Table 2.

Major clinical studies with data related to the prevalence and patho-mechanism of adverse drug reactions (ADR) to neuromuscular blocking agents (NMBA) (case series and case reports not considered).

Title	Relevant Data and Remarks
Anaphylactic and anaphylactoid reactions occurring during anesthesia in France in 1999–2000 [2].	Anaphylactic and anaphylactoid reactions were diagnosed in 518 cases (66%) and 271 cases (34%), respectively. The most common causes of anaphylaxis were NMBA (n = 306, 58.2%). Anaphylaxis was diagnosed on the basis of clinical history, skin tests, and/or specific immunoglobulin E assay. In case of negative tests, an anaphylactoid reaction was diagnosed.
Anaphylactic and anaphylactoid reactions occurring during anaesthesia in France. Seventh epidemiologic survey (January 2001–December 2002) [46].	Anaphylactic and anaphylactoid reactions were diagnosed in 491 cases (69%) and 221 cases (31%), respectively. The most common causes of anaphylaxis were NMBA (n = 271, 55%). Anaphylaxis was diagnosed on the basis of clinical history if skin tests were positive or in case of elevated tryptase values and the presence of specific IgE. In case of negative tests, an anaphylactoid reaction was diagnosed.
Anaphylaxis during Anesthesia in Norway [47].	Eighty-three cases were examined: IgE–mediated anaphylaxis was established in 71.1% of the cases, and NMBA were by far the most frequent culprit drug (93.2%). IgE-mediated anaphylaxis was identified based on a modified categorization grading of causality of the IgE-mediated reactions (investigated by skin prick test, intradermal test, histamine releasing test, specific IgE against morphine and P-aminophenyl phosphoryl choline)
Anaphylaxis during anesthesia: results of a 12-year survey at a French pediatric center [48].	Out of 68 adverse reactions, IgE-mediated anaphylaxis was diagnosed in 51 children: 31 (60.8%) for NMBA, 14 (27%) for latex, seven (14%) for colloids, five (9%) for opioids and six (12%) for hypnotics. IgE-mediated anaphylaxis was diagnosed on the basis of the skin tests results concordant with the patients’ clinical history of adverse reactions and the anesthetic protocol.
Diagnosis of NMBA hypersensitivity reactions using cytofluorimetric analysis of basophils [49].	In 47 NMBA allergic patients, cytofluorimetric analysis of basophils was positive in 17 subjects. The diagnosis of allergy to NMBA was established from a characteristic clinical history (urticaria, bronchospasm and/or anaphylactic shock a few minutes after the start of anesthesia) and the positivity of NMBA skin tests.
Anaphylaxis during general anaesthesia: one-year survey from a British allergy clinic [50].	Out of the 23 patients who presented with anaphylaxis during anesthesia, 15 patients were found to have a positive skin test to at least one NMBA.
Evaluation of a new routine diagnostic test for IgE sensitization to NMBA [51].	In 168 patients exposed to NMBA, quaternary ammonium (QA)-specific IgE was found in 84.2% of skin test-positive reactors. The frequency of QA-specific IgE positivity was significantly higher in skin test-negative reactors (24.6%) than in controls (9.3%), suggesting NMBA sensitivity.
Differentiating the cellular and humoral components of neuromuscular blocking agent-induced anaphylactic reactions in patients undergoing anaesthesia [52].	On the basis of intradermal skin testing and clinical evaluation, allergy to NMBA was considered likely in 48 of 61 patients (79%). Correlation between skin test reactivity to rocuronium and IgE to rocuronium was low. In contrast, striking correlation between IgE to rocuronium and skin test reactivity to succinylcholine was found (p < 0.001).
IgE-sensitization to the cough suppressant pholcodine and the effects of its withdrawal from the Norwegian market [32].	Methods used to identify NMBA induced anaphylaxis are not reported. Decrease of perioperative anaphylaxis after pholcodine withdrawal was noted. However, the total amount of NMBA usage was not reported.
Negative predictive value of skin tests to NMBA [53].	55 patients were diagnosed with an allergy to NMBA, confirmed by clinical history, presence of specific IgE and/or positive skin test. 19 of these 55 patients had a second general anesthesia, 13 without NMBA and 6 using an NMBA for which skin tests were negative. None had had a new reaction to the injected NMBA.
Hypersensitivity reactions during anesthesia. Results from the ninth French survey (2005–2007) [45].	An IgE-mediated or non-IgE-mediated reaction was diagnosed in 786 cases (63%) and 467 cases (37%), respectively. The most common causes of anaphylaxis were NMBA (N = 373, 47.4%). Allergic or IgE-mediated anaphylaxis was diagnosed on the basis of skin test and/or IgE assay results consistent with the clinical history and the anesthetic protocol.
Perioperative allergic reactions: experience in a Flemish referral centre [54].	Out of 119 patients, a diagnosis of IgE-mediated reaction was established by skin tests and/or specific IgE in 76 cases (63.9%). The most common agents were NMBA (61.8%). The remaining 43 cases (36.1%) were considered as non-IgE-mediated reactions.
Predictive value of allergy tests for NMBA: tackling an unmet need [43].	272 patients with a history of perioperative allergy who had received a NMBA were reported. From the 47 patients who were re-exposed to a NMBA, 19 were initially diagnosed with suspected NMBA allergy, 13 had another IgE-mediated allergy suspected, and in the remainder 15, no IgE-mediated allergy was identified (skin test, specific IgE and BAT were used). Negative skin test and negative BAT assisted the selection of alternative NMBA, which were well tolerated in all cases.
Multi-centre retrospective analysis of anaphylaxis during general anaesthesia in the United Kingdom: aetiology and diagnostic performance of acute serum tryptase [55].	In 161 patients, an IgE-mediated cause was identified in 103 patients (64%); NMBA constituted the leading cause (38%). IgE-mediated reactions were diagnosed based on skin prick test [n = 25 (24%)], intradermal test (n = 68 (66%)), serum-specific IgE (n = 9 (9%)) and challenge tests (n = 3 (1%)).
Six years without pholcodine; Norwegians are significantly less IgE-sensitized and clinically more tolerant to NMBA [7].	Five to 10 years after pholcodine withdrawal, very few, if any, individuals were IgE-sensitized to QA ion, and only one case of NMBA-related anaphylaxis per 1–2 years was reported. However, exposure decreased during time of observation and less suxamethonium and more rocuronium were used.