Acute respiratory distress syndrome (ARDS) is associated with high rates of morbidity and mortality. The role of steroids in the treatment of ARDS is controversial, but steroid use has previously demonstrated reduction in mechanical ventilation days and intensive care unit (ICU) lengths of stay. Guidelines for the Diagnosis and Management of Critical Illness-Related Corticosteroid Insufficiency (CIRCI) in Critically Ill Patients (Part I), jointly published by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine (Annane et al. Crit Care Med. 2017;45:2078-2088), recommend the early use of steroids in moderate to severe ARDS. Meduri et al (J Intensive Care. 2018;6:53) make the case for prolonged low-dose methylprednisolone treatment in reducing mechanical ventilation duration in patients with ARDS. However, trials that have guided the use of steroids in ARDS have typically been small; larger randomized control trials of over 60 patients have not shown reduction in mortality. Many of these studies were performed before the widespread adaptation of lung-protective ventilation strategies, and none of these studies used dexamethasone as the steroid of choice.
Villar et al (Lancet Respir Med. 2020;8:267-276) attempted to demonstrate the effect of steroids in patients with moderate to severe ARDS along with modern standard ICU practice, including lung-protective mechanical ventilation. The investigators chose dexamethasone because of its increased potency and duration of action compared to prednisone or methylprednisolone. Patients were included if they had moderate to severe ARDS (defined as Pao2/Fio2 ratio ≤ 200 while on ventilator settings of positive end-expiratory pressure ≥ 10 mm Hg and Fio2 ≥ 50%) that persisted for more than 24 hours after ARDS onset to ensure an ARDS population with a high risk of mortality. Patients with terminal-stage diseases, do-not-resuscitate preferences, a diagnosis of brain death, severe chronic obstructive pulmonary disease, severe congestive heart failure, current steroid or immunosuppressant use, pregnancy, or lactation were excluded.
Patients were randomly assigned to receive either standard care or dexamethasone in addition to standard care. The study drug was unmasked. Patients received 20 mg of dexamethasone daily for the first five days of treatment followed by a reduction in dose to 10 mg daily for the next five days to a maximum of ten days of treatment. Dexamethasone was discontinued if the patient was extubated. The primary outcome was ventilator-free days on day 28 after randomization. The secondary outcome was all-cause mortality 60 days after randomization.
This study was conducted in 17 ICUs in Spain from 2013 through 2018. The groups were well matched by demographics, severity of illness, and underlying cause of ARDS, with pneumonia being the most common cause. During the study period, 1,006 patients were screened, with 630 excluded prior to randomization. The most common reason for exclusion was the use of steroids or immunosuppressants (n = 250). After randomization, 70 patients were excluded because they no longer met the definition of moderate to severe ARDS. Ultimately, only 277 patients were enrolled (88% of the planned sample size) due to slow recruitment. The vast majority of patients met the definition for moderate, rather than severe, ARDS (n = 239).
The group that received dexamethasone had more ventilator-free days, averaging 12.5 days compared to 7.5 days in the control group (p < 0.0001). For the end point of all-cause mortality at 60 days, 21% of patients in the intervention group died compared to 36% in the control group (p = 0.0047). There was no difference in mortality across enrollment sites. Of the 19 patients who had extubation failure (12 in the control group and 7 in the dexamethasone group), there was no difference in ventilator-free days or mortality. When comparing the use of paralytics, prone positioning, recruitment maneuvers, or extracorporeal membrane oxygenation as part of routine ICU care, only prone positioning was more common in the control group. Adverse events of hyperglycemia, new ICU infections, and barotrauma were similar in both groups.
This trial was well designed to ensure that only patients with established ARDS were included. However, this was essentially a study of the effect of dexamethasone on moderately severe ARDS, since only 13% of the patients met the threshold for severe ARDS. The study was multicentered and enrollments were reasonably well spread throughout the various sites without large variations in mortality, which indicates that standard ICU care was consistent among sites. A major weakness of this trial was the strict inclusion criteria, which screened out many patients with chronic illnesses. Additionally, previous studies have shown the efficacy of steroids in the reduction of ventilator days in severe pneumonia (Annane et al. N Engl J Med. 2018;378:809-818). Since most of the patients in the trial had ARDS due to pneumonia, it is conceivable that a portion of the observed benefit is due to the previously established benefit of steroids in severe pneumonia. The trial was stopped early due to slow recruitment, which may have altered the results.
While the results of this trial have significant limitations, dexamethasone may be of benefit when used in conjunction with standard ICU care. Further studies that confirm the optimal duration, dose, and effect of dexamethasone use in the treatment of severe ARDS will be helpful. ARDS has many different underlying causes, so further studies confirming the effects of dexamethasone in different etiologies of ARDS will also be helpful.
Prior studies looking at the use of steroids in Middle East respiratory syndrome and severe acute respiratory syndrome did not show mortality benefit and showed possible harm (delayed viral clearance) (Stockman et al. PLoS Med. 2006;3:e343; Arabi et al. Am J Respir Crit Care Med. 2018;197:757-767). The World Health Organization (January 28, 2020) at this time does not recommend systemic steroids for COVID-19 ARDS unless they are indicated for another reason.
Coauthors of this installment of Concise Critical Appraisal:
Alexander Bracey, MD, is a clinical instructor in emergency medicine and an advanced resuscitation fellow in the Department of Emergency Medicine at Stony Brook Medicine.
Brian J. Wright, MD, MPH, is a clinical assistant professor and the program director for the Advanced Resuscitation Training Program in the Department of Emergency Medicine at Stony Brook Medicine. Dr. Wright is an editor of Concise Critical Appraisal.