Objective:To test the hypothesis that perfluorocarbon (PFC) priming before surfactant administration improves gas exchange and lung compliance, and also decreases lung injury, more than surfactant alone.Design:Prospective, randomized animal study.Setting:Animal research laboratory of Children's Hospital of St. Paul.Subjects:Thirty-two newborn piglets, weighing 1.55 ± 0.18 kg.Interventions:We studied four groups of eight animals randomized after anesthesia, paralysis, tracheostomy, and establishment of lung injury using saline washout to receive one of the following treatments: a) surfactant alone (n = 8); b) priming with the PFC perflubron alone (n = 8); c) priming with perflubron followed by surfactant (n = 8); and d) no treatment (control; n = 8). Perflubron priming was achieved by instilling perflubron via the endotracheal tube in an amount estimated to represent the functional residual capacity, ventilating the animal for 30 mins, and then removing perflubron by suctioning. After all treatments were given, animals were mechanically ventilated for 4 hrs.Measurements and Main Results:We evaluated oxygenation, airway pressures, respiratory system compliance, and hemodynamics at baseline, after induction of lung injury, and at 30-min intervals for 4 hrs. Histopathologic evaluation was carried out using a semiquantitative scoring system and by computer-assisted morphometric analysis. After all treatments, animals had decreased oxygenation indices (p< .001) and increased respiratory system compliance (p< .05). Animals in PFC groups had similar physiologic responses to treatments as animals treated with surfactant only; both the PFC-treated groups and the surfactant-treated animals required lower mean airway pressures throughout the experiment (p< .001) and had higher pH levels at 90 and 120 mins (p< .05) compared with the control group. Pathologic analysis demonstrated decreased lung injury in surfactant-treated animals compared with animals treated with PFC or the controls (p< .02).Conclusions:Priming the lung with PFC neither improved the physiologic effects of exogenous surfactant nor improved lung pathology in this animal model.