Zentralbl Chir 2002; 127(3): 174-179
DOI: 10.1055/s-2002-24252
Sepsis

© Georg Thieme Verlag Stuttgart · New York

Neue Therapieansätze bei Sepsis

New Treatment Approaches in SepsisF. Bloos, K. Reinhart
  • Klinik für Anästhesiologie und Intensivtherapie, Klinikum der Friedrich-Schiller-Universität Jena
Further Information

Publication History

Publication Date:
04 April 2002 (online)

Zusammenfassung

Die Behandlung der Sepsis setzt sich zusammen aus der Fokussanierung sowie aus der supportiven und adjuvanten Therapie. Insbesondere die letztere Behandlungsschiene war während der letzten Jahre Gegenstand vieler Studien. Verschiedenste Ansätze zeigten in tierexperimentellen Untersuchungen und Phase-1-Studien viel versprechende Ergebnisse, konnten in großen Multicenter-Studien jedoch nicht bestehen. So führte die Applikation von TNF-Rezeptoren oder Interleukin-1-Rezeptorantagonisten zu keiner Prognoseverbesserung bei Patienten mit Sepsis. Auch die meisten gegen TNFα gerichteten Studien zeigten keine statistisch signifikanten Therapieergebnisse. Inzwischen liegt jedoch eine große Studie vor, die eine signifikante Verbesserung der Überlebensrate mit monoklonalen TNF-Antikörpern belegt. Mit der kürzlich veröffentlichten PROWESS-Studie konnte auch bei einer großen Patientenpopulation eine Senkung der Mortalität durch die therapeutische Gabe von Protein C nachgewiesen werden. Weiterhin unterstützt die momentane Datenlage die niedrig dosierte Kortisontherapie bei Patienten mit vasopressorabhängigem septischen Schock.

Summary

The treatment of sepsis consists of focus control as well as supportive and adjuvant therapy. Especially the last option has been investigated during the last years. Different approaches showed promising results in animal experiments and phase-I trials but did not prove to be successful in large multicenter studies. The application of TNF-receptors or interleukin-1 receptor antagonists did not lead to an improvement of outcome in patients with sepsis. Most studies with TNF-antibodies also presented negative results. However, a recent large study with a monoclonal antibody against TNFα demonstrated a significant survival benefit. The recently published PROWESS study is the first investigation demonstrating the decrease of mortality in patients with sepsis after administration of protein C. Additionally, current data support the low-dose hydrocortisone therapy in patients with vasopressor dependent septic shock.

