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LETTERS TO THE EDITOR

Prick Testing for Neuromuscular Blocking Drugs

Intensive Therapy Unit, Royal North Shore Hospital of Sydney, St. Leonards, NSW, Australia, mfisher@med.usyd.edu.au

To the Editor:

I was interested to read the study of Dhonneur et al. (1) describing a randomized controlled prick testing study in healthy volunteers. Their study showed a frequent incidence of positive prick tests to undiluted rocuronium and vecuronium.

In 1997, our group published a prospective comparison of prick and intradermal testing in 212 consecutive patients referred to an anesthetic allergy clinic (2). Prick testing was performed with undiluted drugs with the exception of morphine, and a positive prick test was recorded if a wheal of greater than 0.4 cm occurred.

The results have been revisited. A total of 157 patients were tested by prick and intradermal testing with 1:1000 dilutions of vecuronium 4mg/mL and undiluted vecuronium 4mg/mL, respectively (Table 1 on page 1881).

There were no false positive prick tests to undiluted vecuronium in contrast to the French study (1). These results are surprising and could be related to operator or patient factors. We have no data for rocuronium, and unfortunately the study was performed prior to the availability of mast cell tryptase assays, which improve the ability to detect anaphylaxis as a mechanism (6). We note that a Scandanavian study found no positive prick tests to undiluted rocuronium in 30 volunteers (7).

Dhonneur et al. (1) suggest their findings call into doubt whether neuromuscular blocking drugs are the principal cause of anaphylaxis during anesthesia. I believe this statement is not supported by the evidence from large studies that include radioimmunoassay, intradermal testing and mast cell tryptase results as part of the diagnosis (8,9). I note that the Danish study cited (10) uses undiluted and 1:10 dilutions of vecuronium and rocuronium in its exemplary testing protocol; if these concentrations were inappropriate, the investigators should also have found a high incidence of reactions to these drugs. That they do not is because their population is different.

The major weakness of skin testing after anesthetic reactions is that it only explores one mechanism. To validate the results properly would require provocation or challenge, which is difficult to justify when the results of subsequent anesthesia based on available tests show infrequent incidence of second reactions (11).

References

1. Dhonneur G. Combes X. Chassard D. Merle JC. Skin sensitivity to rocuronium and vecuronium: a randomized controlled prick-testing study in healthy volunteers. Anesth Analg 2004; 98: 986–9.[Abstract/Free Full Text]
2. Fisher MM, Bowey CJ. Intradermal versus prick testing in the diagnosis of anaesthetic anaphylactic reactions. Br J Anaesth 1997; 79: 59–63.[Abstract/Free Full Text]
3. Fisher MM. Anaphylaxis to muscle relaxants: cross sensitivity between relaxants. Anaesth Intensive Care 1980; 8: 211–4.[Medline]
4. Baldo BA, Fisher MM. Anaphylaxis to muscle relaxant drugs: cross-reactivity and molecular basis of binding of IgE antibodies detected by radioimmunoassay. Mol Immunol 1983; 20: 1393–1401.[Web of Science][Medline]
5. Moneret-Vautrin DA, Gueant JL, Kamel L, et al. Anaphylaxis to muscle relaxants: cross-sensitivity studied by radioimmunoassays compared to intradermal tests in 34 cases. J Allerg Clin Immunol 1988; 5: 745–52.
6. Fisher MM, Baldo BA. The diagnosis of fatal anaphylactic reactions during anaesthesia: employment of immunoassays for mast cell tryptase and drug-reactive IgE antibodies. Anaesth Intensive Care 1993; 21: 353–7.[Web of Science][Medline]
7. Berg CM, Heier T, Wilhelmsen V, Florvaag E. Rocuronium and cisatracurium-positive skin tests in non-allergic volunteers: determination of drug concentration thresholds using a dilution titration technique.] Acta Anaesthesiol Scand 2003; 47: 576–82.[Web of Science][Medline]
8. Fisher MM, Baldo BA. The incidence and clinical features of anaphylactic reactions during anaesthesia in Australia. Ann Fr Anesth Reanim 1993; 12: 97–104.[Web of Science][Medline]
9. Mertes PM, Laxenaire MC, Alla F; Groupe d’Etudes des Reactions Anaphylactoides Peranesthesiques. Anaphylactic and anaphylactoid reactions occurring during anesthesia in France in 1999–2000. Anesthesiology 2003; 99: 536–45.[Web of Science][Medline]
10. Garvey LH, Roed-Petersen J, Menne T, et al. Danish Anaesthesia Allergy Centre: preliminary results. Acta Anaesthesiol Scand 2001; 45: 1204–9.[Web of Science][Medline]
11. Fisher MM, Doig GS. Prevention of anaphylactic reactions to anaesthetic drugs. Drug Saf 2004; 27: 395–410.

