Clinical pharmacology of doxacurium chloride. A new long-acting nondepolarizing muscle relaxant

Doxacurium chloride (BW A938U) is a bis-quaternary benzylisoquinolinium diester nondepolarizing neuromuscular blocking compound that is minimally hydrolyzed by human plasma cholinesterase. The effect of bolus doses of doxacurium ranging from 10 to 80 micrograms/kg were studied in 81 consenting ASA physical status I and II patients anesthetized with nitrous oxide-oxygen-fentanyl-thiopental. The neuromuscular and cardiovascular effects of doxacurium were compared with those of eight patients receiving 100 micrograms/kg of pancuronium receiving identical anesthesia. The calculated ED95 for evoked twitch inhibition of the adductor pollicis at 0.15 Hz was 30 micrograms/kg. At 1.3 times the ED95 dose of doxacurium, recovery times to 5% and 25% of control twitch height were 59.2 +/- 4.1 (n = 23 of 26) and 75.7 +/- 5.6 (n = 23 of 26) min respectively. For pancuronium comparable recovery times were 81.7 +/- 10.3 (n = 8 of 8) and 83.0 +/- 8.4 (n = 5 of 8) min. Residual doxacurium blockade was readily antagonized by neostigmine. No dose-related effect on heart rate or mean arterial pressure was seen with doxacurium at doses up to and including 2.7 times the ED95 (80 micrograms/kg). Doxacurium administration did not result in any elevation of plasma histamine at doses up to and including 2.7 times the ED95. In this study doxacurium appears to be a long-acting nondepolarizing relaxant with readily reversible neuromuscular blocking effects and devoid of cardiovascular effects. This profile offers clinical advantages over current long-acting agents and further clinical trials seem appropriate.     

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.     

NEUROMUSCULAR BLOCK WITH DOXACURIUM (BW A938U) IN PATIENTS WITH NORMAL OR ABSENT RENAL FUNCTION

The characteristics of neuromuscular block inducedby doxacuriumwere compared in patientswith and without renal function. Seventeenpatientswith end stage chronic renal failure and18 patients with normalrenal function were anaesthetized with 0.5% halothane and nitrousoxidein oxygen and received doxacurium in aninitial dose of 25 µgkg^–1 (estimated from availabledata as an ED95 dose), withincremental doses of 5 µg kg^–1. At the end of surgery,residualneuromuscular block was antagonized witheither edrophonium1.0 mg kg^–1 or neostigmine 0.08 mg kg^–1. There wasno significant difference between the mean maximum blocks achievedwith doxacurium: 17.4% (renal failure group)and 11.6% (controlgroup) of control twitch heights, or between the mean timesto achieve maximum block (10.9 min and 10.8 min, respectively).Themean duration of action of doxacurium, indicated by the timefor twitch height to recover to 25% of control, was longerinthe renal failure group (120.8 min vs 66.7 minin the controlgroup) (ns). Similarly, the meanduration of action of incrementswas longer inthe renal failure group (27.4 min vs 20.5 min inthecontrol group). The rate of spontaneous recovery from doxacuriumas indicated by the time for twitch height to recover from 0to 5%, 5 to 10% and 10 to 25%, was not significantly differentin the two groups. Antagonism of doxacurium was achieved morereliably with neostigmine than with edrophonium in bothgroups.The administration of doxacurium was associated with minimalcardiovascular effects. ^*Department of Anaesthetics, St George's Hospital, BlackshawRoad, London SW17 OQT     

“Priming” with neostigmine: failure to accelerate reversal of single twitch and train-of-four responses

Train-of-four stimulation can shorten the apparent onset time of neuromuscular blocking drugs. This study was designed to verify whether the same occurred with neostigmine-assisted recovery, and whether this apparent acceleration could explain the previously reported effectiveness of the priming technique for reversal agents. Fourteen adults received atracurium, 0.5 mg.kg-1, during a thiopentone-nitrous oxide-enflurane anaesthetic. The ulnar nerves of both arms were stimulated with train-of-four stimulation every 12 seconds until 1 per cent recovery of first twitch, at which time stimulation in one arm was switched to single twitch. When mean first twitch height reached 10 per cent of control, neostigmine, 0.04 mg.kg-1, was administered either as a single bolus, or as a "priming" dose of 0.01 mg.kg-1, followed 3 min later by 0.03 mg.kg-1. No statistically significant differences were observed between single twitch in one arm and first twitch height of the train-of-four in the other arm for the next 10 min. With priming, first twitch height was 45 +/- (SEM) 5 per cent at 5 min and 85 +/- 6 per cent at 10 min, compared with 72 +/- 5 per cent (p less than 0.05) and 91 +/- 2 per cent (NS) respectively without priming. Train-of-four ratio was 28 +/- 3 per cent at 5 min and 65 +/- 5 per cent at 10 min with priming, versus 53 +/- 4 per cent (P less than 0.05) and 73 +/- 3 per cent (NS) respectively without priming.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neuromuscular and cardiovascular effects of mivacurium chloride in surgical patients receiving nitrous oxide-narcotic or nitrous oxide-isoflurane anaesthesia

