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Backgroundthis study aims to evaluate the efficacy of Levo-bupivacaine with the addition of a small dose of cisatracurium by sub-Tenon’s injection on akinesia and mydriasis. Then, to evaluate if such a small dose of cisatracurium could determine a systemic neuromuscular blockade, despite the way of administration. Forty cats were anesthetized for intra-ophthalmic surgery with butorphanol 0,2 mgkg-1, dexmedetomidine 15 mcg/kg and midazolam 0,2 mgkg-1 IM and intubated to receive oxygen and isofluorane by mechanical ventilation. The animals were divided in four groups. Group L received 1.25 mgkg-1 L-bupivacaine, administered by peribulbar injection; group CL received the same dose of L-bupivacaine, combined with 0.01mg/kg of cisatracurium; group C received 0.01 mg kg-1 of peribulbar cisatracurium; group GC received 0.01 mg kg-1 of cisatracurium intravenously. Physiological variables and oculomotor activity were measured before and up to 30 minutes after peribulbar injection.ResultsThe data below, expressed with median and range, show that physiological variables remained in the physiological range. Among the treatments, the LC group showed akinesia, higher midriasis and a decrasing intraocular pressure (IOP); the onset time of akinesia was significantly shorter in group LC than in group L 4(3/5) min and 8(6/10) min respectively, p=0.000; the duration of akinesia was longer in group LC than in group L, 70(68/72) and 60(57/63min), respectively p=0.000. In group C we observed the appearance of akinesia after 5(5/5) minutes from the peribulbar administration and it lasted for 20(20/20) minutes (p=0.000), compared to groups L and LC. In group GC we registered akinesia after 5(5/5) minutes, but the duration observed was shorter 5(5/6). In groups C and GC, additional L bupivacaine peribulbar injection was required. The train of four (TOF) was ≥ 0.9 throughout the study in all of the groups. ConclusionsA combination of cisatracurium and L-bupivicaine, used for peribulbar sub-Tenon’s anesthesia, provides effective akinesia, midriasis of the eye, shortens the onset of akinesia and prolongs its duration, thus providing excellent conditions for intra-ophthalmic surgery, without incurring in a systemic blockade.

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.

Mast cells are primary effectors in allergic reactions, and may have important roles in disease by secreting histamine and various inflammatory and immunomodulatory substances. Although they are classically activated by immunoglobulin (Ig)E antibodies, a unique property of mast cells is their antibody-independent responsiveness to a range of cationic substances, collectively called basic secretagogues, including inflammatory peptides and drugs associated with allergic-type reactions. The pathogenic roles of these substances have prompted a decades-long search for their receptor(s). Here we report that basic secretagogues activate mouse mast cells in vitro and in vivo through a single receptor, Mrgprb2, the orthologue of the human G-protein-coupled receptor MRGPRX2. Secretagogue-induced histamine release, inflammation and airway contraction are abolished in Mrgprb2-null mutant mice. Furthermore, we show that most classes of US Food and Drug Administration (FDA)-approved peptidergic drugs associated with allergic-type injection-site reactions also activate Mrgprb2 and MRGPRX2, and that injection-site inflammation is absent in mutant mice. Finally, we determine that Mrgprb2 and MRGPRX2 are targets of many small-molecule drugs associated with systemic pseudo-allergic, or anaphylactoid, reactions; we show that drug-induced symptoms of anaphylactoid responses are significantly reduced in knockout mice; and we identify a common chemical motif in several of these molecules that may help predict side effects of other compounds. These discoveries introduce a mouse model to study mast cell activation by basic secretagogues and identify MRGPRX2 as a potential therapeutic target to reduce a subset of drug-induced adverse effects.

A liquid chromatography-electrospray-mass spectrometry technique for the screening and determination of five non-depolarizing neuromuscular blocking agents (NDBAs), atracurium and its product of degradation/metabolite laudanosine, rocuronium, pancuronium, vecuronium, and mivacurium has been developed using ambenonium as the internal standard (I.S.). Samples were acidified upon reception by adding 20 micro L 0.5M H(2)SO(4) to 500 micro L of biofluid. Sample preparation consisted of simple blood purification and/or protein precipitation using 1 mL I.S. in acetonitrile. Chromatographic separation was carried out on an X-TERRA trade mark column along with a gradient of acetonitrile in 2mM ammonium formate (pH 3). Detection was carried out in the positive selected ion monitoring mode, targeting one quantitation ion and one confirmation ion per compound. The limit of quantitation was 2.5 micro g/L for mivacurium and laudanosine, 5 micro g/L for rocuronium and pancuronium and 10 micro g/L for atracurium and vecuronium in serum (i.e., in the range of, or less than, therapeutic levels). The technique was found to be linear between the respective LOQs and 2000 micro g/L, with correlation coefficients higher than 0.999 in all matrices. Intra- and interday precision and accuracy in serum fulfilled the international criteria. This method was employed for the investigation of a case of suicide by infusion of drugs. Laudanosine, the metabolite or degradation product of both atracurium and cisatracurium, and rocuronium were found in urine and whole blood, at supratherapeutic concentrations in the latter (rocuronium: 1.53 and 2.18 mg/L, laudanosine: 8.86 and 0.31 mg/L, respectively), and even therapeutic concentrations would have been lethal in the absence of respiratory assistance.

Muscle relaxants and anesthetics are usually associated during intubation. However, their relative role to facilitate the process is not clearly defined. This study was designed to determine, during intubation: i). the relative role of anesthetics and atracurium-induced neuromuscular block and; ii). the effect of different doses of propofol in the presence of complete muscle block.Patients were randomized to four groups and received fentanyl and a standardized anesthetic procedure. Patients from groups high (H; n = 45), medium (M; n = 48) and low (L; n = 47) received 2.5 mg x kg(-1), 2.0 mg x kg(-1), and 1.5 mg x kg(-1) of propofol respectively. Atracurium (0.5 mg x kg(-1)) was then injected and tracheal intubation performed once complete block was achieved at the orbicularis oculi. Patients from group without atracurium (WA; n = 20) received propofol as in group H. Intubation was performed at the expected onset time of action of atracurium.Using the same dose of propofol, the incidence of good or excellent intubating conditions was 35% without atracurium and 95% with atracurium (P0.0001). In patients receiving atracurium, clinically acceptable intubating conditions were more frequently achieved in groups receiving the highest propofol doses (group H or M vs group L; P0.03).Our study confirms the interaction between anesthesia and muscle relaxation to produce adequate intubating conditions. In the conditions described, intubating conditions were more dependent on atracurium-induced neuromuscular blockade than on anesthetics, but both atracurium and propofol improved intubating conditions.

Background. Postoperative residual curarization (PORC) after surgery is common and its detection has a high error rate. Artificial neural networks are being used increasingly to examine complex data. We hypothesized that a neural network would enhance prediction of PORC. Methods. In 40 previously reported patients, neuromuscular function, neuromuscular block/ antagonist usage and time intervals were recorded throughout anaesthesia until tracheal extubation by an observer uninvolved in patient care. PORC was defined as significant ‘fade’ (train of four

Background Residual paralysis following the use of neuromuscular blocking drugs remains a clinical problem. As part of departmental quality assurance, we examined the degree of postoperative residual curarization (PORC) following atracurium. Methods Forty patients undergoing general anaesthesia involving atracurium were studied. Quantitative neuromuscular monitoring (mechanomyography, Myograph 2000, Biometer, Denmark) was performed by assessing the response to supramaximal train-of-four (TOF) stimulation of the ulnar nerve. Anaesthesia was provided by non-participating clinicians who were blinded to the study data. A TOF ratio ≤0.7 at extubation was classified as PORC. Results At antagonism of neuromuscular block, 70% (28/40) of patients had a TOF ratio ≤0.7, and 65% (26/40) of patients had a TOF ratio ≤0.7 at extubation. Peripheral nerve stimulator use was associated with a longer interval from antagonism of block to extubation (P=0.01), but was not associated with differences in atracurium dosage or a reduction in PORC at extubation. Patients with TOF ratio ≤0.7 at extubation had surgery of shorter duration [59 ( sem 6) vs 103 (9) min, P Conclusions PORC remains a clinical problem despite use of intermediate-duration neuromuscular blocking drugs and peripheral nerve stimulators. Patients undergoing procedures of short duration may be at risk of inappropriately early tracheal extubation, possibly due to work pressures. The association between suboptimal antagonism of neuromuscular blockade and short procedures needs reinforcement during postgraduate training and departmental quality assurance.

