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Editorial Views  |   January 2015
Anaphylaxis to Neuromuscular-blocking Drugs: All Neuromuscular-blocking Drugs Are Not the Same
Author Notes
  • From the Strasbourg Medical School, Hôpitaux Universitaires de Strasbourg, Nouvel Hôpital Civil, Strasbourg, Cedex, France (P.M.M.); and Mayo Medical School, Rochester, Minnesota (G.W.V.).
  • Corresponding article on page 39.
    Corresponding article on page 39.×
  • Accepted for publication September 15, 2014.
    Accepted for publication September 15, 2014.×
  • Address correspondence to Dr. Mertes: paul-michel.mertes@chru-strasbourg.fr
Article Information
Editorial Views / Neuromuscular Diseases and Drugs / Pharmacology
Editorial Views   |   January 2015
Anaphylaxis to Neuromuscular-blocking Drugs: All Neuromuscular-blocking Drugs Are Not the Same
Anesthesiology 01 2015, Vol.122, 5-7. doi:10.1097/ALN.0000000000000516
Anesthesiology 01 2015, Vol.122, 5-7. doi:10.1097/ALN.0000000000000516
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Image: ©Thinkstock.
Image: ©Thinkstock.
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In the current issue of Anesthesiology, Reddy et al.1  report a two-hospital, retrospective, observational, cohort study confirming that anaphylaxis is more common with rocuronium and succinylcholine than with atracurium, a topic that is difficult to assess and was first highlighted in this journal in 2003.2  Although any medication can potentially cause perioperative anaphylaxis, neuromuscular-blocking drugs (NMBDs), antibiotics, latex, and chlorhexidine are the most likely to do so. Regional differences regarding the relative risk of allergic reactions to NMBDs do exist. NMBDs represent the dominant causes of anaphylaxis in several countries and regions such as France,2–4  Norway,5  Spain,6  and Australasia,7  whereas other agents may be primarily involved in other countries.8  Nevertheless, allergic reactions to NMBDs remain a serious concern for anesthesiologists because death may occur even when reactions are rapidly and adequately treated.9  The reported incidence of perioperative anaphylaxis is quite varying, ranging between 1:3,500 and 1:20,000. Part of the variability is likely due to difficulty in determining the exact exposures to the numerous drugs, blood products, and agents used in the operative setting. The number of documented cases of intraoperative anaphylaxis is typically reported in aggregate for a large population, leaving the specifics of the total amount and type of medications the population was exposed to in question.
In the study by Reddy et al., the authors take the advantage of their ability to retrieve detailed information concerning new patient exposure to each NMBD from electronic anesthetic records available in the two participating centers over 7 yr. This allowed a more precise estimate of the number of patients exposed as the denominator when calculating the relative risk of allergic reactions associated with the use of each NMBD. This method helps eliminate the primary concern with data based on drug sales, which have the potential to overestimate the exposure resulting in a potential underestimation of anaphylaxis rate. Interestingly, the authors’ findings are similar to the estimates of allergic reactions to NMBDs based on drug sales. This study confirms the increased relative risk of allergic reaction to succinylcholine and rocuronium in countries where a high rate of reaction to NMBDs is reported.
The surveillance of intraoperative adverse drug reactions still represents a clinical and statistical challenge10  because these reactions are rare, random, and mostly independent from the repeated exposure of patients to anesthesia. In addition, possible biases and underreporting make comparison between drugs relatively difficult. Another weakness of any reporting system is that responsible physicians seem to have little understanding of which drug is actually causing the anaphylactic reaction when several drugs are simultaneously administered during anesthesia induction due to a lack of a single confirmatory test.11  With thorough review in this study, it was noted that 9 of the 21 cases of identified NMBD anaphylaxis did not meet the standard skin test criteria for positivity but correctly warranted inclusion based on clinical picture and adjunct testing.
