Endothelial damage in septic shock patients as evidenced by circulating syndecan-1, sphingosine-1-phosphate and soluble VE-cadherin: a substudy of ALBIOS
Authors: Piotti Arianna , Novelli Deborah , Meessen Jennifer Marie Theresia Anna , Ferlicca Daniela , Coppolecchia Sara , Marino Antonella , Salati Giovanni , Savioli Monica , Grasselli Giacomo , Bellani Giacomo , Pesenti Antonio , Masson Serge , Caironi Pietro , Gattinoni Luciano , Gobbi Marco , Fracasso Claudia , Latini Roberto ,   the ALBIOS Investigators, Bruzzone Paola , Pagan Francesca , Russo Riccarda , Confalonieri Andrea , Abbruzzese Chiara , Vergnano Beatrice , Faenza Stefano , Siniscalchi Antonio , Pierucci Elisabetta , Noto Andrea , Pezzi Angelo , Spanu Paolo , Parrini Vieri , Oggioni Roberto , Pasetti Giovanni Stefano , Casadio Maria Cinzia , Buontempo Rosa , Carrer Sara , Piccoli Francesca , Rizzi Tatiana , Caricato Anselmo , La Sala Monica , Antonaci Alessandra , Fassini Paola , Paganini Silvia , Porta Virginia , Moise Gabriella , Marell Silvia , Furia Mirella , Urbano Maria Cristina , Carobbi Roberta , Poleni Simona , Kandil Hassan , Ballotta Andrea , Bettini Fabrizio , Sanseverino Manlio , Gatta Alessandro , Cecchini Francesca , Guatteri Luca , Ciceri Gabriella , Raimondi Ferdinando , Colombo Roberto , Ferraris Sandra , Borelli Massimo , Bellato Valentina , Cancellieri Franco , Senni Silvia , Bertocchi Ester , Ferri Paola , Moioli Gianpietro , Fedele Andrea , Molin Alexandra , Salati Giovanni , Salsi Pierpaolo , Brunori Emanuela , Elisei Daniele , Maggio Giuseppe , Nicola Federico Guardia , Cavana Marco , Morelli Giacomo , Guarino Arturo , Isetta Michele , Tulli Giorgio , Mangani Valerio , Rossi Nicola , Ferrari Marta , Bona Francesco , Vay Monica , Bartoli Teresa , Gallo Mauro , Vettoretto Katiuscia , Morte Mauro Della , Boselli Enrico , Puscio Daniela , Bovo Monia , Galzerano Antonio , Carli Manuela , Zagara Giovanni 
Published: March 2021

Abstract
Background
Septic shock is characterized by breakdown of the endothelial glycocalyx and endothelial damage, contributing to fluid extravasation, organ failure and death. Albumin has shown benefit in septic shock patients. Our aims were: (1) to identify the relations between circulating levels of syndecan-1 (SYN-1), sphingosine-1-phosphate (S1P) (endothelial glycocalyx), and VE-cadherin (endothelial cell junctions), severity of the disease, and survival; (2) to evaluate the effects of albumin supplementation on endothelial dysfunction in patients with septic shock.

Methods
This was a retrospective analysis of a multicenter randomized clinical trial on albumin replacement in severe sepsis or septic shock (the Albumin Italian Outcome Sepsis Trial, ALBIOS). Concentrations of SYN-1, S1P, soluble VE-cadherin and other biomarkers were measured on days 1, 2 and 7 in 375 patients with septic shock surviving up to 7 days after randomization.

Results
Plasma concentrations of SYN-1 and VE-cadherin rose significantly over 7 days. SYN-1 and VE-cadherin were elevated in patients with organ failure, and S1P levels were lower. SYN-1 and VE-cadherin were independently associated with renal replacement therapy requirement during ICU stay, but only SYN-1 predicted its new occurrence. Both SYN-1 and S1P, but not VE-cadherin, predicted incident coagulation failure. Only SYN-1 independently predicted 90-day mortality. Albumin significantly reduced VE-cadherin, by 9.5% (p = 0.003) at all three time points.

Conclusion
Circulating components of the endothelial glycocalyx and of the endothelial cell junctions provide insights into severity and progression of septic shock, with special focus on incident coagulation and renal failure. Albumin supplementation lowered circulating VE-cadherin consistently over time.
Clinical Trial Registration: ALBIOS ClinicalTrials.gov number NCT00707122.