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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.

OBJECTIVE In patients with extreme stature or build, estimation of individual dosage requirements of muscle relaxants by body weight is unreliable. To define a more precise guideline for dosage of atracurium in clinical practice we compared in this prospective study in patients with a wide range of body weights the cumulative effective dose for a 95% twitch depression (ED95), the dosage necessary to maintain a 95% twitch depression (DD95) and the recovery from a 95% neuromuscular block with simple demographic data such as body weight, body size, body surface area and lean body mass (LBM). METHODS 30 patients were divided into three groups according to the individual body weight: underweight, normal, overweight. The electromyographic response was monitored using train-of-four stimuli applied to the ulnar nerve. Neuromuscular block was induced by constant infusion of atracurium; the dose required for a 95% twitch depression was registered as ED95. The infusion rate was then adjusted to maintain a constant electromyographic response of the first twitch of 5 +/- 1% for at least 30 minutes and the required dose of atracurium was recorded as DD95. The neuromuscular recovery was studied regarding T1 and T4-ratio. Data are given as medians (25%-/75%-quartiles). RESULTS AND DISCUSSION The cumulative ED95 in underweight patients (0.34 (0.31/0.48) mg/kg) exceeded (P < 0.05) those in normal (0.29 (0.26/0.30) mg/kg) and in overweight patients (0.22 (0.18/0.26) mg/kg). In contrast to calculations according to the normal weight (Mn) no difference in ED95 was seen between groups (normal: 0.29 (0.26/0.30) mg/kg Mn; underweight: 0.28 (0.26/0.32) mg/kg Mn; overweight: 0.31 (0.25/0.32) mg/kg Mn). The individual DD95 was best correlated with LBM (r = 0.465, p < 0.01). In view of the difficulty of estimating LBM in routine clinical practice it is emphasized that DD95 correlates only slightly less with normal weight (r = 0.404, p < 0.05). In spite of the variability of DD95 with regard to body weight, the recovery of neuromuscular transmission in the patients of the three groups is comparable. As a constant neuromuscular block cannot be maintained without monitoring muscular evoked responses, even if body build is taken into account, neuromuscular monitoring is advocated for longer infusion of atracurium.

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.

BACKGROUND: Neuromuscular blocking agents may exert central nervous system effects when they reach the brain. This study assessed the concentrations and the time course of passage of vecuronium, atracurium, and its metabolite laudanosine in the cerebrospinal fluid (CSF) of patients undergoing intracranial aneurysm clipping. METHODS: Twenty-five patients with subarachnoid hemorrhage were randomly allocated to receive an intravenous infusion of vecuronium (n=13) or atracurium (n=12). Arterial blood and lumbar CSF were sampled before and 1, 2, 3, 4 and 8 h after the start of the relaxant infusion. The samples were analyzed by liquid chromatography-electrospray ionization mass spectrometry (vecuronium) and high-pressure liquid chromatography (atracurium and laudanosine). RESULTS: The data of 20 patients (10 in both groups) were analyzed. In 11 CSF samples from five patients atracurium was detected in concentrations from 10 to 50 ng/ml. Laudanosine was retrieved in all CSF samples at 1, 2, 3, 4 and 8 h; the highest CSF concentration of laudanosine occurred at 3 h [38 (18-63) ng/ml: median (range)]. Vecuronium was not found in any CSF sample. CONCLUSION: Significant concentrations of atracurium and laudanosine but not of vecuronium were detected in the CSF of patients during and immediately after intracranial aneurysm surgery.

