A randomized clinical trial to stimulate the cholinergic anti-inflammatory pathway in patients with moderate COVID-19-pneumonia using a slow-paced breathing technique

Importance

Vagus nerve stimulation via slow-paced breathing could serve as an adjuvant therapeutic approach to reduce excessive inflammation in coronavirus disease 2019 (COVID-19) pneumonia.

Objective

Does a slow-paced breathing technique increasing vagal activity reduce Interleukin-6 (IL-6) in patients hospitalized with moderate COVID-19 pneumonia compared to standard care?

Design

Single-center randomized controlled clinical trial with enrolment from February 23 ^rd 2021 through June 17 ^th 2021 and follow-up until July 22 ^nd 2021.

Setting

Ward for infectious diseases and temporary COVID-19 ward, Ulm University Hospital, Germany

Participants

Consecutive sample of patients hospitalized with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and moderate COVID-19 pneumonia (primary diagnosis). Of 131 patients screened, 48 patients were randomized and 46 patients analyzed (N=23 per group).

Interventions

Slow-paced 20-minute breathing exercise three times a day with six breaths per minute (inhalation-to-exhalation ratio 4:6).

Main outcomes and measures

Differences between intervention and control group in IL-6 calculated using multilevel mixed-effect linear regression models with random slope including the covariates relevant comorbidities, COVID-19 medication, and age.

Results

Mean age 57 years±13 years, N= 28 (60%) male, N=30 (65%) with relevant comorbidities.

The model including group by time interaction revealed a significantly lower trajectory of IL-6 in the intervention group compared to the control group (effect size Cohens f ² =0.11, LR-test p=.040) in the intention-to-treat sample, confirmed by treatment-per-protocol analysis (f ² =0.15, LR-test p=.022). Exploratory analysis using the median split of practice time to predict IL-6 of the next morning indicated a dose-response relationship with beneficial effects of practice time above 45 minutes a day.

Three patients in each group were admitted to ICU, one died. Oxygen saturation increased during slow-paced breathing (from 95.1%±2.1% to 95.4%±1.6%, p=0.006).

Conclusion and relevance

Patients practicing slow-paced breathing had significantly lower IL-6 values than controls with a small to medium effect size and without relevant side effects. Further trials should evaluate clinical outcomes as well as an earlier start of the intervention, i.e., at symptom onset. This would offer an access to a therapy option not only for high-income, but also for low- and middle-income countries.

Trial registration

German register of clinical trials (ID: DRKS00023971) <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://www.drks.de">https://www.drks.de</ext-link> , Universal Trial Number (UTN) U1111-1263-8658;