Myasthenia gravis is an autoimmune disease characterized by a decrease in the number of postjunctional acetylcholine receptors due to their destruction or inactivation by circulating antibodies. The decreased number of postsynaptic receptors results in a reduction in the ‘safety margin’ and an increased sensitivity to nondepolarizing muscle relaxants. Thus, it has been suggested to avoid muscle relaxants on the one hand, or to use short or intermediate-acting drugs in low doses guided by monitoring of neuromuscular blockade using a peripheral nerve stimulator [1,2].
Rapacuronium is a new nondepolarizing muscle relaxant with a rapid onset and short duration of action . We investigated the neuromuscular blockade of rapacuronium in two myasthenic patients undergoing trans-sternal thymectomy.
Case 1: Our first patient was a 38-year-old, 76-kg man, who presented with 2 months’ history of generalized weakness followed by diplopia, ptosis, and difficulty in mastication. The acetylcholine receptor antibody titre was 11.4 nmol L–1. The electromyogram (EMG) showed a decrement of response with repetitive stimulation. Computed tomography (CT scan) revealed an enlarged thymus. He was diagnosed to have myasthenia gravis (Osserman IIB)  and was managed with 60 mg pyridostigmine (orally three times a day) and prednisone 60 mg (orally once a day), which resulted in marked improvement of symptoms. Preoperatively, the patient had normal pulmonary function tests (FVC=3.93 L). Pyridostigmine was stopped two days before surgery, while prednisone was maintained.
Neuromuscular transmission monitoring by EMG was started before induction of anaesthesia using a Datex relaxograph monitor. The ulnar nerve was stimulated supramaximally at the wrist every 20 s and the resulting EMG response of the adductor pollicis muscle was displayed. The monitor uses the train-of-four (TOF) principle at a stimulus frequency of 2 Hz, and computes the ratio of the first twitch of TOF to the control twitch (T1/TC) as well as the ratio of the fourth twitch to the first twitch (T4/T1). After preoxygenation with 100% oxygen, anaesthesia was induced with midazolam 2 mg i.v., propofol 2 mg kg–1 and fentanyl 4 μg kg–1. Rapacuronium 0.5 mg kg–1 was then injected i.v.; when maximal neuromuscular blockade was achieved, the trachea was intubated. Anaesthesia was maintained with 70% N2O in O2, and supplemental doses of rapacuronium 0.1 mg kg–1 were required every 5 min to maintain T4/T1 ratio at 0.25. Surgery lasted 90 min, and neuromuscular blockade was antagonized with neostigmine 0.05 mg kg–1 and glycopyrrolate 0.01 mg kg–1 mixture; T4/T1 ratio of ± 0.7 was reached 10 min after ‘reversal’. The trachea was then extubated and the patient was discharged in good condition.
Case 2: This was a 41-year-old, 71-kg man who complained for six months of proximal muscle weakness, dysarthria, dysphagia, choking and diplopia. Myasthenia gravis (Osserman III) was diagonosed, confirmed by an anticholinesterase antibody titre of 8 nmol L–1 and by a chest CT scan, which showed thymic enlargement. Therapy with prednisone and pyridostigmine was commenced. Three months before surgery, the patient had developed severe dyspnoea necessitating tracheal intubation for three days. Also, azathioprin had been started and 13 sessions of plasmapheresis had been undertaken, after which the patient showed marked respiratory improvement and was scheduled for trans-sternal thymectomy. The technique of anaesthesia and monitoring of neuromuscular blockade were similar to that used in the first patient. Rapacuronium 0.5 mg kg–1 i.v. was administered initially, and incremental doses of 0.1 mg kg–1 were required every 5 min to maintain the T4/T1 ratio at 0.25. Neuromuscular blockade was antagonized at the end of surgery, which lasted 90 min, with a mixture of neostigmine 0.05 mg kg–1 and glycopyrrolate 0.01 mg kg–1; the T4/T1 ratio following ‘reversal’ was ≥ 0.9. The patient was fully awake with a good hand grip, but was unable to sustain a head lift for 5 s or to take a deep breath. The trachea was not extubated, and the patient was transferred to the recovery room and mechanical ventilation of the lungs instituted. The pyridostigmine, azathioprin and prednisone were administered via a nasogastric tube. The next day, he had one session of plasmapheresis and 7 h later, the trachea was extubated.
