# Mortality, morbidity, and impact on future anaesthesia after perioperative anaphylaxis related to neuromuscular blocking agents: an 11-year single-centre retrospective study.

Pierre d'Heudières, Cedric Cireni, Alexandre Bourgeois, Charlotte Geay, Laurine Cadart, Camille Potey, Julien Labreuche, Gilles Lebuffe, Damien Rousseleau

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Pierre d'Heudières, Cedric Cireni, Alexandre Bourgeois, Charlotte Geay, Laurine Cadart, et al. Mortality, morbidity, and impact on future anaesthesia after perioperative anaphylaxis related to neuromuscular blocking agents: an 11-year single-centre retrospective study. British Journal of Anaesthesia, 2025, British Journal of Anaesthesia, 10.1016/j.bja.2025.07.098. hal-05336187

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CLINICAL INVESTIGATION

# Mortality, morbidity, and impact on future anaesthesia after perioperative anaphylaxis related to neuromuscular blocking agents: an 11-year single-centre retrospective study

Pierre d'Heudières¹ ID, Cédric Cirenei¹,² ID, Alexandre Bourgeois¹,²,³ ID, Charlotte Geay³, Laurine Cadart⁴ ID, Camille Potey⁵ ID, Julien Labreuche⁴ ID, Gilles Lebuffe¹,⁶ and Damien Rousseleau¹,⁶,* ID

¹Department of Anaesthesiology and Critical Care, Lille University Hospital, CHU Lille, Lille, France, ²ULR 2694-METRICS: Évaluation des technologies de santé et des pratiques médicales, University of Lille, Lille, France, ³Include Health Data Warehouse, CHU Lille, Lille, France, ⁴Department of Biostatistics, CHU Lille, Lille, France, ⁵Regional Pharmacovigilance Center of Lille, CHU Lille, Lille, France and ⁶ULR 7365-GRITA: Groupe de Recherche sur les formes Injectables et les Technologies Associées, University of Lille, Lille, France

## Abstract

**Background:** Few data are available regarding the morbidity of patients who have experienced anaphylaxis because of neuromuscular blocking agents (NMBAs). This study aimed to describe the outcomes and impact on future anaesthesia in these patients.

**Methods:** This retrospective single-centre study analysed data from adult patients receiving NMBAs during general anaesthesia from 2012 to 2022 at Lille University Hospital (Lille, France) who also experienced a grade II, III, or IV NMBA-related anaphylaxis. Data were collected using an electronic data warehouse and through individual review of medical records.

**Results:** Among the 158 021 general anaesthetics including an NMBA, 94 patients experienced perioperative anaphylaxis, with 82 confirmed by an allergist. This incidence of 58.1 reactions per 100 000 administrations of NMBAs, all agents combined, is higher than that described in the literature. Reporting to a pharmacovigilance centre occurred in only 14.9% of cases. Four patients died within 90 days, and 19 patients (20%) experienced morbidity, including renal failure (n=12), cardiovascular complications (n=8), and neurological complications (n=4). Out of those 19 patients with morbidity, 12 made a full recovery. In the 96 subsequent anaesthetic procedures screened, surgery was successfully completed without the use of NMBAs.

**Conclusions:** This study highlighted a significant underestimation of the incidence of perioperative anaphylaxis related to neuromuscular blocking agents and reporting to the local and national pharmacovigilance centre despite allergy assessment. Morbidity occurred in 20% of patients, primarily involving renal and cardiovascular complications, with most patients making a full recovery. The impact on subsequent anaesthesia is limited, as procedures can typically be performed without use of neuromuscular blocking agents.

**Keywords:** epinephrine; morbidity; neuromuscular blocking agents; outcome; perioperative anaphylaxis; perioperative hypersensitivity; rocuronium; suxamethonium

<footnote>*Corresponding author. E-mail: damien.rousseleau@chu-lille.fr</footnote>
Editor's key points

* Limited data are available regarding the morbidity and outcomes of patients who experience anaphylaxis because of neuromuscular blocking agents.

* Using an extensive data warehouse from a French tertiary medical centre, the incidence of perioperative anaphylaxis associated with neuromuscular blocking agents was underestimated and underreported.

* Most survivors of postoperative anaphylaxis recover without lasting effects, with limited impact on subsequent procedures requiring anaesthesia.

