Anaphylaxis to
Muscle Relaxants
Pr Marie-Claire Laxenaire
Nancy
( France )
All the drugs and adjuvants we inject in anaesthetic practice may be responsible for anaphylactic reactions. But some of them are more allergenic. That is the case of muscle relaxants ( NMBAs ) which induce 50 to 60 % of anaphylactic reactions during anaesthesia ( 1 ).
Anaphylaxis remains the most serious adverse
reaction due to NMBAs, more severe than pharmacological histamine release. It
is unpredictable, may be lethal or responsible for severe anoxic sequelae. The
incidence of NMBA anaphylaxis has been estimated in France, in 1996, as 1 in
6,500 anaesthetics in which a NMBA was used ( 2 ).
Mechanism of anaphylaxis :
Allergy to NMBAs has been known since 1967,
following a publication of Jerums concerning an IgE-dependant anaphylaxis in
response to suxamethonium ( 3 ) . During the last 30 years, it has been proven
that all the NMBAs are allergenic and not exclusively suxamethonium. It
was demonstrated by Baldo and Fisher that the allergenic part of the molecule
is associated with the quaternary ammonium ( QA ) ion ( 4 ) . The fact that all
NMBAs have at least two haptenic determinants in their structure explains that
they may act as true allergens and do not require any carriers to be linked to.
Every NMBA is able to bridge specific IgE antibodies through the QA ion
determinants and produce anaphylactic reaction. This is called “ cross-
reactivity “ which means that a patient who is allergic to one NMBA may react
to the others. However, this cross-reactivity is only found in 70% of cases,
probably because an adjacent side chain to QA ion may also participate in
antigenic properties of some NMBAs.
To become allergic to NMBA, we need to be
sensitised to QA ion. In three quarters of patients, this sensitisation might
have occurred during a previous anaesthetic for which a NMBA was used. But 25 %
of patients who suffered from anaphylaxis to NMBA have never been
anaesthetised beforehand. It has been
suggested that these patients became sensitised by repeated contact with QA
ions contained in cosmetics, antiseptics, detergents…In fact, this hypothesis
has never been demonstrated up to now.
Clinical symptoms :
In our experience based on the French
epidemiological surveys performed since 1985, collecting several
thousands of NMBA anaphylaxis, the reaction can occur at any age, with female
predominance ( sex ratio 2.4 ). No particular risk factors, such as atopy and
various allergies, were pointed to.
Symptoms occur in the first few minutes following the injection of
NMBA. The most frequent clinical symptoms are cardiovascular collapse ( 80 % of
the cases ) with cutaneous signs ( 70 % of the cases ). Bronchospasm is present
in 40 % of the cases. In some patients, collapse may be the sole symptom of
anaphylaxis. The symptoms and clinical grades of severity are identical
whatever the NMBA involved.
Allergological investigations for diagnosing
anaphylaxis to NMBAs :
Criteria for diagnosing anaphylaxis have been recently defined by the French Society of Anaesthesia and the French Society of Allergology ( 5 ). It was recommended to determine tryptase and histamine concentration, and NMBA specific IgEs on blood samples taken 1 hour after the onset of the reaction to determine whether or not an immunologic mechanism is involved. Tryptase concentration over 25 mg / L has a positive predictive value estimated at 92 % but a negative predictive value at 54 % ( 1 ).
Six weeks later, cutaneous tests have to be
carried out with the NMBA injected. The skin tests used are prick tests and
intradermal tests ( IDT ) with decreasing dilutions 10 - 4 to 10 - 2 or 10 - 1
according to the histamine releasing capacity of the muscle relaxant ( 5
). Should cutaneous tests be positive,
all the NMBAs must then be tested to detect cross-reactivity . This is very
important for subsequent anaesthesia because the NMBA which does not elicit a
reaction in the skin testing should be recommended .
A positive diagnosis of anaphylaxis depends on
positive skin tests, laboratory results and coherence of the results with the
clinical history and the anaesthetic protocol.( 5 )
Muscle relaxants responsible for anaphylaxis :
They are clearly identified in the French
epidemiological surveys ( 1, 2, 6, 7).
Succinylcholine , rocuronium and atracurium are in front. But if we compare the
number of cases of anaphylactic reactions to the number of patients exposed to
each NMBA during the same period, it appears that, when combined, succi and
rocu represent 60 % of the reactions for 17 % of market use whereas atrac
represents about 21 % of the reactions but 60 % of market use ( table 1 ).
The
incidence of anaphylaxis is therefore very different according to the NMBA
involved ( table 2 ). In terms of anaphylactic risk, NMBAs could be classified
in 3 groups: high risk ( rocu, succi ), intermediate ( vecu, pancu ), and low
risk ( miva, atrac, cisatrac ).
Risk factors and preanaesthetic screening:
At the moment, some risk factors for
sensitisation to NMBAs and anaphylaxis during anaesthesia have been identified
( 5, 8 ). They are: a history of undocumented anaphylactoid reaction during a
previous anaesthesia or an unexplained serious adverse event during anaesthesia
or a known existence of allergy to NMBA. These patients are at risk and warrant
preanaesthetic testing. All NMBAs must be systematically tested by IDTs to find
out one that will not elicit a positive result
and should then be recommended. If there is no time to carry out these
allergologic investigations, anaesthesia must be conducted without muscle
relaxant.
In conclusion, the prevention of NMBA
anaphylactic reactions goes through preanaesthetic screening exclusively in
patients at risk. Finally the prevention consists in choosing a NMBA in a
well thought-out way in terms of risks and benefits for the patient.
References:
Table
1: Anaphylaxis to NMBAs and patients exposed to each
NMBA in France over
6 years ( 1997-2002 )
Anaphylactic
reactions Patients
exposed
( n =
912 ) (
n = 17 Million )
Rocuronium 301 ( 33 % ) 9.1 %
Succinylcholine 249 ( 27.3 % ) 8.0 %
Atracurium 193 ( 21.2 % ) 60.0 %
Vecuronium 104 ( 11.4 % ) 8.0 %
Pancuronium 37 ( 4.1
% ) 3.2
%
Mivacurium 20 ( 2.2 % ) 4.5 %
Cisatracurium 8 ( 0.8 % ) 7.0 %
Total 912 ( 100 % )
100 %
Table 2: Incidence of anaphylaxis according to the NMBA in France over 6 years
( 1997-2002 )
Rocuronium
1 : 5,100 patients exposed to rocuronium
Succinylcholine 1 : 5,500 patients
exposed to succinylcholine
Vecuronium 1 : 13,000
patients exposed to vecuronium
Pancuronium 1 : 14,700 patients
exposed to pancuronium
Mivacurium 1 : 38,200 patients
exposed to mivacurium
Atracurium 1: 52,800
patients exposed to atracurium
Cisatracurium 1 : 148,7000 patients exposed to cisatracurium