# Impact of cerebral vasospasm therapy on nimodipine exposure in subarachnoid hemorrhage: A population pharmacokinetic study

Adrien Foucher, Matthieu Gregoire, Jérôme Dauvergne, Elodie Boissier, Bertrand Rozec, Guillaume Deslandes, Karim Lakhal

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## ► To cite this version:

Adrien Foucher, Matthieu Gregoire, Jérôme Dauvergne, Elodie Boissier, Bertrand Rozec, et al. Impact of cerebral vasospasm therapy on nimodipine exposure in subarachnoid hemorrhage: A population pharmacokinetic study. Journal of the Neurological Sciences, 2025, 479, pp.125666. 10.1016/j.jns.2025.125666. hal-05389545

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Clinical short communication

# Impact of cerebral vasospasm therapy on nimodipine exposure in subarachnoid hemorrhage: A population pharmacokinetic study

<figure><img src="image_4.png" /></figure>

Adrien Foucher<sup>a</sup>, Matthieu Gregoire<sup>b,e</sup>, Jérôme E. Dauvergne<sup>a</sup>, Elodie Boissier<sup>c</sup>, Bertrand Rozec<sup>a,d</sup>, Guillaume Deslandes<sup>e</sup>, Karim Lakhal<sup>a,*</sup>

## ARTICLE INFO

### Keywords:

Nimodipine [MeSH]

Milrinone [MeSH]

Vasospasm, intracranial [MeSH]

Delayed cerebral ischemia

Subarachnoid hemorrhage [MeSH]

Cerebrovascular circulation / drug effects

[MeSH]

## ABSTRACT

**Background:** To prevent delayed cerebral ischemia (DCI) following non-traumatic subarachnoid hemorrhage (SAH), nimodipine is often administered to adults at a fixed dosage, irrespective of potentially influencing clinical factors. This prospective observational study examined whether hemodynamic augmentation (induced arterial hypertension with or without IV-milrinone), used to prevent or treat vasospasm-related DCI, alters nimodipine plasma concentration ([Nimodipine]plasma) – an unexplored pharmacokinetic aspect.

**Methods:** Adult patients with SAH receiving IV nimodipine for ≥12 h were prospectively included. Population pharmacokinetic analysis identified covariates influencing [Nimodipine]plasma.

**Results:** Sixty-one patients were analyzed corresponding to 212 [Nimodipine]plasma measurements: 51 patients (128 measurements) before potential vasospasm and 30 (84 measurements) during hemodynamic augmentation. Creatinine clearance was high and was even higher during hemodynamic augmentation therapy than before potential vasospasm (180 mL/min [IQR:134; 207] vs. 151 mL/min [IQR:120;184], *p* = 0.02). However, hemodynamic augmentation did not significantly affect total plasma protein level or [Nimodipine]plasma.

Only body surface area (BSA), and mean arterial pressure (MAP) were retained as final covariates influencing [Nimodipine]plasma in the final pharmacokinetic model, with BSA exerting a stronger and more consistent effect than MAP. Beyond MAP's own limited effect, hemodynamic augmentation therapy per se had no significant influence on nimodipine clearance.

**Conclusions:** Hemodynamic augmentation therapy per se did not significantly affect [Nimodipine]plasma in contrast to patient's BSA, and, to a clinically irrelevant extent, MAP level.

## 1. Introduction

Nimodipine is recommended following non-traumatic subarachnoid hemorrhage (SAH) to prevent delayed cerebral ischemia (DCI) [1,2]. Cerebral vasospasm is a contributor to DCI [1,3]. Therapeutic options

for vasospasm remain debated, but typically include induced arterial hypertension (iHTN) with avoidance of hypovolemia, and, when necessary, invasive endovascular angioplasty and/or intravenous (IV) milrinone [1,2,4]. Both iHTN and milrinone – especially in combination – produce significant cerebral and systemic hemodynamic

