1. Rivers E, Nguyen B, Havstad S, et al; Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345:1368-1377.
2. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med. 2000;342:1301-1308.
3. 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.
4. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 2003;348:1546-1554.
5. Alberti C, Brun-Buisson C, Burchardi H, et al. Epidemiology of sepsis and infection in ICU patients from an international multicentre cohort study [published correction appears in Intensive Care Med. 2002;28:525-526]. Intensive Care Med. 2002;28:108-121.
6. Parrillo JE, Parker MM, Natanson C, et al. Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med. 1990;113:227-242.
7. Brun-Buisson C, Doyon F, Carlet J, et al. Incidence, risk factors, and outcome of severe sepsis and septic shock in adults. A multicenter prospective study in intensive care units. French ICU Group for Severe Sepsis. JAMA. 1995;274:968-974.
8. Padkin A, Goldfrad C, Brady AR, et al. Epidemiology of severe sepsis occurring in the first 24 hrs in intensive care units in England, Wales, and Northern Ireland. Crit Care Med. 2003;31:2332-2338.
9. Brun-Buisson C, Meshaka P, Pinton P, Vallet B; EPISEPSIS Study Group. EPISEPSIS: a reappraisal of the epidemiology and outcome of severe sepsis in French intensive care units. Intensive Care Med. 2004;30:580-588.
10. Heyland DK, Hopman W, Coo H, et al. Long-term health-related quality of life in survivors of sepsis. Short Form 36: a valid and reliable measure of health-related quality of life. Crit Care Med. 2000;28:3599-3605.
11. Perl TM, Dvorak L, Hwang T, Wenzel RP. Long-term survival and function after suspected gram-negative sepsis. JAMA. 1995;274:338-345.
12. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992;101:1644-1655.
13. Marshall JC, Cook DJ, Christou NV, et al. Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome. Crit Care Med. 1995;23:1638-1652.
14. Ferreira FL, Bota DP, Bross A, et al. Serial evaluation of the SOFA score to predict outcome in critically ill patients. JAMA. 2001;286:1754-1758.
15. Kandil E, Burack J, Sawas A, et al. B-type natriuretic peptide: a biomarker for the diagnosis and risk stratification of patients with septic shock. Arch Surg. 2008;143:242-246.
16. Meyer B, Huelsmann M, Wexberg P, et al. N-terminal pro-B-type natriuretic peptide is an independent predictor of outcome in an unselected cohort of critically ill patients. Crit Care Med. 2007;35:2268-2273.
17. Giamarellos-Bourboulis EJ, Giannopoulou P, Grecka P, et al. Should procalcitonin be introduced in the diagnostic criteria for the systemic inflammatory response syndrome and sepsis? J Crit Care. 2004;19:152-157.`
18. Uzzan B, Cohen R, Nicolas P, et al. Procalcitonin as a diagnostic test for sepsis in critically ill adults and after surgery or trauma: a systematic review and meta-analysis. Crit Care Med. 2006;34:1996-2003.
19. Claeys R, Vinken S, Spapen H, et al. Plasma procalcitonin and C-reactive protein in acute septic shock: clinical and biological correlates. Crit Care Med. 2002;30:757-762.
20. Meisner M, Tschaikowsky K, Palmaers T, Schmidt J. Comparison of procalcitonin (PCT) and C-reactive protein (CRP) plasma concentrations at different SOFA scores during the course of sepsis and MODS. Crit Care. 1999;3:45-50.
21. Harbarth S, Holeckova K, Froidevaux C, et al; 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.
22. Shorr AF, Bernard GR, Dhainaut JF, et al. Protein C concentrations in severe sepsis: an early directional change in plasma levels predicts outcome. Crit Care. 2006;10:R92.
23. Bouchon A, Dietrich J, Colonna M. Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes. J Immunol. 2000;164:4991-4995.