Literatur

  • 1 Abraham E, Anzueto A, Gutierrez G, Tessler S, San Pedro G, Wunderink R. Double-blind randomized controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock.  Lancet. 1998;  351 929-933
  • 2 Abraham E, Wunderink R, Silverman H. et al . Efficacy and safety of monoclonal antibody to human tumor necrosis factor α in patients with sepsis syndrome. A randomized, controlled, double-blind, multicenter clinical trial.  JAMA. 1995;  273 934-941
  • 3 Abraham E G, Butler T, Garbino J. et al . p55 Tumor necrosis factor receptor fusion protein in the treatment of patients with severe sepsis and septic shock.  JAMA. 1997;  277 1531-1538
  • 4 PACCP/SCCM Consensus Conference Committee . Definition for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis.  Crit Care Med. 1992;  20 864-874
  • 5 Annane D. Effects of the combination of hydrocortisone (HC) -fludro-cortisone (FC) on mortality in septic shock.  Crit Care Med. 2000;  28 A46
  • 6 Arons M M, Wheeler A P, Bernard G R. et al . Effects of ibuprofen on the physiology and survival of hypothermic sepsis. Ibuprofen in Sepsis Study Group.  Crit Care Med. 1999;  27 699-707
  • 7 Bernard G R, Wheeler A P, Russell J A. et al . The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis Study Group.  N Engl J Med. 1997;  336 912-918
  • 8 Beutler B, Millsark I W, Cerami A C. Passive Immunization against cachectin/tumor necrosis factor protects mice from lethal effects of endotoxin.  Science. 1985;  229 869-871
  • 9 Bone R C, Fisher C J, Clemmer T P, Slotman G J, Metz C A, Balk R A. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock.  N Engl J Med. 1987;  317 653-658
  • 10 Briegel J, Kilger E, Thiel M. Adjunctive sepsis therapies: Glucocorticoids - what is proven?.  J Anästhesie Intensivbehandlung. 2001;  2 8-9
  • 11 Casey L C, Balk R A, Bone R C. Plasma cytokine and endotoxin levels correlate with survival in patients with the sepsis syndrome.  Ann Intern Med. 1993;  119 771-778
  • 12 Centers for Disease Control . Increase in National Hospital Discharge Survey rates for septicemia - United States, 1979-87.  MMWR. 1990;  39 31-34
  • 13 Cohen J, Carlet J. The INTERSEPT Study Group . INTERSEPT: An international, multicenter, placebo-controlled trial of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis.  Crit Care Med. 1996;  24 1431-1440
  • 14 Debets J MH, Kampmeijer R, van der Linden M PMH, Buurman W A, van der Linden C J. Plasma tumor necrosis factor and mortality in critically ill septic patients.  Crit Care Med. 1989;  17 489-494
  • 15 deBoisblanc B P, Mason C M, Andresen J. et al . Phase 1 safety trial of Filgrastim (r-metHuG-CSF) in non-neutropenic patients with severe community-acquired pneumonia.  Respir Med. 1997;  91 387-394
  • 16 Dhainaut J F, Tenaillon A, Hemmer M. et al . Confirmatory platelet-activating factor receptor antagonist trial in patients with severe gram-negative bacterial sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. BN 52021 Sepsis Investigator Group.  Crit Care Med. 1998;  26 1927-1931
  • 17 Dhainaut J F, Tenaillon A, Le Tulzo Y, Schlemmer B, Solet J P, Wolff M, Holzapfel L, Zeni F, Dreyfuss D, Mira J P. et al . Platelet-activating factor receptor antagonist BN 52021 in the treatment of severe sepsis: a randomized, double-blind, placebo-controlled, multicenter clinical trial. BN 52021 Sepsis Study Group.  Crit Care Med. 1994;  22 1720-1728
  • 18 Dhainaut J F, Vincent J L, Richard C. et al . CDP571, a humanized antibody to human tumor necrosis factor-alpha: safety, pharmacokinetics, immune response, and influence of the antibody on cytokine concentrations in patients with septic shock. CPD571 Sepsis Study Group.  Crit Care Med. 1995;  23 1461-1469
  • 19 Dofferhoff A S, Bom V J, de Vries Hospers H G. et al . Patterns of cytokines, plasma endotoxin, plasminogen activator inhibitor, and acute-phase proteins during the treatment of severe sepsis in humans.  Crit Care Med. 1992;  20 185-192
  • 20 Fisher CJ J r, Agosti J M, Opal S M. et al . Treatment of septic shock with the tumor necrosis factor receptor: Fc fusion protein. The Soluble TNF Receptor Sepsis Study Group.  N Engl J Med. 1996;  334 1697-1702
