Restoring or maintaining an optimal oxygen supply adjusted to oxygen demand remains the key aim of all clinicians facing a circulatory dysfunction, whatever the cause. Many therapeutic tools are available, ranging from adequate fluid resuscitation, cardio or vaso-active agents, to adjuvant therapies and various ventilatory supports. Most of the challenges for clinicians are the choice of therapeutics, their dosage, and management of their potential interactions. In addition, in the course of circulatory distress, it would be of great help to identify patients at risk of developing organ dysfunction, in order to intensify and adapt treatment of such individuals. As a guide to achieve these purposes, normalisation of mixed venous oxygen saturation and blood lactate has been proposed as endpoint resuscitations but revealed unsuccessful in several clinical studies [1][2][3]. The monitoring of the mixed venous-arterial gradient in partial pressure of carbon dioxide [p(mv-a)CO 2 ] has been recently put forward and revealed promising. A high CO 2 gradient would indicate an inadequate organ perfusion and a risk of delayed organ dysfunction. Have we reached a satisfactory answer to a main clinical question?In this issue Morel et al.[4] retrospectively analysed 220 consecutive patients admitted in intensive care unit after an elective cardiac surgery. Monitoring p(mv-a)CO 2 , they observed at the 6th postoperative hour a group of 55 patients having a gradient greater than 6 mm Hg. Surprisingly and contrary to previous published results, these patients experienced a lower SOFA score, hospital and 6 month mortality. The authors concluded that in this clinical setting, the CO 2 gradient is not predictive of poor outcome. This apparently paradoxical results is on line with other works underlying the poor discriminative value of the gradient [5]. Rather than the premature conclusion of a promising story, this is more likely a plea to gain more insight in our knowledge about a complex indicator.The p(mv-a)CO 2 is the difference between two partial pressures of CO 2 : the mixed venous and the arterial. The normal value is commonly held as lower than 6 mm Hg. The venous pressure depends on several components, the content of mixed venous in CO 2 , and the relationship between the concentration and the pressure. The content itself is a concentration, that is to say the ratio of the amount of CO 2 driven from peripheral organs to the amount of blood arising from the same organs or segments of organs. The arterial pressure depends on the lung function and is strictly proportional to the alveolar ventilation. Given a constant alveolar ventilation, this arterial pressure remains stable provided that the venous pressure is not modified. If an increase in mixed venous pCO 2 occurs, the amount of CO 2 exhaled by the lung will increase, enlarging the venous-arterial gradient. This role of the lung is schematically illustrated by the increase in end-tidal partial pressure of CO 2 occurring soon after the release of a tourniquet. Any small i...