Nonlinear Association Between Calculated Globulin Levels and 28-Day Mortality in Patients with Sepsis: A Retrospective Cohort Study

Sepsis remains a significant global health challenge, causing approximately 11 million deaths annually. The calculated globulin (CG) level, which is derived from total protein and albumin levels, plays crucial roles in the immune response and inflammation. However, the relationship between the CG level and sepsis mortality remains unexplored. This retrospective cohort study analyzed sepsis patients from the eICU Collaborative Research Database. The primary outcome was 28-day ICU mortality. The relationship between the CG level and mortality was examined via generalized additive models with penalized splines and two piecewise linear regression models. Confounders were adjusted in multivariate analyzes. The overall 28-day ICU mortality was 10.0% among 9110 sepsis patients (mean age 65.3 ± 15.9 years, 48.7% male). An L-shaped relationship was observed between CG level and mortality, with a threshold of 2.9 g/dL (95% CI: 2.8-2.9). This pattern revealed that mortality risk decreased sharply as globulin levels increased to 2.9 g/dL and then plateaued thereafter. Below this threshold, each 1 g/dL increase in the CG was associated with a significantly reduced mortality risk (adjusted OR = 0.51, 95% CI: 0.40-0.64, P < 0.0001). Above 2.9 g/dL, no significant association was observed (OR = 1.04, 95% CI: 0.90-1.19; P = 0.622). These findings remained robust in sensitivity analyzes using hospital mortality as the outcome. This study revealed an L-shaped relationship between CG level and sepsis mortality, with lower CG levels independently associated with increased mortality risk. This finding provides a simple and cost-effective indicator for risk stratification in sepsis patients, facilitating early identification of high-risk individuals and informing clinical decision-making.