The neuromuscular and cardiovascular effects of mivacurium chloride were studied during nitrous oxide-oxygen narcotic (fentanyl) (n = 90) and nitrous oxide-oxygen isoflurane (ISO) anaesthesia (n = 45). In addition, a separate group (n = 9) received succinylcholine during fentanyl anaesthesia to compare its neuromuscular effects with mivacurium. Mivacurium was initially administered as a single bolus in doses from 0.03 mg.kg-1 to 0.25 mg.kg-1 to study the dose-response relationships, as well as the cardiovascular effects of mivacurium. Neuromuscular block (NMB) was measured by recording the twitch response of the adductor pollicis muscle following ulnar nerve stimulation (0.15 Hz, 0.2 ms supramaximal voltage). The ED95 values for mivacurium were estimated to be 0.073 mg.kg-1 and 0.053 mg.kg-1 in the fentanyl and ISO groups respectively. The duration of block (time from injection to 95 per cent recovery) for a dose of 0.05 mg.kg-1 mivacurium was 15.3 +/- 1.0 min and 21.5 +/- 1.3 min for fentanyl and ISO anaesthesia, respectively. The recovery index (25-75 per cent) between initial bolus dose (6.1 +/- 0.5 min), repeat bolus doses (7.6 +/- 0.6 min), mivacurium infusion (6.7 +/- 0.7 min) and succinylcholine infusion (6.8 +/- 1.8 min) were not significantly different. There was minimal change in mean arterial pressure (MAP) or heart rate (HR) following bolus doses of mivacurium up to 0.15 mg.kg-1. Bolus administration of 0.20 mg.kg-1 or 0.25 mg.kg-1 of mivacurium decreased MAP from 78.2 +/- 2.5 to 64.0 +/- 3.2 mmHg (range 12-59 per cent of control) (P less than 0.05). The same doses when administered slowly over 30 sec produced minimal change in MAP or HR.     

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.     

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.     

Pharmacokinetics and pharmacodynamics of vecuronium (ORG NC 45) in patients with cirrhosis

To evaluate the effect of liver cirrhosis on the pharmacokinetics and the pharmacodynamics of vecuronium, 12 patients with cirrhosis, aged (mean +/- SD) 52 +/- 12 yr, and 14 control patients, 42 +/- 15 yr, undergoing elective surgery under general anesthesia were studied. The simultaneous time courses of the plasma concentration of vecuronium and of the neuromuscular blockade were studied after the administration of a bolus dose of 0.2 mg X kg-1. Vecuronium plasma concentration declined biexponentially in both groups. Vecuronium plasma clearance was reduced significantly (P less than 0.01) from 4.26 +/- 1.38 ml X min-1 X kg-1 in the controls to 2.73 +/- 1.19 ml X min-1 X kg-1 in the patients with cirrhosis. The elimination half-life was 58 +/- 19 min in the controls and was prolonged significantly to 84 +/- 23 min (P less than 0.01) in the patients with cirrhosis. The total apparent volume of distribution was unchanged in patients with cirrhosis (0.253 +/- 0.086 1 X kg-1 vs. 0.246 +/- 0.092 1 X kg-1 in the controls). Cirrhosis caused a prolongation of the neuromuscular blockade induced by vecuronium: the duration of effect from injection to 50% recovery of the twitch height was prolonged by 100% (P less than 0.01) from 62 +/- 16 min in the controls to 130 +/- 52 min in patients with cirrhosis. The recovery rate (TH 25-75) also was prolonged (P less than 0.05) from 21 +/- 7 min in the controls to 44 +/- 18 min in patients with cirrhosis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Potency and time course of mivacurium block during sevoflurane, isoflurane and intravenous anesthesia

