Death in a Lonely Place: Pathophysiology of the Dying Patient

  • Mike Darwin
  • Phil Hopkins

In the long arc that is my memory I cannot forget her. It was over 20 years ago and that is in good measure the tragedy of this tale; that with the passing of an entire human generation her story is still current, still common, still haunting the corridors of critical care medicine. It was just another day starting at 0600 hours as they all did then. My first patient was a new admission to ICU. The first line in the chart's most recent entry elicited an involuntary groan. This 24-year-old African—American female was admitted to the ICU at 0200 with multisystem organ failure secondary to E. coli septicemia following an intrauterine death. The narrative that followed described a patient in extremis with refractory septic shock, diffuse intravascular coagulation, and adult respiratory distress syndrome, a woman who was clearly dying. As I primed the dialysis circuit with salt-poor albumin I recoiled as I glimpsed a photograph left by her distraught husband. It showed a beautiful, smiling, vibrant woman with extraordinary violet eyes. How had she gone from this to near death in the ICU in just over 24 hours?


Septic Shock Severe Sepsis Respir Crit Adult Respiratory Distress Syndrome Tissue Factor Pathway Inhibitor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Janeway CA Jr. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol 1990;54:1–13.Google Scholar
  2. 2.
    Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol 1994;12:991–1045.PubMedGoogle Scholar
  3. 3.
    Koropatnick TA, Engle JT, Apicella MA, Stabb EV, Goldman WE, McFall-Ngai MJ. Microbial factor-mediated development in a host-bacterial mutualism. Science 2004;306:1186–1188.PubMedCrossRefGoogle Scholar
  4. 4.
    Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 2004;118;229–241.PubMedCrossRefGoogle Scholar
  5. 5.
    DaSilva AMT, Kaulbach HC, Chuidian FS, Lambert DR, Suffredini AF, Danner L. Shock and multiple organ dysfunction after self administration of Salmonella endotoxin. N Engl J Med 1993;328:1457–1460.CrossRefGoogle Scholar
  6. 6.
    Bunnell E, Lynn M, Habet K, et al. A lipid A analog, E5531, blocks the endotoxin response in human volunteers with experimental endotoxemia. Crit Care Med 2000;28:2713–2720.PubMedCrossRefGoogle Scholar
  7. 7.
    Huang Q, Liu D, Majewski P, et al. The plasticity of dendritic cell responses to pathogens and their components. Science 2001;294:870–875.PubMedCrossRefGoogle Scholar
  8. 8.
    Pridmore AC, Wyllie DH, Abdillahi F, et al. A lipopolysaccharide-deficient mutant of Neisseria meningitidis elicits attenuated cytokine release by human macrophages and signals via toll-like receptor (TLR) 2 but not via TLR4/MD2. J Infect Dis 2001;183:89–96.PubMedCrossRefGoogle Scholar
  9. 9.
    Levin J, Poore TE, Zauber NP, Oser RS. Detection of endotoxin in the blood of patients with sepsis due to Gram-negative bacteria. N Engl J Med 1970;283:1313–1316.PubMedGoogle Scholar
  10. 10.
    Tesh VL, Duncan RL Jr, Morrison DC. The interaction of Escherichia coli with normal human serum: the kinetics of serum-mediated lipopolysaccharide release and its dissociation from bacterial killing. J Immunol 1986;137:1329–1335.PubMedGoogle Scholar
  11. 11.
    Danner RL, Elin RJ, Hosseini JM, Wesley RA, Reilly JM, Parillo JE. Endotoxaemia in human septic shock. Chest 1991;99:169–175.PubMedCrossRefGoogle Scholar
  12. 12.
    Haglund U. Systemic mediators released from the gut in critical illness. Crit Care Med 1993;21:S15–S18.PubMedGoogle Scholar
  13. 13.
    Murphy DB, Cregg N, Tremblay L, et al. Adverse ventilatory strategy causes pulmonary-to-systemic translocation of endotoxin. Am J Respir Crit Care Med 2000;162:27–33.PubMedGoogle Scholar
  14. 14.
    Maskin B, Fontan PA, Spinedi EG, Gammella D, Badolati A. Evaluation of endotoxin release and cytokine production induced by antibiotics in patients with Gram-negative nosocomial pneumonia. Crit Care Med 2002;30:349–354.PubMedCrossRefGoogle Scholar
  15. 15.
    Schumann RR, Leong SR, Flaggs GW, et al. Structure and function of lipopolysaccharide binding protein. Science 1990;249:1429–1431.PubMedCrossRefGoogle Scholar
  16. 16.
    Wright SD, Ramos RA, Tobias PS, et al. CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science 1990;249:1431–1433.PubMedCrossRefGoogle Scholar
  17. 17.
    Gegner JA, Ulevitch RJ, Tobias PS. Lipopolysaccharide (LPS) signal transduction and clearance. Dual roles for LPS binding protein and membrane CD14. J Biol Chem 1995;270:5320–5325.PubMedCrossRefGoogle Scholar
  18. 18.
    Poltorak A, He X, Smirnova I, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice; mutations in tlr4 gene. Science 1999;282:2085–2088.CrossRefGoogle Scholar
  19. 19.
    Takeuchi O, Hoshino K, Kawai T, et al. Differential roles of TLR2 and TLR4 in recognition of Gram-negative and Gram-positive bacterial cell wall components. Immunity 1999;11:443–451.PubMedCrossRefGoogle Scholar
  20. 20.
    Chow JC, Young DW, Golenbock DT, Crist WJ, Gusovsky F. Toll-like receptor 4 mediates lipopolysaccharide-induced signal transduction. J Biol Chem 1999;274:19689–19692.Google Scholar
  21. 21.
