Daniel P. Lynam

The pharmacodynamics and pharmacokinetics of vecuronium in patients anesthetized with isoflurane with normal renal function or with renal failure.

The duration of action and the pharmacokinetics of vecuronium were compared in patients with and without renal function. Twenty patients were studied: 12 with renal failure who were to receive kidney transplants from cadaveric donors, and eight with normal renal function. After oral premedication with diazepam, 10 mg, anesthesia was induced with thiopental, 4 mg/kg iv, and maintained with the inhalation of 60% nitrous oxide and 0.9–1.1% isoflurane, end-tidal concentration, in 40% oxygen. The force of thumb adduction in response to supramaximal ulnar nerve stimulation was monitored and recorded. An intravenous bolus of vecuronium, 0.1 mg/kg, was administered after 15 min of a stable end-tidal isoflurane concentration, as measured by mean spectrometry. Venous blood was then sampled at frequent intervals for 4 h following the bolus. Vecuronium concentrations in plasma were quantified by a sensitive and specific gas chromatographic assay. Data were analyzed by nonlinear least squares regression and described by a two-compartment model. The duration of neuromuscular blockade was longer in patients with renal failure than in those with normal renal function. This increased duration may be related to both a decreased plasma clearance duration may be related to both a decreased plasma clearance and a prolonged elimination half-life of vecuronium in the renal failure group.

The Neuromuscular Effects of Desflurane, Alone and Combined with Pancuronium or Succinylcholine in Humans

The neuromuscular effects of desflurane administered alone were studied in ten healthy human volunteers aged 20-27 yr. Also, the dose-response relationships of pancuronium and succinylcholine in surgical patients during anesthesia with desflurane (n = 13) were compared to those during isoflurane anesthesia (n = 14). In the volunteers, we measured the mechanical response of the adductor pollicis muscle to stimulation of the ulnar nerve in a train-of-four (TOF) sequence at 2 Hz and at tetanic frequencies of 50, 100, and 200 Hz, each administered for 5 s. Amplitudes of the first response (T1) in each TOF sequence and the ratios of the fourth TOF response (T4) to the first were similar at 3, 6, and 9% desflurane and decreased significantly only at 12% (P less than 0.05). Desflurane concentrations of 3-12% caused tetanic fade (greater than 10% decrement in amplitude) at 50, 100, and 200 Hz. The addition of N2O and the duration of anesthetic exposure did not alter desfluranes neuromuscular effects. The only neuromuscular variable influenced by CO2 was T1 amplitude, which decreased as arterial CO2 tension (PaCO2) increased. The doses of pancuronium that depressed T1 amplitude by 50% (ED50) were similar during anesthesia with 1.25 MAC desflurane, 10.5 +/- 2.8 micrograms/kg (mean +/- SD) and 1.25 MAC isoflurane, 12.3 +/- 5.0 micrograms/kg. The ED50 doses of succinylcholine were similar during anesthesia with desflurane 132 +/- 76 micrograms/kg and isoflurane 123 +/- 36 micrograms/kg. We conclude that desflurane significantly depresses neuromuscular function and augments the action of pancuronium and succinylcholine to a degree similar to that of isoflurane.

Can early administration of neostigmine, in single or repeated doses, alter the course of neuromuscular recovery from a vecuronium-induced neuromuscular blockade ?

The authors sought to determine whether neostigmine, given at a time when no response to peripheral nerve stimulation could be elicited, hastened recovery from a vecuronium-induced neuromuscular blockade (NMB). The effect of neostigmine (70 micrograms/kg) in antagonizing a profound (no-twitch) vecuronium-induced (0.1 mg/kg) NMB in 40 healthy patients was studied. Patients were randomly assigned to one of four groups specifying the sequence of neostigmine administration. Fifteen minutes after the administration of vecuronium, when there was no detectable twitch response, each patient received either neostigmine (70 micrograms/kg) with glycopyrrolate (15 micrograms/kg) or an equivalent volume of normal saline (placebo). When T1 (the first response in the train-of-four [TOF] sequence) recovered to 10% of control, patients again received either neostigmine with glycopyrrolate in the same doses as before or the placebo. The following variables were measured: times from vecuronium injection until T1 recovered to 10% (t [10]) and 90% (t [90]) of control, and time until the TOF ratio was equal to 75% (t [TOF75]). Mean values of t (90) and t (TOF75) were shorter (54.7-75.2 min and 60.4-79.5 min, respectively) for the three groups who received neostigmine as compared with patients who received two doses of placebo (104.3 and 122.6 min, respectively). There were no differences in the t (90) and t (TOF75) values among the three groups who received neostigmine.(ABSTRACT TRUNCATED AT 250 WORDS)

The Influence of Renal Failure on the Pharmacokinetics and Duration of Action of Pipecuronium Bromide in Patients Anesthetized with Halothane and Nitrous Oxide

