Combined Hemoperfusion and Therapeutic Plasma Exchange for Treatment of Patients With Septic Shock

Sepsis Clinical Trial

Official title:

Consecutive Hemoperfusion and Therapeutic Plasma Exchange in Adult Patients With Septic Shock

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT06404424
• Other study ID #: efferon-2022-08
• Status: Completed
• Start date: May 1, 2022
• Est. completion date: March 1, 2024

Study information

• Verified date: June 2024
• Source: Efferon JSC
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Sepsis is a critical burden for a healthcare. From 2000 to 2020, the number of publications and clinical studies on the topic of Sepsis and septic shock on the National Library of Medicine resource The National Center for Biotechnology Information has tripled. Sepsis is a life-threatening condition that causes significant pathophysiological changes in the body. Currently, sepsis is understood as organ dysfunction caused by a dysregulatory response of the macroorganism to infection. A special role in this process belongs to the innate and adaptive immune response.

Despite the trend towards improving survival rates, mortality in sepsis remains high - about 25%, reaching 60% with the development of septic shock.

Extracorporeal therapy, as an adjuvant method of treatment, has been used for more than 30 years, but conducting large randomized studies confirming its effectiveness is associated with a complex of problems, including the extreme heterogeneity of the population of patients with sepsis and septic shock, different etiologies and complex pathogenesis, non-identical pathophysiological pathways of the dominant organ dysfunction in specific time period and degree of its severity.

Goal of the study is to evaluate safety and efficiency of combined hemoperfusion and therapeutic plasma exchange in adult patients with septic shock.

Description:

Sepsis is a critical burden for a healthcare. From 2000 to 2020, the number of publications and clinical studies on the topic of Sepsis and septic shock on the National Library of Medicine resource The National Center for Biotechnology Information has tripled. Sepsis is a life-threatening condition that causes significant pathophysiological changes in the body. Currently, sepsis is understood as organ dysfunction caused by a dysregulatory response of the macroorganism to infection. A special role in this process belongs to the innate and adaptive immune response.

Despite the trend towards improving survival rates, mortality in sepsis remains high - about 25%, reaching 60% with the development of septic shock.

Modern understanding of the pathophysiology of sepsis allows us to identify several groups of molecules that are of significant interest as targets for targeted therapy. Activation of Toll-like receptors of neurophils and macrophages by the so-called PAMPs (pathogen-associated molecular patterns) - extracellular bacterial DNA, lipopolysaccharides, flagellin, lipoteichoic acid, peptidoglycan) leads to changes in the transcription of genes involved in the regulation of the inflammatory response, cellular metabolism with a significant release of cytokinessuch as IL-1, TNF-α, IL-2, IL-6, IL-8, IL-10, IFN-γ and complement proteins.

Extracorporeal therapy, as an adjuvant method of treatment, has been used for more than 30 years, but conducting large randomized studies confirming its effectiveness is associated with a complex of problems, including the extreme heterogeneity of the population of patients with sepsis and septic shock, different etiologies and complex pathogenesis, non-identical pathophysiological pathways of the dominant organ dysfunction in specific time period and degree of its severity.

The strategy of using separate methods for extracorporeal elimination of LPS and cytokines yielded controversial results, with an obvious association of endotoxemia and high concentrations of inflammatory mediators with mortality and severity of organ failure.

According to a meta-analysis of Li X et al. 2021, which included 13 RCTs, LPS-selective hemoperfusion was associated with a decrease in mortality, concentration and activity level of endotoxin, and improved hemodynamic parameters. The EUPHAS 2 trial showed the effect of LPS elimination on improvement in hemodynamics, oxygenation and survival, but the nature of the data collection was retrospective, there was no control group, and the study population was highly heterogeneous in the source of infection and severity of the condition. The largest RCT, EUPHRATES, also confirmed an increase in mean arterial pressure and 28-day survival, but only in patients with endotoxin activity levels in the range of 0.6-0.89. The ABDOMIX study did not demonstrate an effect of endotoxin adsorption on mortality and was associated with a large number of technical difficulties during extracorporeal treatment that affected the outcome.

The use of plasma exchange as an integral technique that allows one to simultaneously eliminate both high-molecular toxins and mediators and medium-sized factors seems justified from the point of view of pathogenesis. Many studies have shown a correlation of high VWF levels and low ADAMTS-13 activity in sepsis with mortality, disease severity, and the intensity of both systemic inflammation and disseminated intravascular coagulation. There are similar data for other molecules, the normalization of which by plasma exchange can potentially improve outcome - high levels of NETs, IgA, IgG, d-dimer, PAI-1, C3 and C4 factors of the complement system, and, conversely, low levels of plasminogen, fibrinogen, antithrombin III, protein C are associated with increased mortality. But there is relatively little research on plasma exchange.

