Anaphylaxis and NMBAs

 

 

Prof. Marie-Claire Laxenaire (Nancy-France)

 

       Neuromuscular blocking agents (NMBA) are responsible for 60-80% of anaphylactic reactions occurring during anaesthesia [1, 2]. Anaphylaxis incidence has been recently evaluated in France as one reaction for 6,500 anesthesias in which an NMBA was used [1].

       Allergy to NMBAs has been known since 1967 following a publication by Jerums concerning an IgE-dependent anaphylaxis in response to suxamethonium [3]. Subsequently it was demonstrated by Baldo and Fisher that the allergenic part of the NMBA molecule is associated with the quaternary ammonium ion [4]. The fact that muscle relaxants have at least two haptenic determinants in their structure, explain that they may act as true allergens and do not require some carriers to be linked to. Muscle relaxants can bridge IgE antibodies through the ammonium ion determinants and produce anaphylactic reaction. Moreover, it has been clearly demonstrated that a cross-reactivity of IgE antibodies exists with all muscle relaxants based upon their structural similarity [4-6].

       The investigations needed to diagnose anaphylaxis induced by muscle relaxants are based on skin tests, in conjunction, if possible, with detection of circulating specific IgE and cell activation tests. 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 type of NMBA [7-10].

       The specific IgEs against quaternary ammonium ion are detected in serum by radioimmunoassay and their specificity must be confirmed by an inhibition test. There are two techniques that can be recommended due to their excellent sensitivity [11, 12]. They are routinely used in France. This is in contrast with the RAST-Pharmacia for succinylcholine that has a lower sensitivity [11, 13]. With regard to the basophil activation tests, only the leukocyte histamine release test and the flow cytometric assay had been validated for the diagnosis of muscle relaxant allergy [14, 15], but their sensitivity is low. Moreover, they are costly and cannot be applied routinely.

       These in vivo and in vitro allergy investigations are performed ideally 6-8 weeks after the reaction. During the reaction, however, it is recommended to collect blood for tryptase measurement, which is a good marker for anaphylaxis [16] as well as for the detection of specific IgEs. There is actually a very good correlation between the levels of specific IgEs measured during the reaction and 6 weeks after [17].

       The clinical signs of an anaphylactic reaction to NMBA always occur within a few minutes following the injection of the drug and are life-threatening in 70% of cases (severity grades 3-4: collapse, tachycardia, erythema, bronchospasm) requiring intensive resuscitation and adrenaline. On the other hand, if the reaction mechanism is not immunologic but linked to the pharmacological effect of the curare (= anaphylactoid reaction), the symptoms are usually less severe [1]. However, only allergologic investigations allow the confirmation of the mechanism involved, to bring out the drug responsible. This enables to determine, using IDT whether there exists a crossed sensitivity, which in turn allows recommendations to be made for anaesthesia in the future.

        

The NMBAs implicated in anaphylaxis are clearly identified in the French national epidemiological surveys performed every 2-3 years since 1985 [1, 18-20], as well as in the large series of patients tested by M. Fisher in Australia [2]. Suxamethonium, vecuronium and atracurium were the NMBAs most frequently found at the origin of anaphylactic reactions in 1996 [1, 2]. Since 1995, a certain number of anaphylactic reactions to rocuronium have been recorded in France and Australia (M. Fisher, personal communication).

         The risk factors for sensitization to NMBAs are not clearly identified. This means that it is not justified to prescribe a systematic allergological investigation prior to each anaesthesia. On the contrary, a history of anaphylactoid reaction during a previous anaesthesia, or the known existence of NMBA allergy, only warrants pre-anaesthetic testing. In this last case, all NMBAs must be retested by IDT to find the one that will not elicit a cross reaction in the skin test. This NMBA can then be recommended for the subsequent anaesthesia, while all others must be definitively discarded.

       It must be remembered that in case of NMBA allergy, no drug-based pre-treatment exists that would prevent an anaphylactic reaction, whether anti-H1 / anti-H2 or corticosteroids.

 

References

 

1.       Laxenaire MC et le Groupe d'études des réactions anaphylactoïdes peranesthésiques. Epidémiologie des réactions anaphylactoïdes peranesthésiques. Quatrième enquête multicentrique (juillet 1994-décembre 1996). Ann Fr Anesth Réanim 1999 ; 18 : 796-809.

2.       Fisher M, Baldo BA. Anaphylaxis during anaesthesia : current aspects of diagnosis and prevention. Eur. J. Anaesthesiol 1994 ; 11 : 263-84.