    Triantafilou K, Triantafilou M, Dedrick RL. A CD14-independent LPS receptor cluster. Nat Immunol 2001;2:338–345.PubMedCrossRefGoogle Scholar
  22. 22.
    Shimazu R, Akashi S, Ogata H, et al. MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. J Exp Med 1999;189:1777–1782.PubMedCrossRefGoogle Scholar
  23. 23.
    Latz E, Visintin A, Lien E, et al. Lipopolysaccharide Rapidly traffics to and from the Golgi apparatus with the toll-like receptor 4-MD2-CD14 complex in a process that is distinct from the initiation of signal transduction. J Biol Chem 2002;277:47834–47843.PubMedCrossRefGoogle Scholar
  24. 24.
    Akira S, Takeda K. Toll-like receptor signaling. Nat Rev Immunol 2004;4:499–511.PubMedCrossRefGoogle Scholar
  25. 25.
    Ingalls RR, Golenbock DT. CD11c/CD18, a transmembrane signaling receptor for lipopolysaccharide. J Exp Med 1995;181:1473–1479.PubMedCrossRefGoogle Scholar
  26. 26.
    Inohara N, Ogura Y, Chen FF, Muto A, Nunez G. Human Nod1 confers responsiveness to bacterial lipopolysaccharides. J Biol Chem 2001;276:2551–2554.PubMedCrossRefGoogle Scholar
  27. 27.
    Hopkins P, Sriskandan S. Mammalian toll-like receptors: to immunity and beyond. Clin Exp Immunol 2005;140:395–407.PubMedCrossRefGoogle Scholar
  28. 28.
    Iwasaki A, Medzhitov R. Toll-like receptor control of the adaptive immune responses. Nat Immunol 2004;5:987–995.PubMedCrossRefGoogle Scholar
  29. 29.
    Beutler B. Inferences, questions and possibilities in Toll-like receptor signalling. Nature 2004;430:257–263.PubMedCrossRefGoogle Scholar
  30. 30.
    Fleming A. Lysozyme. Proc R Soc London B Biol Sci 1922;93:306–317.CrossRefGoogle Scholar
  31. 31.
    Canny G, Levy O, Furuta GT, et al. Lipid mediator-induced expression of bactericidal/ permeability-increasing protein (BPI) in human mucosal epithelia. Proc Natl Acad Sci U S A. 2002;99:3902–3907.PubMedCrossRefGoogle Scholar
  32. 32.
    Lee JY, Boman A, Chuanxin S, et al. Antibacterial peptides from pig intestine: isolation of a mammalian cecropin. Proc Natl Acad Sci U S A 1989;86:9159–9162.PubMedCrossRefGoogle Scholar
  33. 33.
    Zasloff M. Antimicrobial peptides of multicellular organisms. Nature 2002;415:389–395.PubMedCrossRefGoogle Scholar
  34. 34.
    Singh PK, Parsek MR, Greenberg EP, Welsh MJ. A component of innate immunity prevents bacterial biofilm development. Nature 2002;417:552–554.PubMedCrossRefGoogle Scholar
  35. 35.
    Kaiser V, Diamond G. Expression of mammalian defensin genes. J Leukoc Biol 2000;68:779–784.PubMedGoogle Scholar
  36. 36.
    Giacometti A, Cirioni O, Ghiselli R, et al. Effect of mono-dose intraperitoneal cecropins in experimental septic shock. Crit Care Med 2001;29:1666–1669.PubMedCrossRefGoogle Scholar
  37. 37.
    Walport MJ. Complement. New Engl J Med 2001;344:1058–1066.PubMedCrossRefGoogle Scholar
  38. 38.
    Shin HS, Snyderman R, Friedman E, et al. Chemotactic and anaphylatoxic fragment cleaved from the fifth component of guinea pig complement. Science 1968;162:361–363.PubMedCrossRefGoogle Scholar
  39. 39.
    Goldstein IM, Weissmann G. Generation of C5-derived lysosomal enzyme-releasing activity (C5a) by lysates of leukocyte lysosomes. J Immunol 1974;113:1583–1588.PubMedGoogle Scholar
  40. 40.
    Sacks T, Moldow CF, Craddock PR, Bowers TK, Jacob HS. Oxygen radicals mediate endothelial cell damage by complement-stimulated granulocytes. An in vitro model of immune vascular damage. J Clin Invest 1978;61:1161–1167.PubMedCrossRefGoogle Scholar
  41. 41.
    Huber-Lang MS, et al. Complement-induced impairment of innate immunity during sepsis. J Immunol 2002;169:3223–3231.PubMedGoogle Scholar
  42. 42.
    Riedemann NC. Increased C5a receptor expression in sepsis. J Clin Invest 2002;110:101–108.PubMedGoogle Scholar
  43. 43.
    Stevens JH, et al. Effects of anti-C5a antibodies on the adult respiratory distress syndrome in septic primates. J Clin Invest 1986;77:1812–1816.PubMedCrossRefGoogle Scholar
  44. 44.
    Czermak BJ, et al. Protective effects of C5a blockade in sepsis. Nat Med 1999;5:788–792.PubMedCrossRefGoogle Scholar
  45. 45.
    Palmer RMJ, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987;327:524–526.PubMedCrossRefGoogle Scholar
  46. 46.
    Annane D, Sanquer S, Sebille V, et al. Compartmentalised inducible nitric-oxide synthase activity in septic shock. Lancet 2000;355:1143–1148.PubMedCrossRefGoogle Scholar
  47. 47.
    Imhof BA, Aurrand-Lions M. Adhesion mechanisms regulating the migration of monocytes. Nat Rev Immunol 2004;4:432–444.PubMedCrossRefGoogle Scholar
  48. 48.
