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Dexamethasone In Acute Respiratory Distress Syndrome: A Successful Story

No proven effectivepharmacological therapies for the acute respiratory distress syndrome (ARDS) based on the results of randomized clinical trials (RCTs) had been reported until the publication in 2020 of DEXA-ARDS1 and RECOVERY2 trials, testing the effects of dexamethasone in patients with established ARDS and in hospitalized patients with COVID-19, respectively. Paradoxically, the anti-inflammatory and antifibrotic effects of dexamethasone had been tested successfully in hospitalized patients with bacterial meningitis, community-acquired pneumonia, and chemotherapy-induced lung injury, but never evaluated in a randomized trial in patients with ARDS or with severe acute hypoxemic respiratory failure. Dexamethasone is 20-30 times more potent than the naturally occurring hormone cortisol, and 4-5 times more potent than prednisone. Dexamethasone has pharmacological effects that are long lasting, allowing for a regimen of one dose per day. In the DEXA-ARDS trial (published in February 2020)1, 277 mechanically ventilated patients with established moderate-to-severe ARDS from multiple etiologies were randomized within 24 h of diagnosis to receive conventional treatment or conventional treatment plus intravenous dexamethasone for 10 days (20 mg/day during the first 5 days followed by 10 mg/day from day 6 to day 10). Patients in the dexamethasone group had a greater mean number of ventilator-free days (between-groups difference 4.8 days, p<0.001) and lower 60-day mortality (between-groups difference 15.3%, p<0.005) than patients in the control group. These findings suggested that early therapy with dexamethasone could change the pulmonary and systemic immune responses, and thereby could reduce the duration of mechanical ventilation and overall mortality. In the RECOVERY trial (release of results on June 16, 2020)2, 6425 hospitalized patients with coronavirus disease 2019 (COVID-19) were randomized to 6 mg/day of dexamethasone for 10 days or usual care. Overall, dexamethasone resulted in an absolute reduction in 28-day mortality of 2.8% (22.9% vs. 25.7%). The benefit was greatest for 1007 patients who were receiving invasive mechanical ventilation at the time of randomization with an overall mortality of 29.3% for dexamethasone vs. 41.4% for usual care (an absolute risk of death reduction by 12.1%). The signal seen in this trial led to all ongoing RCTs of corticosteroids in COVID-19 to suspend enrollment. Although there are no data on ARDS in the RECOVERY trial, is plausible that most intubated patients had acute hypoxemic respiratory failure and that a significant proportion of patients met criteria for ARDS. A prospective meta-analysis3that pooled data from 7 RCTs conducted in 12 countries in critically ill patients with COVID-19 (including the RECOVERY trial), evaluated the efficacy of systemic corticosteroids (dexamethasone, hydrocortisone, or methylprednisolone) in 1703 patients. In that prospective meta-analysis, the administration of corticosteroids, compared with usual care or placebo, was associated with lower 28-day all-cause mortality. Although there are many questions about the determinants of efficacy of corticosteroids in ARDS, all these trials results from diverse clinical and geographic settings suggest that in the absence of compelling contraindications, a corticosteroid regimen could serve both to reduce mortality and mitigate the burden on health care for ventilated ARDS patients, with or without COVID-19.