Die Uberwachung der neuromuskularen Blockade gehort zum Standardmonitoring einer Allgemeinanasthesie. Die Blockadetiefe wird allerdings durch verschiedene Erkrankungen beeinflusst. Es wird das neuromuskulare Monitoring bei 4 Patienten mit zentraler Hemiparese mit Hilfe gleichzeitiger Stimulation des N. ulnaris auf der gelahmten und gesunden Seite beschrieben. Nach Gabe von nichtdepolarisierenden Muskelrelaxanzien (Atracurium, Mivacurium, Rocuronium bzw. Vecuronium) zeigte sich in allen Fallen eine Resistenz gegenuber dem Relaxans an der gelahmten Extremitat. Eine mogliche Ursache fur das Phanomen liegt in einer Ausbreitung veranderter Azetylcholinrezeptoren uber die gesamte Oberflache der denervierten Muskelzelle. Eine Fehleinschatzung der Blockadetiefe kann die Folge sein. Fur die klinische Praxis muss daher die Messung der neuromuskularen Blockade stets an der gesunden Extremitat des Patienten erfolgen.

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: Vecuronium depresses carotid body chemosensitivity during hypoxia. We hypothesized that this is caused by inhibition of cholinergic transmission of the carotid body. Methods: The carotid body with its sinus nerve was removed en bloc from thiopentone-anaesthetized adult male New Zealand rabbits and perfused in vitro with modified Tyrodes buffer solution at constant perfusion pressure, temperature, a buffer pH of 7.4 and normocapnia. Chemoreceptor discharge and spike frequencies (fx) were recorded from the whole sinus nerve after administration of 500 µg nicotine, given as duplicated controls and thereafter following 30 min perfusion of equipotent concentrations of atracurium (28.1 µM) or vecuronium(10 µM), after 30 min of neostigmine perfusion (9.2 µM) and finally after 30 min wash-out with buffer solution only. A short-lasting hypoxic test was performed before and at the end of the experimental period to confirm the responsiveness and validity of the preparation. Results: Atracurium (n = 7) and vecuronium (n = 6) reduced chemoreceptor responses to nicotine by 70 ± 30% and 66 ± 19% (SEM) (P

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.

To compare the neuromuscular and hemodynamic effects of rocuronium and atracurium when administered during a desflurane-based anesthetic.Randomized, double-blind clinical trial.51 adult ASA physical status I and II patients scheduled for general surgical operations.University-based NCI-designated cancer center.Patients received either 0.45 mg/kg rocuronium (n = 28) or atracurium 0.5 mg/kg (n = 23). Induction of anesthesia was accomplished by 2 microg/kg fentanyl intravenously (IV) and 1.5 mg/kg propofol IV and maintained by a nitrous oxide/oxygen desflurane anesthetic.A neuromuscular monitor was used at the adductor pollicis to monitor and record twitch response to train-of-four electrical stimulation. Baseline heart rate (HR) and blood pressure (BP) were measured and again at 2, 5, 10, and 15 minutes after muscle relaxant administration. Patients in the rocuronium group were found to have shorter times to 80%T(1)depression (109 +/- 53 vs. 135 +/- 47 sec), although those differences did not reach statistical significance (p = 0.07). Percent of the first twitch (T(1) ) was significantly lower in the patients receiving rocuronium at 60 seconds (53 +/- 24 vs. 73 +/- 27 sec; p = 0.006) and 90 seconds (25 +/- 22 vs. 47 +/- 29 sec; p = 0.003) than in the patients receiving atracurium. Duration was shorter in rocuronium-treated patients (25% T(1) recovery = 32 +/- 12 vs. 54 +/- 14 min; p0.001) than the patients receiving atracurium. Intubation scores were better at 60 seconds after muscle relaxant administration in the rocuronium group. No significant differences in HR or BP were seen between the patients in the two groups.Rocuronium at a dose of 0.45 mg/kg possesses a fairly rapid onset of neuromuscular blockade and has short:intermediate duration of action when used with a desflurane anesthetic. This quality makes it a desirable drug for operations of relatively short duration. Rocuronium at a dose of 0.45 mg/kg has a faster onset and shorter duration than atracurium, at 0.5 mg/kg, when used with a desflurane anesthetic.

