Biomedical subjects
D R Bevan
Publications and source records attributed to D R Bevan.
Reversal of doxacurium and pancuronium neuromuscular blockade with neostigmine in children.
Recovery after doxacurium and pancuronium neuromuscular blockade and their acceleration by neostigmine have not been compared in children. Therefore, 60 paediatric surgical patients aged 2-10 yr (ASA 1-2) were studied. They were randomized to receive doxacurium 30 micrograms.kg-1 or pancuronium 70 micrograms.kg-1 iv during propofol, fentanyl, isoflurane and nitrous oxide anaesthesia. Electromyographic (EMG) responses of the adductor pollicis to train-of-four (TOF) stimulation of the ulnar nerve were recorded every ten seconds using a Datex NMT monitor. Six patients in each relaxant group received neostigmine (0, 5, 10, 20 or 40 micrograms.kg-1) with atropine by random allocation when first twitch height (T1) had recovered to 25% of control. Spontaneous recovery after ten minutes was similar following doxacurium (mean +/- SEM values of 45.0 +/- 3.9 vs 49.5 +/- 10.0% for T1 and 25.2 +/- 3.8 vs 14.8 +/- 3.6% for TOF ratios). Dose-responses to neostigmine were calculated from the log dose vs logit of T1 or TOF ratio after ten minutes. Neostigmine-assisted recovery was not different in the two groups, with ED70 and ED90 doses for T1 of 14.3 +/- 1.8 and 25.7 +/- 2.7 micrograms.kg-1 for doxacurium and 12.5 +/- 1.7 and 25.3 +/- 2.3 micrograms.kg-1 for pancuronium. Time to recovery of TOF ratio to 70% after neostigmine 40 micrograms.kg-1 was 2.3 +/- 1.0 and 4.2 +/- 1.7 min (P = NS) following pancuronium and doxacurium, respectively. Adjusted recovery due to neostigmine alone (spontaneous recovery subtracted from the total) required two to three times higher doses of neostigmine.(ABSTRACT TRUNCATED AT 250 WORDS)
Newer neuromuscular blocking agents.
Four neuromuscular blocking drugs, doxacurium, mivacurium, pipecuronium, and rocuronium have been or are about to be introduced into clinical practice. The purpose of this MiniReview is to describe their pharmacology, to consider their place in clinical anaesthetic practice, and to examine whether the needs of the clinician have been met. Two of the agents (doxacurium, mivacurium) are benzylisoquinolines resembling atracurium and two (pipecuronium, rocuronium) are aminosteroids related to pancuronium and vecuronium. Two (doxacurium, pipecuronium) are long-acting compounds, similar in duration of action to pancuronium, although the need for such a profile is questionable. Rocuronium has an intermediate duration of action and produces its maximum effect within two minutes which is much more rapid than any other non-depolarizing relaxant and this is probably a result of its poor potency. However, the onset of paralysis is not as quick as after succinylcholine. Mivacurium is unique because it is metabolized by plasma cholinesterase which produces a rapid recovery although slower than succinylcholine. All of the new drugs are devoid of serious cardiovascular or other side effects. The anaesthetist is now presented with an armamentarium of safe, nondepolarizing muscle relaxants with varying durations of action. However, the rapid onset and recovery associated with succinylcholine are unique and important in the urgent control of a patient's airway and respiration. The indications for succinylcholine will not disappear and the search for a non-polarizing replacement will continue.
Rocuronium bromide and organ function.
Neuromuscular blocking drugs can be divided into those that are: (i) excreted entirely by the kidney; (ii) predominantly by the kidney but also by the liver; (iii) mainly by the liver but also by the kidney or; (iv) removed by other metabolic pathways. Rocuronium is mainly excreted by the liver and pharmacokinetic and pharmacodynamic studies in humans suggest that its duration of action may be prolonged to a greater extent in patients with hepatic disease than in patients with renal disease. The effect is likely to be modest and not a contra-indication to its use.
