Neuromuscular blocking agents and skeletal muscle relaxants

M. Leuwer, O. Zuzan and J.K. Aronson

12

GENERAL

Neuromuscular blocking agents and skeletal muscle relaxants TOPICS

reactions (SE D-12, 260; SEDA-17, 149; SEDA-18, 150) Anaphylaxis Hypersensitivity

during anesthesia, which is most commonly due to muscle relaxants, has been reviewed (lCr~). It can be life-threatening (2~). Mechanism Neuromuscular blocking drugs can cause the release of histamine. However, although atracurium 0.5 mg/kg caused a rise in plasma histamine concentration from 0.24 to 0.76 ng/ml in 20 patients, none developed hypotension; the plasma histamine concentration was similar in those who did and did not develop a skin rash (3c). Diagnosis The efficacy of skin prick tests in diagnosing hypersensitivity to neuromuscular blocking drugs has been assessed in 51 subjects (43 of whom were women) who had had anaphylactic reactions during anesthesia; at the same time IgE antibodies were sought with R A S T (4c). The drug responsible was definitely or probably identified in 75% of cases. The muscle relaxants that gave positive prick tests most often were atracurium (67%), tubocurarine (48%), and succinylcholine (44%). RAST testing was positive in eight of the 20 with positive prick tests to atracurium, 11 of the 17 with positive prick tests to tubocurarine, and eight of the 14 with positive prick tests to succinylcholine. Prevention Since cross-reactivity between different muscle relaxants is not uncommon, it would be desirable to be able to prevent allergic reactions in patients at risk of anaphylaxis. The use of monovalent haptens for this purpose has been investigated in a study 9 1996 Elsevier Science B.V. All rights reserved.

Side Effects of Drugs, Annual 19 J.K. Aronson and C.J. van Boxtel, eds.

of 21 patients with known allergy to muscle relaxants diagnosed by intradermal testing, 19 of whom had experienced anaphylactic shock during induction of general anesthesia (5c). In 13 patients with a positive leukocyte histamine release test to a specific muscle relaxant, the infusion of a monovalent hapten (2500 mg of cytidylcholine or ethamsylate) led to convincing inhibition of leukocyte histamine release in 57% of cases, when the muscle relaxant was added in vitro. The authors proposed the following protocol in patients with suspected allergy to muscle relaxants: 9 the responsible drug should be identified by skin testing and consequently avoided in these patients; 9 if a muscle relaxant is required for anesthesia in such patients, a drug with weak cross-reactivity, as determined by skin testing, should be selected. Based on their results the authors suggested that patient safety can be further increased if the administration of a weakly cross-reactive muscle relaxant is preceded by the infusion of a monovalent hapten. However, they correctly warned that their findings are not sufficient to ensure safe protection when a muscle relaxant is given intravenously to sensitized patients. Therefore, while confirmation of their results is awaited, every precaution has to be taken to prevent anaphylactic shock in susceptible patients. This includes awareness of the anesthesiologist and prophylactic administration of antihistamines and corticosteroids.

Interactions

It is well known that antibiotics can influence neuromuscular transmission (SED-12, 261; SEDA-16, 138; SEDA-18, 135

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152). T h e clinical r e l e v a n c e of this has b e e n illustrated in a r e c e n t case r e p o r t (6c). A 58-year-old woman developed prolonged paralysis of several hours duration after an overdose of clindamycin (2400 mg). Anesthesia was induced with thiopentone, fentanyl, and succinylcholine after 3 mg of d-tubocurarine. Before the accidental infusion of clindamycin full recovery of neuromuscular transmission was demonstrated by four equal responses to train-of-four stimulation and sustained response to 100 Hz tetanic stimulation. At the end of surgery, which lasted 75 minutes, the patient made no attempt at spontaneous ventilation and had a train-of-four ratio of 0.27. Calcium chloride and anticholinesterases led to only a slight increase in the train-of-four ratio. The patient began to cough 9 hours later and the train-of-four ratio returned to 1.0; 2 hours later the trachea could be extubated. This case r e p o r t confirms earlier reports a n d shows t h a t a high dose of clindamycin may cause p r o l o n g e d p r o f o u n d n e u r o m u s c u lar b l o c k a d e , which can n o t b e r e v e r s e d by anticholinesterases o r calcium.

DEPOLARIZING NEUROMUSCULAR

BLOCKING

(SED-12, 263; SEDA-16, 136; SEDA-18, 150) AGENTS

Succinylcholine (SED-12, 263; SEDA-16, 136; SEDA-18, 150) T h e adverse effects of succinylcholine h a v e recently b e e n reviewed (7R).

