BackgroundNasal continuous positive airway pressure (NCPAP) and nasal intermittent positive pressure ventilation (NIPPV), forms of non-invasive ventilation (NIV) for respiratory support, are increasingly being chosen as the initial treatment for neonates with surfactant (SF) deficiency. Our objective was to compare NCPAP with NIPPV with or without SF administration as a primary mode of ventilation.MethodsTwenty-four newborn piglets with SF-deficient lung injury produced by repetitive bronchoalveolar lavages were randomly assigned to NCPAP or NIPPV, with or without SF administration (InSurE method). We evaluated pulmonary, systemic (hemodynamic and oxygen metabolism), and cerebral effects.ResultsSF-deficient piglets developed respiratory distress (FiO2:1, pH<7.2, PaCO2>70 mm Hg, PaO2<70 mm Hg, and Cdyn<0.5 ml/cmH2O/kg). Gradual improvements in pulmonary status were observed in both NIV groups, with NIPPV achieving lower lung inflammation markers and injury scores. Both SF-treated groups obtained significantly better respiratory outcomes than groups not treated with SF before NIV. All NIV-treated groups showed low brain injury scores.ConclusionIn spontaneously breathing SF-deficient newborn piglets, NIPPV is a suitable NIV strategy. SF administration in combination with NCPAP or NIPPV improves pulmonary status providing extra protection against pulmonary injury. No injury to the developing brain was observed to be associated with these NIV strategies, with or without SF therapy.