Because identification of the anaphylactic mechanism, of the responsible drug, and of the alternative safe agents is not always straightforward, a standard use of tryptase measurements in case of suspected allergic reactions and investigation of these reactions in compliance with established guidelines12  by allergists trained in the field of drug allergy working in close collaboration with anesthesiologists should be promoted.13,14  Reddy et al. confirm that allergic reactions are associated with greater tryptase and greater severity than nonallergic cases. Because no predictive test can help us to identify patients at risk before any reaction, reduction of the risk of perioperative anaphylaxis can only be based on secondary prevention.12  This report provides a strong motivation for a thorough and systematic investigation of any hypersensitivity reactions occurring during the perioperative period15  to avoid any undesirable subsequent exposure to an offending agent toward which one is already sensitized. This necessity is further supported by the small number of minor reactions diagnosed in this study, probably related to under-referral of mild reactions to all agents, a reality clearly demonstrated in the literature.4,15  The authors were not able to determine the number of reactors who were receiving anesthesia for the first time, had a history of multiple anesthetic exposure or even history of previous reaction. This information would be helpful in future studies in determining sensitization patterns. Going forward, studies of intraoperative anaphylaxis should include a standard definition of anaphylaxis, uniform skin testing, specific immunoglobulin E drug testing, tryptase measurements, and review by an allergist in conjunction with an anesthesiologist.
The risk of allergic reactions is not the only drug characteristic that anesthesiologists must take into account when making their clinical choice. In view of the number of side effects associated with the use of succinylcholine, a controversy exists concerning replacing this old drug by rocuronium for rapid sequence induction.16  Nevertheless, because of their rapid onset of effect, both drugs will remain essential in the anesthesiologists’ armamentarium. Another interesting point that must be considered is that rocuronium can be rapidly reversed by sugammadex, a possibility that can make rocuronium a drug of choice in countries where sugammadex is available.17  Sugammadex has also recently been proposed to improve recovery in case of anaphylaxis to rocuronium18 ; however, its ability to play a role in reaction reversal remains controversial.19,20  Moreover, hypersensitivity reactions, either allergic or not, have been reported with sugammadex,21  and this drug has not been approved in the United States at present.
Due to the amount of vecuronium exposures, Reddy et al. were not able to provide specific information concerning the risk associated with its use. This drug has been shown to have a lower risk of anaphylaxis than rocuronium in large epidemiologic studies22  and its effect can also be effectively reversed by sugammadex.23  They considered atracurium to be a safe alternative but were not able to comment on the relative risk associated with cisatracurium because this drug is not in use in Australasia. Cisatracurium has been shown to have the lowest risk of hypersensitivity reactions, either allergic or not, in large cohort studies,3,22  and has also been shown to have the lowest rate of cross-sensitization with other NMBDs in allergic patients.7,22  There are many factors that will influence the choice of a specific NMBD, depending on the clinical situation, but the likely increased allergic risk associated with succinylcholine and rocuronium, and the relatively low risk associated with atracurium and even more so with cisatracurium must be part of the clinical reasoning when considering the use of a NMBD.
Competing Interests
The authors are not supported by, nor maintain any financial interest in, any commercial activity that may be associated with the topic of this article.
References
Reddy, JI, Cooke, PJ, van Schalkwyk, JM, Hannam, JA, Fitzharris, P, Mitchell, SJ Anaphylaxis is more common with rocuronium and succinylcholine than with atracurium.. Anesthesiology. (2015). 122 39–45
Mertes, PM, Laxenaire, MC, Alla, F Anaphylactic and anaphylactoid reactions occurring during anesthesia in France in 1999–2000.. Anesthesiology. (2003). 99 536–45 [Article] [PubMed]
