Comparative cardiotoxicity of bupivacaine and lidocaine in the isolated perfused mammalian heart

This study was designed to compare the direct actions of bupivacaine and lidocaine on the isolated perfused guinea pig Langendorff heart preparation. Sixty min after mounting, either bupivacaine HCl (0.3 or 3 micrograms/ml) or lidocaine HCl (10 or 30 micrograms/ml) was added to the perfusate, and the effect (if any) was compared to untreated control values 30, 60, and 90 min later. Although the highest concentrations of both drugs invariably produced statistically significant reductions in heart rate, df/dt, coronary blood flow, and myocardial oxygen consumption (MVO2), these reductions were consistently greater after bupivacaine. Moreover, arrhythmias occurred in 6 of 12 preparations in those hearts exposed to 3 micrograms/ml of bupivacaine. Most often these arrhythmias consisted of heart block and bi- or trigeminy. Additional studies indicated that the reduction in coronary blood flow and MVO2 produced by 3 micrograms/ml of bupivacaine was a consequence of its direct negative inotropic and chronotropic action. Although the myocardial depression produced by bupivacaine and lidocaine could be reversed readily by substituting fresh perfusate, increasing the extracellular calcium concentration in stepwise increments did not augment the negative inotropic or chronotropic effect produced by 3 micrograms/ml of bupivacaine or 10 micrograms/ml of lidocaine. We conclude that 3 micrograms/ml of unbound bupivacaine is more cardiotoxic than 30 micrograms/ml of unbound lidocaine in this model.     

Assessment of the Presynaptic Effect of Atracurium: Train-of-Four and Tetanic Stimulation in in Vitro Preparations

The present experiments were designed to study the effect of atracurium on the contractile responses produced by repetitive motor nerve stimulation and by depolarizing drugs in frog, chick and rat skeletal muscle-nerve preparations, using electrophysiological and neurochemical techniques. The presynaptic effect of atracurium was assessed using train-of-four (2 Hz) and tetanic stimulation (50 Hz) in isolated chick and rat neuromuscular junctions. A further measure of the presynaptic effect of atracurium was examined by studying its effect on the uptake of labelled choline, 3H-methylcholine, in the control preparations. The effect of atracurium on postjunctional contractile responses of the chick isolated biventer cervicis skeletal muscle was studied using cholinergic drugs such as acetylcholine and tetraethylammonium. The results indicated that in addition to its postjunctional competitive and non-depolarizing blocking effect, atracurium may have a prejunctional inhibitory action at the neuromuscular junction. Atracurium reduced all the contractile responses produced by both electrical and chemical stimulation.     

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.     

Neuromuscular effects of atracurium during halothane-nitrous oxide and enflurane-nitrous oxide anesthesia in humans

To compare the effect of halothane and enflurane on an atracurium-induced neuromuscular blockade, the authors studied 40 patients during elective surgery. During 1.25 MAC enflurane-nitrous oxide (n = 20) or halothane-nitrous oxide (n = 20) (MAC value includes contribution from 60% nitrous oxide), the doses depressing twitch tension 50% (ED50S) for atracurium were 70 and 77 micrograms/kg, respectively. The difference was not significant. Time from injection to peak effect did not differ between groups. However, the duration of action of atracurium (expressed as duration 50 or the duration of a 50% blockade) was longer during enflurane-nitrous oxide anesthesia (34.2 min) than during halothane-nitrous oxide anesthesia (25.5 min) (P less than 0.05). The authors conclude that the potency of atracurium does not differ during halothane-nitrous oxide and enflurane-nitrous oxide anesthesia. Combining the results of this study with a previous study (atracurium ED50 = 68 micrograms/kg and 83 micrograms/kg during isoflurane-nitrous oxide and fentanyl-nitrous oxide anesthesia respectively), the potency of atracurium does not differ by more than 20% among the four anesthetic techniques studied. The background anesthetic appears to have less effect on an atracurium-induced neuromuscular blockade than on one produced by other longer-acting nondepolarizing muscle relaxants (e.g., pancuronium and d-tubocurarine).     

