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

https://doi.org/10.1016/S2213-2600(19)30417-5Get rights and content

Summary

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.

Introduction

Acute respiratory distress syndrome (ARDS) is an intense inflammatory process of the lungs in response to acute pulmonary and systemic insults. Clinically, this heterogeneous syndrome is characterised by acute hypoxaemic respiratory failure and bilateral pulmonary infiltrates on chest x-ray.1 Lung-protective mechanical ventilation using a tidal volume of 4–8 mL/kg predicted bodyweight and limiting end-inspiratory plateau pressure below 30 cm H2O is the standard method for ventilating patients' lungs with ARDS.2

There are no proven effective, specific pharmacological therapies for ARDS based on the results of randomised clinical trials. Several drugs, including nitric oxide, heparin, active protein C, ketoconazole, ibuprofen, and antioxidants have been investigated, but none have been shown to improve patient outcome.3 There has been great interest in the role of corticosteroids to attenuate the pulmonary and systemic damage in patients with ARDS because of their potent anti-inflammatory and antifibrotic properties.4 Different regimens of corticosteroids have been tested in ARDS with inconclusive results.5, 6, 7, 8 Recent guidelines by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine have made a conditional recommendation for glucocorticoids based on evidence of moderate quality from a meta-analysis of nine randomised controlled trials in patients with ARDS.9 Despite no conclusive results, it remains clinically and biologically plausible that corticosteroids might benefit patients with ARDS in the early phase of their disease process, a situation that has not been evaluated in most randomised controlled trials. Paradoxically, these hormones are given to patients with septic shock and pneumonia, both causes of ARDS.7, 10 Of note, most randomised controlled trials testing the efficacy of corticosteroids in ARDS were done in ventilated patients using non-protective mechanical ventilation. It remains uncertain whether corticosteroids in established ARDS, when combined with lung-protective mechanical ventilation, offers a survival benefit.

Research in context

Evidence before this study

There is no proven specific pharmacological treatment for patients with the acute respiratory distress syndrome (ARDS). A meta-analysis of nine small randomised clinical trials investigating prolonged corticosteroid (methylprednisolone or hydrocortisone) treatment in early and late ARDS reported, with consistency, a significant reduction in markers of inflammation, improvement in gas exchange, reduction of duration of mechanical ventilation, and reduction in length of stay in the intensive care unit. However, the aggregate data of these randomised trials provided insufficient evidence for a mortality benefit. A large confirmatory trial was needed. We searched the PubMed and Web of Science databases for all randomised trials describing the effects of dexamethasone as adjunctive therapy for mechanically ventilated patients with the ARDS. We used the search terms “acute respiratory distress syndrome”, OR “adult respiratory distress syndrome”, OR “acute lung injury”, OR “ARDS” AND “dexamethasone” OR “randomized” OR “randomized controlled trial” OR “clinical trials” OR “trials”. We also added “humans” and “NOT infant” for a second search field. No language restrictions were applied. The last search was done in April 23, 2019. No published trials with dexamethasone in ARDS were identified.

Added value of this study

To our knowledge, this is the first randomised clinical trial testing the efficacy of dexamethasone in patients with established ARDS. Our study shows that starting treatment with intravenous dexamethasone at 24 h of ARDS onset for a maximum of 10 days, or until mechanical ventilation and extubation (if occurring before day 10 after randomisation) is not needed, is associated with a substantial reduction in duration of mechanical ventilation and all-cause 60-day mortality in patients with established moderate-to-severe ARDS ventilated with lung-protective mechanical ventilation.

Implications of all the available evidence

Despite the substantial heterogeneity of clinical conditions associated with ARDS in our study, our findings support the notion that early therapy with dexamethasone could change the systemic immune responses and thereby could reduce the duration of mechanical ventilation and the overall mortality in patients with established moderate-to-severe ARDS.

