None of the muscle relaxants used in modern anaesthesiology, particularly in paediatric anaesthesiology, has aroused so much controversy as suxamethonium has. The pharmacokinetic and pharmacodynamic properties of suxamethonium present it in an ambiguous light: on the one hand, its fast onset of relaxation, which enables endotracheal intubation is extremely valuable; on the other hand, the agent can potentially cause adverse side effects. Therefore, the essential issue for practising anaesthesiologists is to determine in which clinical events suxamethonium can or should be used, despite its risks.

The potentiation of suxamethonium-related adverse effects is observed in paediatric anaesthesiology, as children are at particularly high risk of its side effects.

In neonates, infants and young children, the structure of the neuromuscular junction is different compared to adults. In the youngest children, functional insufficiency of the neuromuscular junction and differences in the structure of the postsynaptic nicotinic receptor are observed. In the foetal muscles, the subunit γ replaces ε [1].

Infants and children below 3 years of age metabolise the relaxants quicker than adults do. Therefore, the muscle relaxants have to be administered in higher doses; at the age of 7 years, their pharmacokinetics becomes similar to that in adults.

In clinical practice, muscle relaxation has been applied since 1942. The first use of tubocurarine during anaesthesia completely changed the way the surgical procedures were performed providing a new quality of medical science [2]. Suxamethonium was used for the first time by Thesleff in Sweden in 1951, and by Scurr and Borne in 1952 in Great Britain [3]. Since that time, suxamethonium is continuously present in anaesthesiology and intensive therapy, including paediatric anaesthesiology, although its alleged twilight has been increasingly mentioned in literature [4]. It should be added, however, that the conservative approach towards further use suxamethonium in anaesthetic practice is still observed [5].

Chemically and clinically, suxamethonium resembles acetylcholine, a natural neurotransmitter at the neuromuscular junction, yet its action is longer. The stimulation of nicotinic receptors at the initial stage of its action is characterized by muscle fasciculation, which can be partially prevented using precurarisation, i.e. administration of 10-15% of the intubating dose of a non-depolarising neuromuscular blocking agent before suxamethonium [6].

The short clinical time of action of suxamethonium results from hydrolytic distribution mediated by plasma pseudocholinesterase, whose genetic defect or decreased activity can prolong its action. The activity of plasma pseudocholinesterase is expressed by dibucaine number: its lower activity results in prolonged action of both suxamethonium and mivacurium [7].

SUXAMETHONIUM AND THE DYNAMICS OF NEUROMUSCULAR BLOCKADE

One of the unique features of suxamethonium is the time needed to provide good and very good intubation conditions; with 1 mg kg-1 of iv suxamethonium, this time is 34±12 secs. since its administration [8].

Moreover, the time of clinical action required for spontaneous block reversal is important. At the dose of 1 mg kg-1, the 90% reversal of neuromuscular blockade is observed after 8.3±3.2 min, 7.2±0.5 min and 9.1±3.0 min, for the laryngeal, diaphragmatic and thumb muscles, respectively [9]. 

The features already mentioned, i.e. short onset time to induce neuromuscular block and the shortest time of neuromuscular blockade, compared to all the other muscle relaxants, make suxamethonium unique. Until recently, based on the same features, suxamethonium was the drug of choice in cases of anticipated difficult airways, emergencies and full-stomach patients [10, 11]; hence, its presence in the algorithms for emergency endotracheal intubation [10]. Moreover, the inclusion of suxamethonium in the algorithms for rapid sequence intubation (RSI) is of interest [12].

SUXAMETHONIUM AND THE RISK OF MALIGNANT HYPERTHERMIA

Unfortunately, the uniqueness of suxamethonium should be considered together with its potential adverse side effects. The side effects reported include bradycardia (atropine should be administered simultaneously with suxamethonium) likely to progress to asystole, hyperkalaemia, increased intraocular pressure, particularly in glaucoma patients or those with eye injuries, and increased intracranial pressure. Suxamethonium should be avoided in patients with burns due to its effects on the muscle cell membrane and possible induction of rhabdomyolysis.

