OBJECTIVES: The use of hemoadsorption (HA) has become popular in the treatment of vasoplegic states associated with massive cytokine release, including septic shock. However, this approach does not seem to be based on robust evidence, and it does not follow international guidelines. To understand the pathophysiological rationale and timing of HA, we conducted a large animal septic shock experiment. DESIGN: Prospective randomized large-animal peritoneal septic shock experiment. SETTING: Laboratory investigation. SUBJECTS: Twenty-six anesthetized, mechanically ventilated, and instrumented pigs randomly assigned into (1) sham-operated group with HA (SHAM, n = 5); (2) sepsis animals without HA (SEPSIS, n = 5); (3) sepsis group with HA at norepinephrine initiation (EARLY, n = 8); and (4) sepsis group with HA initiated at norepinephrine rate reaching 0.5 μg/kg/min (LATE, n = 8). INTERVENTIONS: Peritoneal sepsis was induced by cultivated autologous feces inoculation. A CytoSorb cartridge (200 g) with a blood flow rate of 200 mL/min and heparin anticoagulation was used to perform HA. The animals received sedation and intensive organ support up to 48 h or until they experienced cardiovascular collapse. MEASUREMENTS AND MAIN RESULTS: Systemic hemodynamics, multiple-organ functions, and immune-inflammatory response were measured at predefined periods. The HA treatment was not associated with any measurable benefit in terms of systemic hemodynamics and organ support. The systemic inflammatory markers were unaffected by any of the treatment timings. In contrast, the HA resulted in higher vasopressor load and decreased 36-h survival (5 animals in SHAM (100%), 4 (80%) in SEPSIS, 4 (57%) in EARLY, and 2 (25%) in LATE; p = 0.041). The HA exposure in healthy animals was associated with hemodynamic deterioration, systemic inflammatory response, and cytopenia. CONCLUSIONS: In this large-animal-controlled fulminant sepsis study, the HA was unable to counteract the disease progression in the early or advanced septic shock phase. However, findings from the HA-exposed sham animals suggest potential safety concerns.

Department of Anesthesiology Resuscitation and Intensive Care Faculty Hospital in Pilsen Pilsen Czech Republic

Department of Anesthesiology Resuscitation and Intensive Care Faculty of Medicine in Pilsen Charles University Pilsen Czech Republic

Department of Internal Medicine 1 Faculty of Medicine in Pilsen Charles University Pilsen Czech Republic

Department of Physiology Faculty of Medicine in Pilsen Charles University Pilsen Czech Republic

Laboratory of Experimental Cardiology Biomedical Center Faculty of Medicine in Pilsen Charles University Pilsen Czech Republic

Laboratory of Experimental Intensive Care Medicine Biomedical Center Faculty of Medicine in Pilsen Charles University Alej Svobody 1655 76 323 00 Pilsen Czech Republic

Zobrazit více v PubMed

Bauer M, Gerlach H, Vogelmann T, Preissing F, Stiefel J, Adam D. Mortality in sepsis and septic shock in Europe, North America and Australia between 2009 and 2019—results from a systematic review and meta-analysis. Crit Care. 2020;24:1–9. doi: 10.1186/s13054-020-02950-2. PubMed DOI PMC

Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 2021;47:1181–1247. doi: 10.1007/s00134-021-06506-y. PubMed DOI PMC

Hawchar F, Rao C, Akil A, Mehta Y, Rugg C, Scheier J, et al. The potential role of extracorporeal cytokine removal in hemodynamic stabilization in hyperinflammatory shock. Biomedicines. 2021;9:768. doi: 10.3390/biomedicines9070768. PubMed DOI PMC

Scharf C, Schroeder I, Paal M, Winkels M, Irlbeck M, Zoller M, et al. Can the cytokine adsorber CytoSorb® help to mitigate cytokine storm and reduce mortality in critically ill patients? A propensity score matching analysis. Ann Intensive Care. 2021;11:1–8. doi: 10.1186/S13613-021-00905-6. PubMed DOI PMC

Schädler D, Pausch C, Heise D, Meier-Hellmann A, Brederlau J, Weiler N, et al. The effect of a novel extracorporeal cytokine hemoadsorption device on IL-6 elimination in septic patients: a randomized controlled trial. PLoS ONE. 2017;12:e0187015. doi: 10.1371/journal.pone.0187015. PubMed DOI PMC

