The Effect of Cytokine Adsorption on Leukocyte and Platelet Activation after Extracorporeal Cardiopulmonary Resuscitation

Abstract

Background Post-cardiac arrest syndrome (PCAS) is a frequent complication following successful cardiopulmonary resuscitation and correlates with poor outcome. PCAS is characterized by an excessive inflammatory response to whole-body ischemia and reperfusion. Cytokine adsorption was suggested as an adjunctive treatment option for the removal of cytokines from the patients' blood to restore the physiological equilibrium of pro- and anti-inflammatory activity and thus mitigate hemodynamic instability and end-organ complications.

Material and Methods To better understand the cellular effects of cytokine adsorption in patients receiving extracorporeal cardiopulmonary resuscitation (ECPR) after in- and out-of-hospital cardiac arrest, we compared the activation status of neutrophils, monocytes, and platelets as well as the formation of platelet–leukocyte complexes in intravenous whole blood samples from an exploratory subgroup (n = 24) from the randomized CYTER study.

Result At 48 hours after initiation of ECPR, flow cytometry analyses did neither reveal significant differences in neutrophil (CD11b, CD66b, L-selectin, and PSGL-1) and monocyte (CD11b, L-selectin, and PSGL-1) surface molecule expression nor in circulating platelet–monocyte complexes between patients receiving cytokine adsorption and those without.

Conclusion Data did not show a relevant effect of cytokine adsorption on neutrophil and monocyte activation during the first 48 hours after initiation of ECPR.

Keywords

post-cardiac arrest syndrome - cytokine adsorption - platelet–leukocyte complexes - extracorporeal membrane oxygenation - extracorporeal cardiopulmonary resuscitation

^* These authors contributed equally to this work.

