Succinylcholine, despite its many side effects, has been used for more than 50 yr as the standard neuromuscular blocking drug (NMBD) to facilitate tracheal intubation. Its popularity reflects the lack of viable alternatives with rapid onset and short duration. The purpose of this article is to review the important unwanted effects of succinylcholine and to describe the drugs and techniques that modified the action of existing nondepolarizing NMBDs to resemble succinylcholine. The new aminosteroid muscle relaxant, rapacuronium, will be introduced as the first nondepolarizing muscle relaxant with both rapid onset and short duration.
For elective procedures, succinylcholine should be avoided, particularly in infants and children. Rapacuronium appears to have ideal properties when a drug is required only either to facilitate tracheal intubation or for short surgical procedures. Although rapacuronium has been approved by the Food and Drug Administration for use for the induction of anesthesia and rapid sequence endotracheal intubation, further clinical experience is necessary before rapacuronium can be confirmed to provide ideal intubating conditions as a component of rapid sequence induction of anesthesia techniques to avoid the risk of aspiration of gastric contents in patients of various ages with so-called full stomachs.
Features of Succinylcholine
Succinylcholine, a rapid onset, short-duration depolarizing NMBD was introduced into clinical practice 50 yr ago. It proved to be useful when given as a bolus or an infusion to facilitate tracheal intubation, control of ventilation, and surgical muscle relaxation for short or long surgeries. Succinylcholine rapidly produces a more profound effect at the vocal cords than at the adductor pollicis muscle, which generally provides excellent intubating conditions and has rapid recovery from neuromuscular block. In addition, it can be used in relatively small doses to treat intractable laryngospasm and is effective in infants and small children when given IM. When allowance is made for differences in volumes of distribution and for type and concentration of anesthesia, infants and small children appear relatively resistant to succinylcholine, which has a faster clearance, and a longer onset time in adults.
Nonneuromuscular Blocking Effects
Succinylcholine can have a profound cardiovascular effect; can increase intraocular, intragastric, and intracranial pressure; and can be associated with hyperkalemia, myoglobinemia, and malignant hyperthermia.
Succinylcholine exerts variable and paradoxical effects on the cardiovascular system. Given IV, succinylcholine produces initial bradycardia and hypotension, followed after 15–30 s by tachycardia and hypertension. In the infant and small child, profound sustained sinus bradycardia (50–60 bpm) is often observed (1); rarely asystole occurs. Nodal rhythm and ventricular ectopic beats are seen in approximately 80% of children given a single IV injection of succinylcholine; such dysrhythmias are rarely seen after IM injection. In adults and in children, the incidence of bradycardias and other dysrhythmias are more frequent after a second dose of succinylcholine. Atropine offers protection against these bradyarrhythmias in all age groups.
Pulmonary Edema and Hemorrhage.
We have seen several young children who developed fulminant pulmonary edema within minutes after IM succinylcholine (2). It responded to continuous positive pressure ventilation. We speculate that this may represent a hemodynamic form of pulmonary edema from acute elevation of systemic vascular resistance and an acute decrease in pulmonary vascular resistance.
Succinylcholine may increase intragastric pressure. The increase is directly related to the intensity of muscle fasciculations and, in adults, pressures as high as 40 cm H2O have been recorded. When the intragastric pressure exceeds 20 cm H2O, the cardioesophageal sphincter mechanism may become incompetent and regurgitation and aspiration may occur.
Succinylcholine increases intraocular pressure (IOP) in both children and adults (3). Although dilation of choroidal vessels is a contributory factor, the major increase in IOP is caused by contraction of extraocular muscles. The IOP begins to increase within 60 s, peaks at 2–3 min, then decreases to control in 5–7 min after succinylcholine administration. In the presence of a penetrating wound of the eye, the increased IOP can result in extrusion of vitreous and possible loss of vision. In the patient with glaucoma, there may be a falsely elevated IOP, which may lead to unnecessary surgery if tonometry is performed within 5–7 min after succinylcholine.
Hyperkalemia and Myoglobinemia.
In normal adults, succinylcholine increases plasma potassium concentration by 0.3–0.5 mmol/L (4). More modest increases are seen in children (5). Alarming levels, as high as 11 mmol/L, along with cardiovascular collapse, have been reported with succinylcholine in a variety of situations including burns, massive trauma, stroke, and spinal cord injury. Myoglobinemia and elevation of plasma creatine phosphokinase concentration are commonly seen in prepubertal children after succinylcholine even in the absence of fasciculations (6,7). However, the myoglobinemia appears to be of minimal clinical importance.
