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      Decreased endothelial glycocalyx thickness is an early predictor of mortality in sepsis

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          Abstract

          Microcirculatory alterations play an important role in the early phase of sepsis. Shedding of the endothelial glycocalyx is regarded as a central pathophysiological mechanism causing microvascular dysfunction, contributing to multiple organ failure and death in sepsis. The objective of this study was to investigate whether endothelial glycocalyx thickness at an early stage in septic patients relates to clinical outcome. We measured the perfused boundary region (PBR), which is inversely proportional to glycocalyx thickness, of sublingual microvessels (5–25 µm) using sidestream dark field imaging. The PBR in 21 patients with sepsis was measured within 24 h of admission to the intensive care unit (ICU). In addition, we determined plasma markers of microcirculatory dysfunction and studied their correlation with PBR and mortality. Endothelial glycocalyx thickness in sepsis was significantly lower for non-survivors as compared with survivors, indicated by a higher PBR of 1.97 [1.85, 2.19]µm compared with 1.76 [1.59, 1.97] µm, P=0.03. Admission PBR was associated with hospital mortality with an area under the curve of 0.778 based on the receiver operating characteristic curve. Furthermore, PBR correlated positively with angiopoietin-2 (rho=0.532, P=0.03), indicative of impaired barrier function. PBR did not correlate with Acute Physiology and Chronic Health Evaluation IV (APACHE IV), Sequential Organ Failure Assessment score (SOFA score), lactate, syndecan-1, angiopoietin-1 or heparin-binding protein. An increased PBR within the first 24 h after ICU admission is associated with mortality in sepsis. Further research should be aimed at the pathophysiological importance of glycocalyx shedding in the development of multi-organ failure and at therapies attempting to preserve glycocalyx integrity.

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          Most cited references 33

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          The endothelial glycocalyx: composition, functions, and visualization

          This review aims at presenting state-of-the-art knowledge on the composition and functions of the endothelial glycocalyx. The endothelial glycocalyx is a network of membrane-bound proteoglycans and glycoproteins, covering the endothelium luminally. Both endothelium- and plasma-derived soluble molecules integrate into this mesh. Over the past decade, insight has been gained into the role of the glycocalyx in vascular physiology and pathology, including mechanotransduction, hemostasis, signaling, and blood cell–vessel wall interactions. The contribution of the glycocalyx to diabetes, ischemia/reperfusion, and atherosclerosis is also reviewed. Experimental data from the micro- and macrocirculation alludes at a vasculoprotective role for the glycocalyx. Assessing this possible role of the endothelial glycocalyx requires reliable visualization of this delicate layer, which is a great challenge. An overview is given of the various ways in which the endothelial glycocalyx has been visualized up to now, including first data from two-photon microscopic imaging.
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            The Tie-2 ligand angiopoietin-2 is stored in and rapidly released upon stimulation from endothelial cell Weibel-Palade bodies.

            The angiopoietins Ang-1 and Ang-2 have been identified as ligands with opposing functions of the receptor tyrosine kinase Tie-2 regulating endothelial cell survival and vascular maturation. Ang-1 acts in a paracrine agonistic manner, whereas Ang-2 appears to act primarily as an autocrine antagonistic regulator. To shed further light on the complexity of autocrine/paracrine agonistic/antagonistic functions of the angiopoietin/Tie-2 system, we have studied Ang-2 synthesis and secretion in different populations of wild-type and retrovirally Ang-2-transduced endothelial cells. Endogenous and overexpressed endothelial cell Ang-2 is expressed in a characteristic granular pattern indicative of a cytoplasmic storage granule. Light and electron microscopic double staining revealed Ang-2 colocalization with von Willebrand factor, identifying Ang-2 as a Weibel-Palade body molecule. Costaining with P-selectin showed that storage of Ang-2 and P-selectin in Weibel-Palade bodies is mutually exclusive. Stored Ang-2 has a long half-life of more than 18 hours and can be secreted within minutes of stimulation (eg, by phorbol 12-myristate 13-acetate [PMA], thrombin, and histamine). Collectively, the identification of Ang-2 as a stored, rapidly available molecule in endothelial cells strongly suggests functions of the angiopoietin/Tie-2 system beyond the established roles during angiogenesis likely to be involved in rapid vascular homeostatic reactions such as inflammation and coagulation.
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              A high admission syndecan-1 level, a marker of endothelial glycocalyx degradation, is associated with inflammation, protein C depletion, fibrinolysis, and increased mortality in trauma patients.

