Continuous infusions of atracurium and vecuronium,compared with intermittent boluses of pancuronium: dose requirements and reversal

This study was designed to determine the effect of prolonged infusion on the ease of reversal of atracurium and vecuronium, and whether factors which potentiate the block delayed reversal. In phase one, 40 patients were randomized (double blind) to determine the steady state conditions for atracurium and vecuronium. Fourteen atracurium patients and 17 vecuronium patients were evaluable. The unblinded second phase involved the steady state conditions using halothane or isoflurane and atracurium infusions. The infusion required for 95% twitch depression (TD95) for atracurium was 7.6 +/- 1.1 micrograms.kg-1 x min-1. The requirement for vecuronium changes with time: TD95 at 30 min was 1.01 +/- 0.16, at 60 min 0.89 +/- 0.12 and after 90 min 0.85 +/- 0.17 micrograms.kg-1 x min-1 (P < 0.05). The mean TD95 was 0.94 +/- 0.23 micrograms.kg-1 x min-1. Multivariate regression analysis of the infusion data revealed a vecuronium model predicting TD95 by the duration of infusion (P < 0.05) and weight (P = 0.05). Atracurium TD95 was predicted by age (P = 0.05). The addition of an inhalation agent to atracurium reduced the infusion rate by 2.01 +/- 0.28 micrograms.kg-1 x min-1 (P = 0.0001) for each increase in MAC. The mean reversal times for atracurium with three different anaesthetics and for vecuronium were not different. Reversal of pancuronium blockade, from less profound twitch depression (86.4 vs 95%) took twice as long as for atracurium and vecuronium for which the following predictors were identified: age, weight, duration of infusion, level of blockade, and type of anaesthetic, using a stepwise regression model.(ABSTRACT TRUNCATED AT 250 WORDS)     

Incomplete reversal of pancuronium neuromuscular blockade by neostigmine, pyridostigmine, and edrophonium

Three clinically used anticholinesterases--neostigmine, pyridostigmine, and edrophonium--were tested for their ability to reverse two levels (60% and 95%) of neuromuscular blockade produced by pancuronium. A controlled in vitro environment of the rat diaphragm-phrenic nerve system was used for the studies. Concentrations of anticholinesterases spanned the clinical range and were extended beyond to establish dose-response curves. Neostigmine was the most potent reversal drug (ED50 for 95% block 5.5 +/- 4 nM), followed by pyridostigmine (0.27 +/- 0.06 microM) and edrophonium (2.1 +/- 0.05 microM). The three drugs were equally effective at reversal of block and fade as measured by train-of-four stimulation. The dose-response curves for all three drugs showed a ceiling effect for reversal of tension and fade. Supraclinical concentrations of drug did not effect complete reversal, especially at 95% block. High concentrations of anticholinesterase led to randomly appearing hyperactivity manifested by spontaneous twitching and repetitive firing with severe fade on stimulation.     

Cumulation and reversal with prolonged infusions of atracurium and vecuronium

A randomized, double-blind study was undertaken to compare the tendencies for cumulation, and reversal characteristics of atracurium (ATR) and vecuronium (VEC) when administered by continuous infusion for long surgical procedures under balanced anaesthesia. Eligible subjects were between 50 and 75 yr of age and were free of neuromuscular disease. Patients in the ATR group (n = 25) received a loading dose of atracurium 0.25 mg.kg-1, followed by an infusion initially set at 5.0 micrograms.kg-1.min-1. In the VEC group (n = 25) patients received a loading dose of vecuronium 0.05 mg.kg-1, followed by an infusion at 1.0 microgram.kg-1.min-1. During surgery, the infusions of both ATR and VEC were titrated in increments or decrements of 12.5% to maintain first twitch (T1) suppression of 90-95%. Neuromuscular block was measured by recording the integrated evoked electromyographic response (EMG) of the first dorsal interosseous muscle in response to supramaximal TOF stimuli on the ulnar nerve. The durations of infusion were similar for the two groups (164 +/- 42 and 183 +/- 67 min for ATR and VEC, respectively). The infusion rates of ATR (mean +/- SD) remained between 4.0 +/- 0.7 and 5.0 +/- 1.0 microgram.kg-1.min-1 throughout the study period. In contrast, a progressive decrease (P less than 0.05) in the infusion rate of VEC, from 1.0 to 0.47 +/- 0.13 micrograms.kg-1.min-1, was observed during the study period. The number of adjustments required to maintain 90-95% T1 suppression decreased between the second and fourth hours of administration, but were similar at corresponding times when comparing the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dose-response relationships for edrophonium and neostigmine as antagonists of atracurium and vecuronium neuromuscular blockade

