RESPONSE TO ANAESTHETIC DRUGS IN ... - Carbone Editore

Acta Medica Mediterranea, 2010, 26: 47
RESPONSE TO ANAESTHETIC DRUGS IN MYASTHENIC PATIENT
RITA AZZOLINA, FLAVIO VINCENZO EVANDRO RUSSO, MARIA DI DIO, MARCO CAVALERI, CONCETTA MARIA SPOTO, GIOVANNI
LUCA DI BARTOLO, AGOSTINO MESSINA
University of Catania, Department of Medical Biology Chemistry and Molecular Biology, Reanimation and Anaesthesia Section:
(Responsible Prof.ssa Rita Azzolina)
SUMMARY
The authors highlight the responses to anaesthetic drugs
in a myasthenia patient in order to avoid a worsening of the
disease or precipitating in an acute myasthenia crisis. They
address the importance of preoperative evaluation according to
the various stages of myasthenia syndrome and the therapy
implemented that must be controlled until the day of the surgical
procedure. They state that many anaesthetic techniques
have been proposed but none has proved superior to the others
as some prefer to avoid drugs that intervene at the level of neuromuscular
junction(muscle relaxants) and they turn to the use
of inhaled anaesthetics, while others use minimal doses of
muscle relaxants for not prolonged action. They conclude that
Myasthenia Gravis is a disease that still involves many implications
for proper anaesthesia conduct.
Key words: Myasthenia gravis, anaesthetic drugs, neuromuscular
blockers, acetylcholine receptors, respiratory dynamics
Introduction
Myasthenia Gravis was described for the first
time in 1895 by Jolly as a disease that is manifested
by weakness of the eyeballs and skeletal muscle.
Now it is considered a better studied and understood
autoimmune disease. It can be defined as an
immune-mediated disease of the neuromuscular
junction caused by antibodies (Ab) against the
acetylcholine receptors (AChR).
The result is a reduction in the number of
acetylcholine receptors at the endplate resulting in
muscle weakness that may affect the ocular
muscles/eyeballs, with a fluctuating respiratory
rate. In myasthenia patients the anesthetist must
take into account the existence of several drugs that
interfere with neuromuscular transmission: their
misuse can lead to a worsening of the disease and
respiratory depression. The mechanism of interfe-
[Risposta ai farmaci anestetici nel paziente miastenico]
RIASSUNTO
Gli Autori mettono in evidenza le risposte dei farmaci
anestetici in un paziente miastenico allo scopo di evitare un
aggravamento della malattia o di precipitare una crisi miastenica
acuta. Si soffermano sull’ importanza della valutazione preoperatoria
in base alle varie fasi della sindrome miastenica ed
alla terapia attuata che deve essere controllata fino al giorno
della procedura chirurgica. Precisano che sono state proposte
numerose tecniche anestesiologiche ma nessuna si è dimostrata
superiore alle altre in quanto alcuni preferiscono evitare i farmaci
che intervengono a livello della giunzione neuromuscolare
(miorilassanti) e ricorrono ad anestetici per via inalatoria, mentre
altri usano minimi dosaggi di miorilassanti ad azione non
prolungata. Concludono affermando che la Miastenia Gravis è
una malattia che a tutt’oggi comporta molte implicazioni per
una corretta condotta anestesiologica.
Parole chiave: Miastenia gravis, farmaci anestetici, bloccanti
neuromuscolari, recettori dell’acetilcolina, dinamica respiratoria
rence of drugs on neuromuscular transmission is
not unique and the same molecule can have multiple
points of interaction on the transmission.
Schematically the effect can take place either on the
pre-synaptic side of the neuromuscular junction
interfering with the movement of calcium, lowering
the conduction of synaptic ion channels and reducing
the synthesis or the release of acetylcholine, or
on the post-synaptic side with a desensitization or a
blockade of the receptor. The preoperative evaluation
of myasthenia patients includes the degree of
severity of the illness, prepared treatment and neurological
compensation.
There is a need to pay particular attention to
the patient’s ability to protect and maintain the
airway patency (bulbar myasthenia). Lung function
tests (especially the forced vital capacity and aspiratory
and expiratory pressure curves ceiling) can
quantify the strength of respiratory muscles and

48 R. Azzolina, F.V.E. Russo et Al
give you an idea of the need for postoperative ventilator
support. The preoperative management of the
patient can then be influenced by surgical technique
and the choices of the anaesthesiologist. In some
cases, you can stop the administration of anticholinesterases
on the morning of the operation to reduce
the need for the use of curare. Plasmapheresis or
steroids can improve the preoperative condition of a
patient with limited respiratory reserve. For myasthenia
patients already receiving immunosuppressive
treatment (corticosteroids, azathioprine,
cyclophosphamide), the doses of drugs should not
be changed due to the risk of triggering a poussèe
of the disease.
