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Specific features of anesthesia in patients with Myasthenia Gravis/ Specificnost anestezije kod pacijenata sa Miastenijom Gravis.

UDK 616.8-009.17-089.5



Myasthenia gravis (MG) was first described in the seventeenth century, but as an entity it was recognized only 200 years later when Dr Friedrich Jolly described it and named it as "Myasthenia gravis pseudoparalytica". At that time the disease led to death as a rule within one or two years from onset its due to respiratory failure [1].


MG is an autoimmune disease caused by antibodies leading to the destruction of nicotinic acetylcholine receptors on the neuromuscular junction. This destruction results in a reduced number of acetylcholine receptors and reduced number and depth of wrinkles on the postsynaptic membrane on neuromuscular junction of all muscles, including those which are not clinically manifested. Autoantibodies can be detected in most cases ("seropositive patients"), but it is also known that 10-20% of "seronegative patients" also have autoantibodies. The cause of autoimmune reactions leading to MG is still unknown, but it is known that there is a very strong connection between MG and pathology of thymus. In 70-80% of patients with MG there is a thymus hyperplasia and thymoma is present in the 10-15%. The most commonly affected are women between tthe ages of 20 and 30 years, but in males the disease usually occurs after the age of 60 years [2].

Clinical Signs

Myastenia gravis is characterized by muscle weakness that gets aggravated with physical activity and improves at rest. In most patients the disease begins with ocular symptomatology (diplopia and ptosis of the eyelids), followed by bulbar symptoms (difficulty swallowing and speech), weakness of neck and extremity muscles and at the end dyspnea may develop due to the weakness of respiratory muscles. MG can also affect the cardiac muscle resulting in palpitations, hypertension, AV block of first degree, atrial fibrillation and myocarditis [3].


The first classification of MG was made by Dr Osserman in 1971. The division was made according to the affected muscle groups [4] (Table 1).

It was the basis for the American Foundation for MG (Myasthenia Gravis Foundation of AmericaMGFA) to make the clinical classification of MG, which is still in use today [5] (Table 2).


Since 1952 "Tensilon test" has been the gold standard for the diagnosis of MG. This test is carried out by intravenous (IV) injection of edrophonium (Tensilon) and then by following the development of muscle weakness in the next 30-90 seconds. In addition to this test repeated muscular stimulation can be used as well as the analysis of specific autoantibodies according to which patients are divided into "seropositive" and "seronegative" patients [6].

Treatment of Myasthenia Gravis

Conservative Treatment

In conservative treatment of MG anticholinesterases (pyridostigmine), immunosuppressants and plasmapheresis can be used:

1. Pyridostigmine (Mestinon) is the anticholinesterase of choice for MG. The action of this drug starts 30 minutes after its oral administration and the effect lasts for 3 to 6 hours. It can also be crushed and applied through a nasogastric tube or intravenously in an adjusted dose 30: 1, i.e. 30 mg of pyridostigmine given orally (PO) equals 1 mg of neostigmine given intravenously.

2. When the anticholinesterase is not enough for symptomatic disease control then immunosuppressive therapy is indicated. The most commonly used immunosuppressants are corticosteroids (CS). An alternative immunosuppressant is an azathioprine (Imuran). It takes this drug as many as 24 months to achieve the desired effect, but it may reduce the dose of corticosteroids to a minimum. Another available drug from this group is Cyclosporine, which is a very potent immunosuppressant, but with many toxic effects.

3. Plasmapheresis has also been in use since 1976 in the treatment of MG. The aim of plasmapheresis is to reduce titer of acetylcholine receptor antibodies in seropositive patients. Indications for plasmapheresis are: bulbar symptoms of disease, myasthenic crisis and optimization of preoperative status of the patient. It is administered in a series of 3-5 plasma exchanges in one to two weeks. Improvement after plasmapheresis may last for 2 weeks to 2 months [7].