              To investigate the association between markers of acute endothelial glycocalyx degradation, inflammation, coagulopathy, and mortality after trauma. Hyperinflammation and acute coagulopathy of trauma predict increased mortality. High catecholamine levels can directly damage the endothelium and may be associated with enhanced endothelial glycocalyx degradation, evidenced by high circulating syndecan-1. Prospective cohort study of trauma patients admitted to a Level 1 Trauma Centre in 2003 to 2005. Seventy-five patients were selected blindly post hoc from 3 predefined injury severity score (ISS) groups ( 27). In all patients, we measured 17 markers of glycocalyx degradation, inflammation, tissue and endothelial damage, natural anticoagulation, and fibrinolysis (syndecan-1, IL-6, IL-10, histone-complexed DNA fragments, high-mobility group box 1 (HMGB1), thrombomodulin, von Willebrand factor, intercellular adhesion molecule-1, E-selectin, protein C, tissue factor pathway inhibitor (TFPI), antithrombin, D-dimer, tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA), soluble uPA receptor, and plasminogen activator inhibitor-1), hematology, coagulation, catecholamines, and assessed 30-day mortality. Variables were compared in patients stratified according to syndecan-1 median. Patients with high circulating syndecan-1 had higher catecholamines, IL-6, IL-10, histone-complexed DNA fragments, HMGB1, thrombomodulin, D-dimer, tPA, uPA (all P < 0.05), and 3-fold increased mortality (42% vs. 14%, P = 0.006) despite comparable ISS (P = 0.351). Only in patients with high glycocalyx degradation was higher ISS correlated with higher adrenaline, IL-6, histone-complexed DNA fragments, HMGB1, thrombomodulin, and APTT, lower protein C (all P < 0.05), unchanged TFPI and blunted D-dimer response (P < 0.001) because D-dimer was profoundly increased even at low ISS. After adjusting for age and ISS, syndecan-1 was an independent predictor of mortality (OR: 1.01 [95%CI, 1.00-1.02]; P = 0.043). In trauma patients, high circulating syndecan-1, a marker of endothelial glycocalyx degradation, is associated with inflammation, coagulopathy and increased mortality.
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                Author and article information

                Journal
                Anaesth Intensive Care
                Anaesth Intensive Care
                AIC
                spaic
                Anaesthesia and Intensive Care
                SAGE Publications (Sage UK: London, England )
                0310-057X
                1448-0271
                2 June 2020
                May 2020
                : 48
                : 3
                : 221-228
                Affiliations
                [1 ]Department of Biochemistry, Maastricht University, the Netherlands
                [2 ]Cardiovascular Research Institute Maastricht, Maastricht University, the Netherlands
                [3 ]Department of Intensive Care Medicine, Maastricht University Medical Center, the Netherlands
                [4 ]School of Nutrition and Translational Research in Metabolism, Maastricht University, the Netherlands
                [5 ]Department of Biomedical Engineering, Maastricht University, the Netherlands
                [6 ]Department of Surgery, Maastricht University Medical Center, the Netherlands
                [7 ]Department of Cardiology, Maastricht University Medical Center, the Netherlands
                Author notes

                *These authors contributed equally.

                [*]Martine E Bol, P. Debyelaan 25, 6229 HX Maastricht, PO Box 5800, 6202 AZ Maastricht, the Netherlands. Email: martine.bol@ 123456mumc.nl
                Article
                10.1177_0310057X20916471
                10.1177/0310057X20916471
                7328096
                32486831
                4546b13b-2cff-4c5b-90bc-170dd25095ba
                © The Author(s) 2020

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                Funding
                Funded by: Coen Hemker foundation;
                Award ID: Unrestricted grant
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