Insulin-like growth factor-I and human lung fibroblast-derived insulin-like growth factor-I stimulate the proliferation of human lung carcinoma cells in vitro.
The concentration of insulin-like growth factor I (IGF-I) in tissue taken from human non-small cell lung carcinomas (non-SCLC) is 1.4- to 7-fold higher than in the surrounding normal lung tissue, and thus, IGF-I may be involved in the growth of non-SCLC. We report here that non-SCLC cell lines (A549, A427, SK-LU-1) expressed the IGF-I receptor protein, and IGF-I stimulated the proliferation of low-density plated (2000 cells/cm2 growth area) carcinoma cells by 1.6- to 3-fold above control after a 4-day incubation period under serum-free conditions (A549, A427) or in the presence of 0.25% serum (SK-LU-1). Immunoblot data indicated that IGF-I was not secreted by the lung carcinoma cells; however, IGF-I-like proteins were present in the serum-free medium conditioned by human adult lung fibroblasts (CCD-19Lu). The secretion of the immunoreactive IGF-I-like protein was dependent on the passage level of the fibroblasts. At least one of the IGF-I-like factors promoted the serum-free growth of A549 cells (2-fold increase in cell number over control after 4 days) and stimulated a 3-fold increase in the tyrosine kinase activity of detergent-solubilized IGF-I receptors from A549 cells. Both stimulatory effects were neutralized by an anti-IGF-I antibody, suggesting that the fibroblast-derived factor mediated its activity via the IGF-I receptor. Our data indicate that lung fibroblast-derived IGF-I may stimulate the growth of non-SCLC in vivo.
Edrophonium antagonism of vecuronium at varying degrees of fourth twitch recovery.
The purpose of this study was to determine the optimal dose of edrophonium needed for successful antagonism (train-of-four ratio, or T4/T1 > 0.7) of vecuronium-induced blockade when all four twitches were visible in response to indirect train-of-four (TOF) stimulation. Forty patients, scheduled for elective surgical procedures not exceeding 120 min, received vecuronium, 0.08 mg.kg-1, during thiopentone-N2O-isoflurane anaesthesia. Train-of-four stimulation was applied every 20 sec and the force of contraction of the adductor pollicis muscle was recorded. Increments of vecuronium, 0.015 mg.kg-1, were given as required. At the end of surgery, and provided that neuro-muscular activity had recovered to four visible twitches, edrophonium, 0.1 mg.kg-1, was given. Two minutes later, edrophonium, 0.1 mg.kg-1, was given if T4/T1 did not reach 0.7. After another two minutes, edrophonium, 0.2 mg.kg-1, was given if T4/T1 did not reach 0.7 or more. Finally, if T4/T1 was still < 0.7, a dose of 0.4 mg.kg-1 was given. Seventeen patients (42.5%) required 0.1 mg.kg-1 of edrophonium for successful reversal, sixteen patients (40%) needed a cumulative dose of 0.2 mg.kg-1 and six patients (15%) required 0.4 mg.kg-1. Only one patient received 0.8 mg.kg-1. There was a good correlation between T4/T1 two minutes after the first dose of edrophonium and pre-reversal T4/T1 (r = 0.6; P = 0.00014). All patients with pre-reversal T4/T1 > 0.23 required at most 0.2 mg.kg-1 of edrophonium for successful reversal.(ABSTRACT TRUNCATED AT 250 WORDS)
Canadian Anaesthetists' Society Gold Medal. Dr. Douglas B. Craig.
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Anaesthesia pharmacoeconomics.
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Pharmacodynamic behaviour of rocuronium in the elderly.
