Article
Villar J, Ferrando C, Martinez D, et al. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir Med. 2020;8(3):267-276.
OBJECTIVE
To determine the effect of dexamethasone on ventilator-free days and mortality in patients with ARDS.
BACKGROUND
Steroids have been hypothesized to be beneficial in ARDS due to their anti-inflammatory effects. A 2018 meta-analysis of several small randomized trials showed steroids reduced time to extubation, time of hospital stay, and mortality in patients with ARDS. The Society of Critical Care Medicine and European Society of Intensive Care Medicine have both recently incorporated recommendations for use of steroids into their guidelines. However, these trials were small, used various steroid drugs and doses, and did not examine steroids in the context of a lung-protective ventilation strategy. Dexamethasone was chosen for this study because of its larger anti-inflammatory effects with minimal mineralocorticoid effects and because of its longer half-life. This is the first randomized clinical trial to investigate use of dexamethasone in ARDS in the setting of lung protective ventilation.
POPULATION
Intubated and mechanically ventilated patients with acute onset ARDS using European Consensus Conference criteria for ARDS or Berlin criteria for moderate-to-severe ARDS. Criteria included:
- Respiratory symptoms within one week of a clinical insult, or new or worsening respiratory symptoms
- Bilateral infiltrates on imaging
- Respiratory failure not explained by cardiac failure (no left atrial hypertension, pulmonary capillary wedge pressure <18 mm Hg, or no clinical signs of left heart failure)
- Hypoxemia, defined as PaO2/FiO2 < 200 mm Hg on PEEP of 5 cm H2O
Exclusion criteria included age less than 18 years, pregnancy or active lactation, brain death, terminal disease including cancer, a DNR decision, treatment with any corticosteroids or immunosuppressants, COPD or CHF, and inclusion in any other experimental study.
The study included an enrichment strategy to increase power to detect outcome difference by further excluding any patients who did not meet the Berlin criteria for moderate-to-severe ARDS of PaO2/FiO2 < 200 mm Hg at 24 hours after ARDS onset on standardized ventilator settings of PEEP of 10 cm H2O or higher and a FiO2 of 0.5 or higher.
DESIGN
Prospective, multicentered, open-label, randomized controlled trial conducted in 17 hospitals across Spain. Randomization was stratified by hospital.
INTERVENTION
20 mg dexamethasone IV daily from day 1 to day 5, then 10 mg daily from day 6 to day 10. Treatment was continued for a maximum of 10 days or until extubation.
CONTROL
Supportive care with lung protective ventilation.
OUTCOMES MEASURED
Primary
• Ventilator-free days at 28 days after randomization. Death before 28 days was recorded as 0 ventilator-free days.
Secondary
• 60-day all-cause mortality
KEY RESULTS
The trial was stopped early by the data and safety monitoring board due to slow enrollment, after having enrolled 88% of planned patients.
Patients who received dexamethasone had significantly more ventilator free days at 28 days (12.3 days vs 7.5 days, p< 0.0001) and lower 60 day mortality (21% vs 36%, p = 0.0047). These results suggest a NNT of 7 to reduce one death at 60 days.
There was no significant increase in adverse events, including ICU hyperglycemia, new infections in the ICU, or barotrauma.
STRENGTHS
• Well-designed study
• Multi-center
• Enrichment strategy improved ability to measure patient-centered outcomes (mortality)
LIMITATIONS
• Unblinded
• Trial stopped early due to slow enrollment
• Many patients were excluded because they had already been treated with steroids
• Exclusion criteria excluded some patients with common comorbidities that may hinder external validity
EM TAKE-AWAYS
Emergency medicine physicians frequently care for mechanically ventilated patients at high risk for ARDS. The DEXA-ARDS trial provides strong evidence that dexamethasone provides a benefit in both ventilator-free days at 28 days and in 60-day mortality for patients with moderate-to-severe ARDS. The mortality benefit found in the DEXA-ARDS trial is both large (15% ARR) and notably similar to that seen in a meta-analysis of previous trials that used other steroids and did not necessarily use lung-protective ventilation. The addition of dexamethasone did not increase the incidence of adverse events, including hyperglycemia.
References
- Villar J, Ferrando C, Martinez D, et al. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir Med. 2020;8(3):267-276.
- Meduri GU, Siemieniuk RA, Ness RA, Seyler SJ. Prolonged low-dose methylprednisolone treatment is highly effective in reducing duration of mechanical ventilation and mortality in patients with ARDS. J Int Care. 2018;6:53.
- Annane D, Pastores SM, Rochwerg B, et al. Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017. Crit Care Med. 2017;45(12):2078-2088.