Skip to main content
SpringerLink
Log in

The multiple organ dysfunction syndrome and late-phase mortality in sepsis

  • Published:
Current Infectious Disease Reports Aims and scope Submit manuscript

Abstract

Sepsis is a devastating and common syndrome characterized by systemic inflammation. Sepsis accounts for considerable morbidity and mortality among intensive care unit patients. Although the inflammatory response generated by the immune system represents the body’s attempt to clear invading pathogens, it is the failure to modulate this response that leads to dysregulated inflammation and the injury of healthy tissue. A great deal of research has characterized many of the early events and mediators that lead to systemic inflammation and sepsis. However, substantially less is known about the pathogenesis of the late phase of sepsis, which accounts for the vast majority of sepsisrelated mortality (ie, the dysfunction and subsequent failure of the major parenchymal organs).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Levy MM, Fink MP, Marshall JC, et al.: 2001 SCCM/ESICM/ ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003, 31:1250–1256.

    Article  PubMed  Google Scholar 

  2. FinkMP: Cytopathic hypoxia. Mitochondrial dysfunction as mechanism contributing to organ dysfunction in sepsis. Crit Care Clin 2001, 17:219–237.

    Article  PubMed  CAS  Google Scholar 

  3. Brealey D, Brand M, Hargreaves I, et al.: Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet 2002, 360:219–223.

    Article  PubMed  CAS  Google Scholar 

  4. Berg S, Sappington PL, Guzik LJ, et al.: Proinflammatory cytokines increase the rate of glycolysis and adenosine-5′-triphosphate turnover in cultured rat enterocytes. Crit Care Med 2003, 31:1203–1212.

    Article  PubMed  CAS  Google Scholar 

  5. Bundgaard H, Kjeldsen K, Suarez Krabbe K, et al.: Endotoxemia stimulates skeletal muscle Na+-K+-ATPase and raises blood lactate under aerobic conditions in humans. Am J Physiol Heart Circ Physiol 2003, 284:H1028–1034.

    PubMed  CAS  Google Scholar 

  6. L’Her E, Sebert P: A global approach to energy metabolism in an experimental model of sepsis. Am J Respir Crit Care Med 2001, 164:1444–1447.

    PubMed  CAS  Google Scholar 

  7. Gilles RJ, D’Orio V, Ciancabilla F, Carlier PG: In vivo 31P nuclear magnetic resonance spectroscopy of skeletal muscle energetics in endotoxemic rats: a prospective, randomized study. Crit Care Med 1994, 22:499–505.

    Article  PubMed  CAS  Google Scholar 

  8. Hotchkiss RS, Song SK, Neil JJ, et al.: Sepsis does not impair tricarboxylic acid cycle in the heart. Am J Physiol 1991, 260:C50–57.

    PubMed  CAS  Google Scholar 

  9. Hotchkiss RS, Swanson PE, Freeman BD, et al.: Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med 1999, 27:1230–1251. In this study, the authors performed autopsies immediately after death in patients with MODS. Their results demonstrate that apoptosis is a prominent feature of lymphoid and intestinal epithelial tissue; however, the pathology of the organs most commonly involved in MODS does not show substantial apoptosis or necrosis.

    Article  PubMed  CAS  Google Scholar 

  10. Hotchkiss RS, Tinsley KW, Swanson PE, et al.: Prevention of lymphocyte cell death in sepsis improves survival in mice. Proc Natl Acad Sci U S A 1999, 96:14541–14546.

    Article  PubMed  CAS  Google Scholar 

  11. Hotchkiss RS, Chang KC, Swanson PE, et al.: Caspase inhibitors improve survival in sepsis: a critical role of the lymphocyte. Nat Immunol 2000, 1:496–501.

    Article  PubMed  CAS  Google Scholar 

  12. Coopersmith CM, Stromberg PE, Dunne WM, et al.: Inhibition of intestinal epithelial apoptosis and survival in a murine model of pneumonia-induced sepsis. JAMA 2002, 287:1716–1721.

    Article  PubMed  Google Scholar 

  13. Vincent JL, Angus DC, Artigas A, et al.: Effects of drotrecogin alfa (activated) on organ dysfunction in the PROWESS trial. Crit Care Med 2003, 31:834–840.

    Article  PubMed  CAS  Google Scholar 

  14. Green RM, Beier D, Gollan JL: Regulation of hepatocyte bile salt transporters by endotoxin and inflammatory cytokines in rodents. Gastroenterology 1996, 111:193–198.

