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PubMed1994

Clinical pharmacology of ORG 7617, a short-acting non-depolarizing neuromuscular blocking agent.

The dose-response relationship and the time course of action of Org 7617, a short acting non-depolarizing neuromuscular blocking agent, were evaluated during thiopentone, fentanyl, halothane and N2O anaesthesia. Neuromuscular transmission was monitored mechanomyographically. The ED50 and ED90 were calculated after single bolus doses of the drug. Twelve, seven and three patients received 2.5, 3.75 or 5.0 mg.kg-1 Org 7617, respectively. Neuromuscular block was characterized by a short lag time (average 30 s) and rapid development of neuromuscular block (69-84 s). Maximum block approximated to 66%, 91% and 95%, and the duration until clinically adequate recovery (TOF ratio of 0.7) to 7.4, 12.1 and 12.2 min after 2.5, 3.75, 5 mg.kg-1 of Org 7617, respectively. The calculated ED50 and ED90 were 1.8 and 3.4 mg.kg-1. Adverse effects, including a moderate fall in systolic and diastolic arterial blood pressure and a concomitant increase in heart rate appeared to be dose-dependent. Some patients showed flushing. One patient given 5 mg/kg Org 7617 had serious adverse effects suggestive of histamine release, i.e. flushing, urticaria, tachycardia, hypotension and bronchospasm. Therefore further clinical investigations were terminated. Although its low potency and the adverse effects observed will prevent further clinical development of ORG 7617, the results do support the contention that it is feasible to develop short-acting non-depolarizing neuromuscular blocking agents from the steroidal series.

Adolescent↗
PubMed1989

Inhibition by vecuronium of carbachol-induced influx of 22Na+, 45Ca2+ and secretion of catecholamines in cultured bovine adrenal medullary cells.

In cultured bovine adrenal medullary cells, vecuronium, pancuronium and D-tubocurarine reduced carbachol-induced 45Ca2+ influx and catecholamine secretion by inhibiting 22Na+ influx via nicotinic receptor-ion channel complex with IC50 values of 0.43, 7.6 and 3.9 mumol/l, respectively. IC50 values of pancuronium and D-tubocurarine observed in adrenal medulla were one order of magnitude higher than the plasma concentrations of these muscle relaxants reported to produce 50% neuromuscular blockade, while IC50 of vecuronium was quite close between adrenal medulla and skeletal muscle.

Adrenal Medulla↗
PubMed1991

Reversal of neuromuscular blockade in humans by neostigmine and edrophonium: a mathematical model.

Generalizations of the integrated model describing the interaction of nondepolarizing neuromuscular blocking drugs with reversible anticholinesterase drugs described in Unadkat et al. (1) are reported. The models can deal with possible incomplete reversal (irreversible block) and/or noninstantaneous anticholinesterase kinetics. Experimental data were obtained from 22 human volunteers. Different levels of steady-state vecuronium block were induced in each volunteer (in the range of 50% to 95%), and reversed by short infusions of edrophonium (10 volunteers) or neostigmine (12 volunteers). Edrophonium or neostigmine concentrations and twitch tension (measured as the force of thumb adduction) were measured. The generalized integrated models fit the data well. In the case of neostigmine we find a nondistributional delay in its action. We relate this delay to the slow decarbamylation rate of the (neostigmine-induced) carbamylated anticholinesterase observed in vitro, and are able to model such noninstantaneous anticholinesterase kinetic processes. For both edrophonium and neostigmine we detect an inverse relationship between the (induced) level of initial block and maximal percentage recovery.

Adult↗
PubMed1995

A bolus plus continuous infusion protocol for controlling neuromuscular blockade during anesthesia.

Neuromuscular blockade is controlled during anesthesia by administering either bolus doses or a continuous infusion of a blocking agent. To test whether a constant infusion technique requires less attention and provides better control we used a computer to simulate neuromuscular blockade. Using the model we maintained 95% blockade with mivacurium, atracurium, and vecuronium. It required 1.2 changes per hour to maintain the blockade by continuous infusion; an average of 4.5 bolus per hour were required to maintain blockade by the bolus technique. When the bolus and continuous infusion techniques were combined, only 0.16 changes per hour were required. Atracurium was then given to ten patients during anesthesia, following the bolus plus continuous infusion protocol. After a bolus was given to obtain 100% twitch depression, for tracheal intubation, neuromuscular function was assessed by train-of-four stimulation of the ulnar or facial nerves by observing the resultant muscle movement. When the first twitch of the train-of-four returned, relaxation was maintained by continuous infusion. A bolus was given and the drug infusion rate was changed whenever the level of relaxation changed from the desired one twitch of the train-of-four. The infusion rate was adjusted only 1.12 +/- 0.79 times per hour. The desired level of muscle relaxation was easily controlled using the bolus plus continuous infusion protocol. The infusion scheme might be implemented in future drug infusion pumps.