24. Gibot S, Cravoisy A, Kolopp-Sarda MN, et al. Time-course of sTREM (soluble triggering receptor expressed on myeloid cells)-1, procalcitonin, and C-reactive protein plasma concentrations during sepsis. Crit Care Med. 2005;33:792-796.
25. Modlin RL, Brightbill HD, Godowski PJ. The toll of innate immunity on microbial patho-gens. N Engl J Med. 1999;340:1834-1835.
26. Fujita M, Kuwano K, Kunitake R, et al. Endothelial cell apoptosis in lipopolysaccharide induced lung injury in mice. Int Arch Allergy Immunol. 1998;117:202-208.
27. Yamada M, Kubo H, Kobayashi S, et al. Bone marrow-derived progenitor cells are important for lung repair after lipopolysaccharide-induced lung injury [published correction appears in J Immunol. 2004;173:4755]. J Immunol. 2004;172:1266-1272.
28. Aird WC. The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood. 2003;101:3765-3777.
29. Opal SM, DePalo VA. Anti-inflammatory cytokines. Chest. 2000;117:1162-1172.
30. Levi M, Keller TT, van Gorp E, ten Cate H. Infection and inflammation and the coagulation system. Cardiovasc Res. 2003;60:26-39.
31. Levi M, de Jonge E, van der Poll T. Sepsis and disseminated intravascular coagulation. J Thromb Thrombolysis. 2003;16:43-47.
32. Miller DL, Welty-Wolf K, Carraway MS, et al. Extrinsic coagulation blockade attenuates lung injury and proinflammatory cytokine release after intratracheal lipopolysaccharide. Am J Respir Cell Mol Biol. 2002;26:650-658.
33. Zheng X, Li W, Song Y, et al. Non-hematopoietic EPCR regulates the coagulation and inflammatory responses during endotoxemia. J Thromb Haemost. 2007;5:1394-1400.
34. Esmon CT. The protein C anticoagulant pathway. Arterioscler Thromb. 1992;12:135-145.
35. Esmon CT. Regulation of blood coagulation. Biochim Biophys Acta. 2000;1477:349-360.
36. Stearns-Kurosawa DJ, Kurosawa S, Mollica JS, et al. The endothelial cell protein C receptor augments protein C activation by the thrombin-thrombomodulin complex. Proc Natl Acad Sci U S A. 1996;93:10212-10216.
37. Ertel W, Kremer JP, Kenney J, et al. Downregulation of proinflammatory cytokine release in whole blood from septic patients. Blood. 1995;85:1341-1347.
38. Gogos CA, Drosou E, Bassaris HP, Skoutelis A. Pro- versus anti-inflammatory cytokine profile in patients with severe sepsis: a marker for prognosis and future therapeutic options. J Infect Dis. 2000;181:176-180.
39. Chang KC, Unsinger J, Davis CG, et al. Multiple triggers of cell death in sepsis: death receptor and mitochondrial-mediated apoptosis. FASEB J. 2007;21:708-719.
40. 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.
41. Dellinger RP, Levy MM, Carlet JM, et al; International Surviving Sepsis Campaign Guidelines Committee, American Association of Critical-Care Nurses, American College of Chest Physicians, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008 [published correction appears in Crit Care Med. 2008;36:1394-1396]. Crit Care Med. 2008;36:296-327.
42. Micek ST, Roubinian N, Heuring T, et al. Before-after study of a standardized hospital order set for the management of septic shock. Crit Care Med. 2006;34:2707-2713.
43. Nguyen HB, Corbett SW, Steele R, et al. Implementation of a bundle of quality indicators for the early management of severe sepsis and septic shock is associated with decreased mortality. Crit Care Med. 2007;35:1105-1112.
44. Sebat F, Johnson D, Musthafa AA, et al. A multidisciplinary community hospital program for early and rapid resuscitation of shock in nontrauma patients. Chest. 2005;127:1729-1743.