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

Mouse myotubes were used to investigate effects of the nondepolarizing neuromuscular blocking drugs pancuronium and atracurium on embryonic-type nicotinic acetylcholine receptor channels. Experiments were performed using patch-clamp techniques in combination with devices for ultra-fast solution exchange at outside--out patches. Application of 0.1 mM acetylcholine resulted in a fast current transient. When the peak amplitude was achieved, the current decayed monoexponentially due to desensitization. After application of drugs (pancuronium or atracurium), two different mechanisms of block were observed: (1) open channel block of embryonic-type nicotinic acetylcholine receptor channels after coapplication of blocker and acetylcholine, characterized by decrease of the time constant of current decay; (2) competitive block of embryonic-type nicotinic acetylcholine receptor channels by pancuronium or atracurium after preincubation of outside-out patches with the respective blocker. Different affinities of pancuronium (K(B) approximately 0.01 microM) and atracurium (K(B) approximately 1 microM) to embryonic-type nicotinic acetylcholine receptor channels were observed.

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.

The authors have studied 10 critically ill patients with acute respiratory distress syndrome who required a neuromuscular blocking drug to assist mechanical ventilation. Patients received a bolus dose of 1 mg/kg of atracurium followed by a constant infusion rate of 1 mg/kg/h of this drug for 72 hours. Neuromuscular block was monitored using an accelerograph. Blood samples were obtained over a 96-hour period. A preliminary independent analysis was done to estimate the individual pharmacokinetic parameters; data were consistent with a one-compartment model. The pharmacodynamic data analysis was then performed using the changes in train-of-four (TOF) count as an index of the therapeutic effect of atracurium. Pharmacokinetic-dynamic variables were calculated using the Sheiner model and the Hill equation. The elimination half-life of atracurium averaged 22 minutes. Mean volume of distribution and plasma clearance were 217 ml/kg and 550 ml/min, respectively. There was a significant hysteresis loop when the TOF count was plotted against predicted plasma atracurium concentrations. The mean sigmoidicity factor, gamma, was 4.04. The concentration producing 50% of the Emax was 1.36 micrograms/mL, and the mean ke0 was 0.059 min-1. Recovery time ranged from 30 to 80 minutes, and none of the patients of this study had residual paralysis.

Attempts to obtain estimates of pharmacokinetic-pharmacodynamic (PK-PD) parameters for mivacurium with traditional central link models were unsuccessful in many patients. We hypothesized that a link model with the peripheral compartment would be more appropriate for mivacurium in view of its extremely rapid plasma clearance and its potential elimination by tissue pseudocholinesterases. For validation purposes, the peripheral link model was applied to other neuromuscular blocking agents (NMBA), i.e., atracurium and doxacurium which have respectively an intermediate and a long elimination half-life. Assuming peripheral elimination in PK-PD modeling was investigated but found to have no impact on the estimation of PK-PD parameters. Our results indicate that, for drugs having intermediate and long elimination half-lives, EC50 values are similar with either the central or peripheral link model. For mivacurium, a peripheral link model enables PK-PD modeling in all subjects, with more precision in the PK-PD parameter estimates and a better fitting of the effect data when compared to the central link model. For these reasons, a peripheral link model should be preferred for mivacurium.

