Journal Article

Intravenous fluid resuscitation is associated with septic endothelial glycocalyx degradation

Colbert, James F., Angus, Derek C., Tyler, Patrick D., Zhang, Fuming, Schmidt, Eric P., Lindsell, Christopher J., Kellum, John A., Burke, Ryan C., Han, Xiaorui, Uchimido, Ryo, Hippensteel, Joseph A., McMurtry, Sarah A., Linhardt, Robert J., Yealy, Donald M., Shapiro, Nathan I.

2019

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,BMC
• Subject: Administration, Intravenous / Adult / Aged / Angiopoietin-2 - analysis / Angiopoietin-2 - blood / Atrial Natriuretic Factor - analysis / Atrial Natriuretic Factor - blood / Biomarkers - analysis / Biomarkers - blood / Care and treatment / Complications and side effects / Critical Care Medicine / Emergency Medicine / Endothelial glycocalyx / Endothelium / Endothelium - drug effects / Endothelium - metabolism / Endothelium - physiopathology / Female / Fluid resuscitation / Fluid therapy / Fluid Therapy - adverse effects / Fluid Therapy - methods / Fluid Therapy - statistics & numerical data / Glycocalyx / Glycocalyx - drug effects / Glycocalyx - metabolism / Heparitin Sulfate - analysis / Heparitin Sulfate - blood / Homeostasis / Humans / Infection / Intensive / Male / Mass spectrometry / Mass Spectrometry - methods / Medical errors / Medicine / Medicine & Public Health / Middle Aged / Multiple organ failure / Natriuretic Peptide, Brain - analysis / Natriuretic Peptide, Brain - blood / Physiological aspects / Regression analysis / Resuscitation - adverse effects / Resuscitation - methods / Resuscitation - statistics & numerical data / Sepsis / Sepsis - blood / Sepsis - drug therapy / Sepsis - physiopathology / Septic shock / Shock / Spectroscopy / Sulfates / 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