Early plasma proteomic biomarkers and prediction model of acute respiratory distress syndrome after cardiopulmonary bypass: a prospective nested cohort study.

Abstract

Early recognition of the risk of acute respiratory distress syndrome (ARDS) after cardiopulmonary bypass (CPB) may improve clinical outcomes. The main objective of this study was to identify proteomic biomarkers and develop an early prediction model for CPB-ARDS. We conducted three prospective nested cohort studies of all consecutive patients undergoing cardiac surgery with CPB at XXX Hospital. Plasma proteomic profiling was performed in ARDS patients and matched controls (Cohort 1, April, 2021 to July, 2021) at multiple timepoints: before CPB (T1), at end of CPB (T2), and 24 h after CPB (T3). Then, for Cohort 2 (August, 2021 to July, 2022), biomarker expression was measured and verified in the plasma. Furthermore, lung ischemia/reperfusion injury (LIRI) models and sham-operation were established in 50 rats to explore the tissue-level expression of biomarkers identified in the aforementioned clinical cohort. Subsequently, a machine learning-based prediction model incorporating protein and clinical predictors from Cohort 2 for CPB-ARDS was developed and internally validated. Model performance was externally validated on Cohort 3 (January, 2023 to March, 2023). A total of 709 proteins were identified, with 9, 29, and 35 altered proteins between ARDS cases and controls at T1, T2, and T3, respectively, in Cohort 1. Following quantitative verification of several predictive proteins in Cohort 2, higher levels of thioredoxin domain containing 5 (TXNDC5), cathepsin L (CTSL), and NPC intracellular cholesterol transporter 2 (NPC2) at T2 were observed in CPB-ARDS patients. A dynamic online predictive nomogram was developed based on three proteins (TXNDC5, CTSL, and NPC2) and two clinical risk factors (CPB time, massive blood transfusion), with excellent performance (precision: 83.33%, sensitivity: 93.33%, specificity: 61.16%, F1 score: 85.05%). Mean area under the receiver operating characteristics curve (AUC) of the model after 10-fold cross-validation was 0.839 (95% confidence interval (CI): 0.824 to 0.855). Model discrimination and calibration were maintained during external validation dataset testing, with AUC of 0.820 (95% CI: 0.685 to 0.955) and Brier Score of 0.177 (95% CI: 0.147 to 0.206). Moreover, the considerably overexpressed TXNDC5 and CTSL proteins identified in the plasma of patients with CPB-ARDS, exhibited a significant upregulation in the lung tissue of LIRI rats. This study identified several novel predictive biomarkers, developed and validated a practical prediction tool using biomarker and clinical factor combinations for individual prediction of CPB-ARDS risk. Assessing the plasma TXNDC5, CTSL, and NPC2 levels might identify patients who warrant closer follow-up and intensified therapy for ARDS prevention following major surgery.