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Sepsis: From Bench to Bedside

By Eliézer Silva, Rogério Da Hora Passos, Maurício Beller Ferri and Luiz Francisco Poli de Figueiredo


Sepsis is a syndrome related to severe infections. It is defined as the systemic host response to microorganisms in previously sterile tissues and is characterized by end-organ dysfunction away from the primary site of infection. The normal host response to infection is complex and aims to identify and control pathogen invasion, as well as to start immediate tissue repair. Both the cellular and humoral immune systems are activated, giving rise to both anti-inflammatory and proinflammatory responses. The chain of events that leads to sepsis is derived from the exacerbation of these mechanisms, promoting massive liberation of mediators and the progression of multiple organ dysfunction. Despite increasing knowledge about the pathophysiological pathways and processes involved in sepsis, morbidity and mortality remain unacceptably high. A large number of immunomodulatory agents have been studied in experimental and clinical settings in an attempt to find an efficacious anti-inflammatory drug that reduces mortality. Even though preclinical results had been promising, the vast majority of these trials actually showed little success in reducing the overwhelmingly high mortality rate of septic shock patients as compared with that of other critically ill intensive care unit patients. Clinical management usually begins with prompt recognition, determination of the probable infection site, early administration of antibiotics, and resuscitation protocols based on “early-goal” directed therapy. In this review, we address the research efforts that have been targeting risk factor identification, including genetics, pathophysiological mechanisms and strategies to recognize and treat these patients as early as possible

Topics: Review
Publisher: Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo
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Provided by: PubMed Central