Neuromuscular blocking agents (NMBAs) are essential in anaesthesia practice, but their use is associated with a significant risk of perioperative anaphylaxis (POA), a rare yet life-threatening hypersensitivity reaction.¹⁻³ In France, NMBAs are the leading cause of POA, surpassing antibiotics, with an estimated incidence of immunoglobulin E (IgE)-mediated reactions of 18.4 per 100 000 anaesthetic procedures involving an NMBA (95% confidence interval [95% CI], 13.9–23.0).⁴ Rocuronium and suxamethonium are more frequently implicated than other NMBAs, although mortality does not appear to be directly related to the specific agent used.⁵⁻⁷ Despite their severity, NMBA-related reactions remain difficult to study because of their low incidence, complex mechanisms,⁸ and diagnostic limitations. Most studies focus on causality and immune mechanisms, whereas less is known about patient outcomes and the management of future anaesthetics.

On the basis of our registry-like data warehouse that approaches systematicity, we investigated the outcomes of patients who experienced grade II, III, or IV NMBA-related anaphylaxis, classified according to the Ring and Messmer scale.⁹ The primary objective was to describe morbidity and mortality at 1 and 3 months after the event. Secondary objectives included the description of perioperative care pathways and the impact on future anaesthetic management.

Methods

Data management and ethics approval

This retrospective single-centre study analysed data from patients undergoing general anaesthesia at Lille University Hospital (Lille, France) between January 1, 2012, and December 31, 2022. Data were routinely collected from our anaesthesia information medical system (Diane®, Bow Medical, Amiens, France), electronic patient record system (SILLAGE®, SIB, Rennes, France), and stored in our data warehouse (INCLUDE [Integration Center of the Lille University Hospital for Data Exploration]), which has been approved by the Commission Nationale de l'Informatique et des Libertés (CNIL) from 2019 (authorisation number: 1754053)¹⁰, from which the data were extracted. The INCLUDE data warehouse ensures that researchers at Lille University Hospital can process data end to end in a secure, General Data Protection Regulation (GDPR)-compliant environment. The data provided were pseudonymised. An information letter was sent to each included patient, and none expressed opposition. The dataset created for the current work was registered with Lille University Hospital's Data Protection Officer and with the French National Data Protection Commission (Lille, France; reference: DEC24-011).

The analysis was studied by INCLUDE's Scientific and Ethical Committee on April 19, 2024, and received approval (no. 2024-19-04-V-03). The article complied with applicable Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) standards.¹¹

Participants

Adult patients aged 18 yr or older who had undergone general anaesthesia in an operating room with administration of an NMBA were considered for inclusion. To screen for patients suspected of POA, we reviewed all patients in whom NMBA administration or epinephrine or norepinephrine and tryptase or specific IgE measurement were documented simultaneously. To guarantee that all potential cases were identified, we also reviewed patient records that mentioned 'anaphylactic shock', either directly or indirectly.

Diagnosis of NMBA-induced POA was based on a short delay between NMBA administration and the onset of clinical symptoms, with no other plausible causes. Consequently, the presence of any confounding factors, such as antibiotic administration before the onset of hypersensitivity symptoms without allergy assessment, resulted in the exclusion of these patients. Two groups of patients were identified. The first group included patients with POA confirmed by an allergist. The diagnosis was based on the anaesthetic record, skin testing (prick test and intradermal testing [IDT]), and any biological assays carried out (tryptase, histamine, specific quaternary ammonium, or suxamethonium IgE). The diagnostic method was in accordance with the 2011 SFAR (French Society of Anaesthesia and Intensive Care) and SFA (French Society of Allergology) guidelines¹² and consistent throughout the study duration. A second group was composed of patients with suspected POA without allergy assessment, determined by the Hypersensitivity Clinical Scoring Scheme (HCSS score¹³ ≥15 indicating 'probable POA' or 'almost certain to be an immune hypersensitivity reaction'), and mast cell activation defined by 1.2×baseline+2 or a positive specific IgE.

Data collection

Several characteristics were directly obtained from the data warehouse for all included patients (sex, age, BMI, doses of epinephrine). Additional information was collected through individual review of patient records, including medical and allergy history, chronic medications, anaesthetic history, and procedure details. Clinical signs, including the lowest $E_T$CO$_2$ (end-tidal carbon dioxide) value, and management of POA were also recorded. Biological evaluation, when available, included the highest tryptase levels and specific IgE concentrations, and finally, postoperative management including the patient's allergology workup was also assessed.