The most severe adverse effect is possible induction of malignant hyperthermia, especially in genetically predisposed individuals and those with positive family history [13, 14, 15, 16]. Malignant hyperthermia is the complication, which is significantly more common in children. The neurological diseases, e.g. the King-Denborough syndrome or Duchenne muscular dystrophy, predispose to the development of malignant hyperthermia during anaesthesia with suxamethonium and inhalation anaesthetics [17, 18]. Another disease, whose relation to malignant hyperthermia has been proved, is central core congenital myopathy, characterized by stable, progressing muscle weakness of the limbs. It is emphasized, however, that the development of hyperthermia in this case is not unavoidable [19].

The primary damage to cell membranes in individuals susceptible to anaesthetic-induced hyperthermic responses has not been explicitly documented.

The majority of authors believe that the genetically determined mutation involves also the ryanidine receptor (RYDR), which is a kind of connection between the system T and terminal cisterns of the sarcoplasmic reticulum. RYDR is responsible for Ca2+ release from the intracellular stores of striated muscles. Numerous data indicate that malignant hyperthermia is a heterogeneous disorder, thus is not confined only to the abnormal function of RYDR. The most important factor in the pathogenesis of malignant hyperthermia is abnormal intracellular sequestration of Ca2+ ions dependent on the mutation of RYDR, which controls the calcium channel. 

The individuals susceptible to the development of hyperthermic reactions are identified based on history taking, muscle tests, DNA markers, and enzymatic tests (concentration of CPK).

During the premedication visit, the history taking, aimed at identifying the patients at risk of malignant hyperthermia, should include: family history, unexplained deaths or anaesthesia-related complications in the family, osteoarticular and muscular diseases of a patient and his/her family, elevated body temperature of unknown origin in the immediate postoperative period, and dark urine after surgery and anaesthesia [20, 21].

The incidence of malignant hyperthermia is 1:10000-1:15000, although its estimation is difficult and includes all races. In the eighties of the last century, when halothane was the major inhalation anaesthetic, the incidence of malignant hyperthermia was estimated at 1: 12000 [22].

SUXAMETHONIUM OR ROCURONIUM FOR RSI IN CHILDREN?

Given the high risk of inducing malignant hyperthermia by suxamethonium,  rocuronium – a steroid non-depolarising relaxant can be an alternative providing good intubation conditions (including RSI). Intubation following intravenous administration of 1.2 mg kg-1 of rocuronium is possible after 45-60 sec, so the time interval is similar to that provided by suxamethonium [23]. Unfortunately, such a high dose of rocuronium markedly prolongs the neuromuscular blockade. Spontaneous reversal of neuromuscular block to achieve the train-of four ratio (TOFR) ≥0.9 after a standard dose of rocuronium, i.e. 0.6 mg kg-1, can last even 57.8 min and increases with its dose [24].

However, long-lasting neuromuscular blockade induced by rocuronium is of no importance in difficult airway cases as sugammadex – cyclodextrine, a specific antagonist of steroid muscle relaxants may be used.

The approval of sugammadex in the European countries in 2008 revised the knowledge and clinical practice related to muscle relaxation [25]. Sugammadex in the dose of 16 mg kg-1 , given immediately after iv administration of 1.2 mg kg-1 of rocuronium, results in TOFR ≥0.9 after 2.9 min, i.e. much shorter time than spontaneous reversal of block induced by suxamethonium [26]. At more shallow neuromuscular block (expressed as TOFR ≥2) – when cholinesterase inhibitors can be used – the dose of sugammadex sufficient to successfully reverse the neuromuscular blockade is 2 mg kg-1, and the time to obtain TOFR ≥0.9 is 2.1 min [27].

