Veränderungen des Zytokin-Netzwerkes bei eskalierendem SIRS nach herzchirurgischen Operationen[*]

Zusammenfassung.

Die Anwendung der extrakorporalen Zirkulation (EKZ) im Rahmen kardiochirurgischer Operationen führt zu einer ausgeprägten inflammatorischen Reaktion, die jedoch nur bei einem geringen Anteil der betroffenen Patienten zu klinischen Komplikationen und einer erhöhten Letalität führt („eskalierendes SIRS”). In der gegenwärtigen Literatur gibt es nur wenige und unzureichende Angaben über Veränderungen des Immunsystems bei Patienten, die in der frühen postoperativen Phase ein schweres SIRS mit begleitenden Organinsuffizienzen entwickeln. In der vorliegenden Studie wird untersucht, in welchem Ausmaß das eskalierende SIRS in der frühen Phase nach kardiochirurgischen Operationen zu Veränderungen des Zytokin-Netzwerkes führt und ob sich die Expression von Zytokinen bei Überlebenden und Verstorbenen unterscheidet. Dazu untersuchten wir die Serumspiegel der Zytokine IL-1β, IL-6, IL-8, IL-10, IL-12, IL-18, GM-CSF und TGF-β bei 12 Patienten mit eskalierendem SIRS (SIRS-Gruppe) und 15 Patienten mit unauffälligem Verlauf (Kontroll-Gruppe) an den ersten 4 postoperativen Tagen nach elektiver Myokardrevaskularisierung. Die in der Literatur dargestellten Veränderungen von Mediatoren des Immunsystems nach herzchirurgischen Eingriffen können anhand der Ergebnisse bestätigt werden, darüber hinaus findet sich bei eskalierendem SIRS eine bisher noch nicht beschriebene Zunahme der Immun-Dysregulation: Sowohl die Serumspiegel der pro-inflammtorischen Zytokine IL-6, IL-8, IL-18 und GM-CSF, als auch die der immun-inhibierenden Zytokine IL-10 und TGF-beta sind bei den Patienten mit schwerem SIRS signifikant erhöht. Eine nochmalige Zunahme der Expression von IL-8 und IL-18 zeigt sich bei den verstorbenen Patienten der SIRS-Gruppe. Das eskalierende SIRS nach herzchirurgischen Operationen stellt somit ein uneinheitliches immunologisches Geschehen dar, welches sowohl pro- als auch anti-inflammatorische Komponenten beinhaltet. Die Zytokine IL-8 und IL-18 scheinen hierbei bereits zu einem frühen Zeitpunkt die Diskriminierung von Hochrisikopatienten zu ermöglichen.

Changes in the Cytokine Network Through Escalating SIRS After Heart Surgery.

Cardiopulmonary bypass is associated with an injury that may cause pathophysiological changes in form of systemic inflammatory response syndrome (SIRS) or multiple organ dysfunction syndrome (MODS). There is a lot of information about the immunologic alterations in patients undergoing cardiopulmonary bypass, but only little is known about the expression of cytokines in patients with severe SIRS or MODS following cardiovascular surgery. In the present study, we investigated the inflammatory response of patients with an escalating SIRS following open heart surgery. Plasma levels of cytokines (IL-1β, IL-6, IL-8, IL-10, IL-12, IL-18, GM-CSF and TGF-β) were measured at the first four postoperative days in 12 adult male patients with severe SIRS (SIRS-group), and 15 patients with uncomplicated course (control-group) following myocardial revascularization. All cytokines (except IL-1β) were significantly elevated in SIRS-patients, the analysis of differences between the survivors and non-survivors within the SIRS-group showed dramatically elevated levels of IL-8 and IL-18 in non-survivors. From the results of our investigation we can conclude that monitoring of immunologic parameters, e.g. IL-8 and/or IL-18 may be helpful for the early detection and prognosis of high-risk patients with severe SIRS and MODS following cardiac surgery.

