Organ-substituting Technologies in the Treatment of Heart and Pulmonary Failure

Study Overview
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Brief Summary
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The implementation of this project will improve the effectiveness of surgical treatment and reduce the level of complications and mortality among patients with heart failure and heart failure in the terminal stage. The goal of the study. Improvement of organ-substituting technologies in the treatment of heart and respiratory failure. Objectives of the study. Objective 1. To study the restoration of organ function during implantation of extracorporeal membrane oxygenation (ECMO), as an organ replacement, in cardiac and / or respiratory failure. Objective 2. To study the results of applying organ-substituting technologies in the treatment of sepsis.

Detailed Description
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The implementation of this project will improve the effectiveness of surgical treatment and reduce the level of complications and mortality among patients with heart failure and heart failure in the terminal stage. 2.2. The goal of the program. Improvement of organ-substituting technologies in the treatment of heart and respiratory failure. 2.3. Objectives of the program. Objective 1. To study the restoration of organ function during implantation of extracorporeal membrane oxygenation (ECMO), as an organ replacement, in cardiac and/or respiratory failure. Subtask 1.1. Evaluation of the recovery of organ function during ECMO using extracorporal hemo correction procedure. Subtask 1.2. Evaluation of the normalization of the organism's immune response and restoration of organ function when conducting ECMO using the extracorporeal cytokine adsorber. Subtask 1.3. Evaluation of the normalization of the organism's immune response and restoration of organ function when conducting ECMO using the extracorporeal hemoperfusion cartridge. Objective 2. To study the results of applying organ-substituting technologies in the treatment of sepsis. Subtask 2.1. Assessment of the recovery of organ function in the application of extracorporal hemo correction in septic patients. Subtask 2.2. Evaluation of the normalization of the organism immune response and restoration of organ function when using the extracorporeal cytokine adsorber in septic patients. Subtask 2.3. Evaluation of the normalization of the organism's immune response and restoration of organ function when using the extracorporeal hemoperfusion cartridge. In this study, will be developed methods to restore the function of affected organs after implantation of ECMO and patients with sepsis in combination with extracorporeal hem correction, which will improve the results of surgical treatment of patients with end-cardiac and respiratory failure. New methods developed to restore the function of affected organs after implantation of mechanical support devices and patients with sepsis will be of great importance both for Kazakhstan and for countries with similar categories of patients, which will improve the efficiency of surgical treatment and reduce the level of complications and mortality. Clinical research data will form the basis of practical protocols for extracorporeal membrane oxygenation (ECMO) and patients with sepsis, which will improve organ repair, reduce postoperative complications, improve quality of life and reduce mortality after surgery. Research methods and ethical issues Patients before implantation of ECMO and/or patients with sepsis will be enrolled in the study after giving a written, signed informed consent. The participants will be randomized into 3 groups: Intervention group #1 a cytokine adsorber will be used (30 patients): patients on ECMO - subgroup A; septic patients - subgroup B. Intervention group #2 an extracorporeal hemoperfusion cartridge will be used (30 patients): patients on ECMO - subgroup C, septic patients - subgroup D. Control group #3 without using extracorporeal adsorber (30 patients): patients on ECMO subgroup - E, septic patients - subgroup F. The investigators will collect demographic, clinical, and laboratory data about patients before, during, and after the operation The incidence of early cellular or humoral rejection, length of ventilation, ICU and hospital stay, the use of vasopressors and inotropes in the perioperative period, and incidence of perioperative complications and survival will be documented. The level of cytokines (IL-1, IL-6, IL-8, IL-10, tumor necrosis factor-alfa) and complements before, during, and after the use of ECMO, patients with sepsis will be determined if the investigators find the relevant differences between the two groups in clinical variables. Study Design Study Type: Interventional (Clinical Trial) Estimated Enrollment: 90 Participants Allocation: randomized Interventional Model: Parallel assignment Masking: None (Open Label)

Official Title
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Innovative Solutions to Organ-substituting Technologies in the Treatment of Heart and Pulmonary Failure

Conditions
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Acute Respiratory Distress Syndrome, Septic Shock, Sepsis

Intervention / Treatment
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* Device: Cytokine adsorber filter
* Device: Extracorporeal hemoperfusion cartridge


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - ICU patients with ECMO: Hemodynamic support with vasopressors Procalcitonin level ≥ 1 ng/ml Invasive hemodynamic monitoring Written informed content ICU patients with the septic shock of medical origin: Signs of hypoperfusion: serum lactate >2 mmol/L, low central venous oxygen saturation (ScvO2) (<70%) or high ScvO2 (>85%), metabolic acidosis, oligo-anuria, high venous-to-arterial CO2-gap (dCO2 >6 mm Hg) Hemodynamic support with vasopressors Procalcitonin level ≥ 1 ng/ml Invasive hemodynamic monitoring Written informed content Exclusion Criteria: ICU patients with ECMO: age < 18 years acute liver or kidney failure straight before transplantation the patient declines to participate in the study ICU patients with the septic shock of medical origin: Patients under 18 years Pregnancy (bHCG test positivity) Surgical intervention in context with the septic insult New York Heart Association IV heart failure Acute coronary syndrome Acute hematological malignancies Immunosuppression, systemic steroid therapy (>10mg prednisolone/day) Human immunodeficiency virus infection (HIV) and active AIDS Patients with donated organs Thrombocytopenia (<20.000/ml) More than 10%-of body surface area with third-degree burn

