Current Infectious Disease Reports

, Volume 1, Issue 3, pp 224–229

Adjunctive therapies for sepsis and septic shock

  • Gregory Breen
  • Allan R. Tunkel
Article

Abstract

The inflammatory cascade that ensues after an infectious insult is protean in its manifestations, resulting in mild self-limited illness in some patients, while progressing to fulminant sepsis and multisystem organ failure in others. Research into the pathophysiology of this cascade has been intense, but advances in the treatment of sepsis have been few and far between. Although mortality rates have been impacted slightly in patients with sepsis—with improved survival in certain patient subgroups—overall survival still reaches only 55% to 60%. In this paper we will review some of the most recent advances in the therapy of the sepsis syndrome, specifically the roles of cytokine modifiers, supranormal delivery of oxygen, granulocyte colony-stimulating factor administration in leukopenic patients, and parenteral nutrition. Hopefully, these modalities represent additional steps in the path towards a meaningful improvement in survival from this catastrophic condition.

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References and Recommended Reading

  1. 1.
    Wheeler AP, Bernard GR: Treating patients with severe sepsis. N Engl J Med 1999, 340:207–214. An excellent review of the clinical manifestations of the sepsis syndrome, with strong emphasis on therapeutic considerations.PubMedCrossRefGoogle Scholar
  2. 2.
    Chapman PB, Lester TJ, Casper ES, et al.: Clinical pharmacology of recombinant human tumor necrosis factor in patients with advanced cancer. J Clin Oncol 1987, 5:1942–1951.PubMedGoogle Scholar
  3. 3.
    van der Poll T, Bueller HR, ten Cate H, et al.: Activation of coagulation after administration of tumor necrosis factor to normal subjects. N Engl J Med 1990, 322:1622–1627.PubMedCrossRefGoogle Scholar
  4. 4.
    Okusawa S, Gelfand JA, Ikejima T, et al.: Interleukin 1 induces a shock-like state in rabbits: synergism with tumor necrosis factor and the effect of cyclooxygenase inhibition. J Clin Invest 1988, 81:1162–1172.PubMedCrossRefGoogle Scholar
  5. 5.
    Debets JMG, Kampmeijer R, Van der Linden MP, et al.: Plasma tumor necrosis factor and mortality in critically ill septic patients. Crit Care Med 1989, 17:489–494.PubMedCrossRefGoogle Scholar
  6. 6.
    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, multicenter clinical trial. JAMA 1995, 273:934–941.PubMedCrossRefGoogle Scholar
  7. 7.
    Cohen J, Carlet J: 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.PubMedCrossRefGoogle Scholar
  8. 8.
    Abraham E, Anzueto A, Gutierrez G, et al.: Double-blind randomised controlled trial of monoclonal antibody to human tumor necrosis factor in treatment of septic shock. Lancet 1998, 351:929–933. This follow-up to two earlier trials (which demonstrated some benefit with use of monoclonal antibody to TNF-a) showed no benefit on mortality in a large cohort of patients. Patients in the treatment arm did have a significantly decreased incidence of coagulopathy compared with placebo.PubMedGoogle Scholar
  9. 9.
    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, 24:733–742.PubMedCrossRefGoogle Scholar
  10. 10.
    Casey LC, Balk RA, Bone RC: Plasma cytokines and endotoxin levels correlate with survival in patients with the sepsis syndrome. Ann Intern Med 1993, 119:771–778.PubMedGoogle Scholar
  11. 11.
    Abraham E: Status report of soluble receptors in the treatment of septic shock [abstract]. In IBC Sixth Annual International Symposium on Sepsis. Boston, 1996.Google Scholar
  12. 12.
    Fisher CJ, Agosti JM, Opal SM, et al.: Treatment of patients with septic shock with tumor necrosis receptor Fc fusion protein. N Engl J Med 1996, 334:1697–1702.PubMedCrossRefGoogle Scholar
  13. 13.
    Abraham E: Cytokine modifiers: pipe dream or reality? Chest 1998, 113:224S-227S.PubMedGoogle Scholar
  14. 14.
    Doherty GM, Jensen JC, Alexander HR, et al.: Pentoxifylline suppression of tumor necrosis factor gene transcription. Surgery 1991, 110:192–198.PubMedGoogle Scholar
  15. 15.
