Effect of hemoadsorption during cardiopulmonary bypass surgery – a blinded, randomized, controlled pilot study using a novel adsorbent

Bernardi et al. Critical Care (2016) 20:96 DOI 10.1186/s13054-016-1270-0 RESEARCH Open Access Effect of hemoadsorption during cardiopulmonary bypass surgery – a blinded, randomized, controlled pilot study using a novel adsorbent Martin H. Bernardi1*, Harald Rinoesl1, Klaus Dragosits2, Robin Ristl3, Friedrich Hoffelner4, Philipp Opfermann1, Christian Lamm2, Falk Preißing2, Dominik Wiedemann4, Michael J. Hiesmayr1 and Andreas Spittler2,5 Abstract Background: Cardiopulmonary bypass (CPB) surgery initiates a systemic inflammatory response, which is associated with postoperative morbidity and mortality. Hemoadsorption (HA) of cytokines may suppress inflammatory responses and improve outcomes. We tested a new sorbent used for HA (CytoSorb™; CytoSorbents Europe GmbH, Berlin, Germany) installed in the CPB circuit on changes of pro- and anti-inflammatory cytokines levels, inflammation markers, and differences in patients’ perioperative course. Methods: In this first pilot trial, 37 blinded patients were undergoing elective CPB surgery at the Medical University of Vienna and were randomly assigned to HA (n = 19) or control group (n = 18). The primary outcome was differences of cytokine levels (IL-1β, IL-6, IL-18, TNF-α, and IL-10) within the first five postoperative days. We also analyzed whether we can observe any differences in ex vivo lipopolysaccharide (LPS)-induced TNF-α production, a reduction of high-mobility box group 1 (HMGB1), or other inflammatory markers. Additionally, measurements for fluid components, blood products, catecholamine treatment, bioelectrical impedance analysis (BIA), and 30-day mortality were analyzed. Results: We did not find differences in our primary outcome immediately following the HA treatment, although we observed differences for IL-10 24 hours after CPB (HA: median 0.3, interquartile range (IQR) 0–4.5; control: not traceable, P = 0.0347) and 48 hours after CPB (median 0, IQR 0–1.2 versus not traceable, P = 0.0185). We did not find any differences for IL-6 between both groups, and other cytokines were rarely expressed. We found differences in pretreatment levels of HMGB1 (HA: median 0, IQR 0–28.1; control: median 48.6, IQR 12.7–597.3, P = 0.02083) but no significant changes to post-treatment levels. No differences in inflammatory markers, fluid administration, blood substitution, catecholamines, BIA, or 30-day mortality were found. Conclusions: We did not find any reduction of the pro-inflammatory response in our patients and therefore no changes in their perioperative course. However, IL-10 showed a longer-lasting anti-inflammatory effect. The clinical impact of prolonged IL-10 needs further evaluation. We also observed strong inter-individual differences in cytokine levels; therefore, patients with an exaggerated inflammatory response to CPB need to be identified. The implementation of HA during CPB was feasible. Trial registration: ClinicalTrials.gov: NCT01879176, registration date: June 7, 2013. Keywords: Cytokines, Cytokine storm, CytoSorb, Cardiac surgery, Cardiopulmonary bypass, Hemadsorption, Inflammation, Interleukin, High-mobility box group 1 * Correspondence: 1 Department of Cardiothoracic and Vascular Anaesthesia and Intensive Care Medicine, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria Full list of author information is available at the end of the article © 2016 Bernardi et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Bernardi et al. Critical Care (2016) 20:96 Background Cardiopulmonary bypass (CPB) surgery initiates a systemic inflammatory response induced by extrinsic and intrinsic factors [1–3]. Monocytes and high-mobility group box 1 protein (HMGB1), a chromatin protein, encoded by the Hmgb1 gene in humans, are important players in systemic inflammation and belong to the main producers of pro- and anti-inflammatory cytokines [4, 5]. Once activated by the extracorporeal circuit, they might lead to a dysregulation of inflammatory homeostasis and increased levels of both, pro- and anti-inflammatory plasma mediators such as tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), IL-6, IL-10, and IL-18 [4, 6–9]. This strong inflammatory response induces post-surgical monocyte immunosuppression which is indicated by an impaired production of ex vivo lipopolysaccharide (LPS)induced TNF-α exaggeration [10]. All of these factors may lead to a prolonged postoperative course, including a delayed weaning from mechanical ventilation, recovery of organ functions, and discharge from the intensive care unit (ICU). Thus, measures to decrease the inflammatory process have the potential to improve the perioperative course [11]. Hemoadsorption (HA) using the CytoSorb™ adsorber (CytoSorbents Europe GmbH, Berlin, Germany) is a recent technology that has shown rapid elimination of many key cytokines that cannot be filtered by using current blood purification techniques [12]. The primary aim of this first single-center, blinded, randomized, and controlled pilot study was to investigate differences of pro- and anti-inflammatory cytokines in patients undergoing cardiac surgery with CPB using the CytoSorb™ adsorber compared with a control group within the first 5 postoperative days (POD). Furthermore, we investigated whether we can observe any differences in ex vivo LPS-induced TNF-α production, a reduction of HMGB1, or other inflammatory markers. Also, we investigated differences in fluid management or the use of catecholamines and differences in edema formation as determined by analysis of body composition by bioelectrical impedance analysis (BIA). Additionally, we compared length of ICU stay, respirator therapy, and 30-day mortality. Methods Ethics approval This study was approved by the ethics committee of the Medical University of Vienna with reference number EK Nr: 1095/2013. Furthermore, we reported the study to the Austrian Federal Office for Safety in Health Care (INS-621000-0505) and registered it at ClinicalTrials.gov (NCT01879176) before recruitment started. Written informed consent to participate and consent to publish were obtained from each patient. Page 2 of 13 Study design and patients This study was a randomized, blinded (in patients), controlled, single-center trial in 46 adult patients undergoing elective open heart surgery (coronary artery bypass graft [CABG], valve surgery, combined procedure) with an expected CPB duration of more than 120 minute (...truncated)