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Anesthetic Clinical Pharmacology

Incidence of Anaphylaxis Associated With Sugammadex

Miyazaki, Yusuke MD*; Sunaga, Hiroshi MD*; Kida, Kotaro MD*; Hobo, Shotaro MD; Inoue, Nobuyoshi MD*; Muto, Masayuki MD*; Uezono, Shoichi MD*

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doi: 10.1213/ANE.0000000000002562
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Anaphylaxis is defined as a life-threatening hypersensitivity reaction with systemic allergic symptoms; it occurs rarely during surgery and anesthesia. Neuromuscular blocking agents and antibiotics are considered common causes of anaphylaxis.1 When symptoms associated with histamine reaction, such as skin rash, hypotension, tachycardia, and wheezing, appear suddenly after injection of these agents, anaphylaxis is suspected, and treatment should be initiated immediately. As far as is possible, it is essential to know the risk of anaphylaxis for these types of agents.

Sugammadex, a reversal agent for rocuronium and vecuronium, is available for clinical use in many countries. Whereas it has advantages over anticholinesterases, such as faster recovery from neuromuscular blockade and lesser incidence of residual paralysis,2,3 there are concerns regarding allergy and anticoagulation.4,5 A number of cases of hypersensitivity reaction in response to sugammadex have been reported,6 but the incidence of anaphylaxis has not been sufficiently elucidated. Since the first use of sugammadex in Japan in 2010, the Japanese Society of Anesthesiologists has reported an incidence of sugammadex-associated anaphylaxis of 0.0029%,4 based on estimates from the manufacturer. However, given the calculation method, the incidence is likely underestimated and remains unclear.

Our surgical center has not stored anticholinesterases since December 2014, and sugammadex has been commonly administered to reverse neuromuscular blockade. In the present study, we retrospectively investigated the incidence of anaphylaxis potentially caused by sugammadex at a single center in Japan over a period of 3 years. The primary outcome was the incidence of sugammadex-associated anaphylaxis, essential information for patient safety.


This study was approved by the ethics committee of Jikei University School of Medicine (Tokyo, Japan) in November 2015. A retrospective investigation was performed using the databases documenting anesthetic management and perioperative events at the Department of Anesthesiology, Jikei University School of Medicine.

All surgical cases attended by anesthesiologists from September 2012 to August 2015 were evaluated. In each case, an attending anesthesiologist qualified by the Japanese Society of Anesthesiologists completed and submitted an assessment form of perioperative events, including hypersensitivity reactions and other adverse events related to circulation, respiration, the central or peripheral nervous system, airway, catheter insertion, depth of anesthesia, etc. All assessment forms of perioperative events during the study period were reviewed, and cases of intraoperative hypersensitivity reactions were identified in light of the anesthetic records and the free-text comments on the form. Applicable clinical signs of intraoperative hypersensitivity reactions include erythema, urticaria, hypotension, tachycardia, dyspnea, bronchospasm, etc, which were described in the clinical severity scale of immediate hypersensitivity reactions adapted from Ring and Messmer.7,8 These were assessed to determine whether they corresponded to the definition of anaphylaxis according to the World Allergy Organization guidelines (Table 1).9 Cases of potential sugammadex-associated anaphylaxis were examined further in terms of patient background (ie, allergy history, comorbidity of asthma, surgical history, and previous exposure to sugammadex), sugammadex dose, onset of reaction, clinical symptoms, treatments, time to achieve hemodynamic stability, diagnostic tests, and course.

Table 1.
Table 1.:
Clinical Criteria for Diagnosing Anaphylaxis Adapted From World Allergy Organization Guidelines9

The total number of patients who received sugammadex during the study period was determined, along with the incidence of potential sugammadex-associated anaphylaxis. We estimated that this proportion would be approximately 0.04%, and to have a 0.07% width in the 95% confidence interval (CI) of this estimate, 12,539 cases were required for this retrospective study. The 95% CIs for incidence were calculated using the Clopper–Pearson method.


The number of surgical cases attended by anesthesiologists during the study period was 23,608, and an assessment form of perioperative events was submitted for all cases. The overall incidence of intraoperative hypersensitivity reaction was 53 (0.22%; 95% CI, 0.17%–0.29%), and the incidence of anaphylaxis was 14 (0.059%; 95% CI, 0.032%–0.10%). The total number of patients who received sugammadex during the study period was 15,479, and the incidence of anaphylaxis potentially caused by sugammadex was 6 (0.039%; 95% CI, 0.014%–0.084%).