Hawchar F, László I, Öveges N, Trásy D, Ondrik Z, Molnar Z. Extracorporeal cytokine adsorption in septic shock: a proof of concept randomized, controlled pilot study. J Crit Care. 2019;49:172–178. doi: 10.1016/j.jcrc.2018.11.003. PubMed DOI

Stockmann H, Thelen P, Stroben F, Pigorsch M, Keller T, Krannich A, et al. CytoSorb rescue for COVID-19 patients with vasoplegic shock and multiple organ failure: a prospective, open-label, randomized controlled pilot study*. Crit Care Med. 2022;50:964. doi: 10.1097/ccm.0000000000005493. PubMed DOI PMC

Jarczak D, Roedl K, Fischer M, de Heer G, Burdelski C, Frings DP, et al. Effect of hemadsorption therapy in critically ill patients with COVID-19 (CYTOCOV-19): a prospective randomized controlled pilot trial. Blood Purif. 2023;52:183–192. doi: 10.1159/000526446. PubMed DOI PMC

Diab M, Lehmann T, Bothe W, Akhyari P, Platzer S, Wendt D, et al. Cytokine hemoadsorption during cardiac surgery versus standard surgical care for infective endocarditis (REMOVE): results from a multicenter randomized controlled trial. Circulation. 2022;145:959–968. doi: 10.1161/CIRCULATIONAHA.121.056940. PubMed DOI

Supady A, Brodie D, Wengenmayer T. Extracorporeal haemoadsorption: does the evidence support its routine use in critical care? Lancet Respir Med. 2022;10:307–312. doi: 10.1016/S2213-2600(21)00451-3. PubMed DOI

DRKS00017211. Veränderung der Mikrozirkulation unter Haemoadsorption bei Patienten mit Sepsis und septischem Schock n.d. https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00017211.

NCT04963920. An RCT to Assess the Performance of CytoSorb for Shock Reversal in Patients With Vasoplegic Septic Shock (PROCYSS) n.d. https://www.clinicaltrials.gov/ct2/show/NCT04963920?term=PROCYSS&draw=2&rank=1.

Becker S, Lang H, Vollmer Barbosa C, Tian Z, Melk A, Schmidt BMW. Efficacy of CytoSorb®: a systematic review and meta-analysis. Crit Care. 2023;27:215. doi: 10.1186/s13054-023-04492-9. PubMed DOI PMC

Heymann M, Schorer R, Putzu A. The effect of Cytosorb on inflammatory markers in critically ill patients: a systematic review and meta-analysis of randomized controlled trials. Crit Care Med. 2023 doi: 10.1097/CCM.0000000000006007. PubMed DOI PMC

Osuchowski MF, Ayala A, Bahrami S, Bauer M, Boros M, Cavaillon J-M, et al. Minimum quality threshold in pre-clinical sepsis studies (MQTiPSS): an international expert consensus initiative for improvement of animal modeling in sepsis. Shock. 2018;50:377–380. doi: 10.1097/SHK.0000000000001212. PubMed DOI PMC

Kielstein JT, Zarbock A. Is this the beginning of the end of cytokine adsorption?*. Crit Care Med. 2022;50:1026–1029. doi: 10.1097/CCM.0000000000005509. PubMed DOI PMC

Kohoutova M, Horak J, Jarkovska D, Martinkova V, Tegl V, Nalos L, et al. Vagus nerve stimulation attenuates multiple organ dysfunction in resuscitated porcine progressive sepsis. Crit Care Med. 2019;47:e461. doi: 10.1097/CCM.0000000000003714. PubMed DOI

Horak J, Nalos L, Martinkova V, Tegl V, Vistejnova L, Kuncova J, et al. Evaluation of mesenchymal stem cell therapy for sepsis: a randomized controlled porcine study. Front Immunol. 2020;11:126. doi: 10.3389/fimmu.2020.00126. PubMed DOI PMC

Malard B, Lambert C, Kellum JA. In vitro comparison of the adsorption of inflammatory mediators by blood purification devices. Intensive Care Med Exp. 2018;6:1–13. doi: 10.1186/s40635-018-0177-2. PubMed DOI PMC