PURPOSE: To determine the potency and time course of action of mivacurium neuromuscular block under routine clinical conditions during sevoflurane, isoflurane and intravenous anesthesia. METHOD: Patients were anesthetized with nitrous oxide 66% in oxygen and 1.5 MAC sevoflurane or isoflurane or a propofol infusion, neuromuscular block being monitored using mechanomyography. Potency was determined using administration of single doses of mivacurium of 40-100 micrograms.kg-1 and construction of dose-response curves (n = 72). The onset and duration of action were determined following a bolus dose of 0.2 mg.kg-1 of mivacurium (n = 30). RESULTS: The ED50 and ED95 (with 95% confidence limits) were estimated to be 42 (35-51) and 86 (74-98) micrograms.kg-1, 52 (45-60) and 89 (72-110) micrograms.kg-1, and 53 (45-62) and 95 (81-112) micrograms.kg-1 during sevoflurane, isoflurane and propofol anesthesia respectively (P < 0.05 between sevoflurane and propofol). Following administration of the 0.2 mg.kg-1 dose, neither the times (mean +/- SD) to maximum block (1.6 +/- 0.31, 1.7 +/- 0.21 and 1.6 +/- 0.45 min, respectively) nor the times to 25 and 90% recovery of T1 (20 +/- 4.5 and 33 +/- 8.8 min, 21 +/- 3.8 and 33 +/- 6.5 min, and 18 +/- 4.1 and 28 +/- 5.8 min respectively) were different among groups. The times to recovery of TOF ratio to 0.8 were 40 +/- 10.0, 36 +/- 8.5 and 29 +/- 5.5 min in the sevoflurane, isoflurane and propofol groups respectively (P = 0.017 between the sevoflurane and propofol groups). CONCLUSIONS: Under usual conditions of clinical anesthesia the potency of mivacurium was slightly enhanced during sevoflurane compared with intravenous anesthesia but the duration of action was only minimally prolonged during sevoflurane and isoflurane anesthesia.     

Cumulative dose-response curves for atracurium in patients with myasthenia gravis

The potency of atracurium was determined in five patients with moderate to severe generalized myasthenia gravis undergoing thymectomy. Train-of-four stimulation was applied to the ulnar nerve and the force of contraction of the adductor pollicis was measured. Cumulative dose-response curves were obtained during thiopentone-nitrous oxide-fentanyl anaesthesia. The average time to complete the dose-response studies was 12.7 +/- 1.5 minutes. The ED50, ED90 and ED95 of atracurium were (mean +/- SEM) 0.07 +/- 0.01, 0.12 +/- 0.22, and 0.14 +/- 0.04 mg.kg-1, respectively. The time to 25 per cent first twitch recovery was 35 +/- 4 min following maximum blockade. Ten normal patients were studied in the same manner. Their ED50, ED90 and ED95 were 0.13 +/- 0.01, 0.21 +/- 0.02 and 0.24 +/- 0.03 mg.kg-1, respectively. These results demonstrated that, in patients with moderate to severe generalized myasthenia gravis, atracurium was 1.7-1.9 times as potent as in normal individuals.     

Accelerated reversal of atracurium blockade with divided doses of neostigmine

The hypothesis that administration of neostigmine in divided doses might accelerate the antagonism of neuromuscular blockade was investigated. Neostigmine 0.05 mg X kg-1 was administered either in a single bolus dose (Group I, n = 16) or in an initial dose of 0.01 mg X kg-1 followed three minutes later by 0.04 mg X kg-1 (Group II, n = 16) for antagonism of atracurium-induced blockade. Reversal was attempted at 10 per cent spontaneous recovery of twitch height. The mean time (+/- SD) from the first injection of the drug until the train-of-four (TOF) ratio value had reached 0.75 was significantly shorter in Group II (p less than 0.05) than in Group I (391.8 +/- 83.3 and 468.6 +/- 150.3 seconds respectively). The rate of TOF ratio recovery was 2.5 times faster after neostigmine administration in divided doses. It is concluded that administration of neostigmine in divided doses, as described in this study, produced a significantly faster reversal of residual atracurium-induced neuromuscular blockade as compared to a single bolus administration.     

