Muscle relaxants in infants and children

In the first 2 years of life there is physical and biochemical maturation of the neuromuscular junction of man. With this maturation there is an increase in the neuromuscular reserve (margin of safety) of the infant and a change in the contractile properties of skeletal muscle. On a weight basis neonates and young infants are resistant to both depolarizing and non-depolarizing muscle relaxants; when dosage is calculated on the basis of surface area neonates and young infants are not resistant to succinylcholine, but appear sensitive to non-depolarizing relaxants. Variation in extracellular fluid volume probably explains these differences in apparent resistance. Data relating recovery of neuromuscular transmission to plasma or tissue bath concentrations of dTc are conflicting. Awareness of the clinical response of neonates and infants to muscle relaxants and awareness of the non-neuromuscular blocking properties of relaxants in infants and children permits the use of these anesthetic adjuncts in patients of any age.     

Myasthenia gravis and pipecuronium--report of two cases.

The use of pipecuronium in two patients with myasthenia gravis undergoing thymectomy is described. Neuromuscular function was monitored throughout using the train-of-four (TOF) mechanical twitch response. The cumulative dose-response to pipecuronium was determined in both patients during nitrous oxide-oxygen-narcotic anaesthesia. Both patients were sensitive to pipecuronium. The ED50 doses of pipecuronium were 11.6 and 11.1 micrograms.kg-1 and the ED95 doses were 35 and 33.3 micrograms.kg-1 in patients #1 and 2 respectively. Edrophonium 1 mg.kg-1 and neostigmine 0.06 mg.kg-1 were administered to patients #1 and 2 respectively for antagonism of residual neuromuscular blockade at 25 per cent spontaneous recovery of first twitch (T1) of the TOF stimulation. As with other non-depolarizing muscle relaxants pipecuronium in reduced dosage and with careful neuromuscular monitoring can be used to provide surgical relaxation safely in patients with controlled myasthenia gravis.     

Monitoring of neuromuscular function

Clinical monitoring of neuromuscular function can be accomplished by either measuring the evoked mechanical or EMG response of a skeletal muscle via an accessible motor nerve. The pattern of motor nerve stimulation varies from supramaximal single repeated stimuli at a specified frequency to tetanic stimulation, posttetanic single stimuli at the pretetanic frequency, and train-of-four stimuli at 2 Hz. The response to relaxants is unpredictable in the population at large and more so in pathologic states. This makes monitoring of the muscle response to motor nerve stimulation extremely valuable and helpful. The train-of-four technique of measurement has proved to be valuable not only as a reliable clinical tool to measure the response to relaxants and monitoring recovery, but also as a research tool for studies of old and new neuromuscular blocking drugs. Evoked responses and clinical criteria for adequate recovery from muscle relaxants should complement each other. The more criteria fulfilled, the better and safer the conclusion that the patient has recovered from clinical neuromuscular blockade.     

Spontaneous recovery or evoked reversal of neuromuscular block

Recovery from the effects of muscle relaxants can occur either spontaneously by their metabolism in the body or by elimination via the normal excretion pathways, or by the administration of pharmacologic antagonists. The decision as to whether spontaneous recovery should be allowed to take place or pharmacologic reversal should be induced depends upon several factors, principal among them being the duration of action of the muscle relaxant used, its dose, and the time that is available. The recovery times of most relaxants, including atracurium and vecuronium, are such as to require antagonism if adequate recovery is to be attained quickly. An agent such as mivacurium may, however, allow complete spontaneous recovery to take place without the use of antagonists.     

Neuromuskuläre Restblockaden

Even after administration in routine clinical dosages, muscle relaxants can lead to long-lasting residual blockades which increase the risk of severe postoperative pulmonary complications. Even without the additional effects from analgetics, sedatives or anaesthetics, a partial neuromuscular blockade, which cannot reliably be avoided either by the anaesthetist alone or by the additional use of nerve stimulators (train-of-four [TOF] ratio 0.5-0.9), can cause reductions in the vital capacity and the hypoxic breathing response, as well as obstruction of the upper airway and disruption of pharangeal function. The extent of neuromuscular recovery after an operation depends on the muscle relaxant used, the duration of administration, the anaesthetic technique and possible accompanying illnesses of the patient. It must basically be assumed that residual neuromuscular blockades are more frequent after administration of slow acting muscle relaxants such as pancuronium, than after the use of medium or rapid acting substances. If the course of a neuromuscular blockade is continually monitored during the whole anaesthetic procedure using the TOF ratio and not only occasionally at the end, a TOF ratio of 1 measured with an acceleromyograph (e.g. TOF-watch) promises an adequate neuromuscular recovery from the effects of muscle relaxants.     

