Cytokine removal in human septic shock: Where are we and where are we going?

Abstract

Although improving, the mortality from septic shock still remains high despite increased international awareness. As a consequence, much effort has focused on alternative treatment strategies in an effort to improve outcomes. The application of blood purification therapies to improve immune homeostasis has been suggested as one such method, but these approaches, such as high-volume continuous haemofiltration or cytokine and/or endotoxin removal, have enjoyed little success to date. More recently, the use of sorbent technologies has attracted much attention. These adsorbers are highly effective at removing inflammatory mediators, in particular, cytokines, from the bloodstream. This narrative review is the executive summary of meetings held throughout the 6th International Fluid Academy Days in Antwerp, Belgium (Nov 23-25, 2017), focusing on the current understanding regarding the use of such adsorbers in humans with septic shock. We followed a modified Delphi approach involving a combination of evidence appraisal together with expert opinion in order to achieve recommendations for practice and, importantly, future research.

Keywords: Blood purification; Cartridges; Cytokines; Cytosorb; DAMPS; Haemoperfusion; Immune modulation; PAMPS; Sepsis; Septic shock; Sorbents.

Fig. 1

Cytokine response after sepsis. Normal and abnormal immune response after an (infectious) insult (A). Recovery with regaining of the homeostatic balance occurs when pro-inflammatory (solid red line) and anti-inflammatory (solid blue line) mediators (B) return back to baseline levels. Early death or fulminant septic shock (C) can occur following early increased innate pro-inflammatory response (cytokine storm, dotted red line) or after initial adaptive immunosuppression (dashed blue line). Immunoparalysis (D) can occur following early increased adaptive anti-inflammatory response (immunosuppression, dotted blue line) or after initial pro-inflammatory response (dashed red line). Haemoadsorption with Cytosorb^® may attenuate the initial pro- (bold red line) and anti-inflammatory (bold blue line) response resulting in early recovery (E)

Fig. 2

Balance between the pro- and anti-inflammatory mediators. a Following an initial (infectious) insult (A), normally after correct (antibiotic) treatment the antagonistic forces of pro-inflammation (B), and anti-inflammation (C) regain balance (grey area shows net effects) maintaining healthy homeostasis (D), that will lead to recovery and survival (E). Adapted from Pfortmueller et al. with permission (Open Access CC BY Licence 4.0) Intensive Care Medicine Experimental (2017) 5:49 10.1186/s40635-017-0163-0. b Following an (infectious) insult (A), during a dysregulated host response the pro-inflammatory (B) forces initially overwhelm anti-inflammation (C) resulting in an imbalance (D), followed by immunosuppression and increased anti-inflammatory mediators (grey area shows net effects). With different therapeutic interventions recovery (E) can be obtained or delayed (E’) or the patient can evolve into a state of persistent immunosupression or paralysis. Adapted from Pfortmueller et al. with permission (Open Access CC BY Licence 4.0) Intensive Care Medicine Experimental (2017) 5:49 10.1186/s40635-017-0163-0

Fig. 3

The rationale of bulk removal of cytokines during cytokine storm. When homeostasis is normal, the pro-inflammatory (open circles), and anti-inflammatory (closed circles) mediators are in balance, molecules are present evenly as demonstrated in the first panel of the figure (a). When molecules are adsorbed in this scenario, the removal rate of both should be similar. However, if one component is in abundance—which is the case during cytokine storm (b), then the removal rate should be proportionally higher from the mediator that is present in large numbers. This demonstrates the rationale why bulk removal of cytokines during cytokine storm may help to regain homeostatic balance