Publication History

Received: 01 February 2023

Accepted: 09 December 2023

Accepted Manuscript online:
11 December 2023

Article published online:
10 January 2024

• References

• 1 Binks A, Nolan JP. Post-cardiac arrest syndrome. Minerva Anestesiol 2010; 76 (05) 362-368
• 2 Arnold L, Weberbauer M, Herkel M. et al. Endothelial BMP4 promotes leukocyte rolling and adhesion and is elevated in patients after survived out-of-hospital cardiac arrest. Inflammation 2020; 43 (06) 2379-2391
• 3 Langeland H, Damås JK, Mollnes TE. et al. The inflammatory response is related to circulatory failure after out-of-hospital cardiac arrest: a prospective cohort study. Resuscitation 2022; 170: 115-125
• 4 Mandel J, Casari M, Stepanyan M, Martyanov A, Deppermann C. Beyond hemostasis: platelet innate immune interactions and thromboinflammation. Int J Mol Sci 2022; 23 (07) 3868
• 5 Belohlavek J, Smalcova J, Rob D. et al; Prague OHCA Study Group. Effect of intra-arrest transport, extracorporeal cardiopulmonary resuscitation, and immediate invasive assessment and treatment on functional neurologic outcome in refractory out-of-hospital cardiac arrest: a randomized clinical trial. JAMA 2022; 327 (08) 737-747
• 6 Yannopoulos D, Bartos J, Raveendran G. et al. Advanced reperfusion strategies for patients with out-of-hospital cardiac arrest and refractory ventricular fibrillation (ARREST): a phase 2, single centre, open-label, randomised controlled trial. Lancet 2020; 396 (10265): 1807-1816
• 7 Schluep M, Gravesteijn BY, Stolker RJ, Endeman H, Hoeks SE. One-year survival after in-hospital cardiac arrest: a systematic review and meta-analysis. Resuscitation 2018; 132: 90-100
• 8 Bougouin W, Dumas F, Lamhaut L. et al; Sudden Death Expertise Center investigators. Extracorporeal cardiopulmonary resuscitation in out-of-hospital cardiac arrest: a registry study. Eur Heart J 2020; 41 (21) 1961-1971
• 9 Redant S, De Bels D, Honoré PM. Rationale of blood purification in the post-resuscitation syndrome following out-of-hospital cardiac arrest: a narrative review. Blood Purif 2021; 50 (06) 750-757
• 10 Poli EC, Rimmelé T, Schneider AG. Hemoadsorption with CytoSorb^® . Intensive Care Med 2019; 45 (02) 236-239
• 11 Gruda MC, Ruggeberg KG, O'Sullivan P. et al. Broad adsorption of sepsis-related PAMP and DAMP molecules, mycotoxins, and cytokines from whole blood using CytoSorb® sorbent porous polymer beads. PLoS One 2018; 13 (01) e0191676
• 12 Supady A, Brodie D, Wengenmayer T. Extracorporeal haemoadsorption: does the evidence support its routine use in critical care?. Lancet Respir Med 2022; 10 (03) 307-312
• 13 Supady A, Zahn T, Rieder M. et al. Effect of cytokine adsorption on survival and circulatory stabilization in patients receiving extracorporeal cardiopulmonary resuscitation. ASAIO J 2022; 68 (01) 64-72
• 14 Supady A, Zahn T, Kuhl M. et al. Cytokine adsorption in patients with post-cardiac arrest syndrome after extracorporeal cardiopulmonary resuscitation (CYTER) - a single-centre, open-label, randomised, controlled trial. Resuscitation 2022; 173: 169-178
• 15 Degroote RL, Weigand M, Hauck SM, Deeg CA. IL8 and PMA trigger the regulation of different biological processes in granulocyte activation. Front Immunol 2020; 10: 3064
• 16 Dinerman JL, Mehta JL, Saldeen TG. et al. Increased neutrophil elastase release in unstable angina pectoris and acute myocardial infarction. J Am Coll Cardiol 1990; 15 (07) 1559-1563
• 17 Engler RL, Dahlgren MD, Peterson MA, Dobbs A, Schmid-Schönbein GW. Accumulation of polymorphonuclear leukocytes during 3-h experimental myocardial ischemia. Am J Physiol 1986; 251 (1, Pt 2): H93-H100
• 18 Jolly SR, Kane WJ, Hook BG, Abrams GD, Kunkel SL, Lucchesi BR. Reduction of myocardial infarct size by neutrophil depletion: effect of duration of occlusion. Am Heart J 1986; 112 (04) 682-690
• 19 Fortunati E, Kazemier KM, Grutters JC, Koenderman L, Van den Bosch J. Human neutrophils switch to an activated phenotype after homing to the lung irrespective of inflammatory disease. Clin Exp Immunol 2009; 155 (03) 559-566
• 20 Opasawatchai A, Amornsupawat P, Jiravejchakul N. et al. Neutrophil activation and early features of NET formation are associated with dengue virus infection in human. Front Immunol 2019; 9: 3007
• 21 Hughes SF, Cotter MJ, Evans SA, Jones KP, Adams RA. Role of leucocytes in damage to the vascular endothelium during ischaemia-reperfusion injury. Br J Biomed Sci 2006; 63 (04) 166-170