Surgical Treatment

If conservative treatment does not lead to the desired remission, surgical treatment is indicated. First thymectomy for treatment of MG resulting in remission of the disease was performed by Dr Blalock in 1939. There are still controversies regarding the indication of time of surgical intervention and surgical approaches. The most accepted indication for thymectomy is the presence of thymoma with generalized form of MG in adults. Today, thymectomy can be performed with equal efficiency either transsternally or with video-assisted thoracoscopy (VATS), that being the minimum invasive approach [7, 8].

How to Distinguish Myasthenic from

Cholinergic Crisis

In the perioperative period the greatest danger is the possibility of development of myasthenic and cholinergic crisis. The major challenge is to distinguish myasthenic from cholinergic crisis because both are characterized by muscle weakness and respiratory distress. The following is important to make a difference between these two crises: knowledge of the events that preceded the crisis, the size of pupils (in myasthenic crisis pupils are wide due to sympathetic activation, while they are narrow in cholinergic crisis), as well as the presence of muscarinic signs and tensilontest [9].

Myasthenic crisis represents a rapidly progressive decrease in the muscle strength which leads to respiratory failure and life-threatening conditions. The most common causes of myasthenic crisis are: stress, surgery, infection, high body temperature and the use of certain drugs (aminoglycosides, quinolones, macrolides, beta blockers, calcium channel blockers, magnesium salts, iodine contrast, phenytoin, procainamide). When treated for myasthenic crisis the patient should be intubated promptly, then mechanical ventilation support should follow and the dose of anticholinesterase should be increased to achieve the desired effect. It is also necessary to eliminate the potential causes of the crisis and possibly consult a neurologist in order to introduce plasmapheresis or intravenous immunoglobulin (IVIG).

Cholinergic crisis develops due to too much acetylcholine on the cholinergic receptors. Cholinergic crisis is usually caused by anticholinesterase overdose. Its features are fasciculations, muscle weakness and positive muscarinic signs (bradycardia, bronchorea, miosis, salivation, nausea, vomiting, diarrhea, colics, pallor, etc). Once the signs of cholinergic crisis are recognized, it is necessary to suspend further implementation of anticholinesterases, and their further application should be reconsidered depending on the general condition of the patient. The treatment is mostly symptomatic, including 0.5 mg atropine given IV if necessary, and in the case of respiratory insufficiency the patients should be intubated and mechanically ventilated.

Specific Features of Anesthesia in Patients with Myasthenia Gravis

Application of anesthesia in patients with MG is based on pathophysiological changes that cause the underlying disease. This mechanism of the disease development is the reason for the increased sensitivity or resistance of these patients to certain types of drugs used in anesthesia. According to the current recommendations, the following drugs can be administered in anesthesia for patients with MG:

--Intravenous anesthetics which are safe to be used in anesthesia are propofol, ketamine and etomidate because of their minimal effect on neuromuscular transmission. Either total intravenous anesthesia (TIVA) or inhaled anesthesia can be safely used to maintain anesthesia. TIVA and inhaled anesthesia have been proved to be equally efficient and safe to be applied both for the introduction of anesthesia and its maintenance and to create a good condition for rapid extubation, especially if combined with remifentanil [10];

--Opioids should be used very carefully. Remifentanyl, sufentanyl and fentanyl can be applied. They should be titrated very carefully and given at the lowest possible dose because of their depressive effects on the respiratory center. Opioids should not be administered in premedication! Perioperatively, priority is given to short-acting opioids (remifentanyl). Opioids should be avoided postoperatively, priority is given to regional or multimodal analgesia. If necessary, opioids should be given with careful titration [11];

--Volatile anesthetics--sevoflurane and isoflurane can be used safely. Volatile anesthetics can be administered to induce anesthesia and/or maintain it. The good side of volatile anesthetics is that they reduce neuromuscular transmission which reduces the need for neuromuscular relaxants, but therefore they must be carefully titrated so as not to lead to prolonged awakening and extubation. They combine with with regional analgesia and remifentanil [12];

--When neuromuscular relaxants are administered, special attention should be paid to the following issues:

--Depolarizing muscle relaxants (succinylcholine) should not be used! Patients with MG are resistant to succinylcholine because of the loss of nicotinic receptors. Besides, they are much more likely to develop phase II of the dual block.

b) Short-acting and intermediate-acting non-depolarizing muscle relaxants (NDMR) can be used but very cautiously and at minimal doses. Pancuronium SHOULD NOT BE USED! Patients with MG have increased sensitivity to NDMR and it is recommended to avoid their use. In case that they have to be administered, it should be at a dose of 1/5-1/2 of the recommended dose. The safest recommendation is to choose a minimal dose of short-acting NDMR and allow the effect to terminate spontaneously [13]. When they must be administered, monitoring of neuromuscular strength is mandatory.

Thoracic epidural analgesia can be safely used for perioperative and postoperative analgesia [3].

Protocol of Perioperative Anesthesia in Patients with Myasthenia Gravis

Perioperative Investigations

a) Due to the pathophysiology of MG and its impact on the function of various organs and organ systems, the following preoperative investigations are recommended [9] (Table 3).

b) Despite many efforts to determine the exact risk factors that could represent predictive factors for prolonged postoperative mechanical ventilation, they have not been precisely defined yet. However, it is believed that there are certain predictive conditions that represent a high risk for prolonged postoperative mechanical ventilation [9] (Table 4).

c) There are different opinions about preoperative doses of antirholinesterases. One of them is that anticholinesterases should be suspended on the day of surgery to reduce the need for muscle relaxants [14]; another one is that patients with class I and II should take half of dose and with higher class full dose of the anticholinesterases [15]; it is also believed that everyone should take the full dose 1 hour before surgery since the aim is to achieve optimal muscle strength for extubation [13]. We, as well as Slinger, believe that everyone should take the full dose of Mestinon 1 h before surgery because the goal is to achieve the optimum condition of patient for extubation [9] (Table 5).

Protocol for Perioperative Anesthesia

Based on 35 years of experience in the surgical treatment of patients with MG anesthesiologists at the Department of Thoracic Surgery, Institute for Pulmonary Diseases of Vojvodina, made the protocol of anesthesia and perioperative treatment for these patients.


--Atropine 0.5 mg IM

--WITHOUT sedatives and opioids

--cephalosporin of 2nd or 3rd generation IV


--propofol/inhaled induction (Sevoflurane)

--WITHOUT muscle relaxant

--methylprednisolone 125 mg (if the patient received corticosteroids preoperatively)

Maintenance of Anesthesia

--TIVA/inhaled anesthesia (Sevoflurane)

--opioids--the minimal dose of short-acting opioids (remifentanyl)

--nondepolarizing relaxant--if necessary, 1/5-1/2 dose

--monitoring of muscle relaxation

Postoperative Treatment

Day 0:

--cephalosporin 2nd or 3rd generation IV

--nonsteroid antiinflammatory drugs (diclofenac, ketorolac) and/or Tramadol IM

--and/or Paracetamol IV

--and/or opioids with careful titration

--blocker of proton pump

--(neostigmine 2.5 mg + 1 mg atropine + 0.9% NaCl up to 5 ml) - 1 ml IV/4h + pp. 1 ml, if there is muscle weakness

Day 1:

--(neostigmine 2.5 mg + 1 mg atropine + 0.9% NaCl up to 5 ml) - 1 ml/6h IM

--Tbl. Mestinon 60 mg 0 + 1 + 1 PO

Day 2:

--(neostigmine 2.5 mg + lmg atropine + 0.9% NaCl up to 5 ml) - 1 ml/8 h IM

--Tbl. Mestinon a 60 mg 3x1

Day 3:

--Tbl. Mestinon a 60 mg 3x1

Thymectomies Performed to Treat Myasthenia Gravis at the Department of Thoracic Surgery, Institute for Pulmonary Disease of Vojvodina from 2004 to 2014

The first thymectomy for surgical treatment of MG at the Department of Thoracic Surgery, Institute for Pulmonary Diseases of Vojvodina in Sremska Kamenica, was performed by Prim. Jozef Jaso in 1982, via trans-sternal approach. First video-assisted thoracoscopic thymectomy at the Department of Thoracic Surgery was done in 2010 (Table 6).