Hyperkalemic Cardiac Arrest and Occult Myopathies.
In 1992, the Malignant Hyperthermia Association of the United States and the North American Malignant Hyperthermia Registry received reports of cardiac arrest in apparently healthy children given succinylcholine (8). Many of these children were boys with undiagnosed Duchenne dystrophy or unspecified myopathy, and most of the arrests were associated hyperkalemia. The label for succinylcholine was revised in November 1993 and March 1995 to restrict the elective use of succinylcholine in children (9).
Cardiac dysrhythmias occurred abruptly at a median of 18 min and included wide complex bradycardia, ventricular tachycardia with hypotension, ventricular fibrillation, and asystole. Peaked T waves were rare although hyperkalemia was common (serum K+ 7.4 ± 2.8 mmol/L). Massive rhabdomyolysis was rare.
Malignant Hyperthermia (MH) and Masseter Spasm.
The incidence of MH in patients anesthetized with volatile anesthetics and given succinylcholine has been estimated at 1:4,000 to 1:40,000. The typical patient develops profound rigidity or violent fasciculation, increase in heart rate, a rapid increase in temperature, and in increase in Petco2. Trismus is rare and it is uncertain whether isolated trismus is uniformly associated with MH, but trismus or masseter spasm accompanied by rigidity of the entire body may be associated with a high incidence of MH.
There is a high incidence of less intense masseter muscle rigidity after succinylcholine administration in children, but the clinical implications of this condition are not clear. A transient increase in jaw stiffness or in the resting tension of jaw muscles is a normal response to succinylcholine, and is more frequent in children anesthetized with halothane than with thiopental.
Alternatives to Succinylcholine
The introduction of short- (e.g., mivacurium) and intermediate-duration (e.g., atracurium, cisatracurium, vecuronium, rocuronium) muscle relaxants has minimized the need for succinylcholine in elective surgical cases, particularly when priming or timing techniques or the use of large doses or synergistic mixtures are used to accelerate the onset of action.
Mivacurium and Rocuronium
The introduction of mivacurium and rocuronium demonstrated that nondepolarizing relaxants could be of short duration (mivacurium) or of rapid onset (rocuronium).
Mivacurium , a short duration NMBD is a mixture of three optical isomers. The two active isomers (trans-trans, cis-trans) have a short half-life and rapid clearance because of enzymatic hydrolysis. The cis-cis isomer is slowly metabolized and has minimal neuromuscular blocking effects (10). The 95% effective dose (ED95) values of mivacurium during halothane anesthesia administration in infants and children are 85 and 89 μg/kg, respectively (11,12). Mivacurium is metabolized by plasma (butyryl) cholinesterase more slowly than is succinylcholine. At all ages, mivacurium produces complete neuromuscular blockade more slowly than succinylcholine, and intubating conditions are less desirable (13). Mivacurium can induce histamine release, manifested by cutaneous flushing, when large bolus doses are given rapidly. It is usually transient and associated with only mild decreases in blood pressure. Recovery of first twitch tension (T1) to 25% of control is faster in infants (6.3 min) than in children (10 min).
Rocuronium is a nondepolarizing, steroidal NMBD similar to vecuronium but with one-eighth to one-tenth the potency. The reduced potency produces a more rapid onset of paralysis (14). Bolus administration of 0.6 mg/kg (2 × ED95) is associated with a transient increase in heart rate (15) and produces complete neuromuscular blockade of the adductor pollicis in infants and children in 1.1 and 1.3 min, respectively (16). The onset time to maximal block was shorter with succinylcholine but intubating conditions were comparable (Table 1). IM rocuronium (1–1.8 mg/kg) produces complete neuromuscular block in approximately 5 min but does permit tracheal intubation in 2.5–3 min although initial recovery from these doses occurs in 1–1.5 h (17). Larger doses of rocuronium (0.9–1.2 mg/kg) have been suggested as part of a rapid sequence induction technique. The onset of block is more rapid (Table 2) although intubation conditions are not necessarily improved. Prolonged duration of neuromuscular block at these doses precludes their routine use for short duration surgical cases (18).
Priming and Timing Techniques
The priming technique refers to the administration of a small subparalyzing dose, “priming dose,” of a nondepolarizing NMBD several minutes before the “intubating dose” is given (19,20). The priming dose should be large enough to cause moderate inhibition of neuromuscular transmission (i.e., approximately 75% occupancy of end-plate receptors) but small enough not to cause unpleasant symptoms. The efficacy of this technique depends on the choice of the relaxant, the size of the priming dose (usually approximately 15%–20% of the ED95), the intubating dose (multiple of the ED95), and the interval between the two doses. Priming techniques have been described for atracurium, vecuronium, pipecuronium, pancuronium, and rocuronium (21).
