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Experimental and clinical studies have shown reduction in intrapulmonary shunt with improved oxygenation by spontaneous breathing with airway pressure release ventilation (APRV) in acute lung injury. The mechanisms of these findings are not clear. The authors hypothesized that spontaneous breathing results in better aeration of lung tissue and that improvement in oxygenation can be explained by these changes. This hypothesis was studied in a porcine model of oleic acid–induced lung injury.Two hours after induction of lung injury, 24 pigs were randomly assigned to APRV with or without spontaneous breathing at a positive end-expiratory pressure of 5 cm H2O. Hemodynamics, spirometry, and end-expiratory lung volume by nitrogen washout were measured at baseline, after 2 h of lung injury, and after 2 and 4 h of mechanical ventilation in the specific mode. Finally, spiral computed tomography of the chest was performed at end-expiratory lung volume in 22 pigs.Arterial carbon dioxide tension and mean and end-inspiratory airway pressures were comparable between settings. Four hours of APRV with spontaneous breathing resulted in improved oxygenation compared with APRV without spontaneous breathing (arterial oxygen tension, 144 ± 65 vs. 91 ± 50 mmHg, P < 0.01 for interaction time × mode), higher end-expiratory lung volume (786 ± 320 vs. 384 ± 148 ml, P < 0.001), and better aeration. End-expiratory lung volume and venous admixture were both correlated with the amount of lung reaeration (r2 = 0.62 and r2 = 0.61, respectively).The results support the hypothesis that spontaneous breathing during APRV improves oxygenation mainly by recruitment of nonaerated lung and improved aeration of the lungs.