Cytokine clearance with CytoSorb® during cardiac surgery: a pilot randomized controlled trial

Abstract

Background: Cardiopulmonary bypass (CPB) is often associated with degrees of complex inflammatory response mediated by various cytokines. This response can, in severe cases, lead to systemic hypotension and organ dysfunction. Cytokine removal might therefore improve outcomes of patients undergoing cardiac surgery. CytoSorb® (Cytosorbents, NJ, USA) is a recent device designed to remove cytokine from the blood using haemoadsorption (HA). This trial aims to evaluate the potential of CytoSorb® to decrease peri-operative cytokine levels in cardiac surgery.

Methods: We have conducted a single-centre pilot randomized controlled trial in 30 patients undergoing elective cardiac surgery and deemed at risk of complications. Patients were randomly allocated to either standard of care (n = 15) or CytoSorb® HA (n = 15) during cardiopulmonary bypass (CPB). Our primary outcome was the difference between the two groups in cytokines levels (IL-1a, IL-1b, IL-2, IL-4, IL-5, IL-6, IL-10, TNF-α, IFN-γ, MCP-1) measured at anaesthesia induction, at the end of CPB, as well as 6 and 24 h post-CPB initiation. In a consecutive subgroup of patients (10 in HA group, 11 in control group), we performed cross-adsorber as well as serial measurements of coagulation factors' activity (antithrombin, von Willebrand factor, factor II, V, VIII, IX, XI, and XII).

Results: Both groups were similar in terms of baseline and peri-operative characteristics. CytoSorb® HA during CPB was not associated with an increased incidence of adverse event. The procedure did not result in significant coagulation factors' adsorption but only some signs of coagulation activation. However, the intervention was associated neither with a decrease in pro- or anti-inflammatory cytokine levels nor with any improvement in relevant clinical outcomes.

Conclusions: CytoSorb® HA during CPB was not associated with a decrease in pro- or anti-inflammatory cytokines nor with an improvement in relevant clinical outcomes. The procedure was feasible and safe. Further studies should evaluate the efficacy of CytoSorb® HA in other clinical contexts.

Trial registration: ClinicalTrials.gov NCT02775123 . Registered 17 May 2016.

Keywords: Cardio-pulmonary bypass; Coagulation factors; CytoSorb®; Cytokines; Haemoadsorption.

Conflict of interest statement

Ethics approval and consent to participate

The study protocol was approved by the Ethics Committee Vaud (2015-00010) and registered at Consent for publication

All patients enrolled in this trial consented for anonymous utilisation of the data in the form of a scientific publication.

Competing interests

AS has received a grant from the Leenaards foundation. He has received speaker honoraria from Cytosorbent SA. All other authors stated that they have no conflict of interest to declare.

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Figures

Fig. 1

Median pro-inflammatory cytokine measurements throughout the study period. Whiskers indicate IQR. T0, induction of anaesthesia; T2, end of cardio-pulmonary bypass; T3, 6 h after the end of cardio-pulmonary bypass; and T4, 24 h after the end of CPB. IL interleukin; IFN-γ, interferon-gamma; MCP-1, monocyte chemoattractant protein-1; TNF-α, tumour necrosis factor-alpha. Inter-group comparisons performed using the Mann-Whitney U test comparisons at each time point. Effect of time within each group was significant (Kruskal-Wallis one-way analysis of variance) for all measurements (p < 0.05) except for IFN-γ in the control group (p = 0.09) and IL-2 in the control (p = 0.232)

Fig. 2

Coagulation factors cross-adsorber clearance. Pre- and post-adsorber samples were collected 60 min after the initiation of CPB (T1). AT, antithrombin; F, factor; vWF, von Willebrand factor. Comparisons performed using paired Student’s t tests

Fig. 3

Coagulation factors measurements throughout the study period. T0, induction of anaesthesia; T2, end of CPB; T3, 6 h after the end of CPB; and T4, 24 h after the end of CPB. AT, antithrombin; F, factor; vWF, von Willebrand factor. The effect of HA on coagulation factors throughout study time points was assessed by repeated measures’ analysis of variance (ANOVA) and analysis of covariance (ANCOVA) models. Final ANCOVA models included FFP administration, fluid balance and baseline value. Statistical threshold was determined as p = 0.016 after Bonferroni correction