To determine the potencies of edrophonium and neostigmine as antagonists of nondepolarizing neuromuscular blockade produced by atracurium and vecuronium, dose-response curves were constructed for both antagonists when given at 10% spontaneous recovery of first twitch height. Ninety ASA physical status 1 and 2 adults were given either 0.4 mg/kg atracurium or 0.08 mg/kg vecuronium during thiopental-nitrous oxide-enflurane anesthesia. Train-of-four stimulation was applied to the ulnar nerve every 12 s, and the force of contraction of the adductor pollicis muscle was recorded. When spontaneous recovery of first twitch height reached 10% of its initial control value, edrophonium (0.1, 0.2, 0.4, or 1 mg/kg) or neostigmine (0.005, 0.01, 0.02, or 0.05 mg/kg) was administered by random allocation. Neuromuscular function in another ten subjects was allowed to recover spontaneously. Assisted recovery was defined as actual recovery minus mean spontaneous recovery observed in patients who were not given antagonists. First twitch recovery was initially more rapid when vecuronium was antagonized compared with atracurium, but no difference was detected after 10 min. At 10 min the neostigmine ED80 was 0.022 +/- 0.003 (SEM) mg/kg after atracurium and 0.024 +/- 0.003 mg/kg after vecuronium. The edrophonium ED80 was 0.44 +/- 0.11 mg/kg with atracurium and 0.46 +/- 0.12 mg/kg with vecuronium, giving a neostigmine:edrophonium potency ratio of 20. Atracurium train-of-four fade could be antagonized more easily with edrophonium, whereas that of vecuronium was more easily antagonized by neostigmine. It is concluded that edrophonium and neostigmine are not equally effective against atracurium and vecuronium.     

Neostigmine and edrophonium antagonism of varying intensity neuromuscular blockade induced by atracurium, pancuronium, or vecuronium

To compare the time course of neostigmine and edrophonium antagonism of varying intensity neuromuscular blockade induced by atracurium, pancuronium, or vecuronium, the authors studied 98 patients anesthetized with nitrous oxide (60%) and halothane or enflurane. Neuromuscular blockade, as monitored by single stimulus-induced twitch tension (TT), was antagonized at varying degrees of spontaneous recovery (2-80% of control TT). Time to antagonism (time from injection of neostigmine or edrophonium to 90% recovery of control TT) was not different between edrophonium, 0.5 mg/kg, and neostigmine, 0.04 mg/kg, when spontaneous recovery had been allowed to occur to at least 11% of control TT prior to antagonist administration (P greater than 0.05). For profound neuromuscular blockade (TT less than or equal to 10% of control) induced by pancuronium or vecuronium, time (mean +/- SD) to antagonism with neostigmine, 0.04 mg/kg, was 7.0 +/- 2.2 min and 5.6 +/- 1.7 min, respectively, while the same for edrophonium, 0.5 mg/kg, was 20.0 +/- 8.0 min and 15.0 +/- 12.5 min, respectively (P less than 0.05). Time to antagonism of profound atracurium-induced neuromuscular blockade was 8.5 +/- 3.3 min for neostigmine, 0.04 mg/kg, and 9.8 +/- 7.0 min for edrophonium, 0.5 mg/kg, (P less than 0.05). For profound vecuronium-and pancuronium-induced neuromuscular blockade, time to antagonism by edrophonium, 1.0 mg/kg, was 4.6 +/- 3.0 min and 3.9 +/- 1.6 min respectively. The authors conclude that neostigmine, 0.04 mg/kg, antagonizes neuromuscular blockade within 12 min when TT is greater than 2% of control at time of reversal. When TT is greater than 10% of control, edrophonium, 0.5 mg/kg, produces similar time to antagonism.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative clinical studies of vecuronium, atracurium and pancuronium

