c10 Atracurium

Summary

Neuromuscular-blocking agents (NMBA) commonly employed as medication for general anesthesia can elicit perioperative hypersensitivity reactions. The hypersensitivity reactions are both immunoglobulin IgE-mediated and non-IgE-mediated. Among NMBAs, atracurium is associated with severe life-threatening anaphylactic reactions. The main route of exposure to atracurium is the parenteral route via intravenous injection. The key clinical features of atracurium-induced anaphylaxis include hypotension, bronchospasm, and non-urticarial rash. The most common diagnostic methods for atracurium allergy are skin testing and specific IgE measurement. IgE cross-reactivity between different types of NMBA are observed commonly. However, cross-reactivity is more common in the amino-steroid group (rocuronium, pancuronium, vecuronium, etc.) than the benzylisoquinoline group (e.g atracurium, cisatracurium, mivacurium, doxacurium).

Allergen      

Nature

Atracurium, a neuromuscular-blocking agent (NMBA) commonly employed for inducing paralysis, belongs to the benzylisoquinoline class of compounds (Dumitru et al. 2022). Atracurium undergoes metabolism via non-enzymatic hydrolysis, known as Hofmann elimination, and enzymatic ester hydrolysis within tissues and serum (B. Chow 2000).

Hypersensitivity reactions to NMBA can be either immunoglobulin (Ig) E-mediated or non-IgE-mediated. The presence of quaternary ammonium (NH4+) ions in the IgE-binding sites of NMBA is responsible for IgE-mediated response. Non-IgE-mediated reactions predominantly occur due to the release of histamine (Di Leo et al. 2018).

Epidemiology                   

Worldwide distribution

Hypersensitivity reactions to NMBAs (used in general anesthesia) often become very severe and life-threatening leading to increased postoperative mortality (Di Leo et al. 2018). A UK-based study detected that perioperative anaphylaxis was caused mainly by NMBAs (Krishna et al. 2014).

Although the true prevalence of atracurium allergy globally is still unknown, a 10-year retrospective study in Australia (from 2002 to2011) reported the incidence rate of atracurium-related anaphylaxis as 4.01 per 100,000 (Sadleir et al. 2013).

A multi-center retrospective study in the UK on 161 patients with suspected perioperative anaphylaxis during general anesthesia detected NMBA (38%, 61/161) as the leading cause of anaphylaxis and among the different NMBAs used, atracurium (49%, 30/61) was mostly implicated in anaphylaxis, followed by rocuronium (25%, 15/61) and suxamethonium (20%, 12/61) (Krishna et al. 2014).

A study conducted by the National Audit project on 266 reports of Grades 3-5 anaphylaxis in a year in UK hospitals found the total incidence of NMDA-induced anaphylaxis to be 5.3 per 100,000 exposures. NMBAs were identified as allergy triggers in about 25% of cases (64 out of 266), with 32% of these cases resulting in cardiac arrest or death. The responsible NMBAs identified were rocuronium (42%), atracurium (35%), succinylcholine (22%), and mivacurium (1.5 %) (Harper et al. 2018).

A pharmacovigilance survey over 12 years was conducted in France to estimate the incidence and trends of anaphylaxis induced by NMBAs. Among the 680 confirmed cases of IgE-mediated severe anaphylaxis, (grade 3 and grade 4), atracurium and cis-atracurium were attributed to 65.5% and 81.8% cases, respectively (Petitpain et al. 2018).

A retrospective analysis in Germany of 159 children (aged 0-17 years, mean age 8.9 years) with drug-induced anaphylactic reactions identified atracurium as one of the drugs responsible for drug-induced anaphylaxis. Atracurium-induced anaphylaxis was found in five cases and three of them were designated as serious grade III anaphylaxis (Sachs et al. 2019).

A retrospective study was conducted in a Singapore hospital on pediatric patients aged 4-15 years developing perioperative anaphylaxis and subjected to allergy tests. Out of the 15 cases of perioperative anaphylaxis (in 35,361 cases of pediatric anesthesia), five were confirmed to be IgE-mediated showing a positive skin prick test (SPT) (atracurium (n=1), rocuronium (n=1), and cefazolin (n= 3)) (Toh et al. 2021).

A decade-long retrospective study (2012-2021) was conducted in Lebanon on 758 patients experiencing drug hypersensitivity reactions (DHR) to diverse types of drugs. Among patients with DHR, 57 showed positive SPT results for NMBAs and 10 of them showed positive SPT results for atracurium. Besides monosensitization, two patients showed multiple NMBA sensitizations to drugs such as rocuronium, cisatracurium, and atracurium. All SPTs were carried out using commercial extracts. (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 atracurium (Sadleir et al. 2021).

A study with 98 patients having previous antibiotic hypersensitivity reported an increased risk of positive SPT for NMBAs. A significant association (p=0.02) was found between a positive SPT for atracurium and antibiotic hypersensitivity in comparison to pancuronium (p=0.08) rocuronium (p=0.23) and suxamethonium (p=0.26). Commercially available drug solutions were used for skin testing. (Hagau et al. 2016).

Route of exposure           

Main

The main route of exposure to atracurium is the parenteral route (NIH-Pubchem). Individuals are most likely to be exposed to atracurium through intravenous injection (Sachs et al. 2019).

