Background <p>Acute respiratory distress syndrome (ARDS) is the acute hypoxemic respiratory failure that presents with non-cardiogenic pulmonary opacities. Patients receiving non-invasive respiratory support might present with high transpulmonary pressure, pulmonary strain, and <i>pendelluft</i>, which contribute to the development of patient self-inflicted lung injury (P-SILI). Experimental studies have identified that continuous positive airway pressure (CPAP) is successful in attenuating P-SILI effectors compared to high-flow nasal oxygenation (HFNO). However, it remains uncertain whether this attenuation is associated with a reduction in lung injury and improved clinical outcomes.</p> Methods <p>This is a multicenter, randomized, open-label, controlled trial. One hundred&#xa0;and twenty non-intubated patients with established ARDS will be randomly assigned to receive non-invasive respiratory support with either CPAP 12 cmH₂O or HFNO 50 L/min for 48&#xa0;h. The primary outcome is biological lung injury, assessed with plasma levels of the epithelial pulmonary dysfunction biomarker sRAGE (soluble Receptor of Advanced Glycation End-products). Secondary outcomes include plasmatic pulmonary dysfunction biomarkers, P-SILI effectors (pulmonary strain, <i>pendelluft</i>, transpulmonary pressure), 48-h tracheal intubation rate, 90-day tracheal intubation rate, and 90-day mortality. All analyses will be conducted according to the intention-to-treat principle.</p> Discussion <p>This study will assess the potential role of CPAP in attenuating P-SILI effectors and inflicting less biological lung injury compared to HFNO. This physiologic effect may lead to lower rates of tracheal intubation and mortality. This project will provide new knowledge on the respiratory management of non-intubated ARDS patients, a subject where evidence is lacking.</p> Trial registration <p>ClinicalTrials.gov NCT06694311. Registered on 18 November 2024 as HCB/2023/1105.</p>