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Venovenous extracorporeal membrane oxygenation (VV-ECMO) is a therapeutic option in the management of the most severe forms of acute respiratory distress syndrome. Oxygenation during VV-ECMO depends on many parameters, and its management is complex. The management of ECMO is still not completely codified. The aim of this study was to rationalize the management of hypoxemia during VV-ECMO.To build a comprehensive flow diagram for management of hypoxemia during VV-ECMO, we considered (1) relationship between O2 arterial saturation and its determinants; (2) analysis of physiopathology of oxygenation under VV-ECMO; and (3) main guidelines and recommendations recapitulated in troubleshooting charts.We propose a stepwise approach that could guide specific intervention to improve oxygenation during VV-ECMO. The first step is to obtain adequate pump flow, the main determinant of oxygenation, by eliminating a mechanical problem or inadequate venous drainage. Second, if hypoxemia persists, algorithm considers multiple reasons for inadequate oxygenation, namely: (1) excessive recirculation, (2) excessive cardiac output (decrease of ratio pump flow/cardiac output), (3) decrease in SvO2 (oxygen saturation in mixed venous blood), (4) malfunction of oxygenator, and (5) deterioration of residual lung function. Finally, for each modification of oxygenation parameters, specific measures are proposed to restore an adequate oxygenation by extracorporeal membrane oxygenation.If hypoxemia occurs during VV-ECMO, collecting oxygenation parameters and a clear step-by-step algorithm could guide specific intervention to improve oxygenation. This flow diagram is in accordance with current recommendations recapitulated in guidelines or troubleshooting chart but more accurate and complete. Although rational and appealing, it remains to be tested together with a number of still unsolved issues.