A new short-acting non-depolarizing muscle relaxant (SZ1677) without cardiovascular side-effects

BACKGROUND: In order to facilitate rapid tracheal intubation, the development of a rapid onset, short duration, non-depolarizing muscle relaxant without cardiovascular side-effects would be a significant accomplishment in the field of anesthesiology. The aim of the present study was to test the action of a new non-depolarizing muscle relaxant (SZ1677) on neuromuscular transmission, muscarinic (M2, M3) receptors and cardiovascular reactions and to compare it with clinically used muscle relaxants. METHODS: Neuromuscular transmission was studied by recording muscle contractions elicited by indirect electrical stimulation, using (i). in vitro isolated phrenic nerve-hemidiaphragm preparation of mice, rats and guinea pigs and (ii). in vivo sciatic nerve-anterior tibial muscle preparation of anesthetized rats, guinea pigs and cats. Cardiovascular effects of muscle relaxants were evaluated on the grounds of their effects on changes of blood pressure and heart rate induced by electrical stimulation of the right vagal nerve in anesthetized cats. To study postsynaptic antimuscarinic affinity of muscle relaxants on M3 receptors, oxotremorine-induced contractions of longitudinal muscle strip of guinea pig ileum were registered in their presence and absence. RESULTS: One of more than 120 newly synthesized non-depolarizing muscle relaxants compounds, 1-3[alpha-hydroxy-17beta-acetyloxy-2beta-(1,4-dioxa-8-azaspiro[4,5]dec-8-yl)-5alpha-androstane-16beta-il] -1-(2-propenyl)pyrrolidinium bromide (SZ1677), excelled with its advantageous pharmacological properties: relatively short duration of action, no accumulation and lack of unwanted side-effects. Pharmacodynamic studies show that SZ1677 is a non-depolarizing neuromuscular blocking agent with a relatively short duration and rapid onset of action in a variety of laboratory animal species. It is without cumulative effect, does not reduce blood pressure, and fails to produce tachycardia. Significant cardiac vagal blocking effects were not observed even at concentrations or dosages of 8 times the ED90. This compound, unlike many other muscle relaxants, does not have atropine-like effects on human atrial tissue; it does not increase the release of NA from sympathetic innervation in the heart. In all practical ways, at least from the vantage point of the preclinical study, SZ1677 compares favorably with all presently available short-acting muscle relaxants, including rapacuronium. CONCLUSION: In experiments, SZ1677 proved to be a short-acting neuromuscular blocking compound having a large safety margin between the doses required to produce neuromuscular block and those likely to lead to cardiovascular side-effects.     

Anesthetic management of a patient with dermatomyositis--clinical observation of the effect of muscle relaxants

A 58 year old woman suffering from dermatomyositis underwent elective surgery for spinal caries. Concerning the anesthetic management of patient suffering from dermatomyositis, there is little information on the appropriate use of muscle relaxants. It is generally suspected that the patient is sensitive to nondepolarizing muscle relaxants. Anesthesia was with oxygen-nitrous oxide and fentanyl. Pancuronium 6 mg was given intravenously after awake intubation and an additional dose of 2 mg was given after 7.3 hours. During anesthesia neuromuscular function was monitored by neuromuscular transmission monitor (Datex Relaxograph). Duration of neuromuscular block was defined as the time for the twitch height to recover from total paralysis to 25% of the control value. Duration in this patient was 3.1 hours and this was longer as compared with the values of 1.1-1.8 hours obtained in 7 control patients. It is suggested that a usual dose of muscle relaxants results in a relatively higher effect in the patients with dermatomyositis because of their diminished muscle mass. The anesthetist should be careful in using muscle relaxants. The muscle relaxants should be given to such a patient with monitoring closely the neuromuscular function using a neuromuscular transmission monitor.     

Update on neuromuscular pharmacology

Since the introduction of d-tubocurarine into clinical practice, neuromuscular relaxants have been widely used in anaesthesia. Although their clinical use is easy, several points still require further attention and research. There is still a need for a drug with the clinical profile of succinylcholine but fewer unwanted side-effects. A better understanding of the effects of muscle relaxants on different muscles could help in their clinical use during the perioperative period. Much knowledge is needed about residual neuromuscular block and its detection in order to improve the quality of recovery from neuromuscular blockade. If some questions remain to be answered, several recent articles have increased our knowledge and should improve our clinical practice.     

