Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) is an increasingly used rescue therapy forpatients with refractory cardiogenic shock (CS) 1,2 . It provides mechanical circulatory support for both heartand lungs by generating blood flow, oxygenating, and removing carbon dioxide. Although a life-saving therapy,V-A ECMO exposes patients to several complications, in particular bleeding, infections, and cerebrovascularaccidents 3 . Peripheral femoral cannulation (the most used configuration) also brings a physiological paradigmwith a retrograde flow along the abdominal and thoracic aorta. This potentially causes two specific complica-tions: increase in left ventricle (LV) afterload 4 —which can cause LV dilation, secondary cardiac damage andpulmonary oedema—and differential hypoxaemia (DH).DH occurs when the upper body, perfused with deoxygenated blood by the native heart and lungs, has alower oxygen saturation than the lower body perfused with oxygenated blood from the ECMO circuit 5 . This happens in the case of concomitant pulmonary failure, which commonly ensues in the context of pulmonaryoedema and/or pneumoniae. DH causes coronary and cerebral hypoxaemia and is a complication frequentlyencountered by ECMO clinicians. The effects of such DH on cerebral structures and integrity have been, how-ever, poorly investigated.We hypothesised that increasing V-A ECMO flow would lead to an optimized cerebral oxygen delivery andreduce brain injury risks assessed by biological, physiological and histological markers.Thus, in a novel experimental model of severe cardiopulmonary failure supported by V-A ECMO, we aimedto study the impact of the ECMO flow on brain injury.