Extracorporeal CO2 removal (ECCO2R) was introduced in 1977 to control arterial CO2 tension and reduce ven- tilation, thus allowing lung rest in patients with acute respiratory failure (ARF).

Its feasibility has been tested in a clinical trial but clear evidence of benefit is lacking. Furthermore, a recent randomized study comparing standard lung protec- tive ventilation versus an ultra-protective strategy with ECCO2R, in moderate-severe ARF, showed no difference in 90-day survival, but greater adverse events and fewer ventilator-free days in the ECCO2R arm. Unfortunately, the relative contribution of ECCO 2R on total CO 2 clearance and its effects on the natural lung are unex- plored. Indeed, the CO2 excretion from artificial and natural lungs is generally not measured, and the ventilatory strategy does not account for the physiological changes due to ECCO 2 R. In this brief report, we aim to describe the physiological basis of CO 2 removal, extensively studied in healthy animal models. To which extent these concepts might be directly translatable to pathological conditions will require further clinical studies. However, a reappraisal of the physiological basis of ECCO2R–natural lung interactions may clarify the rationale behind its clinical application.