Myasthenia gravis is a rare autoimmune disease that has been surgically treated at the Department of Thoracic Surgery, Institute for Pulmonary Diseases of Vojvodina successfully in past 35 years. In their everyday clinical practice anesthesiologists may have to deal with a patient with myasthenia gravis in different types of surgical interventions. The protocol for anesthesia and perioperative management of these patients herewith presented may greatly help them in their clinical practice.

MG        --Myasthenia gravis
TIVA      --total intravenous anesthesia
NDMR      --nondepolarizing muscle relaxants
PO        --per os
IV        --intravenous
IM        --intramuscular
MGFA      --Myasthenia Gravis Foundation of America
VATS      --video-assisted thoracoscopy
KS        --corticosteroids

DOI: 10.2298/MPNS1610305S


[1.] Pascuzzi R. The history of myastenia gravis. Neurol Clin. 1994; 121:231-42.

[2.] Stoelting RK, Dierdorf SF. Anesthesia and Co-Existing Disease. Philadelphia: Elsevier, Saunders; 2002. p. 522-7.

[3.] Gibson TC. The heart in myastenia gravis. Am Heart J. 1975; 90:389-96.

[4.] Osserman KE, Genkins G. Studies in myastenia gravis: review of the twenty-year ewperience in over 1200 patients. Mt Sinai J Med. 1971; 38(6):497-537.

[5.] Jaretzki III A, Barohn RJ, Ernstoff RM, et al. Myastenia gravis: recommendations for clinical research standards. Ann Thorac Surg. 2000; 70:327-34.

[6.] Daroff RB. The office tensilon test for ocular myastenia gravis. Arch Neurol. 1986; 43:842-4.

[7.] Nicolle MW. Myastenia gravis. Neurologist. 2002; 8(1):2-21.

[8.] Baraka A. Anaesthesia and myastenia gravis. Can J Anaesth. 1992; 39(5):476-86.

[9.] Slinger P, editor. Principles and practice of anesthesia for thoracic surgery. New York: Springer Science+Bussines Media, LLC 2011. p. 211-6.

[10.] Sanjay OP, Prashanth P, Karpagam P, Tauro DI. Propofol or sevoflurane anesthesia without muscle relaxants for thymectomy in myasthenia gravis. Ind J Thorac Cardiovasc Surg. 2004; 20(2):83-7.

[11.] TIVA with propofol and remifentanyl for video-assisted thoracoscopic thymectomy in patients with myastenia gravis. Anesth Analg. 2006; 103(1):256-7.

[12.] Della Rocca G, Coccia C, Diana L, Pompei L, Costa MG, Tomaselli E, et al. Propofol or sevoflurane anesthesia without muscle relaxants allow the early extubation of myastenic patients. Can J Anesth. 2003; 50(6):547-52.

[13.] Krucylak PE, Naunheim KS. Preoperative preparation and anasthetic management of patients with myastenia gravis. Semin Thorac Cardiovasc Surg. 1999; 11(1):47-53.

[14.] Baraka A, Taha S, Yazbeck V, et al. Vecuronium block in a myastenic patient. Influance of anticholinesterase therapy. Anaesthesia. 1993; 48:588-90.

[15.] Girnar DS, Weinreich AI. Anaesthesia for transcervical thymectomy in myastenia gravis. Anesth Analg. 1976; 55:13-7.

Rad je primljen 22. III 2016.

Recenziran 6. VI 2016.

Prihvacen za stampu 8. VI 2016.



