In acute hypoxemic respiratory failure of term and near-term neonates, extra- and intrapulmonary right-to-left shunting contribute to refractory hypoxemia. Inhaled nitric oxide (NO) decreases pulmonary arterial pressure and improves ventilation-perfusion mismatch in a variety of animal models and selected human patients. We report on 10 consecutive term and near-term newborns with severe acute hypoxemic respiratory failure due to diaphragmatic hernia, meconium aspiration syndrome, group B streptococcus sepsis, pneumonia or acute respiratory distress syndrome, who received increasing doses of inhaled NO (up to 80 ppm) to improve the arterial partial pressure of oxygen (PaO2). The response to NO and the optimum NO concentration which improved PaO2 varied considerably between patients. Improvement of PaO2 was absent or poor (less than 10 mm Hg) in the 4 newborns with meconium aspiration syndrome and in 1 patient with congenital diaphragmatic hernia, while in the other 5 patients inhaled NO increased the mean (+/- SE) PaO2 from 41 +/- 6 to 57 +/- 9 mm Hg (P < 0.05). Optimum NO concentrations determined by dose-response measurements performed during the first 8 hr of NO inhalation were 8-16 ppm except for 2 newborns with congenital diaphragmatic hernia who required 32 ppm to effectively increase PaO2. Four of the 5 patients in whom the PaO2 rose by more than 10 mm Hg received inhaled NO for extended periods of time (5 to 23 days) with no signs of tachyphylaxis. The optimum NO concentration dropped to less than 3 ppm after prolonged mechanical ventilation or when intravenous prostacyclin was given concomitantly.(ABSTRACT TRUNCATED AT 250 WORDS)