Efficacy of DEXamethasone in Patients With Acute Hypoxemic REspiratory Failure Caused by INfEctions

Acute hypoxemic respiratory failure (AHRF), and its more severe form termed the acute
respiratory distress syndrome (ARDS), is a catastrophic illness of multifactorial etiology
characterized by a severe inflammatory process of the lung leading to hypoxemic respiratory
failure requiring mechanical ventilation (MV). Pulmonary infections are the leading causes of
AHRF and ARDS. Translational research has established a strong association between
dysregulated systemic and pulmonary inflammation and progression or delayed resolution of
AHRF.2 Glucocorticoid receptor-mediated downregulation of systemic and pulmonary inflammation
is essential to accelerate disease resolution and restore tissue homeostasis, and can be
enhanced with glucocorticoid treatment.

The COVID-19 pandemic is a critical moment for the world, in which even industrially advanced
countries have rapidly reached intensive care units (ICUs) saturation, and intensivists are
forced to make difficult ethical decisions that are uncommon outside war zones. As with other
bacterial or viral infections, severe pneumonia is the main condition leading to AHRF and
ARDS requiring weeks of MV with high mortality (35-55%) in critically ill patients. There has
been great interest in the role of corticosteroids to attenuate the pulmonary and systemic
damage in ARDS patients because of their potent anti-inflammatory and antifibrotic
properties.3 Corticosteroids have been off patent for greater than 20 years, they are cheap,
and globally equitable. However, the efficacy of corticosteroids in AHRF (including ARDS)
caused by infections remains controversial.

Only two large randomized clinical trials (RCT) have shown that the administration of
dexamethasone is able to reduce mortality in patients with AHRF. Villar et al in Spain
observed that moderate doses of dexamethasone (10-20 mg/d x 10 days) caused a 15% absolute
reduction of 60-day mortality in patients with established moderate-to-severe ARDS from
multiple etiologies. Horby et al in the RECOVERY trial in Great Britain reported that
dexamethasone at low doses (6 mg/d x 10 days) reduced 28-day mortality in patients with AHRF
caused by COVID-19. These findings confirmed that corticosteroid therapy is associated with a
sizable reduction in duration of MV and hospital mortality. These two RCTs will change
clinical practice for the management of AHRF and ARDS. However, there is a reasonable doubt
whether dexamethasone at moderate doses (10-20 mg/d) would cause a greater reduction in
mortality than 6 mg/d. Our goal in this study is to respond this question.