Thus, blood purification techniques used for sepsis certainly have a therapeutic effect; it is assumed that their combined use will enhance it, which will potentially improve treatment results.

The need to influence different classes of molecules (weight, kinetics, volume of distribution) of both the immune system and the hemostatic system determines the choice of methods of combined extracorporeal therapy.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 82
• Est. completion date: March 1, 2024
• Est. primary completion date: December 1, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Age over 18 years

• Sepsis (SEPSIS-3)

• No more than 24 hours from the onset of septic shock.

• Septic shock, defined as hypotension in sepsis:

1. Persisting after infusion therapy in a volume of 30 ml/kg

2. Requiring sympathomimetic therapy with one or more of the listed drugs with the indicated doses: norepinephrine - more than 0,05 mcg/kg/min, dopamine - more than 10 mcg/kg/min, adrenaline - more than 0,05 mcg/kg/min,

Exclusion Criteria:

• Inability to achieve and maintain mean arterial pressure more than 65 mm Hg

• History of transfusion reactions, TRALI

• Allergy to heparin, history of HIT

• Uncontrolled bleeding or a high risk of its occurrence

• The presence of cardiovascular events during the last 2 months: AMI, stroke, pulmonary embolism

• Severe congestive CHF

• Terminal CKD, PGD

• HIV infection

• Continuous immunosuppressive therapy

• Severe granulocytopenia (WBC less than 500 cells/mm3)

Related Conditions & MeSH terms

• Sepsis
• Septic Shock
• Shock
• Shock, Septic

Intervention

Device:
• Efferon LPS
Efferon LPS, a medical device, which is a single-use cartridge filled with a polymeric adsorbent that selectively adsorbs endotoxin via surface-immobilized ligand and excessive cytokines via its intrinsic porosity. This device is routinely used for extracorporeal therapy of sepsis to improve hemodynamic function and abrogate septic shock. Plasma exchange procedures will be carried out with a replacement volume of 2 plasma volumes with fresh frozen plasma and albumin solution. Each patient is scheduled to undergo two separate hemoperfusions lasting 8-10 hours within 48 hours. 60 minutes before the start of hemoperfusion, additional administration of antimicrobial drugs is performed, taking into account their elimination during plasma exchange and adsorption
• Efferon CT
Efferon CT, a medical device, which is a single-use cartridge filled with a polymeric adsorbent that adsorbs excessive cytokines via its intrinsic porosity. This device is routinely used for extracorporeal therapy of "cytokine storm" syndrome in the course of severe SARS-CoV-2. Plasma exchange procedures will be carried out with a replacement volume of 2 plasma volumes with fresh frozen plasma and albumin solution. Each patient is scheduled to undergo two separate hemoperfusions lasting 8-10 hours within 48 hours. 60 minutes before the start of hemoperfusion, additional administration of antimicrobial drugs is performed, taking into account their elimination during plasma exchange and adsorption

Locations

Country	Name	City	State
Russian Federation	City clinical hospital named after S. S. Yudin, Moscow City Health Department	Moscow

Sponsors (1)

Lead Sponsor	Collaborator
Efferon JSC

Country where clinical trial is conducted

Russian Federation, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Shock - Free Days	All days of life, without vasopressor or inotropic support. A patient is given a value of 0 if they die before day 7 or are still remains in shock at day 7.	0-7 days
Secondary	ICU - Free Days	All days of life spent outside the intensive care unit within 60 days after inclusion in the study. A patient is given a value of 0 if they die before day 60 or are still receiving MV at day 60.	0-60 days
Secondary	Mechanical ventilation - Free Days	All days of life spent without mechanical ventilation. A patient is assigned a value of 0 if he or she dies before day 60 or continues to be on mechanical ventilation on day 60.	0-60 days
Secondary	Change SOFA score	Value of indicators on the Sequential Organ Failure Assessment (SOFA) Score. Each organ system received a score ranging from 0 (normal) to 4 (most abnormal), with a minimum SOFA score of 0 and a maximum SOFA score of 24.; The change of SOFA score from baseline (hour 0) at the initiation of hemoperfusion to 48 hours post-treatment initiation.	0-48 hours
Secondary	Change oxygenation index	The change in value of oxygenation index (Pa02 / Fi02) from baseline (hour 0) at the initiation of hemoperfusion to 48 hours post-treatment initiation.; Oxygenation index (OI) is commonly used to assess the severity of hypoxic respiratory failure (HRF).; OI < 5 - healthy person; OI 5-25 - indicates lung disease; OI 25-40 - increased mortality; and OI > 40 - consider the use of ExtraCorporeal Membrane Oxygenation	0-48 hours