Response

Thoracic Cardiac and Vascular Surgical Intensive Care Unit, Henri Mondor University Hospital of Creteil, Paris, France, gilles.dhonneur@hmn.ap-hop-paris.fr

In Response:

It is a great honor being criticized by such an expert in the area of allergy in anesthesia. I understand the reactions of major Australian and French specialists in this area to our results published recently in Anesthesia & Analgesia (1). Indeed, our results demonstrate that with our present level of understanding, the current practice in skin testing is invalid, and we cannot formally rely on prick tests to confirm allergy to neuromuscular blocking agents (NMBAs).

I am not sure that the results of our French study are conflicting but rather complete the interesting study performed by Levy et al. (2), which has clearly demonstrated that intradermal 10^–5 M of most NMBAs promoted degranulation-free skin reactions, suggesting that "intradermal nonreactive" NMBA concentration is equal or smaller than 10^–6 M. We have shown that a 100-fold increase of this "intradermal nonreactive concentration" corresponded to prick nonreactive concentration. Our observation is coherent with the hypothesis that skin response to NMBAs is mainly the result of a direct effect upon cutaneous vasculature.

I agree that the results of our French study contrast with those obtained by Professor Fischer. However, both studies are not comparable in either their design or the studied population. We have performed a randomized controlled prick testing study in young healthy anesthesia-naive adult volunteers comparing bioequivalence of rocuronium and vecuronium in terms of skin sensitivity. The Australian study compared prick and intradermal testing in patients suspected to be allergic to vecuronium after an anesthetic reaction (3). Although not comparable in terms of methodology and populations, I believe that operator factors cannot explain the frequent incidence of positive prick tests to undiluted rocuronium and vecuronium we demonstrated. In order to limit this risk factor, our study was performed in the dermatology department of the most important French CRO, a single specialized physician administered all 300 prick tests, wheal and flare measurements were performed by an independent technician, and source data have been revisited by two investigators without any major discordance. We have built and performed a methodologically strong study, and our results question the reliability of prick testing with undiluted solution of steroid-derived relaxants for the diagnosis of allergy.

I am not an expert in epidemiology or evidence-based medicine, but I believe that any diagnostic test, like skin testing, should be evaluated in term of specificity and sensitivity before being exported to clinical practice. In other words, a large cohort of healthy volunteers from several countries and of different skin colors should be tested in order to determine skin sensitivity to NMBAs. Unfortunately, in the absence of major studies for better applications of skin testing and validation of other diagnostic approaches of allergy to anesthetic agents, it is not clear that we are making the correct diagnosis of allergy to rocuronium and vecuronium using prick responses to undiluted stock solutions. I believe that a rate of 40–50% false positive is unacceptable for a diagnostic test, but a 10% incidence of false positive would have been also probably not acceptable. Under these circumstances, unexplained reactions during anesthesia question whether these steroid-derived relaxants are the principal cause of anaphylaxis during anesthesia.

References

1. Dhonneur G, Combes X, Chassard D, Merle JC. Skin sensitivity to rocuronium and vecuronium: a randomized prick-testing study in healthy volunteers. Anesth Analg 2004; 98: 986–9.
2. Levy JH, Gottge M, Szlam F, et al. Weal and flare responses to intradermal rocuronium and cisatracurium in humans. Br J Anaesth 2000; 85: 844–93.[Abstract/Free Full Text]
3. Fischer MM, Bowey CJ. Intradermal versus prick resting in the diagnosis of anaesthetic anaphylactic reactions. Brit J Anaesth 1997; 79: 59–63.

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