Mivacurium: dose-response relationship and administration by repeated injection or infusion.

The dose-response relationship and neuromuscular blockade after infusion or repeated injection of mivacurium were studied in 65 patients in nitrous oxide-narcotic anesthesia. The ED95 (twitch tension) was determined in 45 patients by intravenous injection of a single bolus of 30, 39, 47, 54, or 60 micrograms/kg (9 patients per dose). Another 20 patients received an initial bolus of 2 x ED95 followed either by an infusion started at 5% twitch recovery (i.e., 95% depression) and adjusted to sustain 95% twitch depression (n = 10) or by repeated injection of 0.6 x ED95 whenever twitch tension had recovered to 25% of control (n = 10). Five patients in each of these two groups received 7 micrograms/kg of neostigmine at 25% twitch recovery, and the others recovered twitch tension spontaneously. The mean ED95 was 73 micrograms/kg. A 2 x ED95 bolus was followed by complete twitch depression within 2.2 +/- 0.7 min. The mean infusion rate resulted in 6 +/- 2 micrograms.kg-1.min-1. The ensuing recovery index was 6 +/- 3 min. A 6 +/- 2 min recovery index was found after up to 10 repeat injections given every 9 +/- 3 min. There was no significant effect of neostigmine in both groups. In conclusion, the recovery indices after the infusion or repeat injection of near-equal doses of mivacurium were identical.     

Lack of interaction between propofol and vecuronium.

We estimated the potency of vecuronium and measured the onset and duration of its action during total intravenous anesthesia with propofol to examine the possibility of any interaction between these two drugs. Propofol infusion was administered according to a three-step dosage scheme, and neuromuscular block was monitored by measuring the force of contraction of the adductor pollicis muscle after single-twitch stimulation of the ulnar nerve at 0.1 Hz. A control group of patients were similarly studied during anesthesia with thiopental, nitrous oxide, oxygen, and fentanyl. The ED50 and ED95 (dose required to produce a 50% and 95% depression of twitch tension, respectively) of vecuronium in patients given total intravenous anesthesia (n = 24) were 24 (22-27, 95% confidence limits) and 41 (37-48, 95% confidence limits) micrograms/kg, respectively, and in the control group (n = 24), 20 (17-24) and 39 (34-37) micrograms/kg, respectively. The onset of action of an 80-micrograms/kg dose (2 x ED95) of vecuronium was 3.6 +/- 1.2 and 4.1 +/- 1.7 min (mean +/- SD), in the propofol (n = 10) and control (n = 10) groups, respectively. The respective times to recovery of the twitch height to 25% of control and the recovery indices (25%-75% recovery of twitch height) in the propofol versus control groups were 28.3 +/- 6.6 and 28.0 +/- 1.7 min and 13.3 +/- 6.8 and 15.4 +/- 11.9 min, respectively. There were no significant differences in any of the measured variables between the propofol and control groups, indicating the lack of any interaction between propofol and vecuronium.     

Mivacurium chloride—a comparative profile

Mivacurium is a new nondepolarizing muscle relaxant of the benzylisoquinoline type. Its short duration of action is due to rapid breakdown by plasma cholinesterase. The dose of mivacurium which produces 95% inhibition of twitch response (ED₉₅) is between 60 and 80 μg/kg. Thus, mivacurium is 0.8 times and four times as potent as vecuronium and atracurium, respectively. With 2–3×ED₉₅, tracheal intubation can be accomplished within 2.5 min of intravenous injection. The ensuing DUR25% (time from injection to 25% recovery of control twitch tension) is twice as long as with suxamethonium and about half as long as with equipotent doses of atracurium or vecuronium. For muscle relaxation during long surgical procedures, mivacurium has been used as a continuous infusion. The average 6-min recovery index after infusion of mivacurium is particularly favourable for flexible control of muscle paralysis, whereas the recovery indices after infusion of atracurium or vecuronium are 15–30 min. In conclusion, mivacurium will close the pharmacodynamic gap between suxamethonium and the nondepolarizing muscle relaxants of intermediate duration of action. It will probably also be a suitable alternative to suxamethonium in elective cases.     

