will be replaced in the new Prescribing Information ap- ... new agents with unique properties. .... l'ordre de 200 I~g" kg -Iet ~ condition qu'on attende assez.
465
David R. Bevan MS MRCPFRCA
Succinylcholine is one of the few drugs which has maintained its popularity for forty years. This has been achieved despite a long list of complications. Some of the side effects, such as malignant hyperthermia (MH), are dangerous. Others, such as myalgias, are distressing but not life-threatening. The depolarizing nature of the neuromuscular block is responsible for the initial fasciculations and uncoordinated contractions which cause fasciculations, potassium release and increases in intragastric and intraocular pressures. The reason for its popularity is that succinylcholine remains the only neuromuscular relaxant which has a very quick onset of action and, just as important, rapid recovery. Thus, it is ideally suited to facilitate rapid tracheal intubation, particularly in the emergency patient, but if intubation is not achieved spontaneous respiration is rapidly restored. Because of these unique properties anaesthetists will give it up only with great reluctance. Two articles in the current issue of the Canadian Journal o f Anaesthesia are of particular interest in assessing the place of succinylcholine in clinical practice. In Toronto, Lazzell et al. attempted to determine the incidence of untoward effects, particularly masseter muscle rigidity (MMR), when succinylcholine was used to facilitate intubation in more than 5,000 children. J Also, Sullivan et al. report two further cases of cardiac arrest after succinylcholine in two children with undiagnosed myopathy in Newmarket, Ontario. 2 In some children succinylcholine is followed not by relaxation but contraction of the masseter muscles making intubation difficult or impossible. Masseter muscle rigidity is an accompaniment of malignant hyperthermia. However, MMR is much less frequent than MH (1:100 vs 1:30,000 approx). 3 Also, it is now recognised that some increase in masseter tone is a constant sequel of suecinylcholine. 4 The difficulty lies in separating this normal increase in tone from MMR with its sinister ir0plications. It is not necessary to assume that any increase in masseter tone is interpreted as M M R and a prelude to MH. Littleford et al. showed that it was safe to take an expectant policy in children demonstrating isolated masseter spasm and to continue with anaesthesia and surgery whilst monitoring carefully for signs of generalised hypermetaboFrom the Department of Anaesthesia,Universityof British Columbia, Vancouver, B.C. CAN J A N A E S T H 1994 / 4 1 : 6 / pp465-8
Editorial Succinylcholine lism. 5 The incidence of M M R in this study was 0.3%. In Toronto, the incidence was lower: MMR occurred in three of 5,064 children after succinylcholine I and none progressed to MH. The authors suggest that the incidence was less when succinylcholine was preceded by thiopentone than by halothane. However, the study was not randomised and only 12% of children were anaesthetized with halothane alone or followed by thiopentone. None of the patients in this study developed ventricular arrhythmias or cardiac arrest after su.ccinylcholine. Thus, M M R is not always a harbinger for MH. Lazzell et aL counselled the parents of children who developed M M R but did not encourage the children to undergo muscle biopsy to test for MH susceptibility. When it occurs in isolation, it is appropriate to continue anaesthesia and watch carefully for systemic signs, particularly increase of PETCo2. If some increase in masseter tone always accompanies the use of succinylcholine, one might ask how often optimal intubafing conditions are achieved. In October, 1993, Burroughs Wellcome Inc. sent a letter to all Canadian anaesthetists and US anesthesiologists stating that ~Except when used for emergency tracheal intubafion or in instances where immediate securing of the airway is necessary, succinylcholine is contraindicated in children and adolescent patients." This was met, particularly in Canada, by a storm of protest and the Canadian Journal o f Anaesthesia received a large number of letters 6 and telephone calls mainly from anaesthetists who were disturbed that the use of a drug with unique properties was being jeopardised. Consequently, the company called a meeting of expert paediatric anaesthetists to Toronto to review the Indications, Contraindication, Warnings and Precautions of the Prescribing Information for succinylcholine (ANECTINE*). This led to the elimination of the contra-indication which will be replaced in the new Prescribing Information approved by the Health Protection Branch, Ottawa, by "the addition of a Warning regarding the rare possibility of inducing life-threatening hyperkalaemia in undiagnosed myopathies in infants and children". There is now the intriguing possibility that the package inserts for succinylcholine (ANECTINE*) will be different in Canada from the USA. The reason for the initial contra-indication was repeated reports of a hyperkalaemic cardiac arrest following sue-
