Background

There are no proven therapies specific for pulmonary dysfunction in patients with acute hypoxemic respiratory failure (AHRF) caused by infections, including coronavirus disease 2019 (COVID-19). The full spectrum of AHRF ranges from mild respiratory tract illness to severe pneumonia, acute respiratory distress syndrome (ARDS), multisystem organ failure, and death. The efficacy of corticosteroids in AHRF and ARDS caused by infections remains controversial. In addition to specific antimicrobials, the care of patients with AHRF is primarily supportive, including respiratory and circulatory support.

Results from the Dexamethasone in Acute Respiratory Distress Syndrome (DEXA-ARDS) trial and the preliminary results from the Randomized Evaluation of COVid-19 thERapY (RECOVERY) trial reported a marked reduction in all-cause mortality with dexamethasone (DEXA-ARDS: 20 mg/iv once daily during 5 days followed by 10 mg/iv once daily during 5 days; RECOVERY: 6 mg/iv once daily for 10 days). At present, it is unclear what dose of dexamethasone is most beneficial in patients with AHRF (including ARDS) caused by infections (including COVID-19), and clinical equipoise exists.

Objectives

We aim to assess the effects of higher (20 mg once daily during 5 days followed by 10 mg once daily during 5 days) vs lower doses (6 mg once daily for 10 days) of intravenous dexamethasone on the number of all-cause deaths at 60 days after randomization, and on the number of ventilator-free days at 28 days in adult, mechanically ventilated patients with AHRF caused by infections (including COVID-19).

Design

Multicenter, parallel-group, open-label, centrally randomized, stratified, clinical trial.

Inclusion and exclusion criteria

We will screen all adult patients who have documented pulmonary or systemic infections (including COVID-19) being intubated and mechanically ventilated for an acute onset of AHRF [as defined by a PaO₂/FiO₂≤300 mmHg on positive end-expiratory pressure (PEEP) ≥5 cmH₂O and FiO₂≥0.3]. We will exclude patients who have an indication for chronic use of higher doses of systemic corticosteroids (above 6 mg dexamethasone or equivalent) for other indications than infections, who have received corticosteroids for 5 consecutive days or more, who have known contraindication to corticosteroids or known hypersensitivity to dexamethasone, who are pregnant, and those in whom informed consent cannot be obtained.

Experimental intervention

Dexamethasone 20 mg once daily from day 1 to day 5, followed by 10 mg once daily from day 6 to day 10 will be given as bolus injection in addition to standard care.

Control intervention

Dexamethasone 6 mg once daily for up to 10 days will be given as bolus injection in addition to standard care.

Outcomes

The primary outcome is all-cause mortality at 60 days after randomization. Secondary outcome is the number of ventilator-free days at 28 days. Other secondary outcomes include serious adverse reactions (new episode of sepsis, invasive fungal infection, clinically important gastrointestinal bleeding, or anaphylactic reaction to dexamethasone) at day 28; all-cause mortality in ICU and all-cause mortality in the hospital.