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Anesth Analg 2002;95:109-113
© 2002 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

Sensitivity to Vecuronium in Seropositive and Seronegative Patients with Myasthenia Gravis

Hironori Itoh, MD*, Keizo Shibata, MD{dagger}, and Shunichi Nitta, MD{ddagger}

Departments of *Anesthesiology and Intensive Care Medicine and {dagger}Emergency and Critical Care Medicine, Kanazawa University School of Medicine, Kanazawa, Japan; and {ddagger}Division of Anesthesia, Ishikawa Prefectural Central Hospital, Kanazawa, Japan

Address correspondence and reprint requests to Hironori Itoh, MD, Department of Anesthesiology and Intensive Care Medicine, Kanazawa University School of Medicine, 13-1 Takara-machi, Kanazawa 920-8641, Japan. Address e-mail to hironori{at}med.kanazawa-u.ac.jp


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Patients with myasthenia gravis (MG) are hypersensitive to nondepolarizing neuromuscular blocking drugs. Although antibodies to the acetylcholine receptor (AChR) often are observed in MG patients, 10% to 30% of patients do not show an anti-AChR antibody. Little is known about differences in sensitivity to nondepolarizing neuromuscular blocking drugs between MG patients with and without anti-AChR antibody. Hypothesizing that seronegative patients are as sensitive to vecuronium as seropositive patients, we assessed sensitivity in seropositive and seronegative MG patients and in non-MG patients (n = 8 each). During anesthesia with sevoflurane (2.5%) and nitrous oxide (60%) in oxygen, neuromuscular transmission was monitored by measuring the twitch tension of the adductor pollicis muscle with supramaximal stimulation. After baseline measurements, 10 µg/kg IV dose increments of vecuronium were administered sequentially until blockade exceeded 90%. The degree of blockade and onset time after the initial 10 µg/kg of vecuronium were assessed, and doses required to exceed 90% blockade were recorded. In addition, effective doses of 50% and 95% for vecuronium were calculated from a single data point. Both types of MG patients showed increased sensitivity to vecuronium compared with non-MG patients.

IMPLICATIONS: Hypothesizing that seronegative patients are as sensitive to vecuronium as seropositive patients, we assessed sensitivity in seropositive and seronegative myasthenia gravis (MG) patients and in non-MG patients. They were, indeed, both equally sensitive to vecuronium.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Myasthenia gravis (MG), characterized by fatigue that increases with exertion, is an autoimmune disorder involving the destruction of acetylcholine receptors (AChR) at the postsynaptic membrane at the neuromuscular junction. Numbers and half-life of AChR are diminished by an antibody-related reaction. However, approximately 10% to 30% of MG patients lack increased anti-AChR antibody in serum (1–3), although they respond to therapy for autoimmune disorders. An antibody in these "seronegative" patients apparently interferes with neuromuscular transmission by binding to determinants other than those on the AChR. Mossman et al. (4) have suggested that this type of seronegative myasthenia is immunologically and physiologically distinct from the seropositive type, and thus seronegative MG patients might show different responses to nondepolarizing neuromuscular blocking drugs (NMBDs) from seropositive patients. However, little is known about this possibility; there is only a case report by Kim and Mangold (5). We compared seropositive MG patients, seronegative MG patients, and non-MG patients with thymoma, in terms of neuromuscular responses to vecuronium at the adductor pollicis muscle.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After receiving approval of the study protocol from the institutional ethics committee and obtaining patients’ informed consent, we studied consecutive seropositive MG patients, seronegative MG patients, and non-MG thymoma patients (n = 8 each). Five of these patients have already been described (6). All were scheduled to undergo either minor surgery or thymectomy. The diagnosis of MG was confirmed by typical clinical and laboratory findings (ptosis, diplopia, limb weakness, a decremental conduction response on electrical stimulation, and a positive response to IV injection of 10 mg of edrophonium). Before surgery, seropositive patients showed an excess of binding or blocking antibodies to AChR in serum. To measure binding antibody, 125I-labeled {alpha}-bungarotoxin was allowed to bind with antigenic human AChR (125I-AChR). Sera from patients were incubated with 125I-AChR. Antigen-antibody complexes were precipitated by incubation with anti-human immunoglobulin G. Radioactivity in the precipitate was measured with a gamma counter (7). To measure blocking antibody, sera from patients and controls were incubated with prepared anti-genic AChR followed by incubation with 125I-labeled {alpha}-bungarotoxin. Aliquots then were applied to Sepharose (Amersham Pharmacia Biotech, Inc., Piscataway, NJ) columns to measure the percentage inhibition of labeled toxin binding to AChR (8). Anticholinesterase medication was continued until the morning of surgery. The non-MG patients were ASA grade I or II; patients with hepatic, renal, or neuromuscular disease and those taking any medications known to interfere with neuromuscular transmission were excluded.

