# The Impact of Fluid Resuscitation on Glycocalyx Degradation in Septic Shock

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2021 · $398,769

## Abstract

Despite advances in the understanding of sepsis and sepsis-induced lung injury, patient morbidity and
mortality remain unacceptably high. There is increasing recognition that the endothelial glycocalyx, a
glycosaminoglycan-enriched endovascular layer, is a critical determinant of sepsis outcomes. The glycocalyx
serves to regulate leukocyte adhesion, coagulation, microcirculatory flow, and vascular permeability – functions
vital to vascular homeostasis. Emerging preclinical and small human studies demonstrate that sepsis-mediated
pathologic disturbances degrade the glycocalyx, leading to vascular dysfunction, lung injury and mortality.
This increasing appreciation of the importance of glycocalyx integrity has coincided with recognition that
intravenous fluid administration—long considered an essential component of sepsis resuscitation—may
paradoxically worsen organ injury in sepsis. Interestingly, preclinical and small clinical studies suggest that
excessive fluid resuscitation is associated with pathological glycocalyx degradation, suggesting a mechanism
by which intravenous fluids may cause lung injury. Conversely, loss of glycocalyx integrity prior to sepsis
resuscitation may help define a patient's susceptibility to the deleterious effects of fluids—representing a
potential opportunity to personalize fluid resuscitation approaches.
The Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) trial is a NIH-funded 2,320
subject multi-center, randomized, controlled clinical trial conducted by the ~50-site Prevention and Treatment
of Acute Lung Injury (PETAL) network comparing alternative 24-hour fluid resuscitation strategies (liberal
versus restrictive) in early sepsis and the effect on mortality. While the glycocalyx was not addressed in the
original trial protocol, CLOVERS is ideally positioned to determine the potential causal associations between
fluid resuscitation strategies, glycocalyx degradation, ARDS, and mortality in sepsis.
The broad, long-term objectives of this proposal are to investigate if: 1) different fluid resuscitation strategies
(Restrictive or Liberal) impact glycocalyx degradation in sepsis; 2) glycocalyx degradation is associated with
the development of acute respiratory distress syndrome (ARDS) and/or mortality, 3) circulating markers of
initial glycocalyx integrity can predict patient responses to different volume resuscitation strategies.
To pursue these hypotheses, we will leverage the unique opportunity provided by the CLOVERS study to
perform a comprehensive readout of glycocalyx damage, employing not only state-of-the-art measures of
glycocalyx degradation (mass spectrometry detection of glycocalyx breakdown products such as heparan
sulfate), but also less expensive ELISA-based (syndecan-1) and point-of-care functional assays (e.g.
viscoelastic coagulation monitoring) capable of rapid assessment of glycocalyx integrity. The elucidation and
improved understanding of these mechanisms may lead to s...

## Key facts

- **NIH application ID:** 10249980
- **Project number:** 5R01HL149422-03
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** NATHAN I SHAPIRO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $398,769
- **Award type:** 5
- **Project period:** 2019-09-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10249980

## Citation

> US National Institutes of Health, RePORTER application 10249980, The Impact of Fluid Resuscitation on Glycocalyx Degradation in Septic Shock (5R01HL149422-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10249980. Licensed CC0.

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