Pathophysiologie der Sepsis

Zusammenfassung

Eine dysregulierte, d.h. systemische und überschießende, Immunantwort ist nach derzeitiger Lehrmeinung für die Entstehung des Sepsis-assoziierten Multiorganversagens verantwortlich. Dabei ist der im späteren Verlauf auftretenden Infekt-assoziierten Depression des Immunsystems ein mindestens ebenso hoher Stellenwert wie der in der Initialphase klinisch offenkundigen Inflammation beizumessen. Weitere zentrale Pathomechanismen stellen die septische Koagulopathie und die endotheliale Dysfunktion dar, die aufgrund von zahleichen Interaktionen auf Mediator- und Rezeptorebene lediglich zu didaktischen Zwecken isoliert von der Inflammation betrachtet werden können. Klinisch resultiert die charakteristische Symptomatik aus Störungen der Mikro- und Makrozirkulation mit einer verminderten mikrovaskulären Sauerstofftransportkapazität. Hinzu kommt die Störung des zellulären Energiestoffwechsels („zytopathische Hypoxie“), so dass selbst nach Wiederherstellung normaler Sauerstoffpartialdrücke Beeinträchtigungen der Organfunktionen entstehen. Diese sind zwar meist funktionell und potenziell reversibel, entwickelt sich jedoch ein Multiorganversagen steigt die Letalität auf bis zu 70%.

Abstract

Current evidence suggests that a dysregulated, i.e. systemic and extensive, immune response causes sepsis-induced multiple organ failure. Notably, this does not only imply the initial inflammatory reaction but also the delayed sepsis-associated depression of the immune system. Endothelial dysfunction and sepsis-induced coagulopathy represent additional major pathomechanisms. Based on multiple interactions between mediators und receptors all of these mechanisms can be discussed individually only for didactical purposes. Clinically, there are charateristic microcirculatory disorders and macrocirclatory changes resulting in an impaired oxygen transport capacity. Due to an additional cytopathic hypoxia, organ function might be impaired even if physiological partial pressures of oxygen are restored. Although these changes are often functional and potentially reversible, mortality increases up to 70% in case of multiple organ failure.

Schlüsselwörter

dysregulierte Inflammation - endotheliale Dysfunktion - Mikrozirkulationsstörungen - septische Koagulopathie - zytopathische Hypoxie

Keywords

dysregulated inflammation - endothelial dysfunction - microcirculatory dysfunction - septis-induced coagulopathy - cytopathic hypoxia