45. Talmor D, Greenberg D, Howell MD, et al. The costs and cost-effectiveness of an integrated sepsis treatment protocol. Crit Care Med. 2008;36:1168-1174.
46. Bendjelid K, Romand JA. Fluid responsiveness in mechanically ventilated patients: a review of indices used in intensive care. Intensive Care Med. 2003;29:352-360.
47. Choi PT, Yip G, Quinonez LG, Cook DJ. Crystalloids vs colloids in fluid resuscitation: a systematic review. Crit Care Med. 1999;27:200-210.
48. Schierhout G, Roberts I. Fluid resuscitation with colloid or crystalloid solutions in critically ill patients: a systematic review of randomised trials. BMJ. 1998;316:961-964.
49. Wilkes MM, Navickis RJ. Patient survival after human albumin administration. A meta-analysis of randomized, controlled trials. Ann Intern Med. 2001;135:149-164.
50. Vincent JL, Navickis RJ, Wilkes MM. Morbidity in hospitalized patients receiving human albumin: a meta-analysis of randomized, controlled trials. Crit Care Med. 2004;32:2029-2038.
51. Finfer S, Bellomo R, Boyce N, et al; SAFE Study Investigators. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. 2004;350:2247-2256.
52. Myburgh J, Cooper DJ, Finfer S, et al. Saline or albumin for fluid resuscitation in patients with traumatic brain injury. N Engl J Med. 2007;357:874-884.
53. Sakr Y, Dubois MJ, De Backer D, et al. Persistent microcirculatory alterations are associated with organ failure and death in patients with septic shock. Crit Care Med. 2004;32:1825-1831.
54. Schortgen F, Lacherade JC, Bruneel F, et al. Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicentre randomised study. Lancet. 2001;357:911-916.
55. Hoffmann JN, Vollmar B, Laschke MW, et al. Hydroxyethyl starch (130 kD), but not crystalloid volume support, improves microcirculation during normotensive endotoxemia. Anesthesiology. 2002;97:460-470.
56. Kellum JA. Fluid resuscitation and hyperchloremic acidosis in experimental sepsis: improved short-term survival and acid-base balance with Hextend compared with saline. Crit Care Med. 2002;30:300-305.
57. Kupper S, Mees ST, Gassmann P, et al. Hydroxyethyl starch normalizes platelet and leukocyte adhesion within pulmonary microcirculation during LPS-induced endotoxemia. Shock. 2007;28:300-308.
58. Maciel F, Mook M, Zhang H, Vincent JL. Comparison of hypertonic with isotonic saline hydroxyethyl starch solution on oxygen extraction capabilities during endotoxic shock. Shock. 1998;9:33-39.
59. Dickenmann M, Oettl T, Mihatsch MJ. Osmotic nephrosis: acute kidney injury with accumulation of proximal tubular lysosomes due to administration of exogenous solutes. Am J Kidney Dis. 2008;51:491-503.
60. Nielsen VG. Hydroxyethyl starch enhances fibrinolysis in human plasma by diminishing alpha2-antiplasmin-plasmin interactions. Blood Coagul Fibrinolysis. 2007;18:647-656.
61. Brunkhorst FM, Engel C, Bloos F, et al; German Competence Network Sepsis (SepNet). Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008;358:125-139.
62. Houck PM, Bratzler DW, Nsa W, et al. Timing of antibiotic administration and outcomes for Medicare patients hospitalized with community-acquired pneumonia. Arch Intern Med. 2004;164:637-644.
63. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34:1589-1596.
64. Garnacho-Montero J, Garcia-Garmendia JL, Barrero-Almodovar A, et al. Impact of adequate empirical antibiotic therapy on the outcome of patients admitted to the intensive care unit with sepsis. Crit Care Med. 2003;31:2742-2751.
65. Harbarth S, Garbino 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.
66. Ibrahim EH, Sherman G, Ward S, et al. The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest. 2000;118:146-155.
67. Leibovici L, Shraga I, Drucker M, et al. The benefit of appropriate empirical antibiotic treatment in patients with bloodstream infection. J Intern Med. 1998;244:379-386.