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)     

Maintenance of surgical muscle relaxation by repeat doses of vecuronium and atracurium at three different dose levels.

The time-course of the neuromuscular effects of vecuronium (n = 25) and atracurium (n = 25) has been compared at three different levels of maintenance dose in anaesthetized patients. Following intubation with vecuronium 0.1 mg kg-1 or atracurium 0.5 mg kg-1, surgical muscle relaxation was maintained by using increments of equipotent maintenance doses equivalent to 0.5, 1.0 and 1.5 x ED95 for each drug. Repeat doses were administered each time the twitch height, depressed by the previous dose, returned to 25% of its control value. The apparent increase in the duration of action, i.e. the difference between the duration of the last and the first maintenance dose, did not reach statistical significance and approximated 3 +/- 2, 6 +/- 4, 11 +/- 5 and 3 +/- 2, 8 +/- 13, 5 +/- 7 min following the low, medium and high maintenance doses of vecuronium and atracurium, respectively.     

Effects of propofol and isoflurane on the neuromuscular block induced by atracurium]

Speed of onset, duration of action and recovery time for a bolus injection of atracurium were measured in two groups of patients. In group I anaesthesia considered of propofol, fentanyl, nitrous oxide and oxygen mixture. The induction dose of propofol was 2 mg/kg-1 followed by an infusion of 9.0 mg/kg-1/h-1 for first half hour and 4.5 mg/Kg-1/h-1 subsequently. In group II anaesthesia consisted of isoflurane, fentanyl, nitrous oxide and oxygen mixture. Isoflurane was given upon clinical needs. Speed of onset, duration of action, and recovery time for atracurium were measured in the two groups. No statistically significant differences between speed of onset and duration of action between the two groups were found. The recovery period from T1 = 10% to T1 = 70% twitch response was considerably longer with isoflurane (25 min +/- 6) than with propofol (18 min +/- 3) (p less than 0.01). Results obtained suggest that for adequate relaxation during tracheal intubation smaller doses of atracurium are not needed during isoflurane than propofol administration. Because of the longer recovery period of residual neuromuscular blockade during isoflurane anaesthesia decreasing doses of atracurium and careful monitoring of twitch depression tension are also suggested.     

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.     

Neuromuscular and cardiovascular effects of pipecuronium

Pipecuronium bromide (Arduan) is a bisquaternary, steroid-type neuromuscular blocking agent in clinical use in Eastern Europe. Before its introduction into clinical practice in the USA, in the first phase of this study the neuromuscular potency of pipecuronium was determined under "balanced" and enflurance anaesthesia by the cumulative log dose-response method in 30 patients each. In the second phase the intubation and onset times, clinical duration of the first and repeated doses, spontaneous recovery index, reversibility of its residual neuromuscular effect by an anticholinesterase and its effect on heart rate and blood pressure was compared with the same variables observed in patients, anaesthetized with identical techniques but who had received vecuronium or pancuronium. The neuromuscular potency of pipecuronium was greater under enflurane (ED95 = 23.6 +/- 1.1 micrograms.kg-1 (mean +/- SEM)] than under balanced (ED95 = 35.1 +/- 17 micrograms.kg-1) anaesthesia. Pipecuronium was more potent than vecuronium under both balanced (ED95 = 45.8 micrograms.kg-1) and enflurane anaesthesia (ED95 = 27.4 micrograms.kg-1). Following the administration of 2 x ED95 doses there were no clinically significant differences in the intubation or onset times of pipecuronium, vecuronium and pancuronium. Under balanced anaesthesia the clinical duration of 2 x ED95 dose of pipecuronium (110.5 +/- 0.3 min) or pancuronium (115.8 +/- 8.1 min) were similar and about three times longer than that of vecuronium (36.3 +/- 2.1 min). The recovery indices of pipecuronium (44.5 +/- 8.2 min) and pancuronium (41.3 +/- 4.2 min) were also similar and about three times longer than that of vecuronium (14.3 +/- 1.4 min).(ABSTRACT TRUNCATED AT 250 WORDS)     

