Dear Editor,
Septic shock and the underlying dysregulated inflammatory host-response remain major contributors to mortality in critically ill patients. In contrast to classic hemofiltration strategies, cytokine adsorption through bulk removal of cytokines has been postulated to re-establish inflammatory homeostasis, representing an attractive approach to the treatment of septic shock [1]. Nonetheless, most evidence to date is of descriptive or ambivalent character and cytokine adsorption in severe, refractory septic shock is largely unexplored [2].
To investigate the effect of cytokine adsorption on circulating interleukin (IL)-6, vasopressor requirements and intensive care mortality, patients presenting with severe, refractory septic shock, IL-6 ≥ 1000 ng/l and a vasopressor dependency index ≥ 3, despite adequate volume resuscitation, were prospectively recruited. Cytokine adsorption was provided for three consecutive 24-h sessions initiated within 24 h from shock onset. Forty-eight included patients were matched to 160 patients having fulfilled the same severe, refractory septic shock criteria (e-Fig. 1). Six matching algorithms were evaluated against each other to achieve optimal balancing of covariates, leading to the choice of Genetic Matching as superior algorithm. For further specifications on the employed methodology, see e-Appendix 1.
The baseline characteristics among the 96 matched patients (48 treated with cytokine adsorption, 48 treated without) were equivalent (e-Table 1, e-Fig. 2). Patients were characterized by a SOFA score of 14 ± 3, profound lactatemia (5.8 ± 4.8 mmol/l) and required 0.7 ± 0.5 µg/kg/min norepinephrine. Within the 72-h intervention period, circulating IL-6 levels (p = 0.254) and vasopressor requirements (p = 0.555) decreased irrespective of cytokine adsorption use (Fig. 1a, b, e-Table 2, e-Fig. 3). Intensive care mortality was more pronounced in patients treated with cytokine adsorption than in the control group (control: 20 (42%), cytokine adsorption: 32 (67%), p = 0.024) as evidenced by a competing risks hazard ratio for mortality of 1.82 (95% confidence interval, 1.03–3.2; p = 0.038) (Fig. 1c). Additional analyses are presented in e-Appendix 2.
For almost four decades, the hypothesis that quantitative removal of inflammatory mediators improves survival in sepsis has resulted in negative trials [2]. Unexpectedly however, our data reflect the results of the first multicenter trial having assessed cytokine adsorption in sepsis [3] and, despite the pathophysiological differences, of a recent trial assessing cytokine adsorption in severe patients affected by coronavirus disease 2019 (COVID-19) on extracorporeal membrane oxygenation [4]. It evidenced not only no effect of cytokine adsorption on circulating IL-6 levels, but also strikingly suggested an increased mortality in the cytokine adsorption group.
Cytokines play a pivotal role in the progression of host response in sepsis. Pro-inflammatory cytokines may be associated with a deranged host response and poor outcomes during early sepsis. However, nothing persists for millions of years if it does not offer a substantial evolutionary benefit. Indeed, the dynamic interplay between pro- and anti-inflammatory cytokines is imperative to achieve tissue repair, endothelial integrity and resolution of inflammation. Indiscriminate removal of cytokines could thus lead to a perpetuation of inflammation and prothrombogenicity, leading to sustained microcirculatory and mitochondrial dysfunction, ultimately promoting end-organ damage and death [5].
In conclusion, cytokine adsorption in severe, refractory septic shock was neither associated with reduced IL-6 levels nor vasopressor requirements, and lead to an increased hazard of death. The present results in conjunction with recent evidence plead against the widespread and indiscriminate use of cytokine adsorption outside of investigational settings and urge for a return to qualitative and mechanistic blood purification research in septic shock.
Availability of data and material
All data analyzed and discussed in the framework of this study are included in this published article and its online supplementary information. The corresponding author may provide specified analyses or fully de-identified parts of the dataset upon reasonable request.
Code availability
Not applicable.
References
Honore PM, Hoste E, Molnár Z, Jacobs R, Joannes-Boyau O, Malbrain MLNG, Forni LG (2019) Cytokine removal in human septic shock: where are we and where are we going? Ann Intensive Care 9:56
Poli EC, Rimmelé T, Schneider AG (2019) Hemoadsorption with CytoSorb®. Intensive Care Med 45:236–239
Schädler D, Pausch C, Heise D, Meier-Hellmann A, Brederlau J, Weiler N, Marx G, Putensen C, Spies C, Jörres A, Quintel M, Engel C, Kellum JA, Kuhlmann MK (2017) The effect of a novel extracorporeal cytokine hemoadsorption device on IL-6 elimination in septic patients: a randomized controlled trial. PLoS ONE 12:e0187015
Supady A, Weber E, Rieder M, Lother A, Niklaus T, Zahn T, Frech F, Müller S, Kuhl M, Benk C, Maier S, Trummer G, Flügler A, Krüger K, Sekandarzad A, Stachon P, Zotzmann V, Bode C, Biever PM, Staudacher D, Wengenmayer T, Graf E, Duerschmied D (2021) Cytokine adsorption in patients with severe COVID-19 pneumonia requiring extracorporeal membrane oxygenation (CYCOV): a single centre, open-label, randomised, controlled trial. Lancet Respir Med. https://doi.org/10.1016/S2213-2600(21)00177-6
Bonavia A, Groff A, Karamchandani K, Singbartl K (2018) Clinical utility of extracorporeal cytokine hemoadsorption therapy: a literature review. Blood Purif 46:337–349
Funding
CytoSorbents Europe GmbH (Berlin, Germany) partially funded this study by means of an unrestricted grant. The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Author information
Authors and Affiliations
Contributions
PDWG and MM conceived and designed the research project. PDWG and EMK handled data acquisition. PDWG, EMK and MPH accessed and verified the data. PDWG, MPH, UH and MM performed analysis and interpretation of the data. PDWG performed statistical analysis and wrote the first draft of the manuscript. MM handled funding and supervision of the research project. All authors read, critically revised and approved the final manuscript. All authors had full access to the full data in the study and accept responsibility for the decision to submit for publication.
Corresponding author
Ethics declarations
Conflicts of interest
MM reported receiving research grants from CytoSorbents Europe GmbH (Berlin, Germany) and Baxter International Inc. (Deerfield, USA), as well as personal fees for his work as external consultant from Baxter International Inc. (Deerfield, USA) and Toray Industries Inc. (Tokyo, Japan). All other authors declare no conflicts of interest.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and Swiss national research committee, with the 1964 Helsinki Declaration and its later amendments and with the guidelines on Good Clinical Practice issued by the European Medicines Agency. The study was approved by the cantonal ethics committee of Zurich (BASEC: ZH 201800559).
Consent to participate
Written informed consent for participation from the patient or in case of death or disability, from the next of kin or legal representative, was sought for every patient prospectively treated with the cytokine adsorber. In the historical cohort, a retrospective informed consent collection process was followed.
Consent for publication
Written informed consent for publication from the patient or, in case of death or disability, from the next of kin or legal representative was sought for every patient prospectively treated with the cytokine adsorber. In the historical cohort, a retrospective informed consent collection process was followed.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Wendel Garcia, P.D., Hilty, M.P., Held, U. et al. Cytokine adsorption in severe, refractory septic shock. Intensive Care Med 47, 1334–1336 (2021). https://doi.org/10.1007/s00134-021-06512-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00134-021-06512-0