Schlüsselwörter:

Interleukine - SIRS - MODS - EKZ

Key words:

Interleukins - Severe SIRS - MODS - Cardiopulmonary bypass

1 Herrn Prof. Dr. med. D. Kettler und Herrn Prof. Dr. med. H. Sonntag zum 65. Geburtstag gewidmet.

Literatur

• 1 Goris R JA, Boekhorst T P, Nuytinck J KS, et al. Multiple organ failure. Generalized autodestructive inflammation?.  Arch Surg. 1985;  120 1109-1115
• 2 Kirklin J K, Wetaby S, Blackstone E H, Kirklin J W, Chenoweth D E, Pacifico A D. Complement and the damaging effects of cardiopulmonary bypass.  J Thorac Cardiovasc Surg. 1983;  86 845-857
• 3 Wan S, LeClerc J L, Vincent J L. Inflammatory response to cardiopulmonary bypass. Mechanisms involved and possible therapeutic strategies.  Chest. 1997;  112 676-692
• 4 Royston D. The inflammatory response and extracorporal circulation.  J Cardiothor Vasc Anaesth. 1997;  11 341-354
• 5 Pesonen E J, Korpela R, Peltola K, et al. Regional generation of free oxygen radicals during cardiopulmonary bypass in children.  J Thorac Cardiovasc Surg. 1995;  110 768-773
• 6 Hashimoto K, Miyamoto H, Suzuki K, et al. Evidence of organ damage after cardiopulmonary bypass: The role of elastase and vasoactive mediators.  J Thorac Cardiovasc Surg. 1992;  104 666-673
• 7 Breda M A, Drinkwater D C, Laks H, et al. Prevention of reperfusion injury in the neonatal heart with leukocyte-depleted blood.  J Thorac Cardiovasc Surg. 1989;  97 654-665
• 8 Sablotzki A, Dehne M, Welters I, et al. Alterations of the cytokine network in patients undergoing cardiopulmonary bypass.  Perfusion. 1997;  12 393-403
• 9 Nathan N, Denizot Y, Cornu E, et al. Cytokine and lipid mediator blood concentrations after coronary artery surgery.  Anesth Analg. 1997;  85 1240-1246
• 10 Toft P, Tonnesen E, Zülow I, et al. Expression of adhesion and activation molecules on lymphocytes during open-heart surgery with cardiopulmonary bypass.  Scand Cardiovasc J. 1997;  31 91-95
• 11 Hensel M, Volk T, Döcke W D, et al. Hyperprocalcitoninemia in patients with noninfectious SIRS and pulmonary dysfunction associated with cardiopulmonary bypass.  Anesthesiology. 1998;  89 93-104
• 12 Sablotzki A, Welters I, Lehmann N, et al. Plasma levels of immunoinhibitory cytokines interleukin-10 and transforming growth factor-beta in patients undergoing coronary artery bypass grafting.  Eur J Cardiothorac Surg. 1997;  11 763-768
• 13 Bone R C. Sir Isaac Newton, sepsis, SIRS, and CARS.  Crit Care Med. 1996;  24 1125-1128
• 14 Taylor K M. SIRS - The Systemic Inflammatory Response Syndrome after cardiac operations.  Ann Thorac Surg. 1996;  61 1607-1608
• 15 Pilz G, Fraunberger P, Appel R, et al. Early prediction of outcome in score-identified, post-cardiac surgical patients at high risk for sepsis, using soluble tumor necrosis factor receptor p55 concentrations.  Crit Care Med. 1996;  24 596-600
• 16 Hall R I, Smith M S, Rocker G M. The systemic inflammatory response to cardiopulmonary bypass: Pathophysiological, therapeutic, and pharmacological considerations.  Anesth Analg. 1997;  85 66-86
• 17 Cremer J, Martin M, Redl H. Systemic inflammatory response syndrome after cardiac operations.  Ann Thorac Surg. 1996;  61 1714-1720
• 18 The ACCP/SCCM American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference . Defintions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis.  Crit Care Med. 1992;  20 864-874
• 19 Pilz G, Kääb S, Kreuzer E, et al. Evaluaton of definitions and parameters for sepsis assessment in patients after cardiac surgery.  Infection. 1994;  22 8-17
• 20 Wan S, LeClerc J L, Vincent J L. Cytokine resonses to cardiopulmonary bypass: Lessons learned from cardiac transplantation.  Ann Thorac Surg. 1997;  63 269-276