Dong, SW, Mertes, PM, Petitpain, N, Hasdenteufel, F, Malinovsky, JM GERAP, Hypersensitivity reactions during anesthesia. Results from the ninth French survey (2005–2007).. Minerva Anestesiol. (2012). 78 868–78 [PubMed]
Mertes, PM, Alla, F, Tréchot, P, Auroy, Y, Jougla, E Groupe d’Etudes des Réactions Anaphylactoïdes Peranesthésiques, Anaphylaxis during anesthesia in France: An 8-year national survey.. J Allergy Clin Immunol. (2011). 128 366–73 [Article] [PubMed]
Harboe, T, Guttormsen, AB, Irgens, A, Dybendal, T, Florvaag, E Anaphylaxis during anesthesia in Norway: A 6-year single-center follow-up study.. Anesthesiology. (2005). 102 897–903 [Article] [PubMed]
Lobera, T, Audicana, MT, Pozo, MD, Blasco, A, Fernández, E, Cañada, P, Gastaminza, G, Martinez-Albelda, I, González-Mahave, I, Muñoz, D Study of hypersensitivity reactions and anaphylaxis during anesthesia in Spain.. J Investig Allergol Clin Immunol. (2008). 18 350–6 [PubMed]
Sadleir, PH, Clarke, RC, Bunning, DL, Platt, PR Anaphylaxis to neuromuscular blocking drugs: Incidence and cross-reactivity in Western Australia from 2002 to 2011.. Br J Anaesth. (2013). 110 981–7 [Article] [PubMed]
Gurrieri, C, Weingarten, TN, Martin, DP, Babovic, N, Narr, BJ, Sprung, J, Volcheck, GW Allergic reactions during anesthesia at a large United States referral center.. Anesth Analg. (2011). 113 1202–12 [Article] [PubMed]
Reitter, M, Petitpain, N, Latarche, C, Cottin, J, Massy, N, Demoly, P, Gillet, P, Mertes, PM French Network of Regional Pharmacovigilance Centres, Fatal anaphylaxis with neuromuscular blocking agents: A risk factor and management analysis.. Allergy. (2014). 69 954–9 [Article] [PubMed]
Laake, JH, Røttingen, JA Rocuronium and anaphylaxis—A statistical challenge.. Acta Anaesthesiol Scand. (2001). 45 1196–203 [Article] [PubMed]
Krøigaard, M, Garvey, LH, Menné, T, Husum, B Allergic reactions in anaesthesia: Are suspected causes confirmed on subsequent testing?. Br J Anaesth. (2005). 95 468–71 [Article] [PubMed]
Mertes, PM, Malinovsky, JM, Jouffroy, L, Aberer, W, Terreehorst, I, Brockow, K, Demoly, P Working Group of the SFAR and SFA; ENDA; EAACI Interest Group on Drug Allergy, Reducing the risk of anaphylaxis during anesthesia: 2011 updated guidelines for clinical practice.. J Investig Allergol Clin Immunol. (2011). 21 442–53 [PubMed]
Mertes, PM, Demoly, P, Malinovsky, JM Hypersensitivity reactions in the anesthesia setting/allergic reactions to anesthetics.. Curr Opin Allergy Clin Immunol. (2012). 12 361–8 [Article] [PubMed]
Volcheck, GW, Mertes, PM Local and general anesthetics immediate hypersensitivity reactions.. Immunol Allergy Clin North Am. (2014). 34 525–46, viii [Article] [PubMed]
Malinovsky, JM, Decagny, S, Wessel, F, Guilloux, L, Mertes, PM Systematic follow-up increases incidence of anaphylaxis during adverse reactions in anesthetized patients.. Acta Anaesthesiol Scand. (2008). 52 175–81 [Article] [PubMed]
Perry, JJ, Lee, JS, Sillberg, VA, Wells, GA Rocuronium versus succinylcholine for rapid sequence induction intubation.. Cochrane Database Syst Rev. (2008).  CD002788
Aceto, P, Perilli, V, Modesti, C, Ciocchetti, P, Vitale, F, Sollazzi, L Airway management in obese patients.. Surg Obes Relat Dis. (2013). 9 809–15 [Article] [PubMed]
McDonnell, NJ, Pavy, TJ, Green, LK, Platt, PR Sugammadex in the management of rocuronium-induced anaphylaxis.. Br J Anaesth. (2011). 106 199–201 [Article] [PubMed]
Clarke, RC, Sadleir, PH, Platt, PR The role of sugammadex in the development and modification of an allergic response to rocuronium: Evidence from a cutaneous model.. Anaesthesia. (2012). 67 266–73 [Article] [PubMed]
Leysen, J, Bridts, CH, De Clerck, LS, Ebo, DG Rocuronium-induced anaphylaxis is probably not mitigated by sugammadex: Evidence from an in vitro experiment.. Anaesthesia. (2011). 66 526–7 [Article] [PubMed]
Tsur, A, Kalansky, A Hypersensitivity associated with sugammadex administration: A systematic review.. Anaesthesia. (2014). 69 1251–7 [Article] [PubMed]
Mertes, PM, Aimone-Gastin, I, Guéant-Rodriguez, RM, Mouton-Faivre, C, Audibert, G, O’Brien, J, Frendt, D, Brezeanu, M, Bouaziz, H, Guéant, JL Hypersensitivity reactions to neuromuscular blocking agents.. Curr Pharm Des. (2008). 14 2809–25 [Article] [PubMed]
Malinovsky, JM, Plaud, B, Debaene, B, Mertes, PM [Do we know all indications and side effects of sugammadex?].. Ann Fr Anesth Reanim. (2011). 30 709–10 [Article] [PubMed]
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Image: ©Thinkstock.
Image: ©Thinkstock.
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