Rhabdomyolysis and hyperkalemic cardiac arrest M a n y cases of h y p e r k a l e m i c cardiac arrests after succinylcholine have b e e n rep o r t e d in a variety of underlying diseases a n d conditions ( S E D - 1 2 , 2 6 5 ) . T w o r e c e n t r e p o r t s have e x t e n d e d the list of the types of p a t i e n t s w h o are at risk of this l i f e - t h r e a t e n i n g complication. A 16-year-old male athlete experienced delayed onset rhabdomyolysis and hyperkalemia more than an hour after emerging from general anesthesia (8c). After the administration of succinylcholine, given at the time of induction of anesthesia, he developed intense fasciculations. Anesthesia was maintained with propofol, sufentanil by infusion, and isoflurane, and his further anesthetic course was uneventful, except for a low urine output in

M. Leuwer, O. Zuzan and J.K. Aronson

spite of generous fluid administration. An hour after arrival in the post-anesthesia care unit, peaked T waves were noted on his electrocardiogram. His serum potassium concentration was 6.9 mmol/l. The hyperkalemia was treated aggressively with calcium, dextrose/insulin infusion, and sodium bicarbonate infusion, and some hours later the serum potassium concentration normalized. The first postoperative serum creatine kinase activity was 31 180 U/l, with a maximum of 74 950 U/1 on the day after; the urine myoglobin was over 250 000 ng/ml. The patient remained in the intensive care unit for 2 days and was discharged 9 days postoperatively. He had no previous history of any disease or abnormality, except for a diet that included an anabolic amino acid mixture. B a s e d o n a n o t h e r case of r h a b d o m y o l y s i s in a b o d y b u i l d e r after a course of anabolic steroids, the a u t h o r s s p e c u l a t e d t h a t dietary i n d u c e d alterations in muscle m e t a b o l i s m m a y b e a risk factor for r h a b d o m y o l y s i s , as t h e i r p a t i e n t claimed not to b e taking anabolic drugs. This speculation can n e i t h e r b e confirmed n o r r e f u t e d , a n d the m e c h a n i s m of r h a b d o m y o l y s i s in this case r e m a i n s unclear, as does its r e l a t i o n to succinylcholine administration. Nevertheless, this case r e p o r t d e m o n s t r a t e s the rare possibility of anest h e s i a - r e l a t e d r h a b d o m y o l y s i s in a p p a r e n t l y h e a l t h y athletes. Fatal h y p e r k a l e m i c cardiac arrest has b e e n described after succinylcholine a d m i n i s t r a t i o n in a 15-year-old girl with p u r p u r a f u l m i n a n s (9~). A 15-year-old girl with purpura fulminans experienced rhabdomyolysis unrelated to succinylcholine during a complicated recovery from orthotopic liver transplantation. Three weeks later she had a belowknee amputation of her right leg because of ischemia and gangrene. Her serum creatine kinase activity was 2842 U/1 and her electrolytes were within the reference ranges. Shortly after rapid sequence induction with thiopentone and succinylcholine she went into a pulseless ventrieular tachycardia, unresponsive to cardioversion. Her serum potassium concentration was 9.0 mmol/l. Administration of calcium, sodium bicarbonate, glucose/insulin, adrenaline, lidocaine, and bretylium, in addition to external cardiac massage, failed to restore spontaneous circulation, and resuscitative efforts were terminated after 1 hour. Among other findings autopsy revealed extensive necrosis of the muscles in the leg and degenerating muscle fibers in the psoas muscle. The authors concluded that hyperkalemia a n d associated cardiac arrest h a d resulted

Neuromuscular blocking agents and skeletal muscle relaxants

from an excess release of potassium from damaged muscle after succinylcholine administration. This raises the question of whether purpura fulminans might be a risk factor. Purpura fulminans is a condition with a high mortality, typical elements of which are hemorrhagic infarctions and necrosis of the skin and ischemia and gangrene of the limbs secondary to a variety of infections. As suggested by this case report, it is possible that when there are disseminated muscular lesions succinylcholine can induce massive potassium release. Not knowing the exact mechanism of this potassium release, it seems prudent to avoid the use of succinylcholine in severely ill patients with purpura fulminans. Apparently, patients taking calcium antagonists do not have to be added to the list of those at risk of succinylcholine-inducedhyperkalemia. In contrast to these reports, calcium antagonists did not enhance the hyperkalemia caused by succinylcholine in 36 men of ASA grades III or IV (10c).

