DEXA-ARDS: Dexamethasone in Moderate to Severe ARDS (2020)

“In patients with moderate-to-severe ARDS, treatment with dexamethasone led to an increase in the number of ventilator-free days and a decrease in all-cause mortality.”

  • The DEXA-ARDS Network Investigators

1. Publication Details

  • Trial Title: Dexamethasone in patients with moderate-to-severe acute respiratory distress syndrome and severe COVID-19: a randomised controlled trial
  • Citation: Villar J, Ferrando C, Martínez D, et al. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir Med. 2020;8(3):267-276. DOI: 10.1016/S2213-2600(19)30417-5
  • Published: March 2020, in The Lancet Respiratory Medicine
  • Author: Jesús Villar, M.D., Ph.D.
  • Funding: Instituto de Salud Carlos III, Spain.

2. Keywords

  • ARDS, Corticosteroids, Dexamethasone, Mechanical Ventilation, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with moderate to severe ARDS (Population), does treatment with intravenous dexamethasone (Intervention) compared to standard care without corticosteroids (Comparison) increase the number of ventilator-free days at 28 days (Outcome)?

4. Background and Rationale

  • Existing Knowledge: The use of corticosteroids in ARDS was a long-standing controversy. While they have potent anti-inflammatory effects that could theoretically mitigate the lung injury in ARDS, previous trials had yielded conflicting results, and there were concerns about side effects like hyperglycemia and secondary infections.
  • Knowledge Gap: A definitive, adequately powered randomized controlled trial was needed to clarify whether corticosteroids, specifically the long-acting and potent glucocorticoid dexamethasone, provided a net benefit in patients with established moderate to severe ARDS.
  • Proposed Hypothesis: The authors hypothesized that treatment with dexamethasone, initiated early in the course of moderate to severe ARDS, would be superior to standard care in increasing the number of ventilator-free days.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, open-label, controlled trial (used to test the effectiveness of interventions).
  • Setting: 17 intensive care units (ICUs) in a university hospital network in Spain.
  • Trial Period: Enrollment ran from April 2013 to December 2018.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) with moderate to severe ARDS (PaO2:FiO2 ratio < 200) who had been on mechanical ventilation for less than 48 hours.
    • Exclusion Criteria: Included contraindications to corticosteroids, brain death, and a decision to withhold life-sustaining treatment.
  • Intervention: Patients received intravenous dexamethasone (20 mg once daily for 5 days, then 10 mg once daily for 5 days).
  • Control: Patients received standard care without corticosteroids.
  • Management Common to Both Groups: All patients were managed with a standardized lung-protective ventilation strategy and other supportive care according to best practices.
  • Power and Sample Size: The authors calculated that a sample size of 314 patients would be required to have 90% power to detect a 3-day difference in ventilator-free days. (Power is a study’s ability to find a real difference between treatments if one truly exists; 90% power means the study had a 90% chance of detecting the specified effect, which is considered very high).
  • Outcomes:
    • Primary Outcome: The number of ventilator-free days at 28 days.
    • Secondary Outcomes: Included all-cause mortality at 60 days.

