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

Abstract

Introduction: Infective endocarditis (IE) and other severe infections induce significant changes in the immune response in a considerable number of affected patients. Numerous IE patients develop a persistent functional immunological phenotype that can best be characterized by a profound anti-inflammation and/ or functional "anergy." This is pronounced in patients with unresolved infectious foci and was previously referred to as "injury-associated immunosuppression" (IAI). IAI can be assessed by measurement of the monocytic human leukocyte antigen-DR (mHLA-DR) expression, a global functional marker of immune competence. Persistence of IAI is associated with prolonged intensive care unit length of stay, increased secondary infection rates, and death. Immunomodulation to reverse IAI was shown beneficial in early immunostimulatory (randomized controlled) clinical trials.

Methods: Prospective 1:1 randomized controlled clinical study to compare the course of mHLA-DR in patients scheduled for cardiac surgery for IE. Patients will receive either best standard of care plus cytokine adsorption during surgery while on cardiopulmonary bypass (protocol A) versus best standard of care alone, that is, surgery without cytokine adsorption (protocol B). A total of 54 patients will be recruited and randomized. The primary endpoint is a change in quantitative expression of mHLA-DR (antibodies per cell on CD14+ monocytes/ macrophages, assessed using a quantitative standardized assay) from baseline (preoperation [pre-OP], visit 1) to day 1 post-OP (visit 4).

Discussion: This randomized controlled clinical trial (RECReATE) will compare 2 clinical treatment protocols and will investigate whether cytokine adsorption restores monocytic immune competence (reflected by increased mHLA-DR expression) in patients with IE undergoing cardiac surgery.

Trial registration: This protocol was registered in ClinicalTrials.gov, under number NCT03892174, first listed on March 27, 2019.

Conflict of interest statement

TS, CAP, ASM, and JCS reports grants from Orion Pharma, Abbott Nutrition International, B. Braun Medical AG, CSEM AG, Edwards Lifesciences Services GmbH, Kenta Biotech Ltd, Maquet Critical Care AB, Omnicare Clinical Research AG, Nestle, Pierre Fabre Pharma AG, Pfizer, Bard Medica S.A., Abbott AG, Anandic Medical Systems, Pan Gas AG Healthcare, Bracco, Hamilton Medical AG, Fresenius Kabi, Getinge Group Maquet AG, Dräger AG, Teleflex Medical GmbH, Glaxo Smith Kline, Merck Sharp and Dohme AG, Eli Lilly and Company, Baxter, Astellas, Astra Zeneca, CSL Behring, Novartis, Covidien, Phagenesis Ltd., Philips Medical, Prolong Pharmaceuticals and Nycomed outside the submitted work. The money went into departmental funds. No personal financial gain applied. The other authors declare that they have no competing interests.