Non-invasive Vagus Nerve Stimulation for Respiratory Symptoms of COVID-19: Results From a Randomized Controlled Trial (SAVIOR I)

  1. Carlos Tornero
  2. Ernesto Pastor
  3. María del Mar Garzando
  4. Jorge Orduña
  5. MJ Forner
  6. Irene Bocigas
  7. David L. Cedeño
  8. Ricardo Vallejo
  9. Peter Staats
  10. Eric J. Liebler

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Abstract

Background

Severe coronavirus disease 2019 (COVID-19) is characterized, in part, by an excessive inflammatory response. Evidence from animal and human studies suggests that vagus nerve stimulation can lead to reduced levels of various pro-inflammatory cytokines. We conducted a prospective randomized controlled study (SAVIOR-I) to assess the feasibility, efficacy, and safety of non-invasive vagus nerve stimulation (nVNS) for the treatment of respiratory symptoms and inflammatory markers among patients who were hospitalized for COVID-19 ( ClinicalTrials.gov identifier: NCT04368156 ).

Methods

Participants were randomly assigned in a 1:1 allocation to receive either the standard of care (SoC) alone or nVNS therapy plus the SoC. The nVNS group received 2 consecutive 2-minute doses of nVNS 3 times daily as prophylaxis. Efficacy and safety were evaluated via the incidence of specific clinical events, inflammatory biomarker levels, and the occurrence of adverse events.

Results

Of the 110 participants who were enrolled and randomly assigned, 97 (nVNS, n=47; SoC, n=50) had sufficient available data and comprised the evaluable population. C-reactive protein (CRP) levels decreased from baseline to a significantly greater degree in the nVNS group than in the SoC group at day 5 and overall (ie, all postbaseline data points collected through day 5, combined). Procalcitonin level also showed significantly greater decreases from baseline to day 5 in the nVNS group than in the SoC group. D-dimer levels were decreased from baseline for the nVNS group and increased from baseline for the SoC group at day 5 and overall, although the difference between the treatment groups did not reach statistical significance. No significant treatment differences were seen for clinical respiratory outcomes or any of the other biochemical markers evaluated. No serious nVNS-related adverse events occurred during the study.

Conclusions

nVNS therapy led to significant reductions in levels of inflammatory markers, specifically CRP and procalcitonin. Because nVNS has multiple mechanisms of action that may be relevant to COVID-19, additional research into its potential to be used earlier in the course of COVID-19 and possibly mitigate some of the symptoms associated with post-acute COVID-19 syndrome is warranted.

Article activity feed

  1. Rapid Reviews Infectious Diseases

    Claire Marie-Rangon

    Review 2: "Non-invasive Vagus Nerve Stimulation for Respiratory Symptoms of COVID-19: Results From a Randomized Controlled Trial (SAVIOR I)"

    This preprint claims that nVNS therapy has the potential to reduce pro-inflammatory cytokines in patients with COVID-19. Both reviewers agree on the importance of the issues it raised. They suggested the inclusion of cost-effectiveness analysis in the ongoing SAVIOR II trial.

  2. Rapid Reviews Infectious Diseases

    Abrahão Fontes Baptista

    Review 1: "Non-invasive Vagus Nerve Stimulation for Respiratory Symptoms of COVID-19: Results From a Randomized Controlled Trial (SAVIOR I)"

    This preprint claims that nVNS therapy has the potential to reduce pro-inflammatory cytokines in patients with COVID-19. Both reviewers agree on the importance of the issues it raised. They suggested the inclusion of cost-effectiveness analysis in the ongoing SAVIOR II trial.

  4. ScreenIT

    SciScore for 10.1101/2021.09.24.21264045: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsIRB: The clinical research plan was reviewed and approved by an institutional review board and an ethics committee before patient enrollment.
    Consent: All patients provided written informed consent before participation.
    Sex as a biological variablenot detected.
    RandomizationParticipants: This prospective randomized controlled study was conducted at Hospital Clínico Universitario de Valencia (Valencia, Spain).
    Blindingnot detected.
    Power AnalysisStatistical Analyses: As this was the first study of nVNS for the treatment of patients hospitalized with COVID-19, there are no previously published data on the anticipated effect size in humans, and a formal power analysis could not be performed.

    Table 2: Resources

    Antibodies
    SentencesResources
    As the pandemic progressed, treatment protocols evolved to incorporate glucocorticoids, antivirals, monoclonal antibodies, and prone mechanical ventilation.
    antivirals,
    suggested: None
    Software and Algorithms
    SentencesResources
    Statistical analyses were performed with SAS 9.4 (SAS Institute Inc.).
    SAS Institute
    suggested: (Statistical Analysis System, RRID:SCR_008567)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04368156Active, not recruitingStudy Assessing Vagus Nerve Stimulation in CoViD-19 Respirat…
    NCT04382391Active, not recruitingStudy Assessing Vagus Nerve Stimulation in CoViD-19 Respirat…

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  5. Version published to 10.1101/2021.09.24.21264045v1 on medRxiv