Intravenous fluid resuscitation is associated with septic endothelial glycocalyx degradation

Abstract

Background: Intravenous fluids, an essential component of sepsis resuscitation, may paradoxically worsen outcomes by exacerbating endothelial injury. Preclinical models suggest that fluid resuscitation degrades the endothelial glycocalyx, a heparan sulfate-enriched structure necessary for vascular homeostasis. We hypothesized that endothelial glycocalyx degradation is associated with the volume of intravenous fluids administered during early sepsis resuscitation.

Methods: We used mass spectrometry to measure plasma heparan sulfate (a highly sensitive and specific index of systemic endothelial glycocalyx degradation) after 6 h of intravenous fluids in 56 septic shock patients, at presentation and after 24 h of intravenous fluids in 100 sepsis patients, and in two groups of non-infected patients. We compared plasma heparan sulfate concentrations between sepsis and non-sepsis patients, as well as between sepsis survivors and sepsis non-survivors. We used multivariable linear regression to model the association between volume of intravenous fluids and changes in plasma heparan sulfate.

Results: Consistent with previous studies, median plasma heparan sulfate was elevated in septic shock patients (118 [IQR, 113-341] ng/ml 6 h after presentation) compared to non-infected controls (61 [45-79] ng/ml), as well as in a second cohort of sepsis patients (283 [155-584] ng/ml) at emergency department presentation) compared to controls (177 [144-262] ng/ml). In the larger sepsis cohort, heparan sulfate predicted in-hospital mortality. In both cohorts, multivariable linear regression adjusting for age and severity of illness demonstrated a significant association between volume of intravenous fluids administered during resuscitation and plasma heparan sulfate. In the second cohort, independent of disease severity and age, each 1 l of intravenous fluids administered was associated with a 200 ng/ml increase in circulating heparan sulfate (p = 0.006) at 24 h after enrollment.

Conclusions: Glycocalyx degradation occurs in sepsis and septic shock and is associated with in-hospital mortality. The volume of intravenous fluids administered during sepsis resuscitation is independently associated with the degree of glycocalyx degradation. These findings suggest a potential mechanism by which intravenous fluid resuscitation strategies may induce iatrogenic endothelial injury.

Keywords: Endothelial glycocalyx; Fluid resuscitation; Multiple organ failure; Sepsis.

Fig. 1

Glycocalyx degradation occurs in patients with septic shock. a The endothelial glycocalyx is an apical endothelial layer composed of transmembrane proteoglycans (such as syndecan-1 and thrombomodulin) covalently attached to glycosaminoglycans (primarily heparan sulfate) that project into the vascular lumen. During sepsis, activation of heparanase and matrix metalloproteinases leads to glycocalyx degradation, releasing heparan sulfate and proteoglycan fragments into the plasma. b In a cohort of 56 septic shock patients enrolled in the ProCESS trial, circulating heparan sulfate levels were elevated in comparison to 15 non-infected ED controls. Measurements in septic patients were made 6 h after enrollment (i.e., after initial fluid resuscitation). c Of 56 septic patients, 8 patients eventually died during their hospitalization. There was a non-significant trend towards increased heparan sulfate concentrations (measured after 6 h resuscitation) in non-survivors. Circulating heparan sulfate concentrations (at 6 h) correlated with plasma concentrations of glycocalyx components syndecan-1 (d) and thrombomodulin (e) in septic shock patients. Line represents best fit line. f There was no association between plasma heparan sulfate and atrial natriuretic peptide (ANP) in septic shock patients after 6 h resuscitation. Parentheses in b, c represent number of patients in each group

Fig. 2

Circulating glycocalyx degradation products predict clinically relevant outcomes in sepsis patients presenting to the Beth Israel Deaconess Medical Center or St. Vincent’s Hospital Emergency Departments. a Elevated levels of circulating heparan sulfate at emergency department (ED) presentation were associated with a diagnosis of severe sepsis or septic shock within the ensuing 72 h (n = 100). b Heparan sulfate levels correlated with increased severity of illness (SOFA) at the time of ED presentation (n = 100). c Measures of circulating heparan sulfate in septic patients at ED presentation (n = 100) were significantly associated with mortality. d Receiver operating characteristic (ROC) curve for plasma heparan sulfate (at ED presentation) as a predictor of later in-hospital mortality. e Heparan sulfate plasma concentrations at ED presentation were elevated in septic patients with positive bacterial blood cultures. Three blood samples that grew Staph. epidermidis (contaminant) were excluded. *p < 0.05; **p < 0.0001. Parentheses represent number of patients

Fig. 3

Volume of intravenous fluids administered early in sepsis predicts degree of glycocalyx degradation. The total volume of intravenous fluids administered in the first 24 h after ED presentation predicted the change in plasma heparan sulfate levels from initial blood draw to 24 h blood draw. Model R² = 0.149, fit lines are shown for patients experiencing sepsis, severe sepsis, and septic shock, adjusted for age and baseline SOFA score