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

  1. Elisabeth Maria Balint
  2. Beate Grüner
  3. Sophia Haase
  4. Mandakini Kaw-Geppert
  5. Julian F. Thayer
  6. Harald Gündel
  7. Marc N. Jarczok

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Abstract

A characteristic problem occurring in COVID-19 is excessive elevations of pro-inflammatory cytokines (e.g. IL-6 and CRP) which are associated with worse clinical outcomes. Stimulation of the vagally-mediated cholinergic anti-inflammatory reflex by slow paced breathing with prolonged exhalation may present a clinically relevant way to reduce circulating IL-6.

Method

Single-center randomized controlled clinical trial with enrolment of 46 patients hospitalized with confirmed severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) infection and moderate COVID-19 pneumonia (primary diagnosis). Differences between intervention (4sec inhalation, 6sec exhalation for 20 minutes 3x daily) 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. Both groups received standard care.

Results

Mean age was 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 (effect size Cohens f 2 = 0.11, LR-test p=.040) in the intention-to-treat sample, confirmed by 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 per day. Oxygen saturation remained unchanged during slow-paced breathing (95.1% ± 2.1% to 95.4% ± 1.6%).

Conclusion

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 and an earlier start of the intervention. Slow-paced breathing could be an easy to implement, low-cost, safe and feasible adjuvant therapeutic approach to reduce circulating IL-6 in moderate COVID-19 pneumonia.

Clinical Trial Registration

https://www.drks.de , identifier DRKS00023971, Universal Trial Number (UTN) U1111-1263-8658.

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  1. Version published to 10.3389/fimmu.2022.928979
  2. ScreenIT

    SciScore for 10.1101/2021.12.03.21266946: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: The protocol was approved by the Institutional Review Board of Ulm University (No. 3/21, 01/02/2021) and registered prior to screening start at the German Clinical Trials Register (ID: DRKS00023971), Universal Trial Number (UTN) U1111-1263-8658.
    Consent: All patients provided written informed consent prior to inclusion.
    Sex as a biological variablenot detected.
    RandomizationThe present study design is a prospective, two-arm, open-label, single-center randomized controlled trial.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    No key resources detected.

    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: We detected the following sentences addressing limitations in the study:
    Limitations: First limitation is the sample size that could not address clinical outcomes. Second, early discharge was not included in the model. Third, the intervention was not blinded. Another trial could include a sham intervention. Fourth, we did not control objectively the amount of time spent in slow-paced breathing but relied on self-report. Conclusion: This small, single-center randomized controlled clinical trial showed that reducing breathing frequency to 6/min is effective in reducing IL-6 levels in moderate COVID-19 pneumonia without relevant side effects. Larger RCTs need to confirm these results as well as evaluate clinical outcomes. This would offer an access to a therapy option not only for industrial, but also for low-income countries.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    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

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  3. Version published to 10.1101/2021.12.03.21266946 on medRxiv