The use of ECPELLA in patients with severe lung disease may result in an unfavorable phenomenon of differential hypoxia. The simultaneous evaluation of three arterial blood samples from different arterial line (right radial artery, left radial artery, ECMO arterial line) in patients at risk of Harlequin syndrome (also called differential hypoxemia (DH)) can localize the "mixing cloud" along the aorta. Focusing the attention on the "mixing cloud" position instead of on isolated flows of Veno-Arterial Extracorporeal Membrane Oxygenation (VA ECMO) and Impella CP makes the decision making easier about how to modify MCSs flows according to the clinical context. Herein, we present two cases in which ECPELLA configuration was used to treat a cardiogenic shock condition and how the ECPELLA-induced hypoxia was managed.