DRUG EXPERIENCE

Drug Safety 10 (5): 331-349. 1994 0114-5916194/0005-0331/$09.50/0 © Adis International Limited. All rights reserved.

Adverse Effects of Depolarising Neuromuscular Blocking Agents Incidence, Prevention and Management

W Jeffrey Book, Mark Abel and James B. Eisenkraft

Department of Anesthesiology, The Mount Sinai Medical Center, New York, New York, USA

Contents

331 Summary 332 1. Myalgias 333 2. Increased Intraocular Pressure 334 3. Hyperkalaemia 336 4. Malignant Hyperpyrexia 339 5. Masseter Muscle Spasm 3-10 6. Prolonged Neuromuscular Blockade 342 7. Apparent Resistance 342 8. Arrhythmias 343 9. Increased Intragastric Pressure 3-13 10. Rhabdomyolysis 344 II. Anaphylactoid and Anaphylactic Reactions 344 12. Increased Intracranial Pressure 344 13. Pacemaker Interference 3·/4 14. Revised Label Regarding the Use of Suxamethonium in Children and Adolescents 345 15. Conclusion

Summary Muscle relaxants block neuromuscular transmission, acting at nicotinic acetylcholine receptors of the neuromuscular junction. Suxamethonium (succinylcholine) is a depolarising agent, whereas all other relaxants in clinical use are nondepolarising. The desired neuromuscular block results from the structural similarity of muscle relaxants to acetylcholine, enabling the interaction with receptors at the neuromuscular junction. Adverse effects of suxamethonium are generally related to its agonist mode of action. Autonomic cardiovascular effects may result. Other adverse effects include anaphylactic or anaphylactoid reactions, and histamine release. Various disease states may present specific considerations in the use of muscle relaxants. Although many complications of muscle relaxants (such as prolonged block or resistance) are easily treated, others may require immediate intervention and vigorous therapy. Careful selection of appropriate relaxants for par­ticular patients will usually prevent the occurrence of complications.

332

Muscle relaxants were first used in the clinical practice of anaesthesia with the introduction of cu­rare in the 1940s. In 1954, Beecher and Todd re­ported that with the advent of neuromuscular blocking agents, anaesthesia-related mortality in­creased 6-fold. Some of this increase in mortality was ascribed to the misuse of relaxants and a lack of understanding of their specific complications. The safe use of muscle relaxants evolved over the next 50 years through an understanding of the mechanisms of action of these compounds.

Neuromuscular blocking drugs act by interrupt­ing neuromuscular transmission at the level of the nicotinic acetylcholine receptors at the motor end plate. Their mode of action can be classified as an­tagonist (nondepolarising) or agonist (depolaris­ing), both producing blockade. There are 2 agonist blockers, decamethonium and suxamethonium (succinylcholine). At present, only suxamethon­ium is in clinical use. Nondepolarising blocking drugs will be discussed in the next issue of the Jour­nal (Abel et al. 1994).

Suxamethonium is a depolarising neuromuscu­lar blocking agent consisting of 2 acetylcholine molecules linked through the acetate methyl groups. It was introduced into clinical practice in 1951. Because of its structural similarity to acetyl­choline, it acts as an agonist at the nicotinic recep­tor. It is this property that accounts for its desired actions as well as some of its unwanted effects. The latter range from being benign and causing mere inconvenience to those associated with mortality.

In spite of these complications, suxamethonium remains in clinical use because of its rapid onset and offset of action, otherwise unobtainable with nondepolarising neuromuscular blocking agents. Complications from suxamethonium occur in oth­erwise healthy patients, but are of a different nature and magnitude than the profound complications that may occur in the presence of certain patholog­ical conditions.

1. Myalgias

After suxamethonium administration, 5 to 83% of patients will report myalgia postoperatively

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(Pace 1990). The wide range of reported incidences probably represents poor standardisation of vari­ables between studies. The highest incidence re­ported is in a study of patients undergoing minor gynaecological surgery in whom early ambulation was felt to contribute to the 80% incidence of my­algia (Chestnutt et al. 1985). Gender does not seem to be a factor as was once thought (McLoughlin et al. 1988).

The cause of suxamethonium myalgia is not fully understood. It has been noted that in patients who report myalgia, a significant decrease in serum calcium of 0.37 mg/lOOml is measured as opposed to a rise of 0.52 mg/lOOml (Collier 1978) or no significant change (Shrivastava et al. 1983) in pa­tients without myalgia. Some experimental evi­dence suggests a possible massive calcium influx into muscle cells leading to intracellular damage via phospholipase A2 (Jackson et al. 1984).

Chlorpromazine, which can inhibit phos­pholipase A2, has been used in a dose of 0.1 mg/kg prior to suxamethonium to decrease the incidence of myalgias (McLoughlin et al. 1992). These au­thors found no significant changes in serum cal­cium (unless calcium was administered to the pa­tient), suggesting that intravascular calcium may not be the trigger leading to muscle pains. In mus­cle preparations where halothane and suxamethon­ium caused the release of creatine phosphokinase from muscle cells, chlorpromazine was found to prevent this, further suggesting that phospholipase A2 may be the mediator of intracellular injury caused by suxamethonium (McLoughlin et al. 1991). Alternatively, damage to muscle spindles from asynchronous muscle bundle contractions brought on by a high intracellular calcium ion con­centration has been proposed as a mechanism of myalgia following suxamethonium (Collier 1978).

Many attempts have been made to attenuate the morbidity from suxamethonium-induced myalgia. Small doses of nondepolarising muscle relaxants administered prior to suxamethonium have been shown to decrease the incidence of myalgia by 20 to 40% (Blitt et al. 1981). A possible mechanism is the blockade of intrafusal muscle spindle fibres.

Complications of Depolarising Muscle Relaxants

Various other drugs have been studied for the pre­vention or attenuation of myalgias. A small 'self­taming' dose of suxamethonium ("" 1 Omg) adminis­tered prior to 1 mg/kg of suxamethonium has been used in the past to lessen the degree of fascicula­tions thought to cause myalgias (Baraka 1977). Subjected to study, however, this 'self-taming' dose was not found to attenuate myalgia (Brodsky & Brock-Utne 1979).

Lidocaine (lignocaine) 2mg/kg administered prior to suxamethonium decreased the incidence of myalgia from 45 to 8% (Chatterji et al. 1983). The authors of this study ascribe this to the membrane stabilising effects of lidocaine, which may dimin­ish the ionic shifts associated with suxamethon­ium. Similarly, intravenous calcium gluconate 1 mg/kg has been shown to decrease the incidence of myalgia from 45 to 5% (Shrivasatva et al. 1983). These authors also measured serum calcium and potassium ion concentrations. Suxamethonium ad­ministration is associated with an increase in serum potassium and a decrease in serum calcium con­centr~tions in patients who experience myalgia. Chatterji et al. (1983) found that the control pa­tients (i.e. no lidocaine) with myalgia had signifi­cant ionic shifts while the lidocaine pretreated group had no significant ionic changes and fewer myalgias. Although no mechanism was proposed, the authors considered that the acute ionic shifts may have contributed to the myalgia complicating suxamethonium administration.