Atracurium: neuromuscular blockade in repeated administration

The neuromuscular blocking action of repeated injections of atracurium and vecuronium was studied in 74 surgical patients during balanced anaesthesia (methohexitone or etomidate, intubation after suxamethonium, fentanyl, droperidol, N2O). The initial bolus dose (ID) of atracurium was 0.25 mg/kg and of vecuronium 0.05 mg/kg followed by repeated increments (RD) of atracurium 0.1 mg/kg and vecuronium 0.0125 mg/kg when neuromuscular function (EMG) had recovered to about 30% of pre-relaxant control. Dose-response relationships revealed atracurium to be about 1/5 as potent as vecuronium; the ED50 of atracurium was 0.13 +/- 0.03 mg/kg and of vecuronium 0.023 +/- 0.007 mg/kg. The ID of both relaxants produced a neuromuscular blockade of about 90% within 4 min. The duration from the time of injection to 30% recovery was slightly longer in atracurium 26 +/- 9 min. In all patients the RD produced within 3.5 min satisfactory muscle relaxation with a neuromuscular block of about 85%. The mean duration of atracurium (18 min) was 5-10 min longer than of vecuronium (12 min). To maintain good surgical relaxation (more than 70% blockade) atracurium 0.32 mg/kg X h and vecuronium 0.056 mg/kg X h were required. No cumulation could be measured after repeated injections. The recovery time of atracurium and vecuronium at the end of anaesthesia was 10-12 min. Neither cardiovascular side-effects nor signs of histamine release were observed after both relaxants in our particular dose range. It is concluded, that atracurium is a favourable blocker for anaesthetic practice: The time of onset is approximately the same compared with vecuronium. The duration of action, however, is slightly longer but still truly intermediate long.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

VECURONIUM AND ATRACURIUM IN PATIENTS WITH END-STAGE RENAL FAILURE: A Comparative Study

Twenty patients with end-stage renal failure, undergoing kidneytransplantation, were assigned randomly to receive either vecuroniumor atracurium under evoked twitch tension control. The cumulative-dosetechnique was used to obtain 95% twitch depression (vecuronium:initial bolus 15 µg kg^–1, increments 6 µgkg^–1; atracurium: initial bolus 100 µg kg^–1,increments 40 µg kg^–1). Using ED₉₅ values derivedfrom the log-probit dose-response curves, vecuronium was 4.6times more potent than atracurium. The durations of action ofthe initial cumulativedoses (from end of injection of the lastincrement to 25% recovery) were 11.1± 3.3 min for vecuroniumand 16.2±3.9 min for atracurium (P < 0.05). In termsof duration of action of the maintenance doses (vecuronium one-quarterof the total incremental dose; atracurium one-third) some cumulationwas observed with vecuronium (interaction time x treatment;cumulation ratio 1.46 ±0.31 v. 0.98±0.10 for atracurium,P< 0.001). After 2 h of surgery, the mean recovery times(25% to 75% twitch height) did not differ (18.5±2.8 minand 16.7±4.4 min). It is concluded that vecuronium mightbe less safe than atracurium in patients with end-stage renalfailure undergoing prolonged operations.     

