ANAESTHETIC ASPF.CT OF THYMECTOMY FOR MYASTHENIA GRAVIS JONE CHANG, M.D., F.R.C.P.(C), Jor H. HA_aLAND, :M:.B., :B.Ca., and H. B. GI',AVES,M.D.* SINCE 1936 when B][alock performed the first successful thymeetomy for myasthenla gravls, there has been much dispute about the value of this procedure as a therapeutw mea:mre. Consideration of the usefulness of this operation is outside the scope of the anaesthesaologlst, but readers interested in the pros and cons of this subject may refer to articles by Keynes (1, 2, 3), Eaton and Claggett (4, 5), and Ferguson (6), where varying opinions are set forth. Alt_aough the condition was described by Thomas Willi:~ in 1672, the classical descnptlon was made by Jolly in 1895. He made suggestions as to its physiopathology and its b'eatment with physostigmine, and gave it the name "Myasthema Gravis Pseudo-paralytaca." C L ~ c ~ Pic-rum~ Essentlally the disease is characterizec~by muscle weakness, especially of the small muscles of the hand, the extra-ocular muscles and the muscles of the pharyngeal and laryngeal region. All or any of the skeletal muscles may be revolved in a completely irregulal pattern. It is characterized also by spontaneous remlsslon and exacerbatmn The disease can be divided into a localized ocular group, and a generalized group wlnch is usually progressive. PnYSm-PATHOTOCY Although the process of myasthenia gravis is localized anatomically to the myoneural junctmn, the exact cause of the disease is not known. The reaction of the end-plate in a myasthe~ic dd[ers from that m the normal person as shown ~y achon-potentml recording from the end-plate:when acetylcholine is injected m~a-artermlly followed by the m]ectmn of neostigmine (7). Normally there is an early prompt depres,;ion of action-potential followed by a late phase of depressmn, both these phases being enhanced by neostigmlne. In the myasthemcs, the prompt phase was enhanced and the late phase reversed by neostigmine, indicating a competitive type of block as compared to the normal depolarizing block. Many theories have been advocated to explain the nature of this disease, such as. (1) Increased concentration of cholinesterase. (2) Decreased amounts of aeetylcholine liberated at the end-plate. (3) Decreased susceptibility of ,the receptors to normal acetylchbline concentration, because of locally produced curare-like toxin or systemically produced toxins. The last hypothesis has attracted much attention since it is postulated that the thymus is the site of production of this curare-like toxin. *Department of Anesthesm, Vancouver General Hospital, and the University of British Columbm 13 Can Anaes Soe J, volt 4, no. 1, Jan., 1957
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Weigert suggested in 1901 that a curare-like metabolite elaborated by the thymus is the cause of the disease. In, 1952 Witson (8) demonstrated that an extract from operative specimens contains curare-like substance, Further support of the curare-like toxin was forthcoming in 1953, when Schwarz demonstrated that the serum of myasthenic patients contained a factor capable of producing muscular weakness on administration to normal individuals. D~ACNOSnS Drugs used in the diagnosis of myasthema gravis are (1) neostagmine; (2) edrophonium (Tensflon); (3) d-tubocurarine; (4) quinine. The first two drugs are usually used as the diagnostic agent as they cause temporary improvement of the muscle strength, while the latter drugs are seldom used because the increase in the weakness of the muscles produced by them may lead to respiratory difficulty. "Tensilcn" may be more useful in that its onset of action is brief, whereas neostigmine has a longer onset and duration of action. "Tens~lon" is a poor therapeutic agent because of its short duration. If curare or quinine are used as diagnostic agents, neostigmine must be available to counteract severe muscular weakness. TREAT~:NT