Hydroxyzine (25 to 50 mg) and atropine (0.5 mg) were injected IM as premedication 1 h before the induction of anesthesia. Anesthesia was induced with 4 to 6 mg/kg of thiopental and 2 µg/kg of fentanyl, followed by sevoflurane (2.5%) and nitrous oxide (60%) in oxygen. The lungs were ventilated by mask so that end-tidal CO2 pressure was maintained at approximately 40 mm Hg. Skin temperature over the thenar region was monitored and maintained at 32°C to 33°C. Arterial blood pressure was measured noninvasively every 5 min; if systolic blood pressure decreased to <80 mm Hg, 5 mg of ephedrine was administered IV. Neuromuscular transmission was monitored by measuring the twitch tension of the adductor pollicis muscle. The ulnar nerve was stimulated with supramaximal train-of-four (TOF) square pulses of 0.2 ms duration every 12 s at the wrist with surface electrodes. After patients were rested for at least 10 min to allow the continuous response to stabilize, the baseline height of the first twitch (first TOF response; T1) was measured. The TOF ratio (percentage) was defined as the ratio of the fourth to the first twitch response elicited by a TOF stimulation. After baseline measurements, an initial dose of 10 µg/kg of vecuronium was administered IV. The next incremental dose of vecuronium of 10 µg/kg was given after three consecutive T1 values remained unchanged. When baseline T1 remained unchanged for 4 min after an initial dose of 10 µg/kg of vecuronium, the next incremental dose was given. As long as the percentage of neuromuscular blockade, defined as [1 - (T1/baseline T1)] x 100, remained <90%, additional increments of 10 µg/kg were added until 90% or more blockade had been achieved. The trachea then was intubated, and the inspired concentration of sevoflurane was decreased to 0.5% to 1.5%. Responses in the adductor pollicis muscles were monitored continuously.

Initial blockade by vecuronium (10 µg/kg) and the onset of blockade were calculated according to the following definitions: initial blockade was the maximum neuromuscular blockade achieved after the initial dose of vecuronium (10 µg/kg); onset of blockade was the time interval from the injection of the initial dose of vecuronium to initial blockade. Doses required to achieve >90% blockade also were recorded. After surgery was completed, the concentration of sevoflurane was decreased to 0.2%, and the TOF ratio relative to the baseline value was confirmed in all patients with MG and in >90% of non-MG patients. Then, inhalation of sevoflurane was terminated, and, after patients were able to open their eyes, the tracheal tube was removed without anticholinesterase administration except for one seronegative patient. The patient needed 40 h for recovering from the blockade by vecuronium.

In addition, we calculated the effective doses of 50% and 95% (ED50 and ED95) for vecuronium from a single data point by using the final observed effect (<100%) and a log-dose/logit slope of 4.5 (9), except for the patients who showed 100% blockade by initial dose. This can be done from a single data point if the slope of the dose-response relationship is assumed. The ED95 values of these supersensitive patients were arbitrarily assigned as 9 µg/kg, and the ED50 value was assigned as 4.7 µg/kg, derived from a log-dose/logit slope of 4.5.

Parametric data are presented as the mean ± SD, and nonparametric data are presented as the median and range. Parametric data were analyzed with Student’s t-test or one-way analysis of variance with Scheffé’s comparisons. Nonparametric data were assessed with the Mann-Whitney U-test or the Kruskal-Wallis test with Scheffé’s comparisons. A P value <0.05 was considered to indicate significance.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
No significant differences were noted between seropositive MG, seronegative MG, and non-MG patients with respect to age or weight (Table 1). The duration of disease in seropositive patients was significantly longer than that in seronegative patients. Among seropositive MG patients, three patients represented Type I MG according to the Osserman and Genkins classification (10); four patients, Type IIA; and one patient, Type IIB. Among seronegative MG patients, four were Type I and four were Type IIA. Four patients in the Seropositive group showed excesses of both binding and blocking antibodies to AChR, whereas three patients showed only an increase in binding antibody. One patient was not investigated for blocking antibody, but because binding antibody was increased, we considered the patient to be seropositive. Four seropositive patients and two seronegative patients were treated with pyridostigmine. Before vecuronium was administered, TOF ratios were 66% to 100% in seropositive patients, 23% to 98% in seronegative patients, and 95% to 100% in non-MG patients. A significant difference was seen between seronegative and non-MG patients. After 10 µg/kg of vecuronium was administered, the initial blockade was 0% to 100% in seropositive patients and 16% to 100% in seronegative patients; all non-MG patients showed 0% blockade. Differences were significant between the MG and non-MG patients, but not between seropositive and seronegative patients. The onset of blockade could not be analyzed because one seropositive patient showed 0% blockade. Doses required to achieve >90% blockade were 10 to 40 µg/kg in seropositive patients, 10 to 30 µg/kg in seronegative patients, and 30 to 40 µg/kg in non-MG patients. Significant differences were observed between the MG and non-MG groups, but not between seropositive and seronegative patients. ED50 and ED95 also showed a higher potency for vecuronium in MG groups than in non-MG patients but were not significant between seropositive and seronegative MG patients (Table 2).