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  1. A multicenter, prospective study to evaluate costs of septic patients in Brazilian intensive care units.
  2. A trial of goal-oriented hemodynamic therapy in critically ill patients.
  3. Activation of endothelial cell protease activated receptor 1 by the protein C pathway.
  4. (1999). Adjunctive therapy in sepsis: a critical analysis of the clinical trial program. Br Med Bull.
  5. (1992). American College of Chest Physicians/Society of Critical Care Medicine. Consensus Conference: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med.
  6. (1999). Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med.
  7. Bacteremia and severe sepsis in adults: a multicenter prospective survey in ICUs and wards of 24 hospitals.
  8. (2006). Bacterial recognition and induced cell activation in sepsis. Endocr Metab Immune Disord Drug Targets.
  9. (2004). Bench to Bedside Review: Understanding genetic predisposition to sepsis. Crit Care.
  10. Bench-to-bedside review: toll-like receptors and their role in septic shock. Crit Care.
  11. CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein.
  12. Corticosteroids in sepsis: From bench to bedside?
  13. (1999). Crystalloids vs. colloids in fluid resuscitation: a systematic review. Crit Care Med.
  14. (2003). Current Epidemiology of Septic Shock: the CUB-Rea Network. Am J Respir Crit Care Med.
  15. Cytokine cascade in sepsis.
  16. Cytokine gene promoter polymorphisms and mortality in acute renal failure.
  17. da Cruz Neto LM. Evolutive standard base excess and serum lactate level in severe sepsis and septic shock patients resuscitated with early goaldirected therapy: still outcome markers?
  18. Detection of bacteremia in adults: Consequences of culturing an inadequate volume of blood.
  19. (1999). Digestion of Streptococcus pneumoniae cell walls with its major peptidoglycan hydrolase releases branched stem peptides carrying proinflammatory activity. Biol Chem.
  20. Disease Control and Prevention. Guidelines for the prevention of intravascular catheter-related infections.
  21. Disseminated intravascular coagulation.
  22. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death.
  23. Drotrecogin alfa (activated) treatment in severe sepsis from the global open-label trial ENHANCE: further evidence for survival and safety and implications for early treatment. Crit Care Med.
  24. Dysfunction of endothelial protein C activation in severe meningococcal sepsis.
  25. Earlier positivity of central venous versus peripheral blood cultures is highly predictive of catheter-related sepsis.
  26. Early and innovative interventions for severe sepsis and septic shock: taking advantage of a window of opportunity.
  27. (2005). Early changes in organ function predict eventual survival in severe sepsis. Crit Care Med.
  28. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome.
  29. (1999). Effect of spontaneous breathing trial duration on outcome of attempts to discontinue mechanical ventilation. Spanish Lung Failure Collaborative Group. Am J Respir Crit Care Med.
  30. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock.
  31. (1996). Effect on the duration of mechanical ventilation of identifying patients capable of breathing spontaneously.
  32. (2006). Effectiveness of prolonged glucocorticoid treatment in acute respiratory distress syndrome: the right drug, the right way? Crit Care Med.
  33. (2001). Effects of genomic polymorphisms on the course of sepsis: is there a concept for gene therapy? J Am Soc Nephrol.
  34. (2004). Effects of volume resuscitation on splanchnic perfusion in canine model of severe sepsis induced by live Escherichia coli infusion. Crit Care.
  35. Efficacy and safety of recombinant human activated protein C for severe sepsis.
  36. Elevation of systemic oxygen delivery in the treatment of critically ill patients.
  37. Epidemiology of severe sepsis around the world. Curr Drug Targets Immune Endocr Metabol.
  38. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated cost of care. Crit Care Med.
  39. et al.Early goal-directed therapy in the treatment of severe sepsis and septic shock.
  40. (1998). Evaluation of a ventilation strategy to prevent barotrauma in patients at high risk for acute respiratory distress syndrome. Pressureand Volume-Limited Ventilation Strategy Group.
  41. (1997). Extubation outcome after spontaneous breathing trials with T-tube or pressure support ventilation. The Spanish Lung Failure Collaborative Group. Am J Respir Crit Care Med.
  42. (1998). Fernandez-Mondéjar E, et al.Tidal volume reduction for prevention of ventilator-induced lung injury in acute respiratory distress syndrome. The Multicenter Trial Group on Tidal Volume reduction in ARDS. Am J Respir Crit Care Med.
  43. Fluid resuscitation with colloid or crystalloid solutions in critically ill patients: A systematic review of randomized trials.
  44. for the Surviving Sepsis Campaign management Guidelines Committee. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med.
  45. Genetic polymorphisms and sepsis.
  46. (2006). Ger-Inf-05 Study Group. Effect of low doses of corticosteroids in septic shock patients with or without early acute respiratory distress syndrome. Crit Care Med.
  47. (1998). Has the mortality of septic shock changed with time? Crit Care Med.
  48. (2006). High-mobility group box 1 (HMGB1) protein: friend and foe. Cytokine & Growth Factor Reviews.
  49. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome.
  50. (1999). HMG-1 as a late mediator of endotoxin lethality in mice.
  51. HMG-1 rediscovered as a cytokine.
