Recent Advances in the Pathophysiology and Treatment of Septic Shock

  • Gary L. Simon


Septic shock ranks among the most severe clinical manifestations of systemic microbial infection [1]. The clinical syndrome is characterized by significant derangements in host physiology, the most prominent being systemic hypotension. This is frequently accompanied by evidence of organ dysfunction such as respiratory insufficiency or renal failure. By definition, patients with septic shock have clinical evidence of infection, a systolic blood pressure less than 90 mm Hg or a decrease in blood pressure of greater than 40 mm Hg, and remain hypotensive after receiving 500 ml of saline or Ringer’s lactate solution. In most, but not all patients with septic shock, blood cultures reveal a bacterial pathogen. Gramnegative bacteria are most commonly recognized as etiologic agents, although gram-positive bacteria, viruses and fungi are occasionally implicated.


Nitric Oxide Tumor Necrosis Factor Septic Shock Sepsis Syndrome Endotoxin Challenge 
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  1. 1.
    Bone RC. The pathogenesis of sepsis. Ann Intern Med. 1991;115:457–69.PubMedGoogle Scholar
  2. 2.
    Centers for Disease Control and Prevention. Increase in national hospital discharge survey rates for septicemia — United States, 1979–87. MMWR 1990;39:31–4.Google Scholar
  3. 3.
    Bryant RE, Hood AF, Hood CE, et al. Factors affecting mortality of gram-negative bacteremia. Arch Intern Med. 1071;127:120–128CrossRefGoogle Scholar
  4. 4.
    Dupont HL and Spink WW. Infections due to gram-negative organisms: An analysis of 800 patients with bacteremia at the University of Minnesota medical center, 1958–1966. Medicine 1969;48:307–332.PubMedCrossRefGoogle Scholar
  5. 5.
    Kreger BE, Craven DE, Carling PC, et al. Gram-negative bacteremia. Amer J Med. 1980;68:332–343.PubMedCrossRefGoogle Scholar
  6. 6.
    Young LS, Proctor RA, Beutler B, et al. University of California/Davis Interdepartmental Conference on Gram-Negative Septicemia. Rev Inf Dis 1991;13:666–87.CrossRefGoogle Scholar
  7. 7.
    Rowley D. Endotoxins and bacterial virulence. J Infect Dis 1971;123:317–27.PubMedCrossRefGoogle Scholar
  8. 8.
    Wolff SM. Biological effects of bacterial endotoxins in man. J Infect Dis. 1973;123 (Supplement):S290–4Google Scholar
  9. 9.
    Billiau A, Vandekerckhove F. Cytokines and their interactions with other inflammatory mediators in the pathogenesis of septic schock. Eur J Clin Invest 1991;21:559–73.PubMedCrossRefGoogle Scholar
  10. 10.
    Cannon JG, Tompkins RG, Gelfand JA, et al. Circulating interleukin-1 and tumor necrosis factor in septic shock and experimental endotoxin fever. J Inf Disl 1990;161:79–97.CrossRefGoogle Scholar
  11. 11.
    Parillo JE. Pathogenic mechanisms of septic shock. NEngl J Med 1993;328:1471–7.CrossRefGoogle Scholar
  12. 12.
    Tracey KJ, Beutler B, Lowry SF, et al. Shock and tissue injury induced by recombinant human cachectin. Science 1986;236:470–473.CrossRefGoogle Scholar
  13. 13.
    Beutler B, Cerami A. Cachectin: more than a tumor necrosis factor. N Engl J Med. 1987:379–385.Google Scholar
  14. 14.
    Rouzer CA, Cerami A. Hypertriglyceridemia associated with Trypanosoma brucei brucei infection in rabbits: role of defective triglyceride removal. Mol Biochem Parasitol 1980;2:31–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Kawakami M, Cerami A. Studies of endotoxin-induced decrease in lipoprotein lipase activity. J Exp Med 1981;154:631–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Torti FM, Dieckmann B, Beutler B, et al. A macrophage factor inhibits adipocyte gene expression: An in vitro model of cachexia. Science 1985;229:867–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Beutler B, Greenwald D, Hulmes JD, et al. Identity of tumor necrosis factor and the macrophage-secreted factor cachectin. Nature 1985;316:552–4.PubMedCrossRefGoogle Scholar
  18. 18.
