Treatment effects of Xuebijing injection in patients with sepsis by clinical phenotype: a post hoc analysis of the EXIT-SEP trial.

Background: Xuebijing injection (XBJ) could improve the outcomes of sepsis patients. However, sepsis is a heterogeneous syndrome, and it remains unclear which patients benefit the most. We aimed to identify the sepsis phenotypes most likely to benefit from XBJ treatment. Methods: This post hoc analysis of the EXIT-SEP trial included sepsis patients from 45 intensive care units (ICUs) in China between October 2017 and June 2019. The XBJ group received 100 mL of XBJ every 12 h for 5 days, while the placebo group was given a volume-matched saline. Consensus Findings: Among 1760 patients (878 in the XBJ group and 882 in the placebo group), four sepsis phenotypes (α: 28.2%, β: 24.0%, γ: 28.9%, and δ: 18.9%) were replicated based on the SENECA classification. Phenotype α had the lowest 28-day mortality. Phenotype β was associated with older age, chronic illness, and renal dysfunction. Phenotype γ was characterized by respiratory dysfunction. Phenotype δ was associated with acidosis, elevated alanine transaminase, coagulation dysfunction, shock, and the highest 28-day mortality (32.5%). Compared with placebo, XBJ treatment was associated with lower 28-day mortality in patients with phenotype γ (p = 0.003) and δ (p = 0.033), while the treatment-by-phenotype interaction was not statistically significant. Additionally, patients with phenotype δ who received XBJ had more ventilator-free days and ICU-free days than those with phenotype α, with p for interaction < 0.001 for both outcomes. Finally, a parsimonious classifier model demonstrated good accuracy in phenotype prediction, with AUROCs of 0.937 (95% CI: 0.916-0.957) for α, 0.893 (0.861-0.924) for β, 0.945 (0.927-0.964) for γ, and 0.900 (0.866-0.935) for δ in the internal validation cohort. Interpretation: We replicated four sepsis phenotypes in the EXIT-SEP cohort, with patterns similar to previously established phenotypes. XBJ treatment was associated with lower 28-day mortality in patients with phenotypes γ and δ, but these findings require further validation. Funding: This study was funded by the National Natural Science Foundation of China; Noncommunicable Chronic Diseases-National Science and Technology Major Project; Zhongda Hospital Affiliated to Southeast University, Jiangsu Province High-Level Hospital Construction Funds; Nanjing Technology Development Program; The Pilot Project of the Flagship Hospital of Integrated Traditional Chinese and Western Medicines in Zhongda Hospital affiliated to Southeast University.