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

Paul Michel Mertes; Nadine Petitpain; Charles Tacquard; Marion Delpuech; Cédric Baumann; Jean Marc Malinovsky; Dan Longrois; Aurélie Gouel-Cheron; Diane Le Quang; Pascal Demoly; Jean Louis Guéant; Pierre Gillet; ALPHO Study Group

doi:10.1016/j.bja.2023.02.026

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

Br J Anaesth. 2023 Jul;131(1):150-158. doi: 10.1016/j.bja.2023.02.026. Epub 2023 Mar 24.

Collaborators

ALPHO Study Group:
Emmanuelle Aguinet, Pol André Apoil, Jean Eric Autegarden, Faiza Bettayeb, Céline Biermann, Maryline Bordes-Demolis, Anca Chiriac, Pierre Antoine Darene, Frédéric Deblay, Sabrina Dessard, Charles Dzviga, Hassan El Hanache, Alain Facon, Yannick Fuhrer, Noémie Gest, Marion Gouitaa, Adela Harpan, Cyrille Hoarau, Lisa Le Guillou, Laurence Lepeltier, Claire Mailhol, Delphine Mariotte, Yannick Meunier, Isabelle Migueres, Martine Morisset, Catherine Neukirch, Dalila Nouar, Yann Ollivier, Isabelle Orsel, Omar Outtas, Minaxi Patel, Christelle Pellerin, Isabelle Petit, Anaïs Pipet, Cécile Rochefort-Morel, Claire Schwartz, Sandrine Seltzer, Alice Seringulian, Angèle Soria, Lilia Soufir, Rodolphe Stenger, Céline Tummino, Marion Verdaguer

Affiliations

¹ Department of Anesthesia and Intensive Care, Hôpitaux Universitaires de Strasbourg, Nouvel Hôpital Civil, INSERM U1255, FMTS de Strasbourg, Strasbourg, France. Electronic address: paul-michel.mertes@chru-strasbourg.fr.
² Nancy Regional University Hospital Center, Regional Pharmacovigilance Center of Nancy, Vandoeuvre-lès-Nancy, France.
³ Department of Anesthesia and Intensive Care, Hôpitaux Universitaires de Strasbourg, Nouvel Hôpital Civil, INSERM U1255, FMTS de Strasbourg, Strasbourg, France.
⁴ Department of MPI Unit of Methodology, Data Management and Statistic (UMDS), Nancy Regional University Hospital Center, Vandoeuvre-lès-Nancy, France.
⁵ Anesthesia and Intensive Care Department, CHU de Reims, 51092 Reims Cedex and EA 3801 HERVI, Reims Champagne-Ardenne University, Reims, France.
⁶ Hôpital Bichat-Claude Bernard, Anesthesiology and Critical Care Medicine Department, APHP, DMU PARABOL, Université Paris Cité, Bichat Hospital, Paris, France.
⁷ Anesthesiology and Critical Care Medicine Department, DMU PARABOL, Université Paris Cité, Bichat Hospital, AP-HP, Paris, France; Antibody in Therapy and Pathology, Pasteur Institute, UMR 1222 INSERM, Paris, France.
⁸ Allergology-Anesthesia Department, Hospital of Lyon Sud, Pierre Bénite, France.
⁹ Division of Allergy, Department of Pulmonology, University Hospital of Montpellier, and IDESP, UMR UA11, University of Montpellier - INSERM, Montpellier, France.
¹⁰ Nancy Regional University Hospital Center, Department of Molecular Medicine and National Center of Inborn Errors of Metabolism, Department of Hepato-gastroenterology, and UMRS 1256 N-GERE (Nutrition-Genetics-Environmental Risks), Institute of Medical Research, University of Lorraine, Vandoeuvre-lès-Nancy, France.
¹¹ Nancy Regional University Hospital Center, Regional Pharmacovigilance Center, Ingénierie Moléculaire et Ingénierie Articulaire (IMoPA), UMR-7365 CNRS, Faculté de Médecine, University of Lorraine, Vandoeuvre-lès-Nancy, France.

PMID: 36967281
DOI: 10.1016/j.bja.2023.02.026

Abstract

Background: Neuromuscular 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.

Methods: ALPHO 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.

Results: Overall, 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.

Conclusions: Patients 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 registration: NCT02250729.

Keywords: anaesthesia; anaphylaxis; neuromuscular blocking agents; pholcodine; quaternary ammonium compounds.

Publication types

Multicenter Study

MeSH terms

Ammonium Compounds* / adverse effects
Anaphylaxis* / chemically induced
Anaphylaxis* / diagnosis
Anaphylaxis* / epidemiology
Case-Control Studies
Drug Hypersensitivity* / diagnosis
Drug Hypersensitivity* / epidemiology
Drug Hypersensitivity* / etiology
Humans
Immunoglobulin E
Neuromuscular Blocking Agents* / adverse effects
Quaternary Ammonium Compounds / adverse effects

Substances

Ammonium Compounds
Immunoglobulin E
Neuromuscular Blocking Agents
Quaternary Ammonium Compounds

Associated data

ClinicalTrials.gov/NCT02250729