The details of 6 cases of potential sugammadex-associated anaphylaxis are summarized in Table 2. After achieving hemodynamic stability with treatment for anaphylaxis, 1 patient was transferred to the intensive care unit for overnight observation and was administered a single dose of hydrocortisone (200 mg). The 5 others were moved to the general ward after observation in the postanesthesia care unit, and received no additional medication. All patients who experienced anaphylaxis potentially caused by sugammadex recovered with no major problems, including no biphasic reaction.

Table 2.
Table 2.:
Six Cases of Anaphylaxis That Occurred During Emergence From General Anesthesia


This retrospective, single-center study was undertaken to elucidate the incidence of anaphylaxis associated with sugammadex. The total number of patients who received sugammadex during the study period was 15,479, and the incidence of anaphylaxis potentially caused by sugammadex was 0.039% (6/15,479; 95% CI, 0.014%–0.084%). Although the cause of anaphylaxis was not specifically identified in this study, the clinical observations were that symptoms corresponding to anaphylaxis developed soon after injection of sugammadex.

Neuromuscular blocking agents are considered a common cause of anaphylaxis. A recent study reported that the incidence of anaphylaxis caused by succinylcholine, rocuronium, and atracurium is 0.048% (95% CI, 0.025%–0.084%), 0.04% (95% CI, 0.015%–0.087%), and 0.0045% (95% CI, 0.00092%–0.013%), respectively.10 Differences in study design should be considered, but the results of the present study imply that the incidence of sugammadex-induced anaphylaxis might be as high as that of succinylcholine- or rocuronium-induced anaphylaxis.

According to a report published by the Japanese Society of Anesthesiologists in 2013, which was based on investigation by the manufacturer, the incidence of sugammadex-associated anaphylaxis was 0.0029%;4 our present result of 0.039% is approximately 13 times this value. We used the same definition of anaphylaxis as the manufacturer, which does not specify tests, such as skin test, to identify the cause. Whereas the reason for the apparent difference is likely multifactorial, a possible reason for the discrepancy may be the reporting system for adverse events. In the present study, the perioperative hypersensitivity reactions were reported in all cases with a specific assessment form of perioperative events. In contrast, the data from the manufacturer were based on voluntary reporting. It is very likely that voluntary reporting recognized only a subset of cases of sugammadex-associated anaphylaxis. In addition, population parameters were different. Whereas the parameter in the present study was an actual number based on the total number of patients who received sugammadex, the parameter reported by the manufacturer was estimated cases based on the number of shipments to be distributed. Thus, an amount of unused sugammadex might be included in the population parameter.

Diagnostic tests to indicate that anaphylaxis occurred in response to sugammadex were performed for only 1 case in the present study. The patient showed a positive response with respect to serum tryptase and a negative response to a drug-induced lymphocyte stimulation test, an in vitro test to identify the causative agent of hypersensitivity reactions. Nonetheless, the result cannot rule out sugammadex as the cause of anaphylaxis because the sensitivity of the drug-induced lymphocyte stimulation test is low.11 Although the definitive diagnosis could not be made without objective evidence from diagnostic tests, the 6 cases are suggestive of anaphylaxis caused by sugammadex because the clinical symptoms corresponding to anaphylaxis occurred within 1–4 minutes after injection of sugammadex at the emergence from anesthesia.

A prospective study, including testing for identification of cause of anaphylaxis, will be necessary to confirm the exact incidence of sugammadex-induced anaphylaxis. However, we conclude that the incidence (0.039%; 95% CI, 0.014%–0.084%) may be similar to that for succinylcholine or rocuronium, and it is important to be alert to this possibility.


Name: Yusuke Miyazaki, MD.

Contribution: This author helped collect and analyze the data and write the manuscript.

Name: Hiroshi Sunaga, MD.

Contribution: This author helped design the study, collect and analyze the data, and write the manuscript.

Name: Kotaro Kida, MD.

Contribution: This author helped analyze the data and write the manuscript.

Name: Shotaro Hobo, MD.

Contribution: This author helped design the study and write the manuscript.

Name: Nobuyoshi Inoue, MD.

Contribution: This author helped collect the data and write the manuscript.

Name: Masayuki Muto, MD.

Contribution: This author helped collect the data and write the manuscript.

Name: Shoichi Uezono, MD.

Contribution: This author helped design the study and write the manuscript.

This manuscript was handled by: Ken B. Johnson, MD.


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