Adult↗
PubMed1981

The influence of stimulation parameters on the potency and reversibility of neuromuscular blocking agents.

Voluntary muscle movements in mammalian muscles are initiated by short trains of 16 to 60 Hz impulses (Zierler, 1974). Despite this in most neurophysiological and neuropharmacological studies either single stimuli of 0.1 to 2 Hz or 5 to 10 sec 50 to 500 Hz tetani have been employed. Neither of these two types of stimuli are ideal for the testing of the functional integrity of the motor unit. Stimulation with single impulses, at slow rates, does not reveal incipient pathological or drug induced defects. Recovery of neuromuscular (NM) activity after 5 to 10 sec tetanic stimulation is prolonged and after repeated stimulation of this type the preparations decay rapidly. Stimulation of 0.1 sec trains of 50 Hz impulses applied every 10 to 20 sec eliminate the above disadvantages. This type of stimulation represents adequate challenge for revealing more moderate degrees of functional defects of the myoneural apparatus without causing rapid decay of the in vitro or in vivo preparations. In agreement with this the ED50 of NM blocking agents were found to be significantly lower in both the in vitro phrenic nerve-hemidiaphragm preparation and the in vivo sciatic nervetibialis anterior muscle preparation of rats during stimulation with 0.1 sec trains of 50 Hz impulses, than when single stimuli of 0.1 Hz were used. Recovery of the in vitro preparations after washout or in vivo after discontinuation of the infusion was also slower during stimulation with short trains of tetani. The antagonist potency of anticholinesterases or 4-aminopyridine and maximal recovery after the use of the optimal concentrations of these antagonists was less in the preparations stimulated with short trains of tetani than in those stimulated with single impulses.

Acetylcholine↗
PubMed1982

Org-NC45: a new steroidal non-depolarizing muscle relaxant.

Although pancuronium has fewest side effects compared to other currently used non-depolarizing muscle relaxants, it is still not the ideal relaxant. Its structural analogues have been studied to derive such an ideal relaxant. Org-NC45 meets the requirements for such a relaxant best and is therefore extensively studied. It is more potent than pancuronium, has a shorter onset and duration of action and is free from cardiovascular side effects. Histamine release could not be demonstrated. It can be easily reversed by neostigmine, pyridostigmine or 4-aminopyridine. Interaction with antibiotics and anaesthetic drugs is not different from that of pancuronium.

Humans↗
PubMed2004

Effects of isoflurane on the actions of neuromuscular blockers on the muscle nicotine acetylcholine receptors.

In this study, we tested the hypothesis that volatile anesthetic enhancement of muscle relaxation is the result of combined drug effects on the nicotinic acetylcholine receptors. The poly A m RNA from muscle by isolation were microinjected into Xenopus oocytes for receptor expression. Concentration-effect curves for the inhibition of Ach-induced currents were established for vecuronium, rocuranium, and isoflurane. Subsequently, inhibitory effects of NDMRs were studied in the presence of the isoflurane at a concentration equivalent to half the concentration producing a 50% inhibition alone. All tested drugs produced rapid and readily reversible concentration-dependent inhibition. The 50% inhibitory concentration values were 889 micromol/L (95% CI: 711-1214 micromol). 33.4 micromol (95% CI: 27.1-41.7 nmol) and 9.2 nmol (95% CI: 7.9-12.3 nmol) for isoflurane. rocuranium and vecuronium, respectively. Coapplication of isoflurane significantly enhanced the inhibitory effects of rocuranium and vecuronium, and it was especially so at low concentration of NMDRs. Isoflurane increases the potency of NDMRs, possibly by enhancing antagonist affinity at the receptor site.

Androstanols↗
PubMed1988

Simulating the time-course of clinical paralysis.

This computer program depicts the concentration-time curves for the nondepolarizing neuromuscular blocking agents. It simulates their administration by single and multiple iv injections, and with continuous infusion, alone and in combination. It provides the plasma concentrations related to 75% and 25% depression of the twitch response, using these to calculate clinically useful pharmacodynamic values, such as the duration of surgical relaxation, and the recovery index. These simulations allow the user to contrast the time-course of relaxation to be expected with various dosage regimens.

Atracurium↗
PubMed1996

Optimal surface electrode positioning for reliable train of four muscle relaxation monitoring.