Atracurium infusion in total intravenous anesthesia

The neuromuscular blocking effect of atracurium given as a bolus dose (0.5 mg X kg-1) followed by a maintenance infusion was studied during two different anesthetic techniques. It has been reported that benzodiazepines interact with non-depolarising neuromuscular blockers. In this study no difference was found in the effect of atracurium given with conventional fentanyl/nitrous oxide anesthesia when compared to total intravenous anesthesia using midazolam/alfentanil. More than 90% twitch depression was achieved after 123 and 137 s, respectively. Recovery time to 10% twitch height following the bolus dose was around 32 min. The dosage range for atracurium given by infusion (0.29-0.44 mg X kg-1 X h-1) was confirmed.     

Atracurium and vecuronium: repeated bolus injection versus infusion.

The purpose of this study was to compare the characteristics of recovery from neuromuscular blockade after either atracurium or vecuronium given by intravenous infusion or by repeated injection. Four groups of 10 patients each were studied during nitrous oxide narcotic anesthesia. An initial intravenous dose of 2 x ED95 of either muscle relaxant was followed by an intravenous infusion started at 5% recovery of control twitch tension and adjusted for 95% block or by repeated injection of 0.6 x ED95 administered whenever twitch tension had returned to 25% of control. There were no significant differences between the maintenance doses required based on method of administration: atracurium repeated injection, 1.6 +/- 0.3 x ED95 h-1; atracurium infusion, 1.7 +/- 0.3 x ED95 h-1; vecuronium repeated injection, 1.8 +/- 0.5 x ED95 h-1; and vecuronium infusion, 1.6 +/- 0.4 x ED95 h-1. Nevertheless, differences of up to 20 min were noted in the recovery indices in the following order: atracurium repeated injection = atracurium infusion less than vecuronium repeated injection less than vecuronium infusion. A single dose of neostigmine (7 micrograms/kg) significantly reduced the recovery indices, thereby eliminating their differences.     

Dose-response relations of doxacurium and its reversal with neostigmine in young adults and healthy elderly patients.

Dose-response relationships for doxacurium and neostigmine were established in 24 young (18-40 yr) and 24 elderly (70-85 yr) patients, ASA physical status I or II, anesthetized with thiopental, fentanyl, nitrous oxide, and isoflurane. Mechanomyographic response of the adductor pollicis muscle to the train-of-four stimulation of the ulnar nerve was recorded. Doxacurium (5, 10, 15, or 20 micrograms/kg IV) was administered by random allocation. After maximal blockade, and additional dose, for a total of 30 micrograms/kg, was administered. When first twitch height recovered to 25%, incremental doses of 5 micrograms/kg were administered for maintenance of relaxation. Neostigmine (5, 10, 20, or 40 micrograms/kg) was injected at 25% first twitch recovery, and neuromuscular monitoring was continued for 10 min. The doses of doxacurium (+/- SEM) required to produce a 50%, 90%, and 95% depression of twitch tension in the young patients were, respectively, 13.3 +/- 1.6, 23.6 +/- 2.8, and 28.6 +/- 3.4 micrograms/kg, not statistically different from corresponding values in the elderly, 11.8 +/- 1.3, 21.2 +/- 2.3, and 25.9 +/- 2.9 micrograms/kg, respectively. Time to 25% recovery after 30 micrograms/kg was 80.2 +/- 12.2 min in the young versus 133.0 +/- 17.1 min in the elderly (P less than 0.05). Neostigmine-assisted recovery was not significantly different in both groups. The estimated doses of neostigmine to obtain 70% train-of-four recovery after 10 min were 53.6 +/- 7.5 micrograms/kg in the young and 41.6 +/- 5.8 micrograms/kg in the elderly (P = NS).(ABSTRACT TRUNCATED AT 250 WORDS)     

Resistance to d-tubocurarine in lower motor neuron injury is related to increased acetylcholine receptors at the neuromuscular junction