• 21 Prondzinsky R, Müller-Werdan U, Pilz G, et al. Systemische Entzündungsreaktionen extrakorporaler Therapieverfahren (II): Der kardiopulmonale Bypass.  Wien Klein Wochenschr. 1997;  109 346-353
• 22 Kuhn C, Muller-Werdan U, Schmitt D V, et al. Improved outcome of APACHE II score-defined escalating systemic inflammatory response syndrome in patients post cardiac surgery in 1996 compared to 1988 - 1990: the ESSICS-study pilot project.  Eur J Cardiothorac Surg. 2000;  17 30-37
• 23 Deng M C, Dasch B, Erren M, et al. Arterial and venous cytokine response to cardiopulmonary bypass.  Eur J Cardiothorac Surg. 1995;  9 22-29
• 24 Menasche P, Haydar S, Peynet J, et al. A potential mechanism of vasodilation after warm heart surgery: the temperature-dependent release of cytokines.  J Thorac Cardiovasc Surg. 1994;  107 293-299
• 25 Menasche P. The inflammatory response to cardiopulmonary bypass and its impact on postoperative myocardial function.  Curr Opinion Cardiol. 1995;  10 597-604
• 26 Casey L C, Balk R A, Bone R C. Plasma cytokines and endotoxin levels correlate with survival in patients with the sepsis syndrome.  Ann Intern Med. 1993;  119 771-777
• 27 Metinko A, Kunkel S, Standiford T, et al. Monocyte expression of interleukin-8 in response to oxidant stress.  FASEB J. 1991;  Abstracts part 1 194
• 28 Dinarello C A. IL-18: A th1-inducing, proinflammatory cytokine and new member of the IL-1 family.  J Allergy Clin Immunol. 1999;  103 11-24
• 29 Fantuzzi G, Dinarello C A. Interleukin-18 and Interleukin-1β: Two cytokine substrates for ICE (caspase-1).  J Clin Immunol. 1999;  19 1-11
• 30 Puren A J, Fantuzzi G, Gu Y, Su M S-S, Dinarello C A. Interleukin-18 (IFN-γ-inducing factor) induces IL-1β and IL-8 via TNF-α production from non-CD14+ human blood mononuclear cells.  J Clin Invest. 1998;  101 711-717
• 31 Trinchieri G. Interleukin-12: a proinflammatory cytokine with immuno-regulatory functions that bridge innate resistance and antigen-specific adaptive immunity.  Ann Rev Immunol. 1995;  13 251-274
• 32 Friedman G, Jankowski S, Marchant A, et al. Detection of interleukin-10 in patients with septic shock.  Intensive Care Med. 1994;  20 (1) 9
• 33 Chernoff A E, Granowitz E V, Shapiro L. A randomized, controlled trial of IL-10 in humans. Inhibition of inflammatory cytokine production and immune responses.  J Immunol. 1995;  154 5492-5499
• 34 Oswald I P, Gazzinelli R T, Sher A, et al. IL-10 synergizes with IL-4 and transforming growth factor-β to inhibit macrophage cytotoxic activity.  J Immunol. 1992;  148 3578-3582
• 35 Schmitt E, Hoehn P, Huels C. T helper type 1 development of naive CD4+ T cells requires the coordinate action of interleukin-12 and interferon-γ and is inhibited by transforming growth factor-β.  Eur J Immunol. 1994;  24 793-798
• 36 Hummel M, Docke W D, Friedel N, et al. Monitoring of the cellular immune system in patients with biventricular assist devices awaiting cardiac transplantation.  Clin Transplant. 1994;  8 59-66
• 37 Abe Y, Kawakami M, Kuroki M, et al. Transient rise in serum interleukin-8 concentration during acute myocardial infarction.  Br Heart J. 1993;  70 132-134
• 38 Razzoni F, Cassatella M A, Rossi F, et al. Phagocytosing neutrophils produce and release high amounts of the neutrophi-activating peptide interleukin-8.  J Exp Med. 1991;  173 771-774
• 39 Munder M, Mallo M, Eichmann K, et al. Murine macrophage secrete interferon gamma upon combined stimulation with interleukin(IL)-12 and IL-18: A novel pathway of autocrine macrophage activation.  J Exp Med. 1998;  187 2103-2108
• 40 Puren A J, Fantuzzi G, Gu Y, et al. Interleukin-18 (IFN-γ-inducing-factor) induces IL-1β and IL-8 via TNFα production from non-CD14+ human blood mononuclear cells.  J Clin Invest. 1998;  101 711-724

1 Herrn Prof. Dr. med. D. Kettler und Herrn Prof. Dr. med. H. Sonntag zum 65. Geburtstag gewidmet.