The new relaxants vecuronium (Norcuron) and atracurium (Tracrium) have been compared with pancuronium (Pavulon) with respect to onset and duration of action and intubating conditions under clinical situations. A variant of the balanced anaesthesia technique with flunitrazepam, fentanyl and N2O/O2 was used. The following doses were considered equipotent (mg/kg body weight): vecuronium 0.07/0.10; atracurium 0.35/0.50; pancuronium 0.08/0.115. The degree of neuromuscular block was assessed in a semiquantitative manner, using the train of four. No difference between the three relaxants in onset of action was found. After the high doses, however, full paralysis developed 60 s earlier. The same is true of intubating conditions. Good or very good intubating conditions were obtained in the majority of cases 3 minutes after injection of the drug. Following the higher dose, good intubating conditions are achieved approximatively 1/2-1 min sooner. Both new relaxants allow for relatively rapid intubation without the inconvenience of a long duration of action. After a low initial dose the following time for recovery to 25% was noted (means +/- S.D., min): vecuronium 20.3 +/- 7.0; atracurium 28.0 +/- 3.1; pancuronium 53.3 +/- 14.8. The early recovery phase (from 5% to 25% recovery) was 6.1 +/- 2.4 after vecuronium, 8.3 +/- 1.7 after atracurium, 17.2 +/- 10.8 after pancuronium. There is a good correlation between our semiquantitative results, using the train of four, and quantitative recordings of muscle contractions reported in the literature. Both drugs show no cumulative effect after five repeated administrations.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neostigmine and edrophonium as antagonists of atracurium and pancuronium

Edrophonium 0.5 mg/kg or neostigmine 0.04 mg/kg were administered to two groups of 30 patients each for antagonism of atracurium- or pancuronium-induced neuromuscular block at 25% single twitch recovery. Neuromuscular block was studied using both single twitch and train-of-four (TOF) nerve stimulation. The times to 100% single twitch recovery were significantly more rapid for patients receiving edrophonium (P less than 0.01) in both groups (atracurium and pancuronium); the TOF ratios were similar for atracurium, but for pancuronium they were greater after neostigmine than after edrophonium, and only at 25 min were these ratios similar. It is concluded that edrophonium in a dose of 0.5 mg/kg antagonizes neuromuscular blockade induced by atracurium, as does neostigmine in a dose of 0.04 mg/kg, but the former does not consistently antagonize neuromuscular blockade induced by pancuronium even at 25% of single twitch recovery.     

Comparison of intubating conditions with atracurium, vecuronium and pancuronium

A blind trial, comparing time of onset of satisfactory conditions for tracheal intubation with atracurium 0.6 mg/kg, vecuronium 0.1 mg/kg and pancuronium 0.1 mg/kg is described. Intubation was attempted at 30-second intervals in 60 patients, randomly allocated to receive one of the above muscle relaxants. Patients receiving atracurium 0.6 mg/kg could be intubated from 30 to 120 seconds. Patients receiving either vecuronium 0.1 mg/kg or pancuronium 0.1 mg/kg were able to be intubated between 60 and 240 seconds. The results showed a statistically significant earlier onset of satisfactory intubating conditions with atracurium than with vecuronium or pancuronium in these doses but no difference between vecuronium and pancuronium.     