**Abbreviations:** BSA, body surface area.; DCI, delayed cerebral ischemia.; eGFR, estimated glomerular filtration rate.; iHTN, induced arterial hypertension.; IV, intravenous.; IQR, interquartile range.; MAP, mean arterial pressure.; [Nimodipine]plasma, nimodipine plasma concentration.; OFV, Objective Function Value.; RSE, relative standard error.; SAEM, Stochastic Approximation Expectation-Maximization; SAH, non-traumatic subarachnoid hemorrhage.; UV/P, creatinine clearance calculated from urine output and urine/plasma creatinine concentrations.; WFNS, World Federation of Neurosurgeons scale.

* Corresponding author at: Service d'Anesthésie-Réanimation, Hôpital Laennec, Centre Hospitalier Universitaire, NANTES Cedex 1, F-44093, France.

**E-mail addresses:** adrien.foucher@chu-nantes.fr (A. Foucher), matthieu.gregoire@chu-nantes.fr (M. Gregoire), jerome.dauvergne@chu-nantes.fr (J.E. Dauvergne), elodie.boissier@chu-nantes.fr (E. Boissier), bertrand.rozec@chu-nantes.fr (B. Rozec), guillaume.deslandes@chu-nantes.fr (G. Deslandes), karim.lakhal@chu-nantes.fr (K. Lakhal).

<footnote><sup>a</sup> Service d'Anesthésie-Réanimation, hôpital Laennec, Centre Hospitalier Universitaire, Nantes F-44093, France</footnote>

<footnote><sup>b</sup> Nantes Université, CHU Nantes, Cibles et Médicaments des Infections et de l'Immunité, IICiMed, UR 1155, F-44000 Nantes, France</footnote>

<footnote><sup>c</sup> Laboratoire d'Hématologie, hôpital Laennec, Centre Hospitalier Universitaire, Nantes F-44093, France</footnote>

<footnote><sup>d</sup> Institut du Thorax, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), Université de Nantes, Nantes F-44093, France</footnote>

<footnote><sup>e</sup> Nantes Université, CHU Nantes, Pharmacologie Clinique, F-44000 Nantes, France.</footnote>
augmentation, which might reduce nimodipine plasma concentration [Nimodipine]plasma due to enhanced hepatic or renal clearance, hemodilution, low plasma protein level, and changes in volume of distribution [5]. Nimodipine is commonly administered at a fixed dose [1], yet marked variability in [Nimodipine]plasma is observed after SAH [5]. It remains unclear whether hemodynamic augmentation may prevent some patients from receiving the full therapeutic benefit of nimodipine, as its impact on nimodipine exposure is uncertain and the relationship between exposure and clinical outcomes has not been established due to a lack of robust data [6,7].

This prospective population pharmacokinetic study investigated whether hemodynamic augmentation – used to prevent or treat vasospasm-related DCI after SAH – is also associated with decreased [Nimodipine]plasma, a drug shown to improve DCI-related outcomes [1]. Additional covariates with the potential to impact [Nimodipine]plasma were also investigated.

## 2. Methods

Study protocol was approved by the ethics committee Groupe Nantais d'Éthique dans le Domaine de la Santé on May 15, 2019 (Chair: Prof. P. Barrière). Storage of biological samples (Biocollection N° 6, Neurosciences) was authorized by an independent ethics committee (Comité de Protection des Personnes Ouest IV, April 8, 2015, N° ID-RCB: 06/15). Assays used residual blood from routine samples otherwise discarded. Measurements were performed post-hospitalization and did not affect patient care. Informed consent was obtained from patients or, if inappacitated, from next of kin, then from patients once capacity returned, following oral and written disclosure of their rights.

### 2.1. Patients

Patients admitted to the intensive care unit (referral center) for non-traumatic SAH and treated with continuous IV nimodipine infusion were consecutively included between July 2019 and August 2020.

Exclusion criteria were: refusal to participate (by the patient or his/her next of kin), moribund status, pregnancy, age under 18 years, legal guardianship, or lack of French health insurance coverage.

