SENSITIVITY TO BOTH VECURONIUM AND NEOSTIGMINE IN A SERO-NEGATIVE MYASTHENIC PATIENT

SENSITIVITY TO BOTH VECURONIUM AND NEOSTIGMINE IN A SERO-NEGATIVE MYASTHENIC PATIENTSENSITIVITY TO BOTH VECURONIUM AND NEOSTIGMINE IN A SERO-NEGATIVE MYASTHENIC PATIENT
J.-M. KIM AND J. MANGOLD
Myasthenia gravis is now identified as an auto- immune disease involving the destruction of acetylcholine receptors (AChR) at the postjunc- tional membranes of skeletal muscles. As a result of this antibody-mediated reaction, the number and half-life of receptors are diminished. There- fore, the severity of the disease is approximately related to the titre of ami- AChR antibody and the degree of destruction of the junctional membrane [1]. However, in approximately 30% of those myasthenic patients with symptoms restricted to ocular muscles, anti-AChR antibody could not be demonstrated. Mossman, Vincent and Newsome [2] suggested that this type of sero-negative myasthenia was immunologically and physiologi- cally distinct from the AChR antibody-positive type. An immunoglobulin antibody of these sero- negative patients interferes with neuromuscular transmission by binding to determinants other than those on the AChR. In experimental auto- immune myasthenia gravis, Takamori, Okumora and Yasuda [3] showed that antibody to the receptor site near the acetylcholine (ACh) binding site may act presynaptically and may enhance the evoked release of ACh to compensate for post- synaptic failure.
We report a sero-negative ocular myasthenic patient who developed prolonged depolarizing block with apnoea following administration of neostigmine.
CASE REPORT
For 6 months before admission for thymectomy, a 35-yr-old black female had been followed up for
JONG-MIN KIM, M.D. ; JOEL MANGOLD, M.D. ; Department of Anesthesiology, University of Kansas, College of Health Sciences and Hospital, Kansas City, Kansas 66103, U.S.A. Accepted for Publication: March 15, 1989.
Correspondence to J.-M. K.
SUMMARY
We describe a sero-negative ocular myasthenic patient who showed exaggerated responses to both vecuronium and neostigmine. These hyper- sensitive responses were not anticipated be- cause preoperative clinical and laboratory evalua- tions suggested a negligible impairment of somatic muscles by myasthenic processes. This case report re-emphasizes that, if neuromuscular blocking agents and their antagonists are admin- istered to myasthenic patients, regardless of the degree of impairment, the dose should be titrated carefully with the aid of a neuromuscular trans- mission monitor.
evaluation of ptosis, involving mainly the left eyelid. The degree of ptosis was not associated with the time of day or fatigue. Detailed in- hospital investigations were performed 6 and 3 months before the present admission. Repeated edrophonium tests were equivocal. Electromyo- graphic studies failed to show a decremental response on the right abductor pollicis brevis and the trapezius muscles to repetitive stimulation of the median and the spinal accessory nerves, respectively. The tests for AChR antibody on each admission were within the normal range. A computerized axial tomography of the chest showed a slightly prominent thymus, suggesting hyperplasia. It was concluded that the patient had sero-negative ocular myasthenia gravis. After the initial investigation the patient was given pyrido- stigmine 60 mg orally twice daily. Initially the medication provided some subjective improve- ment of the ptosis. Two months later, the medication was discontinued by the patient because she felt that it was no longer helping the
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ptosis, and this did not exacerbate the condition. During the initial investigation, hyperthyroidism was discovered. After radioactive iodine treat- ment, the patient became hypothyroid and re- quired therapy with L-thyroxine 0.1 mg daily. The patient was referred to the Mayo Clinic for another opinion regarding the management of hyperplastic thymus and ocular symptoms. Fur- ther studies at the Mayo Clinic revealed the following results: electromyography showed a 17 % decrement on 2-Hz stimuli in the left biceps and a lesser decrement in the left trapezius muscle; single fibre electromyography of the left common finger extensor muscles showed no abnormality; tests for AChR antibodies, including binding and modulating antibodies, were in the normal range. Diagnosis of sero-negative ocular myasthenia gravis was confirmed. The following were suggested: although her myasthenia was sero-negative, thymectomy was advised to prevent further progress of the disease; the ptosis could be improved by use of an eyelid clutch; there was no need for the use of an anticholinesterase, azathio- prine, or steroid therapy.