The present study was designed to assess the pharmacodynamics and the plasma levels of atracurium and laudanosine found during a 72-hour fixed rate infusion of atracurium in acute respiratory distress syndrome patients without renal or liver failure. Nine sedated and mechanically ventilated acute respiratory distress syndrome patients without renal or liver failure were paralysed with a bolus of atracurium (1 mg.kg -1 ) followed by a 72-hour continuous infusion (1 mg.kg -1 .h -1 ). The count of train-of-four (TOF) and TOF ratio were monitored by an accelerograph until full neuromuscular recovery (T4/T1 0.7). Atracurium and laudanosine concentrations were measured from the onset to four days after cessation of the infusion. An electroencephalogram was recorded daily. Analysis showed that TOF count was always 3 until cessation of the infusion. Following cessation, neuromuscular recovery occurred between 31 and 96 minutes (median value=45 min). The highest atracurium and laudanosine concentrations ranged from 3.3 to 5.8 μg.ml –1 and from 3 to 20 μg.ml –1 respectively. In four patients with renal impairment, the highest laudanosine concentration was > 10 μg.ml –1. No seizure was recorded. A fixed infusion rate of atracurium in acute respiratory distress syndrome patients provided an effective muscle paralysis with a rapid neuromuscular recovery but can lead to accumulation of laudanosine in patients with renal impairment.

Background We assessed the role of ester hydrolysis as an additional degradation mechanism to Hofmann elimination in the breakdown of cisatracurium and atracurium. Methods Cisatracurium and atracurium were incubated in phosphate buffer (pH 7.4, 37°C) with and without the addition of carboxylesterase. Control measurements with an added esterase inhibitor were performed separately. Cisatracurium/atracurium and their degradation products, laudanosine and monoquaternary acid, were analysed using high-pressure liquid chromatography. Results Degradation of cisatracurium and atracurium proceeded exponentially, and after addition of carboxylesterase, no significant differences in the degradation rates were found. Neither an increase in carboxylesterase activity nor the addition of esterase inhibitor showed any effect. However, areas under the peaks of the chromatogram representing monoquaternary acid increased during incubation with esterase. Conclusion The rate-limiting step in the degradation of cisatracurium/atracurium is Hofmann elimination. Ester hydrolysis is involved in the second degradation step that forms monoquaternary acid, but its contribution to the total elimination rate is negligible.

We tested the influence of atracurium and cisatracurium (final concentrations: 0, 0.96, 3.2, 9.6, 32, and 96 microM) on proliferation of human cells (hepatoma HepG2 cells and human umbilical vein endothelial cells) in vitro. In additional experiments, glutathione, N-acetylcysteine, or carboxyl esterase was added before the addition of either relaxant. The number of cells counted after 72 h of incubation was expressed as a percentage of the mean cell number in wells incubated without additives. Atracurium and cisatracurium progressively decreased cell proliferation in a concentration-dependent pattern. With human umbilical vein endothelial cells, atracurium or cisatracurium (3.2 microM) decreased the cell count to 67.7 % (SD, 14.8%) and 50% (SD, 8.6%), respectively. Cell proliferation was not inhibited by mivacurium. The results were similar to those with HepG2 cells. Glutathione, N-acetylcysteine, and carboxyl esterase partially reversed the effects of atracurium and cisatracurium. When incubated in a buffer with glutathione, atracurium decreased the number of glutathione-sulfhydryl groups. The findings that atracurium and cisatracurium inhibit proliferation of human cell lines in vitro, but that mivacurium does not, and that this effect is alleviated by glutathione and N-acetylcysteine, as well as by the carboxyl esterase, indicate that the inhibition may be caused by the reactive acrylate metabolites.

UNLABELLED The purpose of this investigation was to compare the costs of intermediate-acting neuromuscular blocking drugs in children during routine ambulatory surgery. We studied 200 healthy, 2-10-yr-old children undergoing elective dental restorative surgery. During Part 1 of the study, children received an inhaled anesthetic with halothane and nitrous oxide, whereas in Part 2, the anesthetic was IV propofol with nitrous oxide. The study drugs were atracurium, cisatracurium, mivacurium, rocuronium, and vecuronium. Patients were initially administered 2x the effective dose for 95% of the study drug. After recovery to 10% of baseline neuromuscular function, the neuromuscular blockade was rigidly maintained with an infusion of the study drug at about 10% of baseline function. Neuromuscular drug costs were approximated as drug usage x cost/unit. The initial drug costs were not substantially different for both Parts 1 and 2, but over time, mivacurium became the most expensive drug and cisatracurium the least expensive. In conclusion, based on current costs, cisatracurium is the least expensive intermediate-acting neuromuscular drug. IMPLICATIONS For children undergoing minor ambulatory procedures of 1-2 h, and continuous intraoperative neuromuscular blockade is indicated, cisatracurium currently is the least expensive drug.

Background Newborn neuromuscular junctions are more sensitive to d-tubocurarine than more mature preparations. It is unclear whether the same modifications occur with newer nondepolarizing agents and depolarizing agent succinylcholine. The purpose of this study was to determine the relative sensitivity of newborn neuromuscular junctions to succinylcholine and five nondepolarizing agents. Methods The phrenic nerve-hemidiaphragm preparation from 60 rats was used, 30 aged 9-12 days (newborn) and 30 aged 27-33 days (adult). Five rats from each group were exposed to one of six neuromuscular blocking agents (d-tubocurarine, cisatracurium, atracurium, vecuronium, rocuronium, and succinylcholine). Indirectly elicited twitch tension was measured during control conditions in the absence of blocking agent, followed by four concentrations of one of the six agents. Concentration-response curves were constructed and the EC50 (concentration required to produce 50% depression of twitch tension) was obtained. Potency ratios (EC50adult/EC50newborn) were derived for each agent. Results Newborn preparations were significantly (P < 0.001) more sensitive than their adult counterparts for all six agents tested. For nondepolarizing agents, the potency ratio was in the 6-12 range. The EC50adult/EC50newborn were as follows, in decreasing potency order: d-tubocurarine, 1.68/0.23 microM; cisatracurium, 2.73/0.47 microM; vecuronium, 5.47/0.59 microM; rocuronium, 9.7/0.78 microM; and atracurium, 12.3/1.9 microM. Succinylcholine was three times as potent in newborn rats, with an EC50adult/EC50newborn of 21.3/7.3 microM. The ratio for succinylcholine was significantly less than for all nondepolarizing drugs (P < 0.02). Conclusion The newborn neuromuscular junction of the rat shows an increased sensitivity to all neuromuscular blocking agents tested, including succinylcholine. However, the potency ratio was greater for nondepolarizing than depolarizing drugs. The optimal dose of these agents for certain situations such as cesarean section and anesthesia in neonates should be reassessed.

The frequency and duration of postoperative residual neuromuscular block on arrival of 150 patients in the recovery ward following the use of vecuronium (n = 50), atracurium (n = 50) and rocuronium (n = 50) were recorded. Residual block was defined as a train-of-four ratio of

While using the isolated forearm technique, we wished to determine whether patients who did not respond to commands during general anaesthesia with a total intravenous technique (propofol and alfentanil with atracurium) had any evidence of post-operative explicit or implicit memory. Forty women undergoing major gynaecological surgery were randomized, in a double-blind design, to hear two different tapes during surgery. Psychological tests of explicit and implicit memory were conducted within 2 h of surgery. There was no evidence of implicit or explicit memory, nor any recall, in the seven women who responded to commands during surgery. We conclude that during total intravenous anaesthesia with propofol and alfentanil, there is no evidence that learning takes place when anaesthesia is adequate. Furthermore, with this anaesthetic technique, it would seem that--provided any period of patient responsiveness is short and that unconsciousness is induced rapidly again--there is no evidence of implicit or explicit memory.

