EARLY-SARDS: Early AlveolaR Lung biologY Underling Sepsis-Associated ARDS

Overview

Sepsis-associated acute respiratory distress syndrome (ARDS) remains a major cause of respiratory failure and mortality in critically ill patients. Although only a proportion of patients with sepsis develop ARDS, early identification of those at highest risk remains a major unmet clinical need. Current prediction relies largely on clinical deterioration and oxygenation impairment, which often occur when lung injury has already developed. Increasing evidence suggests that biological responses to sepsis are compartmentalized between the systemic circulation and the alveolar space, while early abnormalities in respiratory mechanics and ventilatory efficiency may provide complementary information on evolving lung injury. However, no prospective study has integrated serial systemic and alveolar biomarkers with bedside respiratory physiology during the earliest phase of sepsis-associated respiratory failure. EARLY-SARDS is a prospective observational cohort study designed to characterize the early biological and physiological trajectories of invasively ventilated patients with sepsis or septic shock. Serial bronchoalveolar lavage (BAL) and plasma samples, together with standardized measurements of respiratory mechanics and gas exchange, will be collected during the first 96 hours after enrollment. The primary objective is to develop an integrated biological-physiological model capable of predicting ARDS development and subsequent peak ARDS severity. Secondary objectives include characterizing biological compartmentalization, identifying integrated biological-physiological subphenotypes, and evaluating their association with clinically relevant outcomes, including duration of mechanical ventilation, ventilator-free days, need for extracorporeal respiratory support, ICU length of stay, and mortality.

Acute respiratory distress syndrome (ARDS) secondary to sepsis is a biologically heterogeneous syndrome that reflects multiple interacting mechanisms of lung injury rather than a single pathological process. Current clinical definitions rely on physiological manifestations of established lung injury and therefore provide limited insight into the underlying biological processes responsible for disease initiation and progression. Experimental and translational studies indicate that the earliest phase of sepsis-associated lung injury is characterized by dynamic interactions between inflammatory activation, epithelial injury, endothelial dysfunction, disruption of the alveolar-capillary barrier, and alterations in pulmonary permeability. These processes evolve rapidly during the first days after sepsis onset and may precede the clinical diagnosis of ARDS by several hours or days. Longitudinal characterization is therefore essential to understand the temporal evolution of lung injury. Because the primary site of injury is the alveolar compartment, circulating biomarkers incompletely reflect the biological events occurring within the lung. Inflammatory mediators, epithelial injury markers, and endothelial activation frequently demonstrate compartmentalization between bronchoalveolar lavage (BAL) fluid and plasma, suggesting that simultaneous assessment of both compartments may provide a more comprehensive characterization of early lung injury than either compartment alone. Respiratory physiology represents a complementary dimension of ARDS pathophysiology. Parameters including respiratory system compliance, driving pressure, plateau pressure, ventilatory ratio, and gas exchange describe the functional consequences of biological injury and the mechanical environment to which the lung is exposed during invasive mechanical ventilation. Mechanical stress and biological injury are closely interconnected and likely contribute jointly to disease progression. By combining repeated assessment of alveolar biology, systemic host response, and respiratory physiology during the earliest phase of sepsis-associated respiratory failure, this study is designed to characterize the temporal evolution of lung injury and provide an integrated description of the biological and physiological mechanisms underlying progression to ARDS.