DEXA-ARDS

In Review

Villar J, et al. "Dexamethasone Treatment for the Acute Respiratory Distress Syndrome: A Multicentre, Randomised Controlled Trial". Lancet Respiratory Med. 2020. 8(3):267-276.
PubMed • Full text • PDF • ClinicalTrials.gov

Clinical Question

In adult, mechanically ventilated patients with moderate to severe ARDS, does the addition of dexamethasone 20mg daily for 5 days and 10mg daily for 5 additional days improve ventilator free days at 28 days

Bottom Line

The addition of dexamethasone therapy for patients with moderate to severe ARDS within 24 hours of meeting ARDS criteria led to more ventilator free days, decreased mortality, and shorter duration of mechanical ventilation without significant increases in adverse events

Major Points

Acute respiratory distress syndrome (ARDS) is associated with a high mortality rate of almost 50% in some reports. One of the few interventions that demonstrated major improvements in mortality was a trial published in 2000, ARDSNet with a low Tidal Volume protocol of 6ml/kg. The 2010 ACURASYS trial, utilizing cisatracurium for therapeutic paralysis, also demonstrated benefit, however, the ROSE trial in 2019 did not. Glucocorticoids have been explored in the past, with several trials and meta-analysis demonstrating faster weaning from mechanical ventilation and decreases in ICU length of stay, the hard endpoint of mortality has not been as conclusive. The joint 2017 guidelines from the Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) recommend early use of steroids in moderate to severe ARDS.

DEXA-ARDS, published in March 2020 in the midst of the SARS-COv-2 pandemic but included (N=277) patients prior to the pandemic in 17 ICUs in teaching centres in Spain, randomized patients with moderate to severe ARDS to receive dexamethasone 20mg IV dialy for 5 days and then 10mg daily for 5 additional days (drug was stopped upon extubation) (n=139) compared to a control group up usual care (n=138). Overall the trial demonstrated almost 5 additional ventilator free days at 28 days (P < 0.0001). In their secondary outcomes they showed a 15% decrease in all cause mortality (P = 0.0047; NNT 7), a 13% decrease in both ICU and hospital mortality (P = 0.0166; NNT 8 and P = 0.0235; NNT 8, respectively), significantly more ventilator free days in survivors, and a more rapid resolution of SOFA scoring at Day 3. With this benefit they saw no significant increase in hyperglycemia or infections in ICU and no difference in barotrauma.

Overall this trial is congruent with the other trials that have come before it for treating ARDS, albeit with methylprednisolone as the main steroid. There are a number of side effects usually associated with glucocorticoid therapy, such as immunosuppression leading to infections, and hyperglycemia. Dexamethasone is associated with minimal minerocorticoid activity, decreasing the risks of fluid retention. There are several limitations with this trial, first is that it is unblinded but with a hard endpoint of mortality it may not be a significant impairment. Their inclusion of only moderate to severe ARDS and exclusion of common comorbidities may limit some of its external validity and applicability to a wider patient population. Finally this trial was ended early due to low recruitment. With a significant finding for benefit this may not be an issue but we may be under powered to find harms.

Guidelines

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, adapted

• Early ARDS (up to day 7 of onset; PaO2/FiO2 of < 200): methylprednisolone IV 1mg/kg/day for 14 days then slow taper over 14 days
• Late persistent ARDS (after day 6 of onset): 2mg/kg/day for 14 days, then slow taper over 14 days

As of July 2020, no guidelines have been published that reflect the results of this trial.

Design

• Multicentered, randomized, controlled trial
• N=277
  • Dexamethasone (n=139)
  • Control (n=138)
• Setting: 17 ICUs in Spain
• Enrollment: 28 March 2013, to 31 Dec 2018
• Analysis: Intention-to-treat
• Primary Outcome: ventilator free days at 28 days after randomization

Population

Inclusion Criteria

• mechanically ventilated
• acute onset of ARDS
  • defined by the American-European Consensus Conference criteria for ARDS, or
  • the Berlin criteria as moderate-to-severe ARDS

Exclusion Criteria

• pregnancy or active lactation
• brain death
• terminal-stage cancer or other disease
• do-not-resuscitate order
• current corticosteroids or immunosuppressive drugs
• treating physician felt corticosteroid treatment indicated
• enrollment in another experimental treatment protocol
• severe chronic obstructive pulmonary disease
• congestive heart failure

Baseline Characteristics

Dexamethasone Group displayed

• Demographics: mean age 56 years,
• Grouping: mean SOFA score8.7, mean days from intubation to randomization 2.1, mean days from ARDS to randomization 1, 85% Moderate ARDS (100 <PaO2/FiO2 ≤200), 15% Severe ARDS (PaO2/FiO2 ≤100)
• Physiologic parameters: mean PaO2/FiO2 142.4 mm Hg, mean Tidal volume 6.9 mL per predicted bodyweight, mean respirator rate 23 breath per minute, FiO2 64%, Positive end-expiratory pressure 12.6 cm H2O, Inspiratory plateau pressure 26.4 cm H2O, PaCO2 47.9 mm Hg, Arterial pH 7.34
• Cause of ARDS: 54% Pneumonia, 24% Sepsis, 103% Aspiration, 8% Trauma, 1% other

Interventions

• Dexamethasone 20mg IV daily for Days 1-5, then 10mg from days 6-10, drug discontinued upon extubation
• Standard of care (placebo viewed as not ethical)

Outcomes

Comparisons are Dexamethasone group vs. control group.

Primary Outcomes

Ventilator-free days at 28 days after randomization

12.3 vs. 7.5, ARR 4.8 (95% CI 2.57 to 7.03) P < 0.0001

Secondary Outcomes

All-cause mortality at day 60

21% vs. 36%, Difference –15.3% (95% CI –25.9 to –4.9) P = 0.0047; NNT 7

ICU mortality

19% vs. 31%, Difference –12.5% (95% CI –22.4 to –2.3) P = 0.0166; NNT 8

Hospital mortality

24% vs. 36%, Difference –12.5% (95% CI –22.9 to –1.7) P = 0.0235; NNT 8

Actual duration of mechanical ventilation in ICU survivors, days

14.2 days vs. 19.5 days, Difference –5.3 (95% CI –8.4 to –2.2) P = 0.0009

Actual duration of mechanical ventilation in survivors at day 60, days

14.3 days vs. 20.2 days, Difference –5.9 (95% CI –9.1 to –2.7) P = 0.0004

Adverse Events

Hyperglycaemia in ICU

76% vs. 70%, difference 5.2% (95% CI –5.2 to 15.6) P = 0.33

New infections in ICU

24% vs. 25%, difference 1.6% (95% CI –8.5 to 11.7) P = 0.75

Barotrauma

10% vs. 7%, difference 2.8% (95% CI –4.0 to 9.8) P = 0.41

Criticisms

• Patients had to have moderate-severe ARDS, unclear if benefit would been seen with more mild ARDS
• Unblinded
• Unclear definition of extubation criteria
• Recruitment stopped early due to low recruitment (~80% of planned sample) but found statistical significance for benefit, may have false finding for lack of harms
• treating physician could exclude patients if they lacked equipoise on steroid benefit
• Common comorbidities in exclusion criteria so this may affect external validity

Funding

• Fundación Mutua Madrileña, Instituto de Salud Carlos III, The European Regional Development’s Funds, Asociación Científica Pulmón y Ventilación Mecánica