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Skin Reactions to Intradermal Neuromuscular Blocking Agent Anesthesiology 2007; 107:245–52 Copyright © 2007, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Skin Reactions to Intradermal Neuromuscular Blocking Agent Injections A Randomized Multicenter Trial in Healthy Volunteers Paul Michel Mertes, M.D., Ph.D.,* Denise Anne Moneret-Vautrin, M.D., Ph.D.,† Francisque Leynadier, M.D.,‡ Marie-Claire Laxenaire, M.D.§ Background: Numerous reports confirm the performance of DESPITE the large number of reports confirming the intradermal tests for the diagnosis of anaphylaxis during anesthe- performance of prick or intradermal tests for the diag- sia; however, there is controversy over their diagnostic value re- nosis of suspected anaphylactic reaction during anesthe- Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/107/2/245/364587/0000542-200708000-00011.pdf by guest on 01 October 2021 garding the newer neuromuscular blocking agents (NMBAs). 1–22 Methods: One hundred eleven healthy volunteers were ran- sia, there is a renewed controversy over their domly assigned to receive intradermal injections of two NMBAs, diagnostic value, especially regarding the newer neuro- at five increasing concentrations. A concentration was consid- muscular blocking agents (NMBAs).23–25 ered as a reactive concentration when it led to a positive reac- This controversy has been partly supported by the tion in more than 5% of the subjects. These concentrations were common idea that the incidence of anaphylactic reaction compared with the maximal concentration recommended for the diagnosis of sensitization to NMBAs. occurring during anesthesia was progressively increas- Results: The maximal nonreactive concentrations were 10؊3 ing with time. It was also supported by differences ؊ M for suxamethonium; 10 4 M for pancuronium, vecuronium, reported regarding their incidence in Europe, Australia, ؊ rocuronium, and cisatracurium; and 10 5 M for atracurium and and New Zealand on one hand and in the United States mivacurium. Except for mivacurium, these nonreactive concen- on the other hand.6,20,26,27 This led some authors to trations were close to the maximal concentrations used for the hypothesize that this increase may be partly related to an diagnosis of sensitization against NMBAs. For mivacurium, the nonreactive concentrations were higher than the maximal con- increased rate of false-positive results when investigating centration currently recommended in clinical practice. newly commercialized agents as potential offending Conclusion: The aminosteroidal NMBAs pancuronium, vecuro- drugs. However, if we carefully examine results from the nium, and rocuronium and the benzylisoquinoline cisatracurium most recently published epidemiologic surveys,20,22,28 have a similar potency to induce a nonspecific skin reactivity. If things seem to be in sharp contrast. The number of the criteria for positivity and the maximal concentrations of the commercially available compounds recommended by French reactions involving NMBAs and latex seems to remain practice guidelines are used, the risk of false-positive results is relatively stable, whereas the incidence of anaphylaxis to limited, and only minor modifications of these recommendations antibiotics has rapidly increased within the same time could be suggested. A slight reduction in the maximal concentra- period. tion used for rocuronium from 1:100 to 1:200 and an increase Neuromuscular blocking agents are highly charged from 1:1,000 to 1:200 for mivacurium can be proposed. molecules that have direct vasodilating effects on the skin vasculature.29 They are able to induce histamine and Additional material related to this article can be found on the tryptase release from mast cells within the skin through ANESTHESIOLOGY Web site. Go to http://www.anesthesiology mechanisms that may vary depending on the com- .org, click on Enhancements Index, and then scroll down to 23,29–31 find the appropriate article and link. Supplementary material pounds studied. The classic idea that benzyliso- can also be accessed on the Web by clicking on the “Arti- quinoline-derived NMBAs have a higher propensity to clePlus” link either in the Table of Contents or at the top of release histamine from mast cells than the aminosteroi- the Abstract or HTML version of the article. dal NMBAs has also been recently contradicted using microdialysis experiments within the skin, which shows that the efficacy of atracurium, but also rapacuronium, * Professor and Head of the Department of Anesthesiology, Service d’Anesthe´sie-Re´animation, Hoˆpital Central, Centre Hospitalier Universitaire de an aminosteroidal NMBA, to release histamine was sig- Nancy, Unite´ Inserm 684, Faculte´deMe´decine de Nancy. † Professor of