Effect of intravenous fluid volume on biomarkers of endothelial glycocalyx shedding and inflammation during initial resuscitation of sepsis

INTRODUCTIONIntravenous (IV) fluid resuscitation is recommended first line therapy in septic shock, but the effectiveness and safety of this approach has been questioned. To investigate potential mechanisms of harm from IV fluid resuscitation, we measured biomarkers of endothelial glycocalyx (EG) shedding, activation of the vascular endothelium and inflammation over the first 24 hours in a clinical trial comparing a fluid-restricted resuscitation regimen to usual care with no IV fluid restriction. METHODSA planned biomarker sub-study of the REFRESH trial in which emergency department (ED) patients) with suspected sepsis and a systolic blood pressure of <100mmHg after at least 1000ml of crystalloid fluid were randomised to restricted fluids (with a vasopressor infusion if needed to restore perfusion targets) or additional IV fluid resuscitation with later vasopressor if required (usual care). Blood samples were collected at randomisation (T0) and at 3 hours (T3), 6 hours (T6)- and 24 hours (T24) for measurement of Pro-Atrial Natriuretic Peptide (Pro-ANP); EG biomarkers - Syndecans 1 & 4 (SYN-1, SYN-4), Hyaluronan, Heparan Sulphate; Endothelial cell markers - Vascular Cell Adhesion Molecule (VCAM), Intercellular Adhesion Molecule (ICAM), E-selectin, Vascular Endothelial Growth Factor 1 (VEGFR-1); and inflammatory biomarkers - Interleukins 6 & 10 (IL-6, IL-10), Neutrophil Gelatinase Associated Lipocalin (NGAL) and Resistin. RESULTSBlood samples were obtained in 95 of 99 enrolled patients (46 usual care, 49 restricted fluid). Differences in the change in biomarker over time between the groups were observed for Hyaluronan (2.2-fold from T3-T24, p=0.03), SYN-4 (1.5-fold T3 to T24, P=0.01) and IL-6 (2.5-fold from T0 to T3, p=0.03). No difference over time was observed between groups for the other biomarkers. CONCLUSIONSDifferences in the change over time for Hyaluronan, SYN-4 and IL-6 were observed during the first 24 hours among patients with suspected sepsis randomised to difference resuscitation regimens. This supports the hypothesis that IV fluids can lead to shedding of the endothelial glycocalyx and promote inflammation. Conversely no effect was seen for other EG components (SYN-1 and Heparan Sulphate), or for a range of endothelial activation and inflammatory markers. TRIAL REGISTRATIONAustralia New Zealand Clinical Trials Registry ACTRN126160000006448 Registered 12 January 2016