Efferon LPS Hemoperfusion for Treatment of Patients With Septic Shock

Introduction. Sepsis, according to the latest consensus definition (SEPSIS-3, 2016), is a disease characterized by life-threatening organ failure resulting from a disordered regulation of the body's response to infection. Sepsis continues to be the leading cause of death in intensive care units in almost any country in the world.

The highest mortality rate in sepsis is associated with the development of septic shock (SS). Septic shock is defined as sepsis (according to the criteria of SEPSIS-3, 2016) accompanied by severe hemodynamic, cellular and metabolic disorders, with a higher risk of fatal outcome than sepsis without shock. On average, SS is detected with a frequency of 8.3-10.4% among ICU patients, and its mortality, according to recent estimates, reaches 38-50% and even higher, exceeding 50-80% with such comorbidity as diabetes mellitus.

Success in treating septic shock is traditionally associated with adequate vasopressor, antibacterial, and anti-shock therapy, including inotropic support. At the same time, such factors as multiple antibiotic resistance of Gram-negative bacteria, changes in the intestinal microbiota and associated profile of bacterial metabolites entering circulation and participating in the pathogenesis of sepsis, other bacterial products such as pathogen-associated molecular patterns and cytokines induced by them, bacterial endotoxins contributing most to the multiorgan failure, nowadays are considered as new targets for developing effective mtools of controlling the septic shock sequelae.

Taking into account the key role of bacterial endotoxins in the pathogenesis of septic shock and the absence of a significant trend for reducing mortality in response to the medication treatment, increasing interest is being focused on extracorporeal methods of clearing the endotoxins and inflammatory immune mediators from the bloodstream. Such methods are designed to reduce the levels of pathogenetically significant molecules in the systemic circulation down to less critical values at least for a certain period of time in order to enable the immune system and antibiotics to reduce the bacterial load and the production of new endotoxin molecules.

The methods used and developed with respect to selective adsorption of endotoxin molecules from the bloodstream are promising. They provide, at early stages of the disease, interruption of the pro-inflammatory cascade initiated by inborn immune cells and causing organ dysfunction. At the same time, the place of LPS-selective hemoperfusion in sepsis therapy is still not clearly defined.

Recently, the first clinical experience of using a new generation of Efferon LPS medical device for successful treatment of a patient with sepsis has been reported [Ushakova N.D., Tikhonova S.N., Rozenko D.A. Hemosorption by a Column Adsorber Based on Hyper-Cross-Linked Styrene-Divinylbenzene Copolymer with Immobilized Lipopolysaccharide-Selective Ligand in Combined Intensive Care of Lung Cancer-Related Postoperative Acute Lung Injury (Case Report). Obshchaya Reanimatologiya=General Reanimatology. 2020; 16 (4): 14-20. [In Russ.] DOI: 10.15360/1813-9779-2020-4-14-20].

This extracorporeal adsorber contains a multimodal sorbent based on a hypercrosslinked styrene-divinylbenzene copolymer with a covalently immobilized ligand to the Lipid A domain of LPS molecule. The combination of a porous matrix containing mesopores and ligand provides selective and simultaneous action of the adsorbent on two types of dissimilar therapeutic targets (cytokines and endotoxins, respectively).

Efferon LPS (Efferon JSC, Moscow, Russia) is a single-use therapeutic device for extracorporeal blood purification using direct hemoperfusion. Detoxification is carried out by selective adsorption of lipopolysaccharides (bacterial endotoxins) and non-selective removal of cytokines by internal porous structure. It is a cylindrical polycarbonate casing filled with spherical granules of LPS-selective polymeric adsorbent mesoporous beads and isotonic sodium chloride solution. The device is registered in Russia as a medical device RZN 2019/8886.

The aim of the study was to evaluate the safety and clinical eligibility of a novel medical device based on a hypercrosslinked styrene divinylbenzene copolymer with an immobilized LPS-selective ligand designed to remove endotoxins from the bloodstream for treatment of patients with septic shock.

Materials and methods. Nine patients (mean age 58 years, 5 men and 4 women, initial median APACHE II score 28 points, SOFA score 10 points) with confirmed gram-negative bacterial infection and septic shock (SEPSIS-3, 2016) underwent LPS-selective hemoperfusion using Efferon LPS for 6 hours, followed by prolonged venous-venous hemodiafiltration. The decision to use LPS-selective hemoperfusion in a particular patient was made by the attending doctor with the participation of a medical consultant team in accordance with clinical indications.

Before hemoperfusion (day 0), immediately after it, one day after its end (day 1) and once a day for the next 4 days, patients were determined hemodynamic parameters, oxygenation, signs of organ failure, leukocyte count, procalcitonin levels, C- reactive protein, IL 1β, clinical chemistry parameters. All patients underwent a test for endotoxin activity at the same time. Endotoxin Activity Assay Kit (EAA TM) (Spectral Medical Inc., Canada; Certificate No. FSZ 2009/04982) was used to determine endotoxin activity (EAA) using chemiluminescent rapid test and immunodiagnostic reagent set according to the manufacturer's protocol.

SOFA and APACHE II scales were used for comprehensive assessment of clinical status and risk of adverse outcomes. In the course of treatment, adverse reactions during the procedures and final outcome of the hospital stay (duration of stay in ICU and other departments, 28-day mortality) were assessed.

Hemoperfusion through the Efferon LPS adsorber was performed in hospitalized patients with unstable hemodynamic parameters, obvious signs of septic shock according to SEPSIS-3 (2016), during the first hours after making the diagnosis of septic shock. The procedures were performed on MultiFiltrate (Fresenius) along the veno-venous bypass. After LPS-selective hemoperfusion procedure, continuous veno-venous hemodiafiltration (CVVHDF) was performed on MultiFiltrate (Fresenius).

Statistical analysis. Statistical analysis of research data was carried out using descriptive statistics. The test for normal distribution of paired variable changes before and after hemosorption was performed for each data group using the Shapiro-Wilk test, the hypothesis of normal distribution was rejected at P<0.05. To assess the statistical significance of differences between groups, in distribution differing from the normal, the bilateral Wilcoxon test for paired samples or Mann-Witney test for independent groups were used. In normal distribution of paired variable changes in groups, the significance of differences was assessed using the Student's paired bilateral t-criterion. The value of P<0.05 was taken as the cutoff value for statistical significance. When comparing groups by categories of treatment outcome "survived-dead" in the group of patients undergoing hemosorption and the group of patients with abdominal sepsis who did not get hemosorbents (control sample), the exact Fisher's test and the calculation of sample power adequacy at alpha=0.05 were used (SigmaPlot 12.5, Systat Software,USA). The Fisher test was also used to compare the percentage of abdominal sepsis and the sex distribution between the above-mentioned groups of patients.

The ultimate goal of the study was to improve treatment outcomes in patients with septic shock and acute renal failure through combined use of LPS-selective hemoperfusion and prolonged venovenous hemodiafiltration.