Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial.

BACKGROUND: There is no proven specific pharmacological treatment for patients with the acute respiratory distress syndrome (ARDS). The efficacy of corticosteroids in ARDS remains controversial. We aimed to assess the effects of dexamethasone in ARDS, which might change pulmonary and systemic inflammation and result in a decrease in duration of mechanical ventilation and mortality. METHODS: We did a multicentre, randomised controlled trial in a network of 17 intensive care units (ICUs) in teaching hospitals across Spain in patients with established moderate-to-severe ARDS (defined by a ratio of partial pressure of arterial oxygen to the fraction of inspired oxygen of 200 mm Hg or less assessed with a positive end-expiratory pressure of 10 cm H2O or more and FiO2 of 0·5 or more at 24 h after ARDS onset). Patients with brain death, terminal-stage disease, or receiving corticosteroids or immunosuppressive drugs were excluded. Eligible patients were randomly assigned based on balanced treatment assignments with a computerised randomisation allocation sequence using blocks of 10 opaque, sealed envelopes to receive immediate treatment with dexamethasone or continued routine intensive care (control group). Patients in the dexamethasone group received an intravenous dose of 20 mg once daily from day 1 to day 5, which was reduced to 10 mg once daily from day 6 to day 10. Patients in both groups were ventilated with lung-protective mechanical ventilation. Allocation concealment was maintained at all sites during the trial. Primary outcome was the number of ventilator-free days at 28 days, defined as the number of days alive and free from mechanical ventilation from day of randomisation to day 28. Secondary outcome was all-cause mortality 60 days after randomisation. All analyses were done according to the intention-to-treat principle. This study is registered with ClinicalTrials.gov, NCT01731795. FINDINGS: Between March 28, 2013, and Dec 31, 2018, we enrolled 277 patients and randomly assigned 139 patients to the dexamethasone group and 138 to the control group. The trial was stopped by the data safety monitoring board due to low enrolment rate after enrolling more than 88% (277/314) of the planned sample size. The mean number of ventilator-free days was higher in the dexamethasone group than in the control group (between-group difference 4·8 days [95% CI 2·57 to 7·03]; p<0·0001). At 60 days, 29 (21%) patients in the dexamethasone group and 50 (36%) patients in the control group had died (between-group difference -15·3% [-25·9 to -4·9]; p=0·0047). The proportion of adverse events did not differ significantly between the dexamethasone group and control group. The most common adverse events were hyperglycaemia in the ICU (105 [76%] patients in the dexamethasone group vs 97 [70%] patients in the control group), new infections in the ICU (eg, pneumonia or sepsis; 33 [24%] vs 35 [25%]), and barotrauma (14 [10%] vs 10 [7%]). INTERPRETATION: Early administration of dexamethasone could reduce duration of mechanical ventilation and overall mortality in patients with established moderate-to-severe ARDS. FUNDING: Fundación Mutua Madrileña, Instituto de Salud Carlos III, The European Regional Development's Funds, Asociación Científica Pulmón y Ventilación Mecánica.

Is Overall Mortality the Right Composite Endpoint in Clinical Trials of Acute Respiratory Distress Syndrome?

OBJECTIVES: Overall mortality in patients with acute respiratory distress syndrome is a composite endpoint because it includes death from multiple causes. In most acute respiratory distress syndrome trials, it is unknown whether reported deaths are due to acute respiratory distress syndrome or the underlying disease, unrelated to the specific intervention tested. We investigated the causes of death after contracting acute respiratory distress syndrome in a large cohort. DESIGN: A secondary analysis from three prospective, multicenter, observational studies. SETTING: A network of multidisciplinary ICUs. PATIENTS: We studied 778 patients with moderate-to-severe acute respiratory distress syndrome treated with lung-protective ventilation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We examined death in the ICU from individual causes. Overall ICU mortality was 38.8% (95% CI, 35.4-42.3). Causes of acute respiratory distress syndrome modified the risk of death. Twenty-three percent of deaths occurred from refractory hypoxemia due to nonresolving acute respiratory distress syndrome. Most patients died from causes unrelated to acute respiratory distress syndrome: 48.7% of nonsurvivors died from multisystem organ failure, and cancer or brain injury was involved in 37.1% of deaths. When quantifying the true burden of acute respiratory distress syndrome outcome, we identified 506 patients (65.0%) with one or more exclusion criteria for enrollment into current interventional trials. Overall ICU mortality of the "trial cohort" (21.3%) was markedly lower than the parent cohort (relative risk, 0.55; 95% CI, 0.43-0.70; p < 0.000001). CONCLUSIONS: Most deaths in acute respiratory distress syndrome patients are not directly related to lung damage but to extrapulmonary multisystem organ failure. It would be challenging to prove that specific lung-directed therapies have an effect on overall survival.

Noninvasive ventilation in acute hypercapnic respiratory failure caused by obesity hypoventilation syndrome and chronic obstructive pulmonary disease.

RATIONALE: Noninvasive ventilation (NIV) is widely used in episodes of acute hypercapnic respiratory failure (AHRF) in patients with chronic obstructive pulmonary disease (COPD). However, there is no evidence on the efficacy of NIV during similar episodes in obesity hypoventilation syndrome (OHS). OBJECTIVES: To compare the efficacy of NIV in episodes of AHRF caused by OHS and COPD. METHODS: We prospectively assessed 716 consecutive patients (173 with OHS and 543 with COPD) with AHRF (arterial pH < 7.35 and Pa(CO(2)) > 45 mm Hg) treated with a similar protocol of NIV. We defined successful NIV as avoidance of intubation and intensive care unit survival at least 24 hours in the ward. Hospital survivors were followed for 1 year to assess hospital readmission and survival. MEASUREMENTS AND MAIN RESULTS: Both groups had similar (mean ± SD) baseline respiratory acidosis (arterial pH, 7.22 ± 0.08; Pa(CO(2)), 86 ± 21 mm Hg). Patients with OHS were older (74 ± 11 vs. 71 ± 10 yr; P < 0.001); were more frequently female (134, 77% vs. 66, 12%; P < 0.001); had less late NIV failure (12, 7% vs. 67, 13%; P = 0.037); had lower hospital mortality (10, 6% vs. 96, 18%; P < 0.001); and had higher 1-year survival (odds ratio, 1.83; 95% confidence interval, 1.24-2.69; P = 0.002). However, survival adjusted for confounders (adjusted odds ratio, 1.41; 95% confidence interval, 0.70-2.83; P = 0.34), NIV failure (11, 6% vs. 59, 11%; P = 0.11), length of stay, and hospital readmission were similar in both groups. Among patients with COPD, obesity was associated with less late NIV failure and hospital readmission. CONCLUSIONS: Patients with OHS can be treated with NIV during an episode of AHRF with similar efficacy and better outcomes than patients with COPD.