Since the 1970s, there has been an increasing trend towards performing surgery in children on a day case basis. Undoubtedly, the main impetus for this change has been economic, as healthcare systems have been subjected to ever-increasing financial constraints. However, day case surgery also offers advantages for the child and the family. By avoiding the stress of hospital admission, children are less prone to develop postoperative behavioural problems such as phobias and regressive traits. Disruption to family life is minimized as is the risk of hospital-acquired infection. It has recently been estimated that more than 60% of all paediatric surgery in the USA is performed on an outpatient basis .
The enormous growth in outpatient surgical services has obliged anaesthetists to adapt their practice to provide more rapid and complete recovery from anaesthesia. This has been aided by the development of anaesthetic drugs and adjuvants with shorter half-times and improved elimination kinetics. In the field of neuromuscular blocking agents, newer short- and intermediate-duration drugs offer more rapid recovery with fewer side-effects.
The properties of the ideal neuromuscular blocking agent for day surgery have been summarized by Apfelbaum (Table 1) . Of these, probably the most specific requirement in relation to day surgery is a short, predictable duration of action, as this provides the anaesthetist with maximum control over the degree of relaxation. For most relaxants, the onset and offset of neuromuscular blockade are faster in paediatric patients than in adults, which may reflect the relatively higher cardiac output and faster circulation times in younger patients. Pharmacological antagonism of non-depolarizing neuromuscular blocking agents (NMBAs) is also achieved more rapidly in paediatric patients than in adults and correlates with a reduction in the incidence of residual neuromuscular blockade in the immediate recovery period . However, the elimination of some NMBAs is delayed in the first 12 months of life, with a resulting increase in their duration of action.
The main indications for muscle relaxants during paediatric day case anaesthesia are tracheal intubation for protection of the airway, for surgery in the head and neck region or to facilitate surgical procedures requiring profound muscle relaxation. Neuromuscular blocking agents can also be used to provide optimal conditions for surgery with lower doses of intravenous and inhalation anaesthetic agents, resulting in fewer drug-induced side-effects and a more rapid recovery. This has special significance for anaesthesia in infants, whose immature respiratory and cardiovascular systems are sensitive to the depressant effects of anaesthetic agents.
In general the long-acting neuromuscular blocking agents are unsuitable for day case procedures. Accordingly, the aim of this article is to review the pharmacology and clinical characteristics of the short- and intermediate-acting relaxants as they pertain to paediatric surgical outpatients.
Succinylcholine is the only depolarizing neuromuscular blocking drug in clinical practice. Until the early 1990s, it was the unrivalled drug for facilitating tracheal intubation in paediatric surgical outpatients due to its rapid onset and ultra-short duration of action (clinical duration ≤8 min). This was despite numerous problems associated with its use including dysrhythmias, hyperkalaemia, muscle pains (although less severe than in adults), malignant hyperthermia, masseter spasm and prolonged neuromuscular block in patients with plasma cholinesterase deficiency. As a result of reports of hyperkalaemic cardiac arrests in children with undiagnosed Duchenne muscular dystrophy , the US Food and Drug Administration (FDA) recommended that the use of succinylcholine in children should be reserved for emergency intubation or instances where immediate securing of the airway was necessary. Although the recommendations of the FDA were initially resisted by paediatric anaesthetists, there are signs that the use of succinylcholine in paediatric anaesthesia is diminishing. While 84% of anaesthetists used succinylcholine routinely in children in a survey in 1996, only 45% were using it in 1999 for procedures such as tonsillectomy [5,6]. A decrease in the use of succinylcholine should reduce the incidence of side-effects and diagnostic problems associated with its use.
Notwithstanding the justifiable decrease in its clinical use, succinylcholine remains the gold standard for intubation of the trachea; a dose of 2 mg kg−1 provides excellent conditions for tracheal intubation in infants and children within 1 min. Onset of maximum block occurs in ≈30 s followed by recovery to 90% control twitch height in 7–10 min (Table 2). Succinylcholine is also effective intramuscularly, which can be particularly valuable if laryngospasm occurs during inhalational induction of anaesthesia in a child. In such circumstances, succinylcholine 4–5 mg kg−1 injected into the deltoid muscle relieves laryngospasm within 60 s and the block resolves in ≈20 min .
Mivacurium is a short-acting nondepolarizing muscle relaxant with a bis-quaternary benzylquinolinium diester structure resembling that of atracurium. It is hydrolysed by plasma cholinesterase into three pharmacologically inactive compounds at a rate in vitro which is 70–90% that of succinylcholine . The half-time of elimination of mivacurium (2.6 min) appears to be intermediate between that of succinylcholine and atracurium (1.8 and 19.1 min, respectively) and is consistent with its short duration of action .
