Intravenous fluid resuscitation is associated with septic endothelial glycocalyx degradation

Crit Care. 2019 Jul 23;23(1):259. doi: 10.1186/s13054-019-2534-2.


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.

MeSH terms

  • Administration, Intravenous
  • Adult
  • Aged
  • Angiopoietin-2 / analysis
  • Angiopoietin-2 / blood
  • Atrial Natriuretic Factor / analysis
  • Atrial Natriuretic Factor / blood
  • Biomarkers / analysis
  • Biomarkers / blood
  • Endothelium / drug effects
  • Endothelium / metabolism
  • Endothelium / physiopathology*
  • Female
  • Fluid Therapy / adverse effects*
  • Fluid Therapy / methods
  • Fluid Therapy / statistics & numerical data
  • Glycocalyx / drug effects*
  • Glycocalyx / metabolism
  • Heparitin Sulfate / analysis
  • Heparitin Sulfate / blood
  • Humans
  • Male
  • Mass Spectrometry / methods
  • Middle Aged
  • Natriuretic Peptide, Brain / analysis
  • Natriuretic Peptide, Brain / blood
  • Resuscitation / adverse effects
  • Resuscitation / methods
  • Resuscitation / statistics & numerical data
  • Sepsis / blood
  • Sepsis / drug therapy*
  • Sepsis / physiopathology
  • Syndecan-1 / analysis
  • Syndecan-1 / blood
  • Thrombomodulin / analysis
  • Thrombomodulin / blood
  • Tissue Plasminogen Activator / analysis
  • Tissue Plasminogen Activator / blood
  • Vascular Endothelial Growth Factor Receptor-1 / analysis
  • Vascular Endothelial Growth Factor Receptor-1 / blood


  • ANGPT2 protein, human
  • Angiopoietin-2
  • Biomarkers
  • SDC1 protein, human
  • Syndecan-1
  • Thrombomodulin
  • Natriuretic Peptide, Brain
  • Atrial Natriuretic Factor
  • Heparitin Sulfate
  • Vascular Endothelial Growth Factor Receptor-1
  • Tissue Plasminogen Activator