Recovery from neuromuscular blockade: residual curarisation following atracurium or vecuronium by bolus dosing or infusions

We conducted a survey of the incidence of Postoperative Residual Curarisation (PORC) in two groups of patients following the use of atracurium or vecuronium. In the first group (B) the neuromuscular blocking drugs were administered by bolus dosing, and in the second group (I) by continuous infusion. On arrival in the recovery room, neuromuscular function was assessed both by compound evoked electromyogram (EMG) in a train of four pattern and also clinically, by the ability to sustain a headlift for >5 seconds, and to cough. Results were obtained from 150 patients (100 in group B and 50 in group I). The incidence of PORC, as defined by a train of four ratio of <0.7, on arrival in the recovery room was 12% in group B, and 24% in group I. Clinical criteria of adequate neuromuscular reversal revealed different results, with the majority of patients being unable to perform either clinical test on arrival in recovery. Those patients in whom a peripheral nerve stimulator was used intra-operatively did not have a reduced incidence of PORC. We have demonstrated that PORC is still a common occurrence even with intermediate duration of action neuromuscular blocking drugs.     

The potencies of edrophonium and neostigmine as antagonists of pancuronium

Dose response curves were constructed for edrophonium and neostigmine when used to antagonise pancuronium, 0.07 mg/kg during thiopentone-nitrous oxide-halothane anaesthesia. The antagonist was given when 10% twitch height had been restored and the effect was measured 10 minutes later. Recoveries to 50% and 90% twitch height were achieved with 167 and 828 micrograms/kg of edrophonium, and 10.5 and 51 micrograms/kg of neostigmine. The dose response curves were parallel and neostigmine was 16 times more potent than edrophonium. Combinations of equipotent doses of edrophonium and neostigmine were also administered and produced additive but not synergistic effects. It is concluded that either edrophonium or neostigmine may be used for the reversal of pancuronium neuromuscular blockade, but the combination of the two offers no advantage.     

Interaction of verapamil with gallamine and pancuronium and reversal of combined neuromuscular blockade with neostigmine and edrophonium

In this in vitro study, the effects and interactions of verapamil with gallamine and pancuronium and reversal by edrophonium and neostigmine of combined neuromuscular blockade, produced by the muscle relaxants and verapamil, were studied in an avian skeletal muscle. The results show that verapamil reduced the amplitude of indirectly-elicited twitch tension and potentiated the neuromuscular blockade produce by the two muscle relaxants. Edrophonium and neostigmine reversed the neuromuscular blockade produce by the muscle relaxants alone, and in combination with verapamil. Edrophonium was more potent than neostigmine in reversing the combined neuromuscular blockade produced by the muscle relaxants with and without verapamil.     

Dose-response studies of atracurium, vecuronium and pancuronium in the elderly

Dose-response curves were constructed for atracurium, vecuronium and pancuronium in elderly subjects in order to assess potency of these relaxants. The results were compared to data previously obtained for adult subjects using the same method. A single-dose method of potency determination was used in both studies. The results indicate no significant difference in the potency of these relaxants between elderly and adult subjects; the ED95S were 249 and 226 micrograms/kg for atracurium, 43.1 and 39.6 micrograms/kg for vecuronium and 65.9 and 60 micrograms/kg for pancuronium respectively in the elderly and the adults.     

Dose-response curves for edrophonium, neostigmine, and pyridostigmine after pancuronium and d-tubocurarine

