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Challenges to Therapies for ARDS Related to COVID-19

The FLARE Four

  • Successful therapies for acute respiratory distress syndrome (ARDS) have focused on lung-protective ventilation, conservative fluid management and treatment of the underlying process
  • The pathogenesis of ARDS is complex and involves interactions between the insult, host immune response, coagulation cascade and pulmonary mechanics
  • Prior studied therapies for ARDS targeted the underlying pathophysiology represented by four categories: reactive oxygen species generation, the coagulation cascade, immune function and alterations in pulmonary mechanical function
  • The COVID-19 pandemic has aroused interest in novel therapies for ARDS. It is important to consider these future studies in the context of failed investigatory therapies for ARDS

A major problem in treating acute respiratory distress syndrome (ARDS) is uncertainty about which biologic processes act to eliminate a pathogen and which negatively impact the affected organ.

This helps explain why essentially all targeted therapies in ARDS have failed in the past, according to Daniel Okin, MD, PhD, fellow in Pulmonary and Critical Care Medicine at Massachusetts General Hospital. He traces the history of targeted ARDS therapies in part 1 of a fast literature assessment and review (FLARE) posted on April 3, 2020, and in part 2, posted on April 4.

Dr. Okin presents the scientific rationale for four major categories of therapies. Brief summaries of clinical evidence are included here.

Targeting Reactive Oxygen Species

Intravenous N-acetylcysteine: Six studies have evaluated whether N-acetyl cysteine (NAC) can regenerate cellular glutathione stores in ARDS, thus reducing reactive oxygen species. Five showed no improvement in mortality and the other was methodologically flawed.

Targeting oxygen saturation <95% to minimize generation of reactive oxygen species (ROS) was not associated with improved mortality in either of two large, multicenter, ARDS-specific randomized controlled trials. One of them was stopped early for potential mortality increase.

Targeting the Coagulation Cascade

Anticoagulants reduce pulmonary inflammation according to multiple in vitro studies, but in clinical trials, neither nebulized heparin nor IV heparin reduced mortality among patients with ARDS.

Tissue plasminogen activator for COVID-19 patients is not considered promising, as discussed in a previous FLARE.

Targeting Host Immune Response

Sivelestat, an investigational neutrophil elastase inhibitor, was administered to patients with acute lung injury in a multicenter RCT. The trial was stopped because of increased mortality in the experimental arm.

Statins have immunomodulatory effects independent of their effect on cholesterol. FLARE pieces posted on March 23 and March 24 discuss the mixed evidence for their use in ARDS.

Immunomodulators (e.g., interleukin-1 receptor antagonists, interferon gamma and TNF-alpha inhibitors) have been investigated in critical illnesses related to ARDS, such as septic shock. Trials showed either no benefit or increased mortality.

Targeting Altered Pulmonary Function

Intravenous salbutamol, a beta-agonist, was examined in a single-center RCT as a way to address reduced alveolar fluid clearance in ARDS. It improved plateau airway pressure but not mortality. A follow-up trial was stopped early because of increased mortality.

Surfactant replacement is highly effective for neonatal respiratory distress syndrome, but in adults with ARDS, none of eight RCTs demonstrated improvement in mortality.


These data don't imply that none of these therapies can benefit an individual patient or a subset of patients. Trials of ARDS therapies enroll patients who have a range of disease severity and variation in immune response, so signals of benefit may have gone unrecognized.

This heterogeneity also occurs in COVID-19, even though that disease is caused by a single pathogen. Mass General strongly encourages caution in the adoption of any unproven therapy in broad populations of ARDS patients.

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