We examined the pharmacokinetics and pharmacodynamics of atracurium besylate and its metabolites in children after orthotopic liver transplantation (OLT), as a suitable model for critically ill children. Ten children were studied after OLT on return to the intensive care unit (ICU). The mean (range) age was 36 (7-78) months, and weight 6-24.2 kg. Atracurium was started at induction of anaesthesia and adjusted in the ICU according to clinical need. Neuromuscular block was measured using accelerometry (TOFguard) and the train-of-four (TOF) ratio or count. Arterial plasma samples for atracurium and metabolites taken before, 12-hourly during, and at frequent intervals after the infusion were analysed by HPLC. The mean (range) maximum infusion rate during steady-state conditions was 1.44 (0.48-3.13) mg kg(-1) h(-1) and the duration of infusion 36.9 (22.5-98.4) h. Tachyphylaxis was not observed. The mean terminal half-life (t1/2) for atracurium was 18.8 (12-32.3) min. The steady-state plasma clearance (CLss) was 13.9 (7.9-20.3) ml min(-1) kg(-1) and the terminal volume of distribution (Vz) 390 (124-551) ml kg(-1); both were higher than in adults after successful OLT. The maximum concentration (Cmax) of laudanosine was 1190 (400-1890) ng ml(-1) and t1/2 was 3.9 (1.1-6.7) h. The renal clearance of laudanosine was 0.9 (0.1-2.5) ml min(-1) kg(-1) and increased with urine flow, but there was no significant relationship with serum creatinine. EEG spikes were confirmed in one child only; the corresponding laudanosine Cmax was 720 ng ml(-1). Monoquaternary alcohol Cmax was 986 (330-1770) ng ml(-1) and t1/2 42.9 (30-57.7) min. Mean recovery time on stopping the atracurium infusion to a TOF ratio0.75 was 23.6 (12-27) min. Atracurium is an effective and safe neuromuscular blocking agent in this population. Laudanosine concentrations are not excessive if graft function is satisfactory.

Background Residual neuromuscular block caused by vecuronium alters pharyngeal function and impairs airway protection. The primary objectives of this investigation were to radiographically evaluate the swallowing act and to record the incidence of and the mechanism behind pharyngeal dysfunction during partial neuromuscular block. The secondary objective was to evaluate the effect of atracurium on pharyngeal function. Methods Twenty healthy volunteers were studied while awake during liquid-contrast bolus swallowing. The incidence of pharyngeal dysfunction was studied by fluoroscopy. The initiation of the swallowing process, the pharyngeal coordination, and the bolus transit time were evaluated. Simultaneous manometry was used to document pressure changes at the tongue base, the pharyngeal constrictor muscles, and the upper esophageal sphincter. After control recordings, an intravenous infusion of atracurium was administered to obtain train-of-four ratios (T4/T1) of 0.60, 0.70, and 0.80, followed by recovery to a train-of-four ratio of more than 0.90. Results The incidence of pharyngeal dysfunction was 6% during the control recordings and increased (P < 0.05) to 28%, 17%, and 20% at train-of-four ratios 0.60, 0.70, and 0.80, respectively. After recovery to a train-of-four ratio of more than 0.90, the incidence was 13%. Pharyngeal dysfunction occurred in 74 of 444 swallows, the majority (80%) resulting in laryngeal penetration. The initiation of the swallowing reflex was impaired during partial paralysis (P = 0.0081). The pharyngeal coordination was impaired at train-of-four ratios of 0.60 and 0.70 (P < 0.01). A marked reduction in the upper esophageal sphincter resting tone was found, as well as a reduced contraction force in the pharyngeal constrictor muscles. The bolus transit time did not change significantly. Conclusion Partial neuromuscular paralysis caused by atracurium is associated with a four- to fivefold increase in the incidence of misdirected swallowing. The mechanism behind the pharyngeal dysfunction is a delayed initiation of the swallowing reflex, impaired pharyngeal muscle function, and impaired coordination. The majority of misdirected swallows resulted in penetration of bolus to the larynx.

UNLABELLED The onset time of neuromuscular blockade at the adductor pollicis (AP) is different among neuromuscular blocking drugs, but these discrepancies had never been studied at the orbicularis oculi (OO). The purpose of this study was to verify if the differences in onset time observed at the AP still existed at the OO and to score the intubating conditions using monitoring at the OO after five muscle relaxants. The study included 172 adults aged 18-75 yr. Anesthesia was induced with fentanyl and propofol. Atracurium (0.5 mg/kg), mivacurium (0.20 mg/kg), rocuronium (0.6 mg/kg), succinylcholine (1.0 mg/kg), or vecuronium (0.08 mg/kg) was injected by random allocation. Time to complete disappearance of the response at the OO was assessed visually after train-of-four stimulation of the facial nerve. Laryngoscopy was then performed, and intubating conditions were determined on a scale of 1-4. Results were based on 150 patients. Onset time at the OO was (mean +/- SD): succinylcholine (57 +/- 17 s) < mivacurium (99 +/-19 s) = rocuronium (99 +/- 47 s) < atracurium (129 +/-33 s) = vecuronium (135 +/- 38 s) (P < 0.05). Overall intubating conditions were excellent (84%), good (14%), poor (1.3%), impossible (0.7%), and were similar among the five groups. We conclude that differences in onset time of muscle relaxants observed at the AP were also found at the OO. Visual estimation of the response at the OO correctly predicted good-to-excellent intubating conditions in more than 90% of cases for all the currently available muscle relaxants. IMPLICATIONS Onset time of neuromuscular blockade, as estimated visually at the orbicularis oculi, depends on the muscle relaxants given. Regardless of the relaxant used, intubating conditions at loss of orbicularis oculi are acceptable.

To compare the laryngeal mask airway (LMA) insertion conditions produced by propofol and a thiopental - low dose atracurium combination.In a randomized controlled double blind study, 120 premedicated patients were allocated into four groups. After pre-oxygenation, anesthesia was induced as follows: 1 microg x kg(-1) fentanyl, 2.5 mg x kg(-1) propofol (group I); 1 microg x kg(-1) fentanyl, 5 mg x kg(-1) thiopental (group II); 1 microg x kg(-1) fentanyl, 5 mg x kg(-1) thiopental, 0.05 mg x kg(-1) or 0.1 mg x kg(-1) atracurium (groups III and IV respectively). The LMA was inserted by a blinded anesthesiologist who also assessed the following insertion conditions on a three point scale; jaw relaxation, biting, gagging, coughing, presence of laryngospasm, adequacy of airway patency, number of attempts at insertion and overall insertion conditions.There was no difference in insertion conditions between groups I, III and IV. Group II produced the worst overall conditions (P0.05). There were no differences in hemodynamic changes and apnea times between all four groups.The combination of fentanyl-thiopental with low dose atracurium (0.05 or 0.1 mg x kg(-1)) provided conditions comparable with those of propofol for LMA insertion.

The goal of this double-blinded, prospective study was to compare the costs incurred by waiting time of intense neuromuscular block while posttetanic count (PTC) was maintained at 0 ‐2 during jet ventilation. Fifty patients were randomized into five groups to receive atracurium (ATR), mivacurium (MIV), rocuronium (ROC), vecuronium (VEC), and succinylcholine (SUCC). PTC #2 was maintained until completion of laryngomicroscopy by administering additional doses of relaxants or by adjusting the speed of the infusion of SUCC. We compared waiting time, i.e., onset time and recovery time, and costs of intense neuromuscular block. The expenses due to waiting time were calculated based on the average costs in the otorhinolaryngological operating room in Tampere University Hospital: FIM 40 (approximately $8) per minute in 1997. MIV and SUCC differ favorably from ATR, ROC, and VEC when waiting time and costs are concerned. The recovery times with MIV and SUCC were considerably shorter than those with ATR, ROC, and VEC (P , 0.001 in all pairwise comparisons). Using the muscle relaxant with the longest waiting time instead of that with the shortest waiting time (difference 21.8 min) cost more than FIM 800 (approximately $160) extra per patient. Implications: In this randomized, double-blinded, prospective study, we evaluated the costs of intense neuromuscular block due to waiting time. Succinylcholine and mivacurium are the most economical muscle relaxants to use when intense neuromuscular block is mandatory. Using intermediate-acting muscle relaxants results in unduly prolonged recovery time and extra costs. (Anesth Analg 1999;88:1335‐9)

Neuromuscular blocking drugs exhibit different degrees of fade in response to train-of-four stimulation believed to represent their relative prejunctional effects. The present study was designed to compare the train-of-four fade after cisatracurium and compare this with other commonly used muscle relaxants. Train-of-four fade during onset and recovery of block were recorded after administration of cisatracurium 0.05 or 0.1 mg.kg-1, atracurium 0.5 mg.kg-1, vecuronium 0.08 mg.kg-1, mivacurium 0.15 mg.kg-1 or rocuronium 0.6 mg.kg-1 to patients anaesthetised with fentanyl, nitrous oxide and a propofol infusion. Neuromuscular monitoring was by stimulation of the ulnar nerve and recording the force of contraction of the adductor pollicis muscle. The onset and recovery of block were also measured. Train-of-four fade during onset of block was greater with the lower dose of cisatracurium compared with the higher dose of cisatracurium and all other relaxants. Train-of-four fade during recovery was similar. The median times (and ranges) for the onset of maximum block were 3.4 (2.1-5.6), 1.5 (1.2-2.3), 2.1 (1.2-2.6), 2.0 (1.5-2.7) and 1.0 (0.7-1.3) min for cisatracurium 0.1 mg.kg-1 and atracurium, mivacurium, vecuronium and rocuronium, respectively. The median times (and ranges) for the recovery of T1 to 25% of control and to a train-of-four ratio of 0.8 were 41 (21-50) and 65 (40-78); 43 (37-54) and 69 (58-79); 15 (11-20) and 25 (19-30); 31 (23-46) and 60 (45-117); and 33 (18-57) and 50 (28-76) min following cisatracurium, 0.1 mg.kg-1, atracurium, mivacurium, vecuronium and recuronium, respectively.