    Zheng J, Orowly J, Chang JH, et al.: Attenuation of tumor necrosis factor-induced endothelial cell cytotoxicity and neutrophil chemoluminescence. Am Rev Respir Dis 1990, 142:1073–1078.PubMedGoogle Scholar
  16. 16.
    Staubach KH, Schroder J, Stuber F, et al.: Effect of pentoxifylline in severe sepsis: results of a randomized, double-blind, placebo-controlled study. Arch Surg 1998, 133:94–100.PubMedCrossRefGoogle Scholar
  17. 17.
    Carter MB, Wilson MA, Wead WB, et al.: Pentoxifylline attenuates pulmonary macromolecular leakage after intestinal ischemia-reperfusion. Arch Surg 1995, 130:1337–1344.PubMedGoogle Scholar
  18. 18.
    Lauterbach R, Pawlik D, Kowalczyk D, et al.: Effect of the immunomodulating agent, pentoxifylline, in the treatment of sepsis in prematurely delivered infants: a placebo-controlled, double-blind trial. Crit Care Med 1999, 27:807–814. This study in premature infants demonstrated improved mortality in those infants with sepsis who received pentoxifylline 5 mg/kg/h for 6 hours on 6 consecutive days compared with placebo. There was also significantly less disordered peripheral circulation, metabolic acidosis, anuria or oliguria, disseminated intravascular coagulation, and necrotizing enterocolitis. The study correlated these findings with measurements of TNF and IL-6 concentrations that were significantly decreased in the treatment group.PubMedCrossRefGoogle Scholar
  19. 19.
    Bellomo R, Tipping P, Boyce N: Continuous veno-venous hemofiltration with dialysis removes cytokines from the circulation of septic patients. Crit Care Med 1993, 21:522–526.PubMedCrossRefGoogle Scholar
  20. 20.
    Matamis D, Tsagourias M, Koletsos K, et al.: Influence of continuous hemofiltration-related hypothermia on hemodynamic variables and gas exchange in septic patients. Intensive Care Med 1994, 20:431–436.PubMedCrossRefGoogle Scholar
  21. 21.
    Hirasawa H, Sugai T, Oda S, et al.: Continuous hemodiafiltration can remove humoral mediators from the bloodstream of patients with SIRS/ MODS [abstract]. Blood Purif 1997, 15:136.Google Scholar
  22. 22.
    Smith JW, Urba WJ, Curti BD, et al.: The toxic and hematologic effects of interleukin-1 alpha administered in a phase I trial to patients with advanced malignancies. J Clin Oncol 1992, 10:1141–1152.PubMedGoogle Scholar
  23. 23.
    Granowitz EV, Porat R, Mier JW, et al.: Hematological and immunomodulatory effects of an interleukin-1 receptor antagonist coinfusion during low-dose endotoxemia in healthy humans. Blood 1993, 82:2985–2990.PubMedGoogle Scholar
  24. 24.
    Fisher 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. Crit Care Med 1994, 22:12–21.PubMedCrossRefGoogle Scholar
  25. 25.
    Fisher CJ, Dhainaut JF, Opal SM, et al.: Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. JAMA 1994, 271:1836–1843.PubMedCrossRefGoogle Scholar
  26. 26.
    Vincent JL: New therapies in sepsis. Chest 1997, 112:330S-338S. concise review of current treatment options for sepsis with explanations of negative trial results.PubMedGoogle Scholar
  27. 27.
    de Waal Malefyt R, Abrams J, Bennett B, et al.: Interleukin 10 inhibits cytokine synthesis by human monocytes: An autoregulatory role of interleukin 10 produced by moncytes. J Exp Med 1991, 174:1209–1220.PubMedCrossRefGoogle Scholar
  28. 28.
    Fiorentino DF, Zlotnik A, Mossmann TR, et al.: Interleukin 10 inhibits cytokine production by activated macrophages. J Immunol 1991, 147:3815–3822.PubMedGoogle Scholar
  29. 29.
    Gerard C, Bruyns C, Marchant A, et al.: Interleukin 10 reduces the release of TNF prevents lethality in experimental endotoxemia. J Exp Med 1993, 177:547–550.PubMedCrossRefGoogle Scholar
  30. 30.
    Howard M, Muchamuel T. Andrade S, et al.: Interleukin 10 protects mice from lethal endotoxemia. J Exp Med 1993, 177:1205–1208.PubMedCrossRefGoogle Scholar
  31. 31.
    Bean AG, Freiberg RA, Andrade S, et al.: Interleukin 10 protects mice against staphylococcal enterotoxin B-induced lethal shock. Infect Immun 1993, 61:4937–4939.PubMedGoogle Scholar
  32. 32.
    Standiford TJ, Strieter RM, Lukacs NW, et al.: Neutralization of IL-10 increases lethality in endotoxemia. Cooperative effects of macrophage inflammatory protein-2 and tumor necrosis factor. J Immunol 1995, 155:2222–2229.PubMedGoogle Scholar
  33. 33.
