Pathophysiologie der Sepsis und deren mögliche Beeinflussung durch HMG-CoA-Reduktase-Inhibitoren

Zusammenfassung

Sepsis, schwere Sepsis und septischer Schock stellen häufige Komplikationen auf Intensivstationen dar und sind mit hoher Mortalität behaftet. Neben einer möglichst frühzeitigen Infektbekämpfung und Fokussanierung stellen Kreislauf- und Organ-Unterstützende Maßnahmen die wesentlichen Säulen der Therapie dar. Zur Therapie der Entzündungsreaktion wurden in den vergangen Jahren zunehmend immunmodulatorische Therapien untersucht.

Aufgrund der pleiotropen Effekte der HMG-CoA-Reduktase-Inhibitoren (Statine), zu denen auch antiinflammatorische Eigenschaften gehören, könnten diese Medikamente zukünftig eine neue adjuvante Therapieoption darstellen. Im Gegensatz zu anderen anti-entzündlichen Therapien wäre hier auch ein prophylaktischer Einsatz bei Hochrisikopatienten möglich. Die pathophysiologischen Hintergründe und erste Studiendaten zur Bedeutung von Statinen bei akuten Entzündungsreaktionen sind in der vorliegenden Arbeit zusammengefasst.

Abstract

Severe sepsis and septic shock are common complications in the intensive care unit and associated with high mortality. Early antimicrobial therapies together with organ-supportive measures are the major therapeutic approaches. However in the last decades immunmodulatory therapies have been investigated due to the notion of a compromised inflammatory response in septic patients.

In addition to lowering circulating cholesterol, statins (HMG-CoA-reductase-inhibitors) have also been shown to possess pleiotropic anti-inflammatory potential. Recent studies indicate that these anti-inflammatory effects also modulate acute inflammatory response and therefore may play a protective role in septic patients. In this review, the pathophysiological backround and first clinical trials of statins as a new adjuvant therapy in sepsis are summarized.

