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Objective: Physiologic and pathologic comparison of two modes of assisted ventilation, nasal intermittent positive-pressure ventilation (NIPPV) and synchronized intermittent mandatory ventilation (SIMV), in spontaneously breathing term newborn piglets with saline lavage-induced lung injury. Design: After inducing acute lung injury via repetitive saline lavage, piglets were randomized to NIPPV (n 12) or SIMV (n 11) and treated for 6 hrs. Setting: Clinical laboratory. Subjects: Spontaneously breathing term newborn piglets. Interventions: Invasive (SIMV) or noninvasive (NIPPV) assisted ventilation for 6 hrs. Measurements: Physiologic parameters and arterial blood gases were continuously monitored. At the conclusion of the study, lung tissue was obtained to analyze for evidence of inflammation, including myeloperoxidase, interleukin-8, and hydrogen peroxide levels, as well as for evidence of pathologic injury. Main Results: Piglets treated with NIPPV demonstrated higher arterial blood gas pH (p < .001), lower PaCO2 (p < .05), and a lower set respiratory rate (p < .0001) as compared with the SIMV-treated piglets. The piglets in the SIMV group had higher PaO2/PAO2 ratio than those in the NIPPV group (p .001). There was significantly more interstitial inflammation (p .04) in the SIMV-treated piglets compared with the NIPPV-treated piglets. Total respiratory rate, heart rate, blood pressure, oxygen saturation, and biochemical markers of lung inflammation were not different between the groups. Conclusion: In surfactant-deficient term newborn piglets, NIPPV offers an effective and noninvasive ventilatory strategy with the potential for less pathologic lung inflammation. (Crit Care Med 2008; 36:183‐187)