For this pilot study, we chose a convenience sample size of 60–65 patients, corresponding to our funding capacity for approximately 200 [Nimodipine]plasma measurements.

### 2.2. SAH management

Patients management followed guidelines [1,2]. Nimodipine (Nimotop®, Bayer Healthcare, Loos, France) was given for 21 days. In the early phase, IV administration (2 mg·h⁻¹ in an opaque syringe) was preferred over the enteral route due to frequent nausea and vomiting. During hemodynamic augmentation, the IV route was favored to prevent blood pressure drops often seen with enteral nimodipine [8]. Vasospasm detection relied on repeated clinical exams and transcranial color-coded duplex Doppler. If considered significant on CT angiography, vasospasm was treated, even without clinical deterioration. Endovascular angioplasty was only performed in severe/refractory cases, when deemed relevant.

Hemodynamic augmentation therapy, the cornerstone of treatment, involved iHTN (mean arterial pressure [MAP] 100–120 mmHg) through maintenance of euvolemia (with saline boluses as needed), withholding all anti-hypertensive drugs except nimodipine, and using norepinephrine if necessary. IV-milrinone (0.5–1.5 µg·kg⁻¹·min⁻¹, no bolus) was added if deemed potentially beneficial [9].

### 2.3. [Nimodipine]plasma measurement

Plasma sampling was planned after a consistent dosing regimen for at least 12 h, with no enteral or intra-arterial nimodipine administration

during this period, to ensure steady-state conditions given its elimination half-life of less than 2 h [10]. Blood (collected in a BD Vacutainer® tube containing ethylene diamine tetra-acetic acid, BD Diagnostics, Le Pont de Claix, France) was sampled (via venipuncture or an arterial catheter) during the morning routine and transported in an opaque plastic bag to protect it from light. Initially, samples were used for blood count (turnaround time < 1 h), with any remaining blood transferred to the pharmacology laboratory. Tubes were centrifuged at 2200g during 10 min and plasma was stored at -80 °C in polypropylene cryotubes for less than three months. Immediately after thawing, [Nimodipine]plasma was measured using liquid-chromatography coupled with triple-quadrupole mass-spectrometry [11].

### 2.4. Data collection

The following data were collected once: patient demographics (age, sex, weight, height); patient history (chronic arterial hypertension, smoking, and alcohol use); and SAH characteristics within the first 24 h after hospital admission (World Federation of Neurosurgeons [WFNS] and modified Fisher scales, presence of seizures). At each sampling time for [Nimodipine]plasma measurement, we also collected data on mechanical ventilation status; fluid balance (input-output during the 24 h preceding sampling); urine creatinine (measured from urine collected over the 24 h preceding sampling, or over 1 h if unavailable); plasma creatinine; creatinine clearance (UV/P, calculated from urine output and urine/plasma creatinine concentrations); estimated glomerular filtration rate (eGFR [12]); prothrombin time; MAP; vasopressor use; total plasma protein level; hemodynamic augmentation for vasospasm; milrinone co-administration; and nimodipine dosing regimen.

### 2.5. Population pharmacokinetic analysis

A population-based approach was used to analyze the pharmacokinetic data. Nonlinear mixed-effects modeling was performed using the Stochastic Approximation Expectation-Maximization (SAEM) algorithm implemented in Monolix software (version 2024R1; Lixoft, Antony, France). A log-normal distribution was assumed for pharmacokinetic parameters, reflecting an exponential model of between-subjects variability. Random effects were assumed to follow normal distributions.

One- and two-compartment structural models with linear elimination were initially tested without covariates to determine the best-fitting model. Additive, proportional and combined residual error models were explored.

During covariate modeling, the following covariates were evaluated: age, sex, weight, height, body surface area (BSA, calculated using Du Bois formula), eGFR, UV/P, MAP, vasopressor use, plasma protein levels, hemodynamic augmentation for vasospasm, milrinone co-administration, mechanical ventilation status, input-output fluid balance, and diuresis.

