Equivalent cumulative energy yields unequal lung injury: effects of tidal volume and ventilation duration in experimental lung injury.

Mechanical ventilation contributes to lung injury in acute respiratory distress syndrome, yet whether cumulative mechanical energy, the time-integrated delivery of ventilatory power, adequately reflects the risk of ventilator-induced lung injury (VILI) remains uncertain. Because lung tissue exhibits nonlinear stress-strain behavior, the rate and amplitude of energy delivered may be as relevant as its magnitude. We tested whether different combinations of tidal volume (VT) and ventilation duration, matched for cumulative energy, produce distinct patterns of VILI following endotoxin-induced lung damage in male Wistar rats. Animals received intratracheal lipopolysaccharide (LPS) and, after 24 h, were mechanically ventilated (PEEP = 3 cmH2O; inspired oxygen fraction = 0.40) using one of three strategies: VT = 6 mL/kg for 150 min (LVT-HMV), VT = 9 mL/kg for 100 min (MVT-MMV), or VT = 12 mL/kg for 75 min (HVT-LMV). Apparatus dead space was adjusted to maintain normocapnia. An LPS-exposed, nonventilated group served as a molecular and histological reference. Despite equivalent cumulative energy exposure, HVT-LMV resulted in higher plateau and driving pressures, greater alveolar overdistension, collapse, and pulmonary edema, and increased expression of interleukin-6 and vascular cell adhesion molecule-1. MVT-MMV produced intermediate structural injury with selective upregulation of mechanosensitive extracellular matrix markers, whereas LVT-HMV was associated with the least injury. Driving and plateau pressures correlated with indices of overdistension and extracellular matrix signaling but showed weaker associations with endothelial activation. These findings indicate that VILI depends not only on total energy delivery but also on its temporal distribution, and that cumulative energy alone is insufficient to predict lung injury risk.NEW & NOTEWORTHY This study reveals that the timing of energy delivery, not just its magnitude, determines ventilator-induced lung injury in endotoxin-induced lung damage. Using a rat model, high tidal volumes delivered over short periods caused disproportionate overdistension, edema, and inflammation compared with lower tidal volumes over longer periods, despite equivalent cumulative energy. These findings challenge the conventional focus on total ventilatory energy and highlight the need for strategies that account for temporal distribution to optimize lung protection.