The authors determined the pharmacokinetics and duration of action of a bolus dose of pipecuronium bromide (0.07 mg.kg-1) in 40 patients anesthetized with halothane and nitrous oxide. Twenty were patients with normal renal function, undergoing a variety of surgical procedures, and 20 were undergoing cadaver renal transplantation because of end-stage renal disease. Plasma concentrations of pipecuronium were measured for 6 h after administration using a sensitive and specific capillary gas chromatographic assay. Plasma concentration versus time data were analyzed by nonlinear regression and fit to a two-compartment or three-compartment model; in addition, the data were analyzed by a non-compartmental method based on statistical moments. Neuromuscular blockade was assessed by measuring the mechanical evoked response of the adductor pollicis muscle to train-of-four stimulation of the ulnar nerve. The pharmacokinetic parameters derived by compartmental modelling were (normal vs. renal failure, respectively): volume of distribution at steady state (309 +/- 103 vs. 442 +/- 158 ml.kg-1, mean +/- SD), plasma clearance, (2.4 +/- 0.6 vs. 1.6 +/- 0.6 ml.kg-1.min-1), mean residence time (140 +/- 63 vs. 329 +/- 198 min), and elimination half-life (137 +/- 68 vs. 263 +/- 168 min). The same parameters as derived by the non-compartmental method were (normal vs. renal failure, respectively): volume of distribution at steady state (307 +/- 80 vs. 426 +/- 119 ml.kg-1, mean +/- SD), plasma clearance (2.4 +/- 0.6 vs. 1.6 +/- 0.6 ml.kg-1.min-1), mean residence time (134 +/- 41 vs. 323 +/- 228 min), and elimination half-life (118 +/- 35 vs. 247 +/- 168 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Vecuronium in alcoholic liver disease: a pharmacokinetic and pharmacodynamic analysis.

To determine the effect of alcoholic liver disease on the pharmacokinetics and pharmacodynamics of vecuronium, the authors administered vecuronium 0.1 mg ± kg-1 iv to ten surgical patients with alcoholic liver disease and ten healthy surgical patients. All patients were anesthetized with nitrous oxide and isoflurane. We recorded and quantitated the force of thumb adduction in response to supramaximal ulnar nerve stimulation. Plasma concentrations of vecuronium and its 3-desacetyl metabolite were determined by a capillary gas chromatography assay. Only the time to attain 100% twitch ± depression (onset time) was prolonged in liver disease patients (2.8 ± 0.7 min; mean ± SD) as compared to control patients (1.9 ± 0.4 min). The time from vecuronium administration to recovery of twitch tension was unaffected by alcoholic liver disease. The time to the reappearance of twitch response was 32.7 ± 9.7 min in patients with liver disease and 36.8 ± 15.5 min in controls. Plasma concentration-time data were fit to two-compartment model. Vecuronium clearance, steady-state volume of distribution, and elimination half-time were unchanged by alcoholic liver disease. The authors conclude that alcoholic liver disease does not affect the pharmacokinetics or duration of action of vccuronium when an intravenou bolus dose of 0.1 mg ± kg-1 is administered.

The Dose-Response Relationship of Mivacurium Chloride in Humans during Nitrous Oxide-Fentanyl or Nitrous Oxide-Enflurane Anesthesia

The dose-response relationships of mivacurium chloride during N2O/fentanyl or N2O/enflurane anesthesia were compared in 70 patients intraoperatively. Responses were defined in terms of percentage changes in the evoked twitch tension of the adductor pollicis muscle, and dose-response curves were constructed following probit transformation of the responses. End-tidal concentrations of enflurane during the were study were 0.9-1.2%. When compared with the dose-response curve determined during N2O/fentanyl anesthesia the curve determined during N2O/enflurane anesthesia was displaced significantly to the left (P less than 0.05). As a result, the doses of mivacurium that depressed twitch tension by 50% (ED50) and 95% (ED95) were 39 and 67 micrograms/kg, respectively, during N2O/fentanyl anesthesia, and 27 and 52 micrograms/kg during N2O/enflurane anesthesia. Regression lines describing the relationship between the maximum depression of twitch tension (response) and the time interval between the injection of mivacurium and the return of twitch tension to 90% of the control value (duration) were constructed. The response-duration line for N2O/enflurane anesthesia was displaced significantly to the left of the line for N2O/fentanyl (P less than 0.05), indicating that enflurane anesthesia was associated with a prolongation of mivacurium-induced neuromuscular blockade. The neuromuscular blocking effect of mivacurium is both enhanced by and prolonged during N2O/enflurane compared with that during N2O/fentanyl anesthesia.

Clinical neuromuscular pharmacology of doxacurium chloride

Abstract The effective dosages, onset times, and durations of action for doxacurium when administered to either adults or children during various types of anesthetics are discussed. In general children require more doxacurium to achieve and maintain a given degree of neuromuscular blockade than adults. The recovery from a doxacurium-induced neuromuscular blockade following the administration of neostigmine occurs quickly at light levels, but is slightly delayed at deeper levels of neuromuscular blockade. The neuromuscular-blocking profile for doxacurium is not influenced by prior dosing with succinyl-choline. Finally, the anticonvulsant drugs carbamazepine and phenytoin cause a resistance to the production and maintenance of a neuro-muscular blockade by doxacurium.