Extracorporeal cfDNA Removal in Septic Shock Patients With Elevated DNA Levels

Sepsis remains a critical problem with significant morbidity and mortality for a modern healthcare. According to the latest definitions, sepsis is a clinical syndrome defined by a systemic response to infection leading to organ failure. Recent breakthroughs in the pathophysiology of sepsis have identified key signaling molecules - including cytokines, toxins, and DAMPs - that initiate and perpetuate the dysregulated immune response. As an adjunctive treatment, extracorporeal therapy has emerged as an effective strategy for the targeted elimination of these mediators.

Current clinical and research methods include: non-selective hemoperfusion, which targets pro-inflammatory middle-molecular-weight proteins (10-60 kDa) such as s IL-1, TNF-α, IL-2, IL-6, IL-8, IL-10, IFN-γ and complement proteins (e.g., CytoSorb, HA330 hemadsorption cartridges); and selective hemoperfusion, designed to eliminate Gram-negative bacterial lipopolysaccharides (LPS) via affinity-binding fibers like Polymyxin B (e.g., Toraymyxin). A meta-analysis by Li et al. (2021), synthesizing data from 13 randomized controlled trials, demonstrated that LPS-selective hemoperfusion significantly reduces mortality and endotoxin levels while stabilizing hemodynamic parameters. The EUPHRATES trial, the largest RCT to date, demonstrated improvements in mean arterial pressure and 28-day survival exclusively within the subgroup of patients exhibiting endotoxin activity levels between 0.6 and 0.89.

Therapeutic Plasma Exchange (TPE) serves as an alternative adjunctive therapy that entails the complete separation and removal of the patient's plasma from cellular components, including cytokines and toxins. A recent EXCHANGE-1 study has demonstrated that TPE is associated with the reduction of acute-phase proteins and improved hemodynamics in patients with septic shock. The clinical potential of TPE in sepsis treatment remains a subject of active investigation.

A prominent frontier in sepsis research focuses on the novel approach extracorporeal removal of cell-free DNA (cfDNA) and neutrophil extracellular traps (NETs), which are now recognized as one more critical drivers of systemic inflammation. Excessive cell-free DNA (cfDNA) acts as DAMP, further activating immune cells and the endothelium through the TLR-9 (Toll-like receptor) signaling pathway. This process leads to cellular damage and microvascular thrombosis. Consequently, cfDNA serves as a primary driver of 'immunothrombosis' - a state of inflammation-induced hypercoagulation. Furthermore, cfDNA is implicated in the pathogenesis of sepsis-associated acute kidney and lung injury. These mechanisms provide a robust hypothetical framework for therapies targeting the extracorporeal elimination of cfDNA in septic shock.

Some hemoadsorption cartridges like 'Nucleocor' bind circulating histones to prevent them from triggering NETosis and systemic inflammation. To date, there are no universally accepted guidelines for the extracorporeal elimination of DNA-containing structures-such as cell-free DNA (cfDNA) and neutrophil extracellular traps (NETs)-from the systemic circulation in sepsis and septic shock. This study will evaluate the efficacy and safety of extracorporeal therapy using 'Nucleocor' plasma adsorption columns in patients with septic shock characterized by prognostically unfavorable elevations in cfDNA levels. The 'Nucleocor' adsorption columns represent a unique, world-first device designed for the selective removal of DNA-containing molecular structures from the bloodstream. The project aims to establish a standardized protocol for this extracorporeal therapy and generate the evidence base required for its inclusion in national clinical guidelines.