    Article  PubMed  CAS  Google Scholar 

  15. Trauner M, Arrese M, Lee H, et al.: Endotoxin downregulates rat hepatic ntcp gene expression via decreased activity of critical transcription factors. J Clin Invest 1998, 101:2092–2100.

    PubMed  CAS  Google Scholar 

  16. Sturm E, Zimmerman TL, Crawford AR, et al.: Endotoxin-stimulated macrophages decrease bile acid uptake in WIF-B cells, a rat hepatoma hybrid cell line. Hepatology 2000, 31:124–130.

    Article  PubMed  CAS  Google Scholar 

  17. Whiting JF, Green RM, Rosenbluth AB, Gollan JL: Tumor necrosis factor-alpha decreases hepatocyte bile salt uptake and mediates endotoxin-induced cholestasis. Hepatology 1995, 22:1273–1278.

    PubMed  CAS  Google Scholar 

  18. Cui Y, Konig J, Leier I, et al.: Hepatic uptake of bilirubin and its conjugates by the human organic anion transporter SLC21A6. J Biol Chem 2001, 276:9626–9630.

    Article  PubMed  CAS  Google Scholar 

  19. Hartmann G, Cheung AK, Piquette-Miller M: Inflammatory cytokines, but not bile acids, regulate expression of murine hepatic anion transporters in endotoxemia. J Pharmacol Exp Ther 2002, 303:273–281.

    Article  PubMed  CAS  Google Scholar 

  20. Vos TA, Hooiveld GJ, Koning H, et al.: Up-regulation of the multidrug resistance genes, Mrp1 and Mdr1b, and downregulation of the organic anion transporter, Mrp2, and the bile salt transporter, Spgp, in endotoxemic rat liver. Hepatology 1998, 28:1637–1644.

    Article  PubMed  CAS  Google Scholar 

  21. Lora L, Mazzon E, Martines D, et al.: Hepatocyte tight-junctional permeability is increased in rat experimental colitis. Gastroenterology 1997, 113:1347–1354.

    Article  PubMed  CAS  Google Scholar 

  22. Han X, Fink MP, Uchiyama T, et al.: Increased iNOS activity is essential for hepatic epithelial tight junction dysfunction in endotoxemic mice. Am J Physiol Gastrointest Liver Physiol 2004, 286:G126–136. This report describes how altered expression and localization of hepatic TJ proteins may play a key role in the pathogenesis of sepsis-induced liver failure.

    Article  PubMed  CAS  Google Scholar 

  23. Brivet FG, Kleinknecht DJ, Loirat P, Landais PJ: Acute renal failure in intensive care units—causes, outcome, and prognostic factors of hospital mortality; a prospective, multicenter study. French Study Group on Acute Renal Failure. Crit Care Med 1996, 24:192–198.

    Article  PubMed  CAS  Google Scholar 

  24. Neveu H, Kleinknecht D, Brivet F, et al.: Prognostic factors in acute renal failure due to sepsis. Results of a prospective multicentre study. The French Study Group on Acute Renal Failure. Nephrol Dial Transplant 1996, 11:293–299.

    PubMed  CAS  Google Scholar 

  25. Dhainaut JF, Laterre PF, Janes JM, et al.: Drotrecogin alfa (activated) in the treatment of severe sepsis patients with multiple-organ dysfunction: data from the PROWESS trial. Intensive Care Med 2003, 29:894–903.

    PubMed  Google Scholar 

  26. Kikeri D, Pennell JP, Hwang KH, et al.: Endotoxemic acute renal failure in awake rats. Am J Physiol 1986, 250:F1098–1106.

    PubMed  CAS  Google Scholar 

  27. Di GiantomassoD, May CN, Bellomo R: Vital organ blood flow during hyperdynamic sepsis. Chest 2003, 124:1053–1059.

    Article  PubMed  Google Scholar 

  28. Wan L, Bellomo R, Di GiantomassoD, Ronco C: The pathogenesis of septic acute renal failure. Curr Opin Crit Care 2003, 9:496–502.

    Article  PubMed  Google Scholar 

  29. Brenner M, Schaer GL, Mallory DL, et al.: Detection of renal blood flow abnormalities in septic and critically ill patients using a newly designed indwelling thermodilution renal vein catheter. Chest 1990, 98:170–179.