Continuous infusion of atracurium in children

Atracurium infusion requirements were determined in 28 children anesthetized with N2O:O2 narcotic, N2O:O2 halothane (1% inspired), and N2O:O2 enflurane (2% inspired). When the patient was recovering from a bolus dose of 0.4 mg/kg atracurium, a continuous infusion of atracurium was started and the rate was adjusted to maintain 90-99% muscle twitch depression. Patients receiving enflurane anesthesia required atracurium at an infusion rate of 4.9 +/- 0.3 micrograms X kg-1 X min-1 which was a significantly lower rate (P = 0.0001) than those anesthetized with halothane (8.3 +/- 0.4 micrograms X kg-1 X min-1) or with N2O:O2 and narcotic (9.3 +/- 0.5 micrograms X kg-1 X min-1). At the onset of neuromuscular blockade, the twitch response disappeared faster after train-of-four stimulation repeated every 10 s than after single twitch rates of stimulation at 0.1 Hz. In children, during halothane anesthesia after 0.4 mg/kg atracurium, the response of the adductor of the thumb was ablated in 2.0 +/- 0.3 min with train-of-four stimulation, and in 3.7 +/- 0.4 min with single twitch stimulation. The authors recommend the use of a nerve stimulator during continuous infusion of atracurium because of the marked interpatient differences in infusion-rate requirements.     

Propofol potentiates the neuromuscular blocking effects of vecuronium in man

The possible interaction between vecuronium and propofol has been investigated in 40 healthy (ASA I-II) patients. They were randomly allocated to two groups according to the method of anesthesia; continuous propofol infusion group (propofol) and droperidol and fentanyl group (control). The electromyographic response of abductor digiti minimi was monitored at 20-s interval after train-of-four stimulations of the ulnar nerve. The ED50 and ED95 (dose required to produce a 50% and 95% depression of twitch tension, respectively,) of vecuronium in the propofol group (n = 20) were 29.4 +/- 0.5 and 56.6 +/- 2.1 micrograms.kg-1 (mean +/- SEM), and in the control group (n = 20), 36.7 +/- 1.8 and 73.6 +/- 5.2 micrograms.kg-1, respectively. Under propofol anesthesia, the cumulative dose-response curves of vecuronium were shifted to the left when compared with control ED50 and the slope showed that propofol had potentiated the action of vecuronium.     

Comparison of the neuromuscular blocking effect of cisatracurium and atracurium on the larynx and the adductor pollicis

BACKGROUND: Cisatracurium unlike atracurium is devoid of histamine-induced cardiovascular effects and this alone would be the greatest advantage in replacing atracurium for the facilitation of tracheal intubation. On the other hand, 2 ED(95) doses of cisatracurium (100 micro g/kg) do not yield satisfactory intubating conditions such as those seen with equipotent doses of atracurium and therefore the recommended intubating dose of cisatracurium is 3 ED(95). To understand this discrepancy better, we evaluated the potency and onset of atracurium and cisatracurium directly at the larynx adductors in humans. METHODS: The study was conducted in 54 patients (ASA class I or II) undergoing peripheral surgery requiring general anesthesia. Cisatracurium 25-150 micro g/kg or atracurium 120-500 micro g/kg intravenous (i.v.) boluses doses were administered during anesthesia with propofol, nitrous oxide, oxygen and fentanyl. Neuromuscular block was measured by electromyography (single twitch stimulation every 10 s) at the larynx and the adductor pollicis. The dose-response effect measured at both muscles included maximum neuromuscular blockade achieved (Emax), the time to maximum depression of twitch height (onset) and time to spontaneous recovery of the twitch height to 25%, 75% and 90% (T25, T75, T90) of control value. RESULT: The onset at the larynx was of 196 +/- 28 s after the 100 micro g/kg cisatracurium dose compared with 140 +/- 14 s after the 500 micro g/kg atracurium dose (P < 0.05). Emax at the larynx was 92 +/- 1% and 98 +/- 1% after 100 micro g/kg cisatracurium and 500 micro g/kg atracurium, respectively (P < 0.05). The time to onset of maximum suppression Emax = 100 +/- 0% after a 150 micro g/kg cisatracurium dose was 148 +/- 29 s. At the larynx, the ED(50) was 25 micro g/kg for cisatracurium and 180 micro g/kg for atracurium and the ED(95) was 87 micro g/kg for cisatracurium compared with 400 micro g/kg for atracurium. CONCLUSION: The slow onset time at the laryngeal muscles after cisatracurium can be explained by the higher potency as compared with atracurium.     