A dose of 0.2 mg kg−1 (2 × ED95) of mivacurium produces satisfactory intubating conditions in children at 90 s . Onset of maximum block occurs in infants and children in less than 2 min, followed by recovery to 25 and 95% control twitch height at 8–11 min and 14–18 min, respectively (Table 2). Complete recovery from mivacurium-induced block is so rapid that pharmacological reversal is frequently unnecessary.
Continuous intravenous infusion of mivacurium can be given safely to adults and children without cumulative effects. Maintenance infusion doses in infants and children at 14–16 µg kg−1 min−1 are somewhat greater than twice the adult dose of ≈6.0 µg kg−1 min−1 [11,12]. These differences may reflect a greater plasma clearance of mivacurium in paediatric patients compared with adults.
Because mivacurium is hydrolysed by plasma cholinesterase, a deficiency in this enzyme may result in prolonged block . In the mild form of this disorder, which affects one in 25 of the population, mivacurium-induced block is prolonged by about 50%, but in view of the short duration of action of mivacurium, this is unlikely to be a clinical problem. In the more severe form, which affects about 1 in 2500 of the population, the block may last from 2 to 4 h, requiring treatment by controlled ventilation with continuing anaesthesia or sedation. Once recovery has commenced, as shown by a response to peripheral nerve stimulation, it may be hastened by administering an anticholinesterase drug . The inconvenience caused by unexpected and prolonged neuromuscular block in a patient given mivacurium would be maximized in a busy day case surgery centre in which there were no facilities for postoperative ventilation of the lungs.
Mivacurium has significant histamine-releasing properties which may be minimized by avoiding high doses and administering bolus doses slowly. In infants and children, a dose of 0.2 mg kg−1 of mivacurium produces a small (<10%) decrease in arterial pressure accompanied by a similarly small increase in heart rate . Cutaneous flushing may also be observed at this dose.
Atracurium is a bis-quaternary benzylquinolinium diester, which was designed to undergo spontaneous degradation at body pH and temperature by a process known as Hofmann elimination, which produces the metabolite laudanosine. Laudanosine lacks significant neuromuscular effects, although it has been reported to produce central nervous system excitation in high doses in animals. Once recovery from atracurium has begun, the rate of recovery appears to be independent of the dose or duration of administration. Little or no cumulative effect is seen with repeated doses . Predictable recovery in patients of all ages is a major benefit of atracurium and mivacurium when used in paediatric anaesthesia.
Ved and his colleagues showed that a 0.25 mg kg−1 dose of atracurium produced 80% depression of twitch height in 2.2 min, which was associated with good or excellent intubating conditions in children anaesthetized with halothane . This dose had a clinical duration of 23.5 min and recovery to 95% of control twitch height in 42.1 min. Thus, low-dose atracurium may be an alternative to mivacurium for children undergoing ambulatory procedures of short duration provided pharmacological reversal is not contraindicated. Atracurium 0.5 mg kg−1 (≈2 × ED95) produces satisfactory intubating conditions within 90 s in infants and children with maximum block and recovery of twitch to 25% of control occurring in 1–1.5 and 27–36 min, respectively (Table 2) .
The adverse effects associated with atracurium relate mainly to histamine release. This commonly results in a localized or general erythaema occasionally accompanied by hypotension, tachycardia or bronchospasm. The cardiovascular changes are dose-related and usually occur at doses greater than 2 × ED95.
Cisatracurium is the R-cis, R-cis isomer of atracurium, and one of 10 stereoisomers that make up the commercially available atracurium mixture. It is approximately six times as potent as atracurium in children during halothane anaesthesia . Cisatracurium undergoes spontaneous degradation by Hofmann elimination, but producing much smaller amounts of laudanosine compared with atracurium.
In children anaesthetized with halothane, a dose of 0.15 mg kg−1 of cisatracurium (3 × ED95) produces satisfactory intubating conditions in over 95% of infants and children at 2 min . Maximum block (100%) occurs in 2–3 min, followed by recovery to 25% control twitch height in 36 min in children and 43 min in infants (Table 2) . Lack of significant histamine release is the major advantage of cisatracurium compared with atracurium. However, its slower onset and longer, less predictable duration of action suggest that cisatracurium may be less suitable than atracurium for paediatric day case patients.