    PubMed  CAS  Google Scholar 

  30. Cunningham PN, Dyanov HM, Park P, et al.: Acute renal failure in endotoxemia is caused by TNF acting directly on TNF receptor-1 in kidney. J Immunol 2002, 168:5817–5823.

    PubMed  CAS  Google Scholar 

  31. Thijs A, Thijs LG: Pathogenesis of renal failure in sepsis. Kidney Int Suppl 1998, 66:S34–37.

    PubMed  CAS  Google Scholar 

  32. Wang J, Dunn MJ: Platelet-activating factor mediates endotoxin-induced acute renal insufficiency in rats. Am J Physiol 1987, 253:F1283–1289.

    PubMed  CAS  Google Scholar 

  33. Song M, Kellum JA, Kaldas H, Fink MP: Evidence that glutathione depletion is a mechanism responsible for the anti-inflammatory effects of ethyl pyruvate in cultured lipopolysaccharide-stimulated RAW 264.7 cells. J Pharmacol Exp Ther 2004, 308:307–316.

    Article  PubMed  CAS  Google Scholar 

  34. Han Y, Englert JA, Yang R, et al.: Ethyl pyruvate inhibits nuclear factor-kappaB-dependent signaling by directly targeting p65. J Pharmacol Exp Ther 2005, 312:1097–1105.

    Article  PubMed  CAS  Google Scholar 

  35. Ulloa L, Ochani M, Yang H, et al.: Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation. Proc Natl Acad Sci U S A 2002, 99:12351–12356.

    Article  PubMed  CAS  Google Scholar 

  36. Miyaji T, Hu X, Yuen PS, et al.: Ethyl pyruvate decreases sepsisinduced acute renal failure and multiple organ damage in aged mice. Kidney Int 2003, 64:1620–1631. The authors report that administration of ethyl pyruvate, a recently described anti-inflammatory compound, up to 12 hours after the onset of experimental sepsis prevents sepsis-induced renal dysfunction.

    Article  PubMed  CAS  Google Scholar 

  37. Yang H, Ochani M, Li J, et al.: Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proc Natl Acad Sci U S A 2004, 101:296–301.

    Article  PubMed  CAS  Google Scholar 

  38. Bonegio R, Lieberthal W: Role of apoptosis in the pathogenesis of acute renal failure. Curr Opin Nephrol Hypertens 2002, 11:301–308.

    Article  PubMed  Google Scholar 

  39. Jo SK, Cha DR, Cho WY, et al.: Inflammatory cytokines and lipopolysaccharide induce Fas-mediated apoptosis in renal tubular cells. Nephron 2002, 91:406–415.

    Article  PubMed  CAS  Google Scholar 

  40. Imai Y, Parodo J, Kajikawa O, et al.: Injurious mechanical ventilation and end-organ epithelial cell apoptosis and organ dysfunction in an experimental model of acute respiratory distress syndrome. JAMA 2003, 289:2104–2112.

    Article  PubMed  Google Scholar 

  41. Martin GS, Bernard GR: Airway and lung in sepsis. Intensive Care Med 2001, 27(Suppl 1):S63–79.

    Article  PubMed  Google Scholar 

  42. Bernard GR, Artigas A, Brigham KL, et al.: The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994, 149:818–824.

    PubMed  CAS  Google Scholar 

  43. Martin C, Papazian L, Payan MJ, et al.: Pulmonary fibrosis correlates with outcome in adult respiratory distress syndrome. A study in mechanically ventilated patients. Chest 1995, 107:196–200.

    PubMed  CAS  Google Scholar 

  44. Bhatia M, Moochhala S: Role of inflammatory mediators in the pathophysiology of acute respiratory distress syndrome. J Pathol 2004, 202:145–156.

    Article  PubMed  CAS  Google Scholar 

  45. Lum H, Roebuck KA: Oxidant stress and endothelial cell dysfunction. Am J Physiol Cell Physiol 2001, 280:C719–741.

    PubMed  CAS  Google Scholar 

  46. Waters CM, Savla U, Panos RJ: KGF prevents hydrogen peroxide-induced increases in airway epithelial cell permeability. Am J Physiol 1997, 272:L681–689.

    PubMed  CAS  Google Scholar 

  47. Kobayashi A, Hashimoto S, Kooguchi K, et al.: Expression of inducible nitric oxide synthase and inflammatory cytokines in alveolar macrophages of ARDS following sepsis. Chest 1998, 113:1632–1639.