On admission for thymectomy, the patient was a well developed and well nourished female, weighing 62 kg. Two previous general anaesthe- tics for bunionectomy and tubal ligation 2 and 3 years previously were uncomplicated. Current medication comprised L-thyroxine 0.1 mg daily. Muscle strength in all four extremities appeared grossly normal. Drooping of the left eyelid was noted. Preoperative laboratory studies, including complete blood count, serum chemistry and coagulation profiles, ECG and chest x-ray, were within normal ranges. Pulmonary function tests
showed predicted normal values for routine spirometry and maximum voluntary ventilation. Arterial blood-gas analysis (FiO2 = 0.2) showed pH 7.40, PaC0! 5.4 kPa, Pao, 14.3 kPa.
In addition to routine intraoperative moni- toring devices, a Datex NMT Monitor 221 was applied to her left forearm. The NMT Monitor delivered supramaximal train-of-four stimuli to the ulnar nerve every 20 s, and measured the evoked compound action potential of the hypo- thenar muscles. The measured values are the ratio of the first to control twitch response (Tl:T0) and train-of-four ratio (T4:T1). Anaesthesia was induced with midazolam 1 mg, fentanyl 0.05 mg and thiopentone 300 mg i.v. During ventilation of the lungs with oxygen and isoflurane by face mask, a stable 3-min control tracing of the NMT Monitor was recorded. There was no train-of- four fade. Vecuronium 2 mg was administered. The maximum twitch depression (Tl :T0 = 5 %) was achieved at 4 min and the trachea was intubated at 5 min. Anaesthesia was maintained with 1-2% isoflurane and 70% nitrous oxide in oxygen; fractional doses of vecuronium (total 3.5 mg), fentanyl (0.1 mg), and midazolam (2 mg) were administered also. When Tl :T0 and T4:T1 recovered to 70% and 50%, respectively, at 45 min after the initial dose, the second dose of vecuronium 0.5 mg resulted in Tl :T0 suppres- sion to 18% and eliminated the T4 response. Forty minutes after the last dose of vecuronium 0.5 mg, Tl :T0 and T4:T1 had recovered 70% and 100%, respectively. These values remained unchanged and the patient resumed spontaneous breathing with good tidal volume during the remaining 20 min of surgery. Even though the
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FIG. 1. Tracing of evoked hypothenar electromyographic responses to train-of-four stimuli in a patient with myasthenia gravis. Two different types of neuromuscular block, one resulting from vecuronium and the other resulting from antagonizing agents, are shown. The former is a typical non-depolarizing block, but the latter resembles a depolarizing block. Two (Tl and T4) train-of-four twitch responses are printed. The light lines are Tl twitch responses, and the overlapped darker lines are T4 twitch
responses. Elapsed times were recorded every 15 min.
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NMT data and clinical criteria indicated a complete recovery of neuromuscular transmis- sion, neostigmine 3 mg and glycopyrrolate 0.6 mg were administered. Shortly thereafter, the NMT Monitor showed an acute onset of neuromuscular block (fig. 1) and the spontaneous breathing was abolished. The patient was sedated with mida- zolam 1.5 mg, transferred to the intensive care unit and underwent mechanical ventilation. At 75 min after the administration of the antagonists, she began to breathe and was able to generate peak inspiratory negative pressures of —15 and —30 cm H2O, at 120 and 225 min, respectively. The trachea was extubated at 225 min. The postopera- tive course was uneventful. The patient was discharged from the hospital on the 5th day after operation.
