Anaphylaxis Induced by Rocuronium, Sugammadex, or Rocuronium–Sugammadex Complex: Summary of Published Cases

Perioperative anaphylaxis is a rare but life-threatening systemic reaction that may rapidly cause cardiovascular collapse, severe bronchospasm, or both. The reported mortality ranges from 1% to 4%.1 Rocuronium and sugammadex are two of the most common triggers of perioperative anaphylaxis.2 Clinical evidence has also indicated that rocuronium–sugammadex complex may elicit anaphylaxis.3 Given their frequent use in general anesthesia, a better understanding of anaphylaxis induced by these agents is warranted. Therefore, the present study was designed to summarize published case reports of anaphylaxis associated with rocuronium, sugammadex, or rocuronium–sugammadex complex, and to systematically characterize risk factors, clinical manifestations, diagnostic approaches, management, and outcomes. METHODS Ethics Statement Institutional Review Board approval was not applicable to the current study, as it involved only a summary of previously published data and did not include identifiable patient information. Search Strategy A systematic search was performed in PubMed, EMBASE, Web of Science, China National Knowledge Infrastructure and Wanfang Data Knowledge Service Platform from database inception to October 2025. Search terms combined “rocuronium,” “sugammadex,” and “anaphyla*.” Detailed search strategies are provided in the Supplemental Digital Content S1, https://links.lww.com/AA/F724. Study Selection Two authors (B.G. and Y.L.) independently reviewed the titles and abstracts of all identified studies and then screened the full-text for final eligibility. Inclusion criteria were: (1) English and Chinese language publications; (2) case report or case series; and (3) anaphylaxis was diagnosed according to clinical diagnostic criteria for anaphylaxis proposed by the World Allergy Organization (WAO). Exclusion criteria were: (1) full-text manuscript not accessible; (2) irrelevant to anaphylaxis induced by rocuronium or/and sugammadex; and (3) reviews or animal studies. Data Abstraction Data extraction was independently performed by two authors (B.G. and Y.Y.) using a standardized data collection form. Extracted variables included the author, year of publication, country, patient gender, age, history of anesthesia, allergy history, prior exposure to rocuronium or sugammadex, latency between drug administration and symptom onset, clinical manifestations of the anaphylaxis, therapeutic interventions, results of skin prick or intradermal testing, relevant diagnostic laboratory findings, and patient outcomes. A detailed summary is provided in Supplemental Digital Content S2, https://links.lww.com/AA/F725. The severity of anaphylaxis was assessed according to the updated WAO Systemic Allergic Reaction grading system (2023),4 which features a scale of Grades 1 to 5. Discrepancies were resolved by discussion among all authors. RESULTS A total of 2368 records were screened, and 109 articles (98 in English and 11 in Chinese) met the inclusion criteria, yielding 133 patient cases. Anaphylaxis was attributed to rocuronium in 83 cases, sugammadex in 43 cases, and rocuronium–sugammadex complex in seven cases. All case reports included in the current study are listed in Supplemental Digital Content S3, https://links.lww.com/AA/F726. Most reported anaphylaxis cases originated from Asia, followed by Europe and the Americas (Figure A). Of the patients included in the study, 72 were female (54.1%) and 57 were male (42.9%) (Figure B). Patient ages ranged from 6 days to 89 years, with the majority (66.2%) aged 18 to 65 years (Figure C). Prior anesthesia exposure was documented in 36.8% of cases, with only 8.3% having known exposure to rocuronium or sugammadex. Additionally, 29.3% had a history of allergy or asthma (Figure D–F).Figure.: Risk factors of anaphylaxis induced by rocuronium or sugammadex.The clinical manifestations of anaphylaxis involved multiple systems. In most cases, symptom onset was observed immediately or within minutes of exposure. Cardiovascular manifestations were dominated by hypotension (80.5%), tachycardia (61.7%), cardiac arrest or pulseless electrical activity (9.8%), and bradycardia (8.3%); ST-segment changes occurred in 4.5%, and five cases of Kounis syndrome were documented (3.0%). Respiratory symptoms included oxygen desaturation (36.1%), bronchospasm (32.3%), increased airway pressure (26.3%), ventilation difficulties or dyspnea (21.1%), and reduced end-tidal carbon dioxide (16.5%). Cutaneous or mucosal findings comprised erythema (51.9%), edema (18.8%), urticaria (15.8%), and pruritus (1.5%). Neurological manifestations predominantly occurred after emergence from anesthesia or extubation. Four patients (3.0%) (Obara 2018, Takazawa 2014, Yamada 2018, Yamaoka 2017) experienced loss of responsiveness, while one patient (0.8%) (Kim 2019) reported anxiety and dizziness. Another patient (0.8%) (Jones 2025) developed neurogenic fatigue and headaches after severe anaphylaxis, with mild executive and visual memory deficits persisting at 1 year. One patient (0.8%) (Iarossi 2025) showed abnormal coagulation with prolonged activated partial thromboplastin time and reduced fibrinogen. According to the updated WAO Systemic Allergic Reaction grading system, 28 cases were classified as Grade 3, 14 as Grade 4, and 86 as Grade 5. Five cases were difficult to grade for incomplete clinical details (Table). Table. - Clinical Manifestations of Included Anaphylaxis Cases (n = 133) Clinical manifestations Number of cases (incidence) (%) Cardiovascular system Hypotension 107 (80.5) Tachycardia 82 (61.7) Cardiac arrest/pulseless electrical activity 13 (9.8) Bradycardia 11 (8.3) ST-segment elevation or depression 6 (4.5) Kounis syndromea 4 (3.0) Respiratory system Oxygen desaturation 48 (36.1) Bronchospasm 43 (32.3) Increased airway pressure 35 (26.3) Difficulty with ventilation or dyspnea 28 (21.1) End-tidal carbon dioxide decreased 22 (16.5) Cutaneous and mucosal system Erythema 69 (51.9) Edema 25 (18.8) Urticaria 21 (15.8) Pruritus 2 (1.5) Central nervous system Impaired consciousness 4 (3.0) Anxiety/dizziness 1 (0.8) Executive and visual memory deficits 1 (0.8) Hematologic system Coagulation abnormality 1 (0.8) World Allergy Organization Gradeb 3 28 (21.1) 4 14 (10.5) 5 86 (64.7) aAn acute coronary syndrome triggered by an allergic or hypersensitivity reaction, characterized by mast-cell–mediated coronary vasospasm, plaque rupture, or stent thrombosis.bGrade 1 (mild): single-system symptoms. Limited skin or mild gastrointestinal symptoms or upper respiratory or conjunctival reddening; Grade 2 (moderate): multisystem involvement. Systemic urticaria, and/or significant angioedema, and/or persistent gastrointestinal symptoms; Grade 3: Respiratory involvement (bronchospasm/stridor/hoarseness) and/or cutaneous features, and/or severe gastrointestinal symptoms, and/or uterine cramps; Grade 4: Severe respiratory compromise and/or cardiovascular instability (hypotension), and/or Glasgow Come Scale <13; Grade 5: Respiratory failure/arrest, and/or anaphylactic shock, and/or cardiac arrest. Grade 3–5 reactions = anaphylaxis. In all anaphylaxis cases, 83 patients received epinephrine as first-line treatment, with 78.3% (65/83) achieving hemodynamic stability. Other interventions included cardiopulmonary resuscitation, electrical defibrillation, and extracorporeal membrane oxygenation or intra-aortic balloon implantation in 19 patients, and rapid fluid resuscitation (250–4000 mL of crystalloid, colloid, or albumin) in 65 patients. Glucocorticoids, vasopressors or vasodilators, and antihistamines were administered in 63.2% (84/133), 46.6% (62/133), and 35.3% (47/133) of cases, respectively, with bronchodilators or β2-agonists used as needed. Twenty-four patients with rocuronium-induced anaphylaxis received sugammadex (2.7–16.6 mg/kg). The treatment was effective in most, with one death 7 days later due to refractory hypotension. Skin prick or intradermal testing was performed in 87 patients and was positive in 84. Of the 56 patients with confirmed rocuronium-induced anaphylaxis, 18 showed cross-reactivity with two or more neuromuscular relaxants. One patient experienced anaphylaxis to both rocuronium and sugammadex, and another to both sugammadex and rocuronium–sugammadex complex. Thirteen patients exhibited elevated serum immunoglobulin E levels, 48 patients demonstrated increased serum tryptase levels, and 14 patients tested positive in the basophil activation test. DISCUSSION The current study demonstrates that reported cases of anaphylaxis associated with rocuronium, sugammadex, or rocuronium–sugammadex complex are highly severe according to the WAO grading system, representing a major clinical challenge. It is possible that milder cases of anaphylaxis are simply not reported. Based on the analysis of these case reports, the risk for perioperative anaphylaxis appears multifactorial, influenced by patient characteristics, prior drug exposures, and underlying atopic predisposition. Interestingly, several patients who had previously tolerated other neuromuscular relaxants or frequently used quaternary ammonium-containing products (such as cosmetics or cleaning agents) later developed immunoglobulin E-mediated hypersensitivity reactions to rocuronium. This observation is consistent with experimental evidence showing that quaternary ammonium compounds can induce dendritic cell maturation and promote immunoglobulin E class switching.5 Likewise, sensitization to sugammadex may occur through prior environmental or pharmaceutical exposure to structurally related cyclodextrins. Although North America and Europe constitute the primary markets for rocuronium and sugammadex, anaphylaxis of both drugs has been reported disproportionately more frequently in Asia. In contrast, the United States Food and Drug Administration’s Adverse Event Reporting System Public Dashboard6 data indicated that the largest number of reported anaphylaxis cases originates from Europe, followed by the Americas and Asia. This apparent discrepancy likely reflects regional differences in pharmacovigilance infrastructure, reporting populations and practices, as well as clinician awareness. Nevertheless, genetic factors cannot be excluded. Previous studies have identified associations between specific human leukocyte antigen alleles and contrast media hypersensitivity,7 suggesting a potential role of genetic variation in immune-mediated drug reactions, a hypothesis that warrants confirmation in large-scale, multiethnic studies. Although it is unclear whether sugammadex can treat anaphylaxis, it may restore hemodynamic stability when epinephrine alone is insufficient.8 The potential value of sugammadex in hemodynamically impaired patients may be explained by its ability to reverse neuromuscular blockade, strengthen muscle tone, and increase venous return.9 Given that both sugammadex and rocuronium–sugammadex complex may induce anaphylaxis, clinicians should weigh the benefits against the risks when considering the use of sugammadex for treating anaphylaxis to rocuronium. Anaphylaxis could result in multisystem dysfunction. In addition to the commonly affected cardiovascular, respiratory, cutaneous, and mucosal systems, the hematologic system should not be overlooked. The association between anaphylaxis and coagulation disorders was initially demonstrated in animal studies10,11 and has since been corroborated by multiple case reports.12,13 During severe anaphylaxis, mast cell degranulation releases mediators such as tryptase, which can disrupt coagulation pathways, the kallikrein-kinin system, and fibrinolytic processes. In addition, the primary targets of mediators released during anaphylaxis are arterial vessels, which may induce cerebral arterial vasospasm. The resulting impairment in cerebral blood flow may be disproportionate to the degree of systemic arterial hypotension and may lead to brain damage.14 Accordingly, anesthesiologists should maintain vigilance for these uncommon clinical manifestations during anaphylaxis. This study is limited by the nature of case report data, including publication and reporting bias, exclusion of non-English and non-Chinese literature, and the presence of incomplete clinical information, which may affect its generalizability. DISCLOSURES Conflicts of Interest: None. Funding: None. This manuscript was handled by: Ken B. Johnson, MD.