I want to thank Mertes et al. for offering such an important tribune to argue comments and remarks about the results, methodology and discussion of our study (1). Before giving a point-by-point response to Mertes et al., I would like to specify that I am not an expert in immunology and I do not make a living in the neuromuscular blocking drugs nor the allergy industry.
Regarding the Methods section, Mertes et al. suggests that we “confused prick testing and intradermal testing.” This remark is not acceptable and I believe that the title of this letter is inappropriate. We did not perform any injection of any sort but just applied Good Clinical Practice (GCP) recommendations for prick testing. GCPs are GCPs! A single investigator working in the cosmetic department of one of the most important French CRO performed all prick tests. A calibrated 50-μL drop of a solution is placed on the skin on the forearm that is pricked with a commercially available device: 1-mm tip at 1 mm deep = 20 nL of active substance delivered. Under these conditions, the amount of active substance, rather than “allergen,” is strictly linked to the concentration of the contact solution.
The present letter also states that we did not follow the recommendations for “positivity” criteria established by SFAR. Of course, we did not. We challenged the skin of selected healthy volunteers, and we defined arbitrarily in the Methods section our criteria of positive skin reaction. Indeed, the association of a wheal and flare characterized in our study a positive reaction irrespective of their size. As written in the introduction section, “this study was performed to determine the concentration-response curves for prick tests with rocuronium and vecuronium in healthy volunteers” but not to diagnose allergy. We did investigate the relationship between dose of relaxants and skin responses looking at a nonspecific effect of aminosteroid drugs that we characterized for the flare responses.
Our results are not disputable because of the study design.
Regarding the Discussion section, we never affirmed that our results were “in contradiction with the recent guidelines published by the SFAR but rather that ”our observations contrast“ with the French group’s estimation of normally nonreactive concentration of rocuronium and vecuronium. Guidelines are guidelines and our results cannot be in contradiction with guidelines. On the other hand, our results question the pertinence of recommendations for clinical diagnosis of allergy. Discussion and interpretation of our results is based on these recommendations.
To put our results in perspective, we strictly applied the one criterion for positive prick test proposed by the French group recalled by Mertes et al. in this letter: an edematous wheal with a diameter at least 3 mm greater than that induced by the negative control solution. Calculation of the area of a wheal reaction is linked to its diameter. Since none of our volunteers reacted to the negative control solution, all prick-tests were considered positive if the surface of the wheal was greater than 7 mm2 [= π * (3.0/2) (2)]. To assess the quality of our results, we applied other criteria for positive prick tests (some are proposed in Europe, other in the United States) such as comparing individual weal or flare surface ratios between that of the positive control and active diluted solutions of relaxants. Interestingly, this quality control procedure demonstrated that wherever the cursor is placed, there are at least 15% of the volunteers being significantly responsive to undiluted rocuronium and vecuronium, respectively. Although allergy is of rare occurrence in anesthesia, I am convinced that a rate of false positive >10% is unacceptable for a diagnostic test. Even under this new insight our conclusion remains pertinent, prick tests to undiluted stock solutions of aminosteroids muscle relaxants should not be used to diagnose or confirm allergy.
Although, the formulation is awkward, our results confirm the observations of both Berg et al. (2) and Levy et al. (3) that demonstrated frequent false positive rate associated with “skin testing” and pleaded in their respective papers for a clinically applicable discriminant test technique able to separate true positive tests from false positive tests. Moreover, I cannot understand how our results can be in contradiction with other large studies published in different countries such as that of Fisher et al. (4) and Leynadier et al. (5), since these studies were performed in patients suspected or known to be allergic but not in healthy volunteers.
As all clinicians, I am still waiting for an important study including a large cohort of healthy volunteers from several countries and of different skin colors tested to determine real skin sensitivity to NMBAs, unless this study has already been performed in France but not published. Unfortunately, in the absence of such major study for better application of skin testing and validation of other diagnostic approach of allergy to anesthetic drugs, it is not certain that we are making the correct diagnostic of allergy to rocuronium and vecuronium using prick responses to undiluted stock solutions.
We are aware that the French group has performed an immense task in the area of allergy and largely “sensitized” all anesthesiologists (not only French professionals) to this risk. We are better prepared for such risk, and special operating diagnostic and therapeutic procedures are now systematically applied in case of suspicion of an allergic accident. The French group did a great job for patients' security. We accept the fact that neuromuscular blocking drugs are probably the most common cause of anaphylaxis during anesthesia. However, real incidence of allergy is difficult to establish and do vary among countries. Reporting problems pollute the numerator, and the denominator is highly variable. Dr. Levy (6) suggested in an editorial that the only way to explain this widely divergent perspective is to understand how the diagnosis is made and to define threshold skin tests concentrations. This was our main goal.
We believe that there is now probably enough material that calls into question the past practice of skin testing in anesthesia for our French eminent specialists, the leaders in this area, to manage indisputable international studies and propose worldwide-agreed guidelines for the diagnostic of allergy in anesthesia.
We also believe that stigmatizing neuromuscular blocking drugs or dealing with fear of allergy is an attitude that promotes “epidermic reactions” and blocks off the potential allergic risk of other drugs used in the clinical practice of anesthesia.
Gilles Dhonneur, MD
Department of Anesthesia and Critical Care Medicine; Henri Mondor University Hospital of Créteil; University of Paris XII Val-de-Marne; School of Medicine of Créteil; Créteil, France; firstname.lastname@example.org
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.
2. 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.
3. Levy JH, Gottge M, Szlam F, et al. Weal and flare responses to intradermal rocuronium and cisatracurium in humans. Br J Anaesth 2000;85:844–9.
4. Fisher MM, Bowey CJ. Intradermal compared with prick testing in the diagnosis of anaesthetic allergy. Br J Anaesth 1997;79:59–63.
5. Leynadier F, Sansarricq M, Didier JM, Dry J. Prick tests in the diagnosis of anaphylaxis to general anaesthetics. Br J Anaesth 1987;59:683–9.
6. JH Levy. Anaphylactic reactions to neuromuscular blocking drugs: are we making the correct diagnosis. Anesth Analg 2005;98:881–2.