Restrictive Versus Standard Intravenous Fluid Therapy and Endothelial Glycocalyx Shedding in <scp>ICU</scp> Patients With Septic Shock—A Preplanned Sub‐Study of the Randomized <scp>CLASSIC</scp> Trial

Shedding of the endothelial glycocalyx may be a pathophysiological mechanism in septic shock, to which intravenous (IV) fluid therapy may contribute. We aimed to investigate the effects of restrictive versus standard IV fluid therapy on glycocalyx shedding in adult intensive care unit (ICU) patients with septic shock. In this preplanned sub-study of the CLASSIC trial, ICU patients with septic shock were randomized to restrictive or standard IV fluid therapy at one Danish and one Swedish ICU between February 2020 and October 2021. Plasma markers of glycocalyx shedding were measured at four timepoints: within the first hour after randomization (T0), the following morning (T1), the morning after (T2), at ICU discharge or up to 90 days after randomization (T3). The primary outcome was the change in plasma hyaluronan levels from T0 to T1. A total of 54 patients were included, below the planned sample size of 200, leading to important differences between groups. Mean hyaluronan levels decreased by 11 ng/mL (95% CI 35-41) more in the restrictive group compared to the standard group from T0 to T1. The interaction effect between group and time was non-significant (p value: 0.872). In this underpowered sub-study we found no statistically significant difference in endothelial glycocalyx shedding between adult ICU patients with septic shock randomized to restrictive versus standard IV fluid therapy. We consider these findings hypothesis-generating; further research is needed to confirm these results. EDITORIAL COMMENT: In this substudy of the CLASSIC trial, glycocalyx degredation products and related substances were measured serially in sepsic study participants randomized to restrictive or usual fluid treatment protocols. No differences between treatment glycocalyx degredation product and related substance levels were observed. Trial Registration: ClinicalTrials.gov identifier: NCT04282252.