Rapacuronium bromide (rapacuronium; ORG-9487) is a nondepolarising muscle relaxant (NMBA) with a low potency [90% effective dose (ED90) 1 mg/kg], which to some extent is responsible for its rapid onset of action. Because of the high plasma clearance (5.3 to 11.1 mg/kg/min) of rapacuronium, its clinical duration of action following single bolus doses up to 2 mg/kg in adults is short (i.e.20 minutes). Rapacuronium forms a pharmacologically active 3-desacetyl metabolite, ORG-9488, which may contribute to a delay in spontaneous recovery after repeat bolus doses or infusions. After rapacuronium 1.5 mg/kg clinically acceptable intubating conditions are achieved within 60 to 90 seconds in the majority of adult and elderly patients undergoing elective anaesthesia. However, in a rapid-sequence setting. intubating conditions are less favourable after rapacuronium 1.5 to 2.5 mg/kg than after succinylcholine. The most prominent adverse effects of rapacuronium (tachycardia, hypotension and bronchospasm) are dose-related, and in particular pulmonary adverse effects are observed more frequently under conditions of a rapid-sequence induction in adults. Therefore, it seems worthwhile to consider only doses of rapacuroniumor = 1.5 mg/kg to facilitate rapid tracheal intubation, and to use succinylcholine or rocuronium rather than rapacuronium in a rapid-sequence setting. Rapacuronium, however, is a suitable alternative to mivacurium chloride (mivacurium) and succinylcholine for short procedures (e.g. ambulatory anaesthesia). Rocuronium bromide (rocuronium) is a relatively low-potent, intermediateacting NMBA. Its main advantage is the rapid onset of neuromuscular block whereby good or excellent intubating conditions are achieved within 60 to 90 seconds after rocuronium 0.6 mg/kg (2 x ED95), and within 60 to 180 seconds after smaller doses (1 to 1.5 x ED95). Larger doses of rocuronium (or = 1 mg/kg) seem to be suitable for rapid-sequence induction under relatively light anaesthesia. However, it is still a matter of controversy whether, in the case of an unanticipated difficult intubation, the long duration of rocuronium administered in such large doses outweighs the many adverse effects of succinylcholine. Rocuronium has mild vagolytic effects and does not release histamine, even when administered in large doses. Rocuronium is primarily eliminated via the liver and its pharmacokinetic profile is similar to that of vecuronium bromide (vecuronium). Unlike vecuronium, rocuronium has no metabolite. Cisatracurium besilate (cisatracurium), the IR-cis, 1'R-cis isomer of atracurium besilate (atracurium) is approximately 4 times more potent than atracurium. The onset time of cisatracurium is significantly slower than after equipotent doses of atracurium. The recommended intubating dose is 0.15 to 0.2 mg/kg (3 to 4 times ED95). Over a wide range of clinically relevant doses the recovery properties of cisatracurium are affected by neither the size of the bolus dose nor by the duration of infusion. Unlike atracurium, cisatracurium does not trigger histamine release. Like atracurium, cisatracurium undergoes Hofmann elimination. In contrast to atracurium, cisatracurium does not undergo hydrolysis by nonspecific plasma esterases. Moreover, about 77% of the drug is cleared by organ-dependent mechanisms.

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.

The aim of the study was to investigate the effect of induced hypothermia on the offset time of atracurium when given by continuous infusion to critically ill children. Over a period of 8 months, six mechanically ventilated children had a steady-state infusion of atracurium discontinued. The offset time of atracurium was assessed by train-of-four (TOF) stimulation of the ulnar nerve; recording the time taken to reach a TOF ratio of 0.9. Nine assessments were carried out. The mean offset time of atracurium was 82 min. This was significantly longer than in patients with temperatures within the normal physiological range. When considering all assessments, performed both in hypothermic and normothermic patients, there is a strong correlation between rectal temperature and the offset time of atracurium. Prolonged moderate hypothermia has a very significant effect on the offset time of atracurium when given by infusion to critically ill children.

The aim of the study was to investigate the offset time of atracurium when given by continuous infusion on a paediatric intensive care unit and to look for evidence of tolerance. Over a period of 8 months, 20 mechanically ventilated children had a steady-state infusion of atracurium discontinued to enable the assessment of their level of sedation. The offset time of atracurium was assessed by train-of-four (TOF) stimulation of the ulnar nerve. The initial TOF reading was documented as was the time taken to reach a TOF ratio of 0.9. Thirty-five assessments were carried out. The mean offset time of atracurium was 28.7 min (SEM 1.76 min, range 8-56 min). There was no correlation between the dose of atracurium at discontinuation and the offset time of the infusion. The duration of infusion was negatively correlated with the offset time of atracurium, and this effect was most prominent in children who had received infusions for longer than 48 h. When given by continuous infusion, the offset time of atracurium is very variable between individual patients. Infusions administered for longer than 48 h are associated with a significant reduction in the offset time as a result of increasing tolerance.

