Abstract
BackgroundDisruption of the endothelial glycocalyx (eGC) is observed in septic patients and its injury is associated with multiple-organ failure and inferior outcomes. Besides this biomarker function, increased blood concentrations of shedded eGC constituents might play a mechanistic role in septic organ failure. We hypothesized that therapeutic plasma exchange (TPE) using fresh frozen plasma might influence eGC-related pathology by removing injurious mediators of eGC breakdown while at the time replacing eGC protective factors.MethodsWe enrolled 20 norepinephrine-dependent (NE > 0.4 μg/kg/min) patients with early septic shock (onset < 12 h). Sublingual assessment of the eGC via sublingual sidestream darkfield (SDF) imaging was performed. Plasma eGC degradation products, such as heparan sulfate (HS) and the eGC-regulating enzymes, heparanase (Hpa)-1 and Hpa-2, were obtained before and after TPE. A 3D microfluidic flow assay was performed to examine the effect of TPE on eGC ex vivo. Results were compared to healthy controls.ResultsSDF demonstrated a decrease in eGC thickness in septic patients compared to healthy individuals (p = 0.001). Circulating HS levels were increased more than sixfold compared to controls and decreased significantly following TPE [controls: 16.9 (8–18.6) vs. septic patients before TPE: 105.8 (30.8–143.4) μg/ml, p < 0.001; vs. after TPE: 70.7 (36.9–109.5) μg/ml, p < 0.001]. The Hpa-2 /Hpa-1 ratio was reduced in septic patients before TPE but normalized after TPE [controls: 13.6 (6.2–21.2) vs. septic patients at inclusion: 2.9 (2.1–5.7), p = 0.001; vs. septic patients after TPE: 13.2 (11.2–31.8), p < 0.001]. Ex vivo stimulation of endothelial cells with serum from a septic patient induced eGC damage that could be attenuated with serum from the same patient following TPE.ConclusionsSeptic shock results in profound degradation of the eGC and an acquired deficiency of the protective regulator Hpa-2. TPE removed potentially injurious eGC degradation products and partially attenuated Hpa-2 deficiency.Trial registration clinicaltrials.gov NCT04231994, retrospectively registered 18 January 2020
Highlights
Disruption of the endothelial glycocalyx is observed in septic patients and its injury is associated with multiple-organ failure and inferior outcomes
We found that stimulation with serum from a representative patient with septic shock before therapeutic plasma exchange (TPE) was sufficient to severely damage the endothelial glycocalyx (eGC) indicated by a reduced heparan sulfate (HS) positive area on the surface of endothelial cells (Fig. 5A)
We investigated the effects of early TPE on the eGC in septic shock
Summary
Disruption of the endothelial glycocalyx (eGC) is observed in septic patients and its injury is associated with multiple-organ failure and inferior outcomes. The endothelial glycocalyx (eGC), a gel-like structure of glycosaminoglycans and proteoglycans covering the entire luminal surface of the endothelium, contributes to the maintenance of vascular hemostasis including tone and permeability as well as inflammation and coagulation [4]. Disruption of this highly dynamic structure is observed early in sepsis, and the resultant eGC injury is strongly associated with later multi-organ failure and inferior outcomes [5,6,7]. The observed positive effects in rapid hemodynamic stabilization [15] could be related to removal of deleterious components or replacement of protective plasma proteins consumed by the disease process [16, 17]
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