Auricular Neuromodulation for Mass Vagus Nerve Stimulation: Insights From SOS COVID-19 a Multicentric, Randomized, Controlled, Double-Blind French Pilot Study

Claire-Marie Rangon, Régine Barruet, Abdelmadjid Mazouni, Chloé Le Cossec, Sophie Thevenin, Jessica Guillaume, Teddy Léguillier, Fabienne Huysman, David Luis, Claire-Marie Rangon, Régine Barruet, Abdelmadjid Mazouni, Chloé Le Cossec, Sophie Thevenin, Jessica Guillaume, Teddy Léguillier, Fabienne Huysman, David Luis

Abstract

Importance: An exacerbated inflammatory response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is believed to be one of the major causes of the morbidity and mortality of the coronavirus disease 2019 (COVID-19). Neuromodulation therapy, based on vagus nerve stimulation, was recently hypothesized to control both the SARS-CoV-2 replication and the ensuing inflammation likely through the inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells pathway and could improve the clinical outcomes as an adjunct treatment. We proposed to test it by the stimulation of the auricular branch of the vagus nerve, i.e., auricular neuromodulation (AN), a non-invasive procedure through the insertion of semipermanent needles on the ears. Objective: The aim of this study was to assess the effect of AN on the clinical outcomes in patients affected by COVID-19. Design, Setting, and Participants: A multicenter, randomized, placebo-controlled, double-blind clinical trial included 31 patients with respiratory failure due to COVID-19 requiring hospitalization. Within 72 h after admission, patients received either AN (n = 14) or sham neuromodulation (SN, n = 15) in addition to the conventional treatments. Main Outcome and Measures: The primary endpoint of the study was the rate of a clinical benefit conferred by AN at Day 14 (D14) as assessed by a 7-point Clinical Progression Scale. The secondary endpoint of the study was the impact of AN on the rate of transfer to the intensive care unit (ICU) and on the survival rate at D14. Results: The AN procedure was well-tolerated without any reported side effects but with no significant improvement for the measures of both primary (p > 0.3) and secondary (p > 0.05) endpoints at the interim analysis. None of the AN-treated patients died but one in the SN group did (81 years). Two AN-treated patients (73 and 79 years, respectively) and one SN-treated patient (59 years) were transferred to ICU. Remarkably, AN-treated patients were older with more representation by males than in the SN arm (i.e., the median age of 75 vs. 65 years, 79% male vs. 47%). Conclusion: The AN procedure, which was used within 72 h after the admission of patients with COVID-19, was safe and could be successfully implemented during the first two waves of COVID-19 in France. Nevertheless, AN did not significantly improve the outcome of the patients in our small preliminary study. It is pertinent to explore further to validate AN as the non-invasive mass vagal stimulation solution for the forthcoming pandemics. Clinical Trial Registration: [https://ichgcp.net/clinical-trials-registry/NCT04341415" title="See in ClinicalTrials.gov">NCT04341415].

Keywords: COVID-19; NF-κB; auricular neuromodulation; cholinergic anti-inflammatory pathway; non-invasive neuromodulation; pandemics; vagus nerve stimulation.

Conflict of interest statement

SEDATELEC gave financial support. The authors declare that the research was conducted with conflict of interest.

Copyright © 2021 Rangon, Barruet, Mazouni, Le Cossec, Thevenin, Guillaume, Léguillier, Huysman and Luis.

Figures

Figure 1
Figure 1
The semipermanent needles (SPNs). (A) SPN packaging. (B) Close-up of a SPN inside its sterile blister. (C) Close-up of a SPN ready to be inserted in the skin of the outer ear. (D) The three-step procedure for SPN insertion: (1) the blister is placed on the disinfected skin point, (2) a pressure exerted on the blister delivers the SPN inside the skin, and (3) the SPN is once again sinked using the bottom end of the blister (images from SedatelecR, Irigny, France).
Figure 2
Figure 2
Neuromodulation with SPNs on the concha. (A) Localization of the four selected acupoints, represented as green circles, of the concha, following the order indicated by the number in the circle: (1) master point of endoderm, (2) master point of reticular formation, (3) thymic plexus, and (4) ACTH point (i.e., ear maps according to Alimi, 2017). Each acupoint is either implanted with SPNs (verum group) or pressed on with the empty needle applicator (sham group). (B) The white square symbolizes the opaque Band-Aid allowing double-blind treatment. Both ears of the patients receive same neuromodulation treatment (i.e., verum or sham group). With the permission of SedatelecR.
Figure 3
Figure 3
Study flowchart.

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