Surfactant Worth Studying as Treatment for COVID-19–Related ARDS
The FLARE Four
- Disruption of surfactant activity is a hallmark of both respiratory distress syndrome (RDS) in neonates and acute respiratory distress syndrome (ARDS) in adults
- Surfactant administration is standard therapy in neonatal RDS and provides proof of concept for surfactant-based therapy of ARDS
- Trials of surfactant in adults have failed to identify a mortality benefit, but these negative results may reflect technical or patient selection issues
- The biologic plausibility of surfactant therapy for ARDS is strong, and prior trials do demonstrate safety and benefit in forms of ARDS driven by primary direct lung injury
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Exogenous surfactant is among the previously studied therapies for acute respiratory distress syndrome (ARDS) that have been proposed for patients with COVID-19–associated respiratory failure. In a fast literature update posted on April 26, 2020, Raghu Chivukula, MD, PhD, and Corey Hardin, MD, PhD, physician-scientists in the Division of Pulmonary and Critical Care Medicine at Massachusetts General Hospital, explain why this idea may be worth exploring.
Lessons from RDS
In neonatal respiratory distress syndrome (RDS), lack of surfactant results in increased opening pressure for affected lung units, predisposing to collapse of airspaces and the need to maintain more negative pleural pressures. These larger pressures contribute to edema and inflammation, resulting in further surfactant inactivation and progressive hypoxemic respiratory failure.
In the 1980s, dozens of trials examined various surfactant preparations for the treatment of RDS. The wealth of accumulated evidence for benefit in this pediatric context led to strong recommendations for the administration of surfactant to decrease mortality.
SARS-CoV-2, the virus responsible for COVID-19, is known to be capable of infecting type II pneumocytes, the alveolar cells responsible for the production of surfactant. Thus, there is strong biologic plausibility for the use of surfactant therapy in COVID-19–related ARDS, a disease proposed to occur primarily through alveolar injury and associated with surfactant dysfunction.
Surfactant and ARDS
ARDS shares pathophysiological and histological features with RDS, suggesting similar therapies might be of benefit in these distinct diseases. Indeed, prior trials of surfactant preparations in ARDS demonstrate safety and suggest beneficial effects on oxygenation in forms of ARDS driven by direct lung injury. However, no study (including any of three large randomized, controlled trials) has found that surfactant administration improves mortality or increases ventilator-free days. These negative results may reflect technical or patient selection issues:
- Most studies did not employ low tidal volumes, so a benefit of surfactant may have been obscured by harm associated with now-outdated ventilatory practices
- Surfactant may have failed to show benefit simply because it failed to reach its intended target in the adult lung
- The heterogeneity of ARDS as a clinical diagnosis may have masked effects of surfactant therapy in subgroups who might benefit
Clinical trials (several of which have been proposed already) will be necessary to determine whether surfactant replacement in COVID-19 ARDS may be beneficial.
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