Sepsis and Clinical Trials: a New Era in Anti-Sepsis Therapies
Over the last decade, we have made great progress in our knowledge and understanding of the pathophysiolgy of sepsis, the mediators involved, and the underlying mechanisms, and yet, until very recently, little advance had been made in the field of sepsis therapeutics. Achievements in basic science and cellular research have not been matched by clinical success, and mortality rates from this disease process have remained virtually unaltered over the past 50 years . Indeed, despite the development of many dozens of new so-called immunomodulatory agents, poor results from clinical trials mean that the treatment of sepsis remains antibiotic therapy, source removal, and organ support. In this chapter we will briefly discuss the reasons behind these ‘failed’ clinical trials before focussing on the recent and exciting results of activated protein C (APC), a drug aimed at the coagulation system, which has been shown to improve mortality rates in patients with severe sepsis.
KeywordsSevere Sepsis Systemic Inflammatory Response Syndrome Drotrecogin Alfa Sepsis Trial Severe Systemic Inflammatory Response Syndrome
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- 9.Clark MA, Plank LD, Connolly AB, Streat SJ, Hill AA, Gupta R, Monk DN, Shenkin A, Hill GL (1998) Effect of a chimeric antibody to tumor necrosis factor-a on cytokine and physiologic responses in patients with severe sepsis–a randomized, clinical trial. Crit Care Med 26: 1650–1659PubMedCrossRefGoogle Scholar
- 13.Greenman RL, Schein RMH, Martin MA, Wenzel RP, Maclntyre NR, Emmanuel G, Chmel H, Kohler RB, McCarthy M, Plouffe J, Russell JA (1991) A controlled clinical trial of E5 murine monoclonal IgM antibody to endotoxin in the treatment of gram-negative sepsis. JAMA 266: 1097–1102PubMedCrossRefGoogle Scholar
- 14.Reinhart K, Wiegand-Löhnert C, Grimminger F, Kaul M, Withington S, Treacher D, Eckert J, Willatts S, Bouza C, Krausch D, Stockenhuber F, Eiselstein J, Daum L, Kempeni J (1996) Assessment of the safety and efficacy of the monoclonal anti-tumor necrosis factor antibody fragment, MAK195F, in patients with sepsis and septic shock: a multicenter, randomized, placebo-controlled, dose ranging study. Crit Care Med 24: 733–742PubMedCrossRefGoogle Scholar
- 15.Abraham E, Glauser MP, Butler T, Garbino J, Gelmont D, Laterre PF, Kudsk K, Bruining HA, Otto C, Tobin E, Zwingelstein C, Lesslauer W, Leighton A, Ro 45–2081 Study Group. (1997) p55 tumor necrosis factor receptor fusion protein in the treatment of patients with severe sepsis and septic shock. JAMA 277: 1531–1538Google Scholar
- 16.Fisher CJ, Dhainaut JF, Opal SM, Pribble JP, Balk RA, Slotman GJ, Iberti TJ, Rackow EC, Shapiro MJ, Greenman RL, Reines HD, Shelly MP, Thompson BW, LaBrecque JF, Catalano MA, Knaus WA, Sadoff JC (1994) Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. JAMA 271: 1836–1843PubMedCrossRefGoogle Scholar
- 17.Dhainaut JF, Tenaillon A, Le Tulzo Y, Schlemmer B, Solet JP, Wolff M, Holzapfel L, Zeni F, Dreyfuss D, Mira JP, et al (1994) 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 22: 1720–1728PubMedGoogle Scholar
- 18.Fein AM, Bernard GR, Criner GJ, Fletcher EC, Good JT, Knaus WA, Levy H, Matuschak GM, Shanies HM, Taylor RW Jr, Rodell TC (1997) Treatment of severe systemic inflammatory response syndrome and sepsis with a novel bradykinin antagonist, deltibant (CP-0127). JAMA 277: 482–487PubMedCrossRefGoogle Scholar
- 19.Baudo F, Caimi TM, deCataldo E, Ravizza A, Arlati S, Casella G, Carugo D, Palareti G, Legnani C, Ridolfi L, Rossi R, D’Angelo A, Crippa L, Giudica D, Gallioli G, Wolfler A, Calori G (1998) Antithrombin III (ATIII) replacement therapy in patients with sepsis and/or postsurgical complications: a controlled, double-blind, randomized, multicenter study. Intensive Care Med 24: 336–342PubMedCrossRefGoogle Scholar
- 22.Reinhart K, RAMSES Study Group (1998). Treatment of severe sepsis in patients with highly elevated IL-6 levels with anti-TNF monoclonal antibody MAK 195F: The RAMSES study (abstract). Crit Care 2: P18Google Scholar
- 23.Panacek EA, Marshall J, Fischkoff S, Barchuk W, Leah T (2000) Neutralization of TNF by a monoclonal antibody improves survival and reduces organ dysfunction in human sepsis: results of the MONARCS trial (abstract). Chest 118: 88SGoogle Scholar
- 33.White B, Schmidt M, Murphy C, Livingstone W, O’Toole D, Lawler M, O’Neill L, Kelleher D, Schwarz HP, Smith OP (2000) Activated protein C inhibits lipopolysaccharide-induced nuclear translocation of nuclear factor kappaB (NF-kappaB) and tumour necrosis factor alpha (TNF-alpha) production in the THP-1 monocytic cell line. Br J Haematol 110: 130–134PubMedCrossRefGoogle Scholar