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To utilize real-time electrical impedance tomography to guide lung protective ventilation in an animal model of acute respiratory distress syndrome.Prospective animal study.Animal research center.Twelve Yorkshire swine (15 kg).Lung injury was induced with saline lavage and augmented using large tidal volumes. The control group (n = 6) was ventilated using ARDSnet guidelines, and the electrical impedance tomography–guided group (n = 6) was ventilated using guidance with real-time electrical impedance tomography lung imaging. Regional electrical impedance tomography–derived compliance was used to maximize the recruitment of dependent lung and minimize overdistension of nondependent lung areas. Tidal volume was 6 mL/kg in both groups. Computed tomography was performed in a subset of animals to define the anatomic correlates of electrical impedance tomography imaging (n = 5). Interleukin-8 was quantified in serum and bronchoalveolar lavage samples. Sections of dependent and nondependent regions of the lung were fixed in formalin for histopathologic analysis.Positive end-expiratory pressure levels were higher in the electrical impedance tomography–guided group (14.3 cm H2O vs. 8.6 cm H2O; p < 0.0001), whereas plateau pressures did not differ. Global respiratory system compliance was improved in the electrical impedance tomography–guided group (6.9 mL/cm H2O vs. 4.7 mL/cm H2O; p = 0.013). Regional electrical impedance tomography–derived compliance of the most dependent lung region was increased in the electrical impedance tomography group (1.78 mL/cm H2O vs. 0.99 mL/cm H2O; p = 0.001). Pao2/FIO2 ratio was higher and oxygenation index was lower in the electrical impedance tomography–guided group (Pao2/FIO2: 388 mm Hg vs. 113 mm Hg, p < 0.0001; oxygentation index, 6.4 vs. 15.7; p = 0.02) (all averages over the 6-hr time course). The presence of hyaline membranes (HM) and airway fibrin (AF) was significantly reduced in the electrical impedance tomography–guided group (HMEIT 42% samples vs. HMCONTROL 67% samples, p < 0.01; AFEIT 75% samples vs. AFCONTROL 100% samples, p < 0.01). Interleukin-8 level (bronchoalveolar lavage) did not differ between the groups. The upper and lower 95% limits of agreement between electrical impedance tomography and computed tomography were ± 16%.Electrical impedance tomography–guided ventilation resulted in improved respiratory mechanics, improved gas exchange, and reduced histologic evidence of ventilator-induced lung injury in an animal model. This is the first prospective use of electrical impedance tomography–derived variables to improve outcomes in the setting of acute lung injury.