  • 21 Fisher C J, Opal S M, Dhainaut J F. et al . Influence of an anti-tumor necrosis factor monoclonal antibody on cytokine levels in patients with sepsis. The CB0006 Sepsis Syndrome Study Group.  Crit Care Med. 1993;  21 318-327
  • 22 Fisher C J, Slotman G J, Opal S M. et al . Initial evaluation of human recombinant interleukin-1 receptor antagonist in the treatment of sepsis syndrome: a randomized, open-label, placebo-controlled multicenter trial. The IL-1RA Sepsis Syndrome Study Group.  Crit Care Med. 1994;  22 12-21
  • 23 Fisher C J, Yan S B. Protein C levels as a prognostic indicator of outcome in sepsis and related diseases.  Crit Care Med. 2000;  28 S49-S56
  • 24 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
  • 25 Fourrier F, Chopin C, Huart J J, Runge I, Caron C, Goudemand J. Double-blind, placebo-controlled trial of antithrombin III concentrates in septic shock with disseminated intravascular coagulation.  Chest. 1993;  104 882-888
  • 26 Gordon R, Vincent J L, Laterre P F, LaRosa S P, Dhainaut J F, Lopez-Rodriguez, Steingrub J S, Garber G E, Helterbrand E, Ely W, Fisher C J. PROWESS Study Group . Efficacy and safety of recombinant human activated protein C for severe Sepsis.  N Engl J Med. 2001;  344 699-709
  • 27 Graham R M, Stephens C J, Silvester W, Leong L L, Sturm M J, Taylor R R. Plasma degradation of platelet-activating factor in severily ill patients with clinical sepsis.  Crit Care Med. 1994;  22 204-212
  • 28 Gramm H J, Reinhart K. Sepsis und septischer Schock - Definition und Epidemiologie. In: van Aken H, Reinhart K und Zimpfer M (Hrsg). Ains Band 2: Intensivmedizin. Thieme, Stuttgart, New York 2001; 756-760
  • 29 Gross-Weege W, Weiss M, Schneider M. et al . Safety of a low-dosage Filgrastim (rhG-CSF) treatment in non-neutropenic surgical intensive care patients with an inflammatory process.  Intensive Care Med. 1997;  23 16-22
  • 30 Harper P L, Williamson L, Park G, Smith J K, Carrel R W. A pilot study of antithrombin replacement in intensive care management: The effects on mortality, coagulation and renal function.  Transfusion Med. 1991;  1 121-128
  • 31 Heering P, Morgera S, Schmitz F J. et al . Cytokine removal and cardiovascular hemodynamics in septic patients with continuous venovenous hemofiltration.  Intensive Care Med. 1997;  23 288-296
  • 32 Hoffmann J N, Hartl W H, Deppisch R, Faist E, Jochum M, Inthorn D. Effect of hemofiltration on hemodynamics and systemic concentrations of anaphylatoxins and cytokines in human sepsis.  Intensive Care Med. 1996;  22 1360-1367
  • 33 Honore P M, Jamez J, Wauthier M, Lee P A, Dugernier T, Pirenne B, Hanique G, Matson J R. Prospective evaluation of short-term, high-volume isovolemic hemofiltration on the hemodynamic course and outcome in patients with intractable circulatory failure resulting from septic shock.  Crit Care Med. 2000;  28 3581-3587
  • 34 Jimenez M E, Marshall J C. Source control in the management of sepsis.  Intensive Care Med. 2001;  27 S49-62
  • 35 Julou-Schaeffer G, Gray G A, Fleming I, Schott C, Parrat J R, Stoclet J C. Loss of vascular responsiveness induced by endotoxin involves L-arginine pathway.  Am J Physiol. 1990;  259 H1038-H1043
  • 36 Majetschak M, Schade F U. Mechanismen der inflammatorischen Wirtsantwort bei schweren Infektionen. In: van Aken H, Reinhart K, Zimpfer M (Hrsg). Ains Band 2: Intensivmedizin. Thieme, Stuttgart, New York 2001; 760-767
  • 37 Massignon D, Lepape A, Bienvenu J, Barbier Y, Boileau C, Coeur P. Coagulation/fibrinolysis balance in septic shock related to cytokines and clinical state.  Haemostasis. 1994;  24 36-48
  • 38 Meier-Hellman A, Reinhart K. Supportive Behandlungsstrategien. In: van Aken H, Reinhart K, Zimpfer M (Hrsg). ains Band 2: Intensivmedizin. Thieme, Stuttgart, New York 2001; 778-784
  • 39 Mesters R M, Helterbrand J, Utterback B G, Yan B, Chao Y B, Fernandez J A, Griffin J H, Hartman D L. Prognostic value of protein C concentrations in neutropenic patients at high risk of severe septic complications.  Crit Care Med. 2000;  28 2209-2216