Dantrolene, a drug used in the treatment of malignant hyperthermia, has been successfully used to attenuate myalgia, but its use is limited by associated significant and prolonged weakness (Collier 1979). The interference of dantrolene with intracellular calcium activity supports the theory of this ion's contribution to post-suxamethonium myalgia.

Several other drugs have been used to attenuate myalgias including aspirin (acetylsalicylic acid) and tocopherol (vitamin E) [McLoughlin et al. 1992]. There are conflicting reports about the effi­cacy of some drugs in preventing myalgia. This prompted a meta-analysis of the results of such

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studies in the English literature. A meta-analysis is an accepted method of statistical analysis of data from several studies if criteria of consistency are met. Pace (1990) reviewed 102 papers, which re­ported on over 5000 patients, on prevention of my­algia. Only 45 met the criteria of being controlled and prospective; both randomised and non­randomised trials were evaluated. Data were com­bined for individual drugs when at least 4 papers were studied and each pretreatment drug analysed separately. These drugs included diazepam, lido­caine, atracurium, pancuronium, gallamine, tubo­curarine, and suxamethonium. Pace (1990) con­cluded that all study drugs except 'self-taming' suxamethonium significantly attenuated suxa" methonium-induced myalgia. Lidocaine 1.5 mg/kg was found to be slightly more effective than the other drugs studied.

2. Increased Intraocular Pressure

Suxamethonium has increased intraocular pres­sure (lOP) by 5 to 15mm Hg for 10 minutes in healthy volunteers (Cook 1981). The mechanism of this sustained increase in lOP is not entirely clear. Extraocular muscles are multiplYcinnervated as opposed to single motor unit innervation in other skeletal muscles. Fibrillar (fast-twitch) and afibril­lar (slow-twitch) fibres are present in extraocular muscles (Dietert 1965). These morphological dis­tinctions may be what leads to the tonic contracture of extraocular muscles on stimulation by suxa­methonium and what was considered to be the mechanism of the subsequent rise in lOP.

In a recent study, lOP was measured in patients in whom the extraocular muscles were detached unilaterally prior to enucleation. Following suxa­methonium, both eyes showed equal increases in lOP, thus refuting the long-held belief that the sus­tained contraction of the extraocular muscles me­chanically caused the rise in lOP (Kelly et al. 1993). The rise in lOP was once thought to be pre­ventable by administration of 'defasciculating' doses of nondepolarising drugs prior to the admin­istration of suxamethonium (Miller et al. 1968). However, more recent studies have refuted this in

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both adults and children (Cook 1981; Meyers et al. 1978). Diazepam pretreatment also does not pre­vent the suxamethonium-induced rise in lOP (Fjeldborg et al. 1985). A transient increase in cho­roidal blood flow through choroidal vascular dila­tation may also occur following suxamethonium, leading to an increase in lOP (Adams & Barnett 1966).

The inability to reliably prevent this complica­tion using many different drugs has led to the con­troversy of the acceptability of the use of suxa­methonium in patients with a penetrating eye injury. Until the publication of a large retrospective study in 1985 (Libonati et al. 1985), suxamethon­ium was thought to aggravate open eye injuries. In this paper 74 patients had received suxamethonium in the presence of an open eye injury. There were no reports of ocular content extrusion, nor was the intraoperative eye examination different from the preoperative examination. This led the study au­thors to conclude that despite theoretical concerns, suxamethonium may be used safely in patients with penetrating eye injuries. In spite of these re­ports, not all anaesthesiologists accept this conclu­sion, and suggest caution in the use of suxamethon­ium in such patients (Calobrisi & Lebowitz 1990). Several factors must be considered when faced with this situation, namely the need for rapid air­way control with the best possible intubating con­ditions versus a transient rise in lOP.

3. Hyperkalaemia

One of the complications associated with suxamethonium is the elevation of serum potas­sium. The increase is small, transient and inconse­quential in most patients (Evers et al. 1969; Weintraub et al. 1969). In otherwise healthy pa­tients the elevation of serum potassium is usually about 0.5 mmollL and is occasionally as high as 1.0 mmollL (Evers et al. 1969). This increase persists for 10 to 15 minutes before returning to baseline. The potassium is thought to be liberated from skel­etal muscle by suxamethonium-induced depolar­isation of the motor endplate (Bali et al. 1975; Gronert & Theye 1975). It may also be released by

Drug Safety 10 (5) 1994

cellular damage (Dundee & Bali 1975) during un­coordinated contractions stimulated by suxa­methonium. This cell damage is suggested by the fact that the serum level of the intracellular enzyme creatine phosphokinase is known to increase fol­lowing suxamethonium (Tammisto & Airaksinen 1966). Tubocurarine (Evers et al. 1976; Weintraub et al 1969), pancuronium (Konchigeri & Tay 1976), magnesium sulphate (Aldrete et al. 1970; James et al. 1986), dantrolene (Collier 1979) and lidocaine (Chatterji et al. 1983) all lessen the in­crease in serum potassium if administered prior to suxamethonium. Some clinicians routinely pre­treat patients to prevent this minor increase.

In some clinical situations (see table I), the rise in serum potassium is precipitous and severe. The postulated mechanism for this exaggerated re­sponse is the proliferation of acetylcholine recep­tors at and beyond the endplate in certain patholog­ical conditions, usually involving denervation. These receptors provide a greater number of open conduits to the egress of potassium from the cell when stimulated by suxamethonium (Gronert & Theye 1975; Martyn et al. 1992). Not only is there an increase in the number of receptors, but also some of these new receptors are structurally differ­ent from the normal nicotinic acetylcholine recep­tor (Gronert & Theye 1975; Martyn et al. 1992) in that they have an alteration in 1 of the 5 protein subunits that make up the receptor. This structural

Table I. Conditions associated with a hyperkalaemic response to suxamethonium (succinylcholine)

Burns

Closed head injury

Guiliain-Barre syndrome

Intra-abdominal infections

Intracranial tumours

Peripheral neuropathies

Rhabdomyosarcoma

Spinal cord injury

Stroke

Subarachnoid haemorrhage

Tetanus

Complications of Oepolarising Muscle Relaxants

change results in an alteration in response charac­teristics. When stimulated by suxamethonium, these 'fetal-type' receptors act as an open ion chan­nel for a longer period of time, allowing a greater flow of potassium into the extracellular and intra­vascular space than normal receptors (Martyn et al. 1992). This acute elevation in serum potassium may lead to malignant arrhythmias and cardiac ar­rest. Conduction block, ventricular tachycardia or fibrillation or sine-wave QRS patterns have all been reported with a 1 to 6 mmollL rise in plasma potassium following suxamethonium (Cooperman 1970).

