Abstract
BackgroundIntravenous 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.MethodsWe 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.ResultsConsistent 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.ConclusionsGlycocalyx 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.
Highlights
Intravenous fluids, an essential component of sepsis resuscitation, may paradoxically worsen outcomes by exacerbating endothelial injury
We used a convenience sample of 56 patients enrolled at sites participating in the Protocolized Care for Early Septic Shock (ProCESS) Microcirculatory Flow Ancillary Study [23] to perform an initial assessment of glycocalyx degradation in sepsis
We have previously demonstrated that this LC-MS/ MS Liquid chromatography-mass spectrometry multiple reaction monitoring (MRM) approach to measuring circulating heparan sulfate is highly sensitive to both septic and non-septic glycocalyx degradation [31] and is an early predictor of glycocalyx degradation-associated organ injury [28]
Summary
Intravenous fluids, an essential component of sepsis resuscitation, may paradoxically worsen outcomes by exacerbating endothelial injury. There is increasing concern that intravenous fluids may unexpectedly augment septic endothelial dysfunction, potentially negating the beneficial hemodynamic effects of fluid resuscitation [3]. Such iatrogenic injury could explain the findings of several recent randomized trials which demonstrated that early bolus intravenous fluids worsened sepsis survival [4, 5], as well as observational studies that identified associations between fluid administration [6, 7], fluid balance [8,9,10,11,12], and adverse outcomes. The presence of circulating glycocalyx constituents such as heparan sulfate or syndecan-1 fragments indicates a loss of glycocalyx integrity and associated endothelial injury [18]
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