British Journal of Anaesthesia, 2001, Vol. 87, No. 6 885-889
© 2001 The Board of Management and Trustees of the British Journal of Anaesthesia
Clinical Investigations |
Difference in sensitivity to vecuronium between patients with ocular and generalized myasthenia gravis
1Department of Anesthesiology and Intensive Care Medicine, Kanazawa University School of Medicine, Kanazawa, Japan. 2Department of Emergency and Critical Care Medicine, Kanazawa University School of Medicine, Kanazawa, Japan. 3Division of Anesthesia, Ishikawa Prefectural Central Hospital, Kanazawa, Japan*Corresponding author: Department of Anesthesiology and Intensive Care Medicine, Kanazawa University School of Medicine, 13-1 Takara-machi, Kanazawa 920-8641, Japan
Accepted for publication: July 23, 2001
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Abstract |
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Patients with myasthenia gravis show sensitivity to non-depolarizing neuromuscular blocking drugs, but little is known about differences in this sensitivity between types of myasthenia. In 10 patients with ocular myasthenia gravis and 10 with generalized myasthenia gravis, twitch tension was monitored in the adductor pollicis muscle by supramaximal train-of-four stimulation of the ulnar nerve during anaesthesia with sevoflurane 2.5% and nitrous oxide 60%. After baseline measurement, an initial dose of vecuronium 10 µg kg–1 was given. When the twitch height stabilized (maximum block after the first 10 µg kg–1), the next incremental dose of 10 µg kg–1 was given and repeated until block, defined as [1–(first twitch/baseline first twitch)]x100 reached 90%. Maximum block after the first dose of vecuronium in ocular patients was significantly less than that in generalized patients (median 51 vs 91%; P<0.05). Onset of block after the first dose of vecuronium was significantly slower in ocular than in generalized myasthenic patients (mean 300 vs 200 s; P<0.05). Doses required to attain a block of 90% or more were significantly higher in ocular than in generalized patients (median 20 vs 10 µg kg–1; P<0.05). Clinicians should consider the type of disease according to the Osserman classification when using non-depolarizing neuromuscular blocking drugs in patients with myasthenia gravis.
Br J Anaesth 2001; 87: 885–9
Keywords: equipment, force transducer; complications, myasthenia gravis; neuromuscular block, Osserman classification
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Introduction |
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Myasthenia gravis is an autoimmune disorder characterized by muscular fatigue that worsens with exertion. Patients with myasthenia gravis require special care during anaesthesia because of their sensitivity to non-depolarizing neuromuscular blocking drugs,1–5 resulting from a reduced number of functioning acetylcholine receptors (AChR) at the neuromuscular junction.6 A wide range of effective doses of vecuronium have been shown to be required to obtain 95% neuromuscular block (ED95) in myasthenic patients, varying from 6 to 44 µg kg–1.2 3 The wide variation in the severity of myasthenia, which is categorized using the Osserman classification,7 may be one explanation for the varied sensitivity to vecuronium, but little has been reported about this possibility. Hypothesizing that ocular myasthenic patients would be less sensitive to vecuronium than generalized myasthenic patients, we compared neuromuscular responses to vecuronium in the adductor pollicis muscle between these groups.
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Methods |
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After we had received approval of the study protocol from the Institutional Ethics Committee of our hospital and obtained individual patients’ informed consent, we studied 20 myasthenic patients (10 with ocular disease and 10 with generalized disease, representing types I and II in the Osserman classification7 respectively) who were scheduled to undergo thymectomy. The diagnosis was confirmed by the presence of circulating antibody to the AChR and a positive response to edrophonium in addition to typical clinical and laboratory findings (ptosis, diplopia, limb weakness, and a decremental conduction response on electrical stimulation of the nerve supply to the orbicularis oculi or the deltoid muscle). The generalized patients showed limb weakness or a decremental response in the deltoid muscle to repetitive motor nerve stimulation.