Comparative Pharmacology of Cisatracurium (51W89), Atracurium, and Five Isomers in Cats

Background: Atracurium has four chiral centers and the marketed product is a mixture of ten optical and geometric isomers. Six of the isomers were prepared and evaluated for neuromuscular blocking activity and autonomic effects in anesthetized cats. This study reports the comparative pharmacology of the six isomers and atracurium that led to the selection of one isomer, cisatracurium (Nimbex, 51W89) for clinical development.

Methods: Purpose bred cats, anesthetized with alpha-chloralose (80 mg/kg) and pentobarbital sodium (7 mg/kg) administered intraperitoneally, were used in this study. Neuromuscular blocking effects were assessed from the effects on the tibialis anterior twitch evoked at 0.15 Hz. Inhibition of the autonomic nervous system was assessed from the effects on the nictitating membrane contraction, in response to preganglionic sympathetic nerve stimulation and the bradycardia/vasodepressor responses to vagal nerve stimulation. Cardiovascular effects and plasma histamine concentrations were determined after a bolus injection of cisatracurium or atracurium.

Results: Like atracurium, all six isomers produced dose-dependent neuromuscular block (NMB). The calculated ED95 NMB values varied approximately tenfold (43+/-2 micro gram/kg-488+/-56 micro gram/kg). The "R-series" isomers were more potent than the corresponding "S series" isomers. With the exception of the S,Trans-S', Trans isomer, the NMB effects, i.e., onset times (range 2.6+/-0.2 min to 4.7+/-0.3 min) and total durations (range 9.9+/- 1.4 min to 14+/-0.9 min), of the other five isomers were very similar to that of atracurium. The former isomer had a relatively short duration of action. The 25-75% recovery times after cisatracurium at 1x ED sub 95 (4.4+/-0.4 min), 4x ED95 (4.5+/-0.4 min), and continuous infusions lasting at least 60 min that maintained 95-99% NMB (4.8+/-0.4 min) indicated a noncumulative effect. The vagal ID50: NMB ED95 ratios for atracurium and the six isomers ranged from 2 to 27. The sympathetic ID25: NMB ED95 ranged from 2.7 to 60. Atracurium and all of the isomers, except cisatracurium, produced cardiovascular effects after intravenous bolus administration at large doses (700-4,800 micro gram/kg). In contrast to atracurium, there were no changes in plasma histamine concentrations associated with the administration of doses of cisatracurium equivalent to 60x the NMB ED95 (62+/-8 micro gram/kg).     

Does intravenous infusion of nitroglycerin potentiate pancuronium- and vecuronium-induced neuromuscular blockade?

The dose requirement for 95% depression of twitch tension and the time course of the neuromuscular blocking effects of the ED95 of pancuronium bromide and vecuronium bromide were studied during intravenous infusion of glucose, 5%, and nitroglycerin, 1 microgram X kg-1 X min-1, in 20 cats anesthetized with pentobarbital. Nitroglycerin administered continuously starting 1 hr before the administration of the ED95 and maintained during at least five maintenance doses of either pancuronium or vecuronium did not significantly potentiate the action of the neuromuscular blocking drugs, nor did it alter their time course of action. A tendency for a decrease (statistically not significant) rather than an increase in the duration of action of maintenance doses of both pancuronium and vecuronium was apparent during the treatment with nitroglycerin. These findings indicate a lack of interaction between pancuronium or vecuronium and nitroglycerin, provided that moderate doses are used.     