To compare the neuromuscular effects, efficacy, and safety of equi-effective doses of rocuronium and atracurium in ambulatory female patients undergoing surgery.Forty-one patients undergoing laparoscopic gynaecological surgery were randomized to receive 2 X ED90 rocuronium (0.6 mg.kg-1; n = 20) or atracurium (0.5 mg.kg-1; n = 21) during intravenous propofol/alfentanil anaesthesia with N2O/O2 ventilation. Neuromuscular block was measured with a mechanomyogram eliciting a train-of-four (TOF) response at the wrist. Intubation conditions 60 sec after administration of muscle relaxant and immediate cardiovascular disturbances or adverse events during the hospital stay were noted by blinded observers.Compared with atracurium, rocuronium was associated with a shorter onset time (59.0 +/- 22.2 vs 98.6 +/- 41.4 sec; P0.001) and clinical duration of action (33.3 +/- 7.1 vs 44.7 +/- 7.2 min; P0.001), but longer spontaneous recovery index (9.6 +/- 2.41 vs 6.9 +/- 1.89 min; P = 0.023) and a similar time to spontaneous recovery to TOF 70%; 53 +/- 6.31 vs 59.2 +/- 7.59 min; P = 0.139). Tracheal intubation was accomplished in90 sec in all patients receiving rocuronium but in only 14 of 21 patients receiving atracurium. The incidence of adverse events and the cardiovascular profiles for the two drugs were similar, although one patient receiving atracurium experienced transient flushing of the head and neck.Rocuronium has minimal side effects, provides conditions more suitable for rapid tracheal intubation, and is associated with a shorter clinical duration than atracurium. Once begun, the spontaneous recovery profile of rocuronium is slightly slower than that of atracurium.

The neuromuscular blocking effects and the reversibility of cisatracurium 0.1 or 0.15 mgkg−1 were compared with those of atracurium 0.5 mgkg−1 during anaesthesia with propofol, nitrous oxide and isoflurane. Neuromuscular block was monitored using train-of-four stimulation while recording the mechanomyographic response of the adductor pollicis muscle. The block was either allowed to recover spontaneously or was antagonised with neostigmine 50 μgkg−1 at 10% or 25% recovery of the first twitch of the train-of-four. The median times to maximum block were 2.7, 2.2 and 1.5 min following cisatracurium 0.1 and 0.15 mgkg−1 and atracurium 0.5 mgkg−1, respectively. After cisatracurium 0.1 mgkg−1 had been given, the median time to recovery of the train-of-four ratio to 0.8 (‘adequate recovery’) was 74 min during spontaneous recovery, 48 min after reversal with neostigmine when the first twitch of the train-of-four had returned to 10% of control and 50 min after reversal when the first twitch of the train-of-four had returned to 25% of control. These times for cisatracurium 0.15 mgkg−1 and atracurium 0.5 mgkg−1 were 90, 66 and 57 min and 75, 56 and 54 min, respectively. Administration of neostigmine significantly shortened the time to adequate recovery for both drugs but there were no significant differences in the case of either neuromuscular blocking drug between the groups of patients given neostigmine at 10 or 25% recovery of the first twitch of the train-of-four.

Cisatracurium besylate (Nimbex Injection, Glaxo Wellcome Inc., Research Triangle Park, NC) is an intermediate-acting bis-benzylisoquinolinium neuromuscular blocking drug that is one of the stereoisomers of atracurium. At dosesor = 8 x ED95, it caused no clinically important cardiovascular side effects or histamine release in healthy patients. The purpose of the present study was to investigate the haemodynamic effects of high doses of cisatracurium in patients with coronary artery disease.One hundred patients undergoing myocardial revascularization participated in a pilot study (seven patients) and a double-blinded, randomized, controlled trial comparing the haemodynamic effects of cisatracurium with vecuronium at three centres. The patients were anaesthetized using oxygen 100%, with etomidate, fentanyl and a benzodiazepine, and tracheal intubation was facilitated using succinylcholine. After baseline haemodynamic measurements, the study drug was administered over 5-10 sec according to group assignment: Group A (pilot) cisatracurium, 0.20 mg.kg-1 (4 x ED95), (n = 7); Group B-cisatracurium, 0.30 mg.kg-1 (6 x ED95), (n x ED95), (n = 31); Group C-vecuronium, 0.30 mg.kg-1 (6 x ED95), (n = 31); Group D cisatracurium, 0.40 mg.kg-1 (8 x ED95), (n = 21); Group E-vecuronium, 0.30 mg.kg-1 (6 x ED95), (n = 10). The haemodynamic measurements were repeated at 2, 5, and 10 min after cisatracurium or vecuronium.Two patients in Group D had20% decreases in MAP, but only one required therapy for hypotension. The haemodynamic changes from pre- to post-injection in the cisatracurium patients were minimal and similar to patients receiving vecuronium.In patients with coronary artery disease, rapid cisatracurium (4-8 x ED95) boluses and vecuronium (6 x ED95) result in minor, clinically insignificant haemodynamic side effects.

We were looking for a clinical test to indicate a train-of-four (TOF) ratio of approximately 0.9. We compared the adductor pollicis muscle (AP) visually evaluated response to ulnar nerve 100-Hz, 5-s tetanus (RF100 Hz) with the measured AP TOF ratio in 30 ASA physical status I or II adult anesthetized (propofol, sufentanil, N2O/O2) patients. After the induction of anesthesia, the left ulnar nerve was stimulated at the wrist (single twitch and TOF) and the resultant isometric force was measured. When TOF was assessed, the independent investigators, unaware of the left AP-measured TOF ratios, visually evaluated the presence or absence of AP fading elicited by right ulnar nerve 100-Hz, 5-s tetanus. The 30 patients were randomly allocated to receive either 0.5 mg/kg atracurium (n = 15) or 0.1 mg/kg vecuronium (n = 15). The neuromuscular blockade was allowed to resolve spontaneously. A multiple logistic regression analysis was performed by computing the 771 visual observations. The probabilities of success of 100-Hz, 5-s tetanus to detect TOF ratios of 0.8, 0.85, and 0.9 were 99%, 96%, and 67%, respectively. The sensitivity and specificity of 100-Hz, 5-s tetanus as an indicator of TOF ratios of 0.85 and 0.9 are 100% and 75%, 54% and 67%, respectively. We conclude that RF100 Hz visual assessment seems to be highly sensitive in evaluating residual paralysis, as the absence of RF100 Hz visual fading at the AP is compatible with a TOF ratio >0.85. Implications: After the administration of muscle relaxants, the absence of visual fading at the adductor pollicis, elicited in anesthetized patients by 100-Hz, 5-s tetanus, is compatible with a train-of four ratio >0.85. Therefore, clinical observation of fading after 100-Hz, 5-s tetanus seems to be a highly sensitive test in evaluating residual paralysis. (Anesth Analg 1998;87:185-9)

To evaluate a rapid and time-saving precurarization technique using rocuronium to prevent succinylcholine-induced myalgia.In a prospective, double blind randomized study, 42 ASA 1-2 patients were assigned to one of three pretreatment groups: 0.01 ml.kg-1 normal saline, 0.1 mg.kg-1 atracurium, and 0.1 mg.kg-1 rocuronium. Anaesthesia commenced with 1.5 micrograms.kg-1 fentanyl and 0.5 mg.kg-1 lidocaine at time zero. Pretreatment was administered 60 sec later, followed by 2.5 mg.kg-1 propofol. At 90 sec, 1.5 mg.kg-1 succinylcholine was injected and 30 sec later, the trachea was intubated and the ease of intubation was graded. The patient was observed for the presence and severity of fasciculations. Myalgias were recorded on postoperative days 1, 2 and 7.The incidence of fasciculations in the rocuronium group (21.4%) was lower (P0.001) than atracurium (78.5%) or placebo (92.8%) groups. On postoperative day 1, the incidence of postoperative myalgia in the rocuronium group (14.2%) was less than the placebo group (78.2%; P0.002) and atracurium group (85.7%; P0.001). The incidence of myalgia in the rocuronium group (7.1%) was lower than in the placebo group (78.5%; P0.001) but not different from the atracurium group (42.8%; P = 0.077) on postoperative day 2. On postoperative day 7, there was no difference among the three groups. Fasciculations were related to postoperative myalgia. There was no difference in intubating conditions among the three groups.Rocuronium pretreatment given just before induction of anaesthesia with propofol reduces fasciculations and succinylcholine-induced myalgia.