Use of anaesthetic drugs in myasthenia patients
Curare drugs are potentially the most dangerous
among those used for myasthenia. Curare
relaxants are theoretically used in untreated myasthenia,
although in some cases you may experience
a relative resistance. During a patient’s recent
treatment with anticholinesterases or plasmapheresis
their use becomes random and their effects
unpredictable with a high risk of establishing a
curarizing prolonged block type II. Indeed electromyography
studies have shown that the response
to succinylcholine is difficult to predict in the case
of myasthenia, whether treated or not. For these
reasons it is appropriate to refrain from using them
in the presence of myasthenia.
The myasthenia patient is sensitive to no depolarizing
curare, in fact the use of small doses as a
priming or prior use of curare relaxants should be
avoided because it may lead to a loss of airway protection
and respiratory distress equivalent to that
induced by normal doses in healthy individuals.
Recommended doses are 4-8 times smaller, yet very
different due to the evolution of the disease from
person to person, the disparity in the muscle groups
involved and the possibility of potentiating associated
with drugs. No rule can be stated precisely.
The use of curare in the course of no depolarizing
myasthenia requires close monitoring.
Sensitivity to no depolarizing curare has been
described in patients with minimal impairment
(ocular symptoms), those with apparent remission
or in those with undiagnosed myasthenia. Longacting
curare such as d-tubocurarine, pancuronium,
pipercuronium and doxacurium should be avoided.
Medium and short half-life curare can be used with
extreme caution and with monitoring of neuromu-
scular transmission, preferably with a
Electromyography (EMG) or meccanomiografia
(MMG), which measures the electrical response or
mechanical change to the stimulation of peripheral
nerves. Although in literature individual doses are
reported (e.g. vecuronium from 0.005 to 0, 03 mg /
kg etc.) there is wide variability in response from
patient to patient and it is difficult to predict the
duration and effect even with short half-life curare
such as mivacurium and pyridostigmine, which
inhibits the metabolism of mivacurium. In the
second case studies are reported which indicate the
rapid onset of cisatracurium and a more prolonged
cuarizing effect. Although the use of curare is possible
through adequate monitoring, their use is seldom
necessary.
Barbiturates in experiments on animals have
shown to moderately increase neuromuscular
blockade induced by no depolarizing curare,
without lengthening the duration. In humans few
changes have been observed. In fact, it was demonstrated
that these drugs increase the amount of
acetylcholine released at the pre-synaptic, but
decrease the sensitivity of the postsynaptic membrane.
Balancing these two effects leads to no change
of neuromuscular blockade. Ketamine leads to a
desensitization of the postsynaptic membrane, but
does not promote the release of acetylcholine.
Its effects lead to more of an aggravation of
neuromuscular blockade. Propofol has the theoretical
advantage of a short duration of action with no
effect on neuromuscular transmission.
Morphinomimetics at usual doses do not interfere
with neuromuscular transmission and can be
used safely as anaesthesia for myasthenia patients
although the danger of respiratory depression
should be considered. Remifenatnil for the short
half-life (9.5 minutes) could be considered the ideal
analgesic, although in literature at present there are
no data on its use. The use of benzodiazepines in
myasthenia is not recommended and for some
authors it is formally contraindicated, however, this
does seem to be excessive.
Their actions at the level of neuromuscular
transmission are relatively small and comparable to
those of barbiturates. Harmful properties of benzodiazepines
are those muscle relaxants, an effect
related to increasing level of medullar inhibitory
GABA on muscle tone but not on neuromuscular
transmission. The use of benzodiazepines during
myasthenia is therefore possible with prudence and
by decreasing the dosage. Droperidol has no effect

Response to anaesthetic drugs in myasthenia patients 49
on neuromuscular transmission while phenothiazines
appear to interfere with neuromuscular transmission
as a result of postsynaptic desensitization.
All halogenated anaesthetic agents can depress the
function of the tractor units muscles. This effect can
be significant and occur at several levels: central
depressant effects, stabilizing effect of the membrane
with a decrease in membrane conductance of
calcium channels and above all depressant effects
on the functioning of the postsynaptic membrane.
They do not seem to have a direct action on ach
receptors. In practice, they determine a depolarizing
block, with a more pronounced effect in the case of
halothane rather than enflorano or the isofluorane.