A stepwise approach was used to evaluate the influence of covariates on pharmacokinetic parameters, with changes in the Objective Function Value (OFV) calculated by Monolix. The OFV was assumed to follow a chi-squared distribution, with a decrease of at least 3.84 units considered statistically significant for forward inclusion (*p* < 0.05) and 6.63 for backward deletion (*p* < 0.01). The best structural and covariate models were identified using classical criteria and diagnostics, including OFV, parameter estimates and their relative standard errors (RSE, values below 30 % were considered satisfactory), goodness-of-fit plots, simulation-based diagnostics with visual predictive checks, and bootstrap analysis (200 replicates).

### 2.6. Other statistical analyses

Categorical data were expressed as counts and percentages. Continuous variables were expressed as median [interquartile range (IQR)]. Mann-Whitney and Wilcoxon tests were used for comparisons, as
appropriate. If multiple measurements of a given parameter were available for the same patient within the same phase (during or outside hemodynamic augmentation for vasospasm), their mean value was used for comparisons. All tests were two-tailed and *p* < 0.05 was considered significant. No data imputation was necessary.

### 3. Results

Over 85 eligible patients, 61 were analyzed (Table 1), corresponding to 212 [Nimodipine]plasma measurements: 51 patients (128 measurements) before potential vasospasm and 30 (84 measurements) during hemodynamic augmentation (Supplemental Fig. 1: Study Flow Chart). At the time of blood sampling, median MAP was 100 mmHg [IQR:94;107], during hemodynamic augmentation, and 86 mmHg

<caption>**Table 1**</caption>

Patients' characteristics.

<table><thead><tr><th>Variable</th><th>Patients<br>N = 61</th><th>Missing values<br>(%)</th></tr></thead><tbody><tr><td>Cause of SAH</td><td></td><td>0 %</td></tr><tr><td>aneurysm</td><td>51 (84 %)</td><td></td></tr><tr><td>arteriovenous malformation</td><td>4 (7 %)</td><td></td></tr><tr><td>unknown (sine materia)</td><td>2 (2 %)</td><td></td></tr><tr><td>other</td><td>4 (7 %)</td><td></td></tr><tr><td>Female sex</td><td>34 (55 %)</td><td>0 %</td></tr><tr><td>Age (years)</td><td>59 [44; 67]</td><td>0 %</td></tr><tr><td>Weight (Kg)</td><td>65 [57; 83]</td><td>5 %</td></tr><tr><td>Tobacco use</td><td>24 (39 %)</td><td>0 %</td></tr><tr><td>Alcohol daily consumption</td><td>13 (21 %)</td><td>1 %</td></tr><tr><td>Initial prothrombin time ± 3 days</td><td>96 [90; 102]</td><td>3 %</td></tr><tr><td>Initial plasma creatinine (µmol/L)</td><td>50 [42; 61]</td><td>11 %</td></tr><tr><td>Initial plasma protein level (g/L)</td><td>66 [63; 71]</td><td>11 %</td></tr><tr><td>Invasive prevention of rebleeding</td><td></td><td>0 %</td></tr><tr><td>coiling</td><td>49 (80 %)</td><td></td></tr><tr><td>other percutaneous procedure</td><td>1 (2 %)</td><td></td></tr><tr><td>surgery</td><td>4 (7 %)</td><td></td></tr><tr><td>none</td><td>7 (11 %)</td><td></td></tr><tr><td>External ventricular drain</td><td>31 (51 %)</td><td>0 %</td></tr><tr><td>Surgical evacuation of intracerebral hematoma</td><td>6 (10 %)</td><td>0 %</td></tr><tr><td>WFNS</td><td></td><td>0 %</td></tr><tr><td>I</td><td>28 (46 %)</td><td></td></tr><tr><td>II</td><td>11 (18 %)</td><td></td></tr><tr><td>III</td><td>6 (10 %)</td><td></td></tr><tr><td>IV</td><td>11 (18 %)</td><td></td></tr><tr><td>V</td><td>5 (8 %)</td><td></td></tr><tr><td>Modified Fisher scale</td><td></td><td>0 %</td></tr><tr><td>I</td><td>6 (10 %)</td><td></td></tr><tr><td>II</td><td>5 (8 %)</td><td></td></tr><tr><td>III</td><td>9 (15 %)</td><td></td></tr><tr><td>IV</td><td>41 (67 %)</td><td></td></tr><tr><td>Invasive mechanical ventilation &gt;24 h</td><td>19 (31 %)</td><td>0 %</td></tr><tr><td>Time from ICU admission to first [Nimodipine]plasma measurement (days)</td><td>3 [2; 4]</td><td>0 %</td></tr><tr><td>Hemodynamic augmentation therapy for vasospasm</td><td></td><td>0 %</td></tr><tr><td>Induced hypertension alone</td><td>15 (25 %)</td><td></td></tr><tr><td>Induced hypertension &amp; IV milrinone</td><td>15 (25 %)</td><td></td></tr><tr><td>Endovascular angioplasty for vasospasm (n patients [%])</td><td>7 (11 %)</td><td>0 %</td></tr><tr><td>Death within the 21 days after SAH</td><td>8 (13 %)</td><td>0 %</td></tr></tbody></table>

