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

Abstract

BackgroundSevere 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 biomarkers of inflammation. 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-min 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 (i.e., 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 use earlier in the course of COVID-19 and its potential to mitigate some of the symptoms associated with post-acute sequelae of COVID-19 is warranted.

A pilot randomized controlled trial of supervised, at-home, self-administered transcutaneous auricular vagus nerve stimulation (taVNS) to manage long COVID symptoms

“…Early evidence from an alternative noninvasive VNS trial (gamma Core device targeting the cervical bundle of the vagus nerve by applying electrical stimulation to the neck landmarked by the carotid sheath) suggests that stimulation of the vagus nerve has mild anti-inflammatory effects in 97 COVID-19 patients (Tornero et al 2022 ). Although non-invasive vagus nerve stimulation may be administered with a variety of different technologies, evidence suggests it potentially engages an anti-inflammatory mechanism that should be further explored in future trials.…”

Understanding the Pivotal Role of the Vagus Nerve in Health from Pandemics

“…Three different articles [ 80 , 81 , 82 ], using three different non-invasive VNS techniques, started randomized controlled trials in 2020 in France (SOS-COVID-19) and Spain (SAVIOR I), and in 2021 in Austria, respectively, enrolling stage 3 hospitalized COVID-19 patients requiring oxygen supply. Rangon et al [ 80 ] treated the patients with four semi-permanent needles on the conchae of both outer ears (without concurrent electrical stimulation) to stimulate the auricular branch of the vagus nerve, once within the first 3 days after admission.…”

“…Tornero el al. [ 81 ] used the GammaCore R device to provide two consecutive 2-min doses of cervical non-invasive VNS, three times daily (5 kHz sine wave burst lasting for 1 ms, repeated once every 40 ms for 2 min per stimulation). Seitz et al [ 82 ] used percutaneous auricular VNS via three miniature needle electrodes (Auristim R device) inserted into vagally supplied regions of one auricle.…”

“…The device delivered intermittent electrical stimulation (3 h on/3 h off) with a 1 Hz frequency, 0.5–0.9 mA peak current (1.5 mA maximum), 1 ms pulse width, and 3.8 V fixed amplitude. No study at all was able to show a significant improvement in the clinical outcomes of the COVID-19-positive inpatients (clinical status assessed either too early (14 [ 80 ] and 5 days [ 81 ] after the first VNS session), or not at all [ 82 ]), but a good tolerance of the neuromodulation treatments was confirmed. Interestingly, two studies reported a significant improvement in the biological inflammation status of the patients (regarding C-reactive protein and procalcitonin levels [ 81 ]; or C-reactive protein, TNF alpha, DDIMER, and IL-10 levels [ 82 ]).…”

Neuromodulation Strategies to Reduce Inflammation and Improve Lung Complications in COVID-19 Patients

“…Two randomized control trials of gammaCore in inpatients with COVID-19 and respiratory distress have since been initiated: SAVIOR-1, performed in Valencia, Spain, was a prospective, randomized controlled trial (RCT) of VNS vs. standard of care, which evaluated a total of 90 patients, 45 in each arm. Improvement in respiratory function and proinflammatory cytokine levels were measured following VNS (NCT04368156) ( 140 ). SAVIOR-2, performed at Allegheny Health Network, was scheduled to study 60 patients and also followed respiratory parameters and cytokines (NCT04382391).…”