Pholcodine exposure increases the risk of perioperative anaphylaxis to neuromuscular blocking agents: the ALPHO case-control study

Paul‐Michel Mertes ,Isabelle Orsel ,A Facon ,Nadine Petitpain ,Minaxi Patel ,D Nouar ,Isabelle Migueres ,C Mailhol ,Catherine Neukirch ,Emmanuelle Aguinet ,C Rochefort-Morel ,Frédéric Deblay ,M Gouitaa ,A Pipet ,Yannick Meunier ,Jean Eric Autegarden ,J M Malinovsky ,Omar Outtas ,Aurélie Gouel-Cheron ,C Tummino ,Yannick Fuhrer ,M Morisset ,S Seltzer ,Pascal Demoly ,Noémie Gest ,C Pellerin ,Maryline Bordes-Demolis ,Adela Harpan ,Isabelle Petit ,Cédric Baumann ,Lisa Le Guillou ,P.a Apoil ,Sabrina Dessard ,Pierre Gillet ,Hassan El Hanache ,Laurence Lepeltier ,C Dzviga ,Yann Ollivier ,Dan Longrois ,C Hoarau ,Céline Biermann ,Claire Schwartz ,Richard J Stenger ,Angèle Soria ,Charles Tacquard ,Faiza Bettayeb ,Lilia Soufir ,Pierre Antoine Darene ,Marion Delpuech ,Jean Louis Guéant ,Alice Seringulian ,Anca Mirela Chiriac ,D Mariotte ,Diane Le Quang ,M Verdaguer

doi:10.1016/j.bja.2023.02.026

Abstract

BackgroundNeuromuscular blocking agents (NMBAs) are among the leading cause of perioperative anaphylaxis, and most of these reactions are IgE mediated. Allergic sensitisation induced by environmental exposure to other quaternary ammonium-containing compounds, such as pholcodine, has been suggested. The aim of this study was to assess the relationship between pholcodine exposure and NMBA-related anaphylaxis. MethodsALPHO was a multicentre case-control study, comparing pholcodine exposure within a year before anaesthesia between patients with NMBA-related perioperative anaphylaxis (cases) and control patients with uneventful anaesthesia in France. Each case was matched to two controls by age, sex, type of NMBA, geographic area, and season. Pholcodine exposure was assessed by a self-administered questionnaire and pharmaceutical history retrieved from pharmacy records. The diagnostic values of anti-pholcodine and anti-quaternary ammonium specific IgE (sIgE) were also evaluated. ResultsOverall, 167 cases were matched with 334 controls. NMBA-related anaphylaxis was significantly associated with pholcodine consumption (odds ratio 4.2; 95% confidence interval 2.3–7.0) and occupational exposure to quaternary ammonium compounds (odds ratio 6.1; 95% confidence interval 2.7–13.6), suggesting that apart from pholcodine, other environmental factors can also lead to sensitisation to NMBAs. Pholcodine and quaternary ammonium sIgEs had a high negative predictive value (99.9%) but a very low positive predictive value (<3%) for identifying NMBA-related reactions. ConclusionsPatients exposed to pholcodine 12 months before NMBA exposure have a significantly higher risk of an NMBA-related anaphylaxis. The low positive predictive values of pholcodine and quaternary ammonium sIgEs precludes their use to identify a population with a high risk of NMBA-related anaphylaxis. Clinical trial registrationNCT02250729.

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