This study compared the potency and time course of action of rocuronium (ORG 9426) in elderly and young patients during nitrous oxide-opioid anaesthesia. One hundred ASA physical status I-II patients (60, aged 65-80 yr, and 40, aged 20-45 yr) were studied by measuring the force of contraction of the adductor pollicis in response to train-of-four stimulation of the ulnar nerve. After induction of anaesthesia with thiopentone and maintenance with N2O/O2 and fentanyl, rocuronium 120, 160, 200, or 240 micrograms.kg-1 was administered to determine dose-response curves. When maximum block had been obtained, further rocuronium to a total of 300 micrograms.kg-1 was given. Additional doses of 100 micrograms.kg-1 were administered when the first twitch height (T1) had recovered to 25% control. At the end of surgery neuromuscular blockade was allowed, whenever possible, to recover spontaneously until T1 was 90% of control before administration of neostigmine. There was no difference in the potency of rocuronium in the elderly and the younger patients. The ED50 was 196 +/- 8 (SEE for the mean) in elderly, vs 215 +/- 17 micrograms.kg-1 in young patients (NS). When individual cumulative dose-response curves were constructed, the ED50 was 203 +/- 7 (SEM) and 201 +/- 10 micrograms.kg-1 in the elderly and the young respectively (NS). However, the onset of maximum neuromuscular block was slower in the elderly 3.7 +/- 1.1 (SD) vs 3.1 +/- 0.9 min, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Influence of aging on the pharmacokinetics and pharmacodynamics of doxacurium.
Doxacurium (30 micrograms/kg) pharmacokinetics and pharmacodynamics were evaluated in nine elderly (age range, 70 to 83 years) and nine young (age range, 19 to 39 years) patients under nitrous oxide-isoflurane anesthesia. The force of contraction of the adductor pollicis was monitored and plasma samples were collected for an 8-hour period. In the elderly group, doxacurium elimination half-life was prolonged (119.7 versus 75.9 minutes) and plasma clearance was significantly reduced (1.75 versus 2.54 ml/min/kg) without any change in volume of distribution. Onset (12.9 versus 8.9 minutes) and recovery times (113.4 versus 48.1 minutes) were longer in the elderly group. The equilibrium rate constant to the effect compartment (kco) was decreased in the elderly (0.039 versus 0.051 min-1), whereas the effect compartment concentration at 50% block was similar in both groups (44.7 versus 54.1 ng/ml). An age-related reduction in muscle blood flow may be responsible for the decrease in kco. The pharmacokinetic changes observed in the elderly are consistent with a decreased function in the organs of elimination.
Onset of maximum neuromuscular block following succinylcholine or vecuronium in four age groups.
BACKGROUND: Increasing age appears to be associated with a slower onset of neuromuscular blockade, but such an effect has not been studied with the same doses of the same drugs across pediatric and adult age groups. METHODS: The authors measured the evoked compound action potential of the adductor pollicis muscle in response to 0.1-Hz stimulation of the ulnar nerve, during fentanyl-thiopental-oxygen anesthesia, in 160 patients aged 1-3 yr, 3-10 yr, 20-40 yr, or 60-80 yr. Subparalyzing doses of vecuronium (0.03 mg/kg) or succinylcholine (0.3 mg/kg), or paralyzing doses of vecuronium (0.1 mg/kg) or succinylcholine (1.0 mg/kg), were administered to ten patients in each age group. RESULTS: Onset time, defined as the time from injection to maximum depression of response with a subparalyzing dose or the time from injection to ablation of visible response with a paralyzing dose, varied with age in all groups (P < 0.001). For 0.3 mg/kg succinylcholine, it increased from 49 +/- 6 s in 1-3-yr-old patients, to 104 +/- 9 s in 60-80-yr-old patients (P < 0.00001). For 0.03 mg/kg vecuronium, onset time was 3.6-5.9 times longer than for succinylcholine, increasing from 219 +/- 15 s in 3-10-yr-old patients to 473 +/- 30 s in 60-80-yr-old patients (P < 0.00001 by linear regression). For paralyzing doses, succinylcholine 1.0 mg/kg had an onset time of 58 +/- 7 s and 95 +/- 7 s, in 1-3-yr-old and 60-80-yr-old patients, respectively (P < 0.001). For 0.1 mg/kg vecuronium, onset time varied between 125 +/- 19 s in 1-3-yr-old patients to 295 +/- 31 s in 60-80-yr-old patients (P < 0.00001), and was 2.1-3.3 times longer than 1 mg/kg succinylcholine. CONCLUSIONS: Increasing age is associated with slower onset for both succinylcholine and vecuronium. When equipotent, subparalyzing doses of succinylcholine and vecuronium are compared, onset time is 4.5 times as long with vecuronium.