Malignant hyperthermia Reviews have recently appeared on the following topics: 9 susceptibility to malignant hyperthermia (11R); 9 whether malignant hyperthermia can occur without anesthesia, how masseter muscle rigidity should be managed, and the role of dantrolene prophylaxis (12R); 9 the structure and functions of the North American Malignant Hyperthermia Registry, which was established in 1987 (13R). The ryanodine contracture test has been proposed as an alternative to other contracture tests in predicting malignant hyperthermia, since the defect is thought to lie in the ryanodine receptor in skeletal muscle sarcoplasmic reticulum (14). However, the ryanodine that has hitherto been used is a mixture of pure ryanodine and 9,21-dehydroryanodine. These two substances have now been compared in an in vitro study on muscle biopsies from 48 patients with suspected susceptibility to malignant hyperthermia, based on caffeine and halothane contracture tests (15c). The authors concluded that a contracture test with high-purity ryanodine should be added to current methods.

Masseter muscle rigidity While it is believed

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that masseter muscle rigidity (SED-12, 264) might represent the first sign of malignant hyperthermia, there is still controversy on what to do when it occurs. A recent paper has contributed new information (16c). Two sisters, aged 31 and 42 years, presented with masseter muscle rigidity and whole body rigidity after succinylcholine. DNA analysis in 16 members of their family showed the same mutation in the sodium channel a-subunit gene in four members, all of whom had myotonia fluctuans on clinical and laboratory examination. The results of in vitro contracture testing in the two sisters were interpreted as susceptibility to malignant hyperthermia. Another member of the family without myotonia fluctuans and without the specific gene mutation had a negative result in the in vitro contracture test. These observations led the authors to conclude that there is a relation between masseter muscle rigidity, a specific mutation in the sodium channel c~-subunit gene, and susceptibility to malignant hyperthermia, indicating that this rare mutation of the sodium channel a-subunit gene might predispose patients to a high risk of anesthesia-related events. Taking into account another investigation (17c), in which in vitro contracture tests were negative in 17 affected and nine unaffected individuals from three families with myotonia fluctuans, the current results do not represent sufficient evidence for assuming that patients with myotonia fluctuans have to be regarded as being susceptible to malignant hyperthermia. On the other hand, these patients are apparently at high risk of succinylcholine-induced muscle rigidity, which can lead to difficulties in airway management and inadequate ventilation and oxygenation. Therefore, it seems wise not to administer a depolarizing muscle relaxant to patients with a diagnosis of myotonia. In an accompanying editorial it was recommended that masseter muscle rigidity should prompt careful investigation of the patient, including neurological examination, laboratory tests to identify a primary muscle disorder, muscle biopsy, an in vitro contracture test, and finally genetic screening (18R). It is worth noting that a simple non-invasive diagnostic test for a specific mutation in the sodium channel a-subunit gene has been described, based on a restriction fragment length polymorphism assay (16c). This, in addition

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to electromyography, could support the clinical diagnosis, if the subtle findings of this disease on preoperative examination lead the anesthesiologist to suspect a neuromuscular disease such as myotonia fluctuans. The possible role of halothane in masseter muscle rigidity has been reported in a study of 5641 infants and children, of whom 5064 received succinylcholine (19c). There were no cases of masseter muscle rigidity in the 4457 patients in whom anesthesia was induced intravenously with thiopentone and succinylcholine before the administration of halothane, and 3 cases in the 607 patients in whom the administration of succinylcholine was preceded by inhalation induction with halothane. In another study of 500 children anesthetized with halothane and succinylcholine 4.4% had incomplete jaw relaxation and one child (0.2%) had masseter muscle rigidity (20c). The authors concluded that incomplete jaw relaxation was not uncommon after this combination and that it did not necessarily presage masseter muscle rigidity. The ambiguous role of masseter muscle rigidity as a warning sign of impending malignant hyperthermia has been illustrated by a case report of a 4-year-old boy with SmithLemli-Opitz syndrome (mental, motor, and growth delay, microcephaly, elfin facies, hypoplasia of the external genitalia, and syndactyly of the toes), who developed generalized muscle rigidity, including impaired respiratory gas exchange owing to a severe reduction in chest wall compliance shortly after the start of general anesthesia with halothane in N20/Oz (21c). Endotracheal intubation had been performed without the use of a muscle relaxant. By 30 minutes after the discontinuation of all anesthetics he began to recover and was able to breathe spontaneously. During and after the whole episode there were no signs of malignant hyperthermia. Nevertheless, the authors advised against the use of halothane or succinylcholine in patients with Smith-LemliOpitz syndrome. This advice appears justified, given the severity of rigidity-related respiratory disturbances in this case. In addition, susceptibility to malignant hyperthermia cannot be safely excluded in such rare diseases. It is worth noting that a non-depolarizing muscle relaxant did not relieve muscle rigidity in this case. The authors speculated that dantrolene