Drugs are one method of treatment. The first group is that of the antichoIinesterases: (a) physostigmine, (b) neostigmine; (c) pyridostigmine (Mestinon); (d) Mysuran (WIN 8077). Until recently neostigmine has been the drug of choice in the treatment of myasthenia gravis. NeoslSgmine has two modes of action, pnmardy It is an anticholinesterase and, in addition, it has a direct depolarizing action at the end-plate. It inactivates not only the true but also the pseudo-cholinesterase of the plasma. Despite the preference for neostigmine for many years, more satisfactory agents are now being used. Both pyridostigmine and "Mysuran" produce similar clinical results with less side reaction and longer duralaon of actaon. These side effects me due to the musearinie action which is responsible for excessive cholinergic stimulation such as discomfort, salivation, bronchorrhea, nausea, urgency, etc. These muscarinic effects may be blocked by atropine. The second group is that of the adjuvant drugs: (a) Atropine, (b) Ephedrine and Amphetamine. Other methods o[ treatment are as follows: (1) Irradiation of the thymus, (2) Surgical removal of the thymus; (3) CombLnatlon of the above ANAESTHETIC CONSmF_~JkTIONS
Preoperative Management Ideally surgery should be performed durin~r a remission, as patients with severe cases are poor surgical risks. The nutritional state of the patient should be improved, since poor nutrition may be present as the result of weakness of the muscles of swallowing. Although Keynes is very emphatic that these patients should not be given a
CHANG
et al.:
TttYMECTOMY FOB ~2r
GRAVIS
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preoperative enema, as it may result in collapse, we have found no adverse effects. Opiates are not directly harfnful but should be prescribed in minimal doses before operation, as anything, diminishing the ability to cough should be avoided. Moreover, large doses may depress the respiration su~ciently to cause anoxia. Belladonna drugs are essential since the anfieholinesterase's stimulate excess secretion. Antieholinesterase drugs are required before opcrati6n in doses equal to or larger than regular amounts (e.g., neostigmine 1 to 9..5 mg. parentera_ly).
Management du~ing Anaest~esia Technique. Endotraeheal anaesthesia is the method of choice for thymectomy, since it not only provides an unobstructed airway at all times, but also affords an easy means for tracheo-bronc]hial toilet when excessive secretion is present. Finally, control of respiration is stmple if the pleura is accidentally opened. It is worth noting that Keyne,;, whose personal experience is unequalled, opposed mtubatlon on the gronnds that it might contribute to postoperative respiratory infection and atelectasls. Relaxant drugs. In severe cases with muscle weakness no relaxant will be reqmred, but in the mdder cases relaxants may facilitate mtubation and control of resplrataon. Any relaxant drugs that are used should be given judiciously and wath care. Curare and other competttive blockers are contraindicated since they interfere with the action of acetylchohne at the end-plate, thereby increasing and prolonging the muscular weakness. Therefore, prolonged muscular relaxation may result with the use of tubocurarine. Theoretically, the rnyasthenic patient should be resistant to the depolarizing group of~relaxants such as decamethonmm and succinylcholine, because of th6ir depolarizing actaon at the end-plate. The work of Churchill-Davidson and others has shown that in the myasthenic patients decamethonilam and succinylcholine act as a competatwe ~ype of blocker, and that their effects are reversed and not potentiated by neostlgrnine (9, 10). Both agents have been used in our hospital without producing prolonged relaxation. Anaesthetic agents. A wade choice of anaesthetic agents has been advocated for th~s procedure. Any gaseous or volatile anaesthetic agent would be satisfactory. Cyclopropane is probably the agent of choxce since it is easily administered, causes httle ~rritatlon of the respiratory tree, and less depression of the muscles. The combination of cyclopropane and neostigmine may theoretically be incompatible because of neostlgmme's stimulation of the sympathetic ganglia with resulting epinephrine discharge into the ciLrculation. Clinically, the amount of neostigmine used preoperatively does not produce any appreciable sympathetic reaction. Ether tends to increase secretion in the respiratory traot and to depress the muscles more than cyclopropane. The combination of nitrous oxide and supplementary agents is satisfactory provided excessive amounts of the latter (t?entothal or Demerol, etc.) are not used. These non-volatile agents are metabolized slowly and will depress respiration cenl~mlly.