The timing technique entails the administration of a single bolus of nondepolarizing NMBD before the IV induction drug, thiopental or propofol, which is given at the onset of clinical weakness or at a fixed time interval. The technique has been described with atracurium, vecuronium, and rocuronium (22,23). Ptosis with diplopia or a reduction in hand grip are the usual clinical end points of weakness. In general, the onset of neuromuscular blockade seems faster with timing techniques (60 s) than priming techniques (90 s) and with larger doses of NMBDs. Care must be used with rocuronium and thiopental in infants and small children because coadministration of these drugs can form a precipitate and lead to loss of the small IV catheter.
Interaction Between Muscle Relaxants
Synergism has been described for several combinations of nondepolarizing relaxants (pancuronium with mivacurium, atracurium with mivacurium, atracurium with vecuronium, vecuronium with mivacurium). In addition, the onset of neuromuscular blockade can be accelerated by some combinations. Onset of mivacurium was accelerated by pancuronium in children, and the recovery from mivacurium was prolonged (24). Naguib (25) also demonstrated that the onset time of mivacurium was accelerated by rocuronium. The clinical use of these observations is unclear.
Rapacuronium is the first nondepolarizing relaxant to have both rapid onset and a short duration of neuromuscular blockade. The onset time of rapacuronium at several doses has been documented in infants and children by Brandom et al. (26) and others (27, 28). At these doses, there was a transient increase in heart rate of up to 30%. No rashes or episodes of bronchospasm were noted, but bronchospasm has been reported in adults (29). The features of rapacuronium are reviewed elsewhere in this supplement.
The elective use of succinylcholine in anesthesia has largely been abandoned because of unwanted side effects. Alternatives now exist for short, intermediate, or long elective surgical procedures. NMBDs are frequently used only to facilitate tracheal intubation; rapacuronium fills an important niche particularly for a short elective case (e.g., same-day surgery). However, an equally critical issue is whether there is a reliable replacement for succinylcholine for the treatment of laryngospasm or for rapid sequence induction in patients with “full stomachs.” Succinylcholine produces more intense block in a shorter time at the laryngeal muscles, compared with the adductor pollicis, compared with vecuronium, rocuronium, mivacurium, and rapacuronium (30). Although most intubations can be facilitated with 80%–90% neuromuscular block, the ideal relaxant for a rapid sequence induction should produce uniformly complete neuromuscular blockade in 1 min. Variability in the degree of neuromuscular blockade and onset time can be compared for various relaxants by using the standard deviation (Table 1), the coefficient of variation (Table 2), or a plot of the degree of maximum neuromuscular block and the time to maximum block. Figure 1 shows such a plot for mivacurium (13). There is less variability in the maximum block at the larger dose of rapacuronium but still variability in onset time. Further studies will be important in defining the role of rapacuronium for rapid sequence induction in various clinical settings.
1. Digby-Leigh M, McLoyd D, Belton MK, et al. Bradycardia following intravenous administration of succinylcholine in anesthetized children. Anesthesiology 1957; 58:519–23.
2. Cook DR, Westman H, Rosenfeld L, et al. Pulmonary edema in infants: possible association with intramuscular succinylcholine. Anesth Analg 1981; 60:220–3.
3. Craythorne NWB, Rottenstein HS, Dripps RD. Effects of succiny1choline on intraocular pressure in adults, infants, and children during general anesthesia. Anesthesiology 1960; 21:59–65.
4. Weintraub HD, Heisterkamp DV, Cooperman LH. Changes in plasma potassium concentration after depolarizing blockers in anesthetized man. Br J Anaesth 1969; 41:1048–52.
5. Henning RD, Bush GH. Plasma potassium after halothane-suxamethonium induction in children. Anaesthesia 1982; 37:802–5.
6. Ryan JF, Kagen U, Hyman AL. Myoglobinernia after a single dose of succinylcholine. N Engl J Med 1971; 285:824–5.
7. Tammisto T, Airaksinen M. Increase of creatine kinase activity in serum as sign of muscular injury caused by intermittently administered suxamethonium during halothane anesthesia. Br J Anaesth 1966; 38:510–5.
8. Rosenberg H, Gronert GA. Intractable cardiac arrest in children given succinylcholine [letter]. Anesthesiology 1992; 77:1054.
