Anesthesia Allergy: NAP6 Reframes Perioperative Anaphylaxis Culprits

According to the NAP6 UK audit published in 2018, antibiotics are the leading cause of perioperative anaphylaxis at 47%, followed by neuromuscular blocking agents (NMBAs) at 33% and chlorhexidine antiseptic at 9%. This was a paradigm shift from historical assumptions that NMBAs or latex were the primary culprits. Latex has dropped to less than 1% of perioperative anaphylaxis cases due to widespread adoption of non-latex gloves. The antibiotic contribution reflects routine perioperative prophylaxis with beta-lactam antibiotics and teicoplanin. This distribution underscores the importance of testing all agents, not just NMBAs, after a perioperative event.

Yes — propofol contains egg lecithin and soybean oil, but egg and soy allergy is NOT a contraindication to propofol. Egg allergy is directed against egg proteins (ovalbumin, ovomucoid), not egg lecithin (a phospholipid). Multiple retrospective and prospective studies have confirmed safe propofol administration in egg-allergic patients. The AAAAI position statement supports this conclusion. Patients should not be denied propofol based on egg or soy allergy labels. Propofol anaphylaxis is exceedingly rare, and when it occurs, it is typically in patients with underlying mastocytosis or severe atopy, not egg or soy cross-reactivity.

The pholcodine hypothesis explains how patients who have never been exposed to NMBAs can experience anaphylaxis on first surgical exposure. Pholcodine, an antitussive in OTC cough syrups, contains a substituted ammonium ion epitope structurally similar to that on NMBAs. Repeated pholcodine exposure through cough syrup use produces IgE antibodies that cross-react with NMBAs. Norwegian and Swedish data showed an odds ratio of 4.2 for NMBA sensitization with pholcodine exposure, and up to 85% of NMBA anaphylaxis occurs in NMBA-naive patients. The European Medicines Agency revoked pholcodine marketing authorization in 2023.

Skin prick and intradermal testing should be performed 4 to 6 weeks after perioperative anaphylaxis. Testing too early yields false-negative results because mast cells are depleted after recent degranulation and need time to recover their releasable mediator stores. However, serial serum tryptase should be drawn acutely — at 1 to 2 hours, 6 hours, and 24 hours after the event — to confirm anaphylaxis before the window closes. Specific IgE blood testing can theoretically be performed at any time but is also most reliable several weeks after the event.

Yes, in the vast majority of cases. Comprehensive skin testing at a specialized anaesthetic allergy clinic identifies the culprit agent and confirms which agents are safe for future use. Most patients have positive skin tests to one or two agents while remaining safely tolerant of alternatives. Even when all NMBAs are positive, NMBA-free anesthesia using total IV anesthesia with propofol and remifentanil or regional anesthesia techniques provides reliable surgical access. The key is thorough pre-operative evaluation and clear communication of results to your surgical team.

Cisatracurium has the lowest allergenic potential among NMBAs and is often the preferred agent when NMBA use is necessary and skin testing confirms tolerance. However, 60 to 70% of patients allergic to one NMBA show cross-sensitization to others due to the shared substituted ammonium ion epitope, so individual skin testing must confirm cisatracurium safety before administration. Skin testing results, not general class assumptions, guide safe NMBA selection. When no NMBA is confirmed safe, anesthetic plans avoiding NMBAs entirely are well-established using total intravenous anesthesia or regional techniques.

Yes, sugammadex — the cyclodextrin reversal agent that encapsulates rocuronium to reverse neuromuscular blockade — carries its own hypersensitivity signal. Reported anaphylaxis rates range from 0.02% to 0.3% in large prospective studies, meaning that the drug used to reverse a suspected NMBA reaction may itself trigger a new allergic event. This clinical paradox complicates post-reaction diagnostic workup: if anaphylaxis occurs after sugammadex administration for rocuronium reversal, the culprit could be rocuronium, sugammadex, or both. Skin testing panels for perioperative anaphylaxis should therefore include sugammadex in addition to all NMBAs. IgE-mediated sugammadex allergy has been confirmed in published case series, and the incidence may increase as sugammadex use for routine rocuronium reversal becomes more widespread.

No — malignant hyperthermia is a pharmacogenetic disorder caused by mutations in the RYR1 gene (ryanodine receptor), not an allergic condition. Susceptible patients develop a hypermetabolic crisis when exposed to volatile inhalational anesthetics (sevoflurane, desflurane, isoflurane) or succinylcholine, characterized by rapidly rising temperature, severe muscle rigidity, hypercarbia, and life-threatening acidosis. Treatment is dantrolene, not epinephrine. The distinction matters clinically: patients with malignant hyperthermia susceptibility can safely receive propofol, all non-depolarizing NMBAs, local anesthetics, opioids, and benzodiazepines — none of which trigger the RYR1-mediated calcium channel dysfunction. Labeling MH susceptibility as anesthesia allergy inappropriately restricts safe agents and delays surgery. EMHG testing through the European MH Group provides genetic and contracture test-based diagnosis.