  • 40 Miura E, Procianoy R S, Bittar C, Miura C S, Miura M S, Mello C, Christensen R D. A randomized, double-masked, placebo-controlled trial of recombinant granulocyte colony-stimulating factor administration to preterm infants with the clinical diagnosis of early-onset sepsis.  Pediatrics. 2001;  107 30-35
  • 41 Opal S M. The therapeutic rationale for the use of Antithrombin-III in sepsis.  Crit Care Med. 2000;  28 S34-S37
  • 42 Opal S M. Antithrombin-III in the treatment of severe sepsis: The result of a phase III multicenter clinical trial.  J Anästhesie Intensivbehandlung. 2001;  2 46-47
  • 43 Panacek E A, Marshall J, Fischkoff S, Barchuk W, Teoh L. Neutralization of TNF by a monoclonal antibody improves survival and reduces organ dysfunction in human sepsis: Results of the MONARCS trial.  Chest. 2000;  118 (Suppl) S88
  • 44 Pittet D, Harbarth S, Suter P M, Reinhart K, Leighton A, Barker C. Impact of immunomodulating therapy on morbidity in patients with severe sepsis.  Am J Resp Crit Care Med. 1999;  160 852-857
  • 45 Reinhart K, Bloos F, Spies C. Vasoactive drug therapy in sepsis. In: Sibbald WJ, Vincent JL (Hrsg). Clinical trials for the treatment of sepsis. Update in intensive care and emergency medicine. Springer, Berlin 1995; 207-224
  • 46 Reinhart K, Menges T, Gardlund B. et al . Randomized, placebo-controlled trial of the anti-tumor necrosis factor antibody fragment afelimomab in hyperinflammatory response during severe sepsis: The RAMSES Study.  Crit Care Med. 2001;  29 765-769
  • 47 Reinhart K, Wiegend-Löhnert C, Grimminger F, Kaul M, Withington S, Treacher D, Eckart J, Willatts S, Bouza C, Krausch D, Stockenhuber F, Eiselstein J, Daum L, Kempeni J. The MAK 195F Sepsis Study Group . Assessment of the safety and efficacy of the monoclonal anti-tumor necrosis factor antibody-fragment, MAK 195F, in patients with sepsis and septic shock: A multicenter, randomized, placebo-controlled, dose-ranging study.  Crit Care Med. 1996;  24 733-742
  • 48 Sands K E, Bates D W, Lanken P N. et al . Epidemiology of sepsis syndrome in 8 academic medical centers.  JAMA. 1997;  278 234-240
  • 49 Schmidt J, Mann S, Mohr V D, Lampert R, Firla U, Zirngibl H. Plasmapheresis combined with continuous venovenous hemofiltration in surgical patients with sepsis.  Intensive Care Med. 2000;  26 532-537
  • 50 Schmidt-Supprian M, Murphy C, While B. et al . Activated protein C inhibits tumor necrosis factor and macrophage migration inhibitory factor production in monocytes.  Eur Cytokine Netw. 2000;  11 407-413
  • 51 Schroder J, Stuber F, Gallati H, Schade F U, Kremer B. Pattern of soluble TNF receptors I and II in sepsis.  Infection. 1995;  23 143-148
  • 52 Sibbald W J. Fluid therapy in sepsis. In: Reinhart K, Eyrich K, Sprung C (Hrsg). Sepsis - Current perspectives in pathophysiology and therapy. Springer, Berlin, Heidelberg 1994; 266-273
  • 53 The Veterans Administration Systematic Sepsis Cooperative Study Group > . Effect of high-dose glucocorticoid therapy on mortality in patients with clinical signs of systemic sepsis.  N Engl J Med. 1987;  317 659-665
  • 54 Thijs L G, de Boer J P, de Groot M CM, Hack C E. Coagulation disorders in septic shock.  Intensive Care Med. 1993;  19 S8-S15
  • 55 Tracey K J, Fong Y, Hesse D G, Manogue K R, Lee A T, Kuo G C. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia.  Nature. 1987;  330 662-664
  • 56 Yi E S, Ulrich T R. Endotoxin, interleukin-1, and tumor necrosis factor cause neutrophil-dependent microvascular leackage in postcapillary venules.  Am J Pathol. 1992;  140 659-663
  • 57 Zeni F, Freeman B D, Natanson C. Antiinflammatory therapies to treat sepsis and septic shock - a reassessment.  Crit Care Med. 1997;  25 1095-1100

Prof. Dr. K. Reinhart

Klinik für Anästhesiologie und Intensivtherapie

Klinikum der Friedrich-Schiller-Universität

07743 Jena

Phone: 0 36 41/93 30 41

Fax: 0 36 41/93 32 56

Email: Konrad.Reinhart@med.uni-jena.de

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