Many disease states have been associated with this hyperkalaemia. A list of associated diseases has been compiled from individual case reports. Some of these reports measured serum potassium, strengthening the association, while other early re­ports simply reported ventricular arrhythmias or cardiac arrest following administration of suxa­methonium. Burn patients were some of the first to be reported as experiencing cardiac arrest after suxamethonium administration (Forest 1959). El­evated serum potassium has been measured on sev­eral occasions (Birch et al. 1969; Gronert et al. 1969; Schaner et al. 1969). A hyperkalaemic re­sponse is unlikely to occur before 14 days after the injury (Gronert et al. 1969; Schaner et al. 1969), but hyperkalaemia following suxamethonium in a patient 9 days postburn has been reported (Vi by­Mogensen et al. 1975). This exaggerated hyper­kalaemic response has been reported up to 66 days after burns, with normal responses reported there­after (Gronert et al. 1969; Schaner et al. 1969). Some authors suggest that a normal response will not occur until the burn has healed and infection resolved (Martyn et al. 1992). The magnitude of the hyperkalaemic response seems to be propor­tional to the magnitude of the burn in most cases (Schaner et al. 1969).

Neurological diseases are commonly associated with the hyperkalaemic response to suxamethon­ium (Cooperman 1970; Azar 1984). Denervation leads to acetylcholine nicotinic receptor prolifera­tion (up-regulation) [Gronert & Theye 1975;

335

Martyn et al. 1992]. Some denervating processes are traumatic while other disease processes are as­sociated with a nonmechanical denervation. Spinal cord injuries have been associated with hyper­kalaemia following suxamethonium (Stone et al. 1970; Toby 1970). The earliest clinical report is at 21 days after the injury (Roth & Wuthrich 1969), with other reports between 23 and 85 days (Cooperman 1970; Stone et al. 1970; Toby 1970). Normal responses to suxamethonium are said to occur after 6 months (Cooperman 1970), but this is poorly documented, and does not seem to be con­sistent with the concept of up-regulation of recep­tors following denervation leading to hyperkalae­mia following suxamethonium administration.

Intracranial lesions have been associated with hyperkalaemia following suxamethonium. These include closed head injury (Stevenson & Birch 1979) even in the absence of paresis (Frankville & Drummond 1987), stroke, subarachnoid haemor­rhage and tumours (Cooperman 1970; Iwatsuki et al. 1980; Smith & Grenvik 1970) associated with paresis. It has been reported in a patient with en­cephalitis who had evidence of peripheral muscle atrophy (Cowgill et al. 1974). In these reports, it may be possible to ascribe an association of the intracranial lesion to the hyperkalaemic response to suxamethonium; however, it has been shown that immobilisation alone may contribute to this complication (Gronert & Theye 1974). Immobi­lisation-associated up-regulation of receptors may be a result of 'functional denervation'.

Several neuromuscular disorders have been im­plicated with hyperkalaemia following suxa­methonium, such as long-standing peripheral neu­ropathies (Nicholson 1971). One report included 3 patients with tetanus who had cardiac arrests fol­lowing suxamethonium (Roth & Wuthrich 1969). Elevated plasma potassium was measured in only one of these patients. Recently, a single case report was published of a patient who had recovered from Guillain-Barre syndrome and who demonstrated a hyperkalaemic response to suxamethonium (Feld­man 1990). The diagnosis of Guillain-Barre was made on clinical grounds, while laboratory confir-

336

mations of the diagnosis (electromyelogram and edrophonium test) were inconsistent. The authors of this report suggest that while a patient may demonstrate clinical recovery, susceptibility to the hyperkalaemic response may persist for some time after. This same phenomenon was reported in a man who had recovered 8 weeks earlier from a brief paraplegic episode related to aortic surgery (Greenwalt 1992).

A moderate hyperkalaemic response to suxa­methonium has been noted in patients with intra­abdominal infections (Khan & Khan 1983; Kohl­schutter et al. 1976), which was related to the severity and duration of the infection. Why this should occur is speculative. No reports have ap­peared of hyperkalaemia with other infections. Massive hyperkalaemia has been reported follow­ing suxamethonium in a patient with rhabdo­myosarcoma (Krikken-Hogenberk et al. 1989). It is suspected that proliferation of nicotinic acetyl­choline receptors on the tumour lead to this re­sponse (Martyn et al. 1992).

Controversy surrounds the use or avoidance of suxamethonium in patients with renal failure who have elevated plasma potassium levels. Normal re­sponses to suxamethonium are reported in these patients (Koide & Waud 1972; Miller et al. 1972). However, a hyperkalaemic response was reported in a patient with uraemic neuropathy (Walton & Farman 1973). The use or avoidance of suxa­methonium in these patients must be individ­ualised based upon baseline plasma potassium levels and the presence or absence of uraemic neu­ropathy.

Avoidance of this complication requires atten­tion to preoperative assessment of patients, includ­ing emergency cases, and the avoidance of suxamethonium when one of the conditions men­tioned is present. A recent change in the product labelling for suxamethonium in the US now states 'Succinylcholine is contraindicated in persons with personal or familial history of malignant hyperthermia, skeletal myopathies .. . in patients af­ter the acute phase of injury following major bums, multiple trauma, extensive denervation of skeletal

Drug Safety 10 (5) 1994

muscle, or upper motor neuron injury' (see section 14). A number of texts suggest that the risk of hyperkalaemia may diminish over time, particu­larly with nonprogressive or inactive diseases. This has not been well documented. In the presence of a static lesion associated with the hyperkalaemic response to suxamethonium, after several months have passed, the clinical decision must be made whether the advantage of suxamethonium (rapid onset) outweighs the potential risk of hyperkalae­mia. Unfortunately, no firm data exist to determine that risk after time has passed.

Treatment of the arrhythmias caused by hyper­kalaemia following suxamethonium involves im­mediate diagnosis, based on a high index of suspi­cion. Arrhythmias may be stimulated by numerous other causes upon induction of anaesthesia, and these must also be considered and ruled out. Treat­ment of life-threatening arrhythmias must include basic cardiopulmonary resuscitation when indi­cated, while therapy must also be directed to the cause; hyperkalaemia. Two basic approaches to the treatment of hyperkalaemia are antagonism of the cardiac electrophysiological effects of hyperkalae­mia by calcium, and the attempt to shift extracel­lular potassium back into the cell via alkalosis and insulin-glucose infusions. Calcium chloride 15 mg/kg intravenously may antagonise the cardiac conduction effects of hyperkalaemia (the electro­physiology is beyond the scope of this article).

Alkalosis is the most effective method of shift­ing potassium into the cell. This may be easily ac­complished by hyperventilation or sodium bicar­bonate 1 to 2 mmollkg intravenously. Insulin­glucose infusions, while effective at shifting potas­sium intracellularly, are often too slow for the urgency of this complication.