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.

Background To determine the effect of atracurium or pancuronium on onset and duration of fetal paralysis, movements and heart rate parameters directly after transfusion, using computer analyzed fetal heart rate recording (c-FHR). Methods. Double blind randomized study of 23 RhD alloimmunized pregnant women requiring an intravascular intrauterine fetal blood transfusion (IUT) between 24 and 36 weeks. Atracurium was injected in 11 fetuses at 17 IUT's and pancuronium in 12 fetuses at 19 lUT's. For statistical analysis the Mann-Whitney test was used. Results. No statistical differences were found in fetal heart rate and movements between both groups before transfusion. The fetal movements returned more rapidly in the atracurium group when compared to the pancuronium-group (median 24 vs. 57 min, range 6-55 vs. 4-220; (p

Background: To identify individual factors and combination of factors predictive of reversal time (defined as time from neostigmine administration to train-of-four (TOF) ratio 0.70) from atracurium-induced neuromuscular block, the present study tested the following variables as possible predictors of reversal time: 1) degree of block at the time of antagonism as quantified by first response to TOF or double-burst stimulation (DBS); 2) time from last supplemental dose of atracurium to administration of neostigmine (pre-reversal time); and 3) time from administration of initial atracurium dose to T1 (the magnitude of the first twitch in TOF) recovered to 10% (duration of action of the initial dose of atracurium). Methods: The study population comprised 83 female patients, ASA physical status 1 or 2, anaesthetized with fentanyl, thiopental, halothane and nitrous oxide. Initial and supplemental doses of atracurium were 0.5 mg · kg−1 and 0.15 mg · kg−1, respectively. Evoked responses to TOF or DBS were recorded mechanomyographically. Neuromuscular block was antagonized with neostigmine, 0.07 mg · kg−1, at varying time intervals (6–50 min) after the final atracurium dose. Results: Multiple linear regression analyses testing T1, D1 (the magnitude of the first twitch in DBS), pre-reversal time and duration of action of the initial dose of atracurium, demonstrated that with superficial block, T1 >15%, T1 is the only significant predictor for reversal time. With moderate block, 0< T1 ≤15%, both T1 and duration of action of the initial atracurium dose are significant predictors for reversal time. With profound block, T1=0, duration of action of the initial dose and pre-reversal time are significant predictors for reversal time. Conclusion: 1) T1 is a more important predictor for reversal time from atracurium-induced neuromuscular block than D1; 2) predictors differ with the degree of block: with T1 >15%, T1 is the only significant predictor; with 0< T1 ≤15%, the duration of action of the initial dose and T1 are predictors for reversal time; with T1=0 , the duration of action of the initial dose and pre-reversal time predict reversal time.

Fragestellung: Muskelrelaxanzien zeigen ein unterschiedliches pharmakodynamisches Wirkungsprofil an verschiedenen Muskelgruppen. Am M. adductor pollicis hat Cisatracurium, bis auf eine langere Anschlagzeit, ein vergleichbares pharmakodynamisches Profil wie Atracurium. Untersuchungen an anderen Muskelgruppen wurden fur Cisatracurium bisher nicht durchgefuhrt. In der vorliegenden klinischen Studie sollte daher die neuromuskulare Wirkung von Cisatracurium am M. orbicularis oculi (OO) – dessen neuromuskulare Reaktion annahernd derjenigen des Diaphragmas und der Larynxmuskulatur entspricht – und am M. adductor pollicis (AP) im Vergleich mit Atracurium untersucht werden.

