Effects of Therapeutic Plasma Exchange on the Endothelial Glycocalyx in Septic Shock
Abstract Background: Disruption 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) against fresh frozen plasma might influence eGC related pathology.Methods: We enrolled 20 norepinephrine dependent (NE > 0.4mg/kg/min) patients with early septic shock (onset < 12h). 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. Results: SDF demonstrated a decrease in eGC thickness in septic patients compared to healthy individuals (p=0.001). Circulating HS levels were increased more than six-fold 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.Conclusions: Septic 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