Atracurium infusion requirements in children during halothane, isoflurane, and narcotic anesthesia

We were interested in determining the dose-response relationship of atracurium in children (2-10 yr) during nitrous oxide-isoflurane anesthesia (1%) and the atracurium infusion rate required to maintain about 95% neuromuscular blockade during nitrous oxide-halothane (0.8%), nitrous oxide-isoflurane (1%), or nitrous oxide-narcotic anesthesia. Neuromuscular blockade was monitored by recording the electromyographic activity of the adductor pollicis muscle resulting from supramaximal stimulation at the ulnar nerve at 2 Hz for 2 sec at 10-sec intervals. To estimate dose-response relationships, three groups of five children received 80, 100, 150 micrograms/kg atracurium, respectively. During isoflurane anesthesia, the neuromuscular block produced by 80 micrograms/kg was 23.6% +/- 6.5 (mean +/- SEM), by 100 micrograms/kg was 45% +/- 7.2, and by 150 micrograms/kg was 64% +/- 8.7. The ED50 and ED95 (estimated from linear regression plots of log dose vs probit of effect) were 120 micrograms/kg and 280 micrograms/kg, respectively. At equipotent concentrations, halothane and isoflurane augment atracurium neuromuscular block to the same extent, compared to narcotic anesthesia. Atracurium steady-state infusion requirements averaged 6.3 +/- 0.6 micrograms . kg-1 . min-1 during halothane or isoflurane anesthesia; the requirements during balanced anesthesia were 9.3 +/- 0.8 micrograms . kg-1 . min-1 (P less than 0.05). There was no evidence of cumulation during prolonged atracurium infusion.     

不同时间失神经支配对小鼠骨骼肌乙酰胆碱受体活性的影响

目的 探讨不同时间失神经支配对小鼠骨骼肌乙酰胆碱受体(AChRs)活性的影响.方法 Balb/C小鼠14只,体重18～22 g.采用切断坐骨神经的方法制备骨骼肌失神经支配模型.于切断坐骨神经前(T0)、切断后1、4、7、14、21和28 d(T1～6)时取2只小鼠,急性分离趾短屈肌后,急性分离骨骼肌细胞,每只小鼠取5个骨骼肌细胞,采用全细胞膜片钳技术记录模式.骨骼肌细胞先用含30μmol/L乙酰胆碱的细胞外液灌注10 s,记录乙酰胆碱电流(I1),随后细胞外液冲洗60 s,然后依次用含0、0.1、1、10、30、100、1000、3000或10 000 nmol/L阿曲库铵的细胞外液平衡灌注3 min,再用含30 μmol/L乙酰胆碱和上述不同浓度阿曲库铵的细胞外液分别灌注10 s,记录乙酰胆碱电流,随后细胞外液冲洗60s,再次用含30 μmlo/L乙酰胆碱的细胞外液灌注10 s,记录乙酰胆碱电流(I2),取I1和I2的平均值作为对照电流,计算对照电流抑制百分比,采用非线性回归分析计算阿曲库铵阻滞AChRs的半数有效抑制浓度(IC50).结果 与T0时比较,T1～6时阿曲库铵IG0升高(P＜0.05)；T1～3时阿曲库铵IG0逐渐升高(P＜0.05)；与T3时比较,T4～6时阿曲库铵IC50逐渐降低(P＜0.05).结论 骨骼肌失神经支配可抑制AChRs的活性,该效应与骨骼肌失神经支配的时间有关.     