    Michalek SM, Moore RN, McGhee JR, et al. The primary role of lymphoreticular cells in the mediation of host responses to bacterial endotoxin. J Infect Dis 1980;141:55–63.PubMedCrossRefGoogle Scholar
  19. 19.
    Beutler B, Milsark IW, Cerami AC. Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science 1985;229:869–71.PubMedCrossRefGoogle Scholar
  20. 20.
    Vogel SN, Moore RN, Sipe DL. BCG-induced enhancement of endotoxin sensitivity in C3h/HeJ mice. I. In vivo studies J. Immunol 1980:124:2004–9.PubMedGoogle Scholar
  21. 21.
    Cerami A, Ikeda Y, Le Trang PJ, et al. Weight loss associated with an endotoxin-induced mediator from peritoneal macrophages: the role of cachectin (tumor necrosis factor). Immunol. Lett: 1985;11:173.PubMedCrossRefGoogle Scholar
  22. 22.
    Dinarello CA. The role of interleukin-1 in disease. N Engl J Med 1993:328:106–113.PubMedCrossRefGoogle Scholar
  23. 23.
    Hack CE, De Groot ER, Felt-Bersma JF, et al. Increased plasma levels of Interleukin-6 in sepsis. Blood 1989;74:1704–10.PubMedGoogle Scholar
  24. 24.
    Dinarello CA, Cannon JG, Wolff SM, et al. Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin-1. J Exp Med 1986;163:143–50.CrossRefGoogle Scholar
  25. 25.
    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;81:1162–72.PubMedCrossRefGoogle Scholar
  26. 26.
    Waage A, Espevik T. Interleukin-1 potentiates the lethal effect of tumor necrosis factor a/cachectin in mice. J Exp Med 1988;167;1987–92.PubMedCrossRefGoogle Scholar
  27. 27.
    Helle M, Brakenhoff JPJ, De Groot ER, et al. Interleukin-6 is involved in interleukin-1-induced activities. EurJ Immunol 1988;18:957–964.CrossRefGoogle Scholar
  28. 28.
    Aderka D, Le J, Vilcek J. IL-6 inhibits lipopolysaccharide-induced TNF production in cultured human monocytes, U937 cells and mice. J Immunol 1989;143:3517–23.PubMedGoogle Scholar
  29. 29.
    Casey LC, Balk RA, Bone RC. Plasma cytokines and endotoxin levels correlate with survival in patients with the sepsis syndrome. AnnlntMed 1993;119:771–8.Google Scholar
  30. 30.
    Calandra T, Baumgartner JD, Grau et al. Prognostic values of tumor necrosis factor/cachectin, interleukin-1, interferon-α, and interferon-y in the serum of patients with septic shock. J Infect Dis 1990;161:982–7.PubMedCrossRefGoogle Scholar
  31. 31.
    Cannon JG. Cytokines and shock. In Kimball ES, ed. Cyokines and inflammation. Boca Raton: CRC Press; 1991:307–29.Google Scholar
  32. 32.
    Vannier E, Miller LC, Dinarello CA. Coordinated antiinflammatory effects of interleukin-4: Interleukin-4 suppresses interleukin-1 production but upregulates gene expression and synthesis of interleukin-1 receptor antagonist. Proc Natl Acad Sci 1992;177:573–6.Google Scholar
  33. 33.
    de Wall Malefyt R, Abrams J, Bennett B. Interleukin 10 inhibits cytokine synthesis by human monocytes. J Exp Med 1991;174:209–220.Google Scholar
  34. 34.
    Nathan CF, Murrray HW, Wiebe, ME, et al. Identification of interferon-y as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity. J Exp Med 1983;158:670–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Beutler B, Tkacenko V, Milsark I, et al. Effect of y interferon on cachectin expression by mononuclear phagocytes. J Exp Med. 1986;164:1791–6.PubMedCrossRefGoogle Scholar
  36. 36.
