Corticosteroids in ARDS
Acute respiratory distress syndrome (ARDS) is an acute diffuse, inflammatory lung injury, leading to capillary leak and loss of aerated lung tissue. While there are many etiologies of ARDS, the most common predisposing diseases are pneumonia, sepsis, aspiration, acute pancreatitis and trauma. ARDS was defined by the American-European Consensus Conference (AECC) in 1994 as a process of non-hydrostatic pulmonary edema causing hypoxemia. In 2011, an international panel developed the consensus Berlin Definition stipulating three mutually exclusive categories of ARDS based on severity of hypoxemia, including mild (PaO2/FiO2 ratio 200-300 mm Hg), moderate (PaO2/FiO2 100-200 mm Hg) and severe (PaO2/FiO2 < 100 mm Hg). Stratifying ARDS by degree of hypoxemia not only informs prognosis, but also guides research on therapeutic interventions. Several drugs have been investigated in patients with ARDS, including epoprostenol, nitric oxide, statins, and methylprednisolone, but have not improved survival. The ACURASYS trial showed that early administration of neuromuscular blockade reduced mortality in patients with severe ARDS; however, the ROSE trial performed nearly a decade later showed no survival benefit and was stopped early for futility.
Meduri et al. performed an RCT demonstrating that methylprednisolone was associated with a reduction in lung injury score and duration of mechanical ventilation. While not powered to evaluate mortality, this trial raised interest in the use of corticosteroid to mitigate inflammatory lung injury. The 2017 Guidelines from the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM) recommend steroids for treatment of ARDS based on a meta-analysis of nine randomized controlled trials demonstrating reduction in markers of inflammation and duration of mechanical ventilation, although many of the trials had a small sample size and some were performed without lung protective ventilation. Sepsis is a common predisposing illness for development of ARDS. Interestingly, two RCTs have showed benefit for septic shock patients treated with corticosteroids in the absence of ARDS: the ADRENAL trial demonstrated decreased ventilator days and the APROCCHSS trial showed lower mortality for septic shock patients treated with hydrocortisone and fludrocortisone.
Dexamethasone is a more potent anti-inflammatory than other corticosteroids and has less mineralocorticoid effects, yet has never previously been evaluated in a randomized controlled trial of ARDS patients. In March 2020, the Lancet published the DEXA-ARDS multicenter randomized controlled trial performed by Villar et al. investigating the impact of dexamethasone on survival and duration of mechanical ventilation in patients with moderate to severe ARDS (PaO2/FiO2 < 200).
The DEXA-ARDS trial was performed in 17 intensive care units across Spain. The investigators enrolled 277 patients that were 18 years or older and met the Berlin definition for moderate to severe ARDS after 24 hours of onset. Over 75 percent of subjects had underlying pneumonia or sepsis as a cause of their ARDS. Patients in the treatment arm received conventional treatment plus dexamethasone 20 mg IV once daily from days 1 through 5, followed by 10 mg once daily for days 6 through 10. If extubation occurred prior to day 10, the last dose of dexamethasone was given prior to extubation. Patients in the control group were randomized to receive conventional care; there was no placebo used in the control group. Both groups received lung protective ventilation and routine supportive critical care at the discretion of the treating physician. Neuromuscular blocking drugs and recruitment maneuvers were similar between groups. Prone positioning was required more frequently in the control group. The trial was stopped early at 88% of the target number due to slow enrollment. For the primary outcome, a greater mean number of ventilator-free days was observed in the dexamethasone group compared to the control group (12.3 vs 7.5), [95% CI (2.57 to 7.03)]; p <0.0001. All-cause mortality at day 60 was also lower in the dexamethasone group compared to the control group (21% vs 36%), [95% CI (-25.9 to -4.9)]; p=0.0047.
DEXA-ARDS is the largest randomized control trial of corticosteroid therapy for moderate to severe ARDS. It is a well-performed trial showing that dexamethasone increased ventilator-free days by greater than 4 days and survival by 15 percent in moderate to severe ARDS. A limitation to the study was that it was not blinded as no placebo was administered. However, there were no significant difference in adverse events between groups and the most common adverse event was hyperglycemia in the dexamethasone group. There were no increase in infectious complications in the dexamethasone group. Additionally, what sets this trial apart from many previous trials is the use of lung protective ventilation and the choice of dexamethasone as the corticosteroid. The lack of mineralocorticoid effect of dexamethasone suggests that it would cause less sodium and water retention, which is ideal for ARDS patients where it is crucial to limit extravascular lung water. Earlier trials of corticosteroids in ARDS were limited by lack of low tidal volume ventilation and more complicated steroid regimens. The DEXA-ARDS protocol for dexamethasone is dose-equivalent to Meduri and colleagues without the complicated taper. Further study of dexamethasone in ARDS should be pursued, but the DEXA-ARDS trial is strong evidence that dexamethasone could improve survival and reduce duration of mechanical ventilation in ARDS patients.
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Villar, J., Ferrando, C., et al. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. The Lancet Respiratory Medicine 2020;8(3):267-276. https://dx.doi.org/10.1016/s2213-2600(19)30417-5
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