Nebulized Furosemide for Pulmonary Inflammation in Intubated Patients With COVID-19: A Phase 2 Randomized Controlled Double-Blind Study

John Muscedere; David M Maslove; Christopher J Barden; Donald F Weaver; J Gordon Boyd; Stephanie Sibley; Tracy Boyd; Oleksa Rewa; Martin Albert; Marios Roussos; Patrick A Norman; Andrew G Day

doi:10.1097/CCE.0000000000001045

Nebulized Furosemide for Pulmonary Inflammation in Intubated Patients With COVID-19: A Phase 2 Randomized Controlled Double-Blind Study

Crit Care Explor. 2024 Feb 2;6(2):e1045. doi: 10.1097/CCE.0000000000001045. eCollection 2024 Feb.

Authors

John Muscedere^{1

2}, David M Maslove^{1

2

3}, Christopher J Barden⁴, Donald F Weaver^{4

5}, J Gordon Boyd^{1

2

5}, Stephanie Sibley^{1

2}, Tracy Boyd¹, Oleksa Rewa⁶, Martin Albert⁷, Marios Roussos⁸, Patrick A Norman^{2

9}, Andrew G Day^{2

9}

Affiliations

¹ Department of Critical Care Medicine, Queen's University, Kingston, ON, Canada.
² Kingston Health Sciences Centre, Kingston, ON, Canada.
³ Department of Medicine, Queen's University, Kingston, ON, Canada.
⁴ Krembil Research Institute, University Health Network, Toronto, ON, Canada.
⁵ Departments of Medicine, Chemistry, and Pharmaceutical Sciences, University of Toronto, Toronto, ON, Canada.
⁶ Department of Critical Care Medicine, University of Alberta, Edmonton, AB, Canada.
⁷ Division of Critical Care, Department of Medicine, Hôpital du Sacré-Coeur Research Center, Université de Montréal, Montreal, QC, Canada.
⁸ Department of Medicine, Division of Critical Care, Hôpital Cité-de-la-Santé, Laval, QC, Canada.
⁹ Kingston General Health Research Institute, Kingston, ON, Canada.

Abstract

Objectives: Respiratory failure secondary to COVID-19 is associated with morbidity and mortality. Current anti-inflammatory therapies are effective but are given systemically and have significant side effects. Furosemide has anti-inflammatory properties, can be administered by inhalation, and is inexpensive. We investigated the efficacy of nebulized furosemide as an adjunctive therapy for COVID-19 respiratory failure.

Design: A double-blind, randomized, placebo-controlled trial.

Setting: Multicenter ICU study.

Patients: Adults requiring invasive mechanical ventilation secondary to COVID-19.

Intervention: Patients were randomized within 48 hours of intubation to receive inhaled furosemide or placebo until day 28, death, or liberation from mechanical ventilation.

Measurements and main results: The study was stopped early due to waning incidence of COVID-19; 39 patients were available for analysis with mean ± sd age of 70.5 (10.8) years, Acute Physiology and Chronic Health Evaluation II 26.1 (7.8) and Fio₂ 60.0% (21.9). Baseline characteristics were similar between the groups. For the primary outcome of change in Pao₂/Fio₂ ratio between day 1 and day 6, it was +31.4 (83.5) in the furosemide arm versus +20.1 (92.8) in the control (p = 0.58). For secondary outcomes, furosemide versus control: 60-day mortality was 48% versus 71% (p = 0.20), hospital stay was 25.6 (21.9) versus 27.4 (25.0) days, p = 0.94 and VFD was 6.0 (9.1) versus 3.1 (7.1), p value of equals to 0.28. A post hoc analysis of the hierarchical composite outcome, alive and ventilator-free favored furosemide. There were no adverse events.

Conclusions: In this trial of inhaled furosemide for COVID-19 respiratory failure, differences in Pao₂/Fio₂ ratio to day 6 and other clinical outcomes were not significantly different, although the trial was underpowered due to early termination. Given the favorable profile of inhaled furosemide, further study is warranted in disease states where acute pulmonary inflammation contributes to the underlying pathophysiology.

Keywords: COVID-19; artificial; furosemide; humans; inflammation; pneumonia; respiration.