9. Package insert: AnectineR
(succinylcholine chloride) injection, USP. Research Triangle Park, Burroughs Wellcome, 1993 and 1995
10. Cook DR, Freeman A, Lai AA, et al. Pharmacokinetics of mivacurium in normal patients and in those with hepatic or renal failure. Br J Anaesth 1992; 69:580–5.
11. Woelfel SK, Brandom BW, McGowan FX, et al. Clinical pharmacology of mivacurium in pediatric patients less than two years old during nitrous oxide halothane anesthesia. Anesth Analg 1993; 77:713–20.
12. Meretoja CA, Taivainen T, Wirtavuori K. Pharmacodynamics of mivacurium in infants. Br J Anaesth 1994; 73:490–3.
13. Brandom BW, Meretoja OA, Simhi E, et al. Age related variability in the effects of mivacurium in paediatric surgical patients. Can J Anaesth 1998; 45:410–6.
14. Kopman A. Pancuronium, gallamine, and d-tubocurarine compared: is speed of onset inversely related to drug potency? Anesthesiology 1989; 70:915–20.
15. O’Kelly B, Frossard J, Meistelman C, et al. Neuromuscular blockade following ORG 9426 in children during N2
O-halothane anesthesia [abstract]. Anesthesiology 1991; 76:A787.
16. Woelfel SK, Brandom BW, McGowan FX, et al. Neuromuscular effects of 600 mg.kg−1
of rocuronium in infants during nitrous oxide-halothane anaesthesia. Pediatr Anaesth 1994; 4:173–7.
17. Reynolds LM, Lau M, Brown R, et al. Bioavailability of intramuscular rocuronium in infants and children. Anesthesiology 1997; 87:1096–105.
18. Fuchs-Buder T, Tassonyi E. Intubating conditions and time course of rocuronium-induced neuromuscular block in children. Br J Anaesth 1996; 77:335–8.
19. Schwartz S, Ilias W, Lackner F, Mayrhofer O, Foldes FF. Rapid tracheal intubation with vecuronium: the priming principle. Anesthesiology 1985; 62:388–91.
20. Mehta MID, Choi W, Gergis SID, Sokoll MID, Adolphson A. Facilitation of rapid sequence endotracheal intubations with divided doses of nondepolarizing neuromuscular blocking drugs. Anesthesiology 1985; 62:392–5.
21. Jahangir AL, Choudhury SN, Rahman K, Hirakawa M. The effect of priming with vecuronium and rocuronium on young and elderly patients. Anesth Analg 1997; 85:663–6.
22. Culling RD, Middaugh RE, Menk EJ. Rapid tracheal intubation with vecuronium: the timing principle. J Clin Anesth 1989; 1:422–5.
23. Silverman SM, Culling RD, Middaugh RE. Rapid-sequence orotracheal intubation: a comparison of three techniques. Anesthesiology 1990; 73:244–8.
24. Brandom BW, Meretoja OA, Taivainen T, et al. Accelerated onset and delayed recovery of neuromuscular block induced by mivacurium preceded by pancuronium in children. Anesth Analg 1993; 76:998–1003.
25. Naguib M. Neuromuscular effects of rocuronium bromide and mivacurium chloride administered alone and in combination. Anesthesiology 1994; 81:388–95.
26. Brandom BW, Margolis JO, Bikhazi GB, et al. Neuromuscular effects of rapacuronium in pediatric patients during nitrous oxide-halothane anesthesia: comparison with mivacurium. Can J Anesth 2000; 47:143–9.
27. Meretoja OA, Taivainen T, Jalkanen L, et al. A fast-onset short-acting neuromuscular blocker, ORG 9487, in infants and children. Br J Anaesth 1996; 76:A304.
28. Kaplan RF, Fletcher JE, Hannallah R, et al. The ED50 of ORG 9487 in infants and children [abstract]. Anesthesiology 1996; 85:A1059.
29. Sparr HJ, Mellinghoff H, Blobner M. Comparison of intubating conditions after rapacuroniurn (Org 9487) and succinylcholine following rapid sequence induction in adult patients. Br J Anaesth 1999; 82:537–41.
30. Goulden MR, Hunter JM. Rapacuronium (Org 9487): do we have a replacement for succinylcholine? Br J Anaesth 1999; 82:489–92.
31. Stoddart PA, Mather SJ. Onset of neuromuscular blockade and intubating conditions one minute after the administration of rocuronium in children. Paediatr Anaeth 1998; 8:37–40.
© 2000 International Anesthesia Research Society
32. Woolf RL, Crawford MW, Choo SM. Dose-response of rocuronium bromide in children anesthetized with propofol: a comparison with succinylcholine. Anesthesiology 1917; 87:1368–72.