Background Although neuromuscular blocking agents do not cross the blood-brain barrier, they may penetrate the central nervous system under particular circumstances and eventually cause neurotoxic consequences. Methods The effects of neuromuscular blocking agents on excitatory and inhibitory transmission in area CA1 of rat hippocampal slices were investigated using extracellular and intracellular recording techniques. Results Application of atracurium in the perfusion medium resulted in a dose-dependent enhancement of excitatory synaptic responses averaging 48.7 +/- 4.3% at a concentration of 10 nM. This effect was correlated with an increase in the size of the presynaptic fiber volley. Laudanosine, but not pancuronium bromide or vecuronium bromide, produced similar changes. In addition, atracurium and laudanosine blocked inhibitory transmission and reduced intracellularly recorded gamma-aminobutyric acidA receptor-mediated potentials. These effects were observed only at concentrations >1 microM and were not reproduced by pancuronium bromide and vecuronium bromide. Conclusions Atracurium and its metabolite, laudanosine, contrary to pancuronium bromide and vecuronium bromide, produce two distinct effects on hippocampal slices. They enhance excitatory transmission and neuronal excitability and they block inhibitory gamma-aminobutyric acidA-mediated synaptic responses.

Friedreich's ataxia is an inherited disorder of the nervous system, requiring special care during anaesthesia, because of increased sensitivity to muscle relaxants. We report a case of Friedreich's ataxia in a 31-year-old woman, anaesthetised on two occasions, for tendinoplasty and pes cavus repair. Atracurium was used for neuromuscular blockade and monitored by a train-of-four twitch technique. The patient's response was normal. She returned to adequate spontaneous breathing within 20 min of the last dose of the muscle relaxant without need for anticholinesterase administration. When neuromuscular function is monitored, normal doses of muscle relaxant can safely be used in these patients.

UNLABELLED Drugs for neurosurgical patients should not increase intracranial pressure (ICP) or change cerebral perfusion pressure (CPP) and cerebral blood flow. This double-blind, cross-over study compares the effects of a single (3 x effective dose producing 95% twitch depression) intravenous bolus dose of cisatracurium 0.15 mg/kg with atracurium 0.75 mg/kg on mean red blood cell flow velocity in the middle cerebral artery (CBFV; transcranial Doppler), ICP (intraventricular or intraparenchymal monitor), mean arterial pressure (MAP), CPP (MAP-ICP), and heart rate (HR) every minute during a 15-min study period. Included in the study were 14 sedated and ventilated adult neurosurgical patients. After the cisatracurium bolus, ICP, CPP, CBFV, MAP, and HR did not change, and no histamine related events were observed. After the atracurium bolus, ICP, CPP, CBFV, and MAP decreased. The lowest values of ICP (-16% of baseline), CPP (-5%), CBFV (-8%), and MAP (-7%) were recorded 2-4 min after the atracurium bolus injection. After this transient decrease, MAP and CPP returned to baseline, whereas CBFV and ICP transiently exceeded baseline values. The highest values of CBFV (5%) and ICP (17%) were recorded 9-12 min after the atracurium bolus injection. Five patients showed a typical histamine response after atracurium, with a decrease in MAP and flushing. Excluding these five patients eliminated statistical significance in ICP, CPP, CBFV, and MAP differences. In conclusion, cisatracurium demonstrated fewer cerebral and cardiovascular hemodynamic side effects in sedated adult neurosurgical patients. IMPLICATIONS This double-blind study in sedated and mechanically ventilated adult neurosurgical patients demonstrates that an intravenous bolus dose of the neuromuscular blocker cisatracurium results in less cerebral (intracranial pressure, cerebral perfusion pressure, middle cerebral artery blood flow velocity) and cardiovascular (blood pressure) hemodynamic side effects, compared with an equipotent dose of atracurium.

UNLABELLED Neither comparisons of the clinical neuromuscular effects of cisatracurium and vecuronium nor comparative studies of their antagonism by neostigmine have been reported. In addition, the efficacy of administering cisatracurium in divided doses has not been investigated. Accordingly, we applied supramaximal electrical stimuli to the ulnar nerve of 165 ASA physical status I and II patients receiving nitrous oxide/alfentanil/propofol anesthesia. Forty-five patients received cisatracurium 5, 10, or 15 microg/kg, and the evoked response at the adductor pollicis was recorded for 15 min. One hundred-twenty patients received cisatracurium 5, 10, or 15 microg/kg or normal saline placebo followed 5 min later by either cisatracurium 100 microg/kg or vecuronium 100 microg/kg (always after placebo). Time to clinical onset (maximal ablation of single twitch response) was measured. When the evoked response spontaneously recovered to 10% of control height, neostigmine 5, 10, 30, or 50 microg/kg or placebo was administered, and recovery of neuromuscular function was recorded for the next 15 min. The clinical onset of vecuronium without priming (2.8 +/- 0.8 min) (mean +/- SD) was significantly (P < 0.05) faster than the onset of cisatracurium without priming (4.6 +/- 1.4 min). Cisatracurium 5, 10, or 15 microg/kg administered before cisatracurium 100 microg/kg significantly (P < 0.05) accelerated the time to complete ablation of the evoked response (3.9 +/- 0.9, 2.9 +/- 0.8, or 3.0 +/- 0.9 min, respectively) compared with cisatracurium 100 microg/kg without priming. The dose of neostigmine required to achieve 50% assisted recovery of the train-of-four ratio at 5 min was significantly (P < 0.05) smaller in patients who received vecuronium (29.1 [17.9-55.3] microg/kg) (mean [95% confidence interval]) compared with those who received cisatracurium (53.7 [31.6-131.5] microg/kg). Given its faster clinical onset and greater sensitivity to antagonism by neostigmine, we conclude that vecuronium may be more suitable than cisatracurium for use in outpatient anesthesia. IMPLICATIONS We investigated the onset of muscle relaxation using intravenous vecuronium and cisatracurium and assessed the ability of neostigmine to antagonize (reverse) this effect. Our results suggest that vecuronium works faster than cisatracurium and is more sensitive to neostigmine. Vecuronium therefore may be more useful than cisatracurium in outpatient anesthesia.

We have compared the pharmacokinetics of cisatracurium with atracurium when given by bolus dose followed by continuous infusion. Twenty healthy patients were anaesthetised with thiopentone, midazolam, fentanyl and 70% nitrous oxide in oxygen. Ten patients (Group C) were randomly allocated to receive cisatracurium 0.1 mg.kg-1 and 10 patients (Group A) were given atracurium 0.5 mg.kg-1. Neuromuscular block was monitored using a mechanomyograph. When the first twitch of the train-of-four had recovered to 5% of control, an infusion of cisatracurium 3 micrograms.kg-1.min-1 was started in Group C and an infusion of atracurium 10 micrograms.kg-1.min-1 was started in Group A. The infusion rates were adjusted to maintain the first twitch of the train-of-four at 5% of control. The times to 90% and maximum depression of the first twitch of the train-of-four were significantly longer after cisatracurium than atracurium (2.2 and 3.4 min compared with 1.3 and 1.8 min, respectively; p < 0.01 in each instance). No significant differences were found in recovery parameters between the two groups. Blood samples were taken at regular intervals following the bolus, during the infusion and for 8 h thereafter. The plasma samples were analysed using high-performance liquid chromatography for cisatracurium and atracurium (using a method which distinguishes between the three geometric isomer groups), laudanosine and monoquaternary alcohol. The results were analysed using the Non-linear Mixed Effects Model program. A two-compartment model was fitted to the data. The different isomer groups of atracurium have different pharmacokinetics, the trans-trans group having the highest clearance (1440 ml.min-1) and the cis-cis group the lowest (499 ml.min-1). The clearance of cisatracurium (425 ml.min-1) is less than that of cis-cis atracurium and its elimination half-life is longer (34.9 min and 21.9 min, respectively). The plasma concentration of laudanosine after cisatracurium was one-fifth of that after atracurium.