In nonmyasthenic patients, only 25–30% of the endplate receptors are required to maintain neuromuscular transmission. The remaining 70–75% of the receptors constitute a ‘safety margin’ . In myasthenic patients, there is a decrease in the number of functional acetylcholine receptors available with a subsequent decrease of the ‘safety margin’ . Rapacuronium is an aminosteroidal analogue of vecuronium with a low potency (ED90 (mean dose required to produce 90% neuromuscular block) is 1.15 mg kg–1), a fast onset, and a short to intermediate duration of action . In our two myasthenic patients, the administration of 0.5 mg kg–1 (1/3ED90) resulted in complete neuromuscular blockade of the adductor pollicis muscle, indicating an increased sensitivity of the myasthenic patients to rapacuronium, as compared with the nonmyasthenic patients. The clinical duration of rapacuronium (time to 25% recovery) is less than 20 min . Renal excretion amounts only to 22% of an administered dose of rapacuronium, so it is possible that its principal route of elimination may be via the liver. The main metabolite is 3-desacetyl-rapacuronium, which is approximately twice as potent as the parent drug . With continued administration of rapacuronium, the metabolite may make a proportionately greater contribution to the neuromuscular blockade and cause delayed recovery . However, in our patients, supplemental doses of rapacuronium were required every 5 min to maintain a T4/T1 ratio of 0.25, suggesting that the duration of neuromuscular blockade of rapacuronium remains short in the myasthenic patients. Also, recovery of neuromuscular transmission of the adductor pollicis muscle was achieved rapidly following antagonism of rapacuronium block by neostigmine.
In normal patients, a maintained response to tetanic nerve stimulation of a peripheral nerve can return to normal, while the pharyngeal and other bulbar muscles necessary to protect the airway can still be paralysed . The different response of peripheral vs. bulbar muscles may be more evident in myasthenic patients, particularly those suffering from bulbar and/or respiratory muscle weakness. This was observed in our Osserman III myasthenic patient, who showed recovery of neuromuscular transmission of the adductor pollicis muscle following antagonism of rapacuronium by neostigmine as evidenced by a T4/T1 ratio ≥ 0.9, while the head lift was unsustained and respiration was inadequate.
Several authors have proposed criteria for predicting myasthenic patients who require postoperative respiratory support . Gracey et al. have shown that the most important preoperative factor signifying the need for postoperative respiratory support is the severity of bulbar involvement (Osserman III and IV), usually indicated by significant dysarthria and dysphagia, along with borderline respiratory function . Our second patient (Osserman III) who had a preoperative history of choking and respiratory failure required postoperative respiratory support and plasmapheresis prior to weaning from the ventilator.
In conclusion, rapacuronium, a nondepolarizing muscle relaxant of short duration of action, could be easily titrated for neuromuscular blockade in our myasthenic patients. However, recovery of neuromuscular transmission of the adductor pollicis muscle does not predict postoperative respiratory function, particularly in the severely myasthenic patients (Osserman III or IV). Monitoring of respiratory efforts and resumption of preoperative therapy are recommended before discontinuation of respiratory support.
1 Baraka A. Anaesthesia and myasthenia gravis. Can J Anaesth
1992; 39: 476–486.
2 Savarese JJ, Caldwell JE, Lien CA, Miller RD. Pharmacology of muscle relaxants and their antagonists. In: Miller RD, ed. Anesthesia.
Pennsylvania, USA: Churchill Livingstone, 2000: 412–490.
3 Wierda JMKH, van den Broek L, Proost JH, Verbaan BW, Hennis PJ. Time course of action and endotracheal intubating conditions of ORG 9487, a new short-acting steroidal muscle relaxant; a comparison with succinylcholine. Anesth Analg
1993; 77: 579–584.
4 Osserman KE, Genkins G. Studies in myasthenia gravis: review of a twenty-year experience in over 1200 patients. Mt Sinai J Med
1971; 38: 497–537.
5 Paton WD, Waud DR. The margin of safety of neuromuscular transmission. J Physiol
1967; 191: 59–90.
6 Pavlin EG, Holle RH, Schoeme RB. Recovery of airway protection compared with ventilation in human after paralysis with curare. Anesthesiology
1989; 70: 381–385.
7 Gracey DR, Divertie MB, Howard FM, Payne WS. Postoperative respiratory care after transsternal thymectomy in myasthenia gravis. A 3-year experience in 53 patients. Chest
1984; 86: 67–71.