Sugammadex: another milestone in clinical neuromuscular pharmacology

Sugammadex is a revolutionary investigational reversal drug currently undergoing Phase III testing whose introduction into clinical practice may change the face of clinical neuromuscular pharmacology. A modified gamma-cyclodextrin, sugammadex exerts its effect by forming very tight water-soluble complexes at a 1:1 ratio with steroidal neuromuscular blocking drugs (rocuronium > vecuronium > pancuronium). During rocuronium-induced neuromuscular blockade, the IV administration of sugammadex creates a concentration gradient favoring the movement of rocuronium molecules from the neuromuscular junction back into the plasma, which results in a fast recovery of neuromuscular function. Sugammadex is biologically inactive, does not bind to plasma proteins, and appears to be safe and well tolerated. Additionally, it has no effect on acetylcholinesterase or any receptor system in the body. The compound's efficacy as an antagonist does not appear to rely on renal excretion of the cyclodextrin-relaxant complex. Human and animal studies have demonstrated that sugammadex can reverse very deep neuromuscular blockade induced by rocuronium without muscle weakness. Its future clinical use should decrease the incidence of postoperative muscle weakness, and thus contribute to increased patient safety. Sugammadex will also facilitate the use of rocuronium for rapid sequence induction of anesthesia by providing a faster onset-offset profile than that seen with 1.0 mg/kg succinylcholine. Furthermore, no additional anticholinesterase or anticholinergic drugs would be needed for antagonism of residual neuromuscular blockade, which would mean the end of the cardiovascular and other side effects of these compounds. The clinical use of sugammadex promises to eliminate many of the shortcomings in our current practice with regard to the antagonism of rocuronium and possibly other steroidal neuromuscular blockers.     

Muskelrelaxanzien Neue Substanzen und neuromuskuläres Monitoring

Introduction: Recent developments in both the quantitative evaluation of neuromuscular blockade and new muscle relaxants are reviewed. With respect to nerve stimulation, neuromuscular recording, and definition of parameters, the results of the 1994 Copenhagen International Consensus Conference are highlighted. Future clinical studies should adhere to these standards. Muscle relaxants: Rocuronium, cisatracurium, and mivacurium are new muscle relaxants that were released for clinical use in 1995/1996. Of these, rocuronium has the shortest time of onset, whereas its recovery characteristics closely resemble those of vecuronium. Rocuronium is five times less potent than vecuronium. Twice the ED₉₅ of rocuronium provides good or excellent intubating conditions within 60 to 90?s. Slight vagolytic effects were reported following injection of 0.6?mg/kg rocuronium, while histamine release was not observed. Cisatracurium is one of the ten steroisomers of atracurium. It is five times as potent as the chiral mixture while having a similar pharmacodynamic and -kinetic profile. Up to eight times the ED₉₅ did not cause significant histamine release or clinically relevant cardiovascular effects. Mivacurium is a short-acting nondepolarizing benzylisoquinoline muscle relaxant that undergoes rapid breakdown by plasma cholinesterase (PChE). Its duration of action is about one-half as long as that of equipotent doses of atracurium and vecuronium and three times as long as succinylcholine. Mivacurium has a moderate histamine-releasing potential. In patients with atypical or reduced PChE activity, the duration of action of mivacurium is prolonged.     

Prolongation of rapacuronium neuromuscular blockade by clindamycin and magnesium.

IMPLICATIONS: We report a prolonged neuromuscular block with the nondepolarizing muscle relaxant rapacuronium in the presence of clindamycin. Even when using "short-acting" muscle relaxants, the anesthesiologist must routinely monitor the neuromuscular function.     

ABSENCE OF "RECURARIZATION" IN PATIENTS WITH DEMONSTRATED PROLONGED NEUROMUSCULAR BLOCK

The possibility of "recurarization" after antagonism of thecompetitive neuromuscular block with anticholinesterases wasstudied. Observations were made on the time-course of the blockin five patients at risk from recurarization because of multipleorgan failure and who demonstrated unusually prolonged blockade.In none of these patients did the block recur. We conclude that,provided spontaneous recovery of neuromuscular transmissionhas made progress before the antagonism, and that the patientdoes not deteriorate or become exhausted afterwards, recurarizationis unlikely.     

Sensitivity to curare in patients with upper and lower motor neurone dysfunction

Sensitivity to the action of nondepolarising relaxants was compared in muscles of upper and lower limbs in four syringomyelic patients undergoing elective neurosurgical procedures. It was observed that muscles with signs of lower motor neurone dysfunction are supersensitive to the action of nondepolarising relaxants. Terminal sprouting of motor axons and the occurrence of newly formed neuromuscular junctions may be responsible for a low synaptic efficacy and may explain the high sensitivity to factors that reduce the safety margin of neuromuscular transmission.     