To determine the attenuation in the incidence of myalgia, fasciculations and changes in serum potassium and creatinine kinase concentrations when atracunum and lidocaine were used in combination and separately as pretreatment before succinylcholine. In a prospective, double blind randomized study, 80 ASA I patients 20–50 yr were assigned to one of four groups. Anaesthesia was induced with thiopentone and fentanyl. Group C received placebo pretreatment before 1.5 mg·kg−1 succinylcholine: Group A 0.05 mg·kg−1 atracunum three minutes before; Group L, 1.5 mg·kg−1 lidocaine 30 sec before; and group AL both atracurium and lidocaine. Serum potassium five minutes after succinylcholine. and creatinine kinase 24 hr after operation were measured and the increases from preinduction values were compared. Fasciculations and postoperative myalgia at 24 and 48 hr were recorded. Patients receivediv mependine orpo paracetamol for postoperative analgesia. The increase in serum potassium concentration (0.36 ± 0.23 mEq·l−1) was not attenuated by any regimen (P < 0.05). The incidence of fasciculations (P < 0.05) and the increase in creatinine kinase (P < 0.01) was less in the atracunum (40%; 20.93IU·I−1) and atracunum-lid ocaine (30%; 22.85IU·I−1) than in the lidocaine (85%; 45.01IU·I−1) and control (100%; 56.05 IU·I−1) groups. Postoperative myalgia on Days 1 and 2 was lowest (P < 0.05) in the atracurium-lidocaine group (5%; 0%) followed by the atracurium (35%; 25%) and lidocaine (30%; 35%) groups and highest in the control (75%; 65%). Atracurium and lidocaine individually reduce postoperative myalgia, with further decrease occurring when used together.

We have assessed the performance of a "self-learning" fuzzy logic controller to administer atracurium to a required depth of neuromuscular block. We studied 20 ASA I and II patients undergoing surgery anticipated to last longer than 90 min. A Datex Relaxograph was used to measure the degree of neuromuscular block, and control to a T1 twitch height set point of 10% of baseline neuromuscular function was selected. The controller commenced with a blank rule-base and instructed a Graseby 3400 infusion pump to administer an atracurium infusion to maintain this level of block. The system achieved stable control of neuromuscular block with a mean T1 error of -0.52% (SD 0.55%) accommodating a range in mean atracurium infusion rate of 0.25-0.44 mg kg-1 h-1. These results compare favourably with the more computationally intensive and unwieldy adaptive control strategies for atracurium infusion used previously. There was less variation in infusion rates than in our previously studied fixed rules fuzzy controller.

The contribution of the anticonvulsant agent, valproic acid, to the interaction between neuromuscular blockers and anticonvulsants remains unclear. Therefore, this study was undertaken to examine the acute neuromuscular effects of valproic acid and its potential for interaction with neuromuscular blocking drugs. Phrenic nerve-hemidiaphragm preparations from rats were mounted in modified Krebs buffer, maintained at 37 degrees C and aerated with a 5% carbon dioxide-95% oxygen gas mixture. Phrenic nerves were stimulated with 0.1 Hz supramaximal pulses of 0.2-ms duration and the elicited tension of the hemidiaphragm was recorded in seven preparations in the presence of valproic acid 100, 500 and 1000 mumol litre-1. In another six preparations, neuromuscular transmission was blocked completely with the non-depolarizing blocker tubocurarine 3 mumol litre-1 and the hemidiaphragm muscle was stimulated directly (2 Hz and 2 ms duration). The effect of the anticholinesterase drug, neostigmine, on an established block induced by valproic acid 1000 mumol litre-1 was also evaluated in five phrenic nerve stimulated preparations. The effect of valproic acid 100, 500 or 1000 mumol litre-1 on suxamethonium- or atracurium-induced neuromuscular block was also evaluated. Valproic acid produced a mean of 29.7 (SEM 1.7)% and 24.7 (1.7) % block of indirectly or directly elicited muscle twitches. The concentration of valproic acid that caused half maximal paralysis did not differ between indirect (460 (59) mumol litre-1) and direct (329 (35) mumol litre-1) stimulation. Neostigmine 1-3 mumol litre-1 failed to significantly alter the block of 19.8% induced by valproic acid 1000 mumol litre-1. Valproic acid 100, 500 or 1000 mumol litre-1 did not alter the concentrations of suxamethonium or atracurium needed to produce paralysis. These findings suggest that valproic acid does not produce significant block at the rat neuromuscular junction. The partial block that is produced is caused predominantly by a direct inhibitory effect on the muscle itself.

Cisatracurium, one of 10 isomers of atracurium, undergoes pH and temperature-dependent Hofmann elimination in plasma and tissues. The clearance of cisatracurium due to Hofmann elimination and organ elimination was estimated by applying a nontraditional two-compartment pharmacokinetic model with elimination occurring from both compartments to plasma cisatracurium concentration-time data from 31 healthy adult surgical patients with normal renal and hepatic function. The elimination rate constant from the central compartment, intercompartmental rate constants, and the volume of the central compartment were obtained from the model fit. The elimination rate constant from the peripheral compartment could not be independently estimated in vivo and was therefore fixed to the rate of degradation of cisatracurium in human plasma (pH 7.4 and 37 degrees C) and held constant in the model. Total body clearance, Hofmann clearance, organ clearance, and the volume of distribution at steady-state were derived from the model parameter estimates. Renal clearance was calculated from cisatracurium urinary excretion data from 12 of the 31 patients. Clearance values (mean +/- SD) were 5.20 +/- 0.86, 4.00 +/- 1.04, 1.20 +/- 0.71, and 0.85 +/- 0.32 mL.min-1.kg-1 for total body clearance, Hofmann clearance, organ clearance, and renal clearance, respectively. Hofmann clearance accounted for 77% of total body clearance. Organ clearance was 23% of total body clearance. Renal clearance, a component of organ clearance, was 16% of total body clearance. The organ-independent nature of the elimination of cisatracurium was characterized by a relationship between steady-state volume of distribution and total body clearance. The half-life is an independent variable and is not dependent on the total body clearance nor the steady-state volume of distribution. Hofmann elimination is the predominant pathway for cisatracurium elimination in humans.

Cisatracurium is a new nondepolarizing muscle relaxant. In patients randomized to receive either cisatracurium (n = 40) or atracurium (n = 20) we compared the time course of neuromuscular block. The initial bolus dose of cisatracurium was 0.1 mg/kg, that of atracurium 0.5 mg/kg. Neuromuscular block, maintained with an infusion of either drug, was reversed with neostigmine 45 micrograms/kg and atropine 20 micrograms/kg in one half of the patients. Neuromuscular transmission was assessed by recording the mechanical twitch response to train-of-four nerve stimulation. Onset times were 3.1 +/- 1.0 min with cisatracurium and 2.3 +/- 1.1 min with atracurium (P = 0.008). The infusion rates for a 95% +/- 4% neuromuscular block were 1.5 +/- 0.4 micrograms.kg-1.min-1 for cisatracurium and 6.6 +/- 1.7 micrograms.kg-1.min-1 for atracurium, 3.3 times those of cisatracurium when referenced to the active cations. After the infusion, the spontaneous recovery intervals 25%-75% of 18 +/- 11 min and 18 +/- 8 min for cisatracurium and atracurium (P = 0.896) were shortened to 5 +/- 2 min and 4 +/- 3 min (P = 0.921) after neostigmine. While attributing different onset times also to differences in the initial doses, we conclude that time profiles for neuromuscular block of both muscle relaxants, when given in equipotent doses, are not different.