The introduction of sugammadex, a novel agent reversing neuromuscular block differently than cholinesterase inhibitors, revised the earlier dogma concerning the use of suxamethonium in RSI.

In paediatric anaesthesia, however, the efficacy of sugammadex for reversal of neuromuscular blockade induced by steroid relaxants is slightly less relevant as in newborns and infants benzylisoquinoline preparations [28], such as atracurium, are preferred, which is also the case in our centre.

In the centres where paediatric anaesthesiology (with premature babies, newborns and infants included) is the major area of clinical activity, all non-depolarising relaxants are successfully used. In Germany, the most commonly used muscle relaxant for endotracheal intubation is mivacurium [29]. In Great Britain, in paediatric intensive therapy units the most common agent used is vecuronium [30].

Since the neuromuscular junctions in younger patients are insufficient, steroid relaxants act longer; yet their doses have to be higher in this group of patients. In neonates and infants benzylisoquinoline are metabolised via Hoffman elimination or broken down by hydrolysis. Reversal of neuromuscular blockade takes place by their elimination and not kinetic redistribution. Moreover, they are poorly metabolised in the liver.

Unfortunately, neuromuscular block induced by benzylisoquinoline agents cannot be reversed with sugammadex, so they cannot be actually used in RSI. Therefore, in algorithms of rapid induction and paediatric intubation, suxamethonium is worth considering, in the iv dose of 2 mg kg-1 in infants <1 year of age and of 1 mg kg-1 in those >1 year of age [31].

LARYNGOSPASM

Laryngospasm is a critical event whose incidence in paediatric anaesthesiology is much higher compared to adults. The procedure of intubation of a child is probably the crucial stage of anaesthesia. The determined risk factors of laryngospasm include respiratory tract infections, anaesthesia conducted by an inexperienced anaesthesiologist, inhalation anaesthesia or anaesthesia without relaxants. During inhalation anaesthesia with spontaneous respiration preserved, the removal of the laryngeal mask during sleep is associated with lower risk of laryngospasm. When laryngospasm occurs, suxamethonium, in the dose of 20-30% of the intubating dose, is the treatment of choice if such a complication has not subsided after institution of oxygen therapy through the facial mask or after the Esmarch manoeuvre [31, 32]. Interestingly, in such a critical event, with no intravenous line inserted, suxamethonium can be administered intramuscularly, intraosseously or intralingually [33].

SUMMARY

Critical, life-threatening events in anaesthesiology are mainly related to airway maintenance. 'Difficult airway', patients with full stomach, laryngospasm are the cases in which the use of suxamethonium should be considered, despite its potential risks.

It is worth remembering that in Great Britain, dissolved and ready-to-use suxamethonium is always available in crucially important hospital wards, e.g. emergency departments or Caesarean section rooms, even though modern relaxants and agents for neuromuscular block reversal (including sugammadex) are widely accessible. Its availability in such places results from its unique properties, i.e. short time needed to provide very good intubation condition.

An ideal muscle relaxant has been sought for years. In the literature describing agents acting on the neuromuscular junction, the term 'non-depolarising suxamethonium' is used [3]. The very name of such an ideal agent recalls its unfavourable mechanism of neuromuscular block induction, responsible for potential adverse effects, but also emphasizes the essence and uniqueness of suxamethonium, used for almost six decades.

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Acknowledgements: The authors wish to thank dr Cezary Żugaj from the Oxford John Radcliffe Hospital for assistance in preparing the manuscript part regarding suxamethonium in British hospitals.

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address:

*Marcin Owczarek
Katedra i Klinika Anestezjologii i Intensywnej Terapii
Szpitala Uniwersyteckiego w Bydgoszczy
Uniwersytet im. Mikołaja Kopernika w Toruniu
Collegium Medicum
ul. Marii Skłodowskiej-Curie 9, 85-095 Bydgoszcz
e-mail: owczarekmarcin@o2.pl
tel.: +48 52 585 49 57

received: 12.12.2010
accepted: 20.04.2011