The present study was performed on 10 patients with severe adult respiratory distress syndrome (ARDS), all suffering from sepsis (mean lung injury score [LIS] (1): 3.25 +/- 0.1; duration of mechanical ventilation upon study entry: 3.1 +/- 0.6 d). Ex vivo analysis of the alveolar surfactant system, obtained by bronchoalveolar lavage (BAL), showed severe impairment of surfactant function. Three hundred milligrams of natural surfactant/kg body weight (Alveofact) was delivered bronchoscopically in separate doses to each segment of both lungs. This caused an immediate increase in PaO2/FlO2 from 85 +/- 7 mm Hg to 200 +/- 20 mm Hg (p < 0.001), mainly due to a decrease in shunt flow (42 +/- 4 to 20 +/- 2% [p < 0.001]). Reanalysis of the alveolar surfactant showed that its function was significantly improved. In five patients the increase in arterial oxygenation was partially lost within the next few hours, and a second dose of 200 mg/kg surfactant was applied 18 to 24 h later, again increasing PaO2/FlO2 values. Eight patients survived the subsequent 14-d observation period with progressive improvement of gas exchange, and five patients were definitely weaned from the respirator. All fatalities were due to non-respiratory causes. We conclude that the bronchoscopic application of a high dose of surfactant aimed at overcoming inhibitory factors in the alveolar space of these patients, may offer a feasible and safe approach to improving gas exchange in severe ARDS.