466
cinylcholine given inadvertently to paediatric patients in whom myopathy, usually Duchenne muscular dystrophy, was subsequently diagnosed. The Malignant Hyperthermia Association of the United States (MHAUS) continued to report patients who developed the syndrome, and it has been estimated that six cases would be expected in the United States each year with an approximate mortality of 60%. 7 The article by Sullivan et al. in this issue, reports two further cases in two boys, one aged three years and the other three months, who developed complex tachyarrhythmia or asystole after suceinyleholine. Both were resuscitated successfully with sodium bicarbonate, calcium and controlled ventilation. In one, anaesthesia had been induced with thiopentone and in the other with halothane. There are now several reports of the syndrome in the international literature. 8-~~The syndrome is rare - anaesthetists in Toronto's Sick Children's Hospital state that they "have established neuromuscular blockade with succinylcholine in hundreds of thousands of infants, children and adolescents without a single death attributable to sueeinylcholine." Clearly, it is premature to abandon the use of sueeinylcholine. Nevertheless, if there were an acceptable alternative, it would be accepted rapidly by anaesthetists. Since the introduction of the intermediate acting neuromuscular blocking drugs, atracurium and veeuronium, they have been used increasingly in place of sueeinylcholine to facilitate tracheal intubation. The onset of block is slower than with succinylcholine and, perhaps more important, recovery is also slower. A new intermediate acting aminosteroid relaxant, rocuronium, is currently under investigation. In duration of action, rate of recovery, and lack of cardiovascular effects it resembles veeuronium but it has a much more rapid onset of block. ~u2 Recent studies have shown that tracheal intubation can be achieved after rocuronium under good to excellent conditions within two minutes, only slightly more slowly than with sueeinylcholine. 13 Mivacurium, is a short duration benzyisoquinolinium compound which, probably, will be available in Canada in 1994. Metabolism by plasma cholinesterase to inactive metabolites ensures a recovery which is twice as rapid as atracurium or vecuronium. ~4 However, onset is no more rapid and the haemodynamic effects are similar to atrac~trium. 15 When used to facilitate intubation, conditions are inferior to those produced by sueeinylcholine unless it is given in large doses, 200 ~g. kg -~, and sufficient time is allowed for the block to develop. However, there are other advantages in using a non-depolarizing relaxant with a rapid rate of spontaneous recovery. It may not be necessary to reverse any residual block and Ding et al. have shown that this reduces the incidence of nausea and vomiting in patients after ambulatory anaesthesia. 17
CANADIAN J O U R N A L OF A N A E S T H E S I A
It seems inevitable that the use of sueeinylcholine during anaesthesia will continue to decline as new drugs gradually provide more of the characteristics that are required to provide ideal intubating conditions safely. The question remains whether a shift from sueeinylcholine to non-depolarizing relaxants will affect patient safety. It might be argued that changing to the currently available drugs might replace the very rare occurrence of severe reactions with the common accompaniments of slowly recovering neuromuscular block - postoperative residual block and ventilatory inadequacy. Js It is too soon to abandon suceinylcholine, particularly in the emergency situation when rapid isolation of the trachea is essential. Elsewhere, the newer agents will continue to encroach on suceinylcholine. One hopes that the current obsession with cost control will not prevent the development of new agents with unique properties. It is inappropriate to use the cheapest drug in all situations, particularly when the savings are small and the cost may be large.
