January 12, 2016/Pulmonary/Clinical Trial

Surfactant Replacement Therapy in ARDS

A rationale for future optimism

Surfactant Replacement Therapy in ARDS

By R. Duncan Hite, MD


Cleveland Clinic is a non-profit academic medical center. Advertising on our site helps support our mission. We do not endorse non-Cleveland Clinic products or services. Policy

In the United States, acute respiratory distress syndrome (ARDS) affects over 250,000 persons per year, leading to death in up to 40 percent of cases. With age as a risk factor for ARDS, patient numbers will increase as the U.S. population ages.

ARDS impact

Survivors encounter prolonged ICU stays on mechanical ventilation and decreased quality of life, while substantial costs impact the individual and the healthcare system. A wide variety of common acute conditions (infection, trauma, transfusions and more) serve as triggers, contribute to the complexity and severity, and influence response to treatment approaches.

Surfactant replacement therapy

Surfactant degradation, inhibition and inactivation is a well-characterized and physiologically important contributor to the pathogenesis of ARDS. Premature newborns (born prior to 32 weeks’ gestation) are at high risk of developing neonatal respiratory distress (nRDS). Over two decades, surfactant replacement therapy (SRT) became a standard component in the care of infants with nRDS, leading to dramatic reductions in infant mortality rates.

The success of SRT in nRDS led both clinicians and researchers to enthusiastically pursue the potential benefits of SRT for ARDS in adults and children. Unfortunately, multiple large multicenter clinical trials with SRT failed to demonstrate improved clinical outcomes, and dampened interest in and support for continued investigation into this therapeutic approach.

Interestingly, several SRT trials reported transient improvements in oxygenation and lung function, which were not sustained after completion of SRT. These observations very likely reflect the impact of degradation of the exogenous SRT via the same mechanisms that resulted in injury of the patient’s endogenous surfactant.

Enhancing SRT approaches

Our research team demonstrated that secretory phospholipases A2 (sPLA2s) hydrolyze surfactant phospholipids and serve as a potent mechanism for surfactant degradation in patients with ARDS, including early and late disease stages. In particular, the Group IIA sPLA2 (PLA2G2A) isoform is increased in the BAL fluid of patients with ARDS and correlates with depletion of phosphatidylglycerol (PG), an anionic phospholipid that contributes a critically important biophysical interaction with surfactant protein B (SP-B). This work also demonstrated that PLA2G2A hydrolyzes alveolar phospholipids at both the air-liquid interface and aqueous subphase, and that hydrophobic surfactant proteins (SP-B and SP-C) protect surfactant from hydrolysis by sPLA2.

hydrolysis of surfactant phospholipid

These data suggest that revised approaches to SRT — that anticipate and account for the kinetics of surfactant degradation, including sPLA2 inhibition and/or uniquely designed surfactant preparations (emphasizing PG and surfactant proteins) — may provide important enhancements that improve on the results of prior clinical trials.


In pursuit of that ambition, our current efforts have focused on animal models of ARDS that can fully characterize the time course for surfactant degradation and dysfunction, including changes in PLA2G2A, PG and SP-B. Using these results, novel SRT approaches that reduce ARDS severity and accelerate ARDS resolution are being developed and will be utilized in future Phase I/II clinical trials.

It is not surprising that the negative results of multicenter SRT trials led to pessimism for many. Despite those deterrents, our optimism persists due to the firm original theory behind SRT and development of novel approaches that seek to revise and refine SRT through an enhanced understanding of SRT pharmacokinetics in the setting of ARDS.

Dr. Hite is Chair of the Department of Critical Care Medicine in Cleveland Clinic’s Respiratory Institute. He can be reached at 216.445.3099 or hited@ccf.org.


Related Articles

Trial Results Offer New Hope for Scleroderma Patients

Nintedanib significantly reduces loss of lung function

December 21, 2018/Pulmonary/Clinical Trial
Improving Treatment Outcomes for Patients with Rheumatic Lung Disease

Three clinical trials testing old and new drugs

August 10, 2017/Pulmonary/Clinical Trial
1-Minute Consult: What Is the Role of Roflumilast in COPD?

Only for patients at high risk of severe exacerbations

September 9, 2015/Pulmonary/Clinical Trial
Transplant Drug Wins FDA Approval for Rare Lung Disease

Rapamycin stabilizes lung function in LAM patients

Man wearing CPAP machine
April 2, 2024/Pulmonary/Research
Treatments for Obstructive Sleep Apnea: CPAP and Beyond

A review of conservative, pressure-based and surgical treatments for OSA

Doctor talking with patient
March 21, 2024/Pulmonary/News & Insight
COVID-19: A Management Update

A review of IDSA and NIH guidelines

Image of lungs
February 28, 2024/Pulmonary/Research
New Cleveland Clinic-Led Research Highlights Novel Disease Monitoring Technique in Heart Failure

Volatile organic compounds have potential in heart failure diagnostics

Clinician performing bronchoscopy
February 16, 2024/Pulmonary/News & Insight
Program Implemented to Standardize Diagnostic Bronchoscopy Data Ensures Quality Care

Caregivers are provided with real-time bronchoscopy patient findings