Anesth Analg 2004;98:881-882
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000115146.70209.4B
EDITORIAL
Anaphylactic Reactions to Neuromuscular Blocking Drugs: Are We Making the Correct Diagnosis?
Jerrold H. Levy, MD
Department of Anesthesiology, Emory University School of Medicine, Cardiothoracic Anesthesiology and Critical Care, Emory Healthcare, Atlanta, Georgia
Address correspondence to Jerrold H. Levy, MD, Department of Anesthesiology, Emory University Hospital, 1364 Clifton Rd., N.E., Atlanta, GA 30322. Address e-mail to jerrold_levy{at}emoryhealthcare.org
Anesthesiologists administer a diversity of parenteral drugs in the perioperative period, including blood products and drugs, or manage patients during exposure to multiple foreign substances, all of which have the potential to produce a spectrum of adverse reactions (1). Allergic reactions are one type of an adverse reaction, and the most severe form is anaphylaxis (1). Anaphylaxis is a life-threatening reaction that causes acute cardiovascular and/or pulmonary dysfunction in the host because of a broad spectrum of mediators that are released after repeated antigenic exposure in a previously sensitized individual (1). Unfortunately, patients may not always know they have been sensitized to a drug or protein by previous exposure.
Intraoperative anaphylaxis, especially after anesthesia induction, is problematic because the patient is exposed to multiple drugs in an extremely short period—including induction drugs, opioids, antibiotics, and neuromuscular blocking drugs (NMBDs)—and occult antigens such as latex or drug additives/preservatives. The clinical diagnosis of intraoperative anaphylaxis is problematic because most anesthetics, including propofol, cause vasodilation, hypotension, and potentially cardiopulmonary dysfunction because of their direct and indirect effects on sympathoadrenergic responses, the heart, and the vasculature. Further, the patient with preexisting cardiovascular disease and hypovolemia may even be more acutely affected by the changes that occur after anesthetic induction (1). Some of our colleagues, including me, have made a career of trying to determine the best perioperative management of patients with underlying cardiovascular dysfunction (2).
Although the incidence of anaphylactic reactions in the perioperative setting has been suggested to be increasing, most of the information in support of this assumption is from case reports and retrospective studies (3). Protamine is perhaps one of the only drugs that has been studied in a large series for the incidence of anaphylaxis (4,5). The drugs that present a potentially greater risk for perioperative anaphylaxis in high-risk patients are the polypeptides (1,4,5).
In recent years, NMBDs, especially steroid-derived drugs, have been reported as potentially causative of anaphylactic reactions during anesthesia (3,6). Data implicating NMBDs, most recently from France, are mainly based on skin testing (3); however, earlier studies have reported that the steroid-derived NMBDs and other molecules produce false-positive skin tests (i.e., wheal and flare) (7–10). One of the major problems is that anaphylaxis to NMBDs is rare in the United States but has been reported more often in Europe. Although suggestions have been made that this is due to under-reporting, the severity of anaphylaxis and its sequelae that produce adverse outcomes clearly makes this highly unlikely on the basis of the current medicolegal climate in the United States. One of the only ways to explain this widely divergent perspective is to understand how the diagnosis is made: the recommended threshold test concentrations have not been defined, and thus results are unreliable.
We previously reported that steroid-derived drugs could induce positive wheal and flare responses independent of mast cell degranulation, even at small concentrations, after intradermal injection (7,9). This effect is likely due to a direct effect on the cutaneous vasculature that occurred with most NMBDs at concentrations as small as 10-5 M with intradermal skin tests in 30 volunteers (9). A positive cutaneous reaction without evidence of mast cell degranulation was noted at small concentrations (100 µg/mL) of rocuronium in almost all volunteers (9). We have used intradermal injections to compare the cutaneous effects of anesthetics and other drugs (7–10).
Because prick tests are often used for the authentication of NMBDs as causative drugs (11), in this edition of the journal, Gilles et al. (12) evaluated 30 volunteers by using prick testing, and each subject received a total of 10 prick tests (50 µL) on both forearms. Gilles et al. studied the wheal and flare responses to prick tests with rocuronium and vecuronium by using 4 dilutions (1:1000, 1:100, 1:10, and 1:1) of rocuronium and vecuronium and 2 controls (on both forearms) and measured wheal and flare immediately after and 15 min after administration. They noted that 50% and 40% of the subjects had a positive skin reaction to undiluted rocuronium and vecuronium, respectively. To avoid false-positive results, they suggest that prick testing with rocuronium and vecuronium should be performed in subjects who have experienced a hypersensitivity reaction during anesthesia, with concentrations less than those which often induce positive reactions in anesthesia-naive, healthy subjects (i.e., for men in a dilution of 1:10 and for women in a dilution of 1:100). Giles et al. also suggest that the absence of clear internationally agreed-upon guidelines for prick testing may explain the seeming different in- cidences of allergy to NMBDs among countries. Concentration-skin response curves to rocuronium and vecuronium have shown that prick tests should be performed with dilution of the commercially available preparation. Female volunteers significantly (P < 0.01) reacted to lower vecuronium and rocuronium concen- trations than male volunteers. In female subjects, positive skin reactions were reported with dilutions of 1:100 of both relaxants. In male subjects, positive skin reactions were noted with the undiluted concentration, except for one volunteer who reacted to rocuronium (1:10 dilution).