M. Leuwer, O. Zuzan and J.K. Aronson

might be therapeutic in alleviating severe rigidity not due to malignant hyperthermia. Fasciculation and muscle pain Fasciculation is common after the administration of succinylcholine and may cause postoperative myalgia and occasionally muscle damage. Methods of preventing fasciculation and muscle pain have been subjected to further study. In 442 patients atracurium, pancuronium, d-tubocurarine, and vecuronium were used to prevent fasciculation (22c). All reduced the frequency of fasciculation, and tubocurarine and atracurium had the greatest effects. Maximum effects were obtained with pretreatment 4 minutes before the administration of succinylcholine. However, the incidence of myalgia was not examined. Meanwhile, the preventive effect of atracurium has been confirmed in another study of 60 patients, in whom the severity of myalgia was also reduced by 60%; in the same study ketorolac given intravenously 3 minutes before succinylcholine had no effect on myalgia, in contrast to the results of previous studies with aspirin and diclofenac (23cr). In 51 women undergoing laparoscopic surgery the incidence of suxamethonium chloride-induced myalgia was reportedly lower when propofol, rather than thiopentone, was used to induce anesthesia in women undergoing laparoscopy (19, vs 63%) (24c). Myalgia was severe in two patients and both had received thiopentone. In another study of 42 adults, postoperative myalgia after the use of succinylcholine was less common in smokers than in non-smokers (25c). The authors suggested that that might be because nicotine receptors are desensitized in smokers. Risk situations Pediatric anesthesia Reports have been sought of all cases of cardiac arrest in children after the use of succinylcholine, regardless of the perceived cause and outcome, in a questionnaire that was sent to the Royal College of Anaesthetist's tutors in each hospital in the UK, in order to ascertain the scale of the problem there (26~R). This study was performed because, in contrast to reports of sudden death, presumably due to the administration of succinylcholine in children with unrecognized muscular dystrophies,

Neuromuscular blocking agents and skeletal muscle relaxants to the North American and German Malignant Hyperthermia hotlines (SEDA-18, 151), no such cases had been reported to the National Malignant Hyperthermia referral center in Leeds. The majority of the replies reported only vagal episodes, which responded promptly to treatment with atropine. Between 1965 and 1993 there were 15 cases of cardiac arrest that could not be confidently attributed to vagal stimulation in non-atropinized children; three of these 15 children died. Most likely seven were children suffering from myopathies. There were two cases with muscular dystrophy known before anesthesia; both had a successful outcome. Another child, a 5-year-old boy, who also survived, was later confirmed as having Becker's muscular dystrophy. Two cases involved children who were mentally handicapped; one of these children apparently died from hyperkalemic cardiac arrest, and histological examination of postmortem muscle specimens showed dystrophic changes; the second child, who survived, showed clinical features suggestive of a myopathic syndrome. These two cases illustrate that a myopathy may be associated with congenital mental handicap, a possibility worth considering when anesthetizing such individuals. In the second fatal case, a 2-year-old boy, muscular dystrophy was diagnosed on examination of post-mortem muscle specimens. In this case the author doubted whether there was any significant increase in serum potassium causing the fatal outcome. The nine remaining cases presented no evidence of preexisting myopathies. One of these cases, insufficiently documented, was that of a 6-yearold child who died during an emergency appendicectomy, in which succinylcholine had presumably been used for intubation. Four patients, all of whom survived, showed biochemical evidence of rhabdomyolysis, of whom three had been investigated for susceptibility to malignant hyperthermia; two were not susceptible, while the third gave an equivocal result. Muscle histology and histochemistry were normal in all three cases. All four remaining cases of cardiac arrest associated with the use of succinylcholine had alternative explanations for the arrest. Three involved children with heart disease and the other was consistent with an anaphylactoid response.

