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During cardiopulmonary bypass (CPB) haemodynamic alterations, haemostasis and the inflammatory response are the main causes of homeostatic disruption. Even with CPB procedures of short duration, the homeostasis of a patient is disrupted and, in many cases, requires intensive postoperative treatment to re-establish the physiological state of the patient. Although mortality is low, disruption of homeostasis may contribute to increased morbidity, particularly in high-risk patients. Over the past decades, considerable technical improvements in CPB equipment have been made to prevent the development of the systemic inflammatory response syndrome (SIRS). Despite all these improvements, only the inflammatory response, to some extent, has been reduced. The microcirculation is still impaired, as measured by tissue degradation products of various organs, indicating that CPB may still be considered as an unphysiological procedure. The question is, therefore, whether we can detect the pathophysiological consequences of CPB in each individual patient with valid bedside markers, and whether we can relate this to determinant factors in the CPB procedure in order to assist the perfusionist in improving the adequacy of CPB. The use of these markers could play a pivotal role in decision making by providing an immediate feedback on the determinant quality of perfusion. Therefore, we suggest validating the proposed markers in a nomogram to optimize not only the CPB procedure, but also the patient's safety.