Fragestellung: Die Bewertung einer nicht depolarisierenden neuromuskularen Blockade mit Hilfe des Train-of-Four-count (TOF-count) hat im Vergleich zu mechanomyographischen Messungen grose Abweichungen ergeben. Die vorliegende Untersuchung soll die Bedeutung dieser Abweichungen fur das Erfassen der 25%igen neuromuskularen Erholung prufen. Hierzu wurden die Zeitintervalle zwischen der mittels TOF-count vermuteten und der gemessenen 25%igen Erholung bestimmt sowie ein 95%-Vertrauensbereich berechnet. Methodik: 89 Patienten aufgeteilt in 6 Dosisgruppen erhielten wahrend Propofol/Fentanyl-Anasthesie randomisiert eine Einzeldosis Atracurium (150, 200, 250 300, 450 bzw. 600 µg/kg). Die neuromuskulare Ubertragung wurde mit Hilfe der evozierten Kontraktionskraft des M. adductor pollicis nach transkutaner TOF-Stimulation des N. ulnaris uberwacht. Die Hohe der ersten Reizantwort (T1) prozentual zum Kontrollwert vor Relaxansgabe wurde bei Auftreten der zweiten und vierten Reizantwort (T2 bzw. T4) erfast. Ebenso wurden die Zeitintervalle zwischen der 25%igen Erholung von T1 und dem Wiederauftreten von T4 gemessen. Ergebnisse: Die Hohe von T1 betrug bei Wiederauftreten von T2 und T4 11±2% bzw. 24±6% des Kontrollwerts, ohne Unterschiede zwischen den Gruppen. Innerhalb der 95%-Vertrauensbereiche lag T1 bei Wiederauftreten von T4 zwischen 14 und 33%. Die 25%ige Erholung erfolgte 5 min vor bis 3 min nach dem Wiederauftreten von T4. Schlusfolgerung: Unsere Daten zeigen, das ein TOF-count von 4 die 25%ige neuromuskulare Erholung wahrend der Relaxation mit Atracurium nur um 3 bis 5 min verfehlt. Diese Fehlerbreite sehen wir als klinisch unbedeutend an. Der TOF-count ist daruber hinaus dosisunabhangig anwendbar. The estimation of a nondepolarizing neuromuscular block using the train-of-four (TOF) count shows wide differences compared to the mechanomyographic measurement. The purpose of this study was to evaluate the clinical significance of these differences. Methods: 89 patients (ASA I–II) in 6 groups received general anesthesia with fentanyl, propofol and a single dose atracurium (150, 200, 250, 300, 450 and 600 µg/kg). Neuromuscular transmission was monitored by stimulation of the ulnar nerve at the wrist with supramaximal TOF stimuli repeated every 15 s using a peripheral nerve stimulator. The isometric force contraction of the m. adductor pollicis was recorded. The height of T1 at reappearance of the second (T2) and fourth (T4) twitch was noted. Also noted was the time difference between the first reappearance of T4 and the 25% recovery of T1. Statistical significance of the results was calculated by the h-test of Kruskal and Wallis. Testing the reliability of the TOF count, a 95% interval of confidence was calculated. Results: There were no significant differences between the mean ages, heights and weights of the six groups. T2 and T4 re-appeared at 11±2% and 24±6% recovery of T1, respectively. Again, there were no significant differences between the six dose groups (Fig. 1). The time difference between the re-appearance of T4 and the 25% recovery was –1.0±2 (range: –5–3) minutes. The calculation of a 95% interval of confidence indicated a recovery between 14% and 33% at reappearance of T4, 25% recovery can be expected 5 min before to 3 min after reappearance of T4, respectively. Conclusions: At reappearance of T4, a recovery of neuromuscular block of 25% is missed only by 3 to 5 min during relaxation with atracurium. We consider this margin of error as unimportant for clinical use. More-over we were able to show that the TOF-count is not dose dependent.