    Eichacker PQ, Hoffman WD, Farese A, et al. Leukocyte CD18 monoclonal antibody worsens endotoxemia and cardiovascular injury in canines with septic shock. J Appl Physiol 1993;74:1885–1892.PubMedCrossRefGoogle Scholar
  49. 49.
    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;27:913–922.PubMedCrossRefGoogle Scholar
  50. 50.
    Hesselvik FJ, Blomback M, Brodin B, Maller R. Coagulation, fibrinolysis and kallikrein systems in sepsis: relation to outcome. Crit Care Med 1989; 17:724–733.PubMedCrossRefGoogle Scholar
  51. 51.
    Gando S, Nanzaki S, Sasaki S, Aoi K, Kemmotsu O. Activation of the extrinsic coagulation pathway in patients with severe sepsis and septic shock. Crit Care Med 1998;26:2005–2009.PubMedCrossRefGoogle Scholar
  52. 52.
    Fourrier F, Chopin C, Goudemand J, et al. Septic shock, multi-organ failure, and disseminated intravascular coagulation: compared to patterns of antithrombin III, protein C and protein S deficiencies. Chest 1992;101:816–823.PubMedCrossRefGoogle Scholar
  53. 53.
    Levi M, ten Cate H, van der Poll T, van Deventer SJH. Pathogenesis of disseminated intravascular coagulation in sepsis. JAMA 1993;270:975–979.PubMedCrossRefGoogle Scholar
  54. 54.
    Yan SB, Helterbrand JD, Hartman DL, Wright TJ, Bernard GR. Low levels of protein C are associated with poor outcome in severe sepsis. Chest 2001;120:915–922.PubMedCrossRefGoogle Scholar
  55. 55.
    Smith OP, White B, Vaughan D, et al. Use of protein-C concentrate, heparin, and haemodiafiltration in meningococcus-induced purpura fulminans. Lancet 1997;350:1590–1593.PubMedCrossRefGoogle Scholar
  56. 56.
    Rintala E, Seppala O-P, Kotilainen P, Pettila V, Rasi V. Protein C in the treatment of coagulopathy in meningococcal disease. Crit Care Med 1998;26:965–968.PubMedCrossRefGoogle Scholar
  57. 57.
    Bernard GR, Vincent JL, Laterre PF, et al. Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699–709.PubMedCrossRefGoogle Scholar
  58. 58.
    Hampton MB, Kettle AJ, Winterbourn CC. Inside the neutrophil phagosome: oxidants, myeloperoxidase, and bacterial killing. Blood 1998;92:3007–3017.PubMedGoogle Scholar
  59. 59.
    Tellado JM, Christou NV. Critically ill anergic patients demonstrate polymorphonuclear neutrophil activation in the intravascular compartment with decreased cell delivery to inflammatory foci. J Leukoc Biol 1991;50:547–553.PubMedGoogle Scholar
  60. 60.
    Simms HH, D’Amico R. Polymorphonuclear leukocyte dysregulation during the systemic inflammatory response syndrome. Blood 1994;83:1398–1407.PubMedGoogle Scholar
  61. 61.
    Steinberg KP, Milberg JA, Martin TR, Maunder RJ, Cockrill BA, Hudson LD. Evolution of bronchoalveolar cell populations in the adult respiratory distress syndrome. Am J Respir Crit Care Med 1994;150:113–122.PubMedGoogle Scholar
  62. 62.
    Belaaouaj A, McCarthy R, et al. Mice lacking neutrophil elastase reveal impaired host defense against Gram-negative bacterial sepsis. Nat Med 1998; 4:615–618.PubMedCrossRefGoogle Scholar
  63. 63.
    Kuang-Yao Y, Arcaroli JJ, Abraham E. Early alterations in neutrophil activation are associated with outcome in acute lung injury. Am J Resp Crit Care Med 2003;167:1567–1574.CrossRefGoogle Scholar
  64. 64.
    Fingerle G, Pforte A, Passlick B, et al. The novel subset of CD14+/CD16+ blood monocytes is expanded in sepsis patients. Blood 1993;82:3170–3176.PubMedGoogle Scholar
  65. 65.
    Belge K, Dayyani F, Horelt A, et al. The proinflammatory CD14+CD16+DR++ monocytes are a major source of TNF. J Immunol 2002;168:3536–3542.PubMedGoogle Scholar
  66. 66.
    Geissmann F, Jung S, Littman DR. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 2003;19:71–82.PubMedCrossRefGoogle Scholar
  67. 67.
    Lin RY, Astiz ME, Saxon JC, et al. Altered leukocyte immunophenotypes in septic shock: studies of HLA-DR, CD11b, CD14 and IL-2R expression. Chest 1993;104:847–853.PubMedCrossRefGoogle Scholar
  68. 68.
    Adib-Conquy M, Adrie C, Moine P, et al. NF-kB expression in mononuclear cells of septic patients resembles that observed in LPS tolerance. Am J Respir Crit Care Med 2000;162:1877–1883.PubMedGoogle Scholar
  69. 69.
    Stout RD, Suttles J. Functional plasticity of macrophages: reversible adaptation to changing microenvironments. J Leuk Biol 2004;76:509–513.CrossRefGoogle Scholar
  70. 70.
    MacConmara M, Lederer JA. B cells. Crit Care Med 2005;33:S514–S516.PubMedCrossRefGoogle Scholar
  71. 71.
    Hotchkiss RS, Tinsley KW, Swanson PE, et al. Sepsis-induced apoptosis causes progressive profound depletion of B and CD4+ T lymphocytes in humans. J Immunol 2001;166:6952–6963.PubMedGoogle Scholar
  72. 72.