• Literatur

• 1 Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol 1994; 12: 991-1045
• 2 Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell 2010; 140: 805-820
• 3 Chan JK, Roth J, Oppenheim JJ et al. Alarmins: awaiting a clinical response. J Clin Invest 2012; 122: 2711-2719
• 4 Reid VL, Webster NR. Role of microparticles in sepsis. Br J Anaesth 2012; 109: 503-513
• 5 Cinel I, Opal SM. Molecular biology of inflammation and sepsis: a primer. Crit Care Med 2009; 37: 291-304
• 6 Russell JA, Boyd J, Nakada T et al. Molecular mechanisms of sepsis. Contrib Microbiol 2011; 17: 48-85
• 7 Kawai J, Ando K, Shimosawa T et al. Regional hemodynamic effects of adrenomedullin in Wistar rats: a comparison with calcitonin gene-related peptide. Hypertens Res 2002; 25: 441-446
• 8 Kawai T, Akira S. The roles of TLRs, RLRs and NLRs in pathogen recognition. Int Immunol 2009; 21: 317-337
• 9 Fourrier F. Severe sepsis, coagulation, and fibrinolysis: dead end or one way?. Crit Care Med 2012; 40: 2704-2708
• 10 Hardaway RM, Williams CH, Vasquez Y. Disseminated intravascular coagulation in sepsis. Semin Thromb Hemost 2001; 27: 577-583
• 11 Russell JA. Management of sepsis. N Engl J Med 2006; 355: 1699-1713
• 12 Fourrier F, Chopin C, Goudemand J et al. Septic shock, multiple organ failure, and disseminated intravascular coagulation. Compared patterns of antithrombin III, protein C, and protein S deficiencies. Chest 1992; 101: 816-823
• 13 Warren BL, Eid A, Singer P et al. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. Jama 2001; 286: 1869-1878
• 14 Ranieri VM, Thompson BT, Barie PS et al. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med 2012; 366: 2055-2064
• 15 Schouten M, Wiersinga WJ, Levi M et al. Inflammation, endothelium, and coagulation in sepsis. J Leukoc Biol 2008; 83: 536-545
• 16 Jourdain M, Carrette O, Tournoys A et al. Effects of inter-alpha-inhibitor in experimental endotoxic shock and disseminated intravascular coagulation. Am J Respir Crit Care Med 1997; 156: 1825-1833
• 17 Raaphorst J, Johan Groeneveld AB, Bossink AW et al. Early inhibition of activated fibrinolysis predicts microbial infection, shock and mortality in febrile medical patients. Thromb Haemost 2001; 86: 543-549
• 18 Levi M, van der Poll T. Inflammation and coagulation. Crit Care Med 2010; 38 (2 Suppl) S26-34
• 19 Coughlin SR. Thrombin signalling and protease-activated receptors. Nature 2000; 407: 258-264
• 20 Ruf W. New players in the sepsis-protective activated protein C pathway. J Clin Invest 2010; 120: 3084-3087
• 21 Sharawy N. Vasoplegia in septic shock: Do we really fight the right enemy?. J Crit Care 2014; 29: 83-7
• 22 van der Heijden M, Pickkers P, van Nieuw Amerongen GP et al. Circulating angiopoietin-2 levels in the course of septic shock: relation with fluid balance, pulmonary dysfunction and mortality. Intensive Care Med 2009; 35: 1567-1574
• 23 Kumpers P, Lukasz A, David S et al. Excess circulating angiopoietin-2 is a strong predictor of mortality in critically ill medical patients. Crit Care 2008; 12: R147
• 24 Dejana E, Orsenigo F, Lampugnani MG. The role of adherens junctions and VE-cadherin in the control of vascular permeability. J Cell Sci 2008; 121 (Pt 13) 2115-2122
• 25 Kumar P, Shen Q, Pivetti CD et al. Molecular mechanisms of endothelial hyperpermeability: implications in inflammation. Expert Rev Mol Med 2009; 11: e19
• 26 Zarbock A, Ley K. Mechanisms and consequences of neutrophil interaction with the endothelium. Am J Pathol 2008; 172: 1-7
• 27 Marechal X, Favory R, Joulin O et al. Endothelial glycocalyx damage during endotoxemia coincides with microcirculatory dysfunction and vascular oxidative stress. Shock 2008; 29: 572-576
• 28 Klijn E, Den Uil CA, Bakker J et al. The heterogeneity of the microcirculation in critical illness. Clinics in chest medicine 2008; 29: 643-654 viii
• 29 Ellis CG, Bateman RM, Sharpe MD et al. Effect of a maldistribution of microvascular blood flow on capillary O(2) extraction in sepsis. Am J Physiol Heart Circ Physiol 2002; 282: H156-164
• 30 De Backer D, Creteur J, Dubois MJ et al. The effects of dobutamine on microcirculatory alterations in patients with septic shock are independent of its systemic effects. Crit Care Med 2006; 34: 403-408
• 31 Pottecher J, Deruddre S, Teboul JL et al. Both passive leg raising and intravascular volume expansion improve sublingual microcirculatory perfusion in severe sepsis and septic shock patients. Intensive Care Med 2010; 36: 1867-1874
• 32 Pope JV, Jones AE, Gaieski DF et al. Multicenter study of central venous oxygen saturation (ScvO(2)) as a predictor of mortality in patients with sepsis. Ann Emerg Med 2010; 55: 40-46 e41
• 33 Reggiori G, Occhipinti G, De Gasperi A et al. Early alterations of red blood cell rheology in critically ill patients. Crit Care Med 2009; 37: 3041-3046
• 34 Yuruk K, Almac E, Bezemer R et al. Blood transfusions recruit the microcirculation during cardiac surgery. Transfusion 2011; 51: 961-967
• 35 Sharshar T, Blanchard A, Paillard M et al. Circulating vasopressin levels in septic shock. Crit Care Med 2003; 31: 1752-1758
• 36 MacKenzie IM. The haemodynamics of human septic shock. Anaesthesia 2001; 56: 130-144
• 37 Weng L, Liu YT, Du B et al. The prognostic value of left ventricular systolic function measured by tissue Doppler imaging in septic shock. Crit Care 2012; 16: R71
• 38 Muller-Werdan U, Buerke M, Ebelt H et al. Septic cardiomyopathy – A not yet discovered cardiomyopathy?. Exp Clin Cardiol 2006; 11: 226-236
• 39 Morelli A, Ertmer C, Westphal M et al. Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock: a randomized clinical trial. JAMA 2013; 310: 1683-1691
• 40 Hotchkiss RS, Swanson PE, Freeman BD et al. Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med 1999; 27: 1230-1251
• 41 Boekstegers P, Weidenhofer S, Kapsner T et al. Skeletal muscle partial pressure of oxygen in patients with sepsis. Crit Care Med 1994; 22: 640-650
• 42 VanderMeer TJ, Wang H, Fink MP. Endotoxemia causes ileal mucosal acidosis in the absence of mucosal hypoxia in a normodynamic porcine model of septic shock. Crit Care Med 1995; 23: 1217-1226
• 43 Fink M. Cytopathic hypoxia in sepsis. Acta Anaesthesiol Scand Suppl 1997; 110: 87-95
• 44 Levy B, Desebbe O, Montemont C et al. Increased aerobic glycolysis through beta2 stimulation is a common mechanism involved in lactate formation during shock states. Shock 2008; 30: 417-421
• 45 Nicholls P, Marshall DC, Cooper CE et al. Sulfide inhibition of and metabolism by cytochrome c oxidase. Biochemical Society transactions 2013; 41: 1312-1316
• 46 Frost MT, Wang Q, Moncada S et al. Hypoxia accelerates nitric oxide-dependent inhibition of mitochondrial complex I in activated macrophages. Am J Physiol Regul Integr Comp Physiol 2005; 288: R394-400
• 47 Singer M. Cellular dysfunction in sepsis. Clinics in chest medicine 2008; 29: 655-660 viii-ix
• 48 Ertmer C, Rehberg S. Pathophysiologie der Sepsis. Intensiv up2date 2014; 10: 217-232