    Florquin S, Amraoui Z, Abramowicz D, et al.: Systemic release and protective role of IL-10 in staphylococcal enterotoxin B-induced shock in mice. J Immunol 1994, 153:2618–2623.PubMedGoogle Scholar
  34. 34.
    Remick DG, Garg SJ, Newcomb DE, et al.: Exogenous interleukin-10 fails to decrease the mortality or morbidity o sepsis. Crit Care Med 1998, 26:895–904.PubMedCrossRefGoogle Scholar
  35. 35.
    Van der Poll T. Marchant A. Buurman WA, et al.: Endogenous IL-10 protects mice from death during septic peritonitis. J Immunol 1995, 155:5397–5401.PubMedGoogle Scholar
  36. 36.
    Shoemaker WC, Appel PL, Kram HB, et al.: Prospective trial of supranormal values of survivors as therapeutic goals in highrisk surgical patients. Chest 1988, 94:1176–1186.PubMedGoogle Scholar
  37. 37.
    Boyd O, Grounds RM, Bennett ED: A randomized clinical trial of the effect of deliberate perioperative increase of oxygen delivery on mortality in high-risk surgical patients. JAMA 1993, 270:2699–2707.PubMedCrossRefGoogle Scholar
  38. 38.
    Fleming A, Bishop M, Shoemaker W, et al.: Prospective trial of supranormal values as goals of resuscitation in severe trauma. Arch Surg 1992, 127:1175–1181.PubMedGoogle Scholar
  39. 39.
    Alia I, Esteban A, Gordo F, et al.: A randomized and controlled trial of the effect of treatment aimed at maximizing oxygen delivery in patients with severe sepsis or septic shock. Chest 1999, 115:453–461. This recent trial of supranormal oxygen delivery in 63 medicalsurgical intensive care unit patients showed no improvement in survival. However, only nine of 31 treatment patients reached the target oxygen delivery index of 600 mL/min/m2.PubMedCrossRefGoogle Scholar
  40. 40.
    Yu M, Burchell S, Nahidh WMA, et al.: Relationship o mortality to increasing oxygen delivery in patients greater than or equal to 50 years of age: A prospective, randomized trial. Crit Care Med 1998, 26:1011–1019.PubMedCrossRefGoogle Scholar
  41. 41.
    Roilides E, Walsh TJ, Pizzo PA, et al.: G-CSF enhances th phagocytic and bactericidal activity of normal and defective human neutrophils. J Infect Dis 1991, 163:579–583.PubMedGoogle Scholar
  42. 42.
    Gorgen I, Hartung T, Wendel A, et al.: G-CSF treatment protects rodents against lipopolysaccharide-induced toxicity via suppression of systemic tumor necrosis factor alpha. J Immunol 1992, 149:918–924.PubMedGoogle Scholar
  43. 43.
    Hartung T, Docke WD, Gantner F, et al.: Effect of granulocyte colony-stimulating factor treatment on ex vivo blood cytokine response in human volunteers. Blood 1995, 85:2482–2489.PubMedGoogle Scholar
  44. 44.
    Hartung T, Volk HD, Wendel A: G-CSF: an anti-inflammatory cytokine (abstract). Shock 1997, (suppl 1):81.Google Scholar
  45. 45.
    Nishida T, Hasegawa J, Nakao K, et al.: G-CSF for gastrointestinal perforation in patients with leukopenia. J Trauma 1996, 40:727–732.PubMedGoogle Scholar
  46. 46.
    Nelson S, Farkas S, Fotheringham N, et al.: Filgrastim in the treatment of hospitalized patients with community acquired pneumonia (abstract). Am J Respir Crit Care Med 1996, 153:A535.Google Scholar
  47. 47.
    Ishikawa K, Tanaka H, Tetsuya M, et al.: Recombinant human G-CSF attenuates inflammatory responses in septic patients with neutropenia. J Trauma 1998, 44:1047–1054. Subcutaneous administration of G-CSF to patients with sepsis and total leukocyte counts less than 5000/mm3 led to significant increases in in vitro neutrophil function as well as improvement in APACHE II and Multiple Organ Failure index scores.PubMedCrossRefGoogle Scholar
  48. 48.
    Garcia-de-Lorenzo A, Ortiz-Leyba C, Planas M, et al.: Parenteral administration of different amounts of branch-chain amino acids in septic patients: clinical and metabolic aspects. Crit Care Med 1997, 25:418–424. Administration of 45% solutions of branch-chain amino acids versus standard concentrations of 23% branch-chain amino acids led to improved survival and increased concentrations of prealbumin and retinol-binding protein compared with controls.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc 1999

Authors and Affiliations

  • Gregory Breen
    • 1
  • Allan R. Tunkel
    • 1
  1. 1.MCP Hahnemann UniversityPhiladelphiaUSA

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