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Innovative Therapies for Sepsis

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Abstract

Sepsis and septic shock continue to be a major cause of morbidity and mortality. Despite numerous advances in the supportive care of patients with sepsis, the overall mortality has changed little in the past 20 years. Many innovative therapies have been attempted in the field of sepsis, primarily aimed at stopping the cycle of cytokine activation which is part of the systemic inflammatory response. Therapies have also targeted other molecular mediators of inflammation and coagulation. Despite encouraging preliminary preclinical results, most of the early trials in sepsis research have failed to offer hope of improving survival with the use of these innovative therapies. Postulated reasons for the failure of clinical trials include the disparity between animal models and clinical reality, the heterogeneous nature of patient populations and sepsis, and the complexity of the inflammatory cascade. On a more hopeful note, three recent trials assessing corticosteroids, anti-tumour necrosis factor strategy and drotrecogin alfa (rhAPC), respectively, have proclaimed positive results. However, only the drotrecogin alfa trial has been peer reviewed and published.

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References

  1. Rangel-Frausto MS. The epidemiology of bacterial sepsis. Infect Dis Clin North Am 1999; 13(2): 299–311

    Article  PubMed  CAS  Google Scholar 

  2. Opal SM, Cross AS. Clinical trials for severe sepsis: past failures, and future hopes. Infect Dis Clin North Am 1999; 13(2): 285–97

    Article  PubMed  CAS  Google Scholar 

  3. Bone RC, Balk RA, Cerra FB, et al. ACCP-SCCM consensus conference: definitions of sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1992; 101: 1644–55

    Article  PubMed  CAS  Google Scholar 

  4. Bone RC, Grodzin CJ, Balk RA. Sepsis: a new hypothesis for pathogenesis of the disease process. Chest 1997; 112: 235–43

    Article  PubMed  CAS  Google Scholar 

  5. Van derPoll T, vanDeventer JH. Cytokines and anticytokines in the pathogenesis of sepsis. Infect Dis Clin North Am 1999; 13(2): 413–26

    Article  PubMed  Google Scholar 

  6. Dinarello CA. Proinflammatory and anti-inflammatory cytokines as mediators in the pathogenesis of septic shock. Chest 1997; 112(6 Suppl.): S321–9

    Article  Google Scholar 

  7. Liu M, Slutsky AS. Anti-inflammatory therapies: application of molecular biology techniques in intensive care medicine. Intensive Care Med 1997; 23: 718–31

    Article  PubMed  CAS  Google Scholar 

  8. Glauser MP. Pathophysiologic basis of sepsis: considerations for future strategies of intervention. Crit Care Med 2000; 28(9 Suppl.): S4–7

    Article  PubMed  CAS  Google Scholar 

  9. Symeonides S, Balk RA. Nitric oxide in the pathogenesis of sepsis. Infect Dis Clin North Am 1999; 13(2): 449–63

    Article  PubMed  CAS  Google Scholar 

  10. Westendorp RGJ, Langermans JAM, Huizinga TWJ, et al. Genetic influence on cytokine production and fatal meningococcal disease. Lancet 1997; 349: 170–3

    Article  PubMed  CAS  Google Scholar 

  11. Westendorp RGJ, Hottenga JJ, Slagboom PE. Variation in plasminogen-activator-inhibitor-1 gene and risk for meningococcal septic shock. Lancet 1999; 354: 561–3

    Article  PubMed  CAS  Google Scholar 

  12. Mira JP, Cariou A, Fral F, et al. Association of TNF2, a TNF-α promoter polymorphism, with septic shock susceptibility and mortality. JAMA 1999; 282: 561–8

    Article  PubMed  CAS  Google Scholar 

  13. Zeigler EJ, McCutchan A, Fierer J, et al. Treatment of gramnegative bacteremia and shock with human antiserum to a mutant Escherichia coli. N Engl J Med 1982; 307: 1225–30

    Article  Google Scholar 

  14. Baumgartner JD, Glauser MP, McCutchan JA, et al. Prevention of gram-negative shock and death in surgical patients by antibody to endotoxin core glycolipid. Lancet 1985; 2: 59–63

