Cardiac output (CO) monitoring is important in the hemodynamic management of critically ill patients. In a previous study, a novel non-invasive technique for CO monitoring based on prolonged expiration was proposed. The novel method showed good agreement with thermodilution on stable mechanically ventilated patients; unstable patients were excluded. The aim of this study is to improve the outcome of the above mentioned method on hemodynamic unstable patients, requiring vasoactive medications, and showing marked cardiogenic oscillations on waveforms related to expired gases. This prospective study has been carried out on three cardiac surgery patients; eighteen CO measurements were performed on each patient, and these values were compared with data obtained by thermodilution. The designed and tested algorithm allowed to reach a good agreement between CO measured by our method and by thermodilution (e.g., the mean percentage differences were 4%, 11% and 3%). Even though further validation is necessary, the results are quite promising and the adopted solution appears to allow the suitability of the prolonged expiration method also on unstable patients.