4. Malignant Hyperpyrexia

Malignant hyperpyrexia (MH) is an inherited metabolic disorder of muscle occurring in 1114 000 children (Britt & Kalow 1970) and 1150 000 adults (Britt 1972). Suxamethonium triggers a severe hypermetabolic response in patients with this dis­order. Hypercapnia, metabolic acidosis, hypoxae-

Complications of Depolarising Muscle Relaxants

mia, muscle rigidity, rhabdomyolysis , arrhyth­mias, hyperpyrexia and/or hyperkalaemia may be seen in these patients following suxamethonium or other triggering agents (Gronert 1980). An un­treated crisis may be rapidly lethal. The lesion re­sponsible for the disease is felt to be an anomaly of the sarcoplasmic reticulum calcium release channel, also called the ryanodine receptor, which results in massive release of intracellular calcium and sustained muscular contraction (MacLennan et al. 1990; Mickelson et al. 1988).

A number of neuromuscular diseases have been associated with MH. This has led some authors to recommend that suxamethonium should be avoided in patients with a neuromuscular disorder. When a patient with a malignant hyperpyrexic re­sponse to suxamethonium (or other triggering agent) has a second neuromuscular disorder, an as­sumption is often made that this disorder predis­poses patients to having an MH or MH-like re­sponse to suxamethonium. The most consistent relationship of neuromuscular diseases to MH is for central core disease. This has been shown by the frequency of positive halothane-caffeine con­tracture testing on muscle biopsies in these patients (Heimann-Paterson et al. 1988), and confirma­tional chromosome mapping (Ball & Johnson 1993; Levitt 1992). Other diseases possibly related include Duchenne' s musc'.Jar dystrophy (Hei­mann-Paterson et al. 19P6; Hey tens et al. 1992; Wang & Stanley 1986), Becker's muscular dystro­phy (Heimann-Paterson et al. 1988), and the King­Denborough syndrome (Brownell 1988; Heimann­Paterson et al. 1988) [see table II].

The associations with MH are based upon case reports (Larsen et al. 1989) and inconsistently pos­itive contracture testing of muscle biopsies (Heimann-Paterson et al. 1988). The halothane­caffeine contracture test, while helpful in diagnos­ing MH, may also be positive in patients with my­opathies alone (Heimann-Paterson et al. 1988). European and North American halothane-caffeine contracture tests have some differences in diagnos­tic criteria, leading to some confusion in the diag­nosis of MH susceptibility (Larch 1993). While a

337

Table II. Association of neuromuscular diseases with malignant

hyperthermia

Central core disease - strongly associated

Duchenne muscular dystrophy - possibly associated

King-Denborough syndrome - possibly associated

Myoadenate deaminase deficiency - possibly associated

Other myopathies - possibly associated

Schwartz-Jampel, Fukuyama type of congenital muscular dys­

trophy, Becker muscular dystrophy, periodic paralysis, myotonia

congenita, the sarcoplasmic reticulum ATPase deficiency

syndrome, and mitochondrial myopathy - possibly associated

Sudden infant death - coincidental association

Neuroleptic malignant syndrome - coincidental association

halothane-caffeine contracture test has been re­ported positive in a patient with myotonia con­genita and negative in another (Heimann-Paterson et al. 1988), there does not appear to be a consistent association between this disease and MH (Leh­mann-Hom & laizzo 1990). These patients may demonstrate prolonged muscle contracture (in­cluding masseter muscle spasm) after the adminis­tration of suxamethonium (Anderson & Brown 1989; Omdahl & Sternberg 1962). The neuroleptic malignant syndrome is sometimes associated with a mild hyperkalaemic response to suxamethonium (George & Wood 1987). It does not appear to be related to the profound metabolic derangement of MH upon exposure to suxamethonium (Addonizio & Susman 1986; Brownell 1988).

If a clear history ofMH susceptibility is present, suxamethonium is contraindicated. If a history of a neuromuscular disorder (but not MH) is present, the risk of potentially precipitating an MH crisis by suxamethonium must be assessed for each case, weighing the advantages of suxamethonium over nondepolarising relaxants against this unknown and potentially lethal risk. The association of MH with neuromuscular diseases remains controver­sial.

Treatment of MH requires early diagnosis and aggressive therapy (table III). The diagnosis is usu­ally first made by the presence of muscle rigidity and a rising end-tidal carbon dioxide. Increased ox­ygen utilisation and increased carbon dioxide pro-

338 Drug Safety 10 (5) 1994

Table III. Suggested therapy for malignant hyperthermia (MH) emergency. The treatment protocol may need to be altered according to

specific patient needs (reproduced from the Malignant Hyperthennia Association of the United States guidelines, with pennission)

1. All inhalation anesthetics and suxamethonium (succinylcholine) should be discontinued and hyperventilation with 100% oxygen begun

at high gas flows.

2. In the absence of blood gas analysis, bicarbonate 1 to 2 mmol/kg should be administered.

3 . Dantrolene should be obtained, mixed with sterile distilled water, and 2.5 mglkg administered intravenously. At present, dantrolene is

packaged as a Iyophilised preparation that contains dantrolene 20mg and mannitol 3g per vial.

4. Simultaneously, cooling should be started by all routes: surface, nasogastric lavage, intravenous cold solutions, wound and rectally.

5 . Arrhy1hmias will usually respond to treatment of acidosis and hyperkalaemia. If they persist or are life threatening, procainamide

200mg should be administered in repeated doses as needed. Avoid the use of calcium channel blockers.

6. Administer further doses of dantrolene as necessary, titrated to the heart rate, muscle rigidity and temperature. Responses to

dantrolene should begin to occur in minutes. If not, more drug should be administered. Although the average successful dose of

dantrolene is about 2.5 mglkg, much higher doses may be needed (~1 0 mg/kg). Fortunately, dantrolene does not produce significant

myocardial depression at these doses.

7 . Change anaesthetic tubing, and if possible, soda lime.

8. Determine and monitor closely urine output, serum potassium, calcium, arterial blood gases, end tidal carbon dioxide, and clotting

studies. Hyperkalaemia is common in the acute phase of MH and should be treated with intravenous glucose and insulin.

9. Observe the patient in an intensive care setting for at least 24 hours, since recrudescence of MH may occur, particularly following a

case that was difficult to treat.

10. Follow creatine phosphokinase, calcium, potassium and clotting studies until such time as they retum to nonnal. Observe for

disseminated intravascular coagulation.

11 . An electrencephalogram (ECG) should be obtained and followed postoperatively.

12. Monitor body temperature closely, since overvigorous treatment of MH may lead to hypothennia. Temperature instability may perSist

for several days after the acute episode. Body temperatures of 41 to 42°C are compatible with survival and nonnal brain function if

treated promptly.

13. Ensure urine output of greater than 1 mglkglhour. Consider central venous pressure monitoring because of fluid shifts that may occur.

14. When the patient's condition has stabilised, convert from intravenous to oral dantrolene. Although data are not available regarding

optimal doses and duration of treatment with dantrolene after an episode, the patient should probably receive a total dosage of 4

mg/kg/day in divided doses for 48 hours postoperatively.

duction may be diagnosed early on venous blood gas sampling, prior to the onset of arterial hypoxae­mia, and respiratory and metabolic acidoses. Signs of sympathetic stimulation may also be present as tachycardia or arrhythmias. Myoglobinuria and hyperthermia are usually late signs.

