Reframing Surgical Risk in Frailty: Causal Mediation Analysis of Mortality and Readmission after Pancreatectomy

BACKGROUND: Frailty predicts poor outcomes after pancreatectomy, but whether excess mortality and readmission reflect more postoperative complications, worse rescue after complications, or broader recovery vulnerability remains unclear. STUDY DESIGN: We performed a retrospective study of the ACS-NSQIP Pancreatectomy database (2014-2023) including 71,104 patients undergoing pancreatic resection. Frailty was defined as modified 5-item frailty index score ≥2. Multivariable logistic regression evaluated associations between frailty and 30-day mortality and readmission. Causal mediation analysis quantified total, direct, and complication-mediated indirect effects. Interaction modeling compared failure-to-rescue and non-precedented deaths by frailty status. RESULTS: Of 71,104 patients, 15,779 (22.2%) were frail. Frailty was independently associated with 30-day mortality (aOR 1.29, 95% CI 1.13-1.46; p<0.001) and readmission (aOR 1.11, 95% CI 1.06-1.16; p<0.001). For mortality, the total effect of frailty was significant (RR 1.32, 95% CI 1.23-1.40; p<0.001), the indirect effect through complications was significant (RR 1.25, 95% CI 1.22-1.27; p<0.001), and the direct effect was not (RR 1.07, 95% CI 0.99-1.14; p=0.400); complications mediated 80.72% of the frailty-mortality association. The largest contributors were unplanned reintubation, bleeding requiring transfusion, septic shock, acute kidney injury requiring dialysis, myocardial infarction, and organ/space surgical site infection. Major complications increased mortality similarly in frail and non-frail patients, without meaningful frailty-related differences in failure-to-rescue. For readmission, complications explained only 17% of the frailty association. CONCLUSIONS: After pancreatectomy, frailty-associated mortality is largely explained by postoperative complications, whereas frailty-associated readmission is driven predominantly by vulnerability beyond complications. These findings support complication prevention, prehabilitation, and intensified post-discharge follow-up for frail patients.