The hypothesis that lower motor neuron injury, with its associated proliferation of acetylcholine receptors (AChR), induces resistance to the neuromuscular effects of d-tubocurarine (dTC) was tested in the rat. The left gastrocnemius was denervated by a 75-80% lesion of the sciatic nerve. The effective dose for 95% twitch depression (ED95) was studied in the denervated gastrocnemius and compared to the contralateral undenervated and sham-injured (control) gastrocnemius muscles approximately 2 weeks after injury. The AChR number was quantitated by the specific ligand 125I-alpha-bungarotoxin (125I-alpha-BT). Plasma dTC concentrations, measured by high-performance liquid chromatography (HPLC), were correlated to twitch tension during spontaneous recovery from neuromuscular blockade in the denervated animal. The ED95 (mean +/- SE) of dTC for the denervated leg was significantly (P less than 0.05) higher (0.26 +/- 0.06 mg.kg-1) than contralateral (0.16 +/- 0.03) and sham-operated left (0.13 +/- 0.03) legs. The twitch tension recovered to 50% of control twitch height at significantly (P less than 0.05) higher plasma dTC concentrations in the denervated (0.78 micrograms.ml-1) compared to contralateral (0.24 micrograms.ml-1) limb. The AChR number was significantly increased in the denervated limb (1041 +/- 96 fmol.mg protein-1) compared to contralateral right (109 +/- 4) and control left limb (113 +/- 11). There was a significant (P less than 0.05) positive correlation (R2 = 0.73) between ED95 and AChR number; that is, 73% of the variability in ED95 could be explained by changes in AChR. This study, therefore, confirms the hypothesis that proliferation of AChR after nerve denervation results in resistance to the neuromuscular effects of dTC.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dose-related effects of succinylcholine on the adductor pollicis and masséter muscles in children

This study was performed to determine the effects of various doses of succinylcholine on resting tension and evoked twitch height at the masseter and adductor pollicis muscles in children. Twenty patients, aged 3-10 yr, ASA physical status I or II, were randomly assigned to receive succinylcholine 0.15, 0.25, 0.50 or 1.00 mg.kg-1, during halothane-nitrous oxide anaesthesia. Supramaximal train-of-four stimulation was applied simultaneously to the ulnar nerve and the nerve to the masseter. Transducers recorded force at the jaw and the thumb. Maximum blockade of the first twitch (T1) and maximum resting tension change were measured. Potency of succinylcholine at the two muscles was estimated by linear regression of the logit transformation of T1 versus log dose. The relationship between resting tension change and log dose was established by linear regression. The masseter muscle was more sensitive to succinylcholine than the adductor pollicis with an ED95 of 0.28 +/- 0.02 (mean +/- SEM) vs 0.44 +/- 0.05 mg.kg-1 (P less than 0.05). Onset of neuromuscular blockade was faster at the masseter, and recovery occurred simultaneously in both muscles. A dose-related increase in resting tension was observed in both muscles, but its magnitude was five times greater at the masseter. With succinylcholine, 1 mg.kg-1, this increase was 51.6 +/- 16.8 g at the masseter and 9.1 +/- 2.3 g at the adductor pollicis. Tension returned to baseline within 1-2 min.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ketamine enhances Phase I and Phase II neuromuscular block of succinylcholine

The effect of intravenous injection of ketamine 2, 5 and 10 mg.kg-1 on the neuromuscular blocking action of succinylcholine was studied on the indirectly stimulated adductor pollicis muscle twitch of monkeys anaesthetized with 0.5-1.0 per cent halothane in oxygen. Neuromuscular block was quantified by single twitches evoked at 0.1 Hz. The changing nature of neuromuscular block from Phase I to Phase II was monitored periodically by train-of-four fade. In the absence of succinylcholine, ketamine had no consistent neuromuscular effect of its own. In the presence of succinylcholine, ketamine in a dose-dependent manner potentiated both the Phase I and the Phase II neuromuscular blocking effect of succinylcholine. In Phase I, 2 mg.kg-1 of ketamine reduced the ED50 of succinylcholine from 0.46 +/- 0.07 mg.kg-1 to 0.33 +/- 0.06 mg.kg-1 (P less than 0.01), and increased its 25-75 per cent recovery index from 4.0 +/- 0.4 min to 5.3 +/- 0.1 min (P less than 0.01). In Phase II, ketamine in the same dose deepened a steady neuromuscular block maintained by succinylcholine infusion from 48 +/- 3 per cent block to 71 +/- 2 per cent block (P less than 0.01). We concluded that ketamine potentiates the Phase I and the Phase II neuromuscular blocks of succinylcholine.     