Binding and blocking antibodies to AChR were measured preoperatively in serum samples. To determine binding antibody, 
-bungarotoxin labelled with 125I was bound to prepared antigenic human AChR (125I-AChR). Sera from patients were incubated with 125I-AChR. Antigen–antibody complexes were precipitated by incubation with anti-human IgG. Radioactivity in the precipitate was measured with a gamma counter.8 When measuring binding antibody, it is impossible to detect the antibody in the area near the acetylcholine binding site of the receptor. Thus, blocking antibody to the acetylcholine binding site was also measured. Sera from patients and controls were incubated with prepared antigenic AChR followed by incubation with 125I-labelled -bungarotoxin. Aliquots were then applied to Sepharose columns to measure the percentage inhibition of labelled toxin binding with AChR.9
Anticholinesterase medication was continued until the morning of surgery. The patients were premedicated with hydroxyzine 50 mg and atropine 0.5 mg, given 1 h before induction of anaesthesia. Anaesthesia was induced with thiopental 4 mg kg–1 and fentanyl 2 µg kg–1 followed by inhalation of sevoflurane 2.5% and nitrous oxide 60% in oxygen. The lungs were ventilated by face-mask so that the end-tidal carbon dioxide pressure was maintained at about 5.3 kPa. Skin temperature over the thenar region was monitored and was maintained at 32–33°C. Non-invasive blood pressure was measured every 5 min, and when systolic blood pressure had decreased to <80 mm Hg ephedrine 5 mg was administered i.v.
Neuromuscular transmission was monitored by measuring twitch tension in the adductor pollicis muscle (Myograph 2000; Biometer International, Odense, Denmark). The ulnar nerve was stimulated at the wrist using surface electrodes with supramaximal train-of-four (TOF) square-wave pulses of duration 0.2 ms every 12 s (Myotest, Biometer International). When the twitch response had remained stable for at least 10 min, the baseline height of the first twitch (T1) was measured. The TOF ratio, expressed as a percentage, was defined as the ratio of the fourth to the first response to TOF stimulation. After baseline measurements, an initial dose of vecuronium 10 µg kg–1 was administered i.v. Maximum block was defined as the maximum effect of the first dose of vecuronium 10 µg kg–1. The next incremental dose of vecuronium 10 µg kg–1 was given after the twitch had again stabilized. As long as neuromuscular block, defined as [1–(T1/baseline T1)]x100, was less than 90%, additional doses of vecuronium were given until 90% or greater block had been achieved. The trachea was then intubated and the inspired concentration of sevoflurane was decreased from 2.5% to between 0.5 and 1.5%. Responses in the adductor pollicis muscle were monitored continuously. Maximum block produced by vecuronium 10 µg kg–1 and the time to the onset of maximum block were recorded.
Statistics
Parametric data are presented as mean (SD) and non-parametric data as median (range). Parametric data were analysed with the t test and non-parametric data with the Mann–Whitney U test. A P value less than 0.05 was considered to indicate significance.
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Results |
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No significant differences were found between the ocular and generalized groups with respect to age, sex, weight, duration of disease or serum concentration of binding antibody to AChR. Blocking antibody was significantly higher in the generalized group than in the ocular group. The generalized group included five type IIa (mild, generalized) and five type IIb (moderate, generalized) patients according to the Osserman classification. Two patients in the ocular group and six patients in the generalized group received pyridostigmine (Table 1). Before vecuronium was administered, median TOF ratios were 95% (range 85–98%) in the ocular group and 91% (55–100%) in the generalized group. No significant difference in TOF ratios was evident between groups. After vecuronium 10 µg kg–1, the ocular group showed a lower maximum block [median (range) 51 (0–98)% vs 91 (40–100)%], a slower onset of block [mean (SD) 300 (73) vs 200 (74) s] and greater total doses needed to exceed 90% block [median (range) 20 (10–30) vs 10 µg kg–1 (10–20 µg kg–1)] than the generalized group (P<0.05). Two patients in the ocular group had at least 90% block, as did six patients in the generalized group. No patient showed 100% block in the ocular group, while three patients did in the generalized group. Mean onset of maximum neuromuscular block took over 200 s in all patients in the ocular group, whereas six patients in the generalized group took less than 200 s. In the ocular group, three patients required vecuronium 30 µg kg–1 to exceed 90% block. In contrast, in the generalized group no patient required 30 µg kg–1 (Table 2).
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blocking antibody to AChR (normally <10%); 
P<0.05 vs generalized group
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P<0.05 vs generalized group
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Discussion |
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Although one might expect to see a difference in sensitivity to neuromuscular blocking drugs between patients with different types of myasthenia gravis, such differences have not been established.10 11 In this study of 20 myasthenic patients, the 10 patients in the ocular group showed significantly less neuromuscular block after vecuronium 10 µg kg–1 than the 10 in the generalized group. The ocular group also showed a more gradual onset of block. The median dose required to produce at least 90% block in the ocular group was twice that required in the generalized group. Thus, ocular myasthenic patients were less sensi tive to vecuronium than the patients with generalized myasthenia.