Treatment is best undertaken in an aggressive manner. Surgery should be stopped if possible and anaesthesia aborted while changing to a 'clean' machine (one which has never been exposed to ha­logenated anaesthetic agents). Hyperventilation with 100% oxygen, a dantrolene 2.5 mg/kg loading dose followed by an infusion to a total of 10 mg/kg, and cold intravenous fluids IS to 45 ml/kg should be initial therapy. Bicarbonate administration will be determined on the basis of results of blood

gases. Active cooling may be accomplished by iced saline applied to the body surface or lavaged in stomach and body cavities. Cooling blankets may also be useful. Arrhythmias may require interven­tion with antiarrhythmics. Attention should be di­rected to maintaining urine output greater than 2 ml/kglh by administering fluids and diuretics. Lab­oratory determinations should be used to follow blood gases, electrolytes and coagulation parame­ters at frequent intervals. Patients will require dan­trolene and close monitoring for at least 48 hours postoperatively. Follow up muscle biopsies (and possibly genetic evaluation), along with family counselling and Medic Alert cards, must not be omitted in the follow-up treatment of an MH reac­tion.

Complications of Depolarising Muscle Relaxants

5. Masseter Muscle Spasm

Suxamethonium blocks neuromuscular trans­mission by depolarising the motor endplate, which may cause an initial uncoordinated contracture fol­lowed by muscle relaxation. Aside from the sus­tained contracture noted in the extraocular muscles, sustained contracture following suxamethonium has been thought to represent a pathological re­sponse. Generalised muscle rigidity after the ad­ministration of suxamethonium has been associ­ated with MH (Ratlaff & Jenkins 1972). Isolated muscle group rigidity (other than extraocular mus­cles) presents a more complex problem. Isolated masseter muscle spasm or trismus following suxa­methonium is known to occur frequently in chil­dren, and less commonly in adults.

The frequency of masseter spasm in the paedi­atric population following halothane and suxamethonium has been reported as between 3 per 1000 (Littleford et a1. 1991) and 1 per 100 patients (Schwartz et a1. 1984). The incidence in children having strabismus surgery may be 4 times that of children having other procedures (Carrol 1987). It has been suggested that masseter muscle spasm following halothane and suxamethonium is associ­ated with MH susceptibility (Donlon et al. 1978). The incidence of MH in the paediatric population has been conservatively estimated at 1 per 14000 (Britt & Kalow 1970). MH susceptibility has been determined by in vitro muscle contracture re­sponses to halothane and caffeine. Until recently, there was no standardisation for this test. However, several studies suggested that of patients demon­strating masseter muscle spasm following suxamethonium and halothane, 50 to 60% will have in vitro muscle contracture tests suggesting MH susceptibility (Christian et a1. 1989; Flewellan & Nelson 1984; Rosenberg & Fletcher 1986). From this, MH susceptibility would exist in 1 per 500 to 1 per 200 in the paediatric population. This is clearly incompatible with a reported incidence of MH of about 1 per 14000 in children (Britt & Kalow 1970). Controversy exists as to the interpre­tation of these data and the significance of masseter muscle spasm.

339

The differential diagnosis of masseter muscle spasm after suxamethonium includes several pos­sibilities. It has been suggested that in children the dosage calculation of suxamethonium by body mass basis rather than surface area may lead to underdosing, and simply poor relaxation, account­ing for 'jaw stiffness ' (Cook & Fischer 1975). The dose requirements, ED90 and ED95 (the average dose that produces 90 and 95% depression, respec­tively, of twitch response), for children aged 1 to 5 years have been measured at 0.35 and 0.42 mg/kg, respectively (Meakin et a1. 1988) while the ED90 in adults is 0.29 mg/kg (Smith et a1. 1988). This difference may be due to differences in volumes of distribution between adults and children. Suxa­methonium is hydrophilic and primarily distrib­utes in the extracellular fluid compartment. Dosage based on weight alone may provide an inadequate drug concentration at the receptor site in children, leading to the impression of masseter spasm (Mea­kin 1988).

Recent clinical work has demonstrated that in the presence of blockade of neuromuscular trans­mission at the adductor pollicis, a reduction in mouth opening may be present, reflecting in­creased masseter muscle tone in patients given hal­othane and suxamethonium (VanDerSpek et a1. 1987). It is known that different muscle groups have different sensitivities to relaxants and differ­ent onset times. However, mechanomyographic re­sponses measured in one study demonstrated an increased sensitivity to the neuromuscular block­ing effect of suxamethonium at the masseter mus­cles compared with the adductor pollicis (Plumley et a1. 1990). This suggests that although masseter muscle spasm may occasionally be diagnosed er­roneously in the presence of an inadequate dose of suxamethonium, it most commonly represents an­other entity.

Some authors have suggested that a prolonged increase in masseter muscle tone following suxa­methonium may be a variation of the normal re­sponse. When children were anaesthetised with halothane, mouth opening and jaw tension meas­urements were made before and after the adminis-

340

tration of suxamethonium (VanDerSpek et al. 1987). Measurements were made after the estab­lishment of peripheral neuromuscular blockade. While wide interindividual variation was noted, the consistency of decreased mouth opening and increased jaw tension led the authors to conclude that an increase in masseter muscle tone following halothane and suxamethonium may be a normal response in children. This has also been demon­strated in children anaesthetised with enflurane (VanDerSpek et al. 1988) and isoflurane (Van­DerSpek et al. 1990). The increase in masseter muscle tone has also been demonstrated in the ab­sence of inhaled anaesthetics in children an­aesthetised with thiopental (thiopentone), fentanyl and nitrous oxide, and given suxamethonium (Marhon & Nagia 1992; Meakin et al. 1990). This response as a variation of normal has been con­firmed by other authors (Plumley et al. 1990).

Saying that masseter muscle tone increase fol­lowing suxamethonium may be a variation of the normal response is not the same as saying that all masseter muscle spasm is normal. Masseter muscle spasm after suxamethonium may herald the onset of MH in some patients (Ratlaff & Jenkins 1972). There is still the strong association of positive mus­cle biopsy contracture testing with masseter spasm (Christian et al. 1989; Flewellan & Nelson 1984; Rosenberg & Fletcher 1986). While generalised muscle rigidity following suxamethonium is more likely to represent MH, isolated masseter muscle spasm represents a clinical dilemma. A large group of patients have continued to receive inhalation an­aesthesia (MH-triggering) after masseter spasm without developing overt clinical signs of MH (Littleford et al. 1991). However, some of these patients developed some of the biochemical abnor­malities associated with MH. Most authors recom­mend either changing to a nontriggering anaes­thetic (Gronert 1987) or aborting the anaesthetic and surgery after masseter spasm (Rosenberg 1987). As genetic testing for MH improves (Ball & Johnson 1993; Levitt 1992), the relationship be­tween masseter spasm and MH may become clearer.

