Br. J. Anaesth. (1989), 63, 497-500

SENSITIVITY TO BOTH VECURONIUMAND NEOSTIGMINE IN A SERO-NEGATIVEMYASTHENIC PATIENT

J.-M. KIM AND J. MANGOLD

Myasthenia gravis is now identified as an auto-immune disease involving the destruction ofacetylcholine receptors (AChR) at the postjunc-tional membranes of skeletal muscles. As a resultof this antibody-mediated reaction, the numberand half-life of receptors are diminished. There-fore, the severity of the disease is approximatelyrelated to the titre of ami- AChR antibody and thedegree of destruction of the junctional membrane[1]. However, in approximately 30% of thosemyasthenic patients with symptoms restricted toocular muscles, anti-AChR antibody could not bedemonstrated. Mossman, Vincent and Newsome[2] suggested that this type of sero-negativemyasthenia was immunologically and physiologi-cally distinct from the AChR antibody-positivetype. An immunoglobulin antibody of these sero-negative patients interferes with neuromusculartransmission by binding to determinants otherthan those on the AChR. In experimental auto-immune myasthenia gravis, Takamori, Okumoraand Yasuda [3] showed that antibody to thereceptor site near the acetylcholine (ACh) bindingsite may act presynaptically and may enhance theevoked release of ACh to compensate for post-synaptic failure.

We report a sero-negative ocular myasthenicpatient who developed prolonged depolarizingblock with apnoea following administration ofneostigmine.

CASE REPORT

For 6 months before admission for thymectomy, a35-yr-old black female had been followed up for

JONG-MIN KIM, M.D. ; JOEL MANGOLD, M.D. ; Department ofAnesthesiology, University of Kansas, College of HealthSciences 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 myasthenicpatient who showed exaggerated responses toboth vecuronium and neostigmine. These hyper-sensitive responses were not anticipated be-cause preoperative clinical and laboratory evalua-tions suggested a negligible impairment ofsomatic muscles by myasthenic processes. Thiscase report re-emphasizes that, if neuromuscularblocking agents and their antagonists are admin-istered to myasthenic patients, regardless of thedegree of impairment, the dose should be titratedcarefully with the aid of a neuromuscular trans-mission monitor.

evaluation of ptosis, involving mainly the lefteyelid. The degree of ptosis was not associatedwith the time of day or fatigue. Detailed in-hospital investigations were performed 6 and 3months before the present admission. Repeatededrophonium tests were equivocal. Electromyo-graphic studies failed to show a decrementalresponse on the right abductor pollicis brevis andthe trapezius muscles to repetitive stimulation ofthe median and the spinal accessory nerves,respectively. The tests for AChR antibody oneach admission were within the normal range. Acomputerized axial tomography of the chestshowed a slightly prominent thymus, suggestinghyperplasia. It was concluded that the patient hadsero-negative ocular myasthenia gravis. After theinitial investigation the patient was given pyrido-stigmine 60 mg orally twice daily. Initially themedication provided some subjective improve-ment of the ptosis. Two months later, themedication was discontinued by the patientbecause 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, hyperthyroidismwas 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 foranother opinion regarding the management ofhyperplastic thymus and ocular symptoms. Fur-ther studies at the Mayo Clinic revealed thefollowing results: electromyography showed a17 % decrement on 2-Hz stimuli in the left bicepsand a lesser decrement in the left trapeziusmuscle; single fibre electromyography of the leftcommon finger extensor muscles showed noabnormality; tests for AChR antibodies, includingbinding and modulating antibodies, were in thenormal range. Diagnosis of sero-negative ocularmyasthenia gravis was confirmed. The followingwere suggested: although her myasthenia wassero-negative, thymectomy was advised to preventfurther progress of the disease; the ptosis could beimproved by use of an eyelid clutch; there was noneed for the use of an anticholinesterase, azathio-prine, or steroid therapy.

On admission for thymectomy, the patient wasa well developed and well nourished female,weighing 62 kg. Two previous general anaesthe-tics for bunionectomy and tubal ligation 2 and3 years previously were uncomplicated. Currentmedication comprised L-thyroxine 0.1 mg daily.Muscle strength in all four extremities appearedgrossly normal. Drooping of the left eyelid wasnoted. Preoperative laboratory studies, includingcomplete blood count, serum chemistry andcoagulation profiles, ECG and chest x-ray, werewithin normal ranges. Pulmonary function tests

showed predicted normal values for routinespirometry and maximum voluntary ventilation.Arterial blood-gas analysis (FiO2 = 0.2) showedpH 7.40, PaC0! 5.4 kPa, Pao, 14.3 kPa.

