Effect of cardiopulmonary bypass on the plasma concentrations of fentanyl and alcuronium.

This study was conducted to examine the effect of cardiopulmonary bypass surgery on the total and unbound plasma concentrations of fentanyl and the total plasma concentrations of alcuronium. Total fentanyl concentrations were measured by gas chromatography, the plasma protein binding of fentanyl by ultrafiltration, and alcuronium concentrations by high-performance liquid chromatography. Sixteen patients were studied. On initiation of cardiopulmonary bypass (CPB), there were mean decreases of 58.8 +/- 7.1% and 47 +/- 3.2% for total concentrations of fentanyl in plasma and haemoglobin in blood, respectively. The magnitude of these reductions in individual patients was significantly related (Spearman p = 0.65, P < 0.05). The unbound fraction of fentanyl rose from 0.23 to 0.34 after the start of CPB. The total fentanyl concentration remained relatively stable during bypass until near the end of CPB when the mean total concentration increased, coinciding with rewarming. The size of the increase was related to the body mass index (BMI) of the patient (Spearman p = 0.85, P < 0.01). The estimated elimination half-life of fentanyl using the grouped data was 4.7 h. The total alcuronium concentration in plasma fell by 29% on initiation of CPB and there was no increase on rewarming. The estimated elimination half-life of alcuronium using the grouped data was 234 min. Despite marked declines in the plasma concentrations of both drugs on initiation of CPB, suitable levels of anaesthesia were maintained throughout the procedure.

Alcuronium: a pharmacodynamic and pharmacokinetic update.

Alcuronium may be considered a muscle relaxant of historical rather than clinical significance. However, recent information from the manufacturer revealed its persisting clinical use in 26 countries worldwide. Thus, a pharmacodynamic-pharmacokinetic update appears mandatory. An intravenous (IV) single-bolus injection of alcuronium (0.25 mg/kg = ED95) was administered to 10 patients undergoing maxillofacial surgery during nitrous-oxide opioid anesthesia. Alcuronium neuromuscular block (evoked twitch tension), plasma concentration, and renal elimination (high-performance liquid chromatography [HPLC] assay) were measured during the 12-h after its administration. The time of onset, the time from end of injection to recovery to 25% of control twitch tension (DUR25%), and the recovery index were 2.2 +/- 1.2, 54 +/- 14, and 37 +/- 11 min, respectively (mean +/- SD). Two hours after the injection of alcuronium, partial recovery from the neuromuscular block had occurred from 100% to 26% +/- 24% depression of twitch tension, although less than 25% of the injected dose was recovered from the urine. The 12-h plasma concentration and urinary recovery were 0.1 +/- 0.08 mg/L (one-sixth of the 50% inhibitory concentration) and 61% +/- 20%, respectively. Recovery from neuromuscular block was dominated by intercompartmental distribution rather than by renal elimination. Since alcuronium does not undergo biodegradation, our data may serv as a reference for the complex pharmacokinetics of readily metabolized modern muscle relaxants. The long plasma half-life with slow excretion merits attention with respect to the erroneous original perception that alcuronium was an intermediate-acting muscle relaxant.

Pharmacokinetics of alcuronium in children with acyanotic and cyanotic cardiac disease undergoing cardiopulmonary bypass surgery.

The aim of this study was to determine the pharmacokinetic parameters for alcuronium in children with cyanotic or acyanotic congenital cardiac disease undergoing cardiopulmonary bypass surgery and to compare these parameters with previously reported values in children and adults with normal cardiac function. Seven children with acyanotic disease and seven with cyanotic disease were studied. Alcuronium (base) was administered in an initial dosage of 0.25 mg.kg-1 with additional doses as needed to maintain paralysis. Using time averaged data, cyanotic children had lower mean clearance, elimination half-life and volume of distribution at steady state than the acyanotic children; none of these differences was, however, statistically significant. In this study, children with acyanotic and cyanotic cardiac disease undergoing bypass, had a diminished clearance (P < 0.05) and a smaller volume of distribution (P < 0.05) than normal children and a shorter elimination half-life (P < 0.05) than adults. Onset of cardiopulmonary bypass caused an immediate marked decrease in alcuronium plasma concentrations which remained low in the acyanotic children at the completion of bypass.

Delayed onset of alcuronium effect in children with cyanotic congenital heart disease.

The effect of alcuronium dichloride (0.3 mg/kg) was studied in seven normal children (Group A), nine with acyanotic congenital heart disease (Group B) and eight with cyanotic disease (Group C). The onset of action was recorded using an integrated electromyograph and blood samples taken for later estimation of plasma concentrations of the drug. The mean time (SD) taken to 75% suppression of twitch height was 1.3(0.8), 1.7(1.0) and 3.8(2.8) minutes, respectively, in each of the three groups. This was significantly slower in Group C compared with both other groups (P < 0.05). While six of the Group A patients and seven from Group B reached 95% paralysis within ten minutes, only two of the cyanosed children achieved this level of relaxation. However, if times to 95% relaxation were extrapolated, there was no significant difference between the groups at 4.5(3.9), 5.8(5.7) and 10.9(6.5) minutes respectively. There was a weak but statistically significant relationship between haematocrit and time to 75% blockade. Maximum twitch depression was similar in all three groups with plasma concentrations at this time being 1.6(0.7), 1.8(0.5) and 2.3(1.4) micrograms/ml respectively. Again, there was no statistically significant difference between these values. These results confirm that the clinical onset of relaxation is delayed in children with cyanotic congenital heart disease, possibly because of delayed distribution of alcuronium.