新型肌肉松弛药拮抗剂舒更葡糖钠在麻醉苏醒期应用的近况

舒更葡糖钠是拮抗非去极化肌肉松弛药（肌松药）的新型药物,它能够快速、安全、可控地拮抗罗库溴铵等甾体类肌松药的神经肌肉阻滞,与传统肌松拮抗剂抗胆碱酯酶药相比,具有拮抗深度神经肌肉阻滞且不影响胆碱能系统活性的优越性,在麻醉苏醒期的临床应用具有广泛前景。文章通过对新型肌松拮抗药舒更葡糖钠的作用机制、使用效能、在特殊患者中的应...     

A new concept in the measurement of neuromuscular transmission and block.

The discovery of the safety margin of neuromuscular transmission has brought forth the requirement for an improvement in the clinical examination of curarization, since the safety margin, i.e. the reserves, should also be measured. For this purpose a peripheral nerve stimulator and an electromechanical recorder unit have been produced, suitable for both the examination of manifest curarization and of the neuromuscular reserves. The measurements of muscle relaxation are performed making use of 30 Hz stimulation, while the safety margin of neuromuscular transmission is measured using stimulation at 200 Hz one.     

Neuromuscular blockade at the larynx, the diaphragm and the corrugator supercilii muscle: a review

PURPOSE: To review recent findings concerning neuromuscular blockade and monitoring at the larynx, the diaphragm, and the corrugator supercilii muscle. SOURCE: This narrative review is based on recent publications. PRINCIPAL FINDINGS: Neuromuscular blockade at the larynx and the diaphragm is less intense than at the adductor pollicis muscle; the onset and offset of neuromuscular blockade is more rapid. The corrugator supercilii muscle reflects better the time course of neuromuscular blockade of the larynx than the adductor pollicis muscle, is better suited to monitor the onset of neuromuscular blockade for intubation, and should give a better reflection of the time course and degree of neuromuscular blockade of the larynx or the diaphragm. Recovery of neuromuscular function at the end of any procedure is best reflected at the adductor pollicis muscle where neuromuscular transmission is last restored. Clinical monitoring of the larynx or the diaphragm is still limited by the absence of a simple method. Acceleromyography of the corrugator supercilii muscle is prone to artifacts that do not occur during monitoring of the adductor pollicis muscle. Phonomyography, a new method of monitoring that is currently being tested, is based on the phenomenon that muscle contraction creates low-frequency sound waves, which can be detected using special microphones to quantify neuromuscular blockade. This method seems promising because it can be easily used on all muscles of interest. CONCLUSION: Research during the last 15 years has greatly enhanced our knowledge about how muscles react differently to muscle relaxants and has enabled us to achieve better surgical conditions with safer use of muscle relaxants. Interesting technologies have been developed to reliably monitor neuromuscular blockade at the larynx and the diaphragm, but are currently restricted to research settings. Our increased understanding should help us in ongoing efforts to develop the "ideal" muscle relaxant and the "ideal" method of neuromuscular monitoring.     

Nondepolarizing neuromuscular blockers inhibit the serotonin-type 3A receptor expressed in Xenopus oocytes

Molecular cloning and sequence comparison indicates a high degree of structural homology between muscle nicotinic acetylcholine (nACh) and serotonin-type 3 (5-HT(3A)) receptors, both members of the direct ligand-gated family of ion channels. Because of the structural similarities and common evolutionary origin of these receptors, neuromuscular blockers (competitive nACh antagonists) may demonstrate pharmacologic cross talk and exhibit attributes of 5-HT(3A) receptor antagonists. We examined six clinically-used neuromuscular blockers for their ability to antagonize currents flowing through the 5-HT(3A) receptors in voltage clamped Xenopus oocytes. The neuromuscular blockers reversibly inhibited the 5-HT(3A) receptor-gated current in the rank order potency of (IC50 mean +/- SEM): d-tubocurarine (0.046 +/- 0.003 microM), atracurium (0.40 +/- 0.03 microM), mivacurium (15.1 +/- 2.93 microM), vecuronium (16.3 +/- 2.24 microM), and rocuronium (19.5 +/- 2.31 microM). Gallamine was essentially inactive as a 5-HT(3A) receptor antagonist with an extrapolated IC50 of 1170 microM. We demonstrate that drugs classically known as competitive nACh receptor antagonists also block 5-HT(3A) receptors. It is likely that certain neuromuscular blockers share pharmacological properties with 5-HT(3A) receptor antagonists, such as a reduction in postoperative nausea and vomiting. With careful drug selection, pharmacological cross talk could potentially be used to minimize polypharmacy and optimize patient management. IMPLICATIONS: Muscle nicotinic acetylcholine and serotonin-type 3A (5-HT(3A)) receptors are similar. Therefore neuromuscular relaxants may block 5-HT(3A) receptors. Our pharmacological study demonstrates that neuromuscular relaxants, as with ondansetron, are 5-HT(3A) receptor antagonists. It is likely that certain neuromuscular relaxants exhibit ondansetron-like clinical properties, such as reduction in postoperative nausea and vomiting.     

