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      Clinical trials in acute respiratory distress syndrome: challenges and opportunities.

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          Abstract

          This year is the 50th anniversary of the first description of acute respiratory distress syndrome (ARDS). Since then, much has been learned about the pathogenesis of lung injury in ARDS, with an emphasis on the mechanisms of injury to the lung endothelium and the alveolar epithelium. In terms of treatment, major progress has been made in reducing mortality from ARDS with lung-protective ventilation, using a tidal volume of 6 mL per kg of predicted bodyweight and a plateau airway pressure of less than 30 cm H2O. In more severely hypoxaemic patients with ARDS, neuromuscular blockade and prone positioning have further reduced mortality, probably by extending the therapeutic effects of lung protective ventilation. Fluid-conservative therapy has also increased ventilator-free days in patients with ARDS. The lack of success of pharmacological therapies for ARDS, however, presents a continued challenge in the field. In addition to presenting a brief summary of previous experience with clinical trials in ARDS, we focus in this Review on future opportunities to improve clinical trial design to maximise the likelihood of identifying beneficial pharmacological therapies. In view of the heterogeneity in ARDS, both prognostic and predictive enrichment strategies are needed that target therapies toward specific subgroups of patients with ARDS on the basis of both severity and biology. Approaches to reducing heterogeneity in ARDS clinical trials include using physiological, radiographic, and biological criteria to select patients for both phase 2 and 3 trials. Additionally, interest is growing in the design of preventive clinical trials in ARDS and to initiate early treatment of patients with acute lung injury before the need for endotracheal intubation. We also present promising new approaches to treating ARDS, including combination therapies, cell-based therapies, and generic pharmacological compounds with low-risk profiles that are already in routine clinical use for other clinical indications.

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          Author and article information

          Journal
          Lancet Respir Med
          The Lancet. Respiratory medicine
          Elsevier BV
          2213-2619
          2213-2600
          Jun 2017
          : 5
          : 6
          Affiliations
          [1 ] Departments of Medicine and Anesthesia and the Cardiovascular Research Institute, University of California, San Francisco, CA, USA. Electronic address: michael.matthay@ucsf.edu.
          [2 ] Centre for Experimental Medicine, Queen's University of Belfast, and Regional Intensive Care Unit, Belfast Health and Social Care Trust, Belfast, UK.
          [3 ] Department of Medicine and Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA.
          Article
          S2213-2600(17)30188-1
          10.1016/S2213-2600(17)30188-1
          28664851
          375f4ffe-ce36-4d4a-ae9f-b36fad04a380

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