To determine the potencies of neostigmine, pyridostigmine, and edrophonium in reversing pancuronium and d-tubocurarine blockade, dose-response curves were established for first twitch height recovery and train-of-four ratio. One hundred and twenty ASA physical status I or II patients scheduled for elective surgery received either 0.06 mg/kg pancuronium or 0.36 mg/kg d-tubocurarine during a thiopental-nitrous oxide-enflurane anesthetic. Train-of-four stimulation was applied every 12 s, and the force of contraction of the adductor pollicis muscle was recorded. When first twitch height had recovered spontaneously to 10% of its initial value, neostigmine (0.005, 0.01, 0.02 or 0.05 mg/kg), pyridostigmine (0.02, 0.04, 0.1, or 0.2 mg/kg), or edrophonium (0.1, 0.2, 0.4 or 1 mg/kg) was injected by random allocation. Recovery was measured 10 min after the injection of the antagonist. First twitch ED50's were 0.013, 0.085, and 0.17 mg/kg after pancuronium, and 0.017, 0.11, and 0.27 mg/kg after d-tubocurarine, for neostigmine, pyridostigmine, and edrophonium, respectively. The ED50 for pyridostigmine and edrophonium obtained after d-tubocurarine was significantly larger (P less than 0.05) than that after pancuronium. The train-of-four dose-response curves were significantly flatter for edrophonium than for the other two agents, indicating a greater ability of edrophonium to antagonize fade at low doses. It is concluded that the potency of reversal agents may be different for different relaxants, and that potency ratios might depend upon the end-point chosen as full neuromuscular recovery.     

Antagonism of vecuronium paralysis: comparison between edrophonium and neostigmine.

The reversal of vecuronium paralysis was studied in three series of anesthetized (methohexital, fentanyl, N2O/O2) informed adult patients receiving either 40 micrograms/kg neostigmine (NEO40) (n = 6), either 500 micrograms/kg edrophonium (EDRO500) (n = 6) or 1000 micrograms/kg edrophonium (EDRO1000) (n = 6). These drugs were given randomly once the adductor pollicis twitch height regained 10% of its initial value. The neuromuscular transmission recovery was assessed during 15 minutes after the antagonist administration, by recording twitch height (TH), train of four--2 Hz--every 3 minutes (TOF Ratio) and finally tetanic fade--50 Herz (TET50) and 100 Hz (TET100), 5 seconds duration, one minute apart--. At 15 minutes, the TH values (mean +/- SEM) were for EDRO500 92% +/- 7, for EDRO1000 93% +/- 3 and for NEO40 100% +/- 4 percent (n.s.). For the TOF Ratio, a statistical difference (p less than 0.05) was found between NEO40 86% +/- 4 and the two other groups: EDRO500 73% +/- 3, EDRO1000 69% +/- 4. For the TET50, the values were: EDRO500 93% +/- 3, EDRO1000 86% +/- 5 and NEO40 94% +/- 2 (n.s.). At 100 Hz, the values were: NEO40 61% +/- 8, EDRO500 43 +/- 151 and EDRO1000 31 +/- 12 (p less than 0.01). In conclusion, in the conditions studied, 40 micrograms/kg neostigmine restores the neuromuscular transmission of the adductor pollicis at a higher level than edrophonium 500 micrograms/kg does. Edrophonium, 1000 micrograms/kg instead of 500 micrograms/kg does not change the neuromuscular transmission recovery.     

Comparative clinical studies on vecuronium, atracurium and pancuronium in older patients

The relaxants vecuronium (Norcuron), atracurium (Tracrium), and pancuronium (Pavulon) have been investigated with respect to onset and duration of action in old patients compared with young patients. A variant of a balanced anaesthesia technique with flunitrazepam, fentanyl and N2O/O2 was used. The following equipotent doses were investigated (mg/kg body weight): vecuronium 0.07/0.10; atracurium 0.35/0.50; pancuronium 0.08/0.115. The neuromuscular function was assessed in a semiquantitative manner with the Train-of-Four (TOF). We found a trend to a delayed onset of action in old patients. This effect, however, reached a significant level with pancuronium only. The degree of relaxation after comparable doses was less after atracurium in old patients. This difference between young and old patients could not be observed after vecuronium and was hardly detectable after pancuronium. The duration of action to a 25% recovery and the early recovery phase from the appearance of the first to the fourth twitch in the TOF showed no difference between young and old patients. It is concluded that there are no considerable differences with respect to the duration of action between young and old patients. However, to obtain a similar degree of relaxation, it is recommended to use a somewhat higher dose level with atracurium.     