DISCUSSION
Because the normal neuromuscular end-organ has a large excess of receptor sites, transmission in response to single pulses or tetanic pulses at 30 Hz is not altered until 70-80% of receptors are occupied by non-depolarizing blockers [4]. This margin of safety is reduced in myasthenic patients, depending upon the severity of the disease. However, non-depolarizing neuromuscular block- ers of intermediate duration (atracurium and vecuronium) have been used safely for surgical relaxation in patients with varying degrees of myasthenic impairment [5-8]. Following antag- onism of atracurium-induced residual neuromus- cular block with neostigmine 5 mg, none of a series of five myasthenic patients suffered res- piratory embarrassment [8].
We used an NMT Monitor to titrate the dose of vecuronium. The observed hypersensitive respon- ses to the initial dose of vecuronium (2 mg) were unexpected because the extensive preoperative investigation suggested that the myasthenia gravis was limited primarily to the ocular muscles, with negligible somatic involvement. As a result of more cautious titration of subsequent doses, neuromuscular transmission recovered spon- taneously at the end of surgery. However, the antagonists were administered to increase the margin of safety. The resultant neuromuscular block showed a well maintained train-of-four ratio (except for the significant train-of-four fades on the first three responses during onset), suggest- ing a depolarizing block.
The i.v. regional curare test on the isolated arm
described by Foldes [9] could not only help to confirm diagnosis, but also disclose hypersensitive reaction to a non-depolarizing neuromuscular blocker. The administration of isoflurane could potentiate the neuromuscular blocking effect of vecuronium in this case. However, the potentia- tion by isoflurane is reported to be much less with vecuronium than with tubocurarine and pancuro- nium [10]. In addition, when the end-tidal concentration of an inhalation agent is low at the beginning of anaesthesia, potentiation may not be manifested. Therefore, the dose of blocker needed to establish block at this time should not be altered, regardless of the type of anaesthesia [11].
The reduced number of AChR in myasthenic muscles cannot explain how anticholinesterases improve muscle strength. In contrast, the pres- ence of a relative excess of ACh on the remaining fewer receptors could induce nicotinic responses. Certainly, cholinergic crisis is a well known complication in myasthenic patients, caused by an overdose of anticholinesterase. Depolarizing neuromuscular block observed in our patient indi- cated that cholinergic crisis was the most likely cause of muscle paralysis. Rolbin and colleagues [12] described a myasthenic patient who became apnoeic acutely following i.v. administration of neostigmine 2.0 mg and atropine 0.4 mg to treat the myasthenic crisis which developed after delivery of a fetus. Similar long-lasting depolari- zing block was reported in a patient with dystro- phia myotonia when pancuronium-induced re- sidual block was antagonized with neostigmine [13]. Payne, Hughes and Azawi [14] reported that first administration of neostigmine 2.5 mg antago- nized non-depolarizing block in anaesthetized patients, whereas a second dose given 2-5 min later depressed the peak tetanic contraction and re-established tetanic fade. In their further studies on non-paralysed patients, one or two injections of neostigmine 2.5 mg caused a substantial re- duction in the peak tetanic contraction and severe tetanic fade. These neostigmine-induced tetanic responses were antagonized by gallamine and potentiated by suxamethonium. They concluded that neostigmine, in sufficient dose, produces an ACh-induced depolarizing block, and cautioned that when full recovery has been achieved, a further dose of neostigmine could be hazardous, because a prolonged depolarizing block with apnoea could ensue.
This report shows that a cholinergic crisis can result with indiscriminate use of anticholinest-
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erase; therefore, administration of antagonizing agents should also be titrated carefully in patients with myasthenia.
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SENSITIVITY TO BOTH VECURONIUM AND NEOSTIGMINE IN A SERO-NEGATIVE MYASTHENIC PATIENT
CASE REPORT