Vecuronium — a monoquaternary derivative of pancuronium — is a compound with a greater selectivity of effect and a shorter duration of action. Administration of vecuronium in a dose of 0.04 mg kg−1 (≈1 × ED95) to children aged 2–10 years during isoflurane anaesthesia produces at least 95% depression of twitch in 2.6 min with initial recovery taking place in just over 8 min . Intubation conditions at this time are satisfactory in over 96% of patients. Therefore, when used in combination with pharmacological reversal, low-dose vecuronium can be used in paediatric surgery of short duration.
A 0.1-mg kg−1 dose of vecuronium administered to children during thiopental or halothane anaesthesia produces excellent or good intubating conditions in over 90% of children at 90 s, with an onset time of 1–3 min and a clinical duration of 20–30 min (Table 2) . By contrast, the block after the same dose of vecuronium lasts for almost an hour in neonates and infants . Therefore, vecuronium can be considered to be a long-acting NMBA in neonates and infants. The prolonged duration of vecuronium in neonates and infants is probably due to a larger volume of distribution (reflecting a larger ECF volume) with no difference in plasma clearance . Vecuronium is well known for its lack of significant cardiovascular and histamine-releasing properties in both paediatric and adult patients.
Rocuronium is a monoquaternary steroidal muscle relaxant structurally related to vecuronium. The drug is characterized by a rapid onset and intermediate duration of action; rapid onset is believed to be due to its low potency . The administration of rocuronium 0.45 mg kg−1 (1.5 × ED95) during halothane anaesthesia has been shown to produce satisfactory intubating conditions in 85% of children when the train-of-four ratio was depressed to 0.25 ; this dose resulted in a clinical duration of 26 min in those who attained a block of 95% or more. Satisfactory intubating conditions at 2 min have also been reported with a dose of 0.3 mg kg−1 (1 × ED95) in children aged 2–7 years anaesthetized with 1 × Minimal alveolar concentration (MAC) of end-tidal sevoflurane with complete neuromuscular recovery in 27 min . Thus, low-dose rocuronium could be useful for surgery of short duration in paediatric patients.
A dose of 0.6 mg kg−1 produces satisfactory intubating conditions in infants and children within 60 s [28,29]. Onset of maximum block occurs in 60–90 s, followed by recovery to 25% control twitch height in 27 min in children and 42 min in infants (Table 2). These results suggest that rocuronium may be longer acting in infants, but the effect is less marked than with vecuronium and the drug retains the characteristics of an intermediate-acting muscle relaxant in these patients. Doses of 1–2 × ED95 of rocuronium in infants and children produce a small and clinically insignificant increase in heart rate with no change in blood pressure.
Rapacuronium, is a monoquaternary aminosteroidal muscle relaxant characterized by a rapid onset and a short duration of action, suggesting a possible use in paediatric day case surgery . It is metabolized in the liver primarily to a 3-hydroxy metabolite (Org 9488), which itself is a neuromuscular blocking drug, having twice the potency of rapacuronium (biophase EC50 0.4 × rapacuronium) and an intermediate to long duration of action . Excretion of rapacuronium and its metabolites is organ dependent and there is some evidence of cumulation of Org 9488 after repeated doses or an infusion .
Following anaesthesia with thiopental and fentanyl, the minimum doses of rapacuronium for satisfactory intubation conditions at 60 s were 1.5 and 2.0 mg kg−1, respectively (≈2–3 × ED95) in infants and children [33,34]. A dose of 2 mg kg−1 produces maximum block in 1.5–2.0 min followed by recovery of T 1 to 25% and 90% in 14–19 and 23–41 min, respectively, in infants and children (Table 2) . Recovery from rapacuronium-induced block is age dependent and slower than that produced by mivacurium [30,33]. The neuromuscular effects of rapacuronium are readily reversed by neostigmine, which is effective even when the block is intense .
The main side-effects of rapacuronium are cardiovascular and pulmonary. The cardiovascular effects consist of a small increase in heart rate, which, in adults, is accompanied by a small reduction in blood pressure [36,37]. In adults, the pulmonary side-effects, bronchospasm and increased airway pressure, are more common in patients with bronchial hyperreactivity and/or undergoing a rapid sequence induction of anaesthesia, and appear to be dose-related with a frequency of greater than 10% with a dose of 2.5 mg kg−1 . These are frequently severe in infants and children, albeit short-lived and self-limiting . In March 2001, rapacuronium was voluntarily withdrawn for modification of the prescribing information by Organon from the US market, following further reports of severe bronchospasm including some fatalities [38–41].