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Postoperative Management (1) Resptratory mfeclaon and atelectasis are potential complicahons after surgery. Good respiratory movement and adequate nursing care will help to prevent them. (2) Excessive secrehons are likely to be troublesome because of: (a) impaired abdity to cough, (b) the use of neostigmme, which produces profuse salivation and bronchorrhea. Atropine and tracheo-bronchial toilet wdl prevent accumulahon of secrehon. (8) The posslbdlty of postoperative pneumothorax from surgery must be borne in mind. (4) Opiates should be used sparingly ~to allay restlessness, as other causes such as anoxla may be the cause of it. Large doses of opiates will further aggravate anoxia. (5) Neostigmme or some other anticholmesterase drug must be administered regularly postoperahvely to anamtam good muscular tone and adequate resplrahon. Neostlgmme m doses of 1.0 to 1.5 rag. may be gtven every two hours m the. immediate postoperative period. The dangel of cverdosage with anhcholinesterase drugs must always be kept m mind. In the event of inadequate response to neoshgmme and other drugs and the patient's inability to maintain adequate resplrahon, Jorgenson and Therkelson (11) have advocated that all drugs be discontinued and that _he patmnt be treated as one would treat a bulbar pohomyehtls, by placing tee pahent m a respirator, adequate tracheo-bronch~al todet, and tracheotomy. CASE 1. Miss A. j , age 15 Patient gave a history of progresswe difficulty m swaUowmg for one year -3rmr to surgery She had not taken any medlcatmn before admlssmn to hospital. In _aospltal she was taking 5 nag of prostlgmme every three hours For preoperative preparation, prostxgmme 1 0 mg was in)eeted one hour ~efore surgery along with Morphine gr 1/19. and Hyoseme 1/200 She was anaesthetized with eyelopropane by endotracheaI teehtuque After operahon, patmnt was earned on prostlgmme 1 0 mg qgh I M. On the second postoperatwe day X-ray of the chest showed a pneumot_aorax on both sides w~th 20 per cent collapse. The pneumothorax absorbed spontaneously without treatment. Case 2. M~ss D. W, age 22 Patient gave a history of weakness for three years She had no medmatmn prior to admlssmn to hospital While m hospital pahent took prostlgmme 15 mg. twine daffy with atropine. Preoperative medmation was SeeonaI grs. Ta 90 minutes preoperahvely, Demerol 100 rag, plus Hyoseme gr 1/150, one hour preoperatwely Pahent was anaesthetlzed with eyclopropane and ether with endotraeheal teetmlque. Postoperatwelv, proshgmme 1 0 mg and atropine gr. 1/150 were administered qgh. On the first postoperative day the patient developed a sudden attack of cyanosls and difficulty in restnratmn Examination lndmated ateleetasls whmh was confirmed by X-ray. Traeheo-bronc.haal todet immediately reehfied the condition. The patient recovered uneventfully after th~s episode. CaSE8 MlssS A , a g e 19 Patient gave a history of weakness since childhood. At age eleven she was so weak that she could not dress herself. Prostigmme was started at age fourteen with 8 to 14 tablets dady. The usual dose of prostigmine was administered, prior to operation. Pre-
CHANG et al.: THYMECTOMY FOR ~YASTHEN].A. GRAVIS
17
operatave sedatmn included Scconal grs. ~ , Mor-~hme gr. 1/8 and Hyoscme gr. 1/t50.. Patmnt was mduced with per,totha1,500 rag: and syncurine 8 ~rag. She x~as maintained wxth endotracheal mtrc,us oxide and ether. Postoperatave mechcation was prostigmme 0.5 rag. q2h. On the first postoperative day, partial pneumothorax was shown by X~rays, The patmnt had no dastress with the pneumothorax. The pne ,umothota~. was reduced by removal of 700 cc. of air. The subsequent course was uneventful. CASE 4. Mrs. E. W., age 80 Mrs E W. gave a h_story of weakness for one year. She had been on plrostigmine and later "Mestmon," which partially controlled her weakness. Befcre operation she had Mestmon 60 mg., Pantapon gr. 1/6 and Hyoseme gr. 1/150. Patient was reduced with pentothal 500 rag. and carrmd on with endotracheal cyclopropane and ether. Proshgmine 0 5 mg was gwen intravenously to the patxent q2h postoperatwely, On