Biological Effects of Hemoadsorption in Septic Shock

Septic shock is the most severe form of sepsis and continues to carry an in-hospital mortality of between 30% and 50% despite advances in compliance with the Surviving Sepsis Campaign care bundles.

The pathophysiology of septic shock is dominated by an uncontrolled immuno-inflammatory response with massive release of mediators, pro- and anti-inflammatory cytokines5, DAMPs (damage-associated molecular patterns) and PAMPs (pathogen-associated molecular patterns), producing vasoplegia, endothelial dysfunction, glycocalyx damage and, in many patients, a subsequent immunoparalysis phase that increases the risk of nosocomial infections and late mortality.

Endothelial damage and glycocalyx degradation are central elements in the pathophysiology of septic shock. The endothelial glycocalyx, a layer of proteoglycans and glycosaminoglycans approximately 0.5 µm thick on the luminal surface of the endothelium, regulates vascular permeability, leukocyte adhesion and the inflammatory response. During sepsis, the release of metalloproteinases, heparanase and other inflammatory mediators causes the shedding of syndecan-1, heparan sulfate and other glycocalyx molecules into the circulation. This process is associated with increased capillary permeability, interstitial edema, third-space fluid leakage, and progression to multiorgan failure. Elevated plasma syndecan-1 levels correlate with greater severity of septic shock, development of acute respiratory distress syndrome (ARDS), extrapulmonary organ dysfunction, and mortality. In parallel, the release of angiopoietin-2 by activated endothelial cells antagonizes Tie2 signaling, destabilizes the endothelial barrier and amplifies vascular dysfunction.

Selective modulation of the immune response through extracorporeal adsorption of medium-sized mediators (5-60 kDa) is an adjunctive strategy whose biological rationale is well established and whose hemodynamic effect has been described by multiple authors. The HA380 HA cartridge (Jafron Biomedical), specifically, uses a synthetic neutral macroporous polymer resin with high affinity for cytokines in the 10-60 kDa range, especially IL-6, TNF-α, IL-8 and IL-10. The device is connected to an extracorporeal therapy circuit (in this protocol, always integrated into a continuous renal replacement therapy \[CRRT\] circuit) and operates for 4-6 hours per cartridge. Removal of proinflammatory cytokines (IL-6, TNF-α, IL-8) with HA380 also aims to reduce their effect on endothelial damage, and recent studies with other cytokine adsorbents have demonstrated the ability to remove circulating angiopoietin-2. Although the specific literature on the effect of HA380 on recovery of glycocalyx integrity is limited, reducing the burden of cytokines and endotoxic mediators could attenuate the glycocalyx degradation cascade and contribute to the hemodynamic stabilization observed in clinical studies. This mechanism provides an additional biological rationale for assessing biomarkers of endothelial dysfunction (angiopoietin-2, syndecan-1, soluble thrombomodulin) as secondary variables in the present study.

Within the spectrum of septic shock, this protocol distinguishes two clinically and biologically relevant severity strata: 1) established septic shock as per Sepsis-3 criteria who, despite requiring vasopressor support and showing hyperlactatemia, do not meet the thresholds of refractoriness. 2) refractory septic shock, a particularly severe subgroup in which standard resuscitation measures-guided fluid therapy, vasopressors, source control, early antibiotic therapy, and hydrocortisone-are insufficient to reverse tissue hypoperfusion and progressive organ dysfunction.

Primary objective To establish whether HA380 hemoadsorption yields a more desirable overall outcome than concurrent standard of care, within each severity stratum, using a pre-specified hierarchical ordinal DOOR endpoint.