The development of neuromuscular blocking drugs characterized by short and intermediate duration of action has facilitated the growth of day surgery in children. Succinylcholine has the advantages of rapid onset and short duration of action. Although there are still situations where succinylcholine may still be the safest option (e.g. rapid sequence induction, possible difficult airway), its routine use should be avoided due to its many side-effects.
Mivacurium and atracurium have a predictable recovery in all age groups when used in paediatric patients, although prolonged block can occur after mivacurium in patients with cholinesterase deficiency; both can also release histamine. Cisatracurium is devoid of histamine-releasing properties effects, but is slower acting, requiring larger doses for facilitating tracheal intubation, with a consequent longer duration of action. Vecuronium has minimum cardiovascular or histamine-releasing effects, but is longer acting in infants. Rocuronium has an onset time similar to that of succinylcholine and an intermediate duration of action in both infants and children. Rapacuronium is a new aminosteroidal muscle relaxant characterized by a rapid onset and short duration of action. This potentially useful drug in paediatric day case surgery was recently withdrawn from the US market due to its possible association with severe bronchospasm.
1 Brennan LJ. Modern day case anaesthesia
for children. Br J Anaesth
1999; 83: 91–103.
2 Apfelbaum JL. Muscle relaxants for outpatient surgery: old and new. J Clin Anesth
1992; 4: 2S–8S.
3 Baxter MRN, Bevan JC, Samuel J, Donati F, Bevan DR. Postoperative neuromuscular function in pediatric day-care patients. Anesth Analg
1991; 72: 504–508.
4 Rosenberg H, Gronert GA. Intractable cardiac arrest in children given succinylcholine
1992; 77: 1054.
5 Robinson AL, Jerwood DC, Stokes MA. Routine suxamethonium in children. Anaesthesia
1996; 51: 874–878.
6 Hatcher IS, Stack CG. Postal survey of the anaesthetic techniques used for paediatric tonsillectomy surgery. Paed Anaesth
1999; 9: 311–315.
7 Liu LMP, DeCook TH, Goudsouzian NG, Ryan JF, Liu PL. Dose response to intramuscular succinylcholine
in children. Anesthesiology
1981; 55: 599–602.
8 Cook DR, Stiller RL, Weakly JN, Chakravorti A, Brandom BW, Welch RM. In vitro
metabolism of mivacurium
chloride (BW B1090U) and succinylcholine
. Anesth Analg
1989; 68: 452–456.
9 Sarner JB, Brandom BW, Woelfel SK et al.
Clinical pharmacology of mivacurium
chloride (BW B1090U) in children during nitrous oxide-halothane and nitrous oxide-narcotic anesthesia. Anesth Analg
1989; 68: 116–121.
10 McCluskey A, Meakin G. Dose–response and minimum time to satisfactory intubation conditions after mivacurium
in children. Anaesthesia
1996; 51: 438–441.
11 Meretoja OA, Olkkola KT. Pharmacodynamics of mivacurium
in children using a computer-controlled infusion. Br J Anaesth
1993; 71: 232–237.
12 Meretoja OA, Taivainen T, Wirtavuori K. Pharmacodynamics of mivacurium
in infants. Br J Anaesth
1994; 73: 490–493.
13 Maddenini VR, Mirakhur RK. Prolonged neuromuscular block following mivacurium
1993; 78: 1181–1184.
14 Woefel SK, Brandom BW, McGowan FX, Cook DR. Clinical pharmacology of mivacurium
in pediatric patients less than two years old during nitrous oxide-halothane anesthesia. Anesth Analg
1993; 77: 713–720.
15 Basta SJ, Ali HH, Savarese JJ et al.
Clinical Pharmacology of atracurium
besylate (BW 33A): a new non-depolarizing muscle relaxant. Anesth Analg
1982; 61: 723–729.
16 Ved SA, Chen J, Reed M, Fleming N. Intubation with low-dose atracurium
in children. Anesth Analg
1989; 68: 609–613.
17 Meakin GH, Shaw EA, Baker RD, Morris P. Comparison of atracurium
-induced neuromuscular blockade in neonates, infants and children. Br J Anaesth
1988; 60: 171–175.
18 Meretoja OA, Taivainen T, Wirtavuori K. Pharmacodynamic effects of 51W89, an isomer of atracurium
, in children during halothane anaesthesia
. Br J Anaesth
1995; 74: 6–11.
19 Waite I, Meakin G, Meretoja OA et al.
Endotracheal intubating conditions following cisatracurium
in infants and children. Br J Anaesth
1998; 80: 139–140.
