Extracorporeal CO2 removal combined with low frequency positive pressure ventilation (ECCO2R-LFPPV) improves gas exchange and decreases peak pressures, respiratory rates, and tidal volumes in animals and in humans. Recent evidence suggests that pulmonary barotrauma results from lung overinflation rather than from high pressures. This study was to test the hypothesis whether ECCO2R-LFPPV could improve gas exchange without causing lung overinflation, despite the use of higher levels of PEEP, when compared with conventional mechanical ventilation. Eleven patients with severe adult respiratory distress syndrome (ARDS) who failed to respond to different modes of mechanical ventilation were treated with ECCO2R-LFPPV. Risk of pulmonary barotrauma was evaluated by static pressure-volume (P-V) curves and dynamic changes in volumes monitored by respiratory inductive plethysmography (Respitrace). ECCO2R-LFPPV PaO2/FIO2 increased from 79 +/- 21 to 207 +/- 108 (p = 0.003). Risk of barotrauma, as shown by the shape of the P-V curve, was present in all patients receiving mechanical ventilation even though most of them were treated with permissive hypoventilation. By contrast, no evidence of persistent lung overinflation could be detected by either static P-V curves or dynamic measurements in nine of 11 patients who were treated by ECCO2R-LFPPV. The two remaining patients had severe airway obstruction because of bleeding, and they remained ventilated with persistent risk of barotrauma. We conclude that ECCO2R-LFPPV improves gas exchange without causing lung overinflation in a majority of patients with ARDS.