6. Key Results

  • Enrollment and Baseline: 277 patients were randomized (139 to dexamethasone and 138 to control). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: Patients in the dexamethasone group had a significantly higher number of ventilator-free days: a mean of 11.0 days in the dexamethasone group vs. 6.5 days in the control group (p<0.0001).
  • Secondary Outcomes: 60-day all-cause mortality was significantly lower in the dexamethasone group: 29 of 139 patients (21%) died, compared with 49 of 138 patients (36%) in the control group (p=0.0047).
  • Adverse Events: The incidence of adverse events was similar in both groups. There was no significant increase in the rate of secondary infections in the dexamethasone group. Hyperglycemia was more common in the dexamethasone group.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a t-test. Mortality was analyzed with a log-rank test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the mean number of ventilator-free days between the two groups.
  • Key Statistic(s) Reported: The key statistics were the mean ventilator-free days and the absolute mortality rates, with their associated P-values.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of <0.0001 for the primary outcome and 0.0047 for 60-day mortality are both well below the 0.05 threshold, indicating that the observed benefits are highly statistically significant and very unlikely to be due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures (for 60-day mortality):
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group)
      • Calculation: ARR = 36% – 21% = 15%.
      • Clinical Meaning: For every 100 patients with moderate-to-severe ARDS treated with this dexamethasone regimen, about 15 additional deaths were prevented at 60 days.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR
      • Calculation: NNT = 1 / 0.15 = 6.7, which is rounded up to 7.
      • Clinical Meaning: You would need to treat only 7 patients with this dexamethasone regimen to prevent one additional death.
  • Subgroup Analyses: The benefit of dexamethasone was consistent across all pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, controlled design provided high-quality evidence on an important clinical question.
  • Generalizability: The inclusion of 17 diverse ICUs increases the applicability of the findings.
  • Statistical Power: The study was adequately powered for its primary outcome and found a large, significant effect.
  • Patient-Centered Outcomes: The study focused on both ventilator-free days and mortality, which are robust and patient-centered endpoints.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was open-label (unblinded), which is a significant limitation that introduces a risk of performance bias, as clinicians’ knowledge of the intervention could have influenced their decisions about co-interventions or weaning.
  • External Validity (Generalizability): The study was conducted in a single country (Spain), and the results may not be fully generalizable to all healthcare systems. The study was conducted before the COVID-19 pandemic, and its findings are specific to non-viral ARDS.
  • Other: The dose of dexamethasone used (20mg/day) is higher than the 6mg/day dose later proven effective in the RECOVERY trial for COVID-19.

10. Conclusion of the Authors

  • In patients with moderate-to-severe ARDS, treatment with dexamethasone led to a significant increase in the number of ventilator-free days and a significant reduction in all-cause mortality at 60 days.

11. To Summarize

  • Impact on Current Practice: This was a landmark trial that provided strong, positive evidence for the use of corticosteroids in non-COVID ARDS, helping to resolve decades of clinical uncertainty. It was highly influential in shaping the early treatment strategies for the COVID-19 pandemic.
  • Specific Recommendations:
    • Patient Selection: For adult patients with moderate to severe ARDS (PaO2:FiO2 < 200) within 48 hours of onset.
    • Actionable Intervention: Administer intravenous dexamethasone for 10 days.
    • Expected Benefit: This intervention can be expected to reduce the duration of mechanical ventilation and prevent approximately one death for every 7 patients treated.
  • What This Trial Does NOT Mean: This trial does NOT mean that steroids are beneficial for mild ARDS, nor does it apply to patients with viral pneumonias where steroids could be harmful (though this was later disproven for COVID-19).
  • Implementation Caveats: Clinicians should be prepared to actively manage hyperglycemia, a common and expected side effect of this treatment.

12. Context and Related Studies

  • Building on Previous Evidence: The DEXA-ARDS trial (2020) was designed to provide a more definitive answer to the question of steroids in ARDS, following many smaller and conflicting earlier studies.
  • Influence on Subsequent Research: The definitive positive result of this trial, published just as the COVID-19 pandemic was beginning, provided a strong rationale for testing corticosteroids in COVID-19 ARDS, which was subsequently confirmed in the landmark RECOVERY trial (2020).

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The optimal dose and duration of corticosteroid therapy in different phenotypes of ARDS remain areas of investigation.
  • Future Directions: Future research is focused on identifying which specific patients with ARDS (e.g., those with a hyper-inflammatory phenotype) are most likely to benefit from corticosteroid therapy.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a common and deadly condition with a controversial but widely available therapy.
  • Methods: The multicenter RCT design was appropriate and robust. The main methodological weakness is the open-label design, which introduces a risk of performance bias. However, the primary outcome (ventilator-free days) is relatively objective, which mitigates this concern.
  • Results: The study reported a large and both statistically and clinically significant benefit for its primary outcome and for the key secondary outcome of mortality (NNT of 7). The findings were consistent and robust.
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair reflection of the data. The high external validity of this pragmatic trial means its findings are broadly applicable to the care of ICU patients with moderate to severe non-viral ARDS.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
Scroll to Top