68. Heyland DK, Dodek P, Muscedere J, et al. Randomized trial of combination versus monotherapy for the empiric treatment of suspected ventilator-associated pneumonia. Crit Care Med. 2008;36:737-744.
69. Paul M, Silbiger I, Grozinsky S, et al. Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis. Cochrane Database Syst Rev. 2006;(1):CD003344.
70. Safdar N, Handelsman J, Maki DG. Does combination antimicrobial therapy reduce mortality in Gram-negative bacteraemia? A meta-analysis. Lancet Infect Dis. 2004;4:519-527.
71. Garnacho-Montero J, Sa-Borges M, Sole-Violan J, et al. Optimal management therapy for Pseudomonas aeruginosa ventilator-associated pneumonia: an observational, multicenter study comparing monotherapy with combination antibiotic therapy. Crit Care Med. 2007;35:1888-1895.
72. LeDoux D, Astiz ME, Carpati CM, Rackow EC. Effects of perfusion pressure on tissue perfusion in septic shock. Crit Care Med. 2000;28:2729-2732.
73. Kirchheim HR, Ehmke H, Hackenthal E, et al. Autoregulation of renal blood flow, glomerular filtration rate and renin release in conscious dogs. Pflugers Arch. 1987;410:441-449.
74. Bourgoin A, Leone M, Delmas A, et al. Increasing mean arterial pressure in patients with septic shock: effects on oxygen variables and renal function. Crit Care Med. 2005;33:780-786.
75. Martin C, Papazian L, Perrin G, et al. Norepinephrine or dopamine for the treatment of hyperdynamic septic shock? Chest. 1993;103:1826-1831.
76. Martin C, Viviand X, Leone M, Thirion X. Effect of norepinephrine on the outcome of septic shock. Crit Care Med. 2000;28:2758-2765.
77. http://www.clinicaltrials.gov. Identifier NCT 00314704. Accessed January 13, 2009.
78. Annane D, Vignon P, Renault A, et al; CATS Study Group. Norepinephrine plus dobutamine versus epinephrine alone for the management of septic shock: a randomised trial [published correction appears in Lancet. 2007;370:1034]. Lancet. 2007;370:676-684.
79. Levy B, Bollaert PE, Charpentier C, et al. Comparison of norepinephrine and dobutamine to epinephrine for hemodynamics, lactate metabolism, and gastric tonometric variables in septic shock: a prospective, randomized study. Intensive Care Med. 1997;23:282-287.
80. Landry DW, Levin HR, Gallant EM, et al. Vasopressin pressor hypersensitivity in vasodilatory septic shock. Crit Care Med. 1997;25:1279-1282.
81. Landry DW, Levin HR, Gallant EM, et al. Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation. 1997;95:1122-1125.
82. Holmes CL, Walley KR, Chittock DR, et al. The effects of vasopressin on hemodynamics and renal function in severe septic shock: a case series. Intensive Care Med. 2001;27:1416-1421.
83. Malay MB, Ashton RC Jr, Landry DW, Townsend RN. Low-dose vasopressin in the treatment of vasodilatory septic shock. J Trauma. 1999;47:699-703.
84. Patel BM, Chittock DR, Russell JA, Walley KR. Beneficial effects of short-term vasopressin infusion during severe septic shock. Anesthesiology. 2002;96:576-582.
85. Russell JA, Walley KR, Singer J, et al; VASST Investigators. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008;358:877-887.
86. Ely EW, Laterre PF, Angus DC, et al; PROWESS Investigators. Drotrecogin alfa (activated) administration across clinically important subgroups of patients with severe sepsis. Crit Care Med. 2003;31:12-19.
87. Abraham E, Laterre PF, Garg R, et al; Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS) Study Group. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med. 2005;353:1332-1341.
