Elevated Syndecan-1 after Trauma and Risk of Sepsis: A Secondary Analysis of Patients from the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) Trial

Abstract

Background: Endotheliopathy of trauma is characterized by breakdown of the endothelial glycocalyx. Elevated biomarkers of endotheliopathy, such as serum syndecan-1 (Synd-1) ≥ 40 ng/mL, have been associated with increased need for transfusions, complications, and mortality. We hypothesized that severely injured trauma patients who exhibit elevated Synd-1 levels shortly after admission have an increased likelihood of developing sepsis.

Study design: We analyzed a subset of patients from the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial who survived at least 72 hours after hospital admission, and we determined elevated Synd-1 levels (≥ 40 ng/mL) 4 hours after hospital arrival. Sepsis was defined a priori as meeting systemic inflammatory response criteria and having a known or suspected infection. Univariate analysis was performed to identify variables associated with elevated Synd-1 levels and sepsis. Significant variables at a value of p < 0.2 in the univariate analysis were chosen by purposeful selection and analyzed in a mixed effects multivariate logistic regression model to account for the 12 different study sites.

Results: We included 512 patients. Of these, 402 (79%) had elevated Synd-1 levels, and 180 (35%) developed sepsis. Median Synd-1 levels at 4 hours after admission were 70 ng/dL (interquartile range [IQR] 36 to 157 ng/dL) in patients who did not develop sepsis, and 165 ng/dL [IQR 67 to 336 ng/dL] in those who did (p < 0.001). Adjusting for treatment arm and site, multivariable analyses revealed that elevated Synd-1 status, Injury Severity Score (ISS), and total blood transfused were significantly associated with an increased likelihood of developing sepsis.

Conclusions: Elevated Synd-1 levels 4 hours after admission in severely injured adult trauma patients who survived the initial 72 hours after hospital admission are associated with subsequent sepsis.

Figure 1.

Simplified conceptual model of how hemorrhagic shock leads to sympathoadrenal activation, inflammation, and ischemia, which affects the endothelial glycocalyx, endothelial permeability, and hemostatic balance, resulting in edema and microcirculatory disturbances that cause organ dysfunction.

Figure 2.

Flow diagram of patient selection. PROPPR, Pragmatic, Randomized Optimal Platelet and Plasma Ratios Trial

Figure 3.

Days to sepsis development in patients with low (< 40 ng/mL) vs high (≥ 40 ng/mL) syndecan-1 levels at 4 hours after admission. The median time to sepsis development was 8 days and 6 days (p = 0.4) in low and high syndecan-1 groups, respectively. The number of patients at risk was derived based on “time to sepsis” data available for 153 patients. Time to sepsis data was missing for 27 patients. The solid and dotted lines represent proportion of patients who are sepsis free out of the total 153 sepsis patients. The majority of patients in both syndecan-1 groups developed sepsis within the first 10 days of admission, and there is substantial overlap of the 95% confidence intervals suggesting that there is no significant differences in time to sepsis between the two groups.