    Meakins JL, Pietsch JB, Bubenick O, et al. Delayed hypersensitivity: indicator of acquired failure of host defenses in sepsis and trauma. Ann Surg 1997; 186:241–250.Google Scholar
  73. 73.
    Heidecke CD, Hensler T, Weighardt H, et al. Selective defects of T lymphocyte function in patients with lethal intraabdominal infection. Am J Surg 1999;178:288–292.PubMedCrossRefGoogle Scholar
  74. 74.
    Venet F, Bohe J, Debard A-L, Bienvenu J, Lepape A, Monneret G. Both percentage of gamma-delta cells and CD3 expression are reduced during septic shock. Crit Care Med 2005;33:2836–2840.PubMedCrossRefGoogle Scholar
  75. 75.
    Hotchkiss RS, et al. Prevention of lymphocyte cell death in sepsis improves survival in mice. Proc Natl Acad Sci U S A 1999;96:14541–14546.PubMedCrossRefGoogle Scholar
  76. 76.
    Hotchkiss RS, et al. Adoptive transfer of apoptotic splenocytes worsens survival, whereas adoptive transfer of necrotic splenocytes improves survival in sepsis. Proc Natl Acad Sci U S A 2003;100:6724–6729.PubMedCrossRefGoogle Scholar
  77. 77.
    Coopersmith CM, et al. Inhibition of intestinal epithelial apoptosis and survival in a murine model of pneumonia-induced sepsis. JAMA 2002;287:1716–1721.PubMedCrossRefGoogle Scholar
  78. 78.
    Michie HR, Manogue KR, Spriggs DR, et al. Detection of circulating tumour necrosis factor after endotoxin administration. N Engl J Med 1988;318:1481–1486.PubMedCrossRefGoogle Scholar
  79. 79.
    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;322:1622–1627.PubMedCrossRefGoogle Scholar
  80. 80.
    Hanasaki K, Yokota Y, Ishizaki J, Itoh T, Arita H. Resistance to endotoxic shock in phospholipase A2 receptor-deficient mice. J Biol Chem 1997;272:32792–32797.PubMedCrossRefGoogle Scholar
  81. 81.
    Beutler B, Milsark IW, Cerami AC. Passive immunization against cachectin/tumour necrosis factor protects mice from lethal effect of endotoxin. Science 1985;229:869–871.PubMedCrossRefGoogle Scholar
  82. 82.
    Tracey KJ, Fong Y, Hesse DG, et al. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature 1987;330:662–664.PubMedCrossRefGoogle Scholar
  83. 83.
    Opal SM, Cross AS, Kelly NM, et al. Efficacy of a monoclonal antibody directed against tumor necrosis factor in protecting neutropenic rats from lethal infection with Pseudomonas aeruginosa. J Infect Dis 1990;161:1148–1152.PubMedGoogle Scholar
  84. 84.
    Bernhagen J, Calandra T, Mitchell RA, et al. MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia. Nature 1993;365:756–759.PubMedCrossRefGoogle Scholar
  85. 85.
    Roger T, David J, Glauser MP, Calandra T. MIF regulates innate immune responses through modulation of Toll-like receptor 4. Nature 2001;414:920–924.PubMedCrossRefGoogle Scholar
  86. 86.
    Wang H, et al. HMG-1 as a late mediator of endotoxin lethality in mice. Science 1999;285:248–251.PubMedCrossRefGoogle Scholar
  87. 87.
    Holmes WE, Lee J, Kuang WJ, Rice GC, Wood WI. Structure and functional expression of a human interleukin-8 receptor. Science 1991;253:1278–1280.PubMedCrossRefGoogle Scholar
  88. 88.
    Harbarth S, Holeckova K, Froidevaux C, et al., and the Geneva Sepsis Network. Diagnostic value of procalcitonin, interleukin-6, and interleukin-8 in critically ill patients admitted with suspected sepsis. Am J Respir Crit Care Med 2001;164:396–402.PubMedGoogle Scholar
  89. 89.
    Chishti AD, Shenton BK, Kirby JA, Baudouin SV. Neutrophil chemotaxis and receptor expression in clinical septic shock. Intensive Care Med 2004;30:605–611.PubMedCrossRefGoogle Scholar
  90. 90.
    Egger G, Aigner R, Glasner A, Hofer HP, Mitterhammer H, Zelzer S. Blood polymorphonuclear leukocyte migration as a predictive marker for infections in severe trauma: comparison with various inflammation parameters. Intensive Care Med 2004;30:331–334.PubMedCrossRefGoogle Scholar
  91. 91.
    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
  92. 92.
    Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. New Engl J Med 2001;345:1368–1377.PubMedCrossRefGoogle Scholar
  93. 93.
    Hayes MA, Timmins AC, Yau EH, Palazzo M, Hinds CJ, Watson D. Elevation of systemic oxygen delivery in the treatment of critically ill patients. N Engl J Med 1994;330:1717–1722.PubMedCrossRefGoogle Scholar
  94. 94.
    Gattinoni L, Brazzi L, Pelosi P, et al. A trial of goal-oriented hemodynamic therapy in critically ill patients. SvO2 Collaborative Group. N Engl J Med 1995;333:1025–1032.PubMedCrossRefGoogle Scholar
  95. 95.
    Yu M, Levy MM, Smith P, Takiguchi SA, Miyasaki A, Myers SA. Effect of maximizing oxygen delivery on morbidity and mortality rates in critically ill patients: a prospective, randomized, controlled study. Crit Care Med 1993;21:830–838.PubMedCrossRefGoogle Scholar
  96. 96.
    Shands JW Jr, McKimmey C. Plasma endotoxin: increased levels in neutropenic patients do not correlate with fever. J Infect Dis 1989;159:777–780.PubMedGoogle Scholar
  97. 97.
