Purpose <p>Real-time risk monitoring is critical but challenging in intensive care units (ICUs) due to the lack of real-time updates for most clinical variables. Although real-time predictions have been integrated into various risk monitoring systems, existing systems do not address uncertainties in risk assessments. We developed a novel framework based on commonly used systems like the Sequential Organ Failure Assessment (SOFA) score by incorporating uncertainties to improve the effectiveness of real-time risk monitoring.</p> Methods <p>This study included 5351 patients admitted to the Cardiothoracic ICU in the National University Hospital in Singapore. We developed machine learning models to predict long lead-time variables and computed real-time SOFA scores using predictions. We calculated intervals to capture uncertainties in risk assessments and validated the association of the estimated real-time scores and intervals with mortality and readmission.</p> Results <p>Our model outperforms SOFA score in predicting 24-h mortality: Nagelkerke’s R-squared (0.224 vs. 0.185, p &lt; 0.001) and the area under the receiver operating characteristic curve (AUC) (0.870 vs. 0.843, p &lt; 0.001), and significantly outperforms quick SOFA (Nagelkerke’s R-squared = 0.125, AUC = 0.778). Our model also performs better in predicting 30-day readmission. We confirmed a positive net reclassification improvement (NRI) of our model over the SOFA score (0.184, p &lt; 0.001). Similarly, we enhanced two additional scoring systems.</p> Conclusions <p>Incorporating uncertainties improved existing scores in real-time monitoring, which could be used to trigger on-demand laboratory tests, potentially improving early detection, reducing unnecessary testing, and thereby lowering healthcare expenditures, mortality, and readmission rates in clinical practice.</p>