    McCabe WR. Serum complement levels in bacteremia due to gram-negative organisms. N Engl J Med 1973;288:21–23.PubMedCrossRefGoogle Scholar
  37. 37.
    Fearon DT, Ruddy S, Schur PH, et al. Activation of the properidin pathway of complement in patients with gram-negative bacteremia. N Engl J Med 1975;292:937–40.PubMedCrossRefGoogle Scholar
  38. 38.
    Frank MM, May JE, Kane MA. Contributions of the classical and alternative pathwaysof complement to the biological effects of endotoxin. J Infect Dis 1973:128(Suppl):S176–81.CrossRefGoogle Scholar
  39. 39.
    Levi M, ten Cate H, van der Poll T, et al. Pathogenesis of disseminated intravascular coagulation in sepsis. JAMA 199;270:975–9.CrossRefGoogle Scholar
  40. 40.
    Smith-Erichsen N, Aasen AO, Gallimore, MJ, et al. Studies of components of the coagulation systems in normal individuals and septic shock patients. Circ Shock 1982:9:491–7.PubMedGoogle Scholar
  41. 41.
    van der Poll T, Buller HR, ten Cate H, et al. Activation of coagulation after administration of tumor necrosis factor to normal subjects. N Engl J Med. 1990;322:1622–7.PubMedCrossRefGoogle Scholar
  42. 42.
    Morrison DC, Cochrane CG. Direct evidence for Hageman factor (factor XII) activation by bacterial polysaccharides (endotoxin). J Exp Med 1974;140:797–811.PubMedCrossRefGoogle Scholar
  43. 43.
    Mason JW, Kleeberg U, Dolan P, et al. Plasma kallikrein and hageman factor in gram-negative bacteremia. Ann lnt Med 1970:73:545–551.Google Scholar
  44. 44.
    Kimball HR, Melmon KL, Wolff SM. Endotoxin-induced kinin production in man. Proc Soc Exp Biol Med 1972;139:1078–2.PubMedGoogle Scholar
  45. 45.
    O’Donnell TF Jr, Clowes GHA, Talamo RC, et ai. Kinin activation in the blood of patients with sepsis. Surg Gynecol Obstet 1976;143:539–545.PubMedGoogle Scholar
  46. 46.
    Locksley Rm, Wilson CB. Cell-mediated immunity and its role in host defense. In: Mandell, Douglas and Bennett (ed). Principles and Practice of Infectious Diseases. New York. Churchill-Livingstone. 1995; 102–149.Google Scholar
  47. 47.
    Suffredini AF, Fromm RE, Parker MM, et al. The cardiovascular response of normal humans to the administration of endotoxin. N Engl JMed 1989;321:280–87.CrossRefGoogle Scholar
  48. 48.
    Parker MM, Shelhamer JH, Bacharach SL, et al. Profound but reversible myocardial depression in patients with septic shock. Ann Intern Med 1984;100:483–490.PubMedGoogle Scholar
  49. 49.
    Zinner SH, Mcabe WR. Effects of IgM and IgG antibody in patients with bacteremia due to gram-negative bacilli. J Infect Dis 1976;133:37–45.PubMedCrossRefGoogle Scholar
  50. 50.
    McCabe WR, Kreger BE, Johns M. Type-specific and cross-reactive antibodies in gram-negative bacteremia. N Engl J Med 1972:287:261–7.PubMedCrossRefGoogle Scholar
  51. 51.
    Elbein AD, Heath EC. The biosynthesis of cell wall lipopolysaccharide in Escherichia coli. I. The biochemical properties of a uridine diphosphate galactose 4-epimeraseless deficient mutant. J Biol Chem 1965;240:1919–25.PubMedGoogle Scholar
  52. 52.
    Ziegler EJ, Douglas H, Sherman JE, et al. Treatment of E. coli and Klebsiella bacteremia in agranulocytic animals with antiserum to a UDP-Gal epimerase-deficient mutant. J Immunol 1973;111:433–42.PubMedGoogle Scholar
  53. 53.
    Ziegler EJ, McCutchan JA, Fierer J, et al. Treatment of gram-negative bacteremia and shock with human antiserum to a mutant Escherichia coli NEJM 1982;307:1225–30.PubMedCrossRefGoogle Scholar
  54. 54.