Morbidity and mortality

Morbidity and mortality data were collected at two intervals, from 24 h to 30 days, and from 31 to 90 days after a POA. The definition of each morbidity type is provided in Supplementary Table 1. Morbidity attributable to POA could be temporary or permanent. Mortality was considered only when directly attributable to POA. All included patient records were reviewed by two anaesthesiologists, and consensus was required for final inclusion.
## Statistical analyses

Categorical variables are expressed as frequencies and percentages. Quantitative variables are expressed as mean (standard deviation) or median (interquartile range [IQR]) in the case of non-Gaussian distributions. The normality of distributions was verified graphically and using the Shapiro-Wilk test. Comparisons between the three NMBA groups (suxamethonium, rocuronium, and combined atracurium-cisatracurium) were conducted based on POA characteristics, post-POA management, and morbidity and mortality outcomes using a $\chi^2$ test (or Fisher's exact test in case of expected cell frequency <5) for categorical variables, or using one-way analysis of variance (or Kruskal-Wallis test in case of non-normal distribution) for quantitative variables. Statistical testing was done at the two-tailed $\alpha$ level of 0.05. Data were analysed using the SAS 9.4 (SAS Institute, Cary, NC, USA).

## Results

A total of 158 021 general anaesthetic procedures in adult patients involving NMBAs were identified from our data warehouse. These procedures accounted for 161 917 NMBA administrations, as some patients received more than one NMBA during a single procedure. Of them, 36 830 were done with rocuronium, 14 293 with suxamethonium, 791 with mivacurium, 66 988 with atracurium, 40 213 with cisatracurium, and 2784 with vecuronium. Pancuronium was not administered in any case in our study cohort, as it had been removed from the French market before initiation of the study period. The evolution of consumption of different NMBAs over the 11-yr period is reported in Supplementary Figure 1. In terms of absolute numbers, use of NMBAs globally increased, with a more pronounced increase after 2020. Regarding the type of agents, rocuronium use tripled, whereas cisatracurium

<figure><img src="image_2.png" /><figcaption>**Fig 1.** Study flowchart. ADR, adverse drug reaction; HCSS, Hypersensitivity Clinical Scoring Scheme; MCA, mast cell activation; NMBA, neuromuscular blocking agent; sIgE, specific immunoglobulin E.</figcaption></figure>
use decreased almost by half (44.5%). Use of atracurium and suxamethonium remained stable.

Among the 158 021 general anaesthesia procedures, 196 met the criteria for further screening (Fig. 1). After review, 94 general anaesthesia procedures were associated with POA, all in different patients. Their characteristics are summarised in Table 1. The mean (standard deviation) age of the patients was 56 (15) yr, range 46–69 yr; 37 (41.1%) were obese, with an equal sex distribution (52.1% male). Of these patients, 51.6% had a confirmed previous exposure to an NMBA: 52 with rocuronium, 25 with suxamethonium, 17 with atracurium/ cisatracurium, and none with vecuronium. The corresponding incidence of POA per 100 000 general anaesthesia procedures conducted in adult patients was 175 for suxamethonium, 141 for rocuronium, 20.9 for atracurium, and 7.5 for cisatracurium, resulting in a total incidence of 58.1 per 100 000 across all NMBA exposures.

Of these 94 cases, 14 were reported to our Regional Pharmacovigilance Center (CRPV), representing a reporting rate of 14.9% and accounting for all reported cases of NMBA-related anaphylaxis during the study period. Figure 2 summarises the incidences based on NMBA-related POA.

## Perioperative anaphylaxis characteristics and management

Most POA events were classified as grade III and therefore corresponded to anaphylactic shock (Table 2). Eighty-two patients (87.2%) underwent comprehensive allergology

investigation. Figure 3 summarises the diagnostic criteria for all included patients. Fifty-seven procedures (60.6%) were interrupted because of the occurrence of POA. The median interval for rescheduling surgery was 126 (59–193) days when it could not be initially performed. Admissions of patients to the ICU (64.5%) were primarily attributable to the administration of vasopressors (37/57 patients, or 62.7%). Two multidisciplinary meetings after POA were held without an anaesthetist, leading to patients being temporarily deemed unsuitable for general anaesthesia, even though other techniques were possible.

## Morbidity and mortality

Four deaths occurred within 90 days after POA. The patients were aged 56, 71, 73, and 75 yr. One patient died in the operating theatre immediately after injection of suxamethonium for treatment of bowel obstruction. The youngest patient died rapidly in the ICU despite early use of extracorporeal life support (ECLS). He had no significant medical history and was not on any medication. Another death occurred after several days of ICU care because of multiorgan failure. The last patient died shortly after hospital discharge because of a delayed intervention for a coronary syndrome.

