Extracorporeal Elimination of Pro- and Anti-inflammatory Modulators by the Cytokine Adsorber CytoSorb® in Patients with Hyperinflammation: A Prospective Study

Abstract

Introduction: The release of pro-inflammatory cytokines in critically ill patients with sepsis leads to endothelial dysfunction resulting in cardiocirculatory insufficiency. Their extracorporeal elimination using the cytokine adsorber CytoSorb^® (CS) (adsorption of especially hydrophobic molecules < 60 kDa) might be promising, but data about the adsorption capacity as well as a potential harmful adsorption of anti-inflammatory cytokines are missing so far.

Methods: The prospective Cyto-SOLVE-study included 15 patients with sepsis or other hyperinflammatory conditions (interleukin 6 > 500 pg/ml), continuous kidney replacement therapy, and the application of CS. Various cytokines and chemokines were measured pre- and post-CS as well as in patients' blood at predefined timepoints. Significant changes in the concentrations were detected with the Wilcoxon test with associated samples. Clearance of the adsorber (ml/min) was calculated with: $bloodflow\ast \frac{concentration\left(pre-post\right)}{concentration\left(\mathrm{pre}\right)}.$ RESULTS: Most of the inflammatory mediators showed a high initial extracorporeal clearance of 70-100 ml/min after CS installation, which dropped quickly to 10-30 ml/min after 6 h of treatment. No difference in clearance was observed between pro- and anti-inflammatory cytokines. Despite extracorporeal adsorption, a significant (p < 0.05) decrease in the blood concentration after 6 h was only observed for the pro-inflammatory cytokines tumor necrosis factorα (TNF-α) (median 284 vs. 230 pg/ml), vascular endothelial growth factor (VEGF) (median 294 vs. 252 pg/ml), macrophage inflammatory protein 1a (MIP-1a) (median 11.1 vs. 9.0 pg/ml), and regulated upon activation, normal T cell expressed and secreted (RANTES) (median 811 vs. 487 pg/ml) as well as the anti-inflammatory cytokines interleukin 4 (median 9.3 vs. 6.4 pg/ml), interleukin 10 (median 88 vs. 56 pg/ml), and platelet-derived growth factor (PDGF) (median 177 vs. 104 pg/ml). A significant (p < 0.05) decrease in patients' blood after 12 h was only detected for interleukin 10.

Conclusions: CS can adsorb pro- as well as anti-inflammatory mediators with no relevant difference regarding the adsorption rate. A fast saturation of the adsorber resulted in a rapid decrease of the clearance. The potential clinical benefit or harm of this unspecific cytokine adsorption needs to be evaluated in the future.

Trial registration: ClinicalTrials.gov NCT04913298, registration date June 4, 2021.

Keywords: Anti-inflammatory cytokines; Critically ill patients; CytoSorb®; Cytokines; Hyperinflammation; Mass-spectrometry; Pro-inflammatory cytokines; Sepsis.

Fig. 1

Study population of the Cyto-SOLVE trial

Fig. 2

Median clearance of the adsorber for different pro-inflammatory mediators. IL interleukin, IFN interferon, TNF tumor necrosis factor, VEGF vascular endothelial growth factor, IP-10 interferon gamma-induced protein 10, MCP-1 monocyte chemoattractant protein-1, MIP-1 macrophage inflammatory protein-1, RANTES regulated upon activation, normal T cell expressed and secreted, ICAM intercellular adhesion molecule, VCAM vascular cell adhesion molecule

Fig. 3

Median clearance of the adsorber for different anti-inflammatory mediators. IL interleukin, FGF fibroblast growth factor, PDGF platelet-derived growth factor

Fig. 4

Relative change (%) of pro- and anti-inflammatory mediators during CytoSorb^® application. IL interleukin, TNF tumor necrosis factor. The boxes of the boxplots represent the interquartile range (IQR) and the line the median. Whiskers were limited to 1.5 times the IQR. The cross represents the mean