3.       Jerums G, Whittingham S, Wilson P. Anaphylaxis to suxamethonium. Br. J. Anaesth. 1967 ; 39: 73-6.

4.       Baldo BA., Fisher M. Substituted ammonium ions as allergenic determinants in drug allergy. Nature 1983 ; 306 : 262-4.

5.       Moneret-Vautrin DA, Kamel L, Guéant JL. Laxenaire MC, le Kholty S, Nicolas JP. Anaphylaxis to muscle relaxants : cross sensitivity studied by radio-iiunoassays compared to intradermal tests, in 34 cases. J. Allergy Clin. Immunol 1988 ; 82 : 745-52.

6.       Laxenaire MC, Gastin I, Moneret-Vautrin DA, Widmer S, Guéant JL. Cross-reactivity of rocuronium with other neuromuscular blocking agents. Eur. J. Anaesth. 1995 ; 12 (Suppl. 11) : 55-64.

7.       Fisher M. Intradermal testing in the diagnosis of acute anaphylaxis during anesthesia. Results of five year's experience. Anaesth. Intens. Care 1979 ; 7 : 58-61.

8.       Galletly DC, Treuren BC. Anaphylactoid reactions during anaesthesia. Seven year's experience of intradermal testing. Anaesthesia 1985 ; 40 : 329-33.

9.       Moneret-Vautrin DA, Laxenaire MC. Skin tests in diagnosis of allergy to muscle relaxants and other anaesthetic drugs. Allergic Reactions to Anaesthetics. Clinical and Basic Aspects. Monogr Allergy 1992; 30, ESK Assem, Basel : Karger : 145-55.

10.   Laurent J. Commission tripartite de consensus en allergologie pourles tests cutanés aux curarisants. Rev. fr. Allergol 1997 ; 37 : 776-7.

11.   Guéant JL, Mata E, Monin B, Moneret-Vautrin DA, Kamel L, Nicolas JP, Laxenaire MC. Evaluation of a new reactive-solid phase for radioimmunoassay of seric specific IgE against muscle relaxant drugs. Allergy 1991 ; 46 : 452-8.

12.   Guilloux L, Ricard-Blum S, Ville G, Motin J. A new radioimmunoassay using a commercially available solid support for the detection of IgE antibodies against muscle relaxants. J Allergy Clin Immunol 1992 ; 90 : 153-9.

13.   Guilloux L, Ricard-Blum S, Ville G, Motin J. Histamine release assay and radioimmunoassay for the detection of IgE antibodies against neuromuscular blocking drugs. Ann Fr Anesth Réanim 1993 ; 12 : 182-6.

14.   Mata E. Clinical evaluation of in vitro leukocyte histamine release in allergy to muscle relaxant drugs. Allergy 1992 ; 47 : 471-6.

15.   Abuaf N. Rajoely B, Ghazouani E, Levy DA, Pecquet C, Chabane H, Leynadier F. Validation of a flow cytometric assay detecting in vitro basophil activation for the diagnosis of muscle relaxant allergy.  J. Allergy Clin. Immunol 1999 ; 104 : 411-8.

16.   Fisher MM, Baldo BA. Mast cell tryptase in anaesthetic anaphylactoid reactions.  Br J Anaesth 1998 ; 80: 26-9.

17.   Laroche D., Lefrançois C, Gérard JL, Dubois F, Vergnaud MC, Guéant JL, Bricard H. Early diagnosis of anaphylactic reactions to neuromuscular blocking drugs. Br J. Anaesth 1992 : 69 : 611-4.

18.   Laxenaire MC, Moneret-Vautrin DA, Widmer S, Mouton C, Guéant JL. Substances anesthésiques responsables de chocs anaphylactiques. Enquête multicentrique française. Ann Fr Anesth Réanim 1990 ; 9 : 501-6.

19.   Laxenaire MC and the Members of the Writing Committee. Drugs and other agents involved in anaphylactic shock occurring during anaesthesia. A French multicenter epidemiological inquiry. Ann Fr Anesth Réanim 1993 ; 12 : 91-6.

20.   Laxenaire MC et le Groupe d'études des réactions anaphylactoïdes peranesthésiques. Substances responsables des chocs anaphylactiques peranesthésiques. Troisième enquête multicentrique française (1992-1994). Ann Fr Anesth Réanim 1996 ; 15 : 1211-8.