    PubMed  CAS  Google Scholar 

  48. Zhu S, Ware LB, Geiser T, et al.: Increased levels of nitrate and surfactant protein a nitration in the pulmonary edema fluid of patients with acute lung injury. Am J Respir Crit Care Med 2001, 163:166–172.

    PubMed  CAS  Google Scholar 

  49. Pittet JF, Mackersie RC, Martin TR, Matthay MA: Biological markers of acute lung injury: prognostic and pathogenetic significance. Am J Respir Crit Care Med 1997, 155:1187–1205.

    PubMed  CAS  Google Scholar 

  50. Han X, Fink MP, Uchiyama T, et al.: Increased iNOS activity is essential for pulmonary epithelial tight junction dysfunction in endotoxemic mice. Am J Physiol Lung Cell Mol Physiol 2004, 286:L259–267. This report describes how altered expression and localization of alveolar TJ proteins may play a key role in the pathogenesis of sepsisinduced lung dysfunction. This reference, in conjuction with the study by Han et al. [22], demostrates that this phenomenon is generalizable.

    Article  PubMed  CAS  Google Scholar 

  51. Pittet JF, Griffiths MJ, Geiser T, et al.: TGF-beta is a critical mediator of acute lung injury. J Clin Invest 2001, 107:1537–1544.

    PubMed  CAS  Google Scholar 

  52. Ware LB, Matthay MA: Alveolar fluid clearance is impaired in the majority of patients with acute lung injury and the acute respiratory distress syndrome. Am J Respir Crit Care Med 2001, 163:1376–1383.

    PubMed  CAS  Google Scholar 

  53. Frank J, Roux J, Kawakatsu H, et al.: Transforming growth factor-beta1 decreases expression of the epithelial sodium channel alphaENaC and alveolar epithelial vectorial sodium and fluid transport via an ERK1/2-dependent mechanism. J Biol Chem 2003, 278:43939–43950.

    Article  PubMed  CAS  Google Scholar 

  54. 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.

    PubMed  CAS  Google Scholar 

  55. Dhainaut JF, Huyghebaert MF, Monsallier JF, et al.: Coronary hemodynamics and myocardial metabolism of lactate, free fatty acids, glucose, and ketones in patients with septic shock. Circulation 1987, 75:533–541.

    PubMed  CAS  Google Scholar 

  56. Heard SO, Perkins MW, Fink MP: Tumor necrosis factor-alpha causes myocardial depression in guinea pigs. Crit Care Med 1992, 20:523–527.

    Article  PubMed  CAS  Google Scholar 

  57. Pagani FD, Baker LS, Hsi C, et al.: Left ventricular systolic and diastolic dysfunction after infusion of tumor necrosis factoralpha in conscious dogs. J Clin Invest 1992, 90:389–398.

    Article  PubMed  CAS  Google Scholar 

  58. Parrillo JE, Burch C, Shelhamer JH, et al.: A circulating myocardial depressant substance in humans with septic shock. Septic shock patients with a reduced ejection fraction have a circulating factor that depresses in vitro myocardial cell performance. J Clin Invest 1985, 76:1539–1553.

    PubMed  CAS  Google Scholar 

  59. Kumar A, Thota V, Dee L, et al.: Tumor necrosis factor alpha and interleukin 1beta are responsible for in vitro myocardial cell depression induced by human septic shock serum. J Exp Med 1996, 183:949–958.

    Article  PubMed  CAS  Google Scholar 

  60. Zhong J, Hwang TC, Adams HR, Rubin LJ: Reduced L-type calcium current in ventricular myocytes from endotoxemic guinea pigs. Am J Physiol 1997, 273:H2312–2324.

    PubMed  CAS  Google Scholar 

  61. Liu S, Schreur KD: G protein-mediated suppression of L-type Ca2+ current by interleukin-1 beta in cultured rat ventricular myocytes. Am J Physiol 1995, 268:C339–349.

    PubMed  CAS  Google Scholar 

  62. Yokoyama T, Vaca L, Rossen RD, et al.: Cellular basis for the negative inotropic effects of tumor necrosis factor-alpha in the adult mammalian heart. J Clin Invest 1993, 92:2303–2312.

    PubMed  CAS  Google Scholar 

  63. Zhu X, Bernecker OY, Manohar NS, et al.: Increased leakage of sarcoplasmic reticulum Ca2+ contributes to abnormal myocyte Ca2+ handling and shortening in sepsis. Crit Care Med 2005, 33:598–604.

