Efferon LPS Hemoperfusion for Treatment of Patients With Septic Shock
Condition: Septic Shock
MeSH terms: Shock, Septic; Shock
Study type: Observational

Summary: 
      Sepsis is a global healthcare burden sepsis, it reaches 20-30 million cases annually (WHO
      data). Numerous studies have shown that extracorporeal hemoperfusion therapies that eliminate
      endotoxin and\or excess of cytokines improve treatment outcomes in patients with septic
      shock. Aim of the study: to evaluate safety and feasibility of clinical use of an
      extracorporeal blood adsorber based on a hypercrosslinked styrene-divinylbenzene copolymer
      with immobilized lipopolysaccharide (LPS)-selective ligand designed to remove endotoxins from
      the bloodstream to treat patients with septic shock.
    

Detailed description: 
      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.
    

Intervention name(s): Efferon LPS
Intervention type(s): Device
Intervention description(s): Efferon LPS 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.
Observational model: Case-Only
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        The study included 9 surgical patients with clinical signs of septic shock (SEPSIS-3, 2016)
        who were admitted to the intensive care unit (ICU) in 2019-2020.
      
Keywords: septic shock; extracorporeal therapy; LPS sequestration; abdominal sepsis