C. E. SMITH, J. M. SADDLER, J. C. BEVAN, F. DONATI. AND D. R. BEVAN. SUMMARY. We have ..... Scott RPF, Norman J. Effect of suxamethonium given.
British Journal of Anaesthesia 1990; 64: 577-581
PRETREATMENT WITH NON-DEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS AND SUXAMETHONIUM-INDUCED INCREASES IN RESTING JAW TENSION IN CHILDREN C. E. SMITH, J. M. SADDLER, J. C. BEVAN, F. DONATI AND D. R. BEVAN
SUMMARY We have studied the effect of prior administration of non-depolarizing neuromuscular blocking drugs on suxamethonium-induced increases in masseter muscle tension in 21 children aged 3-10 yr, anaesthetized with nitrous oxide and halothane using supramaximal stimulation of the ulnar nerve and the nerve to masseter. Resting tension and isometric force of contraction were measured in the adductor pollicis and masseter muscles. A sub-paralysing dose of tubocurarine 0.05 mg kg'1, a paralysing dose of atracurium 0.5 mg kg'1 or saline was given, followed 3 min later by suxamethonium 1 mg kg'1. Onset times of suxamethonium and atracurium block were shorter in the masseter than in the adductor pollicis muscle. When preceded by a subparalysing dose of tubocurarine. suxamethonium produced an increase in masseter tension (47 (SEM 15) g) similar to that produced by suxamethonium alone (59 (13) g). Prior administration of a paralysing dose of atracurium almost abolished this increase in tension (2.5 (2.5) g) (P < 0.05 vs saline). The tension increase in adductor pollicis was 0. 3.2 (2.2) and 5.9(1.1) g in the atracurium. tubocurarine and saline groups. respectively. Tubocurarine and atracurium prevented muscle fasciculations in all patients. It was concluded that increased muscle tone is a normal response to suxamethonium and is greater in the masseter than adductor pollicis. Sub-paralysing doses ofnon- depolarizing neuromuscular blockers have little effect, in contrast with paralysing doses. This suggests that the effect is mediated via postsynaptic receptors.
KEY WORDS Complications: masseter spasm. Neuromuscular relaxants: atracurium, suxamethonium. tubocurarine, drug interactions.
The administration of suxamethonium may be associated with masseter muscle rigidity [1], the incidence of which was reported to be 1 % of normal children [2]. Muscle biopsy studies indicate susceptibility to malignant hyperthermia (MH) in 40-60% of these patients [3,4]. Recently, suxamethonium has been reported to cause increased jaw muscle tension in a large proportion of adults [5] and children [6] and reduced mouth opening and increased jaw stiffness in children [7, 8]. The mechanism of action of this phenomenon is unknown. Theoretically, the site could be at the presynaptic receptor, the postsynaptic receptor or the muscle itself. Pretreatment with a nondepolarizing neuromuscular blocker may help in identifying the site of action. When sub-para-
CHARLES E. SMITH*, M.D., F.R.C.P.C. ; JOHN M. SADDLER-)-, M.B., F.F.A.R.C.S.; JOAN C . BEVANF, M.D., D.R.C.O.G., F.F.A.R.C.S. ; FRANCOIS DONATIJ, PH.D., M.D., F.R.C.P.C. ; DAVID R. BEVANJ, M.B., M.R.C.P., F.F.A.R.C.S.; Departments of An-
aesthesia, Montreal Children's Hospital and Royal Victoria Hospital, McGill University, Montreal, Quebec, Canada. Accepted for Publication: November 3, 1989. Present addresses: •Department of Cardiothoracic Anaesthesia, Cleveland Clinic Foundation, Cleveland, Ohio, U.S.A. tDepartment of Anaesthesia, Montreal Children's Hospital, 2300 Tupper Street, Montreal, Quebec, Canada. tMcGill Department of Anaesthesia, Royal Victoria Hospital, 687 Pine Avenue West, Montreal, Quebec, Canada H3A 1A1. Correspondence to D.R.B.