Schlüsselwörter

Statine - Sepsis - Cholesterin

Keywords

statins - sepsis - cholesterin

Literatur

• 1 Afshari A, Wetterslev J, Brok J, Møller A. Antithrombin III in critically ill patients: systematic review with meta-analysis and trial sequential analysis.  BMJ. 2007;  335 1248-1251
• 2 Almog Y, Shefer A, Novack V. et al . Prior statin therapy is associated with decreased rate of severe sepsis.  Circulation. 2004;  110 880-885
• 3 Angstwurm M, Hoffmann J, Ostermann H, Frey L, Spannagl M. Schwere Sepsis und disseminierte intravasale Gerinnung. Substitution von Antithrombin.  Anaesthesist. 2009;  58 171-179
• 4 Annane D, Bellissant E, Bollaert P E. et al . Corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review.  JAMA. 2009;  301 2362-2375
• 5 Berbée J F, Havekes L M, Rensen P C. Apolipoproteins modulate the inflammatory response to lipopolysaccharide.  J Endotoxin Res. 2005;  11 97-103
• 6 Bernard G R, Vincent J L, Laterre P F. et al . Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. Efficacy and safety of recombinant human activated protein C for severe sepsis.  N Engl J Med. 2001;  344 699-709
• 7 Chalmers J D, Singanayagam A, Murray M P, Hill A T. Prior statin use is associated with improved outcomes in community-acquired pneumonia.  Am J Med. 2008;  121 1002-1007
• 8 Christman J W, Lancaster L H, Blackwell T S. Nuclear factor kappa B: a pivotal role in the systemic inflammatory response syndrome and new target for therapy.  Intensive Care Med. 1998;  24 1131-1138
• 9 Donnino M, Howell M, Cocchi M, Talmor D, Clardy P, Shapiro N. Statin therapy in patients with sepsis.  Acad Emerg Med. 2007;  14 S179
• 10 Engel C, Brunkhorst F M, Bone H G. et al . Epidemiology of sepsis in Germany: results from a national prospective multicenter study.  Intensive Care Med. 2007;  33 606-618
• 11 Falagas M E, Makris G C, Matthaiou D K, Rafailidis P I. Statins for infection and sepsis: a systematic review of the clinical evidence.  J Antimicrob Chemother. 2008;  61 774-785
• 12 Fraunberger P, Gröne E, Gröne H J, Walli A K. Simvastatin reduces endotoxin-induced nuclear factor kappaB activation and mortality in guinea pigs despite lowering circulating low-density lipoprotein cholesterol.  Shock. 2009;  32 159-163
• 13 Fraunberger P, Walli A K. Biomarker bei Sepsis und Entzündung.  J Lab Med. 2007;  31 294-309
• 14 Frost F J, Petersen H, Tollestrup K. et al . Influenza and COPD mortality protection as pleiotropic, dose-dependent effects of statins.  Chest. 2007;  131 1006-1012
• 15 Fruscella P, Romano M, Albani D, Bernasconi S, Luini W, Bruno A, Salmona M, Diomede L. Inhibition of HMG-CoA reductase activity by hypercholesterolaemia reduces leukocyte recruitment and MCP-1 production.  Cytokine. 2000;  12 1100-1103
• 16 Goldstein J L, Brown M S. Progress in understanding the LDL receptor and HMG-CoA reductase, two membrane proteins that regulate the plasma cholesterol.  J Lipid Res. 1984;  25 1450-1461
• 17 Grundy S M, Cleeman J I, Merz C N. et al . Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines.  Arterioscler Thromb Vasc Biol. 2004;  24 149-161
• 18 Guijarro C, Kim Y, Schoonover C M. et al . Lovastatin inhibits lipopolysaccharide-induced NF-kappaB activation in human mesangial cells.  Nephrol Dial Transplant. 1996;  11 990-996
• 19 Gupta R, Plantinga L C, Fink N E. et al . Statin use and hospitalization for sepsis in patients with chronic kidney disease.  JAMA. 2007;  297 1455-1464
• 20 Hackam D G, Mamdani M, Li P. et al . Statins and sepsis in patients with cardiovascular disease: a population-based cohort analysis.  Lancet. 2006;  367 413-418
• 21 Hurley J C. Concordance of endotoxemia with gram-negative bacteremia in patients with gram-negative sepsis: a meta-analysis.  J Clin Microbiol. 1994;  32 2120-2127
• 22 Janda S, Young A, Fitzgerald J M. et al . The effect of statins on mortality from severe infections and sepsis: A systematic review and meta-analysis.  J Crit Care. 2010;  article in press
• 23 Kruger P, Fitzsimmons K, Cook D, Jones M, Nimmo G. Statin therapy is associated with fewer deaths in patients with bacteraemia.  Intensive Care Med. 2006;  32 75-79
• 24 Kruger P S, Freir N M, Venkatesh B, Robertson T A, Roberts M S, Jones M. A preliminary study of atorvastatin plasma concentrations in critically ill patients with sepsis.  Intensive Care Med. 2009;  35 717-721