    Article  PubMed  Google Scholar 

  64. Yasuda S, Lew WY: Lipopolysaccharide depresses cardiac contractility and beta-adrenergic contractile response by decreasing myofilament response to Ca2+ in cardiac myocytes. Circ Res 1997, 81:1011–1020.

    PubMed  CAS  Google Scholar 

  65. Tavernier B, Li JM, El-Omar MM, et al.: Cardiac contractile impairment associated with increased phosphorylation of troponin I in endotoxemic rats. Faseb J 2001, 15:294–296.

    PubMed  CAS  Google Scholar 

  66. Zappavigna V, Falciola L, Helmer-Citterich M, et al.: HMG1 interacts with HOX proteins and enhances their DNA binding and transcriptional activation. EMBO J 1996, 15:4981–4991.

    PubMed  CAS  Google Scholar 

  67. Wang H, Bloom O, Zhang M, et al.: HMG-1 as a late mediator of endotoxin lethality in mice. Science 1999, 285:248–251. This is the first report of the cytokine-like activity of extracellular HMGB1 and its role as a late acting mediator of endotoxin induced lethality.

    Article  PubMed  CAS  Google Scholar 

  68. Wang H, Liao H, Ochani M, et al.: Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nat Med 2004, 10:1216–1221.

    Article  PubMed  CAS  Google Scholar 

  69. Ulloa L, Tracey KJ: The “cytokine profile”: a code for sepsis. Trends Mol Med 2005, 11:56–63.

    Article  PubMed  CAS  Google Scholar 

  70. Sappington PL, Yang R, Yang H, et al.: HMGB1 B box increases the permeability of Caco-2 enterocytic monolayers and impairs intestinal barrier function in mice. Gastroenterology 2002, 123:790–802.

    Article  PubMed  CAS  Google Scholar 

  71. Abraham E, Arcaroli J, Carmody A, et al.: HMG-1 as a mediator of acute lung inflammation. J Immunol 2000, 165:2950–2954.

    PubMed  CAS  Google Scholar 

  72. Sunden-Cullberg J, Norrby-Teglund A, Rouhiainen A, et al.: Persistent elevation of high mobility group box-1 protein (HMGB1) in patients with severe sepsis and septic shock. Crit Care Med 2005, 33:564–573.

    Article  PubMed  CAS  Google Scholar 

  73. Bloom BR, Bennett B: Mechanism of a reaction in vitro associated with delayed-type hypersensitivity. Science 1966, 153:80–82.

    Article  PubMed  CAS  Google Scholar 

  74. Bernhagen J, Calandra T, Mitchell RA, et al.: MIF is a pituitaryderived cytokine that potentiates lethal endotoxaemia. Nature 1993, 365:756–759.

    Article  PubMed  CAS  Google Scholar 

  75. Calandra T, Bernhagen J, Metz CN, et al.: MIF as a glucocorticoid-induced modulator of cytokine production. Nature 1995, 377:68–71.

    Article  PubMed  CAS  Google Scholar 

  76. Calandra T, Echtenacher B, Roy DL, et al.: Protection from septic shock by neutralization of macrophage migration inhibitory factor. Nat Med 2000, 6:164–170.

    Article  PubMed  CAS  Google Scholar 

  77. Bozza FA, Gomes RN, Japiassu AM, et al.: Macrophage migration inhibitory factor levels correlate with fatal outcome in sepsis. Shock 2004, 22:309–313.

    Article  PubMed  CAS  Google Scholar 

  78. Donnelly SC, Haslett C, Reid PT, et al.: Regulatory role for macrophage migration inhibitory factor in acute respiratory distress syndrome. Nat Med 1997, 3:320–323.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Critical Care Medicine and Surgery, University of Pittsburgh School of Medicine, 615 Scaife Hall, 3550 Terrace Street, 15261, Pittsburgh, PA, USA

    Joshua A. Englert MD & Mitchell P. Fink MD

Authors
  1. Joshua A. Englert MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mitchell P. Fink MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Englert, J.A., Fink, M.P. The multiple organ dysfunction syndrome and late-phase mortality in sepsis. Curr Infect Dis Rep 7, 335–341 (2005). https://doi.org/10.1007/s11908-005-0006-0

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11908-005-0006-0

Keywords

Search

Navigation