Identifying a Refractory Shock Phenotype in Pediatric Sepsis Using a Vasoactive-Adjusted Shock Index

OBJECTIVES: This study aimed to: 1) develop a cardiovascular index that includes hemodynamic status and adjusts for vasoactive medication use; 2) identify pediatric patients with refractory septic shock (RSS) using early trends of the adjusted index, and 3) assess the heterogeneity of treatment effect (HTE) to common adjuvant therapies in RSS versus non-RSS patients. METHODS: Children with sepsis across 13 US pediatric intensive care units between 2012 and 2018 were included. The vasoactive-adjusted shock index (VASI) was derived using the shock index (heart rate/systolic pressure) and adjusted for vasoactive use. Group-based trajectory modeling was applied to 8-hour VASI trends following pediatric intensive care unit admission to stratify patients and replicated using K-means with dynamic time warping. HTE between RSS and non-RSS patients was analyzed using inverse-probability weighted logistic regression. RESULTS: 17,216 patients were included (8.6% mortality). VASI demonstrated a robust progressive increase in clinical risk, outperforming other hemodynamic metrics at discriminating poor outcomes. Trajectory analysis identified four clusters, including a trajectory with persistently high VASI consistent with an RSS clinical phenotype. Unlike fluid balance and albumin use, hydrocortisone use on the first day was associated with lower mortality among RSS patients than among non-RSS patients (interaction, P = 0.002). CONCLUSION: The early trajectory of VASI identifies an RSS clinical phenotype associated with poor outcomes and HTE to adjuvant therapies. Integrating hemodynamic status and vasoactive use into early risk assessment in pediatric sepsis can help identify a high-risk RSS group, with both prognostic and therapeutic relevance.