As sensitivity to non-depolarizing neuromuscular blocking drugs is increased in myasthenic patients,1–6 we used an initial dose of vecuronium 10 µg kg–1, which is smaller than the priming dose used ordinarily.12 13 Sensitivity to non-depolarizing neuromuscular blocking drugs is known to vary greatly between myasthenic patients. Several studies using a cumulative technique have shown the ED95 for vecuronium to range from 6 to 44 µg kg–1.2 3 Although one patient in our ocular group showed 98% block with vecuronium 10 µg kg–1, exceeding the median value for maximal block in the generalized group, the ocular myasthenic patients as a whole showed less sensitivity to vecuronium than the generalized myasthenic patients.
In myasthenia gravis, the ocular muscles are affected most commonly, being involved initially in 40% of cases. It is rare for the initial symptoms to be limited to limb muscles.6 However, intraoperative neuromuscular monitoring is commonly performed in the upper limb. Our data show that the limb muscles of ocular myasthenic patients are significantly less sensitive to vecuronium than those of generalized myasthenic patients. Differences in sensitivity between ocular and generalized myasthenia gravis patients probably occur because the disease induces different degrees of change in the margin of safety for neuromuscular transmission in the limb muscles. In ocular patients, clinically important decreases in this margin of safety occur only in ocular muscles. In contrast, generalized myasthenic patients show a decreased margin of safety in all skeletal muscles, including the adductor pollicis.
The ED50 for vecuronium has ranged from 0.3 to 19 µg kg–1 and the ED90 from 5 to 35 µg kg–1 in myasthenic patients.1–3 In these studies, most patients represented type II in the Osserman classification, like the patients with generalized myasthenia in our study. Additionally, type IV patients (with late, severe generalized myasthenia) were included in the study of Eisenkraft and colleagues.2 Only one patient of this type was studied by Buzello and colleagues.1 Patients in our generalized group were similar in disease severity to most subjects in previous studies. However, patients in our ocular group had milder myasthenia than the individuals studied previously. Although we did not calculate effective doses of vecuronium, our data showed a difference in sensitivity between ocular and generalized patients.
Our data were obtained under nitrous oxide–sevoflurane anaesthesia; in previous reports of myasthenic patients, neuromuscular variables were measured in the absence of potent anaesthetic agents. Generally, inhaled anaesthetics decrease the availability of acetylcholine at the neuromuscular junction14 and increase the neuromuscular block produced by non-depolarizing neuromuscular blocking drugs,15–17 but this effect has not been specifically confirmed in myasthenic patients. Vanlinthout and colleagues15 reported ED50 and ED95 values for vecuronium in neurologically healthy patients during anaesthesia with sevoflurane 1.7% of 14.4 and 34.9 µg kg–1 respectively, which are 42 and 32% less than when inhaled anaesthetics are not used. The generalized myasthenic patients in this study, who were apparently similar to the myasthenic patients in previous studies of vecuronium, showed 91% block from vecuronium 10 µg kg–1. Although comparisons between studies have limitations, the block produced appeared to be greater in our study than in previous studies of myasthenia gravis; the sensitivity to vecuronium was probably increased by sevoflurane in myasthenic patients as well as in our patients with normal neuromuscular transmission.
However, the use of inhalational anaesthetics does not affect the results of this study, which compared the sensitivity to vecuronium of two types of myasthenia. One limitation of this study, however, may be that we did continue the morning dose of anticholinesterase. The incidence of TOF fade before administration of vecuronium, which is well tolerated in myasthenia gravis patients, was low in our patients; this may have been caused by the administration of pyridostigmine. The other limitation was the interval between TOF stimuli. It has not been established in patients with myasthenia gravis that an interval as long as 12 s between TOF stimuli is sufficient. The twitches may thus have been affected by preceding stimuli. We standardized the interval at 12 s, as used in neurologically healthy patients, as any effect of myasthenia in this respect has not been shown.
In summary, we estimated neuromuscular block produced by vecuronium in the adductor pollicis muscle in patients with ocular and generalized myasthenia. Ocular myasthenic patients were less sensitive to vecuronium than generalized myasthenic patients. During general anaesthesia, neuromuscular monitoring is essential to avoid problems of prolonged neuromuscular block in myasthenic patients; however, the degree of block produced by a given dose of vecuronium is likely to be less in ocular than in generalized myasthenic patients.
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