Drug Safety 10 (5) 1994

6. Prolonged Neuromuscular Blockade

Shortly after the introduction of suxamethon­ium into clinical practice in 1951, the problem of prolonged neuromuscular blockade was noted. By 1957, an explanation was forwarded with the re­port of the presence of an atypical enzyme respon­sible for the hydrolysis of suxamethonium as an inherited trait (Kalow & Staron 1957). The drug is normally hydrolysed very rapidly by serum cholin­esterase (pseudocholinesterase). The gene locus for the production of this enzyme has been isolated and several variants described (Lockridge 1990). The 4 major alleles are the usual (U) gene, the atyp­ical (A) gene, the fluoride-resistant (F) gene, and the silent (S) gene (table IV). Variants have been described which accelerate the metabolism of suxamethonium (see section 7).

The atypical gene is the most common of the variants, with the homozygous state estimated to occur in 1 per 2000 patients (Whittaker 1980). Re­covery of neuromuscular function following suxamethonium in these homozygous patients usu­ally occurs after 1 hour (Viby-Mogensen 1981a), while in the heterozygote, apnoea may only last 10 to 30 minutes (Viby-Mogensen 1981b). The silent gene is rare, and affected patients show similar clinical responses as those with the atypical gene (Oshita et al. 1983). The fluoride-resistant gene is extremely rare (Lockridge 1990) and reports are

Table IV. Pseudocholinesterase variants

Variant

AA

ss

FF

C5+

Incidence

1/3500 in European populations

1/175 in Iranian Jews

1/25000000 in Orientals and African

Negroes

1/10000000 in European populations

1/58 in Alaskan Eskimos

NA

1/11 in Europeans

1/33 in Asians

1/25 in Africans

1/15 in Americans

Abbreviations: A - atypical ; F = fluoride-resistant; NA = data not

available; S = silent.

Complications of Depolarising Muscle Relaxants

few. Patients with the heterozygote AF (atypical plus fluoride-resistant gene) may have 25 minutes of apnoea and may take 30 minutes to 90% recov­ery of neuromuscular function after suxamethon­ium 100mg, while those with the UF heterozygote (usual plus fluoride-resistant gene) have 8.5 min­utes of apnoea and take only 12 minutes to 90% recovery (Viby-Mogensen 1981b) [see table V]. Recovery from neuromuscular blockade in the ho­mozygote atypical patient demonstrates a pattern on blockade monitoring resembling a phase 2 block (see below) [Bevan et al. 1988]. This may represent the effect of excessive suxamethonium at the endplate.

There may be other causes of prolonged block­ade aside from atypical pseudocholinesterase. Low levels of normal enzyme may be responsible or the enzyme may be inhibited. Clinically significant prolongation of block does not occur until levels fall below 33% of normal activity. During preg­nancy, plasma cholinesterase activity can fall 20 to 30% of normal nonpregnant values (Shnider 1965). It is lowest at 3 days post partum and returns to normal by 2 to 6 weeks (Shnider 1965). The newborn has about 50% enzyme activity, reaching normal levels by 3 to 4 years of age (Lockridge 1990).

Many pathological states are associated with re­duced cholinesterase activity, including hepatitis, cirrhosis, acute infections, carcinomas, chronic de­bilitating disease, uraemia and burns (Lockridge 1990). Rarely are these conditions associated with a serious clinical prolongation of suxamethonium action. Pharmacological irreversible inhibition of the enzyme may cause significantly prolonged blockade. Cyclophosphamide (Zsigmond & Rob­ins 1972), echothiopate iodide eye drops (Gestzes 1966) and organophosphate pesticides (Viby­Mogensen 1983) have all been reported to prolong the action of suxamethonium by irreversible en­zyme inhibition. Seldom is the blockade prolonged more than 15 minutes. Reversible inhibition of pseudocholinesterase is known to occur with a number of drugs, notably the acetylcholinesterase inhibitors (edrophonium, neostigmine, pyridos-

341

Table V. Duration to 90% recovery and duration of apnoea in

homozygous and heterozygote patients with

pseudocholinesterase variants receiving suxamethonium

(succinylcholine)

Time to 90% recovery after

suxamethonium 1 mglkg

UU 3-6 minutes

AA SO-65 minutes

SSNA

FFNA

Duration of apnoea after

suxamethonium 100mg

UA 14.6 minutes

US 12.4 minutes

UF 12.0 minutes

AF 30.0 minutes

FS 30.0 minutes

ASNA

Abbreviations: A = atypical; F = fluoride-resistant; NA = data not

available; S = silent; U = usual.

tigmine) [Lockridge 1990], monoamine oxidase inhibitors, oral contraceptives and pancuronium (Lockridge 1990).

Prolonged neuromuscular blockade following suxamethonium may occur after excessive and prolonged administration. This has been described as phase 2 or desensitisation blockade. Recovery may be unusually prolonged on discontinuation of suxamethonium, and the characteristics of the block changed. The block exhibits the pattern of nondepolarising block, that is fade on train-of-four stimulation, fade in response to tetanic stimulation, and post-tetanic potentiation (Lee 1975). The ap­pearance of this complication is related to the time and dose of suxamethonium administered. Reports of phase 2 block have occurred with doses of 2 to 8mglkg (Lee 1984). The onset may be accelerated by potent inhaled anaesthetics (Donati & Bevan 1982, 1983). Proposed mechanisms for phase 2 block include channel blockade of the receptor by suxamethonium, desensitisation of receptors in the presence of excessive agonists, and ion flux caus­ing distortion of the junctional membrane (Standaert 1990). Recovery from phase 2 block is reported to be accelerated by anticholinesterase agents (Futter et al. 1983).

Neuromuscular blockade from suxamethonium may be potentiated or prolonged by drugs which by themselves have insignificant blocking proper­ties. Of the aminoglycoside antibiotics which po-

342

tentiate blockade by suxamethonium, each has its

own inhibitory action on neuromuscular transmis­sion (described in detail later in this paper). Non­

aminoglycoside antibiotics, such as the polymyx­ins, also have inhibitory effects on neuromuscular

transmission which potentiate the action of suxamethonium by decreasing acetylcholine re­lease (Wright & Collier 1976). Hypermagnesaemia interferes with neuromuscular transmission by de­

creasing the amount of acetylcholine released,

which potentiates the action of suxamethonium (Ghoneim & Long 1970). Local anaesthetics may

act both presynaptically and post synaptically, and

may impair the propagation of the nerve action po­

tential with a reduction in acetylcholine release (Howard 1990). Several other drugs have been shown to interfere with neuromuscular transmis­sion, however, significant interactions with

suxamethonium in man have not been documented (e.g. ~-blockers, calcium channel blockers, pheny­toin, antiarrhythmics) [Howard 1990].

Treatment of prolonged blockade requires con­tinuing positive pressure ventilation and anaes­thetic agents or sedation, which ablate awareness during this state of paralysis, until the block wears off spontaneously. This may take up to several hours . Human cholinesterase has been adminis­tered via plasma or whole blood transfusions; how­ever, the risks associated with blood product ad­ministration makes this practice unacceptable when the risks of prolonged mechanical ventilation

with appropriate monitoring and vigilance are mi­nuscule. With phase 2 block, anticholinesterases have been used to accelerate recovery in some cases.

