Abstract Background Extra-pulmonary multi-organ failure in patients with severe acute respiratory distress syndrome (ARDS) is a major cause of high mortality. Our purpose is to assess whether airway pressure release ventilation (APRV) causes more multi-organ damage than low tidal volume ventilation (LTV). Methods Twenty one pigs were randomized into control group (n = 3), ARDS group (n = 3), LTV group (n = 8) and APRV group (n = 7). Severe ARDS model was induced by repeated bronchial saline lavages. Pigs were ventilated and monitored continuously for 48 h. Respiratory data, hemodynamic data, serum inflammatory cytokines were collected throughout the study. Histological injury and apoptosis were assessed by two pathologists. Results After severe ARDS modeling, pigs in ARDS, LTV and APRV groups experienced significant hypoxemia and reduced lung static compliance (Cstat). Oxygenation recovered progressively after 16 h mechanical ventilation (MV) in LTV and APRV group. The results of the repeated measures ANOVA showed no statistical difference in the PaO2/FiO2 ratio between the APRV and LTV groups (p = 0.54). The Cstat showed a considerable improvement in APRV group with statistical significance (p
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