the second day, proshgmme was increased to 0 5 rag. q l h because of dyspnoea during that period. Twxce, 500 cc, of air were aspirated from the chest. The -~atient had nine doses of proshgmme over a period of less than eight hours during the n ght, so that when morning came she was m a state of collapse wxth gasping respiratmn, cardiovascular collapse,, and chsonentatlon. A bronchoseopy was performed to remove secretion and estabhsh a clear an'way, and the. patmnt was then placed m a resparator. After several hours in the respirator her condltmn became worse, ~r signs of hypoxia. ~n er~dotrachea] tube was inserted, large amounts of thxck secretion were removed from the trachea, and her condltmn improved immedmtely.-During the next 24 ho~ws th~ endotracheal tube was removed and inserted several times. A traeheotomy was performed about 86 horus after the surgery. The patmr~t remained in the respirator for 10 days. During the first few days m the resptrator, antachohnesterase drug was given in a slow intravenous drip. Later the drug wes given by ]evme tube. The pahent made a s][ow recovery and was discharged after a two-month stay in hospital DISCUSSION Although myasthema gravls is a medical disease of unknown etiology, its great interest t o ' t h e anaestheslologlst lies in the site of its pathology, the myoneura] jtmctlon. Myasthenla graws re,some way affects the transmission of the normal neuro-muscular impulses through the end-plate: in anaesfliesia we very commonly alter the transmission at this site, m order to produce muscle relaxation. Like myasthema ~,ravls, the curanform agents mimic the disease by affecting the small muscles of t_le eyes and pharyn~ first. Similarly, drugs which are useful in the treatment o~f myasthenia gl avis are antagonistic to the curariform agents. Prostigmine has been the drug of choice in the treatment of myasthenia gravis, but recently newer drugs winch are more efficacious in relieving the symptoms have become available. Mestinon and Mysuran produce the s.ame therapeutic effects as proshgmme with the advantage of fewer and less severe side effects mid longer duration of action. Surgical treatment of myasthenia gravis is carried out ha m a n y cages, although there are diversified opinions as to its effectiveness in controlling the disease and as to the indications for surgery. The results of thymeetomy vary in different cenecres because of the different criteria for operation. In the early benign ocular cases, the results of thymectomy were good, while in the progressive severe generalized cases, the results were poor. Cases undergoing surgery of the thymus are of great interest to the anaesthesiologist because they present problems with many facets. In the benign early cases the anaesthetic management and post-
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operative care are no real problem, while in the progressive severe cases with generalized weakness the management is a great challenge to the anaesthesiologist. Preoperative preparation of these patients is important. Prostigmine or similar drugs should be gwen immediately prior to surgery. Light pre-anaesthetic sedation is preferable, with special attentaon be:~ng paid to _the belladonna drugs, because the anticholinesterase drugs increase the secretion of the salivary and bronchial glands. The choice of anaesthetic agent:; is of great importance. The volatile or gaseous anaesthetacs are agents ot choice because non-volatile drugs may give prolonged.depression. Relaxant drugs should be avoided. If given, they should be admlmstered with great care, as th,ey directly affect ~ e diseased myoneural juncbon. The competitive curare group will potentiate the disease, and thus may lead to prolonged muscle relaxe.tlon. Similarly, wida altered response of the end-plate, the depolarizing agents rnay give a competltwe type of reaction, again leading to prolonged relaxataon. The immediate postoperative period is the ~aaost ,,;erious stage of the anaesthetic management and requires stnct vigilance. Prolonged relaxation may be present ff relaxant drugs were used In severe cases of