The clinical neuromuscular pharmacology of mivacurium chloride (BW B1090U). A short-acting nondepolarizing ester neuromuscular blocking drug

Mivacurium chloride (BW B1090U), a bis-benzylisoquinolinium diester compound, was found to undergo hydrolysis in vitro by purified human plasma cholinesterase in a pH-stat titrator at 88% of the rate of succinylcholine at pH 7.4, 37 degrees C and 5 microM substrate concentration. In 72 consenting ASA Physical Status I-II patients receiving nitrous oxide/oxygen-narcotic-thiopental anesthesia, the neuromuscular blocking effect of mivacurium was assessed following bolus doses from 0.03 to 0.30 mg/kg, as well as during and following continuous infusions from 35 to 324 min in length. The calculated ED95 for inhibition of adductor pollicis twitch evoked at 0.15 Hz was 0.08 mg/kg. At 0.1 mg/kg, 96% block developed, onset to maximum block required 3.8 +/- 0.5 min, and recovery to 95% twitch height occurred 24.5 +/- 1.6 (SE) min after injection. At 0.25 mg/kg, onset was 2.3 +/- 0.3 min; 95% recovery developed within 30.4 +/- 2.2 min, an increase in duration of action of only 24% versus 150% higher dosage. Comparative recovery indices from 5 to 95% or from 25 to 75% twitch heights did not differ significantly among all dosage groups from 0.1 to 0.3 mg/kg (range 12.9 to 14.7 and 6.6 to 7.2 min, respectively). In 38 patients who received mivacurium by continuous infusion (duration 88.1 +/- 7.1/47.1 min, SE/SD) for maintenance of 95 +/- 4% twitch inhibition, the mean 5-95% and 25-75% recovery indices after discontinuation of infusion were 14.4 +/- 0.6 and 6.5 +/- 0.3 min (P greater than 0.5 vs. all single bolus doses). The train-of-four (T4) ratio, within 2.6 +/- 0.5 min after 95% twitch recovery following bolus doses, averaged 79.5 +/- 1.8% (n = 32). Similarly, after discontinuation of infusions, the T4 ratio reached 73.4 +/- 1.9% within 3.4 +/- 1.9 min after 95% twitch recovery (n = 33). Antagonism of residual block was seldom indicated, but, to test ease of reversal, eight patients electively received neostigmine (0.06 mg/kg) with atropine (0.03 mg/kg) at 67 to 93 (76.6 +/- 3.5) % block. Twitch returned to 95% of control within 4.5 to 9.5 (6.3 +/- 0.5) min after neostigmine. Mivacurium may offer increased versatility in providing clinical muscle relaxation in a variety of situations. Further studies seem appropriate.     

The effect of phenytoin on the magnitude and duration of neuromuscular block following atracurium or vecuronium

Patients chronically receiving anticonvulsants have been reported to be resistant to the long-acting competitive neuromuscular blockers. This study examines the effects of atracurium and vecuronium on 100 neurosurgical patients; 50 receiving chronic phenytoin therapy (group I) and 50 controls (group II). During O2/N2O/halothane anesthesia, five patients in each group were given a bolus of vecuronium 0.1 mg/kg, and a different five patients in each group were given atracurium 0.5 mg/kg, to produce neuromuscular blockade in excess of 95%. The time to maximum blockade and the recovery from atracurium was unaffected by phenytoin therapy. Recovery from vecuronium was enhanced in the phenytoin group, as demonstrated by the recovery index, defined as the time required for recovery from 25-75% of the control neuromuscular response (7.9 +/- 2.2 min compared with 17.8 +/- 5.1 min in controls, P less than 0.005). Similarly, the total duration of neuromuscular blockade, defined as recovery to 90% of control response, was significantly shorter in the phenytoin group (31.9 +/- 6.0 min compared with 69.7 +/- 12.9 min in controls, P less than 0.001). The remaining 40 patients from each group were given a preselected dose of either vecuronium (0.02-0.06 mg/kg) or atracurium (0.10-0.25 mg/kg) during anesthesia with O2/N2O/fentanyl, to generate dose-response curves for the relaxants. Using analysis of covariance, the slopes and elevations for atracurium were found to be essentially identical in the two groups; as were the calculated ED50 and ED95. Patients receiving chronic phenytoin therapy were resistant to vecuronium-induced neuromuscular blockade. With vecuronium, the dose-response curves for the two groups were parallel; the curve for phenytoin patients was shifted to the right.(ABSTRACT TRUNCATED AT 250 WORDS)     