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)

A high-performance liquid chromatographic method coupled with fluorimetric detection has been developed for the determination of atracurium and its major metabolite, laudanosine, in human plasma. The detection is performed at 240 nm for excitation and 320 nm for emission. Verapamil was used as the internal standard. The proposed technique, involving the direct precipitation of plasma proteins is reproducible, selective and sensitive. Linear detector responses were observed for the calibration curve standards in the range of 40 to 2000 ng/ml. Precision, expressed as C.V., was in the range 1 to 14%. The limit of quantification for both atracurium and laudanosine was 40 ng/ml. The method has been validated and stability tests under various conditions have been performed. This method has been used to determine the pharmacokinetic profile of atracurium and laudanosine in patients with acute respiratory distress syndrome.

Aim. The depth of muscular relaxation during general anesthesia is monitored through the analysis of the contraction evoked by selective electrical stimulation of a peripheral nerve. The aim of this study was to compare the method of selective stimulation (SS) to a new method based on non-selective electrical stimulation (NSS) delivered over the muscle. Method. Electrical stimuli were delivered as train-of-four impulses to the ulnar nerve (SS) and to the ventral aspect of the contralateral forearm (NSS). The muscular responses of the adductor pollicis brevis (SS) and the forearm supinator longus (NSS) were studied at 30–60 s intervals with piezoelectric transducers before and after the administration of atracurium bolus doses of 0.5 mg/kg to patients under general anesthesia. SS and NSS evoked muscular responses were quantitized as percentages of the control response and compared with linear correlation and concordance analysis. Results. Twenty patients were studied. Basal and post-atracurium muscular responses were similar for the SS and the NSS methods. Precision between SS and NSS was > 85% and accuracy > 92%. Concordance was: basal < 15%, relaxation < 5%, recovery < 10%. Conclusion. NSS is equivalent to SS for muscular relaxation monitoring during general anesthesia. This has important implications to simplify muscular relaxation monitor design.

Cisatracurium besilate, one of the 10 stereoisomers that comprise atracurium besilate, is a nondepolarising neuromuscular blocking agent with an intermediate duration of action. Following a 5- to 10-sec intravenous bolus dose of cisatracurium besilate to healthy young adult surgical patients, elderly patients and patients with renal or hepatic failure, the concentration versus time profile of cisatracurium besilate is best characterised by a 2-compartment model. The volume of distribution (Vd) of cisatracurium besilate is small because of its relatively large molecular weight and high polarity. Cisatracurium besilate undergoes Hofmann elimination, a process dependent on pH and temperature. Unlike atracurium besilate, cisatracurium besilate does not appear to be degraded directly by ester hydrolysis. Hofmann elimination, an organ independent elimination pathway, occurs in plasma and tissue, and is responsible for approximately 77% of the overall elimination of cisatracurium besilate. The total body clearance (CL), steady-state Vd and elimination half-life of cisatracurium besilate in patients with normal organ function are approximately 0.28 L/h/kg (4.7 ml/min/kg), 0.145 L/kg and 25 minutes, respectively. The magnitude of interpatient variability in the CL of cisatracurium besilate is low (16%), a finding consistent with the strict physiological control of the factors that effect the Hofmann elimination of cisatracurium besilate (i.e. temperature and pH). There is a unique relationship between plasma clearance and Vd because the primary elimination pathway for cisatracurium besilate is not dependent on organ function. There are minor differences in the pharmacokinetics of cisatracurium besilate in various patient populations. These differences are not associated with clinically significant differences in the recovery profile of cisatracurium besilate, but may be associated with differences in the time to onset of neuromuscular block.