    Danner RL, Elin RJ, Hosseini JM, et al. Endotoxemia in human septic shock. Chest 1991;99:169–175.PubMedCrossRefGoogle Scholar
  98. 98.
    Donnelly TJ, Meade P, Jagels M, et al. Cytokine, complement, and endotoxin profiles associated with the development of the adult respiratory distress syndrome after severe injury. Crit Care Med 1994;22:768–776.PubMedCrossRefGoogle Scholar
  99. 99.
    Guidet B, Barakett V, Vassal T, et al. Endotoxaemia and bacteraemia in patients with sepsis syndrome in the intensive care unit. Chest 1994;106:1194–1201.PubMedCrossRefGoogle Scholar
  100. 100.
    Venet C, Zeni F, Viallon A, et al. Endotoxaemia in patients with severe sepsis or septic shock. Intensive Care Med 2000;26:538–544.PubMedCrossRefGoogle Scholar
  101. 101.
    Hurley JC. Endotoxemia and Gram-negative bacteremia as predictors of outcome in sepsis: a meta-analysis using ROC curves. J Endotoxin Res 2003;9:271–279.PubMedGoogle Scholar
  102. 102.
    Danner RL, Natanson C, Elin RJ, et al. Pseudomonas aeruginosa compared with Escherichia coli produces less endotoxemia but more cardiovascular dysfunction and mortality in a canine model of septic shock. Chest 1990;98:1480–1487.PubMedCrossRefGoogle Scholar
  103. 103.
    Hoffman WD, Danner RL, Quezado ZM, et al. Role of endotoxemia in cardiovascular dysfunction and lethality: virulent and nonvirulent Escherichia coli challenges in a canine model of septic shock. Infect Immun 1996;64:406–412.PubMedGoogle Scholar
  104. 104.
    Koike K, Moore EE, Moore FA, Read RA, Carl VS, Banerjee A. Gut ischemia/reperfusion produces lung injury independent of endotoxin. Crit Care Med 1994;22:1438–1444.PubMedCrossRefGoogle Scholar
  105. 105.
    Charpentier C, Audibert G, Dousset B, et al. Is endotoxin and cytokine release related to a decrease in gastric intramucosal pH after hemorrhagic shock? Intensive Care Med 1997;23:1040–1048.PubMedCrossRefGoogle Scholar
  106. 106.
    Calandra T, Glauser MP, Schellekens J, et al. Treatment of Gram-negative septic shock with human IgG antibody to Escherichia coli J5: a prospective, double-blind, randomised trial. J Infect Dis 1998;158:312–318.Google Scholar
  107. 107.
    Greenman RL, Schein RM, Martin MA, et al. A controlled clinical trial of E5 murine monoclonal IgM antibody to endotoxin in the treatment of Gram-negative sepsis: the XOMA Sepsis Study Group. JAMA 1991;266:1097–1102.PubMedCrossRefGoogle Scholar
  108. 108.
    Schedel I, Dreikhausen U, Nentwig B, et al. Treatment of Gram-negative septic shock with an immunoglobulin preparation: a prospective, randomized clinical trial. Crit Care Med 1991;19:1104–1113.PubMedCrossRefGoogle Scholar
  109. 109.
    Cornetta A, Baumgartner JD, Lee ML, et al. Prophylactic intravenous administration of standard immune globulin as compared with core-lipopolysaccharide immune globulin in patients at high risk of postsurgical infection. N Engl J Med 1992;327:234–240.CrossRefGoogle Scholar
  110. 110.
    McClosky RV, Straube RC, Sanders C, et al. Treatment of septic shock with human monoclonal antibody HA-1A: a randomised, double blind, placebo controlled trial. CHESS Trial Study Group. Ann Intern Med 1994;121:1–5.Google Scholar
  111. 111.
    Angus DC, Birmingham MC, Balk RA, et al. E5 murine monoclonal anti-endotoxin antibody in gram-negative sepsis: a randomised controlled trial; E5 Study Investigators. JAMA 2000;l283:1723–1730.CrossRefGoogle Scholar
  112. 112.
    Albertson TE, Panacek EA, MacArthur RD, et al. Multicenter evaluation of a human monoclonal antibody to Enterobacteriaceae common antigen in patients with Gram-negative sepsis. Crit Care Med 2003;31:419–427.PubMedCrossRefGoogle Scholar
  113. 113.
    Suzuki T, Hashimoto S, Toyoda N, et al. Comprehensive gene expression profile of LPS-stimulated human monocytes by SAGE. Blood 2000;96:2584–2591.PubMedGoogle Scholar
  114. 114.
    Bjorkbacka H, Fitzgerald, KA, Huet F, et al. The induction of macrophage gene expression by LPS predominantly utilizes MyD88-independent signalling cascades. Physiol Genomics 2004;19:319–330.PubMedCrossRefGoogle Scholar
  115. 115.
    Remick DG, Newcombe DE, Bolgos GL, et al. Comparison of the mortality and inflammatory response of two models of sepsis: lipopolysaccharide vs cecal ligation and puncture. Shock 2000;13:110–116.PubMedCrossRefGoogle Scholar
  116. 116.
    Echtenacher B, Freudenberg MA, Jack RS, et al. Differences in innate defense mechanisms in endotoxaemia and polymicrobial septic peritonitis. Infect Immun 2001;69:7271–7276.PubMedCrossRefGoogle Scholar
  117. 117.
    Haziot A, Rong GW, Lin XY, Silver J, Goyert SM. Recombinant soluble CD14 prevents mortality in mice treated with endotoxin (lipopolysaccharide). J Immunol 1995;154:6529–6532.PubMedGoogle Scholar
  118. 118.
