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• Post-cardiotomy low cardiac output syndrome is a life-threatening complication. • In the case of refractory shock, circulatory support with ECMO may be necessary. • We developed a machine-learning algorithm to predict the need for rescue ECMO. • Our algorithm showed great performance and also identified predictive features. • The use of this algorithm may help clinicians' decision in this setting. Post-cardiotomy low cardiac output syndrome (PC-LCOS) is a life-threatening complication after cardiac surgery involving a cardiopulmonary bypass (CPB). Mechanical circulatory support with veno-arterial membrane oxygenation (VA-ECMO) may be necessary in the case of refractory shock. The objective of the study was to develop a machine-learning algorithm to predict the need for VA-ECMO implantation in patients with PC-LCOS. Patients were included in the study with moderate to severe PC-LCOS (defined by a vasoactive inotropic score (VIS) > 10 with clinical or biological markers of impaired organ perfusion or need for mechanical circulatory support after cardiac surgery) from two university hospitals in Paris, France. The Deep Super Learner, an ensemble machine learning algorithm, was trained to predict VA-ECMO implantation using features readily available at the end of a CPB. Feature importance was estimated using Shapley values. Between January 2016 and December 2019, 285 patients were included in the development dataset and 190 patients in the external validation dataset. The primary outcome, the need for VA-ECMO implantation, occurred respectively, in 16% (n = 46) and 10% (n = 19) in the development and the external validation datasets. The Deep Super Learner algorithm achieved a 0.863 (0.793−0.928) ROC AUC to predict the primary outcome in the external validation dataset. The most important features were the first postoperative arterial lactate value, intraoperative VIS, the absence of angiotensin-converting enzyme treatment, body mass index, and EuroSCORE II. We developed an explainable ensemble machine learning algorithm that could help clinicians predict the risk of deterioration and the need for VA-ECMO implantation in moderate to severe PC-LCOS patients. [ABSTRACT FROM AUTHOR]