Harm S, Schildböck C, Hartmann J. Cytokine removal in extracorporeal blood purification: an in vitro study. Blood Purif. 2020;49:33. doi: 10.1159/000502680. PubMed DOI

Peng ZY, Wang HZ, Carter MJ, Dileo MV, Bishop JV, Zhou FH, et al. Acute removal of common sepsis mediators does not explain the effects of extracorporeal blood purification in experimental sepsis. Kidney Int. 2012;81:363. doi: 10.1038/ki.2011.320. PubMed DOI PMC

Peng ZY, Carter MJ, Kellum JA. Effects of hemoadsorption on cytokine removal and short-term survival in septic rats. Crit Care Med. 2008;36:1573. doi: 10.1097/CCM.0b013e318170b9a7. PubMed DOI PMC

Kellum JA, Song M, Venkataraman R. Hemoadsorption removes tumor necrosis factor, interleukin-6, and interleukin-10, reduces nuclear factor-κB DNA binding, and improves short-term survival in lethal endotoxemia. Crit Care Med. 2004;32:801–805. doi: 10.1097/01.CCM.0000114997.39857.69. PubMed DOI

Köhler T, Schwier E, Praxenthaler J, Kirchner C, Henzler D, Eickmeyer C. Therapeutic modulation of the host defense by hemoadsorption with Cytosorb®—basics, indications and perspectives—a scoping review. Int J Mol Sci. 2021;22:12786. doi: 10.3390/ijms222312786. PubMed DOI PMC

Supady A, Weber E, Rieder M, Lother A, Niklaus T, Zahn T, et al. 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. 2021;9:755–762. doi: 10.1016/S2213-2600(21)00177-6. PubMed DOI PMC

Linden K, Scaravilli V, Kreyer SFX, Belenkiy SM, Stewart IJ, Chung KK, et al. Evaluation of the cytosorbtm hemoadsorptive column in a pig model of severe smoke and burn injury. Shock. 2015;44:487. doi: 10.1097/SHK.0000000000000439. PubMed DOI

Schultz P, Schwier E, Eickmeyer C, Henzler D, Köhler T. High-dose CytoSorb hemoadsorption is associated with improved survival in patients with septic shock: a retrospective cohort study. J Crit Care. 2021;64:184–192. doi: 10.1016/j.jcrc.2021.04.011. PubMed DOI

Paul R, Sathe P, Kumar S, Prasad S, Aleem M, Sakhalvalkar P. Multicentered prospective investigator initiated study to evaluate the clinical outcomes with extracorporeal cytokine adsorption device (CytoSorb®) in patients with sepsis and septic shock. World J Crit Care Med. 2021;10:22–34. doi: 10.5492/wjccm.v10.i1.22. PubMed DOI PMC

Kogelmann K, Jarczak D, Scheller M, Drüner M. Hemoadsorption by CytoSorb in septic patients: a case series. Crit Care. 2017;21:1–10. doi: 10.1186/s13054-017-1662-9. PubMed DOI PMC

Mehta Y, Mehta C, Kumar A, George JV, Gupta A, Nanda S, et al. Experience with hemoadsorption (CytoSorb®) in the management of septic shock patients. World J Crit Care Med. 2020;9:1. doi: 10.5492/wjccm.v9.i1.1. PubMed DOI PMC

Wendel Garcia PD, Hilty MP, Held U, Kleinert E-M, Maggiorini M. Cytokine adsorption in severe, refractory septic shock. Intensive Care Med. 2021;47:1334–1336. doi: 10.1007/s00134-021-06512-0. PubMed DOI PMC

Torgersen C, Moser P, Luckner G, Mayr V, Jochberger S, Hasibeder WR, et al. Macroscopic postmortem findings in 235 surgical intensive care patients with sepsis. Anesth Analg. 2009;108:1841–1847. doi: 10.1213/ane.0b013e318195e11d. PubMed DOI

Schneider AG, André P, Scheier J, Schmidt M, Ziervogel H, Buclin T, et al. Pharmacokinetics of anti-infective agents during CytoSorb hemoadsorption. Sci Rep. 2021;11:10493. doi: 10.1038/s41598-021-89965-z. PubMed DOI PMC