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To evaluate the effectiveness of high-frequency oscillatory ventilation (HFOV) in pediatric patients with acute respiratory failure, failing conventional ventilation.A prospective, clinical study.Tertiary care pediatric intensive care unit.Twenty pediatric patients (ages 12 days to 5 yrs) with acute respiratory failure (pneumonia, 14; sepsis with acute respiratory distress syndrome, 3; pulmonary edema as a complication of upper airway obstruction, 2; salicylate intoxication with acute respiratory distress syndrome, 1), failing conventional ventilation (median alveolar-arterial oxygen difference [P(a-a)o2] 578 [489–624] torr, median oxygenation index 26 [21–32].HFOV was instituted after a median length of conventional ventilation of 15.5 (3.3–43.5) hrs.Ventilator settings, arterial blood gases, oxygenation index, and P(a-a)o2 were recorded before HFOV (0 hrs) and at predetermined intervals during HFOV and compared using the one-way Friedman rank-sum procedure and a two-tailed Wilcoxon matched-pairs test. Initiation of HFOV caused a significant decrease in Fio2 at 1 hr that continued to 24 hrs (p ≤ .04). In all patients, target ventilation was achieved, and 19 had improved oxygenation. After 1 hr, Paco2 significantly decreased (p = .002) and remained within the target range thereafter. There were significant decreases in P(a-a)o2 and oxygenation index at 1 and 4 hrs, respectively, that were sustained up to 12 hrs (p ≤ .04). No significant complications associated with HFOV were detected. Fifteen patients (75%) survived to hospital discharge. Only one patient died from respiratory failure.In pediatric patients with acute respiratory failure, failing conventional ventilation, HFOV improves gas exchange in a rapid and sustained fashion. However, randomized controlled trials are needed to identify its benefits over conventional modes of mechanical ventilation.