In the clinic, a major problem in train of four (TOF) muscle relaxation monitoring is incorrect placement of stimulation and recording electrodes, frequently resulting in incorrect estimates of the patient's degree of relaxation or in abandonment of relaxation monitoring. The aim of this study was to arrive at recommendations that describe how to find optimal positions for the electrodes, where 'optimal' is taken in the sense that small deviations from these positions introduce no or only a small decline in the accuracy of the computed degree of muscle relaxation. This study, which employed the Relaxograph as the stimulation and measuring device, established that incorrect positioning is a real problem that frequently occurs; that the correctness of positioning is not guaranteed when the calibration of the Relaxograph succeeds; that the inadequacy of the electrode position is sometimes discovered for the first time when relaxation deepens; that positioning errors can be discovered by analysing the shape of the evoked compound action potential (ECAP), not only upon calibration but also when relaxation deepens; that a set of optimal electrode positions can be found; and that recommendations of how to find these optimal positions could help clinicians to place the electrodes in such a way, that reliable relaxation monitoring was possible in 100% of the investigated cases. In a first test in 30 adult patients, we surveyed how clinicians routinely positioned electrodes and found that in 14 of the 30 cases positioning was unsuccessful. In a second test in 10 patients, we tested a variety of electrode positions in order to discover 'optimal' stimulation, recording and ground electrode sites. In a third test in 10 patients, electrodes were positioned at these 'optimal' sites; stimulation and recording at these sites was successful in all 10 cases.

Adult↗
PubMed1989

Atracurium and vecuronium interaction with gentamicin and tobramycin.

Drug interactions between the aminoglycosides (tobramycin and gentamicin) and atracurium and vecuronium were studied prospectively in 44 patients. Twenty-two patients had therapeutic serum levels of tobramycin or gentamicin and 22 served as controls. Onset time, clinical duration, and time to spontaneous recovery of T4/T1 ratio of 0.70 after atracurium or vecuronium injection were measured. No statistically significant differences were found in onset time, but clinical duration and time to recovery were significantly longer in patients receiving tobramycin or gentamicin and paralyzed with vecuronium than for controls (P less than 0.01 for clinical duration and P less than 0.0005 for recovery). The neuromuscular block produced by atracurium was not significantly influenced by the presence of therapeutic serum levels of tobramycin or gentamicin. We conclude that for patients treated with these antibiotics, atracurium may present some advantages over vecuronium when a prolonged block is not desired.

Adult↗
PubMed1990

Clinical, electrical and mechanical correlations during recovery from neuromuscular blockade with vecuronium.

In order to determine correlations between electromyographic (EMG), mecanomyographic (MMG) and clinical criteria of adequate recovery from neuromuscular blockade with vecuronium, seven young healthy conscious volunteers were given subparalysing doses of vecuronium. During recovery from neuromuscular blockade, vital capacity, negative inspiratory pressure, peak expiratory flow rate and five-second head lift were assessed. Neuromuscular monitoring included the evoked EMG response of the adductor digiti minimi and the simultaneous evoked MMG response of the adductor pollicis on the same side. We found that all subjects maintained head lift for five seconds at EMG T4T1 of 0.70, and they achieved normal respiratory tests at EMG T4/T1 of 0.90. The MMG T4/T1 needed for the subjects to perform normal respiratory tests was found to be 0.50, at which time six of the seven subjects were able to perform adequately the head lift test.

Adult↗
PubMed1990

Rapid induction sequence with vecuronium: should we intubate after 60 or 90 seconds?

The purpose of the study was to determine intubating conditions after administration of either succinylcholine or vecuronium in a rapid induction sequence. Patients received either succinylcholine 1.5 mg.kg-1 (Groups I and II) after d-tubocurarine 0.05 mg.kg-1 four minutes earlier, or vecuronium (Groups III and IV) in an initial dose of 0.01 mg.kg-1 followed four minutes later by 0.1 mg.kg-1. In Groups I and III an apnoeic delay of one minute was allowed before intubation whereas in Groups II and IV the delay was 90 sec. There was no significant difference in intubating conditions between Groups I and IV. Intubating conditions in Group III (vecuronium-delay of one minute) were statistically worse than in any of the three other groups. A delay of 90 sec after succinylcholine improved intubating conditions in male patients. Considering that intubating conditions obtained after 90 sec in patients given a priming sequence with vecuronium (Group IV) were not different from those obtained 60 sec after succinylcholine (Group I), the authors conclude that vecuronium is an acceptable alternative for rapid tracheal intubation. In the doses used in this study, intubating conditions 60 sec after vecuronium were unacceptable for rapid induction of anaesthesia.

