Postoperative Day 3 Biomarkers for Risk Stratification and Prediction of Clinically Relevant Pancreatic Fistula After Pancreaticoduodenectomy: A Retrospective Cohort Study

• POD3 biomarker combination (DFA ≤300 U/L + CRP ≤200 mg/L) provides superior CR-POPF risk stratification compared to conventional POD1 criteria • The model achieves 96.2% sensitivity and 98.8% negative predictive value, outperforming established POD1 DFA >5000 U/L criterion • Four distinct risk categories identified with CR-POPF rates ranging from 1.2% to 31.6% (26-fold difference between groups) • 39.6% of patients met low-risk criteria, enabling personalized perioperative management strategies Clinically relevant postoperative pancreatic fistula (CR-POPF) significantly affects patient outcomes after pancreaticoduodenectomy, necessitating accurate risk stratification for personalized perioperative management. This study evaluated postoperative day 3 (POD3) biomarkers for CR-POPF prediction compared to established criteria. We retrospectively analyzed 439 consecutive pancreaticoduodenectomy patients (2019-2023) at a tertiary referral center. Drain fluid amylase (DFA) and serum C-reactive protein (CRP) were measured on postoperative days 1, 3, and 7. Logistic regression identified CR-POPF risk factors, and receiver operating characteristic curves assessed predictive performance. This study followed STROBE guidelines for observational research. CR-POPF occurred in 55 patients (12.5%). Independent risk factors included age >56 years (OR: 2.33), absence of pancreatic duct dilation (OR: 2.33), and soft pancreatic texture (OR: 2.11). POD3 DFA >300 U/L and serum CRP >200 mg/L strongly predicted CR-POPF (OR: 6.62 and 4.42, respectively). The combination demonstrated high predictive capability (AUC: 0.83) and enabled stratification into four distinct risk groups with CR-POPF rates of 1.2%, 8.0%, 10.5%, and 31.6% (p5000 U/L criterion (sensitivity 96.2% vs. 56.4%, NPV 98.8% vs. 92.7%). POD3 biomarker combination provides superior risk stratification with straightforward clinical utility compared to conventional single-parameter approaches. The 26-fold difference in CR-POPF rates between risk groups enables personalized management strategies. POD3 DFA ≤300 U/L combined with CRP ≤200 mg/L reliably identifies patients at low risk for CR-POPF, with 39.6% of patients meeting these criteria. This approach facilitates evidence-based perioperative decision-making and warrants prospective validation.