    Jack RS, Fan XL, Bernheiden M, et al. Lipopolysaccharide-binding protein is required to combat a Gram-negative bacterial infection. Nature 1997;389:742–745.PubMedCrossRefGoogle Scholar
  119. 119.
    Le Roy D, Di Padova F, Tees R, et al. Monoclonal antibodies to murine lipopolysaccharide (LPS)-binding protein (LBP) protect mice from lethal endotoxaemia by blocking either the binding of LPS to LBP or the presentation of LPS/LBP complexes to CD14. J Immunol 1999;162:7454–7460.PubMedGoogle Scholar
  120. 120.
    Schmicke J, Mathison J, Morgiewicz J, Ulevitch RJ. Anti-CD14 mAb treatment provides therapeutic benefit after exposure to endotoxin. Proc Natl Acad Sci U S A 1998;95:13875–13880.CrossRefGoogle Scholar
  121. 121.
    Leturcq D, Moriarty AM, Talbott G, Winn RK, Martin TR, Ulevitch RJ. Antibodies against CD14 protect primates from endotoxin-induced shock. J Clin Invest 1996;98:1533–1538.PubMedCrossRefGoogle Scholar
  122. 122.
    Cross A, Asher L, Seguin M, et al. The importance of a lipopolysaccharide-initiated, cytokine-mediated host defense mechanism in mice against extraintestinal invasive Escherichia coli. J Clin Invest 1995;96:676–686.PubMedCrossRefGoogle Scholar
  123. 123.
    Wenneras C, Ave P, Huerre M, et al. Blockade of CD14 increases Shigella-mediated invasion and tissue destruction. J Immunol 2000;164:3214–3221.PubMedGoogle Scholar
  124. 124.
    Le Roy D, Di Padova F, Adachi Y, Glauser MP, Calandra T, Heumann D. Critical role of lipopolysaccharide-binding protein and CD14 in immune responses against gram-negative bacteria. J Immunol 2001;167:2759–2765.PubMedGoogle Scholar
  125. 125.
    Arbour NC, Lorenz E, Schutte BC, et al. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet 2000;25:187–191.PubMedCrossRefGoogle Scholar
  126. 126.
    Verbon A, Dekkers PE, ten Hove T, et al. IC14, an anti-CD14 antibody, inhibits endotoxin-mediated symptoms and inflammatory responses in humans. J Immunol 2001;166:3599–3605.PubMedGoogle Scholar
  127. 127.
    Hagberg L, Briles DE, Eden CS. Evidence for separate genetic defects in C3H/HeJ and C3HeB/FeJ mice, that affect susceptibility to gram-negative infections. J Immunol 1995;134:4118–4122.Google Scholar
  128. 128.
    Takeuchi O, Hoshino K, Akira S. Cutting edge: TLR2-deficient and MyD88-deficient mice are highly susceptible to Staphylococcus aureus infection. J Immunol 2000;165:5392–5396.PubMedGoogle Scholar
  129. 129.
    Medvedev AE, Lentschat A, Kuhns DB, et al. Distinct mutations in IRAK-4 confer hyporesponsiveness to lipopolysaccharide and interleukin-1 in a patient with recurrent bacterial infections. J Exp Med 2003;198:521–531.PubMedCrossRefGoogle Scholar
  130. 130.
    Hawn TR, Verbon A, Lettinga KD, et al. A common dominant TLR5 stop codon polymorphism abolishes flagellin signaling and is associated with susceptibility to legionnaires’ disease. J Exp Med 2003;198:1563–1572.PubMedCrossRefGoogle Scholar
  131. 131.
    de Groote MA, Martin MA, Densen P, et al. Plasma tumour necrosis factor levels in patients with presumed sepsis: results in those treated with antilipid A antibody vs placebo. JAMA 1989;262:249–251.PubMedCrossRefGoogle Scholar
  132. 132.
    Calandra T, Baumgartner JD, Grau GE, et al. Prognostic values of tumour necrosis factor/cachectin, interleukin-1, interferon-alpha, and interferon-gamma in the serum of patients with septic shock. Swiss-Dutch J5 immunoglobulin study group. J Infect Dis 1990;161:982–987.PubMedGoogle Scholar
  133. 133.
    Marano MA, Fong Y, Moldawer LL, et al. Serum cachectin/tumour necrosis factor in critically ill patients with burns correlates with infection and mortality. Surg Gynecol Obstet 1990;170:32–38.PubMedGoogle Scholar
  134. 134.
    Pinsky MR, Vincent JL, Deviere J, et al. Serum cytokine levels in human septic shock: relation to multiple-system organ failure and mortality. Chest 1993;103:565–575.PubMedCrossRefGoogle Scholar
  135. 135.
    Debets JM, Kampmeijer R, van der Linden MP, et al. Plasma tumour necrosis factor and mortality in critically-ill septic patients. Crit Care Med 1989;17:489–494.PubMedCrossRefGoogle Scholar
  136. 136.
    Damas P, Reuter A, Gysen P, et al. Tumour necrosis factor and interleukin-1 serum levels during severe sepsis in humans. Crit Care Med 1989;17:975–978.PubMedCrossRefGoogle Scholar
  137. 137.
    Lehmann LE, Novender U, Schroeder S, et al. Plasma levels of macrophage migration inhibitory factor are elevated in patients with severe sepsis. Intensive Care Med 2001;27:412–415.CrossRefGoogle Scholar
  138. 138.
    Knaus WA, Harrel FE, LaBreque JF, et al. Predicted risk of mortality to evaluate the efficacy of anticytokine therapy in sepsis. Crit Care Med 1996;24:46–56.PubMedCrossRefGoogle Scholar
  139. 139.