Adult↗
PubMed1990

Sensitivity to vecuronium in myasthenia gravis: a dose-response study.

A cumulative dose plus infusion technique and integrated EMG monitoring of the first dorsal interosseous muscle were used to determine the potency of vecuronium in 20 normal patients and in ten patients with myasthenia gravis under thiamylal, N2O, O2, fentanyl anaesthesia. The mean (+/- SEM) values for ED50, ED90, and ED95 in the normal patients were 19 +/- 1, 31 +/- 1 and 36 +/- 2 micrograms.kg-1, respectively. Myasthenic patients showed increased sensitivity to vecuronium, the mean values for ED50, ED90, and ED95 were 10 +/- 2, 17 +/- 2 and 20 +/- 3 micrograms.kg-1, being 50, 55 and 56 per cent of normal, respectively. We did not demonstrate a difference in sensitivity to vecuronium between those myasthenic patients who received pyridostigmine preoperatively and those who did not, nor among those chronically treated with corticosteroids, compared with those who were not.

Adult↗
PubMed1990

Intravenous lidocaine does not attenuate the haemodynamic response of children to laryngoscopy and tracheal intubation.

The haemodynamic responses to laryngoscopy and intubation after induction of anaesthesia with thiopentone alone or in combination with 1.5 mg.kg-1 IV lidocaine were measured in 125 children age 2 to 12 yr to determine whether lidocaine administered one, two, three or four minutes before tracheal intubation attenuated the pressor response. Lidocaine did not attenuate the increases in heart rate and arterial blood pressure. The pressor response was significantly affected by baseline haemodynamic values, P less than 0.05. The increases in systolic and mean blood pressure were significantly affected by the age of the patient, P less than 0.05. Lidocaine is not a beneficial adjunct to induction of anaesthesia with thiopentone in healthy children for the purpose of attenuating the pressor response to intubation.

Age Factors↗
PubMed1990

Prolonged neuromuscular blockade and ventilatory failure after renal transplantation and cyclosporine.

In a retrospective one-year study, we documented respiratory failure or prolonged neuromuscular blockade in eight of 65 patients with chronic renal failure who had received either vecuronium (four of 29 patients) or atracurium (four of 36 patients) during anaesthesia for kidney transplantation. We reviewed the charts of the patients and recorded all aspects of medication and anaesthesia to try to determine whether there might be a single factor associated with this high incidence (12 per cent) of respiratory failure. Anaesthesia for all patients was induced with thiopentone, isoflurane, and N2O/O2. Tracheal intubation was facilitated with muscle relaxants in a single bolus of vecuronium, 0.07 to 0.1 mg.kg-1, or atracurium, 0.3 to 0.5 mg.kg-1. Additional doses were given according to neuromuscular activity, which was monitored visually by response to train-of-four and tetanic stimulation. Anaesthesia was maintained with fentanyl/isoflurane and N2O/O2. After induction of anaesthesia, each patient received methylprednisolone, cefazolin, mannitol infusion for 24 hr beginning at the start of renal artery anatomosis, and either azathioprine (n = 57) or cyclosporine (n = 8). Relaxation was evaluated toward the end of the operation by train-of-four stimulation. Neuromuscular blockade was reversed with edrophonium (0.75-1 mg.kg-1) or neostigmine (0.06-0.08 mg.kg-1). The eight patients with prolonged neuromuscular blockade received ventilatory support for one to three hours after operation. Respiratory failure was significantly more frequent in patients who received cyclosporine (P less than 0.05).

Adult↗
PubMed1990

Negative pressure pulmonary oedema: a potential hazard of muscle relaxants in awake infants.

We report two cases of healthy infants who were given an IV intubating bolus of a nondepolarizing muscle relaxant (0.1 mg.kg-1 vecuronium) at the beginning of an inhalational induction of anaesthesia. Shortly after the introduction of low concentrations of gaseous agents, both infants exhibited airway obstruction although inspiratory muscle activity was still vigorous. The airway obstruction was due to approximation of the tongue to the posterior pharyngeal wall, and was easily corrected by insertion of an oral airway. The infants immediately exhibited fulminant pulmonary oedema, which responded to conventional therapy. It is postulated that paralysis of glossal muscles occurred prior to diaphragmatic paralysis, creating upper airway obstruction while preserving inspiratory muscle activity. This can rapidly lead to negative pressure pulmonary oedema in the small infant. Meticulous attention to the maintenance of an unobstructed upper airway is required if muscle relaxants are administered to the awake infant.

Airway Obstruction↗