Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23. 315 (8):801-10. [QxMD MEDLINE Link].
Solomkin JS, Mazuski JE, Bradley JS, Rodvold KA, Goldstein EJ, Baron EJ, et al. Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clin Infect Dis. 2010 Jan 15. 50(2):133-64. [QxMD MEDLINE Link].
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 Sep 27. 274(12):968-74. [QxMD MEDLINE Link].
Sands KE, Bates DW, Lanken PN, Graman PS, Hibberd PL, Kahn KL, et al. Epidemiology of sepsis syndrome in 8 academic medical centers. JAMA. 1997 Jul 16. 278(3):234-40. [QxMD MEDLINE Link].
Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S, 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 Jun. 34(6):1589-96. [QxMD MEDLINE Link].
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 Jun. 101(6):1644-55. [QxMD MEDLINE Link].
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. 1992 Jun. 20(6):864-74. [QxMD MEDLINE Link].
Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med. 2003 Apr. 31(4):1250-6. [QxMD MEDLINE Link].
Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, et al. The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med. 1994 Mar. 149(3 Pt 1):818-24. [QxMD MEDLINE Link].
Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012 Jun 20. 307(23):2526-33. [QxMD MEDLINE Link].
Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013 Feb. 41(2):580-637. [QxMD MEDLINE Link].
Sallisalmi M, Tenhunen J, Yang R, Oksala N, Pettilä V. Vascular adhesion protein-1 and syndecan-1 in septic shock. Acta Anaesthesiol Scand. 2012 Mar. 56(3):316-22. [QxMD MEDLINE Link].
Cinel I, Opal SM. Molecular biology of inflammation and sepsis: a primer. Crit Care Med. 2009 Jan. 37(1):291-304. [QxMD MEDLINE Link].
Wheeler AP, Bernard GR. Treating patients with severe sepsis. N Engl J Med. 1999 Jan 21. 340(3):207-14. [QxMD MEDLINE Link].
Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med. 2003 Jan 9. 348(2):138-50. [QxMD MEDLINE Link].
Nguyen HB, Rivers EP, Abrahamian FM, Moran GJ, Abraham E, Trzeciak S, et al. Severe sepsis and septic shock: review of the literature and emergency department management guidelines. Ann Emerg Med. 2006 Jul. 48(1):28-54. [QxMD MEDLINE Link].
Kothari N, Bogra J, Kohli M, Malik A, Kothari D, Srivastava S, et al. Role of active nitrogen molecules in progression of septic shock. Acta Anaesthesiol Scand. 2012 Mar. 56(3):307-15. [QxMD MEDLINE Link].
Crouser ED. Mitochondrial dysfunction in septic shock and multiple organ dysfunction syndrome. Mitochondrion. 2004 Sep. 4(5-6):729-41. [QxMD MEDLINE Link].
Hotchkiss RS, Monneret G, Payen D. Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. Lancet Infect Dis. 2013 Mar. 13(3):260-8. [QxMD MEDLINE Link]. [Full Text].
Kalil AC, Florescu DF. Prevalence and mortality associated with cytomegalovirus infection in nonimmunosuppressed patients in the intensive care unit. Crit Care Med. 2009 Aug. 37(8):2350-8. [QxMD MEDLINE Link].
Lorente JA, Landín L, De Pablo R, Renes E, Rodríguez-Díaz R, Liste D. Effects of blood transfusion on oxygen transport variables in severe sepsis. Crit Care Med. 1993 Sep. 21(9):1312-8. [QxMD MEDLINE Link].
Schuetz P, Jones AE, Aird WC, Shapiro NI. Endothelial cell activation in emergency department patients with sepsis-related and non-sepsis-related hypotension. Shock. 2011 Aug. 36(2):104-8. [QxMD MEDLINE Link]. [Full Text].
Levi M, ten Cate H, van der Poll T, van Deventer SJ. Pathogenesis of disseminated intravascular coagulation in sepsis. JAMA. 1993 Aug 25. 270(8):975-9. [QxMD MEDLINE Link].
Mammen EF. Antithrombin III and sepsis. Intensive Care Med. 1998 Jul. 24(7):649-50. [QxMD MEDLINE Link].
Trzeciak S, Rivers EP. Clinical manifestations of disordered microcirculatory perfusion in severe sepsis. Crit Care. 2005. 9 Suppl 4:S20-6. [QxMD MEDLINE Link].
Landry DW, Oliver JA. The pathogenesis of vasodilatory shock. N Engl J Med. 2001 Aug 23. 345(8):588-95. [QxMD MEDLINE Link].
Katzenstein AL, Myers JL, Mazur MT. Acute interstitial pneumonia. A clinicopathologic, ultrastructural, and cell kinetic study. Am J Surg Pathol. 1986 Apr. 10(4):256-67. [QxMD MEDLINE Link].
Cetinbas F, Yelken B, Gulbas Z. Role of glutamine administration on cellular immunity after total parenteral nutrition enriched with glutamine in patients with systemic inflammatory response syndrome. J Crit Care. 2010 Dec. 25(4):661.e1-6. [QxMD MEDLINE Link].
Hamzaoui O, Carlet J. Organ dysfunctions during severe sepsis and septic-like syndromes: epidemiology, classification, and mechanism. Cavaillon J-M, Adrie C, eds. Sepsis and Non-infectious Systemic Inflammation: From Biology to Critical Care. .Weinheim, Germany: Wiley-VCH Verlag GmbH; 2009. 57-77.
Baluch A, Janoo A, Lam K, Hoover J, Kaye A. Septic shock: review and anesthetic considerations. Middle East J Anesthesiol. 2007 Feb. 19(1):71-86. [QxMD MEDLINE Link].
Kotb M. Diseases due to encapsulated bacteria. Kaslow RA, McNicholl JM, Hill AVS, Kotb M, eds. Genetic Susceptibility to Infectious Diseases. New York, NY: Oxford University Press; 2008. 351-71.
Kramnik I. Genetic dissection of host resistance to Mycobacterium tuberculosis: the sst1 locus and the Ipr1 gene. Curr Top Microbiol Immunol. 2008. 321:123-48. [QxMD MEDLINE Link].
Blackwell JM, Jamieson SE, Burgner D. HLA and infectious diseases. Clin Microbiol Rev. 2009 Apr. 22(2):370-85, Table of Contents. [QxMD MEDLINE Link]. [Full Text].
Kotb M, Norrby-Teglund A, McGeer A, El-Sherbini H, Dