c262 Rocuronium

Summary

Rocuronium is an aminosteroid neuromuscular-blocking agent (NMBA) that facilitates the induction of paralysis during surgery. Among different NMBAs used, rocuronium is majorly implicated in hypersensitive reactions. The main route of exposure to rocuronium is parenteral via intravenous injection. Obesity is one of the risk factors for rocuronium-induced allergy. NMBAs are known to be the most frequent cause of perioperative anaphylaxis, with rocuronium having the greatest incidence reported. The initial clinical features of rocuronium-induced anaphylaxis include bronchospasm and hypotension. The diagnostic methods used for rocuronium allergy are skin testing, specific IgE measurement, and basophil activation test. Rocuronium IgE has been found to cross-react with succinylcholine, vecuronium, and pancuronium due to similarities in their molecular structures.

Allergen      

Nature

Rocuronium is a non-depolarizing, neuromuscular-blocking agent (NMBA) commonly used as an adjunct to general anesthesia to facilitate endotracheal intubation and to induce paralysis during surgery (Capuano et al. 2015). Rocuronium is an aminosteroid and a basic derivative of androstane with an acetylated hydroxyl group. It also has a substituent that contains a quaternary nitrogen atom. This is the reason why bromide salt is used in the formulation of rocuronium (Anzenbacherova et al. 2015).

Rocuronium is known to induce perioperative hypersensitive reactions. Hypersensitive reactions to NMBA can be either immunoglobulin (Ig) E-mediated or non-IgE-mediated. IgE-mediated response occurs due to the presence of a quaternary ammonium group, which is the main antigenic epitope of the NMBAs (Di Leo et al. 2018).

Epidemiology                   

Worldwide distribution

Hypersensitive reactions elicited by NMBAs often become serious and life-threatening. Perioperative anaphylaxis, although a rare occurrence, is a serious event that can often lead to cardiorespiratory failure and mortality (Krishna et al. 2014). NMBAs are the most frequent cause of perioperative anaphylaxis, with rocuronium having the greatest incidence reported (Takise et al. 2020).

A UK-based multi-center, retrospective study on 161 patients with suspected perioperative anaphylaxis during general anesthesia detected that NMBAs (38%, 61/161) were the leading cause of anaphylaxis, and among the different NMBAs used, rocuronium-triggered anaphylaxis occurred in 25% (15/61) cases. (Krishna et al. 2014).

The incidence of anaphylaxis caused by rocuronium globally is not yet clearly known. Moreover, whether the incidence of anaphylaxis is higher with rocuronium than with other NMBAs is a matter of debate. Studies from France, and Australia showed that occurrence of anaphylaxis is higher with rocuronium (about 43-56% of cases) as compared to other NMBAs like vecuronium and succinylcholine (ranging between 11-22%) (Sadleir et al. 2013, Mertes et al. 2003). In contrast there are studies from the USA which were unable to show any difference between rocuronium and vecuronium in terms of anaphylaxis occurrence (Bhananker et al. 2005, Reddy et al. 2015). Moreover, a 7-year retrospective review in New Zealand on the incidence of intraoperative anaphylaxis caused by NMBAs reported the incidence of anaphylaxis for rocuronium was 1 in 2,499 and this was about 10 times more than that for atracurium (1 in 22,451) (Reddy et al. 2015). Similarly, 6^th National Audit project on 266 reports of Grades 3-5 anaphylaxis in a year in UK hospitals found that 25% (64/266) of anaphylaxis was caused by NMBAs. Among the NMBAs, rocuronium was implicated in 42% (27/64) cases with an incidence of 1 in 17,002 (Harper et al. 2018).

A 12-year survey conducted in France with 1624 cases of severe perioperative anaphylactic reactions caused by NMBAs reported that rocuronium was responsible for IgE-mediated severe anaphylaxis in 42% (680/1624) of cases. (Petitpain et al. 2018).

An epidemiologic study in Japan with 55 suspected cases of anaphylaxis (Grade 2 or above) following general anesthesia (total number of cases= 218,936) identified rocuronium as the top causative agent of perioperative anaphylaxis with an incidence of 0.005% (10/ 210,852) (Takazawa et al. 2023).

A retrospective review over 5 years conducted in Singapore with 35,361 pediatric cases found 15 cases of perioperative anaphylaxis of grade 2 and above and among them, 5 was IgE-mediated, of which one was rocuronium-induced (Toh et al. 2021).

A study was conducted in Lebanon to evaluate drug hypersensitivity reactions (DHR) in 758 adult patients and among them, 90 patients (11.9%) had ambulatory DHR and simultaneous DHR. Out of these 90 patients, 57 were positive for NMBAs and 80% (46/57) of these patients were positive for rocuronium (Dagher et al. 2024).

Risk factors

Obesity (particularly basal metabolic index> 29.9 kg/m²) and pholcodine consumption are found to be the risk factors for anaphylaxis caused by NMBA, such as rocuronium. (Sadleir et al. 2021).

Route of exposure            

Main

Rocuronium is administered intravenously to induce paralysis during surgery (Pacifici 2022).  

Clinical relevance           

Anaphylaxis is a rapid, severe, and life-threatening hypersensitive reaction, which is often caused by NMBAs. Rocuronium is the leading cause of perioperative anaphylaxis among other NMBAs (Harper et al. 2018). Anaphylactic reactions are usually immediate reactions occurring within a few minutes (3-20 minutes with a median of 6 minutes) of NMBA administration in hypersensitive patients as observed in a retrospective study (Toh et al. 2021).

Anaphylaxis

A study involving 266 adult cases of perioperative anaphylaxis reported hypotension (46%), bronchospasm (18%), and tachycardia (9.8%) as the initial clinical features of anaphylaxis. Additionally, in patients with rocuronium-induced grades 3-5 anaphylaxis, both bronchospasm and hypotension were equally (nearly 40%) reported as the initial features (Harper et al. 2018).  

The role of rocuronium in inducing anaphylaxis has been reported in several case reports (Morimoto et al. 2018, Macharadze et al. 2019, Takahashi et al. 2019).

Diagnostic relevance

It is important to identify the agent responsible for perioperative anaphylaxis to prevent serious consequences. A standard method used for detection is the allergy skin tests, although the predictability of skin tests is still questionable (Kim et al. 2018). Skin testing is known to lack absolute sensitivity and specificity and the test is required to be performed 4-6 weeks after anaphylaxis to avoid a possible immune refractory period (Rose et al. 2018).  

Besides skin tests, specific IgE can provide additional information on perioperative anaphylaxis and hence can be considered to detect hypersensitivity of the patients towards any anesthetic agents in case emergency surgery is required. A combined morphine and pholcodine specific IgE assays detected NMBA allergy in an increased number of skin test-positive patients than either test alone in a study. The sensitivity and specificity of these combined specific IgE assays regarding detection of all NMBA skin test positive patients were found to be 71.5% and 94.2% (cutoff threshold: 0.35 kUA/l) respectively and for aminosteroid skin test positive patients were 82.1% and 94.2% respectively (Rose et al. 2018).

Basophil activation test (BAT) can be useful as aid in diagnosing NMBA-induced anaphylaxis. A study on 120 patients with 61 patients showing NMBA-induced anaphylaxis and of them, 78.3% (48/61) were rocuronium-positive, found BAT assay to be useful for diagnosis of anaphylaxis in addition to standard assays. A mean BAT sensitivity of 73% and specificity of 78% were obtained (Li et al. 2019).

Prevention and therapy

Avoidance

Rocuronium should be avoided in cases where patients have a history of IgE-mediated anaphylaxis and appropriate alternative agents should be used instead (Toh et al. 2021). Even though it is recommended to avoid agents with positive skin prick test (SPT) results, it is important to consider the risk associated with false negative SPT results (Beyaz et al. 2022).

Molecular aspects

Rocuronium is an aminosteroid and a basic derivative of androstane with an acetylated hydroxyl group. It also has a substituent that contains a quaternary nitrogen atom. This is the reason why bromide salt is used in the formulation of rocuronium (Anzenbacherova et al. 2015).

Cross-reactivity

Cross-reactivity among NMBAs is common due to the presence of ubiquitous IgE epitopes (Di Leo et al. 2018). About 60%-70% of patients with NMBA allergy show cross-reactivity and is more commonly observed in NMBAs belonging to the aminosteroid group (e.g. rocuronium, pancuronium, vecuronium) than those belonging to the benzylisoquinoline group (e.g atracurium, cisatracurium, mivacurium, doxacurium), see references in (Linauskiene et al. 2020).

A 4-year study conducted on 119 patients with perioperative reaction, where an IgE mediated reaction was established in 76 cases, found that 47 patients developed perioperative anaphylaxis due to different NMBAs. The cross-reactivity rate of rocuronium was 22.3%, which was less than that of vecuronium (47.6%) (Antunes et al. 2014). Another study conducted on 80 patients with NMBA-induced anaphylaxis reported that patients with NMBA anaphylaxis were mostly cross-reactive to succinylcholine (>45%), followed by rocuronium (about 32%) (Sadleir et al. 2013).

A retrospective study on patients with perioperative anaphylaxis found 21 patients with allergic anaphylaxis due to NMBA, and of them, one patient positive for succinylcholine allergy cross-reacted with rocuronium. Moreover, positive SPT to succinylcholine, vecuronium, and pancuronium was observed in three patients with rocuronium-induced anaphylaxis.  (Reddy et al. 2015).

Cross-reactivity of rocuronium with vecuronium and pancuronium was detected in another retrospective analysis of cases from the French pharmacovigilance database with 680 confirmed cases of NMBA-induced anaphylaxis. Cross-reactivity was found in 31 out of 55 cases of rocuronium-attributed anaphylaxis with 61.3% (19/31) showing cross-reactivity to vecuronium, 48.4% to suxamethonium (15/31), and 35.5% to pancuronium (11/31) (Petitpain et al. 2018).

Rocuronium and cis-atracurium cross-reactivity and co-sensitization have also been reported. A study on 758 patients with 90 patients showing drug hypersensitivity reactions (DHR) found that rocuronium and cisatracurium were cross-reactive most frequently. Of 57 patients with hypersensitivity to NMBAs, 15 was co-sensitized to 2 molecules and of them, 10 were co-sensitized to rocuronium and cisatracurium. (Dagher et al. 2024).

Explained results

Allergen information.

Rocuronium is an amino steroidal neuromuscular-blocking agent (NMBA) commonly used to induce paralysis (Capuano et al. 2015). It can cause both IgE-mediated and non-IgE-mediated hypersensitive reactions (Di Leo et al. 2018).

Clinical information.

Among NMBAs, rocuronium is found to be the leading cause of anaphylaxis in perioperative settings. Bronchospasm and hypotension were equally reported as the initial features (Harper et al. 2018).

Cross-reactivity.

IgE cross-reactivity among various NMBAs has been observed in about 60%-70% of patients with NMBA allergy, see references in (Linauskiene et al. 2020). Rocuronium cross-reactivity was found mainly with vecuronium (61.3%) suxamethonium (48.4%) and pancuronium (35.5%) (Petitpain et al. 2018).

Author: Turacoz

Reviewer: Dr. Ulrica Olsson