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In critical illness, the gut is susceptible to hypoperfusion and hypoxia. Positive-pressure ventilation can affect systemic hemodynamics and regional blood flow distribution, with potentially deleterious effects on the intestinal circulation. The authors hypothesized that spontaneous breathing (SB) with airway pressure release ventilation (APRV) provides better systemic and intestinal blood flow than APRV without SB.Twelve pigs with oleic acid–induced lung injury received APRV with and without SB. When SB was abolished, either the tidal volume or the ventilator rate was increased to maintain pH and arterial carbon dioxide tension constant as compared to APRV with SB. Systemic hemodynamics were determined by double indicator dilution. Blood flow to the intestinal mucosa–submucosa and muscularis–serosa was measured using colored microspheres.Systemic blood flow increased during APRV with SB. During APRV with SB, mucosal–submucosal blood flow (ml · g−1 · min−1) was 0.39 ± 0.21 in the stomach, 0.76 ± 0.35 in the duodenum, 0.71 ± 0.35 in the jejunum, 0.71 ± 0.59 in the ileum, and 0.63 ± 0.21 in the colon. During APRV without SB and high tidal volumes, it decreased to 0.19 ± 0.03 in the stomach, 0.42 ± 0.21 in the duodenum, 0.37 ± 0.10 in the jejunum, 0.3 ± 0.14 in the ileum, and 0.41 ± 0.14 in the colon (P < 0.001, respectively). During APRV without SB and low tidal volumes, the respective mucosal–submucosal blood flows decreased to 0.24 ± 0.10 (P < 0.01), 0.54 ± 0.21 (P < 0.05), 0.48 ± 0.17 (P < 0.01), 0.43 ± 0.21 (P < 0.01), and 0.50 ± 0.17 (P < 0.001) as compared to APRV with SB. Muscularis–serosal perfusion decreased during full ventilatory support with high tidal volumes in comparison with APRV with SB.Maintaining SB during APRV was associated with better systemic and intestinal blood flows. Improvements were more pronounced in the mucosal–submucosal layer.