L''atracurium chez le sujet âgé

The effects of age on the pharmacodynamics of atracurium have been studied in twenty-four consenting adult patients undergoing elective surgery. They were divided in three groups according to their age (mean +/- SEM): group 1 (n = 8; 26 +/- 3 yr), group 2 (n = 8; 53 +/- 2 yr) and group 3 (n = 8; 76 +/- 2 yr). Anaesthesia was induced with methohexitone (1 mg . kg-1) and fentanyl (5 micrograms . kg-1), and maintained with 66% N2O plus fentanyl on demand. Ventilation was controlled and adjusted to produce normocapnia. The isometric contraction of the adductor pollicis muscle in response to supramaximal cubital nerve stimulation delivered at 0.1 Hz was measured with a force displacement transducer. A loading dose of atracurium (0.3 mg . kg-1) was given before tracheal intubation. Thereafter, twitch height (TH) was maintained at 10% of its baseline reading by adjusting the flow of a Harvard syringe containing 0.5 mg . ml-1 of atracurium in saline. The amount of atracurium required to maintain a stable twitch height, calculated for a 60 min period, was 14.7 +/- 1 mg . m-2 . h-1 for group 1, 13.6 +/- 1.5 mg . m-2 . BSA-1 for group 2 and 15 +/- 2.1 mg . m-2 . BSA-1 for group 3. At the end of the infusion period, the TH25-75 recovery rates were not statistically different in the three groups: 15.4 +/- 1.9 min for group 1, 14.8 +/- 1.1 min for group 2 and 14.5 +/- 1.6 min for group 3.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of volatile anesthetics on vecuronium-induced neuromuscular blockade in children

We studied 60 children undergoing elective surgery to evaluate the effect of interactions between vecuronium and isoflurane or halothane on the potency and duration of neuromuscular blockade, as measured by electromyography. Vecuronium was first administered by a logarithm-based cumulative method (14, 22, 35, 56, 89 micrograms/kg) in 10 children anesthetized with thiopental (5 mg/kg), alfentanil (15 micrograms/kg first dose, then 10 micrograms/kg), and N2O/O2 (60:40) until a 95% +/- 2% twitch depression (ED95) was obtained. Thirty children given the same balanced anesthesia were then randomly assigned to three groups (n = 10 in each) to receive a single ED20 (21 micrograms/kg), ED50 (33 micrograms/kg), or ED80 (47 micrograms/kg) intravenous bolus of vecuronium calculated from the mean regression line of twitch responses of the first 10 children. In the second part of the study, 20 children were anesthetized with isoflurane (1.2%) or halothane (0.7%) and compared with the previous 10 children anesthetized with alfentanil-N2O. Potency of vecuronium determined by single-bolus or logarithm-based cumulative techniques was not significantly different. Isoflurane and halothane significantly decreased ED50 (22.3 +/- 1.6 and 25.4 +/- 1.4 micrograms/kg, respectively; mean +/- SE) and ED95 (41.5 +/- 3.3 and 46.7 +/- 3.2 micrograms/kg, respectively) compared with alfentanil-N2O (ED50: 32.8 +/- 0.8 micrograms/kg, ED95: 70.5 +/- 2.6 micrograms/kg). Recovery rate from vecuronium-induced neuromuscular blockade was significantly longer with isoflurane than with alfentanil-N2O or halothane. We conclude that in children single-bolus and logarithm-based cumulative techniques give similar potency estimates for vecuronium. Isoflurane and halothane increase by similar amounts the neuromuscular potency of vecuronium.(ABSTRACT TRUNCATED AT 250 WORDS)