BACKGROUND: The amount of extracorporeal carbon dioxide removal may influence respiratory drive in acute respiratory distress syndrome (ARDS) patients undergoing extracorporeal membrane oxygenation (ECMO). The authors evaluated the effects of different levels of extracorporeal carbon dioxide removal in patients recovering from severe ARDS undergoing pressure support ventilation (PSV) and neurally adjusted ventilatory assist (NAVA). METHODS: The authors conducted a prospective, randomized, crossover study on eight spontaneously breathing ARDS patients undergoing venovenous ECMO since 28 ± 20 days. To modulate carbon dioxide extraction, ECMO gas flow (GF) was decreased from baseline resting protective conditions (i.e., GF100%, set to obtain pressure generated in the first 100 ms of inspiration against an occluded airway less than 2 cm H2O, respiratory rate less than or equal to 25 bpm, tidal volume less than 6 ml/kg, and peak airway pressure less than 25 cm H2O) to GF50%-GF25%-GF0% during both PSV and NAVA (random order for ventilation mode). Continuous recordings of airway pressure and flow and esophageal pressure were obtained and analyzed during all study phases. RESULTS: At higher levels of extracorporeal carbon dioxide extraction, pressure generated in the first 100 ms of inspiration against an occluded airway decreased from 2.8 ± 2.7 cm H2O (PSV, GF0%) and 3.0 ± 2.1 cm H2O (NAVA, GF0%) to 0.9 ± 0.5 cm H2O (PSV, GF100%) and 1.0 ± 0.8 cm H2O (NAVA, GF100%; P < 0.001) and patients' inspiratory muscle pressure passed from 8.5 ± 6.3 and 6.5 ± 5.5 cm H2O to 4.5 ± 3.1 and 4.2 ± 3.7 cm H2O (P < 0.001). In time, decreased inspiratory drive and effort determined by higher carbon dioxide extraction led to reduction of tidal volume from 6.6 ± 0.9 and 7.5 ± 1.2 ml/kg to 4.9 ± 0.8 and 5.3 ± 1.3 ml/kg (P < 0.001) and of peak airway pressure from 21 ± 3 and 25 ± 4 cm H2O to 21 ± 3 and 21 ± 5 cm H2O (P < 0.001). Finally, transpulmonary pressure linearly decreased when the amount of carbon dioxide extracted by ECMO increased (R = 0.823, P < 0.001). CONCLUSIONS: In patients recovering from ARDS undergoing ECMO, the amount of carbon dioxide removed by the artificial lung may influence spontaneous breathing. The effects of carbon dioxide removal on spontaneous breathing during the earlier acute phases of ARDS remain to be elucidated.