    Article  PubMed  CAS  Google Scholar 

  15. Bone RC, Balk RA, Fein AM, et al. A second large controlled clinical study of E5, a monoclonal antibody to endotoxin: results of a prospective, multicenter, randomized, controlled trial. Crit Care Med 1995; 23(6): 994–1006

    Article  PubMed  CAS  Google Scholar 

  16. Angus DC, Birmingham MC, Balk RA, et al. E5 murine monoclonal antiendotoxin antibody in gram-negative sepsis. JAMA 2000; 283(13): 1723–30

    Article  PubMed  CAS  Google Scholar 

  17. Zeigler EJ, Fisher Jr CJ, Sprung CL, et al. Treatment of gramnegative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin. A randomized, double-blind, placebo-controlled trial. The HA-1A Sepsis Study Group. N Engl J Med 1991; 324: 429–36

    Article  Google Scholar 

  18. McCloskey RV, Straube RC, Sanders C, et al. Treatment of septic shock with human monoclonal antibody HA-1A. Ann Intern Med 1994; 121: 1–5

    PubMed  CAS  Google Scholar 

  19. BeutlerB, Milsark IW, Cerami A. Passive immunization against cachectin/tumor necrosis factor protects mice from lethal levels of endotoxin. Science 1985; 229: 869–71

    Article  Google Scholar 

  20. Tracey K, Fong Y, Hesse DG, et al. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteremia. Nature 1987; 330: 662–4

    Article  PubMed  CAS  Google Scholar 

  21. Fisher CJ, Opal SM, Dhainaut JF, et al. Influence of an anti-tumor necrosis factor monoclonal antibody on cytokine levels in patients with sepsis. Crit Care Med 1993; 21(3): 318–32

    Article  PubMed  Google Scholar 

  22. Abraham E, Wunderink R, Silverman H, et al. Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, controlled, double-blind, multi-center trial. TNF-alpha Mab sepsis study group. JAMA 1995; 273(12): 934–41

    Article  PubMed  CAS  Google Scholar 

  23. Cohen J, Carlet J, for the INTERSEPT Study Group. INTERSEPT: an international, multi-center, placebo-controlled trial of monoclonal antibody to human tumor necrosis factor-α in patients with sepsis. Crit Care Med 1996; 24(9): 1431–40

    Article  PubMed  CAS  Google Scholar 

  24. Abraham E, Anzueto A, Gutierrez G, et al., for the NORASEPT II Study Group. Double-blind randomized controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock. Lancet 1998; 351: 929–33

    PubMed  CAS  Google Scholar 

  25. Fisher CJ, Agosti JM, Opal SM, et al. Treatment of septic shock with the tumor necrosis factor: Fc fusion protein. N Engl J Med 1996; 334: 1697–702

    Article  PubMed  CAS  Google Scholar 

  26. Abraham E, Glauser MP, Butler T, et al. p55 Tumor necrosis factor receptor fusion protein in the treatment of patients with severe sepsis and septic shock. A randomized controlled multicenter trial. Ro 45-2081 study group. JAMA 1997; 277(19): 1531–8

    Article  PubMed  CAS  Google Scholar 

  27. Abraham E, Laterre P, Garbino J, et al. Lenercept (p55 tumor necrosis factor receptor fusion protein) in severe sepsis and early septic shock: a randomized, double-blind, placebo-controlled, multicenter phase III trial with 1,342 patients. Crit Care Med 2001; 29(3): 503–10

    Article  PubMed  CAS  Google Scholar 

  28. Fisher Jr CJ, Slotman GJ, Opal SM, 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-IRA sepsis syndrome study group. Crit Care Med 1994; 22(1): 12–21

    Article  PubMed  Google Scholar 

  29. Opal SM, Fisher CJ, Dhainaut JA, et al. Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. Crit Care Med 1997; 25(7): 1115–24

    Article  PubMed  CAS  Google Scholar 

  30. Fisher Jr CJ, Dhainaut JF, Opal SM, et al. Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, doubleblind, placebo-controlled trial. Phase III rhIL-1ra sepsis syndrome study group. JAMA 1994; 271(23): 1836–43

    Article  PubMed  Google Scholar 

  31. Sprung CL, Caralis PV, Marcial EH. The effect of high dose corticosteroids in patients with septic shock: a prospective, controlled study. N Engl J Med 1984; 311: 1137–43