Neuromuskuläres Monitoring bei Patienten mit neuromuskulären Erkrankungen

The management of general anaesthesia in patients with neuromuscular disorders remains challenging. The underlying causes and clinical presentations of these rare heterogeneous diseases are highly variable and the only common feature is usually skeletal muscle weakness. The appropriate choice and dosage of muscle relaxants are important and an adequate monitoring of the neuromuscular blockade is obligatory. Neuromuscular monitoring can be complicated because of disease-induced alterations in neurophysiology; however, continuous monitoring of the neuromuscular blockade should be realized to accurately determine the recovery from the blockade. These patients very often have an increased risk for postoperative pulmonary complications, which increases further if a residual neuromuscular blockade is present.     

Neuromuskuläres Monitoring

The effect of muscle relaxants varies among people and the extent, the duration and recovery from the neuromuscular block varies. Clinical tests cannot determine the effect of muscle relaxants which is only possible with neuromuscular monitoring. The relaxometry procedure measures the muscular response to electrical stimulation of the corresponding motor nerve and the adductor pollicis muscle is mostly used; however, this muscle is not representative for other muscle groups, such as the muscles of the larynx and diaphragm. The muscles of the larynx and diaphragm are more resistant against nondepolarizing muscle relaxants than the adductor pollicis muscle. The train of four (TOF) is used at the beginning of surgery for monitoring of the optimal time for tracheal intubation; moreover, the TOF is used during surgery for monitoring of the muscle blockade and at the end of surgery for monitoring recovery. Monitoring of deep muscular blockades, however, is only possible with the posttetanic count (PTC) when there are no TOF counts. The PTC allows repetition and higher doses of muscle relaxants during abdominal surgery; therefore, conditions for surgery are optimal and cumulation of muscle relaxants is avoided.     

Train-of-Four recovery after pharmacologic antagonism of pancuronium-, pipecuronium-, and doxacurium-induced neuromuscular block in anaesthetized humans

Previous studies have suggested that the increased duration of action of long-acting neuromuscular relaxants may make their pharmacologic antagonism more difficult and, thus, increase the likelihood of residual block. This hypothesis was tested in healthy, adult humans who received a background of isoflurane/N₂O/fentanyl anaesthesia.
Study subjects were paralyzed with either pancuronium (N=8), pipecuronium (N=8), or the longer-acting relaxant, doxacurium (N=8). Neuromuscular function was monitored, and, using a blinded, randomized study design, the relaxants were titrated to identify the ED₉₅ dose in each patient. Thereafter, spontaneous recovery was observed until there was 25% ofbaseline response to the first supramaximal twitch (Tl) in a train-of-four (TOF). At this time, the block was antagonized with neostigmine 0.07 mg/kg and glycopyrrolate 0.014 mg/kg i.v., and recovery of TOF was recorded.
Spontaneous recovery to 25% of the baseline Tl response occurred at 52± 14 min (mean±SD) following administration of either pancuronium and pipecuronium, and 85 ±33 min following doxacurium ( P <0.05 for doxacurium versus pancuronium and pipecuronium). In doxacurium-rreated patients, reversal of block with neostigmine was less predictable and less complete than with the other two relaxants. For example, the ratio of the fourth to first twitch (T4/T1) of the TOF at 10 and 15 min after reversal was significantly less with doxacurium (59 ±14% and 61±16%, respectively) than with either pancuronium (75±6% and 75±10%) or pipecuronium (76±9% for both). At 30 min post-neostigmine, the incidence of residual block (i.e. T4/T1 <0.70) was: pancuronium 2 patients, pipecuronium 1 patient, and doxacurium 5 patients.
These studies support the hypothesis that incomplete reversal of neuromuscular block is more likely with longer-acting neuromuscular relaxants.