Influence of age on the dose-response relationship of atracurium in paediatric patients

To assess the influence of age on the dose-response relationship of atracurium in paediatric patients during thiopental-fentanyl-N2O-O2-anaesthesia, we studied 85 patients from neonates to adolescents. Each patient was given two doses of atracurium: following the maximum EMG response to the first dose of 150 micrograms/kg, an individual second dose was given, to produce exactly 95% neuromuscular block. The onset time of atracurium (time from administration to maximum effect) was shortest in neonates (2.6 min) and infants (3.3 min) and longest in adolescents (5.5 min) (P less than 0.01). The dose-response curves were parallel in all patients aged 3 months or older. The ED95 of atracurium was comparable for neonates and infants (226 micrograms/kg). This was 28% less than the ED95 for patients aged 1 year or older (316 micrograms/kg) (P less than 0.01). The results explain the slightly longer-lasting neuromuscular block in infants as compared to children following a constant atracurium dose in micrograms/kg. The great individual variability of the neuromuscular response, however, indicates that neuromuscular monitoring is essential in paediatric patients.     

Effect of atracurium on twitch, tetanic and post-tetanic twitch responses at the rat neuromuscular junction

The effect of atracurium on the phenomenon of post-tetanic potentiation, which is believed to be of a presynaptic origin, i.e. due to endogenous transmitter release, was investigated to see if atracurium had a presynaptic inhibitory mechanism at the rat neuromuscular junction. The results showed that atracurium (0.8-80 microM) reduced the indirectly elicited twitch, tetanic and post-tetanic twitch tensions, in a dose-dependent manner. Atracurium (1 microM) produced a tetanic fade in the preparations stimulated at 20 Hz and above. The acetylcholine (ACh) released at high frequencies of nerve stimulation was collected, in the presence of physostigmine (0.77 microM), added to a rat ileum preparation, in which it produced a small contraction which was blocked by atracurium (1 microM), which in turn blocked the contracture produced by ACh (1 microM) added directly to the organ bath. It was concluded that, in addition to its well-known competitive blockade of postsynaptic ACh receptors, atracurium may also have a presynaptic inhibitory effect at the neuromuscular junction.     

Clinical pharmacology of atracurium in infants

The neuromuscular effects of atracurium were studied in 25 infants anesthetized with 1.0% end-tidal halothane and N2O-O2. Neuromuscular blockade was monitored by recording the electromyographic activity of the adductor pollicis muscle resulting from supramaximal stimulation of the ulnar nerve at 2 Hz for 2 sec at 10-sec intervals. To estimate dose-response relationships, three groups of five infants received 60, 80, and 100 micrograms/kg atracurium, respectively; another ten infants received 300 micrograms/kg (2 X ED95). The neuromuscular block produced by 60 micrograms/kg was 27% +/- 10.9 (SEM), by 80 micrograms/kg was 34% +/- 8.0 and from 100 micrograms/kg was 70% +/- 8.3. The ED50 and ED95 (estimated from linear regression plots of log dose vs probit of effect) were 85 micrograms/kg and 150 micrograms/kg, respectively. Neuromuscular blockade lasted 23 +/- 1.6 min at 1 X ED95 and 32.5 +/- 5.2 min at 2 X ED95. Changes in heart rate and mean arterial pressure were clinically insignificant.     

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)     

Pharmacologic basis of responses to midazolam in the isolated, cross-perfused, canine right atrium

The effects of midazolam on atrial rate and contractile force in the isolated canine atrium perfused with donor blood were investigated. When midazolam in a dose range of 100-1000 micrograms was injected directly into the sinus node artery of the isolated atrium, biphasic (negative followed by positive) chronotropic and triphasic (positive, negative followed by positive) inotropic effects were induced. After propranolol or imipramine, the positive chronotropic and the secondary positive inotropic effects were significantly suppressed, but the initial positive inotropic effect was not affected. Tetrodotoxin, atropine, or R05-4864, a selective ligand for peripheral benzodiazepine binding sites, did not modify midazolam-induced effects. When midazolam in a dose of 0.1-1 mg/kg was administered intravenously to the donor dog, monophasic negative chronotropic and inotropic effects in the isolated atrium were observed but were not as prominent. We conclude that midazolam has direct cardiac inhibitory properties including catecholamine release due to a tyramine-like action.     