    Ziegler EJ, Fisher CJ, Sprung CL, et al. Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin. N Eng J Med 1991;324:429–36.CrossRefGoogle Scholar
  55. 55.
    Mathison JC, Wolfson E, Ulevitch RJ. Participation of tumor necrosis factor in the mediation of gram-negaive bacterial lipopolysaccharide-induced injury in rabbits. J Clin Invest 1988;81:1925–37.PubMedCrossRefGoogle Scholar
  56. 56.
    Tracey KJ, Fong Y, Hesse DG, et al. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteremia. Nature 1987;33;662–4.CrossRefGoogle Scholar
  57. 57.
    Scholl RA, Lang CH, Bagby GJ. Hypertriglyceridemia and its relation to tissue lipoprotein lipase activity in endotoxemic, Escherichia coli, bacteremia and polymicrobial septic rats. J Surg Res 1984;37:394–401.PubMedCrossRefGoogle Scholar
  58. 58.
    Bagby GJ, Plessala KJ, Wilson LA, et al. Divergent efficacy of antibody to tumor necrosis factor-α in intravascular and peritonitis models of sepsis. J Infect Dis 1991;163:83–88.PubMedCrossRefGoogle Scholar
  59. 59.
    Abraham E, Wunderink R, Silverman H. Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome: a randomized, controlled, doubleblind, multicenter clinical trial. JAMA 1995;273:934–41.PubMedCrossRefGoogle Scholar
  60. 60.
    Schumann RR, Leong SR, Flaggs GW, et al. Structure and function of lipopolysaccharide binding protein. Science. 1990;249:1429–31.PubMedCrossRefGoogle Scholar
  61. 61.
    Dentener MA, Bazil V, Von Asmuth EJU, et al. Involvement of CD 14 in lipopolysaccharideinduced tumor necrosis factor-a, IL-6 and IL-8 release by human monocytes and alveolar macrophages. J Immunol. 1993;150:2885–91.PubMedGoogle Scholar
  62. 62.
    Girardin T, Baumgartner JD, Grau GE, et al. Imbalance between tumor necrosis factor-alpha and soluble TNF receptor concentrations in severe meningococcemia. Immunology 1992;76:20–3.PubMedGoogle Scholar
  63. 63.
    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.PubMedCrossRefGoogle Scholar
  64. 64.
    Van Zee KJ, Kohno T, Fischer E, et al. Tumor necrosis factor soluble receptors circulate during experimental and clinical inflammation and can protect against excessive tumor necrosis factor in-vitro and in-vivo. Proc Natl Acad Sci U S A. 1992;89:4845–9.PubMedCrossRefGoogle Scholar
  65. 65.
    Nakane A, Minagawa T, Kato K. Endogenous tumor necrosis factor (cachectin) is essential for host resistance against Listeria Monocytogenes infection. Inf Immun 1988;56:2563–9.Google Scholar
  66. 66.
    Michie HR, Manogue KR, Spriggs DR, et al. Detection of circulating tumor necrosis factor after endotoxin administration. N Engl J Med 1988;318:1481–6.PubMedCrossRefGoogle Scholar
  67. 67.
    Ohlsson K, Bjork P, Bergenfeldt M, et al. An interleukin-1 receptor antagonist reduces mortality from endotoxin. Nature. 1990;348:550–2.PubMedCrossRefGoogle Scholar
  68. 68.
    Fischer E, Marano MA, Van Zee KJ, et al. Interleukin-1 receptor blockade improves survival and hemodynamic performance in in E. coli septic shock, but fails to alter host responses to sublethal endotoxemia. J Clin Invest. 1992;89:1551–9.PubMedCrossRefGoogle Scholar
  69. 69.
    Fisher CJ Jr, Dhainaut JFA, 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
  70. 70.
    Hinshaw LB, Beller-Todd BK, Archer LT, et al. Effectiveness of steroid/antibiotic treatment in primates administered LD100 Escherichia coli. Ann Surg. 1981;194:51–56.Google Scholar
  71. 71.
