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

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.

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.

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.

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.