nificantly higher than that of other muscle relaxants.29 Allergology and Head of the Service de Me´decine Interne–Immunologie Clinique, Hoˆpital Central, Centre Hospitalier Universitaire de Nancy. ‡ Professor and Head Therefore, defining the dose-related wheal-and-flare cu- of the Department of Allergology, Hoˆpital Tenon (AP-HP), Universite´ Pierre et taneous response for each compound is of valuable in- Marie Curie, Faculte´deMe´decine Saint Antoine, Paris, France. § Professor of Anesthesiology, Service d’Anesthe´sie-Re´animation, Hoˆpital Central, Centre Hos- terest. Indeed, a prospective definition of the histamine- pitalier Universitaire de Nancy. releasing properties of all NMBAs available within the Received from the Service d’Anesthe´sie-Re´animation, Centre Hospitalier Uni- skin in healthy individuals would help us to standardize versitaire de Nancy, Hoˆpital Central, Nancy, France. Submitted for publication October 9, 2006. Accepted for publication April 26, 2007. Supported by a grant the diagnostic protocol used by the different investiga- from NV Organon, Boxtel, The Netherlands. tors, for the diagnosis of sensitization against NMBAs in Address correspondence to Dr. Mertes: Service d’Anesthe´sie-Re´animation, Centre patients. Hospitalier Universitaire de Nancy, Hoˆpital Central, 29 Avenue de Lattre de Tassigny, 54035 Nancy Cedex, France. [email protected]. Information on purchasing In the current study, we investigated all commercially reprints may be found at www.anesthesiology.org or on the masthead page at the available NMBAs in healthy volunteers. Five increasing beginning of this issue. ANESTHESIOLOGY’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue. log molar concentrations of these NMBAs were injected Anesthesiology, V 107, No 2, Aug 2007 245 246 MERTES ET AL. intradermally on the forearm and the back to determine following NMBAs were administered: rocuronium bro- a concentration–response relation. These dose–response mide (Org 9426, Esmeron®, NV Organon), rapacuro- relations obtained in control subjects were compared nium bromide (Org 9487, Raplon®; NV Organon), vecu- with the maximal concentration recommended by the ronium bromide (Org NC45, Norcuron®; NV Organon), recent French guidelines for the diagnosis of sensitiza- pancuronium bromide (Org NA97, Pavulon®;NVOr- tion to NMBAs by intradermal skin tests in subjects who ganon), atracurium (di)besylate (Tracrium®; GlaxoSmith- have experienced a suspected anaphylactic reaction dur- Kline, Marly le Roi, France), cisatracurium (di)besylate 32,33 ing general anesthesia. (Nimbex®; GlaxoSmithKline), mivacurium (di)chloride (Mivacron®; GlaxoSmithKline), and succinylcholine (di- )chloride (Suxamethonium; Pharmachemie, Haarlem, Subjects and Methods The Netherlands). The specifics of the available presen- Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/107/2/245/364587/0000542-200708000-00011.pdf by guest on 01 October 2021 Subjects tations of these NMBAs are presented in table 1. This was a randomized trial in 111 healthy volunteers, The NMBAs were used as commercially available and Ϫ7 performed in two centers specializing in clinical investi- were diluted to molar concentrations of 10 M (vecu- gation in France (Centre d’Investigation Clinique Inser- ronium, pancuronium, atracurium, cisatracurium, and Ϫ6 Ϫ5 Ϫ4 Ϫ3 m–Centre Hospitalier Universitaire de Nancy and Centre mivacurium), 10 M (all), 10 M (all), 10 M (all), 10 Ϫ2 d’Investigation Clinique Inserm–Centre Hospitalier Uni- M (all), and 10 M (rocuronium, rapacuronium, and versitaire de Paris Saint Antoine). This study was ap- succinylcholine), based on their direct histamine releas- proved by the Ethical Committee of Paris, Saint Antoine, ing properties. Phenol physiologic diluent (Stallerge`nes Paris, France. The subjects were healthy men or non- Laboratoires, Antony, France) was used in a 0.4% con- pregnant, non–breast-feeding women, aged 18–45 yr, centration (4 g phenol in 1,000 ml NaCl, 0.9%) to dilute who had given proper written informed consent. Exclu- the NMBAs. It was also used as a negative control. As a sion criteria were general anesthesia in the past; atopic second negative control, physiologic saline (NaCl, 0.9%) diseases such as hay fever, childhood asthma, and atopic Ϫ4 was used. Histamine (10 M; Stallerge`nes Laboratoires) dermatitis; a history of hypersensitivity reactions; and was used in a concentration of 10 ␮g/ml as a positive known or suspected recent use of steroids, antidepres- control. As a second positive control, codeine (Codeine sants, neuroleptics, or antihistamines. Subjects in whom Phosphate 1%; Stallerge`nes Laboratoires) was used in a determination of wheals and flares was expected to be ␮ difficult because of highly pigmented
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