  52. HMGB1 and LPS induce distinct patterns of gene expression and activation in neutrophils from patients with sepsis induced acute lung injury. Intensive Care Med. 2007;[Epub ahead of print].
  53. Human Nod1 confers responsiveness to bacterial lipopolysaccharides.
  54. Inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes.
  55. Intensive insulin therapy in the critically ill patients.
  56. Intensive insulin therapy in the medical ICU.
  57. Intrinsic conformation of lipid A is responsible for agonistic and antagonistic activity.
  58. (1998). Introduction: the role of innate immunity in the adaptive immune response. Semin Immuno.
  59. Leukocyte-endothelium interactions after hemorrhagic shock/reperfusion and cecal ligation/puncture: an intravital microscopic study in rat mesentery.
  60. Lipopolysaccharide–cell interaction and induced cellular activation in whole blood of septic patients.
  61. Macrophage migration inhibitory factor is a critical mediator of the activation of immune cells by exotoxins of Gram-positive bacteria.
  62. Magnitude and duration of the effect of sepsis on survival.
  63. (2005). Mechanical ventilation in acute respiratory failure: recruitment and high positive end-expiratory pressure are necessary. Curr Opin Crit Care.
  64. (1995). MIF as a glucocorticoid-induced modulator of cytokine production.
  65. (1997). Monocyte deactivation in septic patients: restoration by IFN-g treatment. Nature Med.
  66. Multiorgan failure is an adaptive, endocrine-mediated, metabolic response to overwhelming systemic inflammation.
  67. Nods: a family of cytosolic proteins that regulate the host response to pathogens.
  68. (2004). Optimum treatment of severe sepsis and septic shock: evidence in support of the recommendations. Dis Mon.
  69. Pathogenesis-Oriented targets for adjunctive therapy. Curr Drug Targets Immune, Endocr Metabol.
  70. Peptidoglycan recognition proteins: a novel family of four human innate immunity pattern recognition molecules.
  71. (2000). Pharmacokinetics and Pharmacodynamcis of Anti-infective Agents. In: Principles and Practice of Infectious Diseases. Fifth Edition. Mandell
  72. (1999). Practice parameters for hemodynamic support of sepsis in adult patients. Crit Care Med.
  73. Predicting fluid responsiveness in ICU patients: a critical analysis of the evidence.
  74. Prevention of lymphocyte cell death in sepsis improves survival in mice.
  75. (1997). Proinflammatory and anti-inflammatory cytokines as mediators in the pathogenesis of septic shock.
  76. (1999). Prospective, randomized, controlled clinical trial comparing traditional versus reduced tidal volume ventilation in acute respiratory distress syndrome patients. Crit Care Med.
  77. Protection from septic shock by neutralization of macrophage migration inhibitory factor.
  78. Regulation of inflammatory responses by natural anticoagulants. Immunol Rev.
  79. Ringer’s ethyl pyruvate solution: a novel resuscitation fluid for the treatment of hemorrhagic shock and sepsis.
  80. (1997). Robert D.Prone position in mechanically ventilated patients with severe acute respiratory failure. Am J Respir Crit Care Med.
  81. (2000). Role of Nitric Oxide in the Failure of Neutrophil Migration in Sepsis. J Infect Dis.
  82. Sepsis in european intensive care units: results of the SOAP study. Crit Care Med
  83. Sepsis-induced apoptosis causes progressive profound depletion of B and CD4+ T lymphocytes in humans.
  84. Sepsis: emerging role of nitric oxide and selectins.
  85. Severe sepsis and septic shock: definitions, epidemiology, and clinical manifestations. Crit Care Clin.
  86. Short-lasting systemic and regional benefits of early crystalloid infusion after intravenous inoculation of dogs with live Escherichia coli.
  87. (2006). Small volume of hypertonic saline as the initial fluid replacement in experimental hypodynamic sepsis. Crit Care.
  88. (2001). Source control in the management of sepsis. Intensive Care Med.
  89. Structure–function relationship of cytokine induction by lipoteichoic acid from Staphylococcus aureus.
  90. Surviving sepsis campaign: a project to change sepsis trajectory. Endocr Metab Immune Disord Drug Targets.
  91. (1983). The clinical significance of positive blood cultures: A comprehensive analysis of 500 episodes of bacteremia and fungemia in adults. I. Laboratory and epidemiologic observations. Rev Infect Dis.
  92. (1979). The epidemiology of sepsis in the United States from
  93. The highs and lows of intensive insulin therapy.
  94. (1995). The importance of pharmacokinetic/ pharmacodynamic surrogate markers to outcomes. Focus on antibacterial agents. Clin Pharmacokinet.
  95. The last 100 years of sepsis.
  96. The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study.
  97. TLR2, TLR4, CD14, CD11B, and CD11C expressions on monocytes surface and cytokine production in patients with sepsis, severe sepsis, and septic shock.
  98. (2002). Toll receptors: a central element in innate immune responses. Infect Immun.
  99. Toll-like receptor 4 signaling leads to neutrophil migration impairment in polymicrobial sepsis. Crit Care Med.
  100. Toll-like receptors in the induction of the innate immune response.
  101. TREM-1 amplifies inflammation and is a crucial mediator of septic shock.
  102. (1999). Understanding the mechanism of action of bacterial superantigens from a decade of research. Immunol Rev.
  103. Upregulation of reactive oxygen species generation and phagocytosis, and increased apoptosis in human neutrophils during severe sepsis and septic shock.

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