Concurrent activation of multiple programmed cell death pathways predicts 28-day mortality in pediatric sepsis: a retrospective PICU cohort study with differential sedative agent use between survivors and non-survivors

Objective To systematically characterize the expression profiles of biomarkers associated with multiple programmed cell death (PCD) pathways—including apoptosis, pyroptosis, necroptosis, and ferroptosis—in pediatric intensive care unit (PICU) patients with sepsis, elucidate their associations with organ dysfunction severity and clinical prognosis, and identify independent predictors of 28-day all-cause mortality in children. Methods A retrospective cohort study was conducted on 208 pediatric sepsis patients (aged 1 month to 18 years) admitted to the PICU of Jingzhou First People’s Hospital between January 2021 and December 2023. Based on 28-day survival outcomes, patients were divided into a survival group (n = 148) and a death group (n = 60). Plasma biomarkers for apoptosis (caspase-3, caspase-9, Bcl-2, Bax), pyroptosis (NLRP3, caspase-1, GSDMD, IL-1β, IL-18), necroptosis (RIPK1, RIPK3, MLKL), ferroptosis (GPX4, ferritin, MDA, 4-HNE), and damage-associated molecular patterns (DAMPs: HMGB1, HSP70, S100A8/A9) were measured within 24 h of PICU admission. ROC analysis, Kaplan-Meier survival analysis, and Cox proportional hazards regression were employed for prognostic evaluation. Results The 28-day mortality rate was 28.8% (60/208). Non-survivors demonstrated significantly elevated NLRP3, caspase-1, GSDMD, IL-18, RIPK3, MLKL, HMGB1, ferritin, and MDA, and significantly lower GPX4 and Bcl-2/Bax ratio compared to survivors (all P < 0.001). NLRP3 demonstrated the highest individual predictive value (AUC = 0.836), and the combined biomarker panel (NLRP3+GPX4+HMGB1) substantially outperformed pSOFA score alone (AUC = 0.896 vs. 0.786). Multivariate Cox regression identified NLRP3 >2.45 ng/mL (HR = 2.847, 95%CI: 1.682–4.819), GPX4 <12.3 ng/mL (HR = 2.234, 95%CI: 1.458–3.425), HMGB1 >15.6 ng/mL (HR = 1.856, 95%CI: 1.142–3.015), and pSOFA score >8 (HR = 1.672, 95%CI: 1.089–2.567) as independent predictors of 28-day mortality (C-index = 0.821). Conclusion Multiple PCD pathways are concurrently activated in pediatric sepsis, with NLRP3-driven pyroptosis and GPX4-deficient ferroptosis as the strongest independent mortality predictors. From a pediatric anesthesiology perspective, anesthetic agents with documented anti-pyroptotic or anti-ferroptotic properties—including dexmedetomidine and propofol—may represent adjunctive organ-protective strategies. Combined PCD biomarker profiling provides additive prognostic value beyond conventional severity scores and identifies mechanistically distinct therapeutic targets.