    Article  PubMed  CAS  Google Scholar 

  32. The Veterans Administration Systemic 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(11): 659–65

    Article  Google Scholar 

  33. Hoffman SL, Punjabi NH, Kumala S, et al. Reduction in mortality in chloramphenicol treated severe typhoid fever by high dose dexamethasone. N Engl J Med 1984; 310: 82–8

    Article  PubMed  CAS  Google Scholar 

  34. Lebel MH, Freij BJ, Syrogainnopolous GA, et al. Dexamethasone therapy for bacterial meningitis: results of two doubleblind placebo controlled trials. N Engl J Med 1988; 319: 964–71

    Article  PubMed  CAS  Google Scholar 

  35. Montaner JS, Lawson LM, Levitt N, et al. Corticosteroids prevent early deterioration in patients with moderate severe Pneumocystis carinii pneumonia and the acquired immunodeficiency syndrome. N Engl J Med 1990; 323: 14–20

    Google Scholar 

  36. Briegel J, Forst H, Haller M, et al. Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single center study. Crit Care Med 1999; 27: 723–32

    Article  PubMed  CAS  Google Scholar 

  37. Bollaert PE, Charpentier C, Levy S, et al. Reversal of late septic shock with supraphysiologic doses of hydrocortisone. Crit Care Med 1998; 26: 645–50

    Article  PubMed  CAS  Google Scholar 

  38. Balk RA, Jacobs RF, Tryka AF, et al. Low dose ibuprofen reverses the hemodynamic alterations of canine endotoxin shock. Crit Care Med 1988; 16(11): 1128–31

    Article  PubMed  CAS  Google Scholar 

  39. Bone RC, Jacobs ER, Wilson Jr FJ. Increased hemodynamic and survival with endotoxin and septic shock with ibuprofen treatment. Prog Clin Biol Res 1987; 236A: 327–32

    PubMed  CAS  Google Scholar 

  40. Almqvist PM, Kuenzig M, Schwartz SI. Treatment of experimental canine endotoxin shock with ibuprofen, a cyclooxygenase inhibitor. Circ Shock 1984; 13(3): 227–32

    PubMed  CAS  Google Scholar 

  41. Haupt MT, Jastremski MS, Clemmer TP, et al. Effect of ibuprofen in patients with severe sepsis: a randomized, double-blind, multi-center study. Crit Care Med 1991; 19: 1339–47

    Article  PubMed  CAS  Google Scholar 

  42. Arons MM, Wheeler AP, Bernard GR, et al. Effects of ibuprofen on the physiology and survival of hypothermic sepsis. Crit Care Med 1999; 27: 699–707

    Article  PubMed  CAS  Google Scholar 

  43. Bernard GR, Wheeler AP, Russell JA, et al. The effects of ibuprofen on the physiology and survival of patients with sepsis. N Engl J Med 1997; 336: 912–8

    Article  PubMed  CAS  Google Scholar 

  44. Dhainaut JF, Tenaillon A, Le Tulzo Y, 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(11): 1720–8

    PubMed  CAS  Google Scholar 

  45. Dhainaut JF, 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(12): 1963–71

    Article  PubMed  CAS  Google Scholar 

  46. Vincent JL, Spapen H, Bakker J, et al. Phase II multicenter clinical study of the platelet-activating factor receptor antagonist BB-882 in the treatment of sepsis. Crit Care Med 2000; 28(3): 638–42

    Article  PubMed  CAS  Google Scholar 

  47. Grover R, Zaccardelli D, Colice G, et al. An open-label dose escalation study of the nitric oxide synthase inhibitor, N(G)-methyl-L-arginine hydrochloride (546C88), in patients with septic shock. Glaxo Wellcome International Septic Shock Study Group. Crit Care Med 1999; 27(5): 913–22

    Article  PubMed  CAS  Google Scholar 

  48. Grover R, Lopez A, Lorente A et al: Multicenter, randomized, placebo-controlled, double blind study of the nitric oxide synthase inhibitor 546C88: effect on survival in patients with septic shock [abstract]. Crit Care Med 1999; 27: A33