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It may be true that, according to the author, the rare occurrence of cardiac arrest in children with undiagnosed myopathies might be reduced even further by taking a careful family history, by considering the possibility of co-existing myopathy in cases of congenital mental handicap, and by using, where possible, intravenous as opposed to inhalational induction when succinylcholine is to be used. However, it seems wise to repeat the suggestion that the routine use of succinylcholine in pediatric anesthesia should be abandoned. Its use should be reserved for emergency intubation or instances when immediate securing of the airway is necessary. Altered pharmacokinetics and pharmacodynamics Ester hydrolysis of succinylcholine by plasma cholinesterase is the predominant reason for its short duration of action, and it is well known that patients with greatly reduced activity of plasma cholinesterase can have prolonged neuromuscular blockade after succinylcholine (SED-12,264). However, even with normal plasma cholinesterase activity, succinylcholine can result in prolonged blockade in patients with an abnormal plasma cholinesterase genotype. The results of 20 years of research in the Danish Cholinesterase Research Unit have been reviewed, and the different mechanisms of prolonged succinylcholine-induced blockade discussed (27CR). It is noteworthy that in 40% of the cases referred to the Unit, an apparent abnormal response to succinylcholine was due to factors other than abnormal cholinesterase activity or genotype (e.g. overdosage of neuromuscular blocking agents, central respiratory depression, or hyperventilation). In only 4% of the cases was a low activity of normal enzyme judged to be the sole reason for prolonged blockade. A rare cause of an abnormal response to succinylcholine has been reported in a 25year-old woman who experienced prolonged paralysis after succinylcholine 20 days after attempting suicide with an organophosphate (28c). Plasma cholinesterase activity was 1.1 IU/ml (reference range 5.9--12.2) and the dibucaine number was 68% (70--100%). The authors concluded that reduced plasma cholinesterase activity caused by organophosphate poisoning was the reason for prolonged succinylcholine-induced neuromuscular blockade. While this is not the first report on this

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effect of organophosphate poisoning (SED12, 265), it once again reminds us to keep this rare cause of prolonged succinylcholine blockade in mind, particularly since it can occur even weeks after the poisoning. Myotonia The problems of anesthetizing patients with myotonias have been reviewed (29R).

NON-DEPOLARIZING N E U R O M U S C U L A R BLOCKING A G E N T S (SED-12, 271; SEDA-16, 137; SEDA-17, 150; SEDA-18, 153) Muscle relaxants in intensive care (SED-12, 273; SEDA-16, 139; SEDA-17, 150; SEDA-18, 153) Prolonged paralysis A major cause of concern in the long-term administration of neuromuscular blocking drugs to patients in intensive care is the danger of prolonged paralysis up to several days and even weeks after discontinuation of the drugs. Indeed, there is a growing number o f reports on prolonged paralysis after long-term administration of muscle relaxants (3oR), the majority of which concern pancuronium and vecuronium, probably reflecting the frequent use of these agents (31c, 32c). While some authors favor atracurium for long-term administration, because o f its non-organ dependent elimination (33R), recent reports have described prolonged paralysis after long-term atracurium treatment as well (SEDA-18, 154; 34 c, 35c--38c). Therefore, it is still unclear whether the incidence of prolonged paralysis is influenced by the choice of drug. With this in mind, the pharmacodynamic characteristics of vecuronium by infusion have been compared with those of cisatracurium by infusion in a randomized, double-blind multicenter study in 58 patients in intensive care (39c). Recovery of neuromuscular function was significantly faster with cisatracurium than with vecuronium (the time from discontinuation of drug infusion to T4/TI > O. 7 was 68 vs 387minutes). One patient in the vecuronium group developed prolonged weakness, with

M. Leuwer, O. Zuzan and J.K. Aronson

electrophysiological signs of myopathy a n d neuropathy. In contrast to this study of muscle relaxants of intermediate duration, the long-acting drugs doxacurium and pancuronium during maintenance dose administration have been compared in a multicenter randomized study in 40 patients in intensive care (40c). Recovery time (the time from the last dose to the presence o f four responses to train-of-four stimulation) was significantly shorter with doxacurium than with pancuronium (139 vs 280 minutes) while heart rate after injection was significantly higher in the pancuronium group (120 vs 109 beats per minute). Although the mean pancuronium-induced increase in heart rate was not very impressive in this study, it is well known that pancuronium may cause hazardous tachycardia, predominantly in patients with increased catecholamine concentrations or in patients taking tricyclic antidepressants. When discussing the choice of drugs for neuromuscular blockade in patients in intensive care, it should be remembered that many critically ill patients receive exogenous catecholamines or may have increased endogenous catecholamine concentrations. Therefore in patients who are at risk of dangerous tachydysrhythmias pancuronium should probably be avoided. From both o f the papers cited above one could get the impression that benzylisoquinolone relaxants might be more appropriate for patients in intensive care than steroidal neuromuscular blocking drugs, a view that is supported in an accompanying editorial (41R). However, for the time being this conclusion appears premature. Residual curarization is only one o f the potential reasons for persistent paralysis after long-term neuromuscular blockade in severely ill patients. Other reasons include muscle fiber atrophy (due to inactivation or denervation), critical illness polyneuropathy, and acute myopathy, all of which are probably multifactorial in origin. The interactions of different drugs with these severe neuromuscular abnormalities o f the critically ill still have to be evaluated. Mechanisms of prolonged paralysis Many factors are associated with an increased risk of prolonged paralysis (3oR). They include the duration of blockade, the use of other drugs,