Clinical relevance           

Anaphylaxis has been reported to be the most common allergic reaction caused by atracurium. (Harper et al. 2018, Sachs et al. 2019, Toh et al. 2021). The anaphylactic reactions were immediate and usually found to occur within a few minutes of administration of perioperative agents in patients (Toh et al. 2021).

Anaphylaxis

A study reviewing 266 reports on perioperative anaphylaxis in adult patients observed that the initial clinical features of grade III-V perioperative anaphylaxis were hypotension (46%), bronchospasm (18%), and tachycardia (9.8%). The rash was rarely reported as a clinical feature. Additionally, the initial features of Grades III-V anaphylaxis caused by atracurium were found to be hypotension (>60%), bronchospasm (>25%), and flushing or non-urticarial rash (about 10%) (Harper et al. 2018).

Drug-induced anaphylaxis was reported in a study on a pediatric population (n=159). The most frequent symptoms of anaphylaxis were dyspnea (35.8%; 57/159) and urticaria (33.3%; 53/159). Out of 159 cases of drug-induced anaphylaxis, 5 were due to atracurium; all 5 were severe with symptoms of anaphylactic shock (60%; 3/5) and bronchospasm (40%; 2/5) (Sachs et al. 2019).

Skin erythema

A study conducted on 905 patients to compare the side effects of anesthetic agents like succinylcholine, and atracurium, found an immediate allergic reaction, characterized by erythema on the face, neck, and/or upper back within 10 minutes of administration of the anesthesia. Out of 450 patients administered with atracurium, erythema was found to occur in 6.74 % of cases (Ciobotaru et al. 2020).

Diagnostic relevance

Allergic reactions due to atracurium can be severe and often face diagnostic errors leading to serious consequences. The most common diagnostic methods include skin testing and specific IgE measurements. However, the predictive value of skin testing is not always absolute for atracurium and can lead to false-negative and false-positive results (Uyttebroek et al. 2014). Testing for specific IgE can provide additional information and hence can be considered to detect hypersensitivity of the patients towards any anaesthetic agents in case emergency surgery is required.

The Basophil Activation Test (BAT) can also be used as an aid in diagnosis and to detect potentially IgE cross-reactive NMBAs (Uyttebroek et al. 2014).

It has been reported that quaternary ammonium morphine (QAM) specific IgE assay could be a valuable tool for diagnosing sensitivity to NMBA. A study with 168 patients who received NMBA during surgery found an overall sensitivity of this assay to be 84.2% for NMBA-allergic patients with 75% sensitivity to patients with atracurium allergy. (Laroche D et al. 2011).

Prevention and therapy

Avoidance

Atracurium should be avoided in patients with a history of IgE-mediated anaphylaxis and a suitable alternative drug should be administered instead (Toh et al. 2021). A patient with a history of allergic reactions to NMBA should be tested for cross-reactivity with other agents and accordingly, the drugs should be prescribed (Mallick et al. 2013).

Molecular aspects

Cross-reactivity

An individual developing anaphylaxis to one NMBA can also have an allergic reaction to one or more other NMBAs due to IgE cross-reactivity. The presence of ubiquitous IgE epitopes in NMBA (e.g. substituted ammonium group in IgE-binding site) is responsible for high cross-reactivity among these drugs (Di Leo et al. 2018). Cross-reactivity among various NMBAs has been observed in about 60-70% of patients with NMBA allergy. Cross-reactivity is more common in amino- the steroid group (rocuronium, pancuronium, vecuronium, etc.) than the benzylisoquinoline group (e.g atracurium, cisatracurium, mivacurium, doxacurium) (see references in Linauskiene et al. 2020).

A study involving 680 confirmed cases of anaphylaxis attributed to NMBA, found that 52.4% of patients had skin cross-reactivity to other NMBAs. Positive cross-reactivity was found in 40 out of 84 cases of atracurium-attributed anaphylaxis with 47.5% (19/40) showing cross-reactivity to cisatracurium, followed by 32.5% (13/40) to mivacurium, 27.5% (11/40) to suxamethonium and 15% (6/40) to rocuronium (Petitpain et al. 2018).

Atracurium IgE cross-reactivity is more common to rocuronium and less common to cis-atracurium. (Mertes et al. 2019).

Explained results

Allergen information

Atracurium, a neuromuscular-blocking drug used in general anesthesia, has often been found to cause allergic reactions, which can be both IgE-mediated and non-IgE-mediated types of reactions (McNeil et al. 2015).

Clinical information

Anaphylaxis has been reported to be the most common allergic reaction caused by atracurium. Atracurium-induced anaphylaxis was mostly presented by hypotension, bronchospasm, and non-urticarial rash (Harper et al. 2018).

Cross-reactivity

IgE cross-reactivity among various NMBAs has been observed in about 60-70% of patients with NMBA allergy (Linauskiene, Grinceviciene et al. 2020). Atracurium has demonstrated cross-reactivity to cisatracurium, rocuronium, mivacurium and suxamethonium (Petitpain et al. 2018).

Author: Turacoz

Reviewer: Dr. Ulrica Olsson