This current study by Gilles et al. is important because of previous reports and because the Société Française d’Anesthésie et de Réanimation published recommendations for NMBDs skin testing using undiluted solutions of rocuronium and vecuronium for prick tests (13,14). Because rocuronium and vecuronium are prepared as 10 and 1 mg/mL solutions, respectively, these concentrations are considered by the French group to be normally nonreactive in control subjects (13). The concentrations that Giles et al. have reported to produce a frequent incidence of positive cutaneous responses to rocuronium and vecuronium further support the observation that the incidence of the reported positive cutaneous response may contain a large proportion of false-positive responses. If the French recommendations for prick test validity were applied to the study by Gilles et al., all reacting volunteers would have fulfilled criteria of allergy. Indeed, a positive skin reaction, as defined by a wheal surface exceeding 8 mm2 (3-mm diameter), was almost systematically observed (14).
Any drug administered in the perioperative period has the potential to produce some form of adverse drug reaction. Despite the concerns about NMBDs, antibiotics, blood products, and polypeptides (i.e., aprotinin, latex, and protamine) are well documented to be associated with a more frequent incidence of reactions. More importantly, if a patient has an adverse event in the perioperative period, it is imperative that we follow the current recommendations by Gilles et al. and those we have made in order to avoid false-positive skin tests to NMBDs. Anaphylactic reactions are a continuing challenge to clinicians, but further elucidation of the mechanisms of mast cell degranulation (15), better application of skin testing and other diagnostic testing, and novel therapeutic approaches for acute inflammatory responses that occur in the perioperative period are important because worldwide, older and more critically ill patients will require surgery.
Acknowledgments
The author has received research support from Organon and has served as a consultant to Organon Teknika.
References
- Levy JH. Anaphylactic reactions in anesthesia and intensive care. 2nd ed. Stoneham, MA: Butterworth-Heinemann, 1992.
- Bolling SF, Dickstein ML, Levy JH, et al. Management strategies for high-risk cardiac surgery: improving outcomes in patients with heart failure. Heart Surg Forum 2000; 3: 337–49.[Web of Science][Medline]
- Mertes PM, Laxenaire MC, Alla F. Anaphylactic and anaphylactoid reactions occurring during anesthesia in France in 1999–2000. Anesthesiology 2003; 99: 536–45.[Web of Science][Medline]
- Levy JH, Zaidan JR, Faraj BA. Prospective evaluation of risk of protamine reactions in NPH insulin-dependent diabetics. Anesth Analg 1986; 65: 739–42.[Abstract/Free Full Text]
- Levy JH, Schwieger IM, Zaidan JR, et al. Evaluation of patients at risk for protamine reactions. J Thorac Cardiovasc Surg 1989; 98: 200–4.[Abstract]
- Naguib M, Magboul MA. Adverse effects of neuromuscular blockers and their antagonists. Drug Saf 1998; 18: 99–116.[Web of Science][Medline]
- Levy JH, Adelson D, Walker B. Weal and flare responses to muscle relaxants in humans. Agents Actions 1991; 34: 302–8.[Web of Science][Medline]
- Booij JH, Krieg N, Crul JF. Intradermal histamine releasing effect caused by Org-NC 45: a comparison with pancuronium, metocurine and d-tubocurarine. Acta Anaesthesiol Scand 1980; 24: 393–4.[Web of Science][Medline]
- 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.[Abstract/Free Full Text]
- Levy JH, Brister NW, Shearing A, et al. Weal and flare response to opioids in humans. Anesthesiology 1989; 70: 756–60.[Web of Science][Medline]
- 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.[Abstract/Free Full Text]
- Dhonneur G, Xavier C, Didier C, et al. 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]
- Moneret-Vautrin DA, Kanny G. Anaphylaxis to muscle relaxants: rational for skin tests. Allerg Immunol (Paris) 2002; 34: 233–40.[Medline]
- Commission Tripartite de Consensus en Allergologie. Texte de recommendation pour les test cutanés aux curarisants. Rev Fr Allergol 1997; 42: 776–7.
- Veien M, Szlam F, Holden JT, et al. Mechanisms of nonimmunological histamine and tryptase release from human cutaneous mast cells. Anesthesiology 2000; 92: 1074–81.[Web of Science][Medline]
Accepted for publication December 11, 2003.
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