Dose requirements of vecuronium, pancuronium, and atracurium during orthotopic liver transplantation.

To further elucidate the role of the liver in the clearance of vecuronium, atracurium, and pancuronium, 30 patients undergoing orthotopic liver transplantation were randomly assigned to three comparable groups to receive a continuous infusion of vecuronium, atracurium, or pancuronium. The evoked integrated compound action potential of the hypothenar eminence in response to train-of-four ulnar nerve stimulation was measured and recorded. Anesthesia was induced with 3-5 mg/kg of thiopental, 50 micrograms/kg of midazolam, and 1-5 micrograms/kg of fentanyl IV and was maintained with continuous infusions of midazolam and fentanyl while the lungs were ventilated with an air-oxygen mixture. The infusion rates of vecuronium, atracurium, and pancuronium were adjusted to achieve a T1/Tc ratio of between 0.02 and 0.10 (T1 = height of first twitch, Tc = height of control twitch). Vecuronium and pancuronium requirements, which were 0.072 +/- 0.022 and 0.042 +/- 0.015 mg.kg-1.h-1 (mean +/- standard deviation) respectively during the dissection phase, decreased significantly during the anhepatic phase to 0.036 +/- 0.021 and 0.018 +/- 0.012 mg.kg-1.h-1 and returned toward the initial values in the postreperfusion phase (0.055 +/- 0.018 and 0.032 +/- 0.012 mg.kg.-1.h-1); whereas atracurium requirements remained unchanged during the three phases (0.667 +/- 0.199, 0.567 +/- 0.142, and 0.692 +/- 0.254 mg.kg-1.h-1). These data suggest that the liver has an important role in the elimination of vecuronium and pancuronium, whereas the elimination of atracurium is unaltered during exclusion of the liver from the circulation.     

Recovery of neuromuscular function and postoperative morbidity following blockade by atracurium, alcuronium and vecuronium

Recovery of neuromuscular function and postoperative morbidity were studied in 51 fit female patients who had nonemergency gynaecological laparoscopy as inpatients. They were allocated randomly to one of three groups to receive either atracurium 0.31 mg/kg, alcuronium 0.25 mg/kg, or vecuronium 0.06 mg/kg as part of an otherwise standard anaesthetic technique. There were neither differences in intubation conditions nor in the occurrence of postoperative diplopia whichever muscle relaxant was used. Deficits in grip strength and expiratory force were seen at one hour after reversal with atropine 1.2 mg and neostigmine 2.5 mg in all patients, deficits which persisted for 3 hours in those who received alcuronium. The recovery of inspiratory force was slower and less complete at up to 3 hours in those who received alcuronium and there was a high incidence of minor postoperative morbidity at up to 24 hours in each of the three groups. The only statistical difference in symptomatic morbidity was an increase in muscle weakness in those who received alcuronium compared with atracurium at 3 hours after laparoscopy. Only 25%, 20% and 31% of the patients who received atracurium, alcuronium and vecuronium respectively said that they would have liked to be day stay patients.     

Twitch depression and train-of-four ratio after antagonism of pancuronium with edrophonium, neostigmine, or pyridostigmine

During N2O-O2-halothane anesthesia pancuronium (3 mg/70 kg) was antagonized with neostigmine (2.5 or 5 mg/70 kg), pyridostigmine (10 or 20 mg/70 kg), or edrophonium (50 or 100 mg/70 kg) in 36 human subjects (6 in each group). Reversal was attempted at 10% spontaneous recovery of muscle twitch, which was measured using train-of-four stimulation. When first twitch tension was less than 70% of the control it was found that for the same tension, the train-of-four ratio was greater with edrophonium than with neostigmine, and greater with neostigmine than with pyridostigmine. It was concluded that the three antagonists have different mechanisms of action. In comparison with neostigmine, edrophonium is more and pyridostigmine is less effective at presynaptic (or fade) receptors.