Both the orbicularis oculi (OO) and the adductor pollicis (AP) muscles have been used to indirectly quantify the extent of neuromuscular block of the respiratory muscles. To clarify any differences in response of these muscles to neuromuscular blocking drugs, the effects of two different doses of atracurium, mivacurium, and vecuronium on the AP and OO were studied. A new technique was used to measure the evoked mechanical response of the OO with accelerometry. Fifty premedicated patients were anesthetized with 5-8 mg/kg thiopental and 2 micrograms/kg fentanyl intravenously (i.v.). They were randomly allocated to receive a single dose of either 300 or 500 micrograms/kg atracurium, 150 or 250 micrograms/kg mivacurium, or 60 or 100 micrograms/kg vecuronium i.v. After orotracheal intubation, anesthesia was maintained with nitrous oxide 60% in oxygen, isoflurane 0.5%-1.5% end-tidal, and 1-2 micrograms/kg fentanyl boluses as required. The evoked response of the AP after ulnar nerve stimulation was measured using a force transducer, and that of the OO after facial nerve stimulation was measured with accelerometry using a piezoelectric probe fixed to the eyelid. The following variables were recorded for each muscle: the maximum depression of the first twitch response to the train-of-four (EMAX), the time to achievement of EMAX (TMAX), the time to recovery of the first twitch response to 25%, 50%, 75%, and 90% of control value (TH25, TH50, TH75, and TH90, respectively) and the time to recovery of the train-of-four response to a ratio of 70% (TOF 0.7). The smaller dose of each relaxant was significantly less potent than the larger dose at the OO. TMAX was shorter for the OO than for the AP at the larger dose of each drug. TH 25 was shorter at the OO than at the AP with 0.5 mg/kg atracurium, but there was no significant difference with 0.25 mg/kg atracurium. TH25 and TH50 were both faster at the OO than at the AP with mivacurium, but there was no difference with vecuronium. TOF 0.7 was shorter with the smaller dose of each drug, but there was no difference with the higher doses. It is concluded that it is possible to record the mechanical response of the OO muscle using a noninvasive method. There are differences between the responses of the OO and the AP to neuromuscular blockers that depend upon both the specific drug itself and the dose used.

After administration of doses ranging from 0.025 to 0.25 mg/kg, the neuromuscular blocking effect of cisatracurium was assessed in 119 adult surgical patients receiving N2O-opioid-midazolam-thiopental anesthesia. The calculated 95% effective dose (ED95) for inhibition of adductor pollicis twitch evoked at 0.1 Hz was 0.053 mg/kg. With 0.10 mg/kg injected over 5-10 and 20-30 s, median onset times (range) were 5.8 (3.0-7.7) and 4.8 (1.2-10.2) min, respectively, and median times to 5% and 95% recovery (range) were 27 (19-46) and 48 (25-68) min, respectively. For doses of 0.10, 0.20, and 0.25 mg/kg, median 5%-95% and 25%-75% recovery indexes ranged from 48 to 90 min and 8 to 9 min, respectively. After administration of neostigmine (0.06 mg/kg) at 10%-15% or 16%-30% recovery, the median times to 95% recovery (range) were 6 (2-22) and 4 (2-5) min, respectively. There were no changes in heart rate, blood pressure, or plasma histamine concentrations during the first 5 min after administration of cisatracurium at doses up to 5 x ED95 injected over 5-10 s. No cutaneous flushing or bronchospasm was noted. In summary, cisatracurium is a potent neuromuscular blocking drug with an intermediate duration of action, characterized by excellent cardiovascular stability, with no apparent histamine release.

To evaluate muscle relaxant onset times and tracheal intubating conditions, 60 children (ASA physical status I or II) aged 18 to 72 mo were randomly assigned to receive a bolus of either rocuronium 0.6 mg/kg, vecuronium 0.1 mg/kg, or atracurium 0.5 mg/kg. After induction of anesthesia with etomidate 0.2-0.4 mg/kg and fentanyl 1-3 mg/kg, lungs were ventilated with 50% nitrous oxide in oxygen via a face mask. The evoked electromyogram of the adductor pollicis to a train-of-four stimulation every 20 s was monitored. After administration of the muscle relaxant, endotracheal intubation was attempted every 30 s, beginning 30 s after drug administration, until intubation could be achieved with good or excellent conditions. Rocuronium produced acceptable intubating conditions significantly faster (all tracheas intubated within 60 s) compared with vecuronium (120 s) and atracurium (180 s). The quality of intubating conditions at the time of completed intubation was rated significantly better with rocuronium than with vecuronium or atracurium. However, onset to 95% block at the adductor pollicis muscle was not significantly different after rocuronium (92 +/- 46.9 s), vecuronium (112 +/- 33.3 s), or atracurium (134 +/- 57.1 s), and mean neuromuscular block achieved at the point of successful intubation was not complete in all groups. We conclude that clinically acceptable intubating conditions are produced more rapidly with rocuronium than with atracurium or vecuronium.

Accelerometry is increasingly being used for neuromuscular monitoring. We sought to determine whether this system is sensitive to the period of stabilization of muscle twitch prior to the administration of neuromuscular relaxant. We recruited 20 patients. No premedication was given, and anesthesia was induced with propofol and alfentanil and maintained by a propofol infusion. An accelerometer was attached to each wrist. One of the ulnar nerves was stimulated for 20 min and the other for 3 min using a train-of-four pattern at 15-s intervals. Ten patients then received vecuronium 0.1 mg/kg and a subsequent 10 received atracurium 0.5 mg/kg. The time to onset of maximum block was recorded. The data collected was subjected to a paired t-test with P < 0.05 taken as significant. The mean onset times for patients who received vecuronium was 148.5 s for the arms stabilized for 3 min and 151.5 s for the arms stabilized for 20 min, and in those who received atracurium it was 138.0 s and 130.5 s, respectively. We conclude that there is no significant difference in the onset of neuromuscular block with either vecuronium or atracurium after stabilization periods of 3 or 20 min when assessed by accelerometry.

We have studied 12 critically ill, sedated patients who required a neuromuscular blocking drug to assist mechanical ventilation in an intensive care unit. Patients were randomized to receive an infusion of cis-atracurium 0.18 mg kg-1 h-1 (group 1, n = 6) or atracurium 0.6 mg kg-1 h-1 (group 2, n = 6) preceded, if necessary, by a bolus dose of 2 x ED95 of the same drug (cis-atracurium 0.1 mg kg-1 or atracurium 0.5 mg kg-1). Neuromuscular block was monitored using an accelerograph and the infusion rate adjusted regularly so that it was possible to detect the first response to train-of-four (TOF) stimulation of the ulnar nerve at the wrist. Blood samples were obtained for estimation of plasma cis-atracurium and laudanosine concentrations (group 1) or the three groups of atracurium isomers and laudanosine (group 2). There was no apparent haemodynamic or allergic response to either drug. The mean infusion time in group 1 was 37.6 h and in group 2, 27.5 h. On termination of the infusion, the time for the TOF ratio to reach 0.7 was similar in the two groups (group 1 = 60 min; group 2 = 62 min). The mean infusion rate of cis-atracurium was 0.19 mg kg-1 h-1 and of atracurium 0.47 mg kg-1 h-1 (expressed as mg of bis-cation): cis-atracurium was 2.5 times more potent than atracurium. Using the NONMEM program, a single compartment pharmacokinetic model was fitted to the plasma concentrations of cis-atracurium and the cis-cis, cis-trans and trans-trans isomers of atracurium. The mean population pharmacokinetic values for cis-atracurium were: volume of distribution (V) = 21,900 (SEM 416) ml; clearance (Cl) = 549 (79) ml min-1; half-life (T1/2) = 27.6 (3.6) min; and for the three groups of atracurium isomers were: cis-cis, V = 15,100 (720) ml, Cl = 449 (42) ml min-1, T1/2 = 23.4 (1.2) min; cis-trans, V = 18,000 (667) ml, Cl = 1070 (43) ml min-1, T1/2 = 11.7 (0.1); trans-trans, V = 13,100 (1280) ml, Cl = 1560 (55) ml min-1, T1/2 = 5.8 (0.4) min. Plasma laudanosine concentrations were lower in the cis-atracurium (peak value 1.3 micrograms ml-1) than in the atracurium (maximum 4.4 micrograms ml-1) group.

Background : To determine which of atracurium or vecuronium is associated with fewer adverse cardiovascular and pulmonary events in high-risk patients, the authors administered these drugs to patients with known asthma. Methods : Sixty patients aged 18-75 yr taking bronchodilators chronically for asthma were anesthetized with midazolam, fentanyl, nitrous oxide, and isoflurane ; the trachea was intubated without paralysis. When anesthetic conditions and mechanical ventilation were stable, patients were randomly given 0.5 mg/kg atracurium or 0.1 mg/kg vecuronium over 5-10 s, and a blinded observer recorded cardiovascular, pulmonary, and cutaneous signs of adverse reactions for 6 min. Results : Arterial pressures and heart rate decreased after atracurium, and systolic pressure and heart rate decreased with vecuronium ; these changes were small in magnitude. Cardiovascular effects (decrease in blood pressure or change in heart rate) >10% were common with both atracurium (60% of patients) and vecuronium (57%). Cardiovascular effects >20% were more frequent with atracurium (37%) than with vecuronium (13%, P 5 cmH 2 O, tidal volume decrease >10%, rashes, and wheezing) did not differ between atracurium (17%) and vecuronium (7%). The largest increase in peak airway pressure was 5.1 cmH 2 O in a patient whose tidal volume decreased 16% with vecuronium; in the remaining patients, tidal volume decreased

To ascertain the effects of chronic renal failure on the pharmacokinetics of 1R-cis 1'R-cis atracurium besylate (a stereoisomer, designated 51W89), we gave a bolus dose of 0.1 mg kg-1 (2 x ED95) to 17 patients with end-stage renal failure and to 15 patients with normal renal function undergoing elective surgery. All patients received thiopentone, fentanyl and midazolam i.v. and 70% nitrous oxide in oxygen. Blood samples were obtained over 8 h and plasma analysed for 51W89 and laudanosine concentration, using high pressure liquid chromatography. A two-compartment model was fitted to the 51W89 plasma concentration data using the NONMEM program, to estimate pharmacokinetic variables and to determine the influence of renal failure, age, weight and sex. Clearance of 51W89 was found to be reduced by 13% in renal failure. The typical value of T1/2 beta was 4.2 min longer in renal failure than in the healthy patients (34.2 vs 30.0 min, P0.005). In the healthy patients, clearance of 51W89 was greater in males, but it decreased with increasing age by approximately 1.5 ml min-1 yr-1. Mean plasma laudanosine concentrations were significantly higher in the renal failure group; nevertheless, they were approximately one-tenth of those reported after atracurium.

