Cytokine REmoval in CRitically Ill pAtients Requiring Surgical Therapy for Infective Endocarditis (RECReATE)

Study Overview
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Brief Summary
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Infectious endocarditis (IE) and other severe infections are well-known to induce significant changes in the immune response including immune functionality in a considerable number of affected patients. In fact, numerous patients with IE develop a persistent functional immunological phenotype that can best be characterized by a profound anti-inflammation and/or functional anergy. This was previously referred to as injury-associated immunosuppression (IAI) by Pfortmüller et al., published in Intensive Care Medicine Experimental 2017. IAI can be assessed by measurement of cellular (functional) markers. Persistence of IAI is associated with prolonged ICU length of stay, increased secondary infection rates, and death. Immunomodulation to reverse IAI was shown beneficial in immunostimulatory (randomized controlled) clinical trials. CytoSorb® treatment is currently used as standard of care in some institutions in surgically treated IE patients. The investigators aim to investigate two accepted treatment protocols and aim to explore whether adsorption with a cytokine adsorption filter can increase immune competence in treated individuals.

Official Title
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Cytokine REmoval in CRitically Ill pAtients Requiring Surgical Therapy for Infective Endocarditis (RECReATE) - an Investigator-initiated Prospective Randomized Controlled Clinical Trial Comparing Two Established Clinical Protocols

Conditions
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Endocarditis, Sepsis, Septic Shock

Intervention / Treatment
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* Other: Treatment protocol with adsorption


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects scheduled for routine cardiac surgery for infectious endocarditis (diagnosed according to the predefined DUKE criteria) with antibiotic therapy for ≤ 14 days. Presence of informed consent Age ≥18 yrs. Exclusion Criteria: Previous treatment (last 6 months) with immunologically-active biologicals or specific immunomodulatory drugs (e.g. Rituximab) high-dose chronic (i.e. before onset of infectious endocarditis) steroid medication with prednisone equivalent of >30 mg/d Patients on Extracorporeal membrane oxygenation (ECMO), or any other (pre-operative) cardiac assist device Moribund patient (life expectancy <14 days)

Ages Eligible for Study
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Minimum Age: 18 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Treatment protocol without adsorption<br> | |
| Active Comparator: Treatment protocol with adsorption<br> | Other: Treatment protocol with adsorption<br>* Adsorption while patients are in the OR on the extracorporeal circuit<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in quantitative expression of monocytic Human Leukocyte Antigen (mHLA)-DR expression (Antibodies per cell on Cluster of Differentiation (CD)14+ monocytes/macrophages, assessed using a quantitative standardized assay) |  | From baseline (pre-OR, t1) to day 1 post-OR (t3) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in mHLA-DR from baseline (pre-OR) to post-Or and 3 days post-Or. | Course of mHLA-DR | Baseline (pre-OP) to post-OR and 3 days post-Or | 
| Area under the curve of quantitative mHLA-DR expression | Area under the curves mHLA-DR | Between baseline (pre-OR), post-OR, and day 1 and 3 post-OR (multiple assessments). | 
| Change in inflammatory markers including cytokines (Interleukin (IL)-6, IL-10, C-reactive protein, White blood cell count, multiplex Enzyme linked immunosorbent assay, and inflammatory prohormones) | Change in inflammatory parameters | From baseline (pre-OR) to post-OR, and day 1 and 3 post-OR | 
| Change in organ dysfunction (Sepsis-related organ failure (SOFA) scores incl. subscores and Simplified acute physiology score (SAPS II scores) daily | Course of organ dysfunction | 7-day timeframe (starting from ICu admission, assessed at day 90) | 
| Length of ICU and hospital stay (days after surgical intervention). | Length of stay | Number of days on ICU and in hospital (assessed at day 90) | 
| Cumulative Therapeutic Intervention Scoring System (TISS) points (resource need) until ICU-discharge | Resource use | Total number of TISS points on ICU (cumulative), assessed at day 90 | 
| Total amount of infused volume/transfusions on ICU | Need for fluid therapy | 90 days | 
| Duration of vasoactive drug therapy | Vasopressor use | 90 days | 
| Duration of invasive mechanical ventilation | Use of organ support therapy (number of days on mechanical ventilation) | 90 days | 
| ICU mortality rate | Number of non-surviving patients in both study groups | ICU stay (assessed at day 90) | 
| Hospital mortality rate | Number of non-surviving patients in both study groups | hospital stay (assessed at day 90) | 
| 28 day mortality rate | Number of non-surviving patients in both study groups | 28 days beginning from ICU admission (assessed at day 90) | 
| 90 day mortality rate | Number of non-surviving patients in both study groups | 90 days beginning from ICU admission (assessed at day 90) | 
| Duration of renal replacement therapy | Use of organ support therapy (number of days on renal replacement therapy) | 90 days |