In addition to routine intraoperative moni-toring devices, a Datex NMT Monitor 221 wasapplied to her left forearm. The NMT Monitordelivered supramaximal train-of-four stimuli tothe ulnar nerve every 20 s, and measured theevoked compound action potential of the hypo-thenar muscles. The measured values are the ratioof the first to control twitch response (Tl:T0)and train-of-four ratio (T4:T1). Anaesthesia wasinduced with midazolam 1 mg, fentanyl 0.05 mgand thiopentone 300 mg i.v. During ventilation ofthe lungs with oxygen and isoflurane by facemask, a stable 3-min control tracing of the NMTMonitor 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 wasintubated at 5 min. Anaesthesia was maintainedwith 1-2% isoflurane and 70% nitrous oxide inoxygen; fractional doses of vecuronium (total3.5 mg), fentanyl (0.1 mg), and midazolam (2 mg)were administered also. When Tl :T0 and T4:T1recovered to 70% and 50%, respectively, at45 min after the initial dose, the second dose ofvecuronium 0.5 mg resulted in Tl :T0 suppres-sion to 18% and eliminated the T4 response.Forty minutes after the last dose of vecuronium0.5 mg, Tl :T0 and T4:T1 had recovered 70%and 100%, respectively. These values remainedunchanged and the patient resumed spontaneousbreathing with good tidal volume during theremaining 20 min of surgery. Even though the

S3 oto

8Vecuronium 0.5 mg Antagonists100

a

FIG. 1. Tracing of evoked hypothenar electromyographic responses to train-of-four stimuli in a patientwith myasthenia gravis. Two different types of neuromuscular block, one resulting from vecuroniumand the other resulting from antagonizing agents, are shown. The former is a typical non-depolarizingblock, but the latter resembles a depolarizing block. Two (Tl and T4) train-of-four twitch responses areprinted. 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 acomplete recovery of neuromuscular transmis-sion, neostigmine 3 mg and glycopyrrolate 0.6 mgwere administered. Shortly thereafter, the NMTMonitor showed an acute onset of neuromuscularblock (fig. 1) and the spontaneous breathing wasabolished. The patient was sedated with mida-zolam 1.5 mg, transferred to the intensive careunit and underwent mechanical ventilation. At75 min after the administration of the antagonists,she began to breathe and was able to generate peakinspiratory negative pressures of —15 and —30 cmH2O, at 120 and 225 min, respectively. Thetrachea was extubated at 225 min. The postopera-tive course was uneventful. The patient wasdischarged from the hospital on the 5th day afteroperation.

DISCUSSION

Because the normal neuromuscular end-organ hasa large excess of receptor sites, transmission inresponse to single pulses or tetanic pulses at 30 Hzis not altered until 70-80% of receptors areoccupied by non-depolarizing blockers [4]. Thismargin of safety is reduced in myasthenic patients,depending upon the severity of the disease.However, non-depolarizing neuromuscular block-ers of intermediate duration (atracurium andvecuronium) have been used safely for surgicalrelaxation in patients with varying degrees ofmyasthenic impairment [5-8]. Following antag-onism of atracurium-induced residual neuromus-cular block with neostigmine 5 mg, none of aseries of five myasthenic patients suffered res-piratory embarrassment [8].

We used an NMT Monitor to titrate the dose ofvecuronium. The observed hypersensitive respon-ses to the initial dose of vecuronium (2 mg) wereunexpected because the extensive preoperativeinvestigation suggested that the myasthenia graviswas limited primarily to the ocular muscles, withnegligible somatic involvement. As a result ofmore cautious titration of subsequent doses,neuromuscular transmission recovered spon-taneously at the end of surgery. However, theantagonists were administered to increase themargin of safety. The resultant neuromuscularblock showed a well maintained train-of-fourratio (except for the significant train-of-four fadeson 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 toconfirm diagnosis, but also disclose hypersensitivereaction to a non-depolarizing neuromuscularblocker. The administration of isoflurane couldpotentiate the neuromuscular blocking effect ofvecuronium in this case. However, the potentia-tion by isoflurane is reported to be much less withvecuronium than with tubocurarine and pancuro-nium [10]. In addition, when the end-tidalconcentration of an inhalation agent is low at thebeginning of anaesthesia, potentiation may not bemanifested. Therefore, the dose of blocker neededto establish block at this time should not bealtered, regardless of the type of anaesthesia [11].

The reduced number of AChR in myasthenicmuscles cannot explain how anticholinesterasesimprove muscle strength. In contrast, the pres-ence of a relative excess of ACh on the remainingfewer receptors could induce nicotinic responses.Certainly, cholinergic crisis is a well knowncomplication in myasthenic patients, caused byan overdose of anticholinesterase. Depolarizingneuromuscular block observed in our patient indi-cated that cholinergic crisis was the most likelycause of muscle paralysis. Rolbin and colleagues[12] described a myasthenic patient who becameapnoeic acutely following i.v. administration ofneostigmine 2.0 mg and atropine 0.4 mg to treatthe myasthenic crisis which developed afterdelivery 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 thatfirst administration of neostigmine 2.5 mg antago-nized non-depolarizing block in anaesthetizedpatients, whereas a second dose given 2-5 minlater depressed the peak tetanic contraction andre-established tetanic fade. In their further studieson non-paralysed patients, one or two injectionsof neostigmine 2.5 mg caused a substantial re-duction in the peak tetanic contraction and severetetanic fade. These neostigmine-induced tetanicresponses were antagonized by gallamine andpotentiated by suxamethonium. They concludedthat neostigmine, in sufficient dose, produces anACh-induced depolarizing block, and cautionedthat when full recovery has been achieved, afurther dose of neostigmine could be hazardous,because a prolonged depolarizing block withapnoea could ensue.

This report shows that a cholinergic crisis canresult with indiscriminate use of anticholinest-

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erase; therefore, administration of antagonizingagents should also be titrated carefully in patientswith myasthenia.

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