Neuromuscular blocking agents and skeletal muscle relaxants the severity of the underlying illness, the length of therapy, the monitoring techniques used, and perhaps the method of drug administration. Nicotinic acetylcholine receptor numbers have been measured in post-mortem specimens of the rectus abdominis muscle of 14 critically ill patients (42c). There was a significantly higher receptor density in the subgroup of patients who had received high doses of vecuronium (mean 33 mglday) compared with patients who had received moderate vecuronium doses (mean 5 mglday) and patients who had received no neuromuscular blockers. Based on these data, the authors suggested that acetylcholine receptor upregulation could underlie the increased requirements for muscle relaxants seen in some patients. Furthermore, they speculated that denervation-like changes (e.g. increased acetylcholine receptor density) might be one of the mechanisms of prolonged paralysis after the use of muscle relaxants in patients in intensive care. While it is tempting to follow their conclusions, there were some drawbacks in the study design which should prevent us from accepting their data as proof of this assumed pathophysiological mechanism. There is no information in the paper indicating that the high-dose vecuronium subgroup really required larger doses of vecuronium. Except for one patient who received a vecuronium infusion, the patients were given vecuronium bolus doses without any monitoring, i.e. without objective criteria. It is therefore possible that patients were given higher doses for reasons other than increased requirements owing to changes of neuromuscular transmission. In agreement with that suspicion, all of the patients in the high-dose subgroup had adult respiratory distress syndrome and were ventilated for longer periods than the patients in the other subgroups. So it could have been the disease itself (e.g. reduced pulmonary compliance) that resulted in increased airway pressures and led to the administration of higher doses. In addition, prolonged immobilization may have caused an increase in acetylcholine receptor density, a possibility admitted by the authors. Meanwhile the observation of muscle relaxant-induced upregulation of acetylcholine receptor density is supported by recent animal data. To exclude the influence of immobilization, which itself may cause upregulation of

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acetylcholine receptors, rats were given subparalytic doses of d-tubocurarine by long-term infusion (43). Both d-tubocurarine and immobilization alone (without d-tubocurarine) increased the number of acetylcholine receptors. The infusion of equivalent doses of d-tubocurarine in combination with immobilization resulted in the greatest upregulation. In addition, the magnitude of the increase in blood potassium concentration in response to succinylcholine depended on the acetylcholine receptor density. In another study using the same technique, the burn-induced upregulation of acetylcholine receptors was accentuated by the infusion of subparalytic doses of d-tubocurarine (44). For the time being this seems to be enough evidence to advise restrictive use of long-term administration of neuromuscular blocking drugs, a view that has been expressed in an accompanying editorial (45R). In addition to changes at the neuromuscular junction, muscle pathology may contribute to the muscle weakness in these patients; the use of corticosteroids has been blamed for this (SEDA-16, 140), and this has again been suggested in the context of two patients who had loss of myosin thick filaments on muscle biopsy (46cr). The long-term use of pancuronium in children in intensive care has been addressed in two studies. In an open-label study of the cost-effectiveness of infusion of pancuronium compared with drugs o f intermediate duration in 25patients aged 3 months to 17 years, there were no cases of prolonged paralysis, but no information was provided about whether at-risk patients (e.g. patients with renal failure or with concomitant corticosteroid therapy) were included (47c). The authors' conclusion, that pancuronium is an efficient and cost-effective drug for long-term use in children in intensive care, might be doubted if even a few reports appeared of pancuronium-associated persistent paralysis with prolonged ventilator dependency in these patients, which would result in a dramatic increase in cost. Risks in children

On the background of some anecdotal reports of muscle contractures in infants, a prospective study has been performed on the effect of long-term pancuronium adJoint immobility

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ministration on joint mobility in eight critically ill premature infants (48c). There was reduced mobility of selected joints in the pancuronium group, which the authors explained by the effect o f gravity on limb position and by the loss o f flexor muscle tone. They concluded that paralysed premature infants require special physiotherapy to prevent those abnormalities. Another cause of impaired joint mobility associated with long-term neuromuscular blockade has been described (49c). A 44-year-old woman had a 7-week stay on the intensive care unit after developing acute necrotizing pancreatitis and consequent adult respiratory distress syndrome. She received curarefor 3 weeks and then began to complain of pain and reduced movement in her shoulders and elbows, later diagnosed as generalized periarticular myositis ossificans. Owing to fixation of her major joints she made slow physical progress. At the time of discharge she could just lift her arms off the bed. The authors speculated that this acquired form o f myositis ossificans was related to the long-term use of curare. While this possibility can neither be confirmed nor refuted, their conclusion should be endorsed. They stated that while further investigation o f the predisposing factors and prevention of generalized myositis ossificans is needed, early mobilization and restrained use o f immobilizing drugs in intensive care patients are to be advocated.

