Exogenous Surfactant Therapy in Acute Lung Injury/Acute Respiratory Distress Syndrome: The Need for a Revised Paradigm Approach

To the Editor:

We were interested to read the meta-analysis on exogenous surfactant therapy in adult patients with acute respiratory distress syndrome (ARDS)/acute lung injury (ALI) conducted by Meng et al.¹ Although the results were disappointing, the findings were not surprising, and they were in line with 2 previously published meta-analyses.2, 3 The surfactant clinical trials included here are highly informative, albeit producing negative clinical outcomes, and suggest the necessity for a revised paradigm approach for future surfactant clinical trials.

It is prudent to differentiate neonatal respiratory distress syndrome from adult ARDS/ALI; the former is characterized primarily by inadequate surfactant synthesis. In the adult form of the disease, alveolar surfactant biology is complex, comprising a combination of altered synthesis and secretion by injured alveolar epithelial type II cells, functional inhibition by plasma constituents, and accelerated breakdown by oxidation and hydrolysis, all contributing to the clinical picture of surfactant dysfunction.⁴

In addition to the limitations of the delivery methods as alluded to by the authors, future surfactant preparations may need to be tailored to withstand hydrolytic and phospholipase-mediated breakdown, and some novel preparations are under investigation with the incorporation of phospholipase-resistant lipid analogs.⁴ One crucial reason for the lack of clinical benefit in exogenous surfactant trials may be the heterogeneity of the underlying disease mechanism in ARDS/ALI. Currently, disturbances of surfactant composition, function, synthesis, and turnover do not contribute to the definition or potential disease stratification of patients with ARDS/ALI, partly because of the lack of readily available surrogate biomarkers that reflect the dynamic synthetic capacity of alveolar epithelial type II cells. However, recent advances in nonradioactive isotope labeling of surfactant precursors means that it is now possible to quantify the dynamic turnover of surfactant phospholipids and proteins.5, 6 Initial studies in ARDS/ALI patients show a variation in surfactant synthetic patterns, suggesting the possibility of different underlying biochemical phenotypes.⁶ Future studies should consider the incorporation of such methodologies to stratify ARDS/ALI patients according to alveolar surfactant synthetic capability. When surfactant breakdown or functional inhibition is the primary contributory pathology leading to surfactant dysfunction, a holistic approach may need to be adopted with modifications of surfactant preparations to overcome such issues.