Among the 94 cases of anaphylaxis, 19 (20.2%) experienced morbidity at 30 days. The affected systems and severity of complications varied, with renal and cardiovascular issues being the most prevalent (Table 3). Renal complications were observed in 12 (12.8%) patients and cardiovascular

<table><caption>Table 1 Patient characteristics of the study population. Data are presented as n (%) or median (25–75th percentiles). ACE, angiotensin-converting enzyme; NMBA, neuromuscular blocking agent.</caption><thead><tr><th rowspan="3">Characteristics</th><th colspan="4">NMBA</th></tr><tr><th>Overall</th><th>Suxamethonium</th><th>Rocuronium</th><th>Atracurium and cisatracurium</th></tr><tr><th>(n=94)</th><th>(n=25)</th><th>(n=52)</th><th>(n=17)</th></tr></thead><tbody><tr><td>Age (yr), mean (SD)</td><td>56.5 (15.4)</td><td>56.5 (15.4)</td><td>58.9 (13.0)</td><td>49.0 (19.9)</td></tr><tr><td>Sex</td><td></td><td></td><td></td><td></td></tr><tr><td>Male</td><td>49 (52.1)</td><td>11 (44.0)</td><td>29 (55.8)</td><td>9 (52.9)</td></tr><tr><td>Female</td><td>45 (47.9)</td><td>14 (56.0)</td><td>23 (44.2)</td><td>8 (47.1)</td></tr><tr><td>BMI (kg m<sup>-2</sup>)</td><td>28.0 (25.0–35.0)</td><td>27.6 (24.2–33.0)</td><td>28.4 (25.8–36.8)</td><td>28.0 (24.8–33.1)</td></tr><tr><td>Obesity (BMI ≥30 kg m<sup>-2</sup>)</td><td>37 (41.1)</td><td>9 (39.1)</td><td>22 (43.1)</td><td>6 (37.5)</td></tr><tr><td>ASA physical status</td><td></td><td></td><td></td><td></td></tr><tr><td>1</td><td>12 (12.8)</td><td>3 (12.0)</td><td>7 (13.5)</td><td>2 (11.8)</td></tr><tr><td>2</td><td>60 (63.8)</td><td>18 (72.0)</td><td>29 (55.8)</td><td>13 (76.5)</td></tr><tr><td>3</td><td>22 (23.4)</td><td>4 (16.0)</td><td>16 (30.8)</td><td>2 (11.8)</td></tr><tr><td>Reported allergic history</td><td>28 (29.8)</td><td>8 (32.0)</td><td>13 (25.0)</td><td>7 (41.2)</td></tr><tr><td>Smoker</td><td>15 (16.0)</td><td>3 (12.0)</td><td>10 (19.2)</td><td>2 (11.8)</td></tr><tr><td>Certain previous exposure to NMBA</td><td>32 (51.6)</td><td>9 (52.9)</td><td>19 (55.9)</td><td>4 (36.4)</td></tr><tr><td>Chronic medication</td><td></td><td></td><td></td><td></td></tr><tr><td>Beta blocker</td><td>17 (18.1)</td><td>3 (12.0)</td><td>12 (23.1)</td><td>2 (11.8)</td></tr><tr><td>ACE inhibitor or angiotensin receptor blocker</td><td>22 (23.4)</td><td>6 (24.0)</td><td>11 (21.2)</td><td>5 (29.4)</td></tr><tr><td>Surgical procedures</td><td></td><td></td><td></td><td></td></tr><tr><td>Emergency procedure</td><td>23 (24.5)</td><td>12 (48.0)</td><td>7 (13.5)</td><td>4 (23.5)</td></tr><tr><td>Rapid sequence induction</td><td>36 (38.3)</td><td>10 (40.0)</td><td>21 (40.4)</td><td>5 (29.4)</td></tr><tr><td>Skin, abscess, wound care</td><td>4 (4.3)</td><td>1 (4.0)</td><td>2 (3.8)</td><td>1 (5.9)</td></tr><tr><td>Chest, cardiothoracic, and vascular</td><td>8 (8.5)</td><td>1 (4.0)</td><td>4 (7.7)</td><td>3 (17.6)</td></tr><tr><td>Ear-nose-throat, dental</td><td>3 (3.2)</td><td>3 (12.0)</td><td>0 (0.0)</td><td>0 (0.0)</td></tr><tr><td>Endoscopic and interventional procedures</td><td>9 (9.6)</td><td>4 (16.0)</td><td>5 (9.6)</td><td>0 (0.0)</td></tr><tr><td>Urinary and reproductive organs</td><td>17 (18.1)</td><td>3 (12.0)</td><td>11 (21.2)</td><td>3 (17.6)</td></tr><tr><td>Neurological and ophthalmological</td><td>9 (9.6)</td><td>4 (16.0)</td><td>1 (1.9)</td><td>4 (23.5)</td></tr><tr><td>Orthopaedic and traumatologic</td><td>3 (3.2)</td><td>0 (0.0)</td><td>1 (1.9)</td><td>2 (11.8)</td></tr><tr><td>Digestive, thyroid, adrenal</td><td>41 (43.6)</td><td>9 (36.0)</td><td>28 (53.8)</td><td>4 (23.5)</td></tr></tbody></table>
<figure><img src="image_3.png" /><figcaption>**Fig 2.** Number of anaphylactic shock events. Data are presented per †100 000 administrations or per ‡100 000 vials sold by the GERAP.² Comparisons were performed using Poisson regression models, with all patients in this study as the reference group: **<0.01; ***<0.001. ATRA, atracurium; CIS, cisatracurium; CRPV, Regional Pharmacovigilance Center; GERAP, Perioperative Anaphylactoid Reactions Study Group; NAP6, 6th National Audit Project of the Royal College of Anaesthetists; NA, not applicable; NMBA, neuromuscular blocking agent; ROC, rocuronium; SUX, suxamethonium.</figcaption></figure>