Institute for Pulmonary Disease of Vojvodina, Sremska Kamenica

Corresponding Author: Dr Ivana Spasojevic, Institut za plucne bolesti Vojvodine, 21204 Sremska Kamenica, Put Doktora Goldmana 4, E-mail:
Table 1: Modified Osserman grades
Tabela 1. Modifikovana Osermanova klasifikacija

Type I Tip I                Disease localized to ocular muscles
                       Tends not to progress if remains confined to
                             ocular muscles for first 2 years
                              Zahvaceni samo okul ami misici.
                      Nema tendecije progresije ako su zahvaceni samo
                               ovi misici u prve dve godine.
                                Mild generalized myasthenia

Type IIa Tip IIa      Slowly progressive often from ocular muscles to
                     skeletal and bulbar muscles; however. muscles of
                                  respiration are spared
                      Good response to drug therapy and low mortality
                             Blaga generalizovana miastenija.
                      Spora progresija na skeletne i bulbame mi sice,
                             postedeni su respiratomi misici.
                        Dobar odgovor na terapiju,nizak mortalitet.
                              Moderate generalized myasthenia
                    Gradual onset, usually ocular, progressing to more
                         generalized, bulbar and skeletal muscles
                           Respiratory muscles are not involved

Type IIb Tip IIb               More bulbar symptoms than Ha
                        Less responsive to medical therapy than Ha
                            Srednja generalizovana miastenija.
                     Veca je zahvacenost skeletnih i bulbarnih misica
                                    nego kod tipa Ila.
                            Nisu zahvaceni respiratomi misici.
                         Slabiji odgovor na terapiju od tipa Ila.
                                      Severe disease/
                    Progression may be gradual or sudden deterioration

Type III Tip III               Poor response to drug therapy
                                      High mortality
                                     Teska miastenija.
                      Progresija postepena ili iznenadno pogorsanje.
                        Slab odgovor na terapiju,visok mortalitet.
                        Myasthenic crisis with respiratory failure

Type IV Tip IV                      Require intubation
                   Miastenicna kriza sa respiratornom insuficijencijom.
                                    Zahteva intubaciju.

Table 2. MGFA clinical classification
Tabela 2. Myastenia Gravis Foundation of America (MGFA) klinicka

Class Description/                           Sub-classification/
Opis klase                                   Potklasa

I                     Isolated ocular        No sub-classification

                      Izolovana okularna

II                    Mild weakness of       Predominantly
                      extra-ocular muscles   affecting limb,
                                             axial muscles, or
                      Blaga slabost          both
                      misica                 Predominantly
                                             respiratory muscles,
                                             or both

                                             vecinom zahvaceni
                                             ekstremiteti, ramena
                                             ili oba

                                             vecinom zahvaceni
                                             respiratomi misici
                                             ili oba

III                   Moderate weakness of   Predominantly
                      extra-ocular muscles   affecting limb,
                                             axial muscles, or
                      Srednja slabost        both
                      misica                 Predominantly
                                             respiratory muscles,
                                             or both

                                             a) vecinom zahvaceni
                                             ekstremiteti, ramena
                                             ili oba

                                             b) vecinom zahvaceni
                                             respiratomi misici
                                             ili oba

IV                    Severe weakness of     IVb Use of feeding
                      extra-ocular muscles   tube without

                      Teska slabost          Upotreba
                      ektraokularnih         nazogastricne sonde
                      misica                 bez intubacije

V                     Intubation/            No subclassification

Table 3. Suggested preoperative investigations for the patient with
myasthenia gravis
Tabela 3. Preporucene preopertivne pretrage kod bolesnika sa MG

Complete blood count           May have pernicious anemia, red cell
Kompletna krvna slika         aplasia, bone marrow suppression from
                              immunosuppresants/Perniciozna anemija,
                             supresija kostane sr[]i imunosupresivima

Electrolytes                   Optimized for neuromuscular function
Elektrolitski status         Optimizovati zbog neuromisicne funkcije

Creatinine, liver function         As required based on use of
Kreatinin, funkcija jetre              Zbog imunosupresiva

TSH                          Commonly have thyroid dysfunction/Cesto
                                   postoji tiroidna disfunkcija

Chest X-ray                     Rule out thymoma/mediastinal mass,
                               pneumonia (particular aspiration if
                                         bulbar symptoms)

RTG grudnog kosa               Timom/mediastinalne mase; pneumonija
                               (aspiracionapneumonija kodbulbarnih