• 22 Kharbanda RK, Peters M, Walton B. et al. Ischemic preconditioning prevents endothelial injury and systemic neutrophil activation during ischemia-reperfusion in humans in vivo. Circulation 2001; 103 (12) 1624-1630
• 23 McEver RP, Zhu C. Rolling cell adhesion. Annu Rev Cell Dev Biol 2010; 26: 363-396
• 24 Vestweber D. How leukocytes cross the vascular endothelium. Nat Rev Immunol 2015; 15 (11) 692-704
• 25 Ivetic A, Hoskins Green HL, Hart SJ. L-selectin: a major regulator of leukocyte adhesion, migration and signaling. Front Immunol 2019; 10: 1068
• 26 Santen S, Schramm R, Menger MD, Wang Y, Jeppsson B, Thorlacius H. P-selectin glycoprotein ligand-1 regulates chemokine-dependent leukocyte recruitment in colonic ischemia-reperfusion. Inflamm Res 2007; 56 (11) 452-458
• 27 Sreeramkumar V, Adrover JM, Ballesteros I. et al. Neutrophils scan for activated platelets to initiate inflammation. Science 2014; 346 (6214) 1234-1238
• 28 Bouti P, Webbers SDS, Fagerholm SC. et al. β2 Integrin signaling cascade in neutrophils: more than a single function. Front Immunol 2021; 11: 619925
• 29 Soo A, Maher B, McCarthy J, Nölke L, Wood A, Watson RW. Pre-operative determination of an individual's neutrophil response: a potential predictor of early cardiac transplant cellular rejection. J Heart Lung Transplant 2009; 28 (11) 1198-1205
• 30 Soo AW, Maher BM, Daly L, Wood AE, Watson WR. Preoperative neutrophil response as a predictive marker of clinical outcome following open heart surgery and the impact of leukocyte filtration. Interact Cardiovasc Thorac Surg 2010; 11 (05) 604-611
• 31 Bulger EM, Cuschieri J, Warner K, Maier RV. Hypertonic resuscitation modulates the inflammatory response in patients with traumatic hemorrhagic shock. Ann Surg 2007; 245 (04) 635-641
• 32 Schmidt T, Zündorf J, Grüger T. et al. CD66b overexpression and homotypic aggregation of human peripheral blood neutrophils after activation by a gram-positive stimulus. J Leukoc Biol 2012; 91 (05) 791-802
• 33 Ristagno G, Masson S, Tiainen M. et al; FINNRESUSCI Study Group. Elevated plasma heparin-binding protein is associated with early death after resuscitation from cardiac arrest. Crit Care 2016; 20 (01) 251
• 34 Park SO, Ahn JY, Lee YH. et al. Plasma neutrophil gelatinase-associated lipocalin as an early predicting biomarker of acute kidney injury and clinical outcomes after recovery of spontaneous circulation in out-of-hospital cardiac arrest patients. Resuscitation 2016; 101: 84-90
• 35 Loguinova M, Pinegina N, Kogan V. et al. Monocytes of different subsets in complexes with platelets in patients with myocardial infarction. Thromb Haemost 2018; 118 (11) 1969-1981
• 36 Glezeva N, Gilmer JF, Watson CJ, Ledwidge M. A central role for monocyte-platelet interactions in heart failure. J Cardiovasc Pharmacol Ther 2016; 21 (03) 245-261
• 37 Mansour A, Roussel M, Gaussem P. et al. platelet functions during extracorporeal membrane oxygenation. platelet-leukocyte aggregates analyzed by flow cytometry as a promising tool to monitor platelet activation. J Clin Med 2020; 9 (08) 2361
• 38 Wallner B, Schenk B, Paal P. et al. hypothermia induced impairment of platelets: assessment with multiplate vs. ROTEM-an in vitro study. Front Physiol 2022; 13: 852182
• 39 Hung SK, Lan HM, Han ST, Wu CC, Chen KF. Current evidence and limitation of biomarkers for detecting sepsis and systemic infection. Biomedicines 2020; 8 (11) 494
• 40 Jansen A, Waalders NJB, van Lier DPT, Kox M, Pickkers P. CytoSorb hemoperfusion markedly attenuates circulating cytokine concentrations during systemic inflammation in humans in vivo. Crit Care 2023; 27 (01) 117
• 41 Monard C, Bianchi N, Poli E. et al. Cytokine hemoadsorption with CytoSorb^® in post-cardiac arrest syndrome, a pilot randomized controlled trial. Crit Care 2023; 27 (01) 36
• 42 Schädler D, Pausch C, Heise D. 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 (10) e0187015
• 43 Diab M, Lehmann T, Bothe W. et al; REMOVE Trial Investigators*. Cytokine hemoadsorption during cardiac surgery versus standard surgical care for infective endocarditis (REMOVE): results from a multicenter randomized controlled trial. Circulation 2022; 145 (13) 959-968
• 44 Supady A, Weber E, Rieder M. 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 (07) 755-762