Background The inability of edrophonium to rapidly reverse a deep nondepolarizing neuromuscular block may be due to inadequate dosage or a ceiling effect to antagonism of neuromuscular block by edrophonium. A ceiling effect means that only a certain level of neuromuscular block could be antagonized by edrophonium. Neuromuscular block greater than this could not be completely antagonized irrespective of the dose of edrophonium administered. The purpose of this study was to determine whether a ceiling effect occurred for antagonism of an atracurium-induced neuromuscular block by edrophonium and, if so, the maximum level of block that could be antagonized by edrophonium. Methods In 30 adult patients, atracurium was administered to maintain a constant neuromuscular block. The level of block varied between patients. Evoked adductor pollicis twitch tension was monitored. Incremental doses of edrophonium were administered while the infusion of atracurium continued. Increments were given until adequate recovery occurred, as defined by a train-of-four (TOF) ratio > or = 70%, or until no further antagonism of the block could be achieved. The probability of being able to effect adequate recovery by antagonism with edrophonium was determined using a logistic regression model. Cumulative dose-response curves were constructed using the logit transformation of the neuromuscular effect versus the logarithm of the cumulative dose of edrophonium. Results In 14 patients with a block of 25-77% depression of the first twitch response, antagonism by edrophonium to a TOF ratio > or = 70% was possible, whereas in 16 patients with a 60-92% depression of T1, a TOF ratio > or = 70% was not achievable, indicating that a ceiling effect for antagonism by edrophonium occurred. A block of 67 +/- 3% (mean +/- SE) had a 50% probability of adequate antagonism. In patients in whom block was antagonized to a TOF ratio < 70%, 95% of the peak antagonistic effect occurred with an edrophonium dose of 0.8 +/- 0.33 mg.kg-1 (mean +/- SD). Conclusions There is a maximum level of neuromuscular block that can be antagonized by edrophonium to effect adequate recovery. The level corresponds approximately to the reappearance of the fourth response to TOF stimulation. It is probably safest to wait until this level of block occurs before edrophonium is given for reversal. Earlier administration will not hasten recovery.

We have studied the pharmacodynamics of the 1R cis-1'R cis isomer of atracurium (51W89) in 15 healthy subjects and in 17 patients with chronic renal failure using a bolus dose of 51W89 0.1 mg kg-1 (2 x ED95). Fifteen patients with normal renal function were investigated also using an approximately equipotent dose of atracurium (0.4 mg kg-1). The compound surface action potential of the adductor pollicis muscle, in response to train-of-four stimulation of the ulnar nerve at the wrist, was recorded until recovery of the height of the first response of the train-of-four compared with baseline (T1:T0) had reached at least 85% and the train-of-four ratio (T4:T1) at least 80%. In the healthy and renal failure patients who received 51W89, there were no significant differences in any of the onset or recovery variables except for the time to 90% depression of T1:T0, which was longer in patients with renal failure (mean 3.7 min vs 2.4 min; P0.05). Of the healthy patients who were given either 51W89 or atracurium, there were no significant differences in the onset data, except for time to maximum block, which was longer in the 51W89 group (mean 7.7 min vs 6.2 min; P0.01). The mean times to 10%, 25%, 50% and 75% recovery of T1:T0 and the time for T4:T170% were significantly longer in patients receiving 51W89.(ABSTRACT TRUNCATED AT 250 WORDS)

Background Residual paralysis of suprahyoid muscles may occur when the adductor pollicis response has completely recovered after the administration of a neuromuscular blocking agent. The response of the geniohyoid muscle to intubating doses of muscle relaxants is evaluated and compared to that of adductor pollicis. Methods Sixteen patients undergoing elective surgery under general anesthesia were given 5-7 mg.kg-1 thiopental and 2 micrograms.kg-1 fentanyl intravenously for induction of anesthesia. Eight (half) patients then received 0.5 mg.kg-1 atracurium, and the other eight received 0.1 mg.kg-1 vecuronium. The evoked response (twitch height, TH) of the adductor pollicis was monitored by measuring the integrated electromyographic response (AP EMG) on one limb and the mechanical response, using a force transducer (AP force), on the other. The activity of geniohyoid muscle (GH EMG) was measured using submental percutaneous electrodes. The following variables were measured: maximal TH depression; onset time for neuromuscular blockade to 50%, 90%, and maximal TH depression (OT50, OT90, and OTmax); times between administration of neuromuscular blocking agent and TH recovery to 10%, 25%, 50%, 75%, and 90% of control; and time for return of train-of-four ratio to return to 0.7. Results The principal findings were (1) OTmax was significantly (P < 0.01) shorter for geniohyoid than for adductor pollicis after either atracurium or vecuronium (OTmax was 216, 256, and 175 s for AP force, AP EMG, and GH EMG, with atracurium and 181, 199, and 144 s with vecuronium, respectively), and (2) the evoked EMG of geniohyoid recovered at the same speed as the EMG of adductor pollicis after an intubating dose of atracurium or vecuronium (recovery of TH to 75% of control at 50, 48, 42 min with AP force, AP EMG, and GH EMG with atracurium and 46, 45, and 42 min with vecuronium, respectively). Conclusions Once the adductor pollicis response has returned to normal values after a single intubating dose of atracurium or vecuronium, the risk of residual depression of the TH of the geniohyoid muscle, one of the principal muscles contributing to airway patency, appears unlikely.

An 18-yr-old male asthmatic was paralyzed with atracurium for a period of seven days to facilitate mechanical pulmonary ventilation. After withdrawal of the muscle relaxant, train-of-four neuromuscular monitoring demonstrated rapid recovery of normal function. Three days later he developed acute quadriparesis without respiratory compromise. Electrophysiological studies showed normal conduction velocities, low compound muscle action potential amplitudes and evidence of denervation. Most cases of post-ventilatory weakness in the ICU involve the use of vecuronium and pancuronium. It has been suggested that the steroid nucleus in these muscle relaxants may be responsible. Our patient developed generalised weakness after treatment with atracurium, a benzylisoquinolinium muscle relaxant. Thus, it appears that the steroid nucleus of vecuronium and pancuronium is not essential in causing post-ventilatory weakness.

We have compared intubating conditions at 60 seconds, onset times and reversal characteristics of the new steroidal nondepolarizing muscle relaxant rocuronium with atracurium and vecuronium. A dose of approximately 1.75 × ED90 of each agent was used to assess their relative suitability for brief day case dental procedures requiring intubation. The anaesthetic technique included propofol, fentanyl, nitrous oxide/oxygen and isoflurane. Electromyography was used to assess neuromuscular blockade. The percentage of good or excellent intubating conditions at 60 seconds was 80% for rocuronium but only 12.5% each for atracurium and vecuronium. The mean percentage bleck at 60 seconds was 55.1% for rocuronium, compared to 9.2% for atracurium and 8.3% for vecuronium. Rocuronium had the fastest onset time to maximum block (mean 313 sec) compared to atracurium (mean 391.9 sec) and vecuronium (mean 331.9 sec). The duration of action of rocuronium was shorter than either atracurium or vecuronium, times for spontaneous recovery to 75% block being 22.2 min, 29.6 min and 26.3 min respectively. The neostigmine evoked recovery indices were. rocuronium 4.2 min, atracurium 6.6 min and vecuronium 3.7 min. Maximum blockade of greater than 97% was achieved with all three relaxants.