Plasma concentrations of laudanosine, but not of atracurium, are increased during the anhepatic phase of orthotopic liver transplantation in pigs

To quantify the changes in plasma concentrations of atracurium and laudanosine induced by the lack of hepatic function and circulation, the authors studied nine domestic pigs (22-25 kg) undergoing an orthotopic liver transplantation, and three control animals without surgery, using atracurium as the muscle relaxant. After intubation facilitated by isoflurane 2-3%, anesthesia was maintained with isoflurane (0.5% in oxygen) and fentanyl (4 micrograms.kg-1.hr-1). Ventilation was controlled to keep end-tidal CO2 at 35-40 mmHg, body temperature maintained at 35.5-37.5 degrees C, and arterial pH at 7.35-7.50. The right sciatic nerve was stimulated with a nerve stimulator delivering a single twitch at 0.1 Hz with 0.2-ms duration, at supramaximal stimulation. The force of the corresponding evoked isometric muscle contraction was continuously measured by a force-displacement transducer. A single iv bolus of atracurium (2 mg/kg) was given to obtain a 90-95% twitch depression, followed 5 min later by a constant-rate iv infusion of atracurium at 120 micrograms.kg-1.min-1 maintained during the entire investigation. Blood samples for plasma atracurium and laudanosine concentrations were drawn every 15 min. In the control group, plasma concentrations of atracurium remained stable between 6.5-8.0 micrograms/ml following initial bolus injection; plasma concentrations of laudanosine increased during the first 60 min, then remained stable between 0.69-0.74 micrograms/ml up to the end of the study. In animals undergoing transplantation, plasma concentrations of atracurium remained stable between 10-12 micrograms/ml, despite a 90-min duration of liver exclusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

The prolonged use of atracurium in a patient with tetanus

A case of a patient with tetanus is reported in whom an atracurium infusion and artificial ventilation were needed in addition to sedation to control the muscle spasms. The atracurium infusion was used for 71 days, the longest time ever recorded, at a mean rate of 1.3 mg/kg/hour at the end of infusion. The plasma atracurium and laudanosine concentrations were 1.5 micrograms/ml and 0.985 micrograms/ml respectively. Subsequently there was an exponential decline in the serum laudanosine concentration which had decreased to 0.014 micrograms/ml 24 hours later. These results suggest that prolonged use of atracurium by infusion is not associated with excessive cumulation of laudanosine when renal and hepatic function are normal.     

Effects of volatile anesthetics on response to norepinephrine and acetylcholine in guinea pig atria

The in vitro chronotropic and inotropic effects of norepinephrine and acetylcholine in isolated right and left guinea pig atria were examined in the absence and presence of halothane, isoflurane, and enflurane (0.6 and 1.2 MAC). All three anesthetics elicited dose-dependent reductions in contractile force and spontaneous pacemaker activity. The maximal developed tension observed in the presence of norepinephrine was not altered by the anesthetics and corresponding ED50 values increased only in the presence of 1.2 MAC halothane and 1.2 MAC isoflurane. The anesthetics did not affect (a) the maximal positive chronotropic effect of norepinephrine, (b) the ED50 values for its positive chronotropic effect, and (c) acetylcholine-induced negative inotropic and chronotropic actions and did not induce arrhythmic activity even in the presence of the maximally effective neurotransmitter concentrations. These findings indicate that in isolated guinea pig atria volatile anesthetics, in concentrations up to 1.2 MAC, do not alter the inotropic and chronotropic effects of norepinephrine or acetylcholine and do not induce arrhythmogenic action in the presence of the neurotransmitters. These data suggest that altered atrial responsiveness to adrenergic or muscarinic stimulation does not contribute to the development of anesthetic-induced cardiac arrhythmias.     