Cardiovascular In 30 patients of A S A grades III or IV undergoing cardiac valve surgery, pipecuronium and doxacurium produced no significant changes in a variety of hemodynamic measurements compared with the values found at the time of induction (50c). Similar results were found in 40 elderly and 20 young patients who received mivacurium as a single dose with or without a subsequent infusion (51c). The hemodynamic effects of pancuronium and vecuronium have been compared in the treatment of 30 patients with shivering after cardiac surgery (52c). Vecuronium caused smaller rises in heart rate, mean arterial pressure, and pressure work index than pancuronium. A I D S In five patients with AIDS recovery after vecuronium was signifiRisk situations

M. Leuwer, O. Zuzan and J.K. Aronson

cantly prolonged compared with a control group (53c). While these preliminary results need to be confrmed, the possibility of prolonged neuromuscular blockade should lead to the use of neuromuscular monitoring when muscle relaxants are administered to patients with AIDS. Asthma There has been a double-blind randomized comparison of the adverse effects of atracurium and vecuronium in 60 asthmatic patients who randomly received either atracurium 0.5 mg/kg or vecuronium 0.1 mg/kg (54c). The patients were observed for changes in heart rate and blood pressure, peak airway pressure, expired tidal volume, and hemoglobin oxygen saturation (measured by pulse oximetry), and for skin rashes or wheals and auscultatory signs of bronchospasm. Except for a higher incidence of falls in blood pressure with atracurium, there were no significant differences between the two drugs. Although there were no significant pulmonary changes with atracurium, the higher incidence of cardiovascular changes led the authors to conclude that atracurium is not the optimal muscle relaxant for asthmatic patients. This raises the question of whether the higher incidence of a moderate fall in blood pressure (which is probably not a specific effect restricted to asthmatic patients) justifies abandoning the use of atracurium in this group. Presumably most anesthesiologists would have been more concerned about atracurium-induced bronchospasm. Unfortunately, this well-designed study was somewhat marred by the use of isoflurane, a potent bronchodilator. It would be interesting to know if an intravenous anesthetic technique would have resulted in different observations. While atracurium is probably not the drug of choice in asthmatic patients, its strict avoidance (because of the danger of severe bronchospasm) does not appear necessary for the time being. Neurofibromatosis It has not hitherto been clear whether patients with neurofibromatosis have abnormal responses to neuromuscular blocking agents. While prolonged blockade after non-depolarizing muscle relaxants has been described (SED-12, 275), reports on the response to succinylcholine have been contradictory. Recently, this question has been tackled by a retrospective review of the anesthetics charts of 44 patients with yon

Neuromuscular blocking agents and skeletal muscle relaxants Recklinghausen's neurofibromatosis who received 114 anesthetics (55c). Responses to muscle relaxants were graded abnormal if standard doses had resulted in longer than expected paralysis, as expressed by clinical signs of weakness, or by the presence of fewer than four responses to train-of-four stimulation by means of a peripheral nerve stimulator. There was no evidence of prolonged responses either to succinylcholine or to nondepolarizing muscle relaxants. The authors therefore recommended no alteration in the dosage of muscle relaxants for patients with neurofibromatosis type 1. However, they cautiously stated that they could not conclude from this study that patients with neurofibromatosis have normal responses to neuromuscular blocking agents. Furthermore, their criteria for abnormal responses cannot be regarded as precise enough to exclude relevant residual paralysis in their patients. This study shows that patients with neurofibromatosis do not have such striking deviations from the expected responses to neuromuscular blocking agents as patients with certain other neuromuscular diseases, such as myasthenia gravis. Therefore, in principle, standard doses of muscle relaxants may be administered to patients with neurofibromatosis. Nevertheless, neuromuscular monitoring is highly recommended in these patients, to exclude prolonged or unexpected neuromuscular responses. Mivacurium (SEDA-17, 152)