ECG                             Arrhythmias, atrial fibrillation/.
                                 Iritmije, atrijalna fibrilacija

Echo                             If signs or symptoms of cardiac

EHO srca                       Kodpostojanja simptoma zahvacenosti
                                          sreanog misica

Pulmonary function tests        Useful to compare to previous for

Plucna funkcija                 Procena inicijalne plucne funkcije

Table 4. Prediction of myasthenia gravis patients at high risk of
prolonged ventilator support
Tabela 4. Bolesnici sa MG sa visokim rizikom za prolongiranu
postoperativnu mehanicku ventilaciju

Advanced diseasdUznapredovala bolest

Myasthenia gravis foundation class II or higher/A/G klase > II

Myasthenia gravis > 6 years/A/G > 6 godina

History of steroids requirements for myasthenia gravis/Upotreba
kortikosteroida u terapiji MG

History of myasthenia gravis-induced respiratory
insufficiency/Respiratorna insuficijencija uzrokovana MG

Vital capacity< 2,9 Witalni kapacitet < 2,91

Pyridostigmine dose > 750 mg/day/Doza Pyridostigmina > 750 mg/dan

Maximum expiratory force < 40-50 cm[H.sub.2]O/Maximum expiratory force
(MEF) < 40-50 cm[H.sub.2]O

Table 5. Prediction of myasthenia gravis patients at high risk of
prolonged ventilator support
Tabela 5. Bolesnici sa MG sa visokim rizikom za prolongiranu
postoperativmi mehanicku ventilaciju

Drug and formulation              Dose equivalent
Lek i nacin davanja              Ekvivalentna doza

Pyridostigmine oral (Mestinon)       60 mg PO
Neostigmine oral (Prostigmine)       15 mg PO
Neostigmine IM                        1.5 mg
Neostigmine IV                        0.5 mg

Drug and formulation                   Onset
Lek i na?in davanja               Pocetak dejstva

Pyridostigmine oral (Mestinon)        40 min.
Neostigmine oral (Prostigmine)          1 h
Neostigmine IM                        30 min.
Neostigmine IV                   Immediate/Trenutno

Drug and formulation                Time to maximum response
Lek i na?in davanja              Vreme do maksimalnog odgovora

Pyridostigmine oral (Mestinon)                1 h
Neostigmine oral (Prostigmine)               1.5 h
Neostigmine IM                                1 h
Neostigmine IV                              20 min.

Table 6. Thymectomies performed in treatment of myasthenia gravis at
the Department of Thoracic surgery. Institute for Pulmonary Diseases
of Vojvodina from 2004 to 2014
Tabela 6. Prikaz timektomija uraaenih u svrhu lecenja miastenije
gravis na Klinici za grudnu hirurgiju, Instituta za plucne bolesti
Vojvodine u periodu 2004-2014. godine.

Total number of patients/                       48
Ukupan broj pacijenata

Sex Pol                        Women--33 (68.75%)/Zene--33 (68.75%)
                              Men--15 (31.25%)/Muskarci--15 (31.25%)

Average age                    Women--37.48 years/Zewe--37.48 godina
Prosecna starost                 Men--52 years/Muskarci--52 godine
                                   [SIGMA] = 42.02 years/godine

Class of MGFA clinical                     I--7 (14.5%)
classification                            IIa--6 (12.5%)
Klasa MGFA klinicke                       IIb--8 (16.7%)
klasifikacije                            IIIa--9 (18.75%)
                                         IIIb--16 (33.33%)
                                            V-1 (2.08%)
Surgical approach/                    Sternotomy--37 (77.03%)
Hirurski pristup                         VATS--11 (22.92%)

Complications IKomplikacije                  1 (2,08%)
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Title Annotation:Seminar for physicians/Seminar za lekare u praksi
Author:Spasojevic, Ivana; Hajdukovic, Danica; Komarcevic, Milena; Petrovic, Stanislava; Jovanovic, Jelena;
Publication:Medicinski Pregled
Article Type:Report
Date:Sep 1, 2016
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