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

Claire Marie-Rangon

doi:doi:10.1162/2e3983f5.0f1329a3

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.

by Claire Marie-Rangon

Published onOct 28, 2021

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

by Carlos Tornero, Ernesto Pastor, María del Mar Garzando, Jorge Orduña, MJ Forner, Irene Bocigas, David L. Cedeño, Ricardo Vallejo, Peter Staats, and Eric J. Liebler

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dx.doi.org

Description

ABSTRACTBackgroundSevere 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).MethodsParticipants 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.ResultsOf 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.ConclusionsnVNS 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.

RR:C19 Evidence Scale rating by reviewer:

Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

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Review:

The strength of evidence of this study is reliable.

Firstly, the evidence is reliable due to the method used: randomized and controlled trial. The control group is of particular importance. The study lasted almost one year, allowing rapid evolution of the clinical standards of care for COVID-19 with a significant impact on the inflammation markers by itself (glucocorticoids, antivirals, monoclonal antibodies...).
Moreover, although there was no stratification of the study population, randomization (small but sufficient with 97 patients enrolled) allowed for similar baseline characteristics between the two arms. (The mean participant age was only six years higher in the SoC group than in the nVNS group, respectively 55.5 and 61.3 years old. Males represented roughly 70% in both arms, smoking status and comorbidities were similar in both groups).

Secondly, the results and conclusion are likely to be similar to the hypothetical, ideal study because two validated inflammatory biomarkers (CRP and procalcitonin) were significantly reduced in the nVNS group.
Besides, the efficacy of nVNS is assessed on a short but suitable period (only five days). COVID-19 patients are known to undergo respiratory failure rapidly, within a few days and sometimes within a few hours after hospital admission.

However, this study has some minor limitations: it is a monocentric study, enrolling a small population without assessing the long-term outcomes. In addition, considering that a pandemic is very challenging for consistent data collection, Heart rate variability monitoring should be considered in the ongoing trial SAVIOR II or the next one.

At last, this manuscript contributes to broader research understanding (how to reduce the cytokine storm and improve respiratory symptoms of COVID-19) and supports the advancement of ambulatory non-invasive therapeutics. Thus, paying attention to ethics, diversity, and inclusion. Therefore, I would recommend this manuscript for publishing, provided the authors include a more detailed discussion of the limitations and a better positioning within the current literature.

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

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