Cholinesterase levels and activity should be

measured in patients with prolonged blockade sus­pected of having decreased cholinesterase activity. Patients with genetic variants should be informed

and counselled to wear some form of medical alert. Family members should also be counselled and have their cholinesterase activity determined.

Drug Safety 10 (5) 1994

7. Apparent Resistance

Apparent resistance to suxamethonium may oc­cur because of problems with the quality of the drug injected, extremely rapid hydrolysis of the drug before an adequate clinical response is noted, or a patient's disease leading to true resistance to the effect of suxamethonium. If suxamethonium is stored improperly (i.e. at room temperature for more than 4 weeks) [Boehm et al. 1984] the solu­tion will begin to hydrolyse and lose potency. When it is then injected, the response may be inad­equate or absent.

A variant of cholinesterase with higher than nor­mal activity has been described (Robson & Harris 1966). This variant is present in 9% of Europeans (Locke ridge 1990), yet not often recognised. These patients demonstrate resistance to suxamethon­ium. This variant is referred to as C5+ (table V). The Cynthiana variant is another variant of cholin­esterase with increased activity. This variant is quantitatively not qualitatively more active than the C5+ (Neitlich 1966).

Patients with myasthenia gravis have been dem­onstrated to be resistant to suxamethonium (Eisen­kraft et al. 1988). The mechanism for this is un­clear: a decrease in the number of acetylcholine receptors is probably responsible (Martyn et al. 1992).

8. Arrhythmias

Because of its structural similarity to acetylcho­line, suxamethonium stimulates nicotinic and mus­carinic cholinergic receptors. Bradycardia follow­ing suxamethonium has long been recognised (Buliough 1959; Leigh et al. 1957), possibly caused by muscarinic receptor stimulation. Stimu­lation of muscarinic receptors may cause bradycar­dia, and this has been reported as a complication of suxamethonium. It is usually seen with repeated doses at intervals of greater than 3 minutes. This is thought to be related to the presence of the meta­bolic breakdown products of suxamethonium, succinylmonocholine or choline, which sensitise the sinus node to the muscarinic effects of

Complications of Depolarising Muscle Relaxants

suxamethonium (Schoenstadt & Witcher 1963). However, this is inconsistent with the fact that bradycardia is not common with suxamethonium infusions. Also, anaesthetic agents may affect the appearance of muscarinic adverse effects. Thio­pental induction of anaesthesia decreases the bradycardic response while halothane may accen­tuate it (Williams et al. 1961). Pretreatment with

an antimuscarinic agent, like intravenous atropine, may attenuate bradycardia (Williams et al. 1961),

but not completely block the bradycardic response to a second dose of suxamethonium (Sorenson et al 1980). Children are more likely than adults to demonstrate bradycardia after suxamethonium, even after a single dose (Craythom et al. 1960). This may be related to incomplete sympathetic de­velopment in infants. Intravenous antimuscarinics will attenuate this arrhythmia in children (Lerman & Chinyanga 1983).

Occasionally, tachyarrhythmias, premature atrial or ventricular beats, or ventricular bigeminy are seen after suxamethonium. In a small number of patients, noradrenaline (norepinephrine) levels have been reported to rise after suxamethonium (McCullough et al. 1982; Nigrovic et al. 1983), suggesting a possible cause for these arrhythmias. A proposed mechanism for the noradrenaline re­lease is the stimulation of presynaptic nicotinic re­ceptors on the postganglionic sympathetic nerve terminals by suxamethonium (Nigrovic 1984). It is suggested that this noradrenaline release balances the muscarinic effects of suxamethonium in adults, resulting in minimal rate and rhythm changes seen

in most patients. It is further theorised that desensitisation of these presynaptic receptors al­

lows muscarinic receptor effects to predominate with repeated doses of suxamethonium (Nigrovic 1984). Nodal rhythms have also been seen, sug­gesting muscarinic adverse effects. Earlier, some attention was given to the possibility that digitalis may predispose to these arrhythmias, however, this does not appear to be a problem (Bartolone & Rao 1983).

343

9. Increased Intragastric Pressure

Raised intragastric pressure has been recorded in some patients following suxamethonium. This complication seems to be related to the degree of visible fasciculations (Miller & Way 1971) and was felt at one time to represent a potential for increasing the risk of aspiration of gastric contents. It has since been recognised that lower oesopha­geal sphincter tone increases as well as intragastric pressure (Smith et al. 1978). Pretreatment with nondepolarising neuromuscular blocking agents prior to suxamethonium decreases visible fascicu­lations and the rise in intragastric pressure (Miller & Way 1971).

10. Rhabdomyolysis

Rhabdomyolysis results from a breakdown of muscle fibres , releasing myoglobin. As a compli­cation of suxamethonium in the absence of MH it is usually benign, and more common in children than adults (Ryan et al. 1971). Myoglobinaemia, without development of massive rhabdomyolysis, may be detected in 40% of children after a single dose of suxamethonium, while only 1 of 30 adults will develop myoglobinaemia in the absence of neuromuscular disease (Ryan et al. 1971). It is ac­centuated in the presence of halothane and by re­peated doses of suxamethonium (Tammisto & Air­aksinen 1966). It appears to be related to visible fasciculations (Tammisto & Airaksinen 1966) and can be attenuated by pretreatment with tubocura­rine (Tammisto et al. 1967). The mechanism of the muscle breakdown is unknown. The possibility ex­ists of massive rhabdomyolysis after suxamethon­ium in the absence of MH, resulting in renal failure caused by deposition of myoglobin in the renal tu­bules (Hool et al. 1984). The relationship of rhabdomyolysis following suxamethonium to MH or other neuromuscular disease is unclear.

Rhabdomyolysis can cause myoglobinuria, which may result in renal failure. Renal failure from deposition of myoglobin in the tubules may be prevented by early diagnosis and aggressive treatment. Therapy is directed towards mainte-

344

nance of adequate urine flow by the liberal admin­istration of fluids and diuretics.

11. Anaphylactoid and Anaphylactic Reactions

Anaphy lactoid reactions caused by mast cell de­granulation and histamine release have been re­ported following suxamethonium. Flushing of the skin is most common, but urticaria, bronchospasm and profound hypotension may also occur (Bow­man 1982). In true anaphylactic reactions, the IgE antibody triggers explosive release of vasoactive substances from the mast cell, leading to circula­tory collapse. Suxamethonium is the muscle relax­ant most frequently reported to cause both reac­tions. Such reactions were rarely reported according to an earlier review, with only 36 cases of anaphylaxis reported between 1957 and 1981 (Bevan et al. 1988). A recent study of anaphylaxis to anaesthetics reported a significantly higher inci­dence, with 821 cases of anaphylaxis, 80% of which were to muscle relaxants, with suxamethon­ium accounting for 54% of these cases (Laxenaire et al. 1990). Mechanisms and treatment of anaphy­lactoid and anaphylactic reactions are discussed elsewhere in this review.