BRITISH JOURNAL OF ANAESTHESIA
578
lysing doses of such agents are used, their prevention of suxamethonium- induced fasciculations is most probably presynaptic in origin [9-11]. Much larger doses of non-depolarizing neuromuscular blocker are required to produce a measurable effect at postsynaptic receptors. This study was undertaken to examine the interactions between suxamethonium and subparalysing and paralysing doses of nondepolarizing blocker, with emphasis on increases in masseter tension. The investigation was conducted in children aged 3-10 yr, a group of patients in whom this effect has been recognized as a normal response to suxamethonium [6]. PATIENTS AND METHODS
We studied 21 children, ASA physical status I, aged 3—10 yr, undergoing elective day-care surgery. Institutional approval and informed parental consent were obtained. Patients with neuromuscular, renal, hepatic or electrolyte disorders, or those taking medications known or thought to interfere with neuromuscular transmission were excluded. Patients with evidence of trigeminal nerve dysfunction, abnormal dentition or mandibular configuration were excluded from the study, as were patients with a history of atypical plasma cholinesterase, masseter rigidity or malignant hyperthermia. No premedicatdon was given. Monitoring included automatic oscillotonometry, electrocardiography, a precordial stethoscope and an oesophageal temperature probe. Anaesthesia was induced with halothane and 66% nitrous oxide in oxygen, or thiopentone 5—7 mg kg"1 i.v. Atropine 0.01 mg kg"1 i.v. was administered, and tracheal intubation was performed under deep halothane anaesthesia without the use of myoneural blockers. Supramaximal train-of-four stimulation was applied to the ulnar nerve at the elbow and to the mandibular branch of the trigeminal nerve inferior to the zygomatic arch, anterior to the mandibular condyle, as described previously [12]. Stimulation of the ulnar nerve resulted in adductor pollicis contraction which was measured with a Grass F-10 force displacement transducer and recorded on paper. Stimulation of the trigeminal nerve resulted in masseter contraction and jaw closure which was measured by a force transducer system attached to both an oral airway and a metal frame fixed to the operating table 10 cm caudad to the chin. Supramaximal train-of-
four stimulation of the nerve to masseter was assured by progressively increasing the voltage until the jaw response had stabilized. The voltage was then set 15% greater than this value. After stabilization of adductor pollicis and masseter muscle twitch, seven patients in each group received, by random allocation, a sub-paralysing dose of tubocurarine (0.05 mg kg"1), a paralysing dose of atracurium (0.5 mg kg"1), or saline, followed 3 min later by suxamethonium l.Omgkg"1. The time to onset, maximum effect and duration of suxamethoniuminduced changes in masseter and adductor pollicis tensions were measured and compared using Student's t test with Bonferroni correction where applicable. Similarly, the time from injection of suxamethonium to 100% neuromuscular block and 100% recovery were measured at both muscles in the tubocurarine and saline groups. Time from injection of atracurium to 100 % block was measured also. At the end of the study, both adductor pollicis and masseter force transducers were calibrated with known weights. Thus the magnitude of the imposed baseline tension, baseline tension change and control contraction could be determined for both muscles. Results are expressed as mean (SEM). Muscle fasciculations were graded as absent, fine or moderate to vigorous. P < 0.05 was considered to indicate a statistically significant difference. RESULTS
The groups were similar with respect to sex, age, weight and height (table I). There were no differences in resting and control twitch tensions between the three groups for each muscle (table II). There was no change in twitch height following tubocurarine or saline. All patients had complete neuromuscular block of both muscles within 1 min following suxamethonium (table III) and within 2 min after atracurium. The onset of neuromuscular block was faster at the masseter than at the adductor pollicis. For atracurium, the time to 100% T l TABLE
Sex (M/F) Age (months) Weight (kg) Height (cm)
I. Patient data (mean (SEM)) Saline
Tubocurarine
Atracurium
6/1 72(7) 22(2) 120 (6)
4/3 70(8) 23(4) 114(6)
5/2 61(8) 20(2) 110 (4)
NMB DRUGS AND SUXAMETHONIUM-INDUCED FASCICULATIONS
579
TABLE II. Resting muscle tension and control twitch height (mean (SEM))
Adductor Resting Control Masseter Resting Control
Saline (g)
Tubocurarine
pollicis tension twitch height
18(2) 114(14)
30(7) 93(6)
34(9) 85 (12)
tension twitch height
102 (26) 455 (56)
154 (27) 317(47)
147(17) 377 (44)
Atracurium (g)
0.61 (0.07) 4.8 (0.3)
0.69(0.11) 4.9 (0.06)
the masseter compared with adductor pollicis. However, only one patient pretreated with a paralysing dose of atracurium demonstrated a detectable increase in masseter tension, and none of these patients had any change in adductor pollicis tension (table IV). Five patients, all in the saline group, had muscle fasciculations (two, fine tremor; three, moderate contractions).