For anesthetic drugs undergoing nonorgan-based elimination, there is a definite trend towards using pharmacokinetic (PK) models in which elimination can occur from both central (k10) and peripheral compartments (k20). As the latter cannot be assessed directly, assumptions have to be made regarding its value. The primary purpose of this paper is to evaluate the impact of assuming various degrees of peripheral elimination on the estimation of PK parameters. For doing so, an explanatory model is presented where previously published data from our laboratory on three muscle relaxants, i.e., atracurium, doxacurium, and mivacurium, are used for simulations. The mathematical aspects for this explanatory model as well as for two specific applications are detailed. Our simulations show that muscle relaxants having a short elimination half-life are more affected by the presence of peripheral elimination as their distribution phase occupies the major proportion of their total area under the curve. Changes in the exit site dependent PK parameters (Vdss) are also mostly significant when k20 is smaller than k10. Although the physiological processes that determine drug distribution and those affecting peripheral elimination are independent, the two are mathematically tied together in the two-compartment model with both central and peripheral elimination. It follows that, as greater importance is given to k20, the rate of transfer from the central compartment (k12) increases. However, as a result of a proportional increase in the volume of the peripheral compartment, peripheral concentrations remain unchanged whether or not peripheral elimination is assumed. These findings point out the limitations of compartmental analysis when peripheral elimination cannot be measured directly.

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.

Fragestellung: Aufgrund von Kasuistiken war zu vermuten, das die muskelrelaxierende Potenz von Atracurium beim Vorliegen eines intrathorakalen Eiterherds reduziert ist. In einer prospektiven, klinischen Untersuchung sollte diese Hypothese uberpruft werden. Methodik: Untersucht wurden 52 erwachsene Patienten, bei denen ein elektiver, thoraxchirurgischer Eingriff in Narkose (Methohexital, Flunitrazepam, Sufentanil, N2O, Enfluran) durchgefuhrt wurde. Zur Relaxation wurde Atracurium verwendet. Nach der Intubationsdosis von 0,6 mg/kg folgte die kontinuierliche Applikation zur Aufrechterhaltung einer 90%igen Suppression des evozierten Elektromyogramms. Entsprechend der operativen Diagnose wurden die Patienten drei Kategorien zugeteilt: 1) benigner intrathorakaler Tumor als Kontrollgruppe (n=15), 2) Bronchialkarzinom (n=22), 3) intrathorakaler Eiterherd ohne Tumor (n=15). Die Gruppen wurden hinsichtlich Anschlagzeit, Wirkdauer (DUR 10%) und Erhaltungsdosis von Atracurium verglichen. Ergebnisse: Die Karzinompatienten unterschieden sich hinsichtlich der muskelrelaxierenden Wirkung von Atracurium nur unwesentlich von der Kontrollgruppe. Im Gegensatz hierzu war die Anschlagzeit von Atracurium beim Vorliegen eines intrathorakalen Eiterherds signifikant langer (6,3±2,5 vs. 2,9±0,8 min, p

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.

We compared the dose-response relationships of cisatracurium, mivacurium, atracurium, vecuronium and rocuronium and examined the interactions of cisatracurium with mivacurium, atracurium, vecuronium and rocuronium in humans by isobolographic and fractional analyses. We studied 180 adult patients during nitrous oxide-fentanyl-propofol anaesthesia. Neuromuscular block was monitored using mechanomyography to detect the twitch response of the ulnar nerve at the wrist. The dose-response curves were determined by probit analysis. The calculated ED50 values and their 95% confidence intervals were 40.9 (38.1-43.7), 49.8 (47.0-52.6), 187.2 (175.1-199.3), 36.6 (34.7-38.5) and 136.4 (129.2-143.6) micrograms.kg-1 for cisatracurium, mivacurium, atracurium, vecuronium and rocuronium, respectively. Corresponding ED95 values were 57.6 (53.5-61.7), 91.8 (88.1-95.5), 253.1 (238.9-267.3), 52.9 (49.1-56.7) and 288.7 (276.2-301.2) micrograms.kg-1, respectively. The interaction between cisatracurium and mivacurium, vecuronium or rocuronium was found to be synergistic, but the interaction between cisatracurium and atracurium was found to be additive. Synergy between cisatracurium and vecuronium or rocuronium was greater than between cisatracurium and mivacurium.

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.