Reclassifying Anaphylaxis to Neuromuscular Blocking Agents Based on the Presumed Patho-Mechanism: IgE-Mediated, Pharmacological Adverse Reaction or “Innate Hypersensitivity”?

Abstract

Approximately 60% of perioperative anaphylactic reactions are thought to be immunoglobulin IgE mediated, whereas 40% are thought to be non-IgE mediated hypersensitivity reactions (both considered non-dose-related type B adverse drug reactions). In both cases, symptoms are elicited by mast cell degranulation. Also, pharmacological reactions to drugs (type A, dose-related) may sometimes mimic symptoms triggered by mast cell degranulation. In case of hypotension, bronchospasm, or urticarial rash due to mast cell degranulation, identification of the responsible mechanism is complicated. However, determination of the type of the underlying adverse drug reaction is of paramount interest for the decision of whether the culprit drug may be re-administered. Neuromuscular blocking agents (NMBA) are among the most frequent cause of perioperative anaphylaxis. Recently, it has been shown that NMBA may activate mast cells independently from IgE antibodies via the human Mas-related G-protein-coupled receptor member X2 (MRGPRX2). In light of this new insight into the patho-mechanism of pseudo-allergic adverse drug reactions, in which as drug-receptor interaction results in anaphylaxis like symptoms, we critically reviewed the literature on NMBA-induced perioperative anaphylaxis. We challenge the dogma that NMBA mainly cause IgE-mediated anaphylaxis via an IgE-mediated mechanism, which is based on studies that consider positive skin test to be specific for IgE-mediated hypersensitivity. Finally, we discuss the question whether MRGPRX2 mediated pseudo-allergic reactions should be re-classified as type A adverse reactions.

Rocuronium anaphylaxis in a 7-year-old boy during the induction of anesthesia

“…Recently, rocuronium was described to elicit hypersensitive reaction through activation of the Mas-related G-protein coupled receptor member X2 (MRGPRX2) receptor on mast cells [8]. This MRGPRX2-mediated mast cell stimulation rather than IgE-mediated pathway is equipped to explain why skin tests with rocuronium may be positive in the absence of rocuronium-specific IgE [9].…”

“…Readministration of responsible drug with MRGPRX2 dependent hypersensitivity is possible with reduced speed or low doses theoretically [9]. Flare and wheal: long diameter  short diameter (mm); NT: not tested.…”

An update on allergy and anaphylaxis in pediatric anesthesia

“…The benzolisoquinolinium compounds (atracurium, mivacurium, cisatracurium) also cause direct mast cell histamine release which may present as a non‐IgE‐mediated anaphylaxis. A recent discovery of drug‐receptor interactions between NMBDs and the “MRGPRX2” mast cell receptor has been postulated as a mechanism for nonallergic reactions to these drugs …”

Drug-induced anaphylaxis—elicitors, mechanisms and diagnosis

“…Drugs, which have been identified as triggers of druginduced anaphylaxis, can elicit an immediate drug reaction through different mechanisms. IgE-dependent and IgE-independent pathomechanisms must be differentiated [2]. Penicillins are a classic example of drugs triggering IgE-mediated anaphylaxis, while fluoroquinolones, opioids, X-ray contrast agents and neuromuscular muscle relaxants probably mostly act via the recently identified G-protein signalling pathway (MRG-PX2) [3].…”