Cytokine adsorption in patients with severe COVID-19 pneumonia requiring extracorporeal membrane oxygenation (CYCOV): a single centre, open-label, randomised, controlled trial

Alexander Supady, Enya Weber, Marina Rieder, Achim Lother, Tim Niklaus, Timm Zahn, Franziska Frech, Sissi Müller, Moritz Kuhl, Christoph Benk, Sven Maier, Georg Trummer, Annabelle Flügler, Kirsten Krüger, Asieb Sekandarzad, Peter Stachon, Viviane Zotzmann, Christoph Bode, Paul M Biever, Dawid Staudacher, Tobias Wengenmayer, Erika Graf, Daniel Duerschmied, Alexander Supady, Enya Weber, Marina Rieder, Achim Lother, Tim Niklaus, Timm Zahn, Franziska Frech, Sissi Müller, Moritz Kuhl, Christoph Benk, Sven Maier, Georg Trummer, Annabelle Flügler, Kirsten Krüger, Asieb Sekandarzad, Peter Stachon, Viviane Zotzmann, Christoph Bode, Paul M Biever, Dawid Staudacher, Tobias Wengenmayer, Erika Graf, Daniel Duerschmied

Abstract

Background: We sought to clarify the benefit of cytokine adsorption in patients with COVID-19 supported with venovenous extracorporeal membrane oxygenation (ECMO).

Methods: We did a single-centre, open-label, randomised, controlled trial to investigate cytokine adsorption in adult patients with severe COVID-19 pneumonia requiring ECMO. Patients with COVID-19 selected for ECMO at the Freiburg University Medical Center (Freiburg, Germany) were randomly assigned (1:1) to receive cytokine adsorption using the CytoSorb device or not. Randomisation was computer-generated, allocation was concealed by opaque, sequentially numbered sealed envelopes. The CytoSorb device was incorporated into the ECMO circuit before connection to the patient circuit, replaced every 24 h, and removed after 72 h. The primary endpoint was serum interleukin-6 (IL-6) concentration 72 h after initiation of ECMO analysed by intention to treat. Secondary endpoints included 30-day survival. The trial is registered with ClinicalTrials.gov (NCT04324528) and the German Clinical Trials Register (DRKS00021300) and is closed.

Findings: From March 29, 2020, to Dec 29, 2020, of 34 patients assessed for eligibility, 17 (50%) were treated with cytokine adsorption and 17 (50%) without. Median IL-6 decreased from 357·0 pg/mL to 98·6 pg/mL in patients randomly assigned to cytokine adsorption and from 289·0 pg/mL to 112·0 pg/mL in the control group after 72 h. One patient in each group died before 72 h. Adjusted mean log IL-6 concentrations after 72 h were 0·30 higher in the cytokine adsorption group (95% CI -0·70 to 1·30, p=0·54). Survival after 30 days was three (18%) of 17 with cytokine adsorption and 13 (76%) of 17 without cytokine adsorption (p=0·0016).

Interpretation: Early initiation of cytokine adsorption in patients with severe COVID-19 and venovenous ECMO did not reduce serum IL-6 and had a negative effect on survival. Cytokine adsorption should not be used during the first days of ECMO support in COVID-19.

Funding: None.

Conflict of interest statement

Declarations of interests All authors have completed the ICMJE form (available on request from the corresponding author). ASu reports research grants and lecture fees from CytoSorbents and lecture fees from Abiomed, both outside of the submitted work. MR reports funding by the IMM-PACT-Programme for Clinician Scientists, Department of Medicine II, Medical Center, University of Freiburg and Faculty of Medicine, funded by the Deutsche Forschungsgemeinschaft (German Research Foundation)—413517907 and financial support from CytoSorbents for attending a scientific meeting. AL reports a research grant from the German Center for infectious diseases, outside of the submitted work and is a member of SFB1425, funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation #422681845). SMa reports honoraria from CytoSorbents for a presentation during a scientific workshop. CBe and GT are shareholders of Resuscitec, they received personal fees from Resuscitec and they hold patents US 10695407 and EU 3016675 issued to Resuscitec. GT reports grants from Resuscitec and payments from Medela, both outside of the submitted work. CBe reports lecture honoraria from CytoSorbents. DS reports lecture fees from Orion Pharma, Abiomed, Getinge Group, AstraZeneca, MedCaptain, and Medtronic, travel support for the attendance of scientific meetings from Orion Pharma and Abiomed, and fees from Orion Pharma for medical writing work. EG reports consulting fees from Roche Pharma, Germany, for statistical consulting, outside of the submitted work. DD reports research grants, lecture fees and travel support from CytoSorbents, all outside of the submitted work and is a member of SFB1425, funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation #422681845). All other authors declare no conflicts of interest.

Copyright © 2021 Elsevier Ltd. All rights reserved.

Figures

Figure 1
Figure 1
Trial profile ECMO=extracorporeal membrane oxygenation.
Figure 2
Figure 2
IL-6 concentrations at baseline and after 72 h of venovenous ECMO with or without cytokine adsorption IL-6 values in the cytokine adsorption group and control group before and 72 h after initiation of venovenous ECMO are displayed on the logarithmic scale. Medians are shown as horizontal lines. No significant differences were detected between the two groups after 72 h of ECMO (p=0·54). IL-6=interleukin-6.
Figure 3
Figure 3
Kaplan–Meier curves for survival in the cytokine adsorption group and control group Survival in the group receiving cytokine adsorption during the first 72 h of venovenous ECMO support was lower. ECMO=extracorporeal membrane oxygenation.

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