Succinylcholine Exceptionnellement et malgr6 ses inconvtnients, la suecinylcholine a maintenu sa popularit6 pendant 40 ans. Ses effets indtsirables, comme l~ayperthermie maligne, sont toujours aussi craints. D'autres eomme les myalgies sont incommodants sans 8tre dangereux. La dtpolarisation est responsable des fasciculations et des mouvements incoordonnts qui les provoquent, de la libtration de potassium et de l'augmentation des pressions intragastrique et intraoeulaire. Mais cette popularit6 vient du fait que la succinylcholine est le seul myorelaxant qui agit et dont on rtcuptre aussi rapidement. La succinylcholine reprtsente done l'agent idtal pour l'intubation immtdiate, sptcialement en urgence; si on ne rtussit pas l'intubation, on peut alors compter sur un retour h une respiration spontante quasi imm&tiate. A cause de ces qualitts, il est difficile pour les anesthtsistes de la mettre de cttt. Le Journal Canadien d'Anesthtsie public ce mois-ci deux articles fort inttressants sur la place occupte par la suecinylcholine en clinique. De Toronto, Lazzell et al. tentent de dtterminer l'incidence des effets dtfavorables, particulitrement, la rigidit6 du muscle masstter (RMM) chez 5000 enfants intubts sous succinylcholine, i De Newmarket en Ontario, Sulivan et al. rapportent deux arrSts cardiaques survenus chez deux patients ptdiatriques porteurs @une myopathie insoupgonnte. 2
EDITORIAL
Chez certains enfants, la contraction du muscle mass6ter provoqu6e par l'administration de succinylcholine rend l'intubation difficile ou m~me impossible. La rigidit6 du muscle mass6ter (RMM) pr6c6de g6n6ralement l'hyperthermie maligne (HM). Cependant la RMM est moins fr6quente que I'HM (1:I00 vs 1:30,000 environ). 3 De plus, on reconnait maintenant qukme certaine hausse du tonus mass6t6rin accompagne souvent la succinylcholine.4 I1 est difficile de d6partager cette augmentation normale de tonus de sa connotation catastrophique. On ne peut pr6sumer que l'augmentation du tonus mass6terin signifie n6cessairement une R M M et qu'elle constitue un signe avant-coureur de I'HM. Littleford et al. ont d6jh 6none6 que chez renfant, apr6s un spasme isol6 du mass&er, on peut rester sur l'expectative et continuer ranesth6sie et la chirurgie tout en portant son attention sur toute manifestation 6ventuelle dkm hyperm6tabolisme g6n6ralis6.5 Dans cette 6tude, l'incidence de RMM 6tait de 0,3%. A Toronto, l'incidence est encore plus faible. La RMM apr6s succinylcholine survient en effet chez trois des 5,064. enfants et ne progresse jamais vers I'HM. Les auteurs sugg6rent que son incidence est moindre quand le thiopentone pr6c~de la succinylcholine au lieu de l'halothane. Cependant, l'6tude n'est pas randomis6e et seulement 12% des enfant ont 6t6 anesth6si6s avec l'halothane seul ou suivi de thiopentone. Aucun des patients de cette &ude n'a pr6sent6 d'arythmies ou d'arr~t cardique apr6s la succinylcholine. La RMM nest donc pas toujours un signe avant-coureur d'HM. Lazzell et al. ont conseill6 les parents des enfants qui ont exhib6 une RMM mais ils les ont pas incit6s/t rechercher la susceptibilit6/l I'HM par biopsie musculaire. Quand la RMM survient seule, il est justifi6 de continuer l'anesth6sie et de surveiller avec soin les signes vitaux et sp6cialement raugmentation de la PETCO2. Si raugmentation du tonus du mass6ter est la r6gle, il est permis de se demander combien de fois les conditions d'intubation seront optimales. En octobre 1993, la compagnie Burroughs Wellcome exp6diait une lettre ~ tous les anesth6sistes canadiens et am6ricains; celle-ci affirmait qu'~t l'exception de rintubation trach6ale urgente ou du contr61e imm&tiat des voles a6riennes en situation critique, l'administration de succinylcholine 6tait contreindiqu6e chez les enfants et les adolescents. Au Canada, plus particuli6rement, cette consigne a 6t6 accueiilie avec un to116g6n6ral et le Journal Canadien d'Anesth6sie a re~u un grand nombre de lettres 6 et d'appels t616phoniques d'anesth6sistes qui s'inqui6taient de devoir abandonner une drogue aux propri6t6s uniques. Par la suite, la compagnie a r6uni ~ Toronto un comit6 d'experts en anesth6sie p6diatrique pour revoir les indications, contreindications, mises en garde, pr6cautions et directives cliniques de la succinylcholine (ANECTINE*). Ceci a conduit ~ l'abandon des contreindications
