Prone positioning of patients with moderate hypoxaemia due to covid-19: multicentre pragmatic randomised trial (COVID-PRONE)

  1. Michael Fralick
  2. Michael Colacci
  3. Laveena Munshi
  4. Kevin Venus
  5. Lee Fidler
  6. Haseena Hussein
  7. Karen Britto
  8. Rob Fowler
  9. Bruno R da Costa
  10. Irfan Dhalla
  11. Richard Dunbar-Yaffe
  12. Leora Branfield Day
  13. Thomas E MacMillan
  14. Jonathan Zipursky
  15. Travis Carpenter
  16. Terence Tang
  17. Amanda Cooke
  18. Rachel Hensel
  19. Melissa Bregger
  20. Alexis Gordon
  21. Erin Worndl
  22. Stephanie Go
  23. Keren Mandelzweig
  24. Lana A Castellucci
  25. Daniel Tamming
  26. Fahad Razak
  27. Amol A Verma

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Abstract

Objectives

To assess the effectiveness of prone positioning to reduce the risk of death or respiratory failure in non-critically ill patients admitted to hospital with covid-19.

Design

Multicentre pragmatic randomised clinical trial.

Setting

15 hospitals in Canada and the United States from May 2020 until May 2021.

Participants

Eligible patients had a laboratory confirmed or a clinically highly suspected diagnosis of covid-19, needed supplemental oxygen (up to 50% fraction of inspired oxygen), and were able to independently lie prone with verbal instruction. Of the 570 patients who were assessed for eligibility, 257 were randomised and 248 were included in the analysis.

Intervention

Patients were randomised 1:1 to prone positioning (that is, instructing a patient to lie on their stomach while they are in bed) or standard of care (that is, no instruction to adopt prone position).

Main outcome measures

The primary outcome was a composite of in-hospital death, mechanical ventilation, or worsening respiratory failure defined as needing at least 60% fraction of inspired oxygen for at least 24 hours. Secondary outcomes included the change in the ratio of oxygen saturation to fraction of inspired oxygen.

Results

The trial was stopped early on the basis of futility for the pre-specified primary outcome. The median time from hospital admission until randomisation was 1 day, the median age of patients was 56 (interquartile range 45-65) years, 89 (36%) patients were female, and 222 (90%) were receiving oxygen via nasal prongs at the time of randomisation. The median time spent prone in the first 72 hours was 6 (1.5-12.8) hours in total for the prone arm compared with 0 (0-2) hours in the control arm. The risk of the primary outcome was similar between the prone group (18 (14%) events) and the standard care group (17 (14%) events) (odds ratio 0.92, 95% confidence interval 0.44 to 1.92). The change in the ratio of oxygen saturation to fraction of inspired oxygen after 72 hours was similar for patients randomised to prone positioning and standard of care.

Conclusion

Among non-critically ill patients with hypoxaemia who were admitted to hospital with covid-19, a multifaceted intervention to increase prone positioning did not improve outcomes. However, wide confidence intervals preclude definitively ruling out benefit or harm. Adherence to prone positioning was poor, despite multiple efforts to increase it. Subsequent trials of prone positioning should aim to develop strategies to improve adherence to awake prone positioning.

Study registration

ClinicalTrials.gov NCT04383613 .

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  1. Version published to 10.1136/bmj-2021-068585
  2. ScreenIT

    SciScore for 10.1101/2021.11.05.21264590: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: The trial protocol was approved by the institutional review board at each site (or by a centralized institutional review board as applicable) and was overseen by the trial’s steering committee (NCT04383613).
    Consent: Informed consent was obtained from each patient.
    Sex as a biological variablenot detected.
    RandomizationTRIAL DESIGN: We conducted an unblinded pragmatic randomized clinical trial of prone positioning of patients hospitalized with confirmed or suspected COVID-19 in 15 hospitals in Canada and the United States from May 2020 until May 2021.
    BlindingAn independent data monitoring committee was established and reviewed the interim analysis results so that the trial investigators were blinded.
    Power AnalysisWe planned for 80% power and a two-sided alpha of 0.05, and assumed the risk of our composite outcome would be 45%(1,11).

    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:
    The most important limitation of our study was poor adherence to time spent prone. As described, this likely reflects the real-world challenges of lying in a prone position when sick with a respiratory and multisystem viral illness, and without high nurse-to-patient ratios. Future studies are needed to determine whether a greater amount of time spent in the prone position is associated with clinical benefit including whether specific devices or interventions (e.g., smartphone apps, pillows/padding, prone positioning teams) can increase time spent prone. Second, our expected event rate was lower than anticipated because our study was planned prior to effective treatments being available. These treatments (e.g., dexamethasone, remdesivir, tocilizumab), at least in part, resulted in a lower event rate that we anticipated and thus larger randomized trials would be needed to identify a smaller absolute risk reduction. Third, we lacked data on PPE use and the number of times a healthcare provider had to enter the room to help reposition a patient to aid with prone positioning. Both are important to evaluate when considering the potential drawbacks of prone positioning. Fourth, FiO2 for non-intubated patients depends on multiple physiologic factors and needs to be estimated for certain devices (e.g., a non-rebreather mask) based on the flow rate of oxygen delivered.

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

    IdentifierStatusTitle
    NCT04383613Active, not recruitingProne Positioning for Patients on General Medical Wards With…

    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 10.1101/2021.11.05.21264590v1 on medRxiv