0.44 (0.07)* 4.8 (0.3)
0.44(0.10)* 5.3 (0.8)
DISCUSSION
TABLE III. Time to 100% depression and recovery of the first twitch of TOF stimulation after suxamethonium (mean (SEM)). * P < 0.05 vs adductor pollicis muscle Saline (min) Adductor pollicis Onset Recovery Masseter Onset Recovery
(g)
Tubocurarine (min)
depression was 1.0 (0.2) vs 1.6 (0.3) min for masseter and adductor pollicis, respectively (P < 0.05). For suxamethonium, onset times are shown in table III. Suxamethonium did not alter the magnitude of the block in patients who received atracurium. Recovery times after suxamethonium were similar in both muscles. Tubocurarine pretreatrnent did not affect either onset or recovery times (table III). All patients in the tubocurarine- and salinetreated groups exhibited increases in masseter and adductor pollicis tension after suxamethonium. The magnitude and time course of these changes were similar. Maximum resting changes occurred during maximal twitch depression. The increase in tension was approximately 10 times as great in
The present study demonstrated that, although a sub-paralysing dose of tubocurarine was effective in preventing suxamethonium-induced fasciculations, it was ineffective in reducing changes in baseline muscle tension. However, the changes in masseter and adductor pollicis tension caused by suxamethonium were abolished by a paralysing dose of atracurium. The maximum increase in masseter muscle tone occurred at a time when block of neuromuscular transmission had commenced or was completed. The differences observed between patients pretreated with tubocurarine and atracurium may have been drug induced, but are more likely to have been the result of different doses. Tubocurarine was chosen because it is commonly used clinically to prevent fasciculations. The dose used in this study, 0.05 mg kg"1, equivalent to about 10% of the ED,j [13], produces no detectable
TABLE IV. Increases in resting muscle tension after suxamethonium (mean (SEM)). P < 0.05 vs masseter muscle; \ P < 0.05 vs saline and tubocurarine groups Saline Adductor pollicis Maximal increase (g) Time to onset (min) Duration (min) Masseter Maximal increase (g) Time to onset (min) Duration (min)
Tubocurarine
Atracurium
5.9 (1.1)* 0.29 (0.04) 1.10(0.12)
3.2 (2.2)* 0.25 (0.03) 0.72 (0.25)
0 — —
59 (13) 0.26(0.05) 1.70(0.67)
47(15) 0.25 (0.07) 1.70(0.70)
2.5(2.5)t — —
580
neuromuscular block but helps in preventing fasriculations [14-18]. None of the patients in this study demonstrated neuromuscular block after administration of this dose. Atracurium was chosen in the group which received a paralysing dose of non-depolarizing myoneural blocker because the cardiovascular effects and prolonged duration of action of an equipotent dose of tubocurarine would be clinically unacceptable. The dose of atracurium was approximately twice the ED86 [13] and was probably sufficient to block more than 96% of receptors, while a subparalysing dose of tubocurarine would have blocked fewer than 70% of receptors [19]. Thus the present study indicated that block of the postsynaptic receptors was effective in preventing tension increases produced by suxamethonium. However, a large proportion of receptors must be occupied before the effect is abolished, suggesting that only a few receptors are needed for suxamethonium-induced tension changes. The ineffectiveness of sub-paralysing doses of tubocurarine in preventing tension increases suggests that this effect of suxamethonium is not presynaptic. In animals, only small doses of tubocurarine or vecuronium are required to abolish presynaptic activity [9-11] and fasciculations [9]. Similarly, the changes in muscle tension associated with suxamethonium are unlikely to be the effect of a direct action of suxamethonium on muscle, as a drug which acts at the neuromuscular junction effectively blocks this response. However, it was not possible to determine if the postsynaptic receptors involved are junctional or extrajunctional. The present study supports the contention that increases in muscle tension are a normal response to suxamethonium in both children and adults [5-8]. It also suggests that the masseter is not qualitatively different from other muscles. Changes in tension were found also in the adductor pollicis, supporting previous work [6]. Interestingly, the time course of changes observed after suxamethonium in this study were similar to, although quantitatively less than, those observed previously in patients with myotonia [20]. This suggests that treatment of a myotonic response or masseter muscle rigidity following suxamethonium could perhaps be accomplished by large doses of non-depolarizing blocking drugs. Such abnormal responses may be considered as an exaggerated form of the normal pharmacological effect of suxamethonium [6-8].
BRITISH JOURNAL OF ANAESTHESIA The onset of neuromuscular block was more rapid at the masseter than at the adductor pollicis, and this was demonstrated for both suxamethonium and atracurium. Part of this difference might be explained by the greater potency of suxamethonium at the masseter than at the adductor pollicis muscle [6]. However, differences in circulation time and blood flow between the muscles probably explain most of the difference. Pretreatment with tubocurarine did not prolong the onset time or shorten its duration of action, as could have been expected from adult studies [14, 16, 17]. The possibility that children might be different in this regard should be considered. Suxamethonium did not antagonize the nondepolarizing block produced by atracurium. Such antagonism has been described previously for non-depolarizing block in the range 50-100% [21-23]. In the present study, however, the block produced by atracurium was probably too intense to be antagonized. This study was performed in patients without evidence of malignant hyperthermia, and extrapolation of these results to responses seen after suxamethonium in that condition may be inappropriate. However, if masseter spasm is an exaggerated form of the normal pharmacological response to suxamethonium, pretreatment with a defasciculating dose of non-depolarizing neuromuscular blocker is unlikely to affect the clinical course. If masseter rigidity is encountered, administration of paralysing doses of nondepolarizing blockers may decrease the response, but this possibility has not been tested independently. Furthermore, this solution might be impossible to apply in clinical practice. Masseter spasm is associated usually with inability to secure the airway. In this case, adminstration of a drug which causes prolonged neuromuscular block is not recommended. REFERENCES 1. Donlon JV, Newfield P, Streter I, Ryan JF. Implications of masseter spasm after succinylcholine. Anesthesiology 1978; 49: 298-301. 2. Schwartz L, Rockoff MA, Koka BV. Masseter spasm with anesthesia: Incidence and implications. Anesthesiology 1984; 61: 772-775. 3. Rosenberg H, Fletcher JE. Masseter muscle rigidity and malignant hyperthermia susceptibility. Anesthesia and Analgesia 1986; 65: 161-164. 4. Rosenberg H, Reed S. In vitro contracture tests for susceptibility to malignant hyperthermia. Anesthesia and Analgesia 1983; 62: 415-420.
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