgery for primary breast cancer, were studied to assess the effect of alcohol intake on alfentanil pharmacodynamics. Patients in group 1 (n = 6) had an average daily consumption of 20-40 g alcohol. Patients in group 2 (n = 8) were life-long abstainers or drank only occasionally (less than 60 g per year). Anesthesia was induced and maintained with 66% N2O in O2 and alfentanil. Alfentanil was administered by a computer-controlled infusion pump. If during surgery the patient exhibited somatic, hemodynamic, or other autonomic signs of inadequate anesthesia (response), the target alfentanil plasma concentration was increased by 50-100 ng/ml. If there was no response during a 15-min period, the target concentration was decreased by 50-100 ng/ml. Arterial blood samples were taken before any change of the target concentration, 4 min after a new predicted target concentration was achieved, and at extubation. Plasma concentrations were determined by capillary gas chromatography. Alfentanil protein binding was measured by equilibrium dialysis. Plasma alfentanil concentration-effect data were analyzed by nonlinear regression, where effect was either response or no response to surgical stimuli. The average total alfentanil requirement was significantly (P less than 0.005) higher in group 1 (3.7 +/- 1.2 micrograms.kg-1.min-1) than in group 2 (1.9 +/- 0.4 micrograms.kg-1.min-1). The average Cp50 (the plasma concentration for which the probability of no response during surgery is 50%) was significantly (P less than 0.001) higher in group 1 (522 +/- 104 ng/ml) than in group 2 (208 +/- 26 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)     

Hemodynamic responses to alfentanil in halothane-anesthetized dogs

Alfentanil is an opioid that has been used both as a sole anesthetic and in conjunction with other inhalation anesthetics. However, its effects on myocardial performance and regional blood flow are not clearly known. Using sonomicrometry and radioactive microsphere techniques, we examined the hemodynamic responses to alfentanil when given as a loading dose (45 micrograms/kg) followed by continuous infusion (3 micrograms X kg-1 X min-1) in dogs anesthetized with halothane. Similar plasma levels of alfentanil were observed after the loading and infusion doses, and both techniques of administration produced a significant reduction in arterial pressure without change in global or regional function of the left ventricle. Although cardiac output and left ventricular end-diastolic pressure remained unchanged, heart rate and systemic vascular resistance decreased significantly after the loading dose and recovered slightly when alfentanil was infused continuously. Despite the systemic hypotension, alfentanil did not alter perfusion to the heart, brain, muscle, and skin; however, blood flow to the renal cortex and the arterial supply to the liver decreased by 25 and 60%, respectively. Reduction in blood flow to the kidneys and the liver suggests that alfentanil should be used with caution when normal function of these organs is in question.