Oral dantrolene prevents rise of myoglobin due to suxamethonium

Forty patients were studied in a randomised trial to investigate the effect of pre-operative oral dantrolene on the increase of serum myoglobin and creatinine kinase due to suxamethonium administration. Twenty patients in the treatment group were given 1.5 mg/kg dantrolene orally 4 hours pre-operatively. Blood was drawn immediately pre-induction and 5, 10 and 20 minutes after suxamethonium 1.2 mg/kg administration, following which surgery could commence. Myoglobin was measured by radioimmunoassay. The increase in mean myoglobin values was greatly reduced following suxamethonium in the treatment group (10.6 micrograms/litre at 20 minutes) compared to the control group (54.8 micrograms/litre at 20 minutes), (p less than 0.01). Total fasciculation score was not significantly reduced by the dantrolene pretreatment. No increase in creatinine kinase values occurred in any patient and the changes in mean potassium values in both groups were negligible. The only side effect attributed to dantrolene was pre-operative nausea in two patients. No interference with the action of suxamethonium, or difficulty with reversal was noticed. Oral dantrolene may be almost as effective as pretreatment with non-depolarising neuromuscular blocking drugs in preventing suxamethonium-induced increase in myoglobin with less interaction with other anaesthetic agents.     

Use of vecuronium bromide and atracurium besylate in continuous intravenous infusion in urologic surgery

The effects of continuous i.v. infusion of atracurium and vecuronium monitored by TOF supplied by an ABM monitor have been compared in 60 patients subdivided into four groups and submitted to anaesthesia with isoflurane for urological surgery interventions. Groups A and V received respectively an initial bolus of 0.5 mg/kg atracurium and of 0.08 mg/kg vecuronium followed immediately by continuous i.v. infusion of 5.5 micrograms/kg/min. Atracurium or 0.9 micrograms/kg/min of vecuronium; recovery of neuromuscular function happened spontaneously. Groups A' and V' differed by virtue of the use of 0.04 mg/kg prostigmin in the recovery phase. Average consumption of atracurium and vecuronium were respectively 5.1 +/- 1.75 micrograms/kg/min (2.6-9.03) and 0.75 +/- 0.20 micrograms/kg/min (0.5-1.2) in groups A-A' and V-V'. In groups A and V Recovery time 25-75" of T1 and TR presented a statistically significant difference (p less than 0.05) in favour of atracurium. In groups A' and V' the same parameters presented a statistically non-significant difference (p greater than 0.05). The ratio TI/TR does not vary to a statistically significant extent in the 4 groups. The number of infusion rate variations needed to maintain stable neuromuscular block was lower in the atracurium groups.     

Supersensitivity mismatch of adenosine in the transplanted human heart: chrono- and dromotropy versus inotropy

Supersensitive negative chronotropic and dromotropic effects have been described for adenosine after human heart transplantation. The present study investigated a potential antiadrenergic negative inotropic effect of adenosine in heart transplant recipients compared to normal subjects. Sinus cycle length, PR interval, blood pressure, and inotropic response in vivo were compared in seven orthotopic heart transplant recipients and seven healthy volunteers (controls). Fractional shortening, velocity of circumferential fiber shortening, and systolic pressure/dimension ratio were calculated using M-mode echocardiography. Baseline ventricular contractility was normal in both groups. Although adenosine induced a significant exaggeration of the negative chronotropic and dromotropic effect in the transplant group, the positive inotropic effect of 20 ng/kg x min isoproterenol (FS 53.2±8.8 vs 51.0±4.6 %, P/D 5.8±1.9 vs 6.0±0.8 mm Hg/mm, V_cf 0.21±0.04 vs 0.20±0.02 %/ms for heart recipients vs controls) was not reduced by the additional administration of 150 g/kg adenosine (FS 52.2±8.6 vs 51.7±5.6 %, P/D 5.5±1.5 vs 5.4±0.8 mm Hg/mm, V_cf 0.24±0.07 vs 0.21±0.02 %/ms for transplant recipients vs controls). In contrast to a chronotropic and dromotropic supersensitivity, adenosine does not attenuate the catecholamine-induced increase in contractility in the human ventricle in vivo after heart transplantation.     

