Phenotype-Guided Surfactant Therapy in ARDS: From Failed Replacement to Targeted Biological Intervention, Narrative...

Acute respiratory distress syndrome (ARDS) is associated with profound pulmonary surfactant dysfunction, yet clinical trials of exogenous surfactant have not demonstrated consistent outcome benefits in adults. This review reassesses these failures in light of current understanding of ARDS heterogeneity, surfactant biology and intrapulmonary drug delivery.

Surfactant dysfunction in ARDS reflects not only quantitative depletion but also inhibition by plasma proteins, altered lipid and protein composition, impaired synthesis and recycling, epithelial injury and heterogeneous alveolar flooding. Previous trials frequently enrolled biologically unselected populations and used variable formulations, doses and delivery strategies. Available evidence provides a rationale for a phenotype-guided approach integrating patient selection, assessment of surfactant dysfunction, formulations capable of maintaining activity under inhibitory conditions and optimized alveolar delivery. Next-generation synthetic surfactants containing surfactant protein B and C analogues, together with surfactant-based delivery of anti-inflammatory or other biologically active compounds, may address limitations of earlier replacement strategies. Future studies should move beyond testing surfactant in unselected ARDS. Clinical translation will require biologically enriched populations, mechanistically appropriate formulations, early treatment and verified delivery to recruitable lung regions.