Discussion
The etiological diagnosis of perioperative anaphylaxis relies on a triad of evidences, including clinical, biological, and allergological evidence [
9]. We report here three cases, in which both clinical symptoms and positive skin test reactions were observed in response to sugammadex injection.
The first line of evidence for diagnosing anaphylaxis includes clinical signs. The National Institute of Allergy and Infectious Disease (NIAID) and the Food Allergy and Anaphylaxis Network (FAAN) proposed clinical criteria for diagnosing anaphylaxis [
10]. All three of our cases fulfilled these criteria, as evidenced by the acute onset of symptoms, with involvement of the skin and hypotension.
The second line of evidence for diagnosing anaphylaxis is biological assessment, including plasma histamine and tryptase measurements. Typically, anaphylaxis results from mast cell activation, which causes release of mast cell tryptase into the circulation, although a variety of other pathways, including basophil or complement activation, may combine to produce anaphylaxis. We were unable to perform any blood tests in our patients. The currently available tryptase assay has a relatively low sensitivity; hence, some cases of anaphylaxis might be missed [
11]. However, given the high specificity of tryptase assay [
12], such assessment should be done for diagnosing anaphylaxis. During anaphylaxis, tryptase peaks by approximately 1 h and its half-life in the circulation is about 2 h [
11], suggesting that elevation of tryptase can still be seen at least 1-2 hours after onset of the reaction, by which time the patient should be stabilized.
Skin tests, the third line of evidence, remain the gold standard for the detection of IgE-mediated reactions, and involve exposure of the mast cells of the skin of patients who experience anaphylaxis to the suspected allergen [
13]. In previous reports, either skin-prick [
3,
4] or intradermal [
7,
8] tests were performed to detect hypersensitivity to sugammadex. However, there are no established guidelines with respect to skin testing for hypersensitivity to sugammadex. Moreover, it is still unknown which of the two tests is superior. In our three cases, we performed prick or intradermal tests in the operation room several weeks after the incidents, with drugs to treat anaphylaxis readily available. The results showed a positive reaction to only sugammadex in all cases. We chose relatively low concentrations (i.e., 1:1000 or 1:100) of sugammadex for both prick and intradermal tests to avoid false-positive reactions, because it is known that intradermal tests sometimes produce false-positive reactions [
14]. A recent study showed that dilutions of 100 mg/ml sugammadex at 1:77 and 1:770 for intradermal tests did not cause skin irritation or false positive reactions in 11 volunteers, suggesting that 1:100 and higher dilutions of sugammadex are not likely to produce false-positive reactions [
15]. However, it was difficult to exclude the possibility that the positive reaction to sugammadex might have been a non-specific cutaneous irritant effect, because of the lack of a positive control skin test with histamine. In addition to skin tests, tests for serum-specific IgE antibodies and basophil activation using flow-cytometry may also be useful for the diagnosis of anaphylaxis [
11,
16,
17]. Taken together, the immediate development of anaphylaxis in response to sugammadex and the results of skin tests were highly suggestive of sugammadex-induced anaphylactic shock, although biological assessments and positive control skin tests were lacking.
None of our patients had prior exposure to sugammadex. Cyclodextrins, one of the components of sugammadex preparations, are present in various foods, which may partly explain the cross-reaction with sugammadex. A recent report suggested that the appropriate dose of sugammadex for reversal of rocuronium should be determined by the results of neuromuscular monitoring [
18]. However, we did not monitor neuromuscular transmission in our patients.
Sugammadex-induced anaphylaxis typically presents when the patient is already extubated and is being transferred to the hospital bed, PACU, ICU, etc. [
3], time points when the patient is typically less monitored. Therefore, rapid diagnosis and appropriate treatment of anaphylaxis, including administration of adrenaline, oxygen, and large volumes of crystalloids, are required. In the current report, patients 1 and 2 were treated with 0.1 and 0.5 mg adrenaline IV, respectively. Although the maximum intravenous bolus dose of adrenaline recommended by recent guidelines for anaphylaxis during anesthesia is variable [
17,
19], the IV bolus dose of 0.5 mg adrenaline administered to case 2 appears to be a larger dose than that recommended by guidelines.
The Japanese Society of Anesthesiologists has issued a warning about sugammadex-induced anaphylactic shock three times since March 2011. The latest one, issued in June 2013, included 95 cases of sugammadex-related allergies that occurred between April 2010 and January 2013, although with no incidents of death. In all 95 cases, the relationship between the reaction and sugammadex was definitively ascertained by the anesthesiologists. Seventy-eight out of 95 cases fulfilled the validated criteria for anaphylaxis [
10]. The incidence rate of anaphylactic reactions due to sugammadex was estimated as 29 per million cases, based on the estimated number of patients (3.09 millions) in whom sugammadex was injected during the survey period. The alert also pointed out that the incidence rate may have been underestimated, because the survey was based on spontaneous reports from anesthesiologists and not on prospective studies. It is uncertain whether this incidence rate is higher in Japan than in other countries, because there is no epidemiological survey regarding this so far. The other possibility is that these warnings may simply reflect a high level of sugammadex usage in Japan. The drug company, MSD (Tokyo, Japan), has reported that sugammadex usage in Japan in 2010, in terms of monetary value, was more than 4 times higher than that in Spain, the country that showed the second highest usage in the world.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
TT: Preparation of the manuscript and involvement in case 1. YT: Anesthesiologist involved in the management of cases 2 and 3. NY and AT: Anesthesiologists involved in the management of case 1. TH: Preparation of the manuscript. CN: Anesthesiologist involved in the management of case 2. MO, MHY, and SS: Preparation of the manuscript. All authors read and approved the final manuscript.