**Legend.** IQR, interquartile range; SAH, subarachnoid hemorrhage; IV, intravenous infusion; IA, intraarterial infusion; WFNS, World Federation of Neurological Societies grade (a specific scale of SAH initial clinical severity) [13]; Modified Fisher scale, a specific scale of SAH initial severity on the computerized tomography scan [14]; ICU, intensive care unit; [Nimodipine]plasma, plasma concentration of nimodipine.

Results are expressed as median [interquartile range] or count (%).

*: "initial" refers to the morning of the first blood sampling for measurement of [Nimodipine]plasma.

[IQR:80;93] otherwise (*p* < 0.001). Hemodynamic augmentation consisted in iHTN alone for 41 (19 %) [Nimodipine]plasma measurements and, for 38 (18 %) measurements, combination of iHTN and IV-milrinone. Augmentation therapy necessitated norepinephrine in 30 (100 %) patients (0.9 µg.kg⁻¹.min⁻¹ [IQR:0.4;1.3]).

For 8 [Nimodipine]plasma measurements (7 patients), IV nimodipine was given at 1 mg.h⁻¹ while the remainder were measured at 2 mg.h⁻¹.

### 3.1. UV/P and total plasma protein level

No patient received renal replacement therapy and minimal UV/P was 64 mL/min.

Median UV/P was higher during hemodynamic augmentation than before potential vasospasm: 180 mL/min [IQR:134;206.9] vs. 151 mL/min [IQR:120;184], *p* = 0.02. The adjunction of IV-milrinone to iHTN was not associated with higher levels of UV/P than that observed with iHTN alone: 182 mL/min [IQR:157;207] and 178 mL/min [IQR:121;207], respectively (*p* = 0.2).

Total plasma protein level was similar between the 2 phases: 65 [62;70] and 66 g/L [58;70], respectively, *p* = 0.54.

Even after excluding eight [Nimodipine]plasma measurements obtained while the patient was receiving intravenous nimodipine at 1 mg. h⁻¹ rather than 2 mg.h⁻¹, the relationship between [Nimodipine]plasma and UV/P remained weak, as it was for total plasma protein level, fluid balance over the preceding 24 h, urine output over the preceding 24 h, height, weight, and norepinephrine dosage (R² ≤ 0.16, Supplemental Fig. 2).

### 3.2. Univariate analysis of the impact of hemodynamic augmentation on [Nimodipine]plasma

[Nimodipine]plasma was 34 ng/mL [IQR:28;41] before potential vasospasm and 31 ng/mL [IQR:28;35] during hemodynamic augmentation (*p* = 0.02). In the 19 patients with measurements at both phases (45 and 56 measurements before and during vasospasm, respectively), [Nimodipine]plasma was 36 ng/mL [IQR:30;43] and 30 ng/mL [IQR:27;33], respectively, *p* < 0.001.