    Article  Google Scholar 

  49. Fein AM, Bernard GR, Criner GJ, et al. Treatment of severe systemic inflammatory response syndrome and sepsis with a novel bradykinin antagonist, Deltibant (CP-0127): results of a randomized, double-blind, placebo-controlled trial. JAMA 1997; 277(6): 482–7

    Article  PubMed  CAS  Google Scholar 

  50. Kox WJ, Volk T, Kox SN, et al. Immunomodulatory therapies in sepsis. Intensive Care Med 2000; 26: S124–8

    Article  PubMed  Google Scholar 

  51. Weiss M, Moldawer LL, Schneider EM. Granulocyte colonystimulating factor to prevent the progression of systemic nonresponsiveness in systemic inflammatory response syndrome and sepsis. Blood 1999; 93(2): 425–39

    PubMed  CAS  Google Scholar 

  52. Dale DC. The use of colony-stimulating factors for the prevention and treatment of infections. Shock 1997; 7 (Suppl.): 81

    Google Scholar 

  53. Wunderink RG, Leeper KV, Schein R, et al. Filgrastim in patients with pneumonia and severe sepsis or septic shock. Chest 2001; 119(2): 523–9

    Article  PubMed  CAS  Google Scholar 

  54. Kox WJ, Bone RC, Krausch D, et al. Interferon gamma 1b in the treatment of compensatory anti-inflammatory response syndrome. A new approach: proof of principle. Arch Intern Med 1997; 157: 389–93

    Article  PubMed  CAS  Google Scholar 

  55. Schetz M. Non-renal indications for continuous renal replacement therapy. Kidney Int 1999; 56 Suppl. 72: S88–94

    Article  Google Scholar 

  56. Rogiers P. Hemofiltration treatment for sepsis: is it time for controlled trials? Kidney Int 1999; 56 Suppl. 72: S99–103

    Article  Google Scholar 

  57. Werdan K.Supplemental immune globulins in sepsis. Clin Chem Lab Med 1999; 37(3): 341–9

    Google Scholar 

  58. Werdan K, Pilz G, and the SBITS Study Group. Polyvalent immune globulins. Shock 1997; (7 Suppl.): 5

  59. Dominioni L, Bianchi V, Imperatori A, et al. High-dose intravenous IgG for treatment of severe surgical infections. Dig Surg 1996; 13: 430–4

    Article  Google Scholar 

  60. The Intravenous Immunoglobulin Study Group. Prophylactic intravenous administration of standard immune globulins compared with core-lipopolysaccharide immune globulin in patients at high risk of postsurgical infections. N Engl J Med 1992; 327: 234–40

    Article  Google Scholar 

  61. Zeni F, Freeman B, Natanson C. Anti-inflammatory therapies to treat sepsis and septic shock: a reassessment [editorial]. Crit Care Med 1997; 257: 1095–100

    Article  Google Scholar 

  62. Abraham A. Why immunomodulatory therapies have not worked in sepsis. Intensive Care Med 1999; 25: 556–66

    Article  PubMed  CAS  Google Scholar 

  63. Levin M, Quint PA, Goldstein B, et al. Recombinant bactericidal/permeability-increasing protein (rBPI21) as adjunctive treatment for children with severe meningococcal sepsis: a randomized trial. Lancet 2000; 356: 961–7

    Article  PubMed  CAS  Google Scholar 

  64. Danner RL, Elin RJ, Hosseini JM, et al. Endotoxemia in septic shock. Chest 1991; 99(1): 169–75

    Article  PubMed  CAS  Google Scholar 

  65. Opal SM. Therapeutic rationale for antithrombin III in sepsis. Crit Care Med 2000; 28(9 Suppl.): S34–7

    Article  PubMed  CAS  Google Scholar 

  66. Fourrier F, Jourdain M, Tournoys A. Clinical trial results with antithrombin III in sepsis. Crit Care Med 2000; 28(9 Suppl.): S38–43

    Article  PubMed  CAS  Google Scholar 

  67. Fourrier F, Chopin C, Huart JJ, et al. Double-blind, placebocontrolled trial of antithrombin III concentrates in septic shock with disseminated intravascular coagulation. Chest 1993; 104(3): 882–8

