Hemodynamic instability during weaning from mechanical ventilation is one proposed cause of weaning failure. This study evaluated cardiac power output (CPO) as an indicator of significant hemodynamic alteration and cardiac reserve during the transition from controlled mechanical ventilation to spontaneous ventilation using three clinical weaning modes. It also compared CPO with commonly used indicators of hemodynamic instability during weaning. The data suggest that CPO is a sensitive indicator of significant hemodynamic alteration and could be used to optimize cardiovascular function during weaning from mechanical ventilation to increase the likelihood of weaning success.