In healthy subjects they allow for a decrease
of 25% to 50% in the need for curare, while in
myasthenia patients they often determine an acceptable
muscle relaxant for the duration of surgery. If
nitrous oxide has no documented effect on neuromuscular
transmission and can be used in such
patients without any precaution, isofluorane reduces
T1 and train of four, T1 on T4 relationship with
an effect of muscle relaxant two times higher than
halothane.
Enflorano instead can lead to muscle relaxant
with varying and heavily dependent on the severity
of myasthenia. Sevofluorane 2.5% suppresses the
electromyographic response to T1/Tc with 47% and
T4/T1 at 57% so much so that it has been used in
some cases of thymectomies by transternale both as
vapour and as a muscle relaxant anaesthetic. In normal
patients undergoing anaesthesia with desflorane
the curare request is reduced, and this gas due to
its low solubility and its subsequent rapid washout
may have interesting implications in myasthenia,
both for muscle relaxant properties that would
allow for the surgical procedure without the addition
of curare, and for the rapid elimination.
Local anaesthetics act as agents for rapid ion
channel blockers, suppressing the propagation of
nervous transmission, the release of Ach, the sensitivity
of the postsynaptic membrane and the exciting
of muscle cell. Local anaesthetics also increase
neuromuscular blockade of all no depolarizing
curari and seem able to decrease neuromuscular
transmission in myasthenia gravis. Loco-regional or
local anaesthesia should be practiced using smaller
doses of local “amid” anaesthetics with the
“Estereo” group (procaine, tetracaine), already
widely out of use, should not be used in myasthenia
treated with anticholinesterases as they are metabolized
by plasma cholinesterase, with an increase in
the rate of serum and with it toxic effects. The
blocking of the nerves of the intercostals is not
advised due to deficiency of respiratory dynamics,
and recently there have been reports of epidural
anaesthesia in thymectomies by trasternale.
Discussion
The considerable progress in anaesthesia, in
recent years has allowed for the use of new drugs
such as propofol, mivacurium, cisatracurium, sevorane,
desfluorane and remifenatanil, due to their
easy handling and reduced side effects allow for the
execution of a balanced anaesthesia or a TIVA
without risks in myasthenia patients.
Volatile anaesthetics and curare with longer
half-life make the approach even more secure in
myasthenia patients. Studies previously mentioned
and the experience gained in the field led to the
embrace of surgery such as the attitude of “Miniinvasive
Anaesthesiology”or rather minimal
“Pharmacological Aggression” in patients with
myasthenia. Current guidance is designed to favour
recently introduced drugs such as propofol and
remifentanil, intravenous anaesthesia (TIVA) in
accordance with the more recent method of infusion
(TCI site effect or plasma concentration), the
desfluorane or sevorane if the choice is to use a
balanced anaesthesia.
These drugs are united by the following common
properties; easy handling, a rapid wash-in, low
half-life, and therefore rapid wash-out with fast elimination
and minimal side effects.
References
1) Abel M, Eisenkraft JB. Anesthetic Implication of
Myasthenia Gravis. The mountsinai journal of medicine
January/March 2002: 32-36.
2) Jaretzki A III, Barohn R J, Ernstoff R M. Myasthenia
gravis: Recommendations for clinical research standards.
Neurology Vol 55 (1), 12 July 2000: 16-23.
3) Kawamata M, Miyabe M, Nakae Y, et al. Contunuous
thoracic epidural blockade in combination with general
anaesthesia with nitrous oxide, oxygen, and
sevoflurane in two patients with myasthenia gravis.
Masui 1993; 42: 898-901.
4) Leventhal S R, Orkin F K, Hirsh R A. Prediction of the
need for post-operative mechanical ventilation in
myasthenia gravis. Anestesiology, 1980, 53: 26-30.

50 R. Azzolina, F.V.E. Russo et Al
5) Osserman KE. Clinical aspects. In Osserman KE, ed
Myasthenia gravis. New York, NY: Grun & Stratton,
1958: 79-80.
6) Riacciardi R e Fontana G.P., Vivere la miastenia.
Franco Angeli, 2006.
7) Reider P, Louis M, Jolliet P et al. The repeated measurement
of vital capacity is a poor predictor of need for
mechanical ventilation in myasthenia gravis. Intensive
Care Med. 1995 Aug; 21 (8): 663-8.
__________
Request reprints from
Dott. RUSSO FLAVIO VINCENZO
Via Messina, 109
97011 Acate (RG)
(Italy)