88. Vincent JL, Bernard GR, Beale R, et al. 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. 2005;33:2266-2277.
89. Levi M, Levy M, Williams MD, et al; Xigris and Prophylactic HepaRin Evaluation in Severe Sepsis (XPRESS) Study Group. Prophylactic heparin in patients with severe sepsis treated with drotrecogin alfa (activated). Am J Respir Crit Care Med. 2007;176:483-490.
90. Angus DC, Linde-Zwirble WT, Clermont G, et al; PROWESS Investigators. Cost-effectiveness of drotrecogin alfa (activated) in the treatment of severe sepsis. Crit Care Med. 2003;31:1-11.
91. Green C, Dinnes J, Takeda A, et al. Clinical effectiveness and cost-effectiveness of drotrecogin alfa (activated) (Xigris) for the treatment of severe sepsis in adults: a systematic review and economic evaluation. Health Technol Assess. 2005;9(11):1-126, iii-iv.
92. Manns BJ, Lee H, Doig CJ, et al. An economic evaluation of activated protein C treatment for severe sepsis. N Engl J Med. 2002;347:993-1000.
93. Annane D, Bellissant E, Bollaert PE, et al. Corticosteroids for severe sepsis and septic shock: a systematic review and meta-analysis. BMJ. 2004;329:480.
94. Bone RC, Fisher CJ Jr, Clemmer TP, et al. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med. 1987;317:653-658.
95. Cronin L, Cook DJ, Carlet J, et al. Corticosteroid treatment for sepsis: a critical appraisal and meta-analysis of the literature. Crit Care Med. 1995;23:1430-1439.
96. Sprung CL, Caralis PV, Marcial EH, et al. The effects of high-dose corticosteroids in patients with septic shock. A prospective, controlled study. N Engl J Med. 1984;311:1137-1143.
97. Annane D, Sébille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock [published correction appears in JAMA. 2008;300:1652]. JAMA. 2002;288:862-871.
98. Bollaert PE, Charpentier C, Levy B, et al. Reversal of late septic shock with supraphysiologic doses of hydrocortisone. Crit Care Med. 1998;26:645-650.
99. Briegel J, Forst H, Haller M, et al. Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single-center study. Crit Care Med. 1999;27:723-732.
100. Sprung CL, Annane D, Keh D, et al; CORTICUS Study Group. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008;358:111-124.
101. Vincent JL, Baron JF, Reinhart K, et al; ABC (Anemia and Blood Transfusion in Critical Care) Investigators. Anemia and blood transfusion in critically ill patients. JAMA. 2002;288:1499-1507.
102. Nguyen BV, Bota DP, Mélot C, Vincent JL. Time course of hemoglobin concentrations in nonbleeding intensive care unit patients. Crit Care Med. 2003;31:406-410.
103. Hébert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group [published correction appears in N Engl J Med. 1999;340:1056]. N Engl J Med. 1999;340:409-417.
104. Claessens YE, Fontenay M, Pene F, et al. Erythropoiesis abnormalities contribute to early-onset anemia in patients with septic shock. Am J Respir Crit Care Med. 2006;174:51-57.
105. Rogiers P, Zhang H, Leeman M, et al. Erythropoietin response is blunted in critically ill patients. Intensive Care Med. 1997;23:159-162.
106. Corwin HL, Gettinger A, Rodriguez RM, et al. Efficacy of recombinant human erythropoietin in the critically ill patient: a randomized, double-blind, placebo-controlled trial. Crit Care Med. 1999;27:2346-2350.
107. Corwin HL, Gettinger A, Pearl RG, et al; EPO Critical Care Trials Group. Efficacy of recombinant human erythropoietin in critically ill patients: a randomized controlled trial. JAMA. 2002;288:2827-2835.
108. Corwin HL, Gettinger A, Fabian TC, et al; EPO Critical Care Trials Group. Efficacy and safety of epoetin alfa in critically ill patients. N Engl J Med. 2007;357:965-976.