    Article  PubMed  CAS  Google Scholar 

  68. Eisele B, Lamy M, Thijs LG, et al. Antithrombin III in patients with severe sepsis. A randomized, placebo-controlled, double-blind multi-center trial plus a meta-analysis on all randomized, placebo-controlled, double-blind trials with antithrombin III in severe sepsis. Intensive Care Med 1998; 24(7): 649–50

    Article  Google Scholar 

  69. Abraham E. Tissue factor inhibition and clinical trial results of tissue factor pathway inhibitor in sepsis. Crit Care Med 2000; 28(9 Suppl.): S31–2

    Article  PubMed  CAS  Google Scholar 

  70. Creasy AA, Chang AC, Feigen L, et al. Tissue factor pathway inhibitor reduces mortality from Escherichia coli septic shock. J Clin Invest 1993; 91: 2850–6

    Article  Google Scholar 

  71. Camerota AJ, Creasey AA, Patia V, et al. Delayed treatment with recombinant human tissue factor pathway inhibitor improves survival in rabbits with gram-negative peritonitis. J Infect Dis 1998; 177: 668–76

    Article  PubMed  CAS  Google Scholar 

  72. Esmon C. The protein C pathway. Crit Care Med 2000; 28(9 Suppl.): S44–8

    Article  PubMed  CAS  Google Scholar 

  73. Bernard G, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344(10): 749–62

    Article  Google Scholar 

  74. Angus DC, Vincent J, Artigas A, et al. The effect of recombinant human activated protein C (rhAPC) on organ dysfunction and functional recovery in severe sepsis [abstract]. Crit Care Med 2000; 28 (12 Suppl.): A48 abstract))

  75. Annane D. Effects of the combination of Hydrocortisone (HC)-Fludro-cortisone (FC) on mortality in septic shock [abstract]. Crit Care Med 2000; 28(12 Suppl.): A46

    Google Scholar 

  76. Reinhart K, Wiegand-Lohnert C, Grimminger F, et al. 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; 25(5): 727–9

    Google Scholar 

  77. Reinhart K, Menges T, Gardlund B, et al. Randomized, placebocontrolled trial of the anti-tumor necrosis factor antibody fragment afelimomab in hyperinflammatory response during severe sepsis: the RAMSES study. Crit Care Med 2001 Apr; 29(4): 765–9

    Article  PubMed  CAS  Google Scholar 

  78. Panacek E, Marshall J, Fischkoff S, et al. Neutralization of TNF by a monoclonal antibody improves survival and reduces organ dysfunction in human sepsis: results of the MONARCS Trial. Chest 2000; 118(4 Suppl.): S88

    Google Scholar 

  79. Marshall JC. Clinical trials of mediator-directed therapy in sepsis: what have we learned? Intensive Care Med 2000; 26: S75–83

    Article  PubMed  Google Scholar 

  80. Odell, JR. Anticytokine therapy — a new era in the treatment of rheumatoid arthritis? N Engl J Med 1999; 340(4): 310–2

    Article  CAS  Google Scholar 

  81. The Phase II PAFASE ARDS Prevention Study Group and ICOS Corporation. Recombinant platelet activating factor acetylhydrolase (PAFASE™) decreases the incidence of acute respiratory distress syndrome (ARDS) and 28-day all cause mortality. Presented at the European Society of Intensive Care Medicine (ESICM) 13th Annual Meeting; 2000 Oct 1-4; Rome, Italy

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Acknowledgments

Dr Dellinger has received speaker honoraria or consultant fees from Bayer (anti-tumour necrosis factor antibody, no longer under development), Synergon (interleukin-1 receptor antagonist, no longer under development for the treatment of sepsis), Knoll (anti-tumour necrosis factor antibody) and Lilly [drotrecogin alpha (rhAPC)].

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  1. Section of Critical Care Medicine, Rush Medical College, Rush-Presbyterian-St. Luke’s Medical Center and Cook County Hospital, Room 979 Jelke, 1653 West Congress Parkway, Chicago, Illinois, 60612-3833, USA

    Sreenandh Krishnagopalan &  R. Phillip Dellinger

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Krishnagopalan, S., Dellinger, R.P. Innovative Therapies for Sepsis. BioDrugs 15, 645–654 (2001). https://doi.org/10.2165/00063030-200115100-00002

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