Pharmacokinetics of alcuronium in elderly patients undergoing total hip replacement or aortic reconstructive surgery.

The pharmacokinetic behaviour of alcuronium was studied in three patients undergoing resection of an aortic aneurysm, and in another two patients undergoing total hip replacement (group I). A control group of five elderly patients undergoing relatively minor surgery was included (group II). In group I patients, the values of the pharmacokinetic parameters such as plasma clearance, elimination half-life and the apparent volume of distribution of the drug were found to be comparable to those obtained in normal young patients in previous studies. The group II patients, however, were found to have a prolonged elimination half-life as a result of reduced plasma clearance, possibly an age-related effect. The differences between these two groups of patients may be explained by the differences in the extent of haemorrhage and fluid replacement or changes in blood circulation, or both. However, alcuronium must still be used cautiously in both groups of patients, especially in the light of a recent finding that patients undergoing aortic reconstructive surgery have a high frequency of functional renal failure after operation.

Alcuronium kinetics and plasma concentration-effect relationship.

The kinetics and dynamics of the neuromuscular blocker alcuronium were investigated in 12 surgical patients who received bolus and infusion regimens. In six patients the duration of the infusion was sufficiently long so that a steady-state alcuronium plasma concentration was reached (mean SD, 0.80 +/- 0.23 micrograms/ml). In the remaining six patients a steady state was not reached but the alcuronium concentration at the end of the infusion was 0.91 +/- 0.39 micrograms/ml. Alcuronium kinetic parameters did not differ between the two groups or from those obtained previously after bolus doses. In six patients for whom sufficient alcuronium concentration-time response data were available over the 0 to 100% response range, various mathematic models were used to characterize the concentration-effect relationship. A dynamic model incorporating a separate effect compartment connected to the central compartment was found to be the most appropriate. The (mean +/- SD) rate constant for equilibration of alcuronium concentration and effect was found to be 0.24 +/- 0.11 min-1, whereas the steady-state concentration required to induce 95% paralysis was 0.91 +/- 0.35 micrograms/ml (mean +/- SD).

Alcuronium kinetics in patients undergoing cardiopulmonary bypass surgery.

1 The disposition of alcuronium was investigated in 10 patients undergoing surgery involving cardiopulmonary bypass (CPB) and compared with results from a group of non-cardiac patients studied previously. 2 After intravenous administration of a combined bolus and infusion dosage regimen, plasma concentrations fell in a bi-exponential fashion to a mean value of 0.55 micrograms/ml immediately before the start of extracorporeal circulation. 3 During CPB an apparent steady-state of alcuronium was reached immediately after commencement of CPB, however plasma concentrations were some 50% higher than those noted prior to commencement of CPB and those predicted using previous pharmacokinetic data from normal surgical patients. 4 Once CPB was completed and the alcuronium infusion terminated, post-infusion alcuronium plasma concentrations again appeared to decline bi-exponentially with time. 5 Of the pharmacokinetic parameters which were calculated model-independently, the apparent volume of distribution (Vss) was unchanged (329 vs 313 ml/kg) and the elimination half-life (t1/2,z) (532 vs 199 min) was prolonged and the plasma clearance (CL) (0.8 vs 1.34 ml min-1kg-1) markedly reduced in these patients compared to non-cardiac surgical patients. 6 As a result of these changes in alcuronium concentration during CPB and the diminished elimination of alcuronium following CPB, a closer monitoring of neuromuscular function may be necessary in cardiac patients undergoing CPB.

Caesarean section and placental transfer of alcuronium.

The placental transfer of alcuronium was studied in twelve patients undergoing elective or emergency caesarean section. Umbilical cord vein and maternal plasma was analysed for alcuronium at dose-delivery time intervals ranging from 5 to 10.5 minutes. The mean umbilical vein concentration of the relaxant was 0.41 +/- 0.18 (SD) microgram/ml, and the mean foetal/maternal concentration ratio was 0.26 +/- 0.11. A positive correlation between foetal and maternal concentrations of alcuronium was demonstrated. Although alcuronium appears to cross the placenta rapidly and in reasonably high concentration, no apparent adverse effects on the neonates was evident as judged by measurement of Apgar scores.

Clinical pharmacokinetics of alcuronium chloride in man.

The pharmacokinetic behaviour of alcuronium is described for nineteen patients undergoing anaesthesia for elective surgery. Eleven patients received a single bolus intravenous dose of 0.25 mg/kg, while 8 patients required additional doses of 0.125 mg/kg. A two-compartment open model was found to describe adequately both the single dose and multiple dose data for the majority of patients. No significant differences were found in the model-independent pharmacokinetic parameters between the single and multiple dose studies. Mean values for the pooled data for the half-life (t 1/2 beta), apparent volume of distribution (Vd beta), volume of distribution at steady-state (Vdss), volume of the central compartment (Vc) and plasma clearance (Clp) were 198.75 min, 24.261, 20.891, 8.181 and 90.22 ml/min respectively. Evoked muscle twitch response was monitored in 17 of the patients to assess the degree of relaxant blockade. The bolus dose of alcuronium produced complete block in 9 patients and between 95 and 99% block in the remainder. The time of onset to maximum block ranged from 3 to 30 min with the concurrently measured plasma levels of alcuronium being 0.79 to 2.25 microgram/ml. The time taken following bolus administration to 5% recovery (95% paralysis) was a mean of 42 min and the corresponding mean alcuronium plasma concentration was 0.78 microgram/ml.