Over the past few decades, highly significant progress has been made in understanding the pathophysiology of the acute respiratory distress syndrome (ARDS). Recognition of ventilation-induced lung injuries (VILI) has led to the radical modification of the ventilatory management of these patients. The landmark trial by the ARDSnet trial group demonstrated in 2000 that ventilating ARDS patients with a low tidal volume (VT) of 6 ml/kg (calculated from predicted body weight), and with a maximum end-inspiratory plateau pressure (Pplat) of 30 cmH2O decreased mortality from 39.8% (in the conventional arm treated with a VT of 12 ml/kg PBW) to 31% . However, recent studies have shown that lung hyperinflation still occurs in approximately 30% of ARDS patients even though they are being ventilated using the ARDSNet strategy. Additionally, Hager and coworkers found that mortality decreased as Pplat declined from high to low levels at all levels of Pplat on the data collected by the "ARDSNet" trial group. Their analysis suggested a beneficial effect of VT reduction even for patients who already had Pplat\<30 cm H2O before VT reduction.Similar observation was also recently reported by Needham et al on a cohort of 485 patients with ARDS. Because VT reduction to \<6 ml/kg to achieve very low Pplat may induce severe hypercapnia and may cause elevated intracranial pressure, pulmonary hypertension, decreased myocardial contractility, decreased renal blood flow, and the release of endogenous catecholamines, this strategy using "ultraprotective" MV settings is not possible for most patients on conventional mechanical ventilation for moderate to severe ARDS.

Extracorporeal carbon dioxide removal (ECCO2R) may be used in association with mechanical ventilation to permit VT reduction to \<6 ml/kg and to achieve very low Pplat (20-25 cm H2O). In an observational study conducted in the 80's, Gattinoni showed that use of venovenous ECCO2R at a flow of 1.5-2.5 l/min in addition to quasi apneic mechanical ventilation with peak inspiratory pressures limited to 35-45 cmH2O and PEEP set at 15-25 cmH2O resulted in lower than expected mortality in an observational cohort of severe ARDS patients. However, a randomized, controlled single-center study using that same technology and conducted in the 1990s by Morris's group in Utah was stopped early for futility after only 40 patients had been enrolled and failed to demonstrate a mortality benefit with this device (58% in the control group vs. 70% in the treatment group).

In recent years, new-generation ECCO2R devices have been developed. They offer lower resistance to blood flow, have small priming volumes and have much more effective gas exchange. With ECCO2R the patient's PaCO2 is principally determined by the rate of fresh gas flow through the membrane lung. In an ECCO2R animal model, CO2 removal averaged 72±1.2 mL/min at blood flows of 450 mL/min, while CO2 production by the lung decreased by 50% with reduction of minute ventilation from 5.6 L/min at baseline to 2.6 L/min after insertion of the device. Lastly, Terragni et al (15)demonstrated that ECCO2R could improve pulmonary protection by allowing very low tidal volume ventilation (3.5-5 ml/kg of PBW) in a proof-of-concept study of ten patients with ARDS. This strategy was also associated with a significant decrease in pulmonary inflammatory biomarkers.