    Zeni F, Freeman B, Natanson C. Inflammatory therapies to treat sepsis and septic shock: a reassessment. Crit Care Med 1997;25:1095–1100.PubMedCrossRefGoogle Scholar
  140. 140.
    van Dissel JT, van Langevelde P, Westendorp RG, Kwappenberg K, Frolich M. Anti-inflammatory cytokine profile and mortality in febrile patients. Lancet 1998;351:950–953.PubMedGoogle Scholar
  141. 141.
    Taniguchi T, Koido Y, Aiboshi J, Yamashita T, Suzaki S, Kurokawa A. The ratio of interleukin-6 to interleukin-10 correlates with severity in patients with chest and abdominal trauma. Am J Emerg Med 1999;17:548–551.PubMedCrossRefGoogle Scholar
  142. 142.
    Eickacker PQ, Parent C, Kalil A, et al. Risks and the efficacy of anti-inflammatory agents:retrospective and confirmatory studies of sepsis. Am J Respir Crit Care Med 2002;166:1197–1205.CrossRefGoogle Scholar
  143. 143.
    Girardin E, Grau GE, Dayer JM, Roux-Lombard P, Lambert PH. Tumor necrosis factor and interleukin-1 in the serum of children with severe infectious purpura. N Engl J Med 1998;319:397–400.CrossRefGoogle Scholar
  144. 144.
    Eskandari MK, Bolgos G, Miller C, Nguyen DT, DeForge LE, Remick DG. Anti-tumor necrosis factor antibody therapy fails to prevent lethality after cecal ligation and puncture or endotoxemia. J Immunol 1992;148:2724–2730.PubMedGoogle Scholar
  145. 145.
    Oberholzer A, Harter L, Feilner A, Steckholzer U, Trentz O, Ertel W. Differential effect of caspase inhibition on proinflammatory cytokine release in septic patients. Shock 2000;14:253–257.PubMedCrossRefGoogle Scholar
  146. 146.
    Stueber F, Peterson M, Bokelmann F, et al. A genomic polymorphism within the tumour necrosis factor locus influences plasma tumour necrosis factor-alpha concentrations and outcome of patients with severe sepsis. Crit Care Med 1996;24:381–384.CrossRefGoogle Scholar
  147. 147.
    Gordon AC, Lagan AL, Aganna E, et al. TNF and TNFR polymorphisms in severe sepsis and septic shock: a prospective multicentre study. Genes Immun 2004;5:631–640.PubMedCrossRefGoogle Scholar
  148. 148.
    Fischer CJ Jr, Opal SM, Dhainaut JF, et al. Influence of an anti-tumor necrosis factor mononuclear antibody on cytokine levels in patients with sepsis. The CB0006 Sepsis Syndrome Study Group. Crit Care Med 1993;21:318–327.CrossRefGoogle Scholar
  149. 149.
    Abraham E, Wunderink R, Silverman H, et al. Efficacy and safety of monoclonal antibody to human tumour necrosis factor alpha in patients with sepsis syndrome: a randomised, controlled, double-blind, multicentrer clinical trial. TNF-alpha Mab Sepsis Study Group. JAMA 1995;273:934–941.PubMedCrossRefGoogle Scholar
  150. 150.
    Reinhart K, Wiegland-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, randomised, placebo-controlled, dose-ranging study. Crit Care Med 1996;24:733–742.PubMedCrossRefGoogle Scholar
  151. 151.
    Opal SM, Fischer CJ, Dhainaut JF, 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;25:1115–1124.PubMedCrossRefGoogle Scholar
  152. 152.
    Warren BL, Eid A, Singer P, et al., and the KyberSept Trial Study Group. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 2001;286:1869–1878.PubMedCrossRefGoogle Scholar
  153. 153.
    Dhainaut JF, Tenaillon A, Hemmer M, et al. Confirmatory platelet-activating factor antagonist trial in patients with severe gram-negative bacterial sepsis: a phase III, randomised, double-blind, placebo-controlled, multicentre trial. BN 52021 Sepsis Investigator Group. Crit Care Med 1998;26:1927–1931.CrossRefGoogle Scholar
  154. 154.
    Abraham E, Reinhart K, Opal S, et al. OPTIMIST trial study group. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis. JAMA 2003;290:238–247.PubMedCrossRefGoogle Scholar
  155. 155.
    Lopez A, Lorente JA, Steingrub J, et al. Multiple-centre, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: effect on survival in patients with septic shock. Crit Care Med 2004;32:21–30.PubMedCrossRefGoogle Scholar
  156. 156.
    Ertel W, Keel M, Bonaccio M, et al. Release of anti-inflammatory mediators after mechanical trauma correlates with severity of injury and clinical outcome. J Trauma 1995;39:879–885.PubMedCrossRefGoogle Scholar
  157. 157.
    Munford RS, Pugin J. Normal responses to injury prevent systemic inflammation and can be immunosuppressive. Am J Respir Crit Care Med 2001;163:316–321.PubMedGoogle Scholar
  158. 158.
    Ayala A, Song GY, Chung CS, Redmond KM, Chaudry IH. Immune depression in polymicrobial sepsis: the role of necrotic (injured) tissue and endotoxin. Crit Care Med 2000;28:2949–2955.PubMedCrossRefGoogle Scholar
  159. 159.
    Hartemink KJ, Paul MA, Spijkstra JJ, Girbes AR, Polderman KH. Immunoparalysis as a cause for invasive aspergillosis? Intensive Care Med 2003;29:2068–2071.PubMedCrossRefGoogle Scholar
  160. 160.
    Benjamin CF, Hogaboam CM, Kunkel SL. The chronic consequences of severe sepsis. J Leukoc Biol 2004;75:408–412.CrossRefGoogle Scholar
  161. 161.
    Kollef MH, Sherman G, Ward S, et al. Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality amoung critically ill patients. Chest 1999;115:462–474.PubMedCrossRefGoogle Scholar
  162. 162.