• 25 Laufs U, Custodis F, Böhm M. Who does not need a statin: too late in end-stage renal disease or heart failure?.  Heart. 2008;  94 1138-1140
• 26 Liappis A P, Kan V L, Rochester C G, Simon G L. The effect of statins on mortality in patients with bacteremia.  Clin Infect Dis. 2001;  33 1352-1357
• 27 Liu P Y, Liu Y W, Lin L J, Chen J H, Liao J K. Evidence for statin pleiotropy in humans: differential effects of statins and ezetimibe on rho-associated coiled-coil containing protein kinase activity, endothelial function, and inflammation.  Circulation. 2009;  119 131-138
• 28 Majumdar S R, McAlister F A, Eurich D T. et al . Statins and outcomes in patients admitted to hospital with community acquired pneumonia: population based prospective cohort study.  BMJ. 2006;  333 999
• 29 Merx M W, Liehn E A, Graf J, van de Sandt A, Schaltenbrand M, Schrader J, Hanrath P, Weber C. Statin treatment after onset of sepsis in a murine model improves survival.  Circulation. 2005;  112 117-124
• 30 Novack V, Eisinger M, Frenkel A, Terblanche M, Adhikari N K, Douvdevani A, Amichay D, Almog Y. The effects of statin therapy on inflammatory cytokines in patients with bacterial infections: a randomized double-blind placebo controlled clinical trial.  Intensive Care Med. 2009;  35 1255-1260
• 31 O’Donnell M P, Kasiske B L, Kim Y, Atluru D, Keane W F. The mevalonate pathway: importance in mesangial cell biology and glomerular disease.  Miner Electrolyte Metab. 1993;  19 173-179
• 32 Parrillo J E, Parker M M, Natanson C. et al . Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy.  Ann Intern Med. 1990;  3 227-242
• 33 Rietschel E T, Brade H, Holst O. et al . Bacterial endotoxin: Chemical constitution, biological recognition, host response, and immunological detoxification.  Curr Top Microbiol Immunol. 1996;  216 39-81
• 34 Rosch J W, Boyd A R, Hinojosa E, Pestina T, Hu Y, Persons D A, Orihuela C J, Tuomanen E I. Statins protect against fulminant pneumococcal infection and cytolysin toxicity in a mouse model of sickle cell disease.  J Clin Invest. 2010;  120 627-35
• 35 Schlienger R G, Fedson D S, Jick S S. et al . Statins and the risk of pneumonia: a population based, nested case-control study.  Pharmacotherapy. 2007;  27 325-32
• 36 Schmidt H, Hennen R, Keller A. et al . Association of statin therapy and increased survival in patients with multiple organ dysfunction syndrome.  Intensive Care Med. 2006;  32 1248-1251
• 37 Shinozaki S, Inoue Y, Yang W, Fukaya M, Carter E A, Ming-Yu Y, Fischman A, Tompkins R, Kaneki M. Farnesyltransferase inhibitor improved survival following endotoxin challenge in mice.  Biochem Biophys Res Commun. 2010;  391 1459-1464
• 38 Shyamsundar M, McKeown S T, O’Kane C M. et al . Simvastatin decreases lipopolysaccharide-induced pulmonary inflammation in healthy volunteers.  Am J Respir Crit Care Med. 2009;  179 1107-1114
• 39 Stepien K, Tomaszewski M, Czuczwar S J. Neuroprotective properties of statins.  Pharmacol Rep. 2005;  57 561-569
• 40 Swank G M, Deitch E A. Role of the gut in multiple organ failure: bacterial translocation and permeability changes.  World J Surg. 1996;  20 411-417
• 41 Takata M, Urakaze M, Temaru R. et al . Pravastatin suppresses the interleukin-8 production induced by thrombin in human aortic endothelial cells cultured with high glucose by inhibiting the p44/42 mitogen activated protein kinase.  Br J Pharmacol. 2001;  134 753-762
• 42 Takemoto M, Liao J K. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors.  Arterioscler Thromb Vasc Biol. 2001;  21 1712-1719
• 43 Terblanche M, Almog Y, Rosenson R S, Smith T S, Hackam D G. Statins and sepsis: multiple modifications at multiple levels.  Lancet Infect Dis. 2007;  7 358-368
• 44 Thomsen R W, Riis A, Kornum J B, Christensen S, Johnsen S P, Sørensen H T. Preadmission use of statins and outcomes after hospitalization with pneumonia: population-based cohort study of 29,900 patients.  Arch Intern Med. 2008;  168 2081-2087
• 45 Tleyjeh I M, Kashour T, Hakim F A, Zimmerman V A, Erwin P J, Sutton A J, Ibrahim T. Statins for the prevention and treatment of infections: a systematic review and meta-analysis.  Arch Intern Med. 2009;  169 1658-1667
• 46 van de Garde E MW, Hak E, Souverein P C. et al . Statin treatment and reduced risk of pneumonia in patients with diabetes.  Thorax. 2006;  61 957-961
• 47 Vincent J L, Sun Q, Dubois M J. Clinical trials of immunomodulatory therapies in severe sepsis and septic shock.  Clin Infect Dis. 2002;  34 1084-1093