467 qui seront remplac6es par de nouvelles directives dhtilisation approuv6es par la Direction g6n6rale de la protection de la sant6 d'Ottawa avec rajout dkme raise en garde sur la possibilit6 61oign6e de provoquer une hyperkali6mie potentiellement 16tale dans les myopathies infantiles non diagnostiqu6es. Curieusement, il est possible qu'au Canada le feuillet ins6r6 dans l'embaUage de la succinylcholine (ANECTINE*) soit maintenant diff6rent de celui des Etats-Unis. La contreindication initiale a 6t~ motiv6e par le rapport d'arr~ts cardiaques hyperkali6miques cons6cutifs ~ radministration inadvertante de succinylcholine chez des enfants porteurs dkme myopathie (ordinairement une maladie de Duchenne) diagnosfiqu6e subs6quemment. L'association am6ricaine de l'hyperthermie maligne (MHAUS) continue de signaler les cas de patients qui d6veloppent le syndrome d'HM; elle estime ~ six le nombre de patients qui developperont chaque ann6e le syndrome d'HM aux Etats-Unis avec un taux de mortalit6 approximatif de 60%. 7 L'article publi6 ce mois-ci par Sulfivan et al. concerne deux nouveaux cas de dysrythmies: deux garcons, un de trois ans, l'autre de trois mois, ont pr6sent6 des tachyarythmies complexes et une asystolie apr~s la succinylcholine. Les deux enfants ont 6t6 r6anim6s avec succ6s avec du bicarbonate de soude, du calcium et de la ventilation contr616e. La litt6rature internationale a rapport6 jusqu'~ maintenant plusieurs cas de ce syndrome. 8-1~I1 est toutefois inusit6: en effet, les anesth6sistes du Sick Children's Hospital de Toronto affLrment qu~ls ont produit le bloc neuromusculaire avec de la succinylcholine chez des centaines de milliers de nouveauxn6s, d'enfants et d'adolescents sans qu'ils ne puissent rendre responsable la succinylcholine d'une seule mortalit6. I1 est 6vident qu'il serait pr6matur6 d'abandonner la succinylcholine. Cependant, si une alternative valable devenait disponible, elle serait certainement adopt6e sans tarder par les anesth6sistes. Depuis leur introduction, on utilise de plus en plus les myorelaxants interm6diaires, atracurium et v6curonium, ~ la place de la succinylcholine pour l'intubation. Le bloc d6bute plus lentement qu'avec la succinylcholine, et ce qui est peut-~tre encore plus important, la r6cup6ration se produit aussi plus lentement. Un nouveau myorelaxant amino-st6roidien d'action interm6diaire, le rocuronium est pr6sentement h l'6tude. Au regard de la dur6e d'action, de la vitesse de r6cup6ration et de l'absence d'effets cardriovasculaires, il s'apparente au v6curonium mais son d6but d'action est beaucoup plus rapide. "J2 Des 6tudes r6centes montrent que ILntubation est r6alis6e avec le rocuronium dans des conditions jug&.s de bonnes excellentes en der de deux minutes, soit un peu plus lentement qu'avec la succinylcholine. ~3Le mivacurium est un produit ~ courte dur6e d'action d6riv6 du benzyliso-
468 quinolium qui scion toutes probabilit~s deviendra disponible en 1994 au Canada. Le m6tabolisme par la cholinest6rase plasmatique en m6tabolites inactifs permet une r6cup6ration deux fois plus rapide que l'atracurium ou le v6curonium. ~4Cependant, son d6but d'action n'est pas plus court que celui de l'atracurium et ses effets h6modynamiques sont semblables, is Lorqu'on lkltilise pour faciliter rintubation, les conditions sont inf6rieures ~ celles de la succinylcholine ~t moins d'administrer des doses de l'ordre de 200 I~g" kg - I e t ~ condition qu'on attende assez longtemps pour permettre au bloc de s'6tablir. La r6cup6ration spontan6e rapide que procure ce non d6polarisant offre toutefois d'autres avantages. I1 peut ne pas 8tre n6cessaire de renverser le bloc r6siduel et scion Ding et al., il r6duirait l'incidence des naus6es et des vornissements en chirurgie ambulatoire. 