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During veno-venous extracorporeal membrane oxygenation (VV-ECMO) support, optimization of oxygenation can be achieved by therapeutic interventions on both patient physiological variables and adjustment of ECMO settings. Based on the physiology of oxygen delivery during VV-ECMO support, we established the mathematical relationship between the variables which define the oxygenation state: hemoglobin (Hb), extracorporeal blood flow (ECBF), cardiac output (Q), and systemic oxygen consumption (VO2). Assuming constant values for Q and VO2, the model was applied to elucidate the interplay between Hb and ECBF in determining arterial oxygen saturation (SaO2), and the resultant systemic oxygen delivery (DO2) and native venous oxygen saturation (SvO2) in static conditions. At constant VO2 and Q, an inverse relationship exists between Hb and ECBF in determining SaO2 and SvO2. Despite the same value of SaO2, the DO2 resulting from the different combinations of Hb and ECBF progressively decreases with decreasing Hb. By demonstrating the quantitative relationship between Hb and ECBF as determinants of oxygenation during VV-ECMO support, this mathematical model could provide a theoretical basis for a rational approach to strategies to optimize oxygenation in patients on VV-ECMO.