Dexamethasone has never been evaluated in a randomised controlled trial in patients with ARDS, despite it having potent anti-inflammatory and weak mineralocorticoid effects compared with other corticoids.10 Dexamethasone is 20–30 times more potent than the naturally occurring hormone cortisol, and 4–5 times more potent than prednisone.4 Dexamethasone has pharmacological effects that are long lasting, allowing for a regimen of one dose per day.10 The benefits of the addition of dexamethasone to supportive treatment are unknown in patients with ARDS. We postulated that early adjunctive treatment with intravenous dexamethasone in patients with established moderate-to-severe ARDS might attenuate the pulmonary and systemic inflammatory responses, and thereby might decrease both duration of mechanical ventilation and all-cause mortality.

Section snippets

Study design and patients

This trial was an investigator-initiated, multicentre, randomised controlled trial done in a network of 17 intensive care units (ICUs) in teaching hospitals across Spain (appendix p 4). Eligible patients were aged 18 years or older; intubated and mechanically ventilated; had acute onset of ARDS, as defined by the American-European Consensus Conference criteria for ARDS,11 or by the Berlin criteria as moderate-to-severe ARDS,12 which includes having an initiating clinical condition (eg,

Results

Between March 28, 2013, to Dec 31, 2018, we enrolled 277 patients and randomly assigned 139 patients to the dexamethasone group and 138 patients to the control group (figure 1). The trial was stopped following recommendations by the data and safety monitoring board due to low enrolment numbers (appendix p 14), after enrolling more than 88% (277/314) of the planned sample size (appendix p 11). Patients were most commonly excluded at the time of ARDS diagnosis due to receiving corticosteroids or

Discussion

To our knowledge, this is the first randomised trial testing the efficacy of dexamethasone in patients with ARDS and investigating prolonged corticosteroid treatment in patients with ARDS receiving lung-protective mechanical ventilation. In patients with established moderate-to-severe ARDS administered intravenous dexamethasone, we observed a reduction in the number ventilator-free days of more than 4 days and a 15% increase in the 60-day survival compared with patients in the control group.

We

Data sharing

All data needed to evaluate the conclusions in this Article are present and tabulated in the main text or the appendix. This article is the result of an original randomised controlled trial in patients with established moderate-to-severe ARDS. For individual de-identified raw data that underlie the results reported in this article, please contact the corresponding author.

References (48)

  • D Annane et al.

    Effect of low doses of corticosteroids in septic shock patients with or without early acute respiratory distress syndrome

    Crit Care Med

    (2006)
  • D Annane et al.

    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

    Crit Care Med

    (2017)
  • GR Bernard et al.

    The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination

    Am J Respir Crit Care Med

    (1994)
  • VM Ranieri et al.

    Acute respiratory distress syndrome: the Berlin Definition

    JAMA

    (2012)
  • Enrichment strategies for clinical trials to support determination of effectiveness of human drugs and biological products. Guidance for industry

  • N Yehya et al.

    Re-appraisal of ventilator-free days in critical care research

    Am J Respir Crit Care Med

    (2019)
  • C Guérin et al.

    Prone positioning in severe acute respiratory distress syndrome

    N Engl J Med

    (2013)
  • Early neuromuscular blockade in the acute respiratory distress syndrome

    N Engl J Med

    (2019)
  • J Villar et al.

    Evaluating the efficacy of dexamethasone in the treatment of patients with persistent acute respiratory distress syndrome: study protocol for a randomized controlled trial

    Trials

    (2016)
  • J Villar et al.

    An early PEEP/FIO2 trial identifies different degrees of lung injury in patients with acute respiratory distress syndrome

    Am J Respir Crit Care Med

    (2007)
  • World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects

    JAMA

    (2013)
  • É Azoulay et al.

    Dexamethasone in patients with acute lung injury from acute monocytic leukaemia

    Eur Respir J

    (2012)
  • L Papazian et al.

    A contributive result of open-lung biopsy improves survival in acute respiratory distress syndrome patients

    Crit Care Med

    (2007)
  • JL Vincent et al.

    The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the working group on sepsis-related problems of the european society of intensive care medicine

    Intensive Care Med

    (1996)
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    Full list of investigators of the DEXA-ARDS Network is in the appendix

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