myasthema gravis the disease itself, plus depression by the anaesthetic agents may be enough to produce poor muscular tone. Prostlgmme at the end of the operabon will u~ually provide sumcient control of the disease to maintain adequate respiration. Dyspnoea, causes of winch may not be immediately evident, must be recognized and treated. Of the many aetlologies, pare from the surgical insult is commonly the cause of dyspnoea. Judicious use of analgesics will ehmmate this discomfort. Pneumothorax may give rise to the sensation of dyspnoea alo~g wath the symptoms of inadequate ventilaCaon such as cyanosls, tachycardla, sweating and vasomotor collapse. Weakness of the muscles of respiration, from the lack of anticholinesterase drugs, will cause dyspnoea with associated symptoms of anoraa. Excessive secretion from the stimulation of the bronchial glands by the antlcholinesterases may cause obstruction, dyspnoea and atelectas~s. Finally, over, medicatipn with the anbcholmesterase drugs gives a picture similar to undermedication; that is, weakness of the muscles and diflaeulty in respiration Recognition of these causes of respiratory d~fficulty is essentT[al because the treatment of each is specific. Pneumothorax can be found by physical examination and confirmed by X-ray of the chest. Withdrawal of air from the chest gives dramatic recovery. Similarly a tracheo-bronchiaI toilet will dramatically reheve the symptoms of excessive secretion and will cure atelectasis. In severe cases, bronchoscopy may be required to remove the secretions. The recognition of the state of the anticholinesterases is a more diftqcult problem, since the signs and symptoms of too much drug and too little drug are similar. Over-medication with anticholinesterase drugs is known as "ChLolinergic Crisis," and has the following manifestations, muscle weakness; gas~xointestinal stimulation; salivation; excessive bronchial secretion; pallor; cold sweat; urgency; fasiculation of voluntary muscles; constriction of the pupils; increased b ood pressure with or without bradycardia; faintness and collapse; subjective symptoms such as anxiety and internal trembling. "Tensilon" has been advocated, for the diagnosis of
crIANG e t al.: qCI-IYMECTOMY FOR MYASTI-IENIA GlqAVIS
19
eholinergm crisis because of its brief duration of action. In crisis, weakness would be potentiated, whereas the strength is increased if too little dxug was given,. The treatment of crisis consists of: stopping all anticholineste~rase drugs; administration of atropine to block the muscarinic effects; artificial ventilation untd adequate respiration is restored; tracheotomy to provide fbr proper tracheobronchml toilet. The problem of tracheotomy must be considered seriously. Although it'rs a life saving procedure, tracheotomy in the early post-thymectomy permd may predispose t~he patient to mediastinitas. S U M M.A_RY
The authors have presented flora then: experience some ot the difficulties encountered in the anaesthetm management of myasthenic pati(~nts for thymectomy. The hypotheses concerning the nature os the disorder and the physi 9pathology have been outlined bnefly to prowde a better understanding of the problem Methods of treatment end m~aesthetic management of these patients have been outlined, and comphcations discussed. l~str~ La myasth4me gravis est caract4ris4e essentiellement par de la falblesse muscula~re, faiblesse locahs4e phts sp4cialement aux petits muscles de la main, aux muscles extra-oculmres et aux muscles du larynx et du .phar/nx. Indistinctement, tous les muscles du squelet-te peuvent 8tre affect4s et de ~a~on tout-~-fait lrr4guh~re. Bien que la pathologic soit localis4e anatomiquement ~t la jonction myo-neurale, la nature exacte de,, troubles demeure inconnue. Plusieurs th6ories ont ~t4 4nuses pour explique~r la nature de cette maladle. Parmi ces th4ories, l~une a pr6tendu que le thymus s4er4talt une substance eurarfforme qm dlmmualt, ~t la ]onetlon myo-neurale, la suscep6bfllt4 aux concentrations normales d'acetylchohne d'ofl est n4 le traltement ehlrurgical de ces malades par la thymeetomle. La n~ostigmme et l'6drophonmm (tenslion) am~horent temporairement la force museulatre dans la myasth6nxe graws et on les emploie pour pr4ciser le diagnostm de la maladxe La d-tuboeurarine et la quimne augmentent la faiblesse musculalre, on peut 6galement les emp][oyer pour pr6clser le diagnostic, rams plus rarement. Jusqu% ees dermers temps, la n6ost/gmine 4tait le m6dlcament de ehoix pour trmter la myasth4nie, maintenant de nouveaux m4dicaments tels clue la Pyridostigmine (Mestinon) et le Mysuran '(Win 8077) donnent plus de satisfaction parce que leur action est plus prolong4e et ils front pas d'aetion muscarinique comme la n4ostigrnine. Le moment id4al d'appliquer le traitement chirurgieal, c'est au tours d'une r4mlssmn de la maladie. Avant d'op4rer, ll s'impose d'am41iorer l'4tat de nutriOon du malade qm peut laIsser ~t d~;sirer h cause de la faiblesse ties muscles de la d4glutltion. Avant l'op~ration, il est sugg6r4 de r4duire au minimum les opiae6s oour ne oas d4pnmer les r6flexes ~ la toux. Les m4clicaments du type belladone
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sont ~t consefller car les m6dmaments antlchohnest6raslques favonsent l'aceumulatmn de t'ac6tylchohne. Ces m6dmaments, avant l'op6ratmn, sont presents doses 6gales et mSme ~ doses sup6neure,,, h celles donn~es ordmmrement (e.g., N6osfigmine 1 ~ 2.5 mgm en mlectton). Pour la thymectomm, l'anesth6sm endotrach3ale est la technique de cholx: elle permet de maintenn- fibres les voles resplratou'es, d'enlever les s~cr6tions s'fl y a lieu et aussi de mamtemr une pressrun positive sg accldentellement, la pl6vre est ouverte. Ce n'est qu'avec de grandes pr6cautaons qu'H s recourrr ~t l'usage des agents curansants. Le Ctlrale et les autres bloqueurs ~t comp6titmn sont contrmdlqu6s. Dans la myasth6nie, le d~cam6thomum et la succmylchohne aglssent comme des bloqueurs ~ comp~tltaon et leurs effets sont d6trmts et non potentmhs6s par la n~ostlgmme (9, 10). Les auteurs ont falt l'usage de ces deux m6dmaments chez des myasth6niques sans observer d'atonie prollong6e. Le cyclopropane est probablement l'agent de chmx. L'6ther tend h augmenter les s6cr6tlons dans les voles resplratolres et fl d6p~lme les muscles plus que le cyclopropane. Les agents non volatds sont m6tabohs6s lenternent, fis auront tendance ~t d6pnmer les centres resplratolres et leur emplox dolt s'aecompagner d'une grande prudence. Parm~ les complications post-op6ratoires possibles, cltons les refections resp~ratolres et l'at61ectasm. I1 peut ex~ster des s~.cr6tnons abondantes et ennuyeuses r6sultant de sahvation et de bronchorrh6e favor~s6es par la n6ostagmme en mSme temps qu'une incapac~t6 de tousser I1 y a 3galement posslbfllt~ de pneumothorax post-op6ratolre r6sultant de la chirurgie. I1 faut fa~re usage des opxac~s avec d~scr6taon pour calmer l'ag~tatmn, car cette agffatlon peut 8tre caus6e par un manque d'oxyg3ne qm ne pourrait cu'Stre accentu6 par les opmc6s Dans les states op6rato~res, fi est consefll5 de conner de la n6ostlgmme ou un autre m6d~cament antaeholinest6raslque reguli6rement pour mamtentr un bon tonus musc ula~re et une respiratmn ad6quate Toutefo~s, fl ne {aut pas oubher la posslbfllt6 de surdosage de ces m6d~caments Un malade qm ne r6pondrait pas de fa~'on satlsfmsante aux m6dmaments anticholinest6ras~ques devralt dtre plac6 dons un respirateur. I1 peut devenlr n6cessalre de prat~quer une trachSotomle pour aspirer ad6quatement les s6cr#hons bronchlques excesswes, partacuh6rement au moment des crises chohnerg~ques REFERENCES 1 K~YNES, (3 Bnt Med J, 11 611 (1949)
2 KEYNES, G 8 4 5 6 7 8 9. 10 11
Annals of Royal College Surg, 12. 88 (1958).
KE~CNES, G Lancet, I 1197 (1954). CLACCETr, O T & EATON, L M J Thoracic Surg, 16 6fl (1947). CLACCETT; O T, EATON, L M & GLOVEn, B P. Surgery, 26:852 (1949). FFfaGUS~N, F R, HUTCHESON, E. C. & LEVEaSmGE, h A. Lancet, 269. 686 (1955) GRoB, ~, Joi~Ns, R G & McGEm~E, H Trans. Assoc. Ann. Phys., 68 50 (1955) WILSON. Lancet, 11 868 (1958). CItXJtlCHILL-DAvIDSON, H C & RmIL~m~SON, A. T. J Physml, 122" 252 (1953) ZALM~S, ] E J. Physlol, I 2 2 : g 3 8 ('1958). ]OaCENSEN, ] B & TI-IEI'aCELSON, F 1{, Acta chit. Scanchnav, 107:414 (1954)