Abstract Rationale Degradation of the endothelial glycocalyx, a layer of glycosaminoglycans (GAGs) and proteoglycans (e.g., syndecan-1), is crucial to the pathogenesis of critical illness syndromes, including sepsis and ARDS. However, the duration of glycocalyx shedding following critical illness is unknown. Additionally, many critically ill patients survive their ICU stay, but do not fully, often requiring hospitalization at long-term acute care hospitals (LTACHs) for ventilator weaning. These patients, who are described as having chronic critical illness (CCI), have very high mortality; however, the mechanisms underlying the failure to recover from critical illness are understudied. To address these knowledge gaps we examined the relationship between plasma syndecan-1 and mortality in CII patients. Methods We conducted an observational cohort study of individuals who had undergone tracheostomy in the ICU and were then transferred to an LTACH for ventilator weaning. Exclusion criteria were cystic fibrosis and lung transplant. Weekly blood samples were collected for up to eight weeks. Syndecan-1 was measured using commercially available ELISA. IL-6 and IL-8 were measured using O-link proteomics. The hazard ratio (HR) for death for syndecan-1 was determined using a cubic spline in an exponential survival model, and the syndecan-1 trajectory in survivors vs non-survivors was determined using a mixed effects model. Spearman coefficients were calculated to determine the relationship between syndecan-1 and inflammatory cytokines. Results Our study included 36 CCI patients. The median plasma syndecan-1 concentration was 173 ng/mL (IQR 83-873), with a long right tail (range 27-3620 ng/mL). The HR for death for syndecan-1 (natural log) was 1.84 (95% CI 1.03-3.27, p = 0.038) and rose with increasing syndecan-1 (Figure 1A). Mixed effects modeling revealed that although the syndecan-1 levels were similar at the start of the CCI study, log syndecan-1 decreased over time in patients who survived, but not in those who died (p = 0.004 for the interaction between survival status and time) (Figure 1B). Syndecan-1 correlated with the inflammatory cytokines IL-6 (rho=0.46, p = 1.7e-5) (Figure 1C) and IL-8 (rho=0.66, p = 2.7e-11) (Figure 1D). Conclusions We report for the first time that there is ongoing endothelial glycocalyx degradation in patients who fail to recover after acute critical illness and that the trajectory of plasma syndecan-1 is associated with mortality even months after acute illness onset. These results suggest that patients can experience ongoing inflammatory vascular injury for months after acute critical illness, which is characterized by a failure of the endothelial glycocalyx to return to homeostasis. This abstract is funded by: National Institute of Health and the Parker B Francis Foundation
Rizzo et al. (Fri,) studied this question.