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  		Table 1. Characteristics of Patients
 

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  		Table 2. Neuromuscular Data
 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
In this study, varied degrees of increased sensitivity to vecuronium were seen in MG patients. Of the 16 MG patients, including seropositive and seronegative subjects, 12 required no more than 20 µg/kg of vecuronium to achieve >90% blockade; among non-MG patients, all needed at least 30 µg/kg of vecuronium to achieve such blockade. ED50 and ED95 were also significantly lower in MG patients than in non-MG patients. Thus, MG patients generally showed hypersensitivity to vecuronium, but some showed only a normal reaction to vecuronium, at least in the adductor pollicis muscle.

In neurologically healthy patients, the neuromuscular junction has a large excess of receptor sites. As a result, transmission in response to single or repetitive pulses at 30 Hz is not altered until 70% to 80% of receptors are occupied by nondepolarizing NMBDs (11). In MG patients, this margin of safety is considered to be reduced according to severity of disease. Because sensitivity to nondepolarizing NMBDs is increased in MG patients (12–16), we used an initial dose of 10 µg/kg of vecuronium, which is considerably smaller than the usual dose, especially because sensitivity to nondepolarizing NMBDs is known to vary greatly between MG patients. In our patients, all non-MG patients showed 0% blockade with 10 µg/kg, whereas only one MG patient did.

How detectable antibodies to AChR are related to sensitivity to nondepolarizing NMBDs has been unclear. Nilsson and Meretoja (13) reported a significant correlation between the ED95 for vecuronium and AChR antibody titers in MG patients, obtaining a logarithmic curve for the relationship. However, a contrary result has been reported (16). Although one report concluded that the severity of MG was roughly related to the titer of anti-AChR antibody and the degree of destruction of the junctional membrane (17), studies have found no relationship between AChR antibody titers and severity of symptoms in individual patients (18–20).

Approximately 10% to 30% of MG patients do not show anti-AChR antibody increases in serum (1–3). Although antibodies to AChR are undetectable in these patients, the patients are considered to have an autoimmune disease. Infants born to seronegative and seropositive mothers with MG may have transient neonatal MG (21). Plasma exchange and immuno-suppressive therapy, such as the administration of prednisolone and azathioprine, result in clinical improvement (2,4,22,23). Mice injected with plasma immunoglobulin fractions from seronegative MG patients showed a defect in neuromuscular transmission characterized by increased sensitivity to d-tubocurarine (4). Moreover, some seronegative patients have shown prejunctional changes, suggesting that seronegative MG may be a heterogenous disorder (1). Mossman et al. (4) suggested that seronegative myasthenia was immunologically and physiologically distinct from the seropositive type. The target of antibodies relating to sero-negative MG is thought to be a constituent of the neuromuscular junction other than the AChR. Despite reported immunologic and physiologic differences between seronegative and seropositive MG, the pharmacodynamics of vecuronium were not clearly different between the two disease types in this study.

Some investigators have reported differing severity of MG between seropositive and seronegative patients (1–3). Oh (3) showed a tendency toward more marked impairment in seropositive patients than in seronegative patients, but this difference was not statistically significant. Vincent et al. (1) reported that in 480 consecutive MG patients, clinical features in seronegative patients generally did not differ from those in seropositive patients. In particular, the proportion of patients within the various Osserman classes was very similar. Seronegative MG patients should be treated identically to seropositive patients when general anesthesia is necessary, as indicated in a case report by Kim and Mangold (5) describing an exaggerated response to vecuronium.

Inhalation of sevoflurane could have potentiated the neuromuscular blocking effect of vecuronium in this study, because our data were obtained under N2O/sevoflurane anesthesia; in some previous reports, neuromuscular data were determined without inhaled anesthetics. Inhaled anesthetics decrease the availability of acetylcholine at the neuromuscular junction (24) and increase the neuromuscular blockade produced by nondepolarizing NMBDs (25–27); although this pattern has not yet been confirmed in MG patients, the possibility was demonstrated in a case report (28). Taivainen and Meretoja (25) showed that the ED50 and ED95 for vecuronium in the presence of 1 minimum alveolar anesthetic concentration of sevoflurane were 64% and 50% less, respectively, than values obtained without inhaled anesthetics in neurologically healthy patients. Blockade in MG patients in this study may have been influenced by sevoflurane. We do not believe that background anesthetics affected the result of the study, which compared the two types of MG with respect to the sensitivity of vecuronium, although it makes potency comparisons with other studies unnecessarily difficult. In addition, during the test period, the lungs were ventilated by mask, and the end-tidal concentration of sevoflurane was not measured. An unstable concentration of sevoflurane might influence the blockade by vecuronium. Two non-MG patients showed a very steep dose-response reaction with 40 µg/kg despite no reaction with 30 µg/kg. These are the limitations of our study.

In summary, we estimated blockade by vecuronium in seropositive MG, seronegative MG, and non-MG patients. Both seropositive and seronegative MG patients showed hypersensitivity to nondepolarizing NMBDs. The degree of blockade resulting from a given dose is likely to be the same in seropositive and seronegative MG patients.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication February 28, 2002.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press