In 60 women undergoing laparoscopic tubal ligation, mivacurium was associated with a reduced incidence of postoperative nausea and vomiting compared with succinylcholine (18 vs. 37%); however, this benefit was lost in women in whom the effects of mivacurium were reversed with anticholinesterases (56c). Rocuronium

Rocuronium is a new neuromuscular blocking drug structurally related to vecuronium, but with a quicker onset and a similar or slightly longer duration of action (57R). It usually does not cause histamine release and is metabolized in the liver. Rocuronium-in-

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duced neuromuscular block is potentiated by isoflurane (see Chapter 10). In a prospective, non-randomized multicenter study of the use of rocuronium 0.6 mg/kg in 40 women having cesarean sections, there were no major adverse effects in the mothers or neonates (58c). The heart rate increased significantly between time of induction and time of delivery. Placental transfer (assessed as the ratio of umbilical venous to maternal venous concentrations) was 0.16, between that of vecuronium (0.11) and pancuronium (0.21). This article was followed by some correspondence stressing the problem of rocuronium-induced duration of paralysis in case of failed intubation; it was agreed that rocuronium should be considered for rapidsequence induction for cesarean section only when succinylcholine is contraindicated (7274).

SKELETAL MUSCLE RELAXANTS (SED-12, 287; SEDA-16,

141; SEDA-17, 155; SEDA-18, 156) Baelofen (SED-12, 288; SEDA-16, 141;

SEDA-17, 155) The uses and adverse effects of intrathecal baclofen have been briefly reviewed (59 r, 60R). Tolerance to intrathecal baclofen, in three of 23 patients with spinal spasticity, has again been reported (61e). In two of the 23 patients mentioned above (61 c) severe hypotension occurred after intrathecal baclofen 50/~g.

Cardiovascular

Nervous system

There have previously been reports of an encephalopathy in patients receiving baclofen. These have now been reinterpreted as having been possibly due to non-convulsive status epilepticus, in the light of the case of a 50-year-old woman who had been taking baclofen 110 mg/day and who presented with an acute confusional state and an epileptiform E E G (62c). Generalized convulsive seizures have also been reported during intrathecal administration and during withdrawal of baclofen, and

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there has been a further report of focal seizures in two of eight patients who were given a bolus dose of baclofen intrathecally (63c).

Psychiatric

There have been anecdotal reports of psychiatric adverse effects of oral baclofen. However, in a small prospective study, although there were significantly reduced feelings of vigor and increased feelings of fatigue, no formal psychiatric effects were noted

(64Cr).

Botulinum toxin (SED-12, 289; SEDA-16, 141; SEDA-17, 156) The common adverse effects of botulinum toxin are on the muscles into which the toxin has been injected, and include weakness and pain. Other local adverse effects may occur. All are transient, lasting no more than a few weeks. In a series of 76 patients with a variety of disorders, adverse effects occurred in 12 (16%): difficulties with swallowing in nine of 40 patients treated for torticollis, facial weakness in two of eight patients treated for hemifacial spasm, and visual problems in one of 14 patients treated for blepharospasm (65c). In most cases the symptoms were mild and transient. In a similar study of 98 patients with various dystonias, adverse effects lasting for 2--3 weeks occurred in 64% (66c). Ptosis was the most common adverse effect in the 36 with blepharospasm, affecting 16 (44%); diplopia

M. Leuwer, O. Zuzan and J.K. Aronson

occurred in eight, dropped comer of the mouth in five, dysphagia in three, and edema of the eyelid and ectropion in one case each. In 41 patients with torticollis, dysphagia was the most common adverse effect (29%); other effects were uncommon, and included dysphonia (three cases), headache and malaise (two cases each), and neck weakness, sore throat, tiredness, and diarrhea (one case each). In 10 patients with focal tics associated with Tourette's syndrome, injection of botulinum toxin into the affected muscles caused temporary ptosis (lasting 4 weeks) in two and neck pain, stiffness, or weakness in three (67c). In nine subjects in whom botulinum toxin was injected into 30 facial muscles for cosmetic purposes (e.g. to stop frowning) there was minor local swelling in five cases, bruising in three, a burning sensation on injection in five, mild exaggeration of pre-existing ptosis in one, headache in four, and mild nausea in one (68c). All these effects lasted less than 24 hours, except the ptosis, which persisted for 6 weeks. The use of botulinum toxin in treating masseter muscle hypertrophy has been described in eight patients (69c, 70c). Mild discomfort in the muscle into which the toxin was injected was the only adverse event noted. In 12 patients with acquired nystagmus and oscillopsia, injection ,of botulinum toxin into the horizontal recti or into the retrobulbar space caused transient ptosis in seven cases (71r

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