17 I1 est in6vitable que lkltilisation de la succinylcholine pendant l'anesth6sie continuera A d6cliner ~ mesure qu'on mettra ~ notre disposition de nouvelles drogues capables de produire en toute s6curit6 des conditions id6ales pour l'intubation. I1 faut toutefois se demander si en changeant la succinylcholine pour un non d6polarisant, on affecte la s~urit6 du patient. I1 est permis de penser que changer pour une des drogues pr6sentement disponibles aura pour effet de substituer les r6actions graves exceptionnelles aux inconv6nients plus frequents du blocage neuromusculaire r6cup6ration lente, dont le bloc r6siduel et l'hypoventilation postop~ratoires. ~s I1 est trop tbt pour abandonner la succinylcholine surtout en situation d'urgence 1~ o~ l'intubation rapide est essentielle. Ailleurs, les nouveaux myor6solutifs vont continuer d'empi6ter sur la suecinylcholine. Esp6rons que la hantise du contr61e des coflts actuelle n'emp~chera pas le d6veloppement de nouveaux agents ~ propri6t6s sp6ciales. I1 est malvenu dk~tiliser les drogues les moins ch6res dans toutes les situations, sp6cialement quand l'6conomie r6alis~e est minime et que les coot engendr~s peuvent devenir 6normes. References 1 Lazzell VA, Cart AS, Lerman J, Burrows FA, Creighton RE. The incidence of masseter muscle rigidity after succinylcholine in infants and children. Can J Anaesth 1994; 41: 475-9. 2 Sullivan M, Thompson WK, Hill GD. Sueeinylcholineinduced cardiac arrest in children with undiagnosed myopathy. Can J Anaesth 1994; 41: 497-501. 3 Bevan DR, Bevan JC, Donati F. Muscle Relaxants in Clinical Anesthesia. Chicago, London, Boca Raton: Year Book Medical Publishers, 1988, 278. 4 Saddler JM, Bevan JC, Plumley MH, Polomeno RC, Donati F,, Bevan DR. Jaw tension after suecinylcholinein children undergoing strabismus surgery. Can J Anaesth 1990; 37: 21-5.
CANADIAN JOURNAL OF ANAESTHESIA
5 Littleford JA, Patel LR, Bose D, Cameron CB, McKillop C. Masseter muscle spasm in children: implications of continuing the triggering anesthetic. Anesth Analg 1991; 72: 151-60. 6 Lerman J, Berdock SE, Bissonnette Bet al. Succinylcholine warning (Letter). Can J Anaesth 1994; 41: 165. 7 Rosenberg H, Gronert GA. Intractable cardiac arrest in children given succinylcholine(Letter). Anesthesiology 1992; 77: 1054. 8 Genever EE. Suxamethonium-induced cardiac arrest in unsuspected pseudohypertrophic muscular dystrophy. Br J Anaesth 1971; 43: 984-6. 9 Larsen UT, Juhl B, Hein-SCrensen, de Fine Olivarius B. Complications during anaesthesia in patients with Duchenne's muscular dystrophy (a retrospectivestudy). Can J Anaesth 1989; 36:; 418-22. 10 Schulte-Sasse U, Eberlein HI,, Schm~cker I, Underwood D, Wolbert R. Should the use of succinylcholineduring pediatric anesthesia be reevaluated? Anaesthesiol Reanim 1993; 18: 13-9. 11 WierdaJMKH, Kleef UW, Lambalk LM, Kloppenburg WD, Agoston S. The pharmacodynamics and pharmacokinetics of Org 9426, a new non-depolarizing neuromuscular blocking agent, in patients anaesthetized with nitrous oxide, halothane and fentanyl. Can J Anaesth 1991; 38: 430-5. 12 Meistelman C, Plaud B, Donati E Rocuronium (ORG 9426) neuromuscular blockade at the adductor muscles of the larynx and adductor pollicis in humans. Can J Anaesth 1992; 38: 665-9. 13 Magorian T, Flannery KB, Miller RI~ Comparison of rocuronium, sucinylcholine,and veeuronium for rapidsequence induction of anesthesia in adult patients. Anesthesiology 1993; 79: 913-8. 14 Cook DR, Freeman JA, Lai AA et at Pharrnacokinetics of mivacurium in normal patients and in those with hepatic or renal failure. Br J Anaesth 1992; 69: 580-5. 15 Savarese JJ,, Ali HH, Basta SJ et al. The cardiovascular effects of mivaeurium chloride (BW BI090U) in patients receiving nitrous oxide-opiate-barbiturate anesthesia. Anes9 thesiology 1989; 70: 386-94. 16 Maddineni VR, Mirakhur RK, McCoy EP, Fee JP, Clarke RS. Neuromuscular effects and intubating conditions following mivaeurium: a comparison with suxamethonium. Anaesthesia 1993; 48: 940-5. 17 Ding Y, Fredman B, White PE Use of mivacurium during laparoscopic surgery: effect of reversal drugs on postoperative recovery. Anesth Analg 1994; 78: 450-4. 18 Viby-Mogensen J,, JCrgensen BC, ~rding H. Residual curarization in the recovery room. Anesthesiology 1979; 50: 539-41.