The mechanism of the positive chronotropic action of diethyl ether on rat atria.

Diethyl ether elicited a dose-dependent increase in the intrinsic frequency of contraction of isolated rat atrial preparations. The maximum effect (plus 34 per cent) occurred with 230 mg ether/100 ml medium. This ether concentration corresponds to a partial pressure of 29.2 mm Hg or 3 MAC. The positive chronotropic action of ether was not reduced in atria obtained from rats pretreated with reserpine (4 mg/kg, ip) although this treatment markedly reduced the effect of tyramine on frequency of contraction. The positive chronotropic response to 0.01 muM isoproterenol was inhibited by the beta-adrenergic antagonist 0.3 mgM dl-propranolol but remained unimpaired in the presence of 0.3 mgM d-propranolol (a much weaker antagonist). In contrast, the atrial response to ether was similar in the presence of either d- or dl-propranolol. Atropine, in concentrations that completely blocked the negative chronotropic action of acetylcholine, did not increase the frequency of contraction, suggesting that the positive chronotropic effect of ether is not due to an atropine-like activity of ether. Our results indicate that the positive chronotropic effect of ether on isolated rat atrial preparations is not mediated via catecholamine release, nor does it represent direct stimulation of beta-adrenergic receptors or block of cholinergic receptors. (Key words: Anesthetics, volatile, diethyl ether; Heart, atria, diethyl ether.).     

Priming doses of atracurium and vecuronium depress swallowing in humans.

The administration of low doses of muscle relaxant may cause peripheral muscular weakness including difficulty in swallowing. In the present study, the effect of priming doses of atracurium and vecuronium on swallowing was studied. Sixty patients undergoing elective surgery under general anesthesia were divided randomly into four groups of 15 patients and received as a priming dose either vecuronium (10 or 15 micrograms/kg) or atracurium (50 or 75 micrograms/kg). Swallowing muscle activity was measured by electromyography using submental surface electrodes. Swallowing was initiated by administration of 0.3 ml distilled water through an oral catheter. Swallowing reflex was determined by measuring the latency time (i.e., time from water administration to start of EMG activity of glossal muscles). Swallowing activity was determined by integration of the EMG of glossal muscles during swallowing. Peripheral muscle strength was determined by hand grip strength. Swallowing reflex activity and peripheral muscle strength were measured before and 3 and 6 min after administration of vecuronium or atracurium. Latency time remained unchanged after any of the priming doses. Integrated EMG decreased significantly (P < .001) 3 and 6 min after all priming doses tested (42-75% of baseline value). Only after atracurium 75 micrograms/kg was the hand grip strength significantly decreased (P < .01). These results suggest that owing to its effect on swallowing, the priming dose should be used with caution.     

Train–of–four fade during onset of neuromuscular block with nondepolarising neuromuscular blocking agents

Fade in the train-of-four (TOF) responses during onset of neuromuscular block was studied following administration of atracurium (225 or 450 micrograms/kg), vecuronium (40 or 80 micrograms/kg), pancuronium (60 or 120 micrograms/kg) and tubocurarine (450 micrograms/kg). TOF ratios were measured at approximate heights of T1 (first response in the TOF) of 75, 50 and 25%. Fade in TOF increased as the height of T1 decreased, with maximum fade being observed at T1 of 25%. The greatest difference between relaxants was observed at T1 of 25%, vecuronium showing the least fade and pancuronium, atracurium and tubocurarine showing increasing fade, in that order. The difference between atracurium and tubocurarine or between vecuronium and pancuronium was not significant, but the degree of TOF fade was significantly greater with atracurium and tubocurarine in comparison to vecuronium or pancuronium.