### 3.3. Population pharmacokinetic analysis

The final model was a one-compartment model configured with total body clearance of nimodipine and central volume of distribution. The latter was initially estimated but subsequently fixed due to instability observed during the bootstrapping procedure. The residual error model included only proportional error. Parameter estimates for the final model are presented in Table 2. BSA and MAP were retained as covariates in the final model, both correlated with the nimodipine clearance as a power relationship. All model parameters were estimated with

<caption>**Table 2**</caption>

Final Population Pharmacokinetic Model Parameters for Nimodipine.

<table><thead><tr><th>Parameter</th><th>Estimate<br>(SAEM)</th><th>RSE<br>(%)</th><th>Bootstrap median<br>[95 % CI, 200 replicates]</th></tr></thead><tbody><tr><td>Volume of distribution (L)</td><td>314.0</td><td>—</td><td>—</td></tr><tr><td>Nimodipine clearance (L/h)</td><td>54.8</td><td>3.2</td><td>55.1 [51.9-58.4]</td></tr><tr><td>Effect of BSA on clearance</td><td>1.1</td><td>22.1</td><td>1.02 [0.42-1.53]</td></tr><tr><td>Effect of MAP on clearance</td><td>0.4</td><td>37.7</td><td>0.43 [0.14-0.73]</td></tr><tr><td>Interindividual variability of the<br>nimodipine clearance<br>(Coefficient of variation, %)</td><td>19.1</td><td>12.7</td><td>0.18 [0.10-0.23]</td></tr><tr><td>Residual error parameter (b)</td><td>0.17</td><td>6.1</td><td>0.17 [0.14-0.21]</td></tr></tbody></table>

**Legend.** SAEM, stochastic approximation expectation-maximization; CI, confidence intervals; RSE, relative standard error of the estimate (values below 30 % were considered satisfactory); MAP, mean arterial pressure; BSA, body surface area; b, proportional component of the residual error model.
satisfactory precision (RSE <30 %), except for the power coefficient associated with MAP, which had an RSE of 37.7 % – considered acceptable. The model’s ability to describe the relationship between MAP and [Nimodipine]plasma was assessed using a prediction-corrected visual predictive check. The final model adequately described the observed data, as shown in Fig. 1.

## 4. Discussion

The main finding of this study is that only BSA and MAP were retained as covariates in the final one-compartment model, both influencing nimodipine clearance, with BSA exerting a stronger and more reliable effect than MAP. Beyond MAP’s own limited effect, hemodynamic augmentation for vasospasm – even in case of milrinone coadministration– was not significantly associated with [Nimodipine]plasma.

Parameter estimates were consistent with values reported in the literature, supporting the model’s validity [5]. We chose to fix the volume of distribution, as the available data did not permit reliable estimation of its variability, likely due to the continuous infusion of nimodipine. Notably, the effect of MAP on [Nimodipine]plasma appeared limited and is likely of minimal clinical relevance compared to the more pronounced influence of BSA.

Since the relationship between nimodipine exposure and clinical outcomes has not been established due to a lack of robust data [6,7], further research is warranted to determine whether our findings support [Nimodipine]plasma monitoring in patients with extreme BSA, or whether dose adjustment based on hemodynamic tolerance is sufficient.

We had no access to direct measurements of liver metabolism. Nimodipine is metabolized by cytochrome P450 3A4 and 3A5 enzymes, producing less active metabolites [5]. We did not investigate potential coadministered drugs that might affect these enzymes. Furthermore, we did not have access to data on potential changes in hepatic blood flow

induced by hemodynamic augmentation. However, our findings suggest that nimodipine metabolism was not significantly altered by this therapy.