    Hinshaw LB, Beller BK, Archer LT, et al. Recovery from lethat Escherichia coli shock in dogs. Surg Gynecol Obstet. 1979;149:545–53.PubMedGoogle Scholar
  72. 72.
    Schumer W. Steroids in the treatment of clinical septic shock. Ann Surg 1976;333–341.Google Scholar
  73. 73.
    Sprung CL, Caralis PV, Marcial EH, et al. The effects of high-dose corticosteroids in patients with septic shock. N Engl J Med 1984;311:1137–43.PubMedCrossRefGoogle Scholar
  74. 74.
    Bone RC, Fisher CJ Jr, Clemmer TP, et al. A controlled clinical trial of high-dose methyprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med 1987;317:653–8.PubMedCrossRefGoogle Scholar
  75. 75.
    The Veterans Administrative Systemic Sepsis Cooperative Study Group. Effect of high-dose glucocorticoid therapy on mortality in patients with clinical signs os systemic sepsis. N Engl J Med; 317:659–65.Google Scholar
  76. 76.
    Beutler B, Cerami A. Cachectin: More than a tumor necrosis factor. N Engl J Med 1987;316:379–85.PubMedCrossRefGoogle Scholar
  77. 77.
    Beutler B, Krochin N, Milsark IW. Control of cachectin (tumor necrosis factor) synthesis: mechanisms of endotoxin resistance. Science 1986;232:977–80.PubMedCrossRefGoogle Scholar
  78. 78.
    Kilbourn RG, Traber DL, Szabo C. Nitric oxide and shock. Disease-a-Month. 1997;43:287–347.CrossRefGoogle Scholar
  79. 79.
    Nathan CF, Hibbs JB Jr. Role of nitric oxide synthesis in macrophage antimicrobial activity. Curr Opin Immunol 1991;3:65–70.PubMedCrossRefGoogle Scholar
  80. 80.
    Kilbourn RG, Gross SS, Lodato RF, et al. NG-amino-arginine inhibits interleukin la-induced nitric oxide synthase in vascular smooth muscle and fully reverses interleukin-la-induced hypotension. J Natl Cancer Inst. 1992;84:1008–16.PubMedCrossRefGoogle Scholar
  81. 81.
    Kilbourn RG, Gross SS, Jubran A, et al. NG-amino-arginine inhibits tumor necrosis factorinduced hypotension; implications for the invovlement of nitric oxide. Proc Natl Acad Sci USA 1990;87:3629–32.PubMedCrossRefGoogle Scholar
  82. 82.
    Teale D, Atkinson A. Inhibition of nitric oxide synthesis improves survival ina murine model of sepsis that is not cured by antibiotic alone. J Antimicrob Chemother 1992;30:83042.CrossRefGoogle Scholar
  83. 83.
    Pastor C, Teisseire B, Vicaut E. Effects of L-argininie and L-nitro arginine treatment on blood pressure and cardiac output in a rabbit endotoxin shock model. Crit Care Med 1994;22:465–9.PubMedCrossRefGoogle Scholar
  84. 84.
    Cobb P, Natanson C, Solomon M. NG-amino-arginine, an inhibitor of nitric oxide synthase, increases lethality in canine endotoxic shock. Clin Res 1991;21:1287–95.Google Scholar
  85. 85.
    Kilbourn R, Szabo C, Taber D. Beneficial versus detrimental effects of nitric oxide synthase inhibitors in circulatory shock: lessons learned from experimental and clinical studies Shock. 1997;7:235–46.PubMedCrossRefGoogle Scholar
  86. 86.
    Petros A, Lamb G, Leone A, et al. Effects of a nitric oxide synthase inhibitor in humans with septic shock. Card. Res 1994;28:34–39.CrossRefGoogle Scholar
  87. 87.
    Kilbourn R, Fonseca G, Price K, et al. Clinical evaluation of NG-methyl-L-arginine in cancer patients with shock. Endothelium 1995;3(suppl):57.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2000

Authors and Affiliations

  • Gary L. Simon
    • 1
  1. 1.Department of MedicineThe George Washington University School of Medicine and Health SciencesWashington, DCUSA

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