Prolonged mivacurium-induced neuromuscular block.
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Importance of early blood sampling on vecuronium pharmacokinetic and pharmacodynamic parameters.
The effect of early blood sampling on the description of the vecuronium pharmacokinetic-pharmacodynamic relationship was studied following a bolus injection. Sample collection every 10 sec during the first 2 min showed a high concentration peak at 30 to 40 sec, accounting for an important proportion of the total area under the plasma concentration-time curve (AUC). Neglecting it, using only blood samples drawn at 1 and 2 min (limited sampling), led to a significant overestimation of noncompartmentally derived values of mean residence time, clearance, volume of distribution at steady-state and rate of transfer of vecuronium into the effect compartment. Compartmental pharmacokinetics could not be applied to concentration-time curves constructed with early samples, but limited sampling data were fitted to a 2-compartment model. Derived compartmental pharmacokinetic and pharmacokinetic-pharmacodynamic parameters were similar to those obtained noncompartmentally with complete sampling every 10 sec, because back-extrapolation to time zero contributed to the increase in the AUC. However, compartmental analysis does not provide an accurate description of concentration changes following injection.
Anesthesia and myasthenia gravis.
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Speed of action of various muscle relaxants at the neuromuscular junction binding vs. buffering hypothesis.
The speed of action of several nondepolarizing muscle relaxants (gallamine, rocuronium, D-tubocurarine, atracurium, vecuronium, pancuronium and doxacurium) was tested iontophoretically at the frog cutaneous pectoris neuromuscular junction at various temperatures. If differences in rate of onset and offset are due to different molecular rates of binding (and unbinding), and of resulting conformational changes, they should be strongly temperature dependent. In contrast, if differences are due to differences in buffered diffusion, temperature dependence should be low to moderate. The onset and recovery time constants of inhibition of brief acetylcholine pulses, caused by long pulses of relaxants for all of the muscle relaxants, were inversely related to apparent dissociation constants (KD values), that ranged from 4.56 microM (gallamine) to 0.11 microM (doxacurium). The kinetics showed only modest temperature dependence (Q10 values of 1/time constant of offset were typically < 1.4). Because KD values of all muscle relaxants were even less temperature dependent (Q10 < 1.3), this suggests that the kinetics of inhibition is probably determined by the extent of buffering in the synaptic cleft, and not by binding and unbinding. Diffusion of relaxants from the synaptic cleft is expected to be strongly buffered, because the nerve terminal presents a physical barrier to diffusion, and because of extremely high density of acetylcholine receptors. The density of acetylcholine receptors can be calculated from the time constant of offset and KD values of various relaxants, assuming that buffer diffusion is determining the kinetics of action of muscle relaxants.(ABSTRACT TRUNCATED AT 250 WORDS)
High-performance liquid chromatography-electrochemical detection of vecuronium and its metabolites in human plasma.
A high-performance liquid chromatographic assay coupled with electrochemical detection has been developed for the determination of vecuronium and its three putative deacetylated metabolites in human plasma. A novel solid-phase extraction procedure allowed good recovery of both vecuronium and its metabolites, together with ease and speed of execution. This method was sensitive, reproducible and accurate over the therapeutic range of concentrations of vecuronium and its metabolites, and was applied successfully to a study of the pharmacokinetics of vecuronium in anaesthetized patients.
A visor attachment for the Royal Berkshire Halo: a simplified method of craniofacial fixation.
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