Effect of cimetidine on neuromuscular blockade by succinylcholine and pancuronium

The effect of cimetidine on neuromuscular blockade by succinylcholine and pancuronium was investigated in 54 adult patients scheduled for elective surgery. The neuromuscular blocking properties were estimated with single twitch height (T1) which was obtained by measuring the acceleration of adduction of the thumb in response to the ulnar nerve stimulation under N2O-fentanyl anesthesia. In cimetidine group, cimetidine 200 mg was administered orally on the night before surgery and 90 mins before anesthesia. Succinylcholine 1 mg.kg-1 (n = 14) or 1.5 mg.kg-1 (n = 20) was injected intravenously, and the onset time (from injection to 0% T1), the duration of maximal block (0% T1), and the recovery time from injection to 50% and 75% of control twitch height were evaluated. ED25 and ED50 of pancuronium were calculated from the dose response curve obtained by incremental administration of the drug (n = 20) whose total cumulative dose was 0.1 mg.kg-1. The recovery index of pancuronium was determined by measuring the 25%-75% recovery time. There was no significant difference between cimetidine pretreated patients and non-pretreated patients regarding these parameters of neuromuscular blockade with both succinylcholine and pancuronium. In conclusion, cimetidine has no influence on neuromuscular blockade of succinylcholine and pancuronium under N2O-fentanyl anesthesia.     

Pretreatment with pancuronium before suxamethonium administration in patients heterozygous for the usual and the atypical plasma cholinesterase gene

The object of this study was to investigate whether pretreatment with pancuronium before i.v. injection of suxamethonium could cause prolonged neuromuscular blockade in patients heterozygous for the usual and the atypical plasma cholinesterase gene (E1uE1a). Forty-three patients, 23 with genotype E1uE1a and 20 with normal genotype (E1uE1u), were pretreated with pancuronium 0.01 mg.kg-1 followed by suxamethonium 1.5 mg.kg-1, and received either neurolept anaesthesia or halothane anaesthesia. Seven patients (E1uE1a) were given suxamethonium 1.5 mg.kg-1 without pretreatment. The duration and type of neuromuscular block were evaluated using train-of-four (TOF) nerve stimulation. Type of anaesthesia did not significantly influence the results. The duration of block following pretreatment was significantly longer in heterozygous patients than in normal patients. Time to 90% twitch height recovery was 10.7 +/- 1.2 min (mean +/- s.d.) in genotypically normal patients, and 18.0 +/- 4.2 min in patients with genotype E1uE1a. Pretreatment with pancuronium caused a significantly slower recovery of the TOF ratio (phase II block). Thus, a TOF ratio of 0.7 was always reached within 13 min in genotypically normal patients. In genotypically abnormal patients, the same TOF ratio was reached within 20 min in all but three patients. In these three patients time to 90% twitch height recovery was prolonged (18-31 min), and TOF ratio did not return to normal, but stabilized at about 0.35, 0.50, and 0.65, respectively. Injection of edrophonium restored normal neuromuscular function in 10 min. It is concluded that in patients heterozygous for the usual and the atypical gene, pretreatment with pancuronium in combination with an increased dose of suxamethonium may cause a phase II block and thus a prolonged neuromuscular block.     

Neuromuscular and cardiovascular effects of mivacurium in children

The neuromuscular and cardiovascular effects of mivacurium chloride (BW B1090U) were evaluated in 90 children (2-12 yr) during N2O:O2 halothane or N2O:O2 narcotic anesthesia. Neuromuscular response was evaluated by recording the force of contraction of the adductor of the thumb during train-of-four stimulation at 0.1 Hz. The children were divided into two groups. Patients in group A (n = 45) were anesthetized with N2O:O2 and halothane (1% inspired) and patients in group B (n = 45) were anesthetized with N2O:O2 and fentanyl or morphine. Each group was further divided into five subgroups of nine children. Children in the first three sets of subgroups (A1-A3, B1-B3) received an initial dose of 0.02, 0.04, 0.05, 0.06 or 0.07 mg/kg mivacurium to determine dose response relationships under the different anesthetic regimens. The ED50 and ED95 neuromuscular blocking doses calculated from this single dose technique were 0.051 mg/kg and 0.095 mg/kg, respectively, in children anesthetized with halothane N2O:O2, and 0.059 mg/kg and 0.11 mg/kg in children anesthetized with N2O:O2 narcotic. The fourth subset of each group (A4 and B4) received 0.09 mg/kg and 0.11 mg/kg mivacurium, the estimated ED95 for each respectively. The last subsets (A5 and B5) received 0.2 mg/kg. This dose induced 100% depression of the twitch response in all 18 patients in 1.8 +/- 0.1 min, with recovery to 5%, 25%, and 95% of control occurring in 8.4 +/- 0.5, 11.2 +/- 0.6 and 18.4 +/- 1.6 min, respectively. The recovery indices for all patients were 4.6 +/- 0.6 min for 25-75% recovery and 9.7 +/- 1.3 min for 5-95% recovery.(ABSTRACT TRUNCATED AT 250 WORDS)