complications in eight (8.5%) patients. Detailed description of the complications is available in the **Supplementary Table 2**. Out of the 19 patients who experienced complications, 12 made a full recovery. None of the patients alive at 3 months without complications during the first 30 days experienced complications between 30 and 90 days.

## Impact on future anaesthesia

A total of 97 anaesthetic procedures were performed after the diagnosis of POA, involving 69 patients; six were performed under regional anaesthesia, and 91 were general anaesthesia. Twenty-four (25%) of the general anaesthetics required a modified rapid sequence induction. Induction was performed using propofol combined with sufentanil in 50% of cases, and with remifentanil in the remaining 50%.

Neuromuscular block was required in 45 surgeries for visceral or thoracic procedures. The preferred alternatives in combination with general anaesthesia were thoracic peridural

anaesthesia in 36 cases (80%), epidural anaesthesia in two cases (4.5%), and no specific alternative in seven cases (15.5%). Surgical difficulty was reported in only one case, which could be attributed to the patient's BMI of 70. In the other 96 anaesthetic procedures, surgery was successfully completed without the use of an NMBA.

## Discussion

This study updates data on POA related to NMBAs. Suxamethonium and rocuronium were the two agents most frequently implicated in these adverse reactions. The calculated overall incidence of POA to NMBAs is 58.1 reactions per 100 000 injections. Four deaths occurred during the study period, with a sequelae rate of 20%, although direct attribution to POA remains difficult to establish. Among patients who experienced complications, 12 of 19 made a full recovery. Avoidance of NMBAs was the strategy chosen after POA, allowing surgery to be completed. We also noted that reporting of these serious adverse drug
<table><caption>**Table 2** Perioperative anaphylaxis characteristics and overall management, according to the neuromuscular blocking agent. Data are presented as n (%), median (25–75th percentiles), or mean (sd). E~T~CO~2~, end-tidal carbon dioxide; IgE, immunoglobulin E; RRT, renal replacement therapy. *Three patients with grade II and 84 patients with grade III. †Fisher's exact test. ‡Kruskall-Wallis test. §χ~2~ test. ¶One-way analysis of variance.</caption><thead><tr><th rowspan="3">Characteristics</th><th colspan="4">Neuromuscular blocking agent</th><th rowspan="3">P-value</th></tr><tr><th>Overall</th><th>Suxamethonium</th><th>Rocuronium</th><th>Atracurium and cisatracurium</th></tr><tr><th>(n=94)</th><th>(n=25)</th><th>(n=52)</th><th>(n=17)</th></tr></thead><tbody><tr><td>Grade of perioperative anaphylaxis</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>II and III*</td><td>87 (92.6)</td><td>22 (88.0)</td><td>48 (92.3)</td><td>17 (100.0)</td><td></td></tr><tr><td>IV</td><td>7 (7.4)</td><td>3 (12.0)</td><td>4 (7.7)</td><td>0 (0)</td><td>0.42<sup>†</sup></td></tr><tr><td>Perioperative anaphylaxis management</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Epinephrine (µg)</td><td>265 (100–650)</td><td>300 (100–800)</td><td>210 (50–625)</td><td>280 (100–550)</td><td>0.51<sup>‡</sup></td></tr><tr><td>Norepinephrine, n</td><td>44 (46.8)</td><td>9 (36.0)</td><td>26 (50.0)</td><td>9 (52.9)</td><td>0.44<sup>‡</sup></td></tr><tr><td>Crystalloids (ml)</td><td>1500 (1000–2000)</td><td>1500 (1000–2000)</td><td>1500 (1000–2000)</td><td>1370 (1000–1500)</td><td>0.62<sup>‡</sup></td></tr><tr><td>Clinical and biological characteristics</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Hypersensitivity Clinical Scoring Scheme</td><td>18.0 (15.0–23.0)</td><td>17.0 (15.0–22.0)</td><td>17.0 (16.5–22.5)</td><td>21.0 (15.0–24.0)</td><td>0.59<sup>†</sup></td></tr><tr><td>Cutaneous signs</td><td>46 (48.9)</td><td>11 (44.0)</td><td>24 (46.2)</td><td>11 (64.7)</td><td>0.35<sup>‡</sup></td></tr><tr><td>Cardiovascular signs</td><td>90 (95.7)</td><td>24 (96.0)</td><td>49 (94.2)</td><td>17 (100.0)</td><td>0.82<sup>†</sup></td></tr><tr><td>Bronchospasm</td><td>50 (53.2)</td><td>11 (44.0)</td><td>31 (59.6)</td><td>8 (47.1)</td><td>0.37<sup>‡</sup></td></tr><tr><td>Lowest E~T~CO~2~ level (kPa)</td><td>2.6 (1.0)</td><td>2.9 (0.9)</td><td>2.4 (1.0)</td><td>2.9 (1.3)</td><td>0.11<sup>§</sup></td></tr><tr><td>Peak tryptase concentration (µg ml<sup>-1</sup>)</td><td>24.3 (8.3–65.3)</td><td>29.1 (9.6–46.6)</td><td>26.1 (8.8–71.4)</td><td>15.9 (4.8–26.1)</td><td>0.23<sup>†</sup></td></tr><tr><td>Mast cell activation</td><td>58 (71.6)</td><td>14 (60.9)</td><td>35 (81.4)</td><td>9 (60.0)</td><td>0.12<sup>‡</sup></td></tr><tr><td>Anti-quaternary ammonium IgE (kU L<sup>-1</sup>)</td><td>1.3 (0.2–6.8)</td><td>0.7 (0.3–2.7)</td><td>1.8 (0.4–8.8)</td><td>0.5 (0.0–4.0)</td><td>0.065<sup>‡</sup></td></tr><tr><td>Organisational characteristics</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Procedure termination</td><td>57 (60.6)</td><td>10 (40.0)</td><td>37 (71.2)</td><td>10 (58.8)</td><td>0.032<sup>‡</sup></td></tr><tr><td>Admission to the ICU</td><td>60 (64.5)</td><td>15 (62.5)</td><td>32 (61.5)</td><td>13 (76.5)</td><td>0.52<sup>‡</sup></td></tr><tr><td>Increase length of stay</td><td>51 (54.8)</td><td>16 (64.0)</td><td>27 (52.9)</td><td>8 (47.1)</td><td>0.51<sup>‡</sup></td></tr><tr><td>Admission to the ICU with mechanical ventilation</td><td>30 (47.6)</td><td>9 (52.9)</td><td>16 (48.5)</td><td>5 (38.5)</td><td>0.73<sup>‡</sup></td></tr><tr><td>Admission to the ICU with intravenous vasopressor(s)</td><td>37 (58.7)</td><td>10 (58.8)</td><td>22 (66.7)</td><td>5 (38.5)</td><td>0.22<sup>‡</sup></td></tr><tr><td>RRT in ICU</td><td>5 (7.9)</td><td>2 (11.8)</td><td>3 (9.1)</td><td>0 (0)</td><td>0.70<sup>†</sup></td></tr></tbody></table>

reactions to the CRPV remains insufficient, even though allergology assessment was performed in most cases.