12. Increased Intracranial Pressure

The effect of suxamethonium on intracranial pressure in humans is controversial. Some work has been done in animals, but the applicability to humans is questionable. It appears that suxa­methonium may produce elevation of intracranial pressure in some humans with intracranial tu­mours. This effect may be attenuated by pretreat­ment with the nondepolarising drug, metocurine (Stirt et al. 1987). Concomitantly with the eleva­tion in intracranial pressure, an increase in cerebral blood flow and electroencephalogram (EEG) evi­dence suggestive of CNS activation has been noted in dogs (Lanier et al. 1986). This is thought to be a result of muscle spindle activation. This rise in in­tracranial pressure in dogs from suxamethonium stimulation can be blunted by deep anaesthesia (Lanier et al. 1986). In humans, the effect of suxa-

Drug Safety 10 (5) 1994

methonium is difficult to separate from the effects of actions performed while the patient is under the effect of this and other drugs. Some authors (Lam & Gelb 1984) believe that in the absence of inade­quate anaesthesia and/or hypercapnia, the use of suxamethonium is compatible with safe practice, while others (Cottrell et al. 1983), on the basis of experimental evidence in animals, consider that it may be contraindicated in neurosurgical anaesthe­sia because of the potential of increasing intracran­ial pressure.

Recently, in an elegant study, Kovarik et al. (1994) clearly demonstrated that in brain-injured patients, suxamethonium did not alter cerebral blood flow velocity, cortical activity or intracranial pressure.

13. Pacemaker Interference

Suxamethonium causes fasciculations. These fasciculations create electrical activity called myopotentials. When this occurs in the large mus­cles of the chest wall, like the pectorals, electrical activity may be sensed by a unipolar demand pace­maker. This electrical activity may be enough to inappropriately inhibit pacemaker firing (Pinfer 1991; Zaiden 1984). Reports of this complication are few, however, and suxamethonium has been used safely in many patients with pacemakers. Most modern pacemakers are bipolar and are less likely to be inhibited by myopotentials.

14. Revised Label Regarding the Use of Suxamethonium in Children and Adolescents

At the end of 1993, manufacturers of suxa­methonium in the US, in response to a recommen­dation by the US Food and Drug Administration (FDA), revised the labels regarding the use of suxamethonium in children and adolescents. This change in labelling was prompted by reports in the European and American literature of cardiac ar­rests following administration of the drug to appar­ently healthy children and adolescents who were subsequently found to have previously undiag­nosed myopathies. Most recently, Schulte-Sasse et

Complications of Depolarising Muscle Relaxants

a1. (1993) reported 9 cases of cardiac arrest within a few minutes of suxamethonium administration, all of whom were later shown to have occult my­opathies. Five of these children did not survive.

Similar case reports have occurred in the litera­ture since 1971 (Genever 1971; Henderson 1984; Linter et a1. 1982; Schaer et a1. 1977). In 1987, Delphin et a1. reported a similar case, stating that 'The use of succinylcholine in elective paediatric anaesthesia introduces a small but significant risk that can easily be avoided'. Reports continued to appear in the literature of similar cases (Gurgey et a1. 1989; Mehler et a1. 1991; Rosenberg & Gronert 1992), and warnings in a major paediatric anaes­thesia textbook that' ... the routine use of succinyl­choline is avoided because of its possible adverse side effects, particularly the rare but severe ones such as malignant hyperthermia and cardiac arrest' (Goudsouzian 1993), prompted the manufacturers to change their labelling to include this new infor­mation.

In the US, the package insert for suxamethon­ium now states 'Except when used for emergency tracheal intubation or in instances where immedi­ate securing of the airway is necessary, succinyl­choline is contraindicated in children and adoles­cent patients' . Subsequent correspondence expressed concerns over the impact of this state­ment (Badgwell et a1. 1994; Cox & Goresky 1994; Doyle et a1. 1994; Lerman et al. 1994; Morell et a1. 1994). Certainly, not all practitioners are in agree­ment with this statement of contradiction.

With the development and introduction of non­depolarising agents with the same advantages (rapid onset and short duration of action) as suxamethonium, this issue may be soon laid to rest. Rocuronium, a new nondepolarising neuromuscu­lar blocking drug, has been shown to have a rapid onset of action approaching that of suxamethon­ium in adults, when used in large doses (Magorian et a1. 1993). However, this dose of 1.2 mg/kg (5 times the ED9s) had a long duration of action of 38 to 150 minutes compared with 5 to 14 minutes for suxamethonium 1 mg/kg. No drug has yet matched the rapid onset and offset of action which has made

345

suxamethonium so useful in spite of its many potential complications.

15. Conclusions

Since its introduction in 1951, suxamethonium remains an important pharmacological agent. No other drug can match its ability to block neuromus­cular transmission within 1 minute of administra­tion. This attribute makes it the most useful drug for obtaining rapid control of the airway when nec­essary. Its use is associated with some minor com­plications as well as serious adverse reactions, which may quickly lead to cardiac arrest in some patients. It is only through an understanding of the mechanisms of these complications and the pa­tients in whom they occur, that the vigilant clini­cian can prevent or treat them.

Recently, because of these complications, the manufacturers of suxamethonium have stated that the drug is contraindicated for routine use in chil­dren and adolescents. Yet, it remains the relaxant of choice in appropriate patients in whom rapid control of the airway is critical.

To date, none of the depolarising neuromuscular blocking drugs have been able to match the unique pharmacodynamic profile of suxamethonium (rapid onset and offset of action) that makes this drug stilI useful 40 years after its introduction.

Acknowledgements

The authors are grateful to Colette Bradford for her research assistance and Joanne Delerme for her secretarial assistance in preparing the manuscript.

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Haeytens L, Martin JJ, Van De Kelft E, Bossaert JL. In vitro contrac­ture tests in patients with various neuromuscular diseases. British Journal of Anaesthesia 68: 72-75, 1992

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Kelly RE, Dinner M, Turner LS, Haik B, Abramson DH, Daines P. Succinylcholine increases lOP in the human eye with the extraocu­lar muscles detached. Anesthesiology 79: 948-952, 1993

Kohlschutter B, Bauer H, Roth E Suxamethonium-induced hyperkalemia in patients with severe intra-abdominal infections. British Journal of Anaesthesia 48: 557-562, 1976

Koide M, Waud BE. Serum potassium concentrations after succinylcholine in patients with renal failure. Anesthesiology 36: 142-145,1972

Konchigeri HN, Tay C. Influence of pancuronium on potassium ef­flux produced by succinylcholine. Anesthesia and Analgesia 55: 474-477,1976

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Lam AM, Gelb AW. Succinylcholine and intracranial pressure - a cause for pause. Anesthesia and Analgesia 63: 620-622,1984

Lanier WL, Milde JH, Michenfelder JD. Cerebral stimulation fol­lowing succinylcholine in dogs. Anesthesiology 64: 551, 1986

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Correspondence and reprints : Dr W Jeffrey Book, Department of

Anesthesiology, Box 1010, The Mount Sinai Medical Center, One Gustave L. Levy Place, New York, NY 10029, USA.