As another limitation, this pilot study, with only IV-administration of nimodipine did not assess the impact of hemodynamic augmentation on the bioavailability of enteral nimodipine. We cannot exclude an influence given that it could theoretically be increased by enhanced splanchnic blood flow.

In conclusion, in adults, nimodipine is recommended at a fixed dosage, regardless of patient morphology, renal or hepatic function, or the phase following SAH. Our findings are reassuring regarding the latter: hemodynamic augmentation therapy per se did not significantly affect [Nimodipine]plasma, in contrast to patient BSA and, to a probably clinically irrelevant extent, MAP.

### Details

This manuscript complies with all instructions to authors.

Authorship requirements have been met and the final manuscript was approved by all authors.

This manuscript has not been published elsewhere and is not under consideration by another journal.

**Use of reporting checklist:** STROBE checklist has been attached as supplemental file.

### Additional information

Institution where the work was performed: University Hospital of Nantes, France (department of Anesthesia and Critical Care, Laennec Hospital and department of Pharmacology and Toxicology, Hôtel Dieu).

Meeting presentation: Annual congress of the French Society of Anesthesia and Critical Care (Société Française d'Anesthésie-Réanimation), September 2022.

<figure><img src="image_5.png" /><figcaption>**Fig. 1.** Prediction-corrected visual predictive check of nimodipine concentrations as a function of mean arterial pressure and body surface area.</figcaption></figure>

**Legend.** Observed concentrations are overlaid with prediction intervals derived from simulations (n = 500). The solid line represents the median of the observed prediction-corrected concentrations. The dotted line and the shaded areas correspond to the median of the prediction and the 95 % prediction intervals (5th–95th percentiles) from the Monte Carlo simulations respectively.
This submission includes supplemental material: Yes.

### CRediT authorship contribution statement

**Adrien Foucher:** Writing – review & editing, Validation, Investigation, Formal analysis. **Matthieu Gregoire:** Writing – review & editing, Validation, Formal analysis. **Jérôme E. Dauvergne:** Writing – review & editing, Investigation, Data curation. **Elodie Boissier:** Writing – review & editing, Resources, Investigation. **Bertrand Rozec:** Writing – review & editing, Supervision, Resources. **Guillaume Deslandes:** Validation, Resources, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. **Karim Lakhal:** Writing – original draft, Validation, Supervision, Investigation, Formal analysis, Data curation.

### Ethical approval

Study protocol was approved by the ethics committee Groupe Nantais d'Éthique dans le Domaine de la Santé on May 15, 2019 (Chair: Prof. P. Barrière). Storage of biological samples (Biocollection N° 6, Neurosciences) was authorized by an independent ethics committee (Comité de Protection des Personnes Ouest IV, April 8, 2015, N° ID-RCB: 06/15).

### Funding

This work was fully funded by departmental funds. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

### Declaration of competing interest

Adrien Foucher has no conflict of interest in connection with the work submitted.

Matthieu Grégoire has no conflict of interest in connection with the work submitted.

Jérôme E. Dauvergne has no conflict of interest in connection with the work submitted.

Elodie Boissier has no conflict of interest in connection with the work submitted.

Bertrand Rozec has no conflict of interest in connection with the work submitted. BR receives consulting fees and congress registration support from LFB, NordicPharma, Aguettant & i-SEP.

Guillaume Deslandes has no conflict of interest in connection with the work submitted.

Karim Lakhal has no conflict of interest in connection with the work submitted. In addition, KL declares having received consulting fees from Philips since 2024. Over the past three years, KL has also received congress registration support from Pfizer (once in 2022), as well as congress registration and travel fees from Advanz Pharma/Correvio (once in 2024) and AOP Health (once in 2024).

### Acknowledgements

We are grateful to Mrs. Laurence Pacaud (research nurse in the Department of Anesthesia and Critical Care) and to the laboratory staff at the University Hospital of Nantes for their valuable contributions.

## Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.

org/10.1016/j.jns.2025.125666.

### Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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