20 Taivainen T, Meakin GH, Meretoja OA et al.
The safety and efficacy of cisatracurium
0.15 mg kg−1
during nitrous oxide-opioid anaesthesia
in infants and children. Anaesthesia
2000; 55: 1047–1051.
21 Frediani M, Capanna M, Casini L, Lorenzetti MG, Bianchini G, Pacini P. The use of low doses of intermediate acting muscle relaxants in adenotonsillectomy. Minerva Anestesiol
1993; 59: 109–114.
22 Kalli I, Meretoja OA. Duration of action of vecuronium
in infants and children anaesthetized without potent inhalation agents. Acta Anaesthesiol Scand
1989; 33: 29–33.
23 Meretoja OA. Is vecuronium
a long-acting neuromuscular blocking agent in neonates and infants? Br J Anaesth
1989; 62: 184–187.
24 Fisher DM, Castagnoli BA, Miller RD. Vecuronium
kinetics and dynamics in anesthetized infants and children. Clin Pharmacol Ther
1985; 37: 402–406.
25 Bowman WC, Rodger IW, Houston J, Marshall RJ, McIndewar I. Structure: action relationships among some desacetoxy analogues of pancuronium and vecuronium
in the anesthetized cat. Anesthesiology
1988; 69: 57–62.
26 Ross AK, Dear GL, Dear RB, Margolis JO, Ginsberg B. Onset and recovery of neuromuscular blockade after two doses of rocuronium
in children. J Clin Anesth
1998; 10: 631–635.
27 Eikermann M, Peters J. Low dose rocuronium
optimizes both intubating conditions and time-course of action during anesthesia with sevoflurane in children. Anesthesiology
1999; 91 (Suppl. 1): A1275.
28 Woefel SK, Brandon BW, Cook DR, Sarner JB. Effects of bolus administration of ORG-9426 in children during nitrous oxide-halothane anesthesia. Anesthesiology
1992; 76: 939–942.
29 Woelfel SK, Brandon BW, McGowan FX, Gronert BJ, Cook DR. Neuromuscular effects of 600 mg kg−1
in infants during nitrous oxide-halothane anaesthesia
. Paed Anaesth
1994; 4: 173–177.
30 Brandom BW, Margolis JO, Bikhazi GB et al.
Neuromuscular effects of rapacuronium
in pediatric patients during nitrous oxide-halothane anesthesia: comparison with mivacurium
. Can Anaesth Soc J
2000; 47: 143–149.
31 Schiere S, Proost JH, Schuringa M, Wierda JM. Pharmacokinetics and pharmacokinetic-dynamic relationship between rapacuronium
(Org 9487) and its 3-desacetyl metabolite (Org 9488). Anesth Analg
1999; 88: 640–670.
32 van den Broek L, Wierda JMKH, Smeulers NJ, Proost JH. Pharmacodynamics and pharmacokinetics of an infusion of Org 9487, a new short-acting steroidal neuromuscular blocking agent. Br J Anaesth
1994; 73: 331–335.
33 Meakin GH, Meretoja OA, Motsch J et al.
A dose-ranging study of rapacuronium
in pediatric patients. Anesthesiology
2000; 92: 1002–1009.
34 Kaplan RF, Fletcher JE, Hannallah RS et al.
The potency (ED50
) and cardiovascular effects of rapacuronium
(Org 9487) during narcotic nitrous oxide-propofol anesthesia neonates, infants and children. Anesth Analg
1999; 89: 1172–1176.
35 Purdy R, Bevan DR, Donati FL, Ichtor JL. Early reversal of rapacuronium
with neostigmine. Anesthesiology
1999; 91: 51–57.
36 Brandom BW, Bikhazi G, Ginsberg B et al.
Org 9487 or mivacurium
in children anaesthetized with nitrous oxide-halothane. Eur J Anaesthesiol
1997; 14: 34–35.
37 Blobner M, Mirakhur RK, Wierda JMKH et al. Rapacuronium
2.0 or 2.5 mg kg−1
for rapid sequence induction: comparison with succinylcholine
1.0 mg kg−1
. Br J Anaesth
2000; 85: 724–731.
38 Meakin GH, Pronske EH, Lerman J et al.
Bronchospasm after rapacuronium
in infants and children. Anesthesiology
2001; 94: 926–927.
39 Goudsouzian NG. Rapacuronium
and bronchospasm. Anesthesiology
2001; 94: 727–728.
40 Kron SS. Severe bronchospasm and desaturation in a child associated with rapacuronium
2001; 94: 923–924.
41 Naguib M. How serious is the bronchospasm induced by rapacuronium
2001; 94: 924–925.