    Harbarth S, Garbonio J, Pugin J, et al. Inappropriate initial antimicrobial therapy and its effect on survival in a clinical trial of immunomodulating therapy for severe sepsis. Am J Med 2003;115:529–535.PubMedCrossRefGoogle Scholar
  163. 163.
    Leroy O, Meybeck A, d’Escrivan T, et al. Impact of adequacy of initial antimicrobial therapy on the prognosis of patients with ventilator-associated pneumonia. Intensive Care Med 2003;29:2170–2173.PubMedCrossRefGoogle Scholar
  164. 164.
    Bochud P-Y, Bonten M, Marchetti O, et al. Antimicrobial therapy for patients with severe sepsis and septic shock: an evidence based review. Crit Care Med 2004;32:S495–S512.PubMedCrossRefGoogle Scholar
  165. 165.
    Rello J, Ausina V, Ricart M, et al. Impact of previous antimicrobial therapy on the aetiology and outcome of ventilator-associated pneumonia. Chest 1993;104:1230–1235.PubMedCrossRefGoogle Scholar
  166. 166.
    Kollef MH. Ventilator-associated pneumonia: a multivariate analysis. JAMA 1993;270:1965–1970.PubMedCrossRefGoogle Scholar
  167. 167.
    Hanberger H, Garcia-Rodriguez JA, Gobernado M, et al. Antibiotic susceptibility among aerobic Gram-negative bacilli in intensive care units in 5 european countries. JAMA 1995;281:67–71.CrossRefGoogle Scholar
  168. 168.
    Lepper PM, Held TK, Schneider EM, Bolke E, Gerlach H, Trautmann. Clinical implications of antibiotic-induced endotoxin release in septic shock. Intensive Care Med 2002;28:824–833.PubMedCrossRefGoogle Scholar
  169. 169.
    van Saene HK, Petros AJ, Ramsay G, Baxby D. All great truths are iconoclastic: selective decontamination of the digestive tract moves from heresy to level 1 truth. Intensive Care Med 2003;29:677–690.PubMedGoogle Scholar
  170. 170.
    Kollef MH. Selective digestive decontamination should not be routinely employed. Chest 2003;123(5 Suppl):464S–468S.PubMedCrossRefGoogle Scholar
  171. 171.
    de Jonge E, Schultz MJ, Spanjaard L, et al. Effects of selective decontamination of digestive tract on mortality and acquisition of resistant bacteria in intensive care: a randomised controlled trial. Lancet 2003;362:1011–1016.PubMedCrossRefGoogle Scholar
  172. 172.
    O’Suilleabhain C, O’Sullivan ST, Kelly JL, Lederer J, Mannick JA, Rodrick ML. Interleukin-12 treatment restores normal resistance to bacterial challenge after burn injury. Surgery 1996;120:290–296.PubMedCrossRefGoogle Scholar
  173. 173.
    Nelson S, Belknap SM, Carlson RW, et al. A randomized controlled trial of filgrastim as an adjunct to antibiotics for treatment of hospitalized patients with community-acquired pneumonia. J Infect Dis 1998;178:1075–1080.PubMedCrossRefGoogle Scholar
  174. 174.
    Root RK, Marrie TJ, Lodato RF, et al. A multicentre, double-blind, placebo-controlled study of the use of filgrastim in patients hospitalized with pneumonia and severe sepsis. Crit Care Med 2003;31:367–373.PubMedCrossRefGoogle Scholar
  175. 175.
    Benjamin CF, Lundy SK, Lukacs NW, Hogaboam CM, Kunkel SL. Reversal of long-term sepsis-induced immunosuppression by dendritic cells. Blood 2005;105:3588–3595.CrossRefGoogle Scholar
  176. 176.
    Silva AT, Cohen J. Role of interferon-gamma in experimental gram-negative sepsis. J Infect Dis 1992;166:331–335.PubMedGoogle Scholar
  177. 177.
    Ertel W, Morrison MH, Ayala A, Dean RE, Chaudry IH. Interferon-gamma attenuates hemorrhage-induced suppression of macrophage and splenocyte functions and decreases susceptibility to sepsis. Surgery 1992;111:177–187.PubMedGoogle Scholar
  178. 178.
    Docke WD, Randow F, Syrbe U, et al. Monocyte deactivation in septic patients: restoration by IFN-gamma treatment. Nat Med 1997;3:678–681.PubMedCrossRefGoogle Scholar
  179. 179.
    Houdijk AP, Rijnsburger ER, Jansen J, et al. Randomised trial of glutamine-enriched enteral nutrition on infectious morbidity in patients with multiple trauma. Lancet 1998;352:772–776.PubMedCrossRefGoogle Scholar
  180. 180.
    Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. New Engl J Med 2001;345:1359–1367.PubMedCrossRefGoogle Scholar
  181. 181.
    Tsuneyoshi I, Yamada H, Kakihana Y, Nakamura M, Nakano Y, Boyle W 3rd. Hemodynamic and metabolic effects of low-dose vasopressin infusions in vasodilatory septic shock. Crit Care Med 2001;29:487–493.PubMedCrossRefGoogle Scholar
  182. 182.
    Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288:862–871.PubMedCrossRefGoogle Scholar
  183. 183.
    Heyland DK, Dhaliwal R, Suchner U, Berger MM. Antioxidant nutrients: a systematic review of trace elements and vitamins in the critically ill patient. Intensive Care Med 2005;31:327–337.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Mike Darwin
    • 1
  • Phil Hopkins
    • 2
  1. 1.Independent Critical Care ConsultantAsh ForkUSA
  2. 2.ICU Consultant, Department of Critical CareKings College HospitalLondonUK

Personalised recommendations