Inhaled Prostacyclin Improves Oxygenation in Patients with COVID-19-induced Acute Respiratory Distress Syndrome

  1. Helene A. Haeberle
  2. Stefanie Calov
  3. Peter Martus
  4. Lina Maria Serna Higuita
  5. Michael Koeppen
  6. Almuth Goll
  7. Alexander Zarbock
  8. Melanie Meersch
  9. Raphael Weiss
  10. Martin Mehrländer
  11. Gernot Marx
  12. Christian Putensen
  13. Bernhard Nieswandt
  14. Valbona Mirakaj
  15. Peter Rosenberger

Reviewed by

Read the full article

Listed in

Log in to save this article

Abstract

Background

Acute Respiratory Distress Syndrome (ARDS) results in significant hypoxia, and ARDS is the central pathology of COVID-19. Inhaled prostacyclin has been proposed as a therapy for ARDS, but data regarding its role in this syndrome are unavailable. Therefore, we investigated whether inhaled prostacyclin would affect the oxygenation and survival of patients suffering from ARDS.

Methods

We performed a prospective randomized controlled single-blind multicenter trial across Germany. The trial was conducted from March 2019 with final follow-up on 12 th of August 2021. Patients with moderate to severe ARDS were included and randomized to receive either inhaled prostacyclin (3 times/day for 5 days) or sodium chloride. The primary outcome was the oxygenation index in the intervention and control groups on Day 5 of therapy. Secondary outcomes were mortality, secondary organ failure, disease severity and adverse events.

Findings

Of 707 patients approached 150 patients were randomized to receive inhaled prostacyclin (n=73) or sodium chloride (n=77). Data from 144 patients were analyzed. The baseline oxygenation index did not differ between groups. The primary analysis of the study was negative, and prostacyclin improved oxygenation by 20 mmHg more than NaCl (p=0·17). Oxygenation was significantly improved in patients with ARDS who were COVID-19-positive (34 mmHg, p=0·04). Mortality did not differ between groups. Secondary organ failure and adverse events were similar in the intervention and control groups.

Interpretation

Although the primary result of our study was negative, our data suggest that inhaled prostacyclin might be a more beneficial treatment than standard care for patients with ARDS.

Article activity feed

  1. ScreenIT

    SciScore for 10.1101/2021.11.15.21266343: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: The study was approved by the Institutional Review Board of the Research Ethics Committee of the University of Tübingen (899/2018AMG1) and the corresponding ethical review boards of all participating centers.
    Consent: The trial was also approved by the Federal Institute for Drugs and Medical Devices (BfArM, EudraCT No. 2016-003168-37) and registered at clinicaltrials.gov (NCT03111212) For further details, please see Supplemental Data. Patients: Before the inclusion of patients into the study, the trial coordinators obtained consent for participation in the study.
    Sex as a biological variablenot detected.
    RandomizationStudy design, Ethics and Oversight: We conducted a prospective randomized controlled, single-blind multicenter trial administering prostacyclin to critically ill patients with ARDS for 5 days.
    Blindingnot detected.
    Power AnalysisSample size: In our study, we assumed an effect size of 0.525, leading to 116 error degrees of freedom to achieve a power of 80% using a level of significance of 0.05 in the two-sided t-test.

    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:
    Of course, our trial also has several limitations. First, the trial was started before the COVID-19 pandemic to evaluate the effects of prostacyclin on oxygenation and outcomes of critically ill patients with ARDS. Then, shortly after the start of the trial, the first wave of patients with COVID-19-induced ARDS were treated in Germany and German ICUs, including ours. Given the potential differences in the pathologies of ARDS and COVID-19-induced ARDS, this factor might have significant implications for therapy with prostacyclin. However, we decided to include all patient groups with ARDS and not exclude patients with COVID-19, since our trial should also take advantage of the opportunity to compare patients with different ARDS etiologies and their responses to prostacyclin treatment. Second, our sample size was moderate, and our study was probably underpowered. This interpretation seems justified, as we obtained the expected effect, i.e., a superiority of 21mmHg in PaO2/FiO2, but the standard deviations were much larger, as expected (80mmHg in the controls, 91mmHg in the prostacyclin group vs. 40 mmHg assumed). Third, the intervention group and the control group differed significantly in age, which could have a potential effect on the overall outcome in this patient group. The average age was older in the intervention group, and therefore, one would expect this factor to have a potential negative effect if any effect at all, based on the literature (21, 22). However, in our s...

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

    IdentifierStatusTitle
    NCT03111212RecruitingIloprost in Acute Respiratory Distress Syndrome

    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

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2021.11.15.21266343v1 on medRxiv