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Study Design Study Type: Interventional (Clinical Trial) Estimated Enrollment: 90 Participants Allocation: randomized Interventional Model: Parallel assignment Masking: None (Open Label)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cytokine adsorber patients on ECMO<br>Cytokine adsorber filter will be installed into the (hemodialysis or cardiopulmonary bypass (CPB) (15 patients on ECMO) | Device: Cytokine adsorber filter<br>* • Intervention group #1 a cytokine adsorber will be used (30 patients): patients on ECMO - subgroup A; septic patients - subgroup B.<br>|
| Experimental: Cytokine adsorber patients with sepsis<br>Cytokine adsorber filter will be installed into the (hemodialysis or cardiopulmonary bypass (CPB) (15 patients with sepsis) | Device: Cytokine adsorber filter<br>* • Intervention group #1 a cytokine adsorber will be used (30 patients): patients on ECMO - subgroup A; septic patients - subgroup B.<br>|
| Experimental: Extracorporeal hemoperfusion cartridge patients on ECMO<br>Extracorporeal hemoperfusion cartridge will be installed into the (hemodialysis or cardiopulmonary bypass (CPB) (15 patients on ECMO) | Device: Extracorporeal hemoperfusion cartridge<br>* • Intervention group #2 an extracorporeal hemoperfusion cartridge will be used (30 patients): patients on ECMO - subgroup C, septic patients - subgroup D.<br>|
| Experimental: Extracorporeal hemoperfusion cartridge patients with sepsis<br>Extracorporeal hemoperfusion cartridge will be installed into the (hemodialysis or cardiopulmonary bypass (CPB) (15 patients with sepsis) | Device: Extracorporeal hemoperfusion cartridge<br>* • Intervention group #2 an extracorporeal hemoperfusion cartridge will be used (30 patients): patients on ECMO - subgroup C, septic patients - subgroup D.<br>|
| No Intervention: Control (subgroups)1<br>No filter will be installed into the ECMO in this study group (15 patients) | |
| No Intervention: Control (subgroups) 2<br>No filter will be installed into the patient with sepsis (15 patients) | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference of Cytokine response - ECMO patients | Level of pro- and anti-inflammatory cytokines (IL-1, IL-6, IL-8, IL-10, tumor necrosis factor-alfa) before initiation of ECMO, 2 hours after initiation ECMO support, at explantation of ECMO support, 6-12-24 hours after explantation of ECMO support. | 6-24 hours | 
| Difference of Cytokine response - Patients with septic shock | Level of procalcitonin, Level of C-reactive protein, Level of interleukin-1, Level of interleukin-6, Level of interleukin-8, Level of interleukin-10, Level of Tumor Necrosis Factor- αinterleukin-8, interleukin-10, Tumor Necrosis Factor- α at 24, 48 hours. | 24-48 hours of septic shock | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Inflammatory reaction - Patients with septic shock | Level of C reactive protein (CRP), white blood cells and procalcitonin immediately after induction of anesthesia, before initiation of adsorber, 2 hours after initiation of adsorber, at termination of adsorber, 6-12-24 hours after wean of adsorber. | 6-24 hours | 
| Ventilator free days (VFD) - ECMO patients | ventilator days. VFD=0, if the patient dies in the first 30 days after randomization | 30 days | 
| Time to extubation from ventilation and explantation from ECMO - ECMO patients | Time to extubation from ventilation and explantation from ECMO. Death under ventilation and/or ECMO will be analyzed as a competing event. The time will be censored at the time of last visit for surviving patients under ventilation and/or ECMO. | 30 days | 
| Difference of d-dimers - ECMO patients | Comparison to enrollment or between 3 groups at 24, 48, 72 h | 24, 48, 72 hours | 
| Difference of Serum lactate - ECMO patients | Comparison to enrollment or between 3 groups at 24, 48, 72 h | 24, 48, 72 hours | 
| SOFA-Score - ECMO patients | Sequential Organ Failure Assessment Score at 24, 48, 72 h (values from 6 to 24, where the higher values explain higher disease severity) | 24, 48, 72 hours | 
| serious adverse device effects - ECMO patients | serious complications or malfunctions related to the CytoSorb device | 30 days | 
| adverse event of special interest: air in the ECMO system - ECMO patients | unintended air in the ECMO system during operation of the device | 30 days | 
| adverse event of special interest: blood-clotting in the ECMO system | unintended blood-clotting in the ECMO system during operation of the device | 30 days | 
| adverse event of special interest: bleeding complications - ECMO patients | major bleeding events | 30 days | 
| Difference of serum interleukin-6 level - Patients with septic shock | Comparison to enrollment or between 3 groups at 48, 72 h | 48, 72 hours | 
| Difference of serum interleukin-1β level - Patients with septic shock | Comparison to enrollment or between 3 groups at 24, 48, 72 h | 24, 48, 72 hours | 
| Difference of serum interleukin-10 level - Patients with septic shock | Comparison to enrollment or between 3 groups at 24, 48, 72 h | 24, 48, 72 hours | 
| Difference of serum procalcitonin level - Patients with septic shock | Comparison to enrollment or between 3 groups at 24, 48, 72 h | 24, 48, 72 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Organ-substituting technologies, Heart failure, Pulmonary failure, Sepsis, Extracorporeal membrane oxygenation, Adsorber