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To prospectively evaluate the oxygenation effect of inhaled nitric oxide (INO) delivered during high-frequency oscillatory ventilation in adult patients with the acute respiratory distress syndrome and oxygenation failure.Prospective, clinical study.Intensive care unit of a university teaching hospital.A total of 23 adults (14 women, 9 men, 44.9 ± 17.5 yrs, Acute Physiology and Chronic Health Evaluation II score of 28.6 ± 7.1) with acute respiratory distress syndrome (lung injury score, 3.5 ± 0.4) with Fio2 of ≥0.6 and mean airway pressure of ≥28 cm H2O.INO was initiated at a dose of 5 ppm, and subsequently titrated according to a protocol, to determine the dose (5, 10, or 20 ppm) resulting in the greatest increase in Pao2/Fio2. Blood gas measurements were obtained 10–15 mins after initiation or any increase in INO dosage to assess the effect on Pao2/Fio2.Arterial blood gases and ventilator settings were recorded at four time points: during conventional ventilation just before initiating high-frequency oscillatory ventilation, during high-frequency oscillatory ventilation just before initiating INO, after 30 mins on the optimal dose of INO, and 8–12 hrs after starting INO. Oxygenation index ([Fio2 × mean airway pressure × 100]/Pao2) and Pao2/Fio2 ratios were calculated at the same time intervals. At 30 mins after INO initiation, 83% of patients had a significant increase in blood oxygen tension, defined as ≥20% increase in Pao2/Fio2. The mean change in Pao2/Fio2 at 30 mins was 38%. In these 19 patients, Pao2/Fio2 was highest at 20 ppm in four patients, at 10 ppm in eight patients, and at 5 ppm in seven patients. Compared with baseline measurements, Pao2/Fio2 improved significantly at both 30 mins (112 ± 59 vs. 75 ± 32, p = .01) and 8–12 hrs after INO initiation (146 ± 52 vs. 75 ± 32, p < .0001). In addition, oxygenation index was reduced at 8–12 hrs compared with baseline measurements (26 ± 13 vs. 40 ± 17, p = .08).INO delivered at doses of 5 to 20 ppm during high-frequency oscillatory ventilation increases Pao2/Fio2 and may be a safe and effective rescue therapy for patients with severe oxygenation failure.