We aimed to specifically explore morbidity after anaphylaxis to NMBAs. Some studies have focused on morbidity after POA but not specifically linked to NMBAs. The 6th National Audit Project of the Royal College of Anaesthetists (NAP6),¹⁴,¹⁵ based on self-reporting at two different times, collected the sequelae occurring after POA regardless of cause (266 reports, including 65 related to NMBAs), with classification according to the severity stage. Early sequelae were found in 104 patients (67 mild, 'Minimal harm necessitating extra observation or minor treatment'; 29 moderate, 'Significant, but not permanent harm, or moderate increase in treatment includes delayed cancer surgery'; and eight severe harm, 'Permanent harm because of the incident, also including cardiac arrest'; definitions from Cook and colleagues¹⁶). In 2020, a multicentre study was conducted to investigate the sequelae of anaphylaxis from all causes in patients admitted to the ICU.¹⁷ A total of 339 patients admitted were included, and 130 were related to an NMBA (70 cases linked to suxamethonium and 37 to rocuronium). The observed complications included 9% coagulopathy, 6% hematocellular insufficiency, 16 myocardial infarctions, and two

cases of Tako-Tsubo cardiomyopathy. Renal insufficiency was reported in seven patients who required renal replacement therapy. Although the underlying causes differ (POA in our study vs all-cause anaphylaxis in NAP6), the proportions of each complication varied between studies, likely attributable to differences in data collection methods and study design.

Our study demonstrated an incidence of severe POA of 56 reactions per 100 000 injections across the five NMBAs studied. Several studies have previously estimated this incidence, notably by French,²,¹²,¹⁸ American,¹⁹ British,¹⁴ and Australian⁷ teams; however, our results are three times higher than those reported by our French colleagues from GERAP (Perioperative Anaphylactoid Reactions Study Group). These differences are likely attributable to the data collection methodology. To our knowledge, this is the first study of NMBAs using this specific collection technique, allowing for a more registry-like comparison of findings. Higher incidences for suxamethonium and rocuronium are found in several studies,²,⁷ which aligns with our results, in the same way that atracurium and cisatracurium remain the NMBAs least associated with POA. Although we observe the same ranking of NMBAs by incidence, our findings consistently report higher values, even
<figure><img src="image_4.png" /><figcaption>Fig 3. Diagnostic assessment of the 94 included patients. HCSS, Hypersensitivity Clinical Scoring Scheme; MCA, mast cell activation; sIgE, specific immunoglobulin E; ST, skin test.</figcaption></figure>

when considering only patients who experienced grade II, III, or IV anaphylaxis and whose definitive diagnosis was confirmed by an allergist.

Our results demonstrate a reporting rate of grade II, III, or IV anaphylaxis to the national pharmacovigilance systems of 14.9%, in contrast with an allergology consultation rate of 87.2%. Those results corroborate the findings of the NAP6 audit, which estimated that only 24% of life-threatening POA cases were reported to the national pharmacovigilance system (Yellow Card Scheme).¹⁴ Collecting incidence data is essential, especially as the NMBA market continues to evolve. We observed an evolution in the use of different NMBAs, with increasing use of rocuronium, likely facilitated by the

availability of sugammadex, and decreasing use of cis-
atracurium. However, the occurrence of POA over time
remained stable when adjusted by the number of injections.

In line with the ‘do no harm’ principle,²⁰ all NMBAs were avoided in future surgeries and anaesthetics for patients with a history of POA. In cases where the use of NMBAs was surgically indicated, general anaesthesia combined with neuromaxial anaesthesia was the preferred technique. Complete avoidance of NMBAs was the most frequent technique. This strategy might be criticised, as cross-reactivity to all NMBAs is rare⁷ and in some cases, surgery can be deemed infeasible, resulting in potentially less optimal treatment, as observed in two patients.

