Stratified Causal Inference for Intensive Care Unit Risk Prediction: Informatics-Based Modeling of Anesthetic Drug Combinations

Background: Postoperative intensive care unit (ICU) admission affects 15% to 20% of surgical patients and represents a major source of morbidity and health care costs. Current anesthetic dosing relies on empirical guidelines rather than individualized risk assessment. We developed a counterfactual dose-response model to identify optimal fentanyl-propofol combinations. Objective: This study aimed to develop and evaluate a stratified, causal machine learning framework using electronic health record data to identify optimal fentanyl-propofol dose combinations and predict postoperative ICU admission risk, enabling precision anesthesia and individualized clinical decision support. Methods: We analyzed perioperative electronic health records of 67,134 surgical procedures from UC Irvine Medical Center (2017‐2022). A hierarchical learning framework was used to estimate causal effects while controlling for confounding variables. A total of 6 dose-sensitive subgroups were identified through stratified analysis. The primary end point was postoperative ICU admission. Results: High-risk combinations (fentanyl >5 mcg/kg with propofol <1 mg/kg) increased ICU admissions’ absolute risk difference by 36% (absolute risk increase; 95% CI 0.351-0.509; P<.001). A total of 6 patient subgroups demonstrated distinct dose-response patterns, with populations considered vulnerable (high glucose, elevated creatinine) showing elevated risk even at standard doses. The optimal dose range for decision-making was determined to be 1.25 to 4.25 mg/kg for propofol and 3.5 to 4.0 mcg/kg for fentanyl. Conclusions: Fentanyl-propofol combinations exhibit complex, nonlinear dose-response relationships with ICU admission risk. High-dose combinations markedly increase risk through synergistic effects, while specific patient subgroups require enhanced monitoring even at standard doses. These findings support the development of individualized dosing algorithms and risk assessment tools that could inform future decision support tools aimed at reducing postoperative ICU use, although their predictive performance and clinical impact would require external validation.