<table><caption>Table 3 Morbidity and mortality complications after anaphylactic shock, overall and according to the neuromuscular blocking agent.¹Fisher's exact test. ⁴χ² test.</caption><thead><tr><th rowspan="3">Outcome, n (%)</th><th colspan="4">Neuromuscular blocking agent</th><th rowspan="3">P-value</th></tr><tr><th>Overall</th><th>Suxamethonium</th><th>Rocuronium</th><th>Atracurium and cisatracurium</th></tr><tr><th>(n=94)</th><th>(n=25)</th><th>(n=52)</th><th>(n=17)</th></tr></thead><tbody><tr><td>Mortality at 30 days</td><td>3 (3.2)</td><td>2 (8.0)</td><td>0 (0)</td><td>1 (5.9)</td><td>0.09*</td></tr><tr><td>Mortality at 90 days</td><td>4 (4.3)</td><td>2 (8.0)</td><td>1 (1.9)</td><td>1 (5.9)</td><td>0.29*</td></tr><tr><td>Morbidity at 30 days</td><td>19 (20.2)</td><td>8 (32.0)</td><td>10 (19.2)</td><td>1 (5.9)</td><td>0.11<sup>†</sup></td></tr><tr><td>Cardiovascular</td><td>8 (8.5)</td><td>2 (8.0)</td><td>5 (9.6)</td><td>1 (5.9)</td><td>1.00*</td></tr><tr><td>Respiratory</td><td>5 (5.3)</td><td>1 (4.0)</td><td>3 (5.8)</td><td>1 (5.9)</td><td>1.00*</td></tr><tr><td>Renal</td><td>12 (12.8)</td><td>5 (20.0)</td><td>7 (13.5)</td><td>0 (0)</td><td>0.14*</td></tr><tr><td>Disability</td><td>1 (1.1)</td><td>0 (0)</td><td>0 (0)</td><td>1 (5.9)</td><td>0.18*</td></tr><tr><td>Psychiatric</td><td>1 (1.1)</td><td>1 (4.0)</td><td>0 (0)</td><td>0 (0)</td><td>0.45*</td></tr><tr><td>Hepatic</td><td>2 (2.1)</td><td>1 (4.0)</td><td>1 (1.9)</td><td>0 (0)</td><td>0.70*</td></tr><tr><td>Infectious</td><td>4 (4.3)</td><td>1 (4.0)</td><td>2 (3.8)</td><td>1 (5.9)</td><td>1.00*</td></tr><tr><td>Neurological</td><td>2 (2.1)</td><td>1 (4.0)</td><td>1 (1.9)</td><td>0 (0)</td><td>0.70*</td></tr></tbody></table>
The strength of this study lies in the use of data extracted from a data warehouse. Digitisation of anaesthesia records allowed us to screen more than half a million procedures, including more than 155 000 involving NMBAs, providing a novel quantitative perspective on the sequelae after such adverse events. A key strength of this study is the individual review of anaesthesia records suspected of adverse events. Additionally, by using a cross-technique to identify cases of anaphylaxis among anaesthesia records, we approached near-exhaustive case identification. This approach enabled us to update and refine the incidence data of anaphylaxis related to NMBAs, similar to a registry. The scale of our data supports the reliability of our results and highlights the potential benefits of incorporating big data approaches in similar studies of rare events.

Our study has several limitations. Although a single-centre study, our hospital is a tertiary care centre serving a large and diverse population base. Conducting multicentre studies would, however, increase statistical power and make it possible to apply propensity score matching. Also, it could be relevant to weigh the impact of each complication according to its clinical severity. Data collection was also retrospective, introducing the possibility of incomplete data, especially for therapies not systematically recorded in the electronic anaesthesia records. This can be particularly relevant in emergency situations where the focus is on immediate clinical management rather than precise documentation. Some morbidity outcomes, such as post-traumatic stress disorder, might have been underreported because of the retrospective nature of the study. Attributing specific complications to POA remains a challenge, especially in the perioperative setting, where factors such as patient history, emergency conditions, and the type of surgery can influence outcomes. Finally, the incidence of anaphylaxis might be underestimated owing to the search strategy excluding patients who were not treated with epinephrine or norepinephrine, or who did not undergo allergy-related testing. This is particularly the case for patients who experienced grade II POA.

In conclusion, we describe the mortality, morbidity, and impact on future anaesthetics for patients suffering from a POA associated with NMBAs included based on registry-like patient records. We reconfirmed that the incidence of anaphylaxis is underestimated and underreported. Most survivors of postoperative anaphylaxis recover without lasting effects. The impact on subsequent procedures requiring anaesthesia is limited, as procedures can typically be performed without NMBAs. Further research using a multicentre design could help confirm these findings.

## Authors' contributions

Study design: DR, PdH

Data acquisition and management: AB, CG, CP, DR, PdH

Data analysis: DR, CC, LC, JL, PdH

Manuscript drafting: AB, CC, CP, DR, GL, LC, PdH

Final manuscript approval: all authors

## Declarations of interest

CC received fees from Grünenthal for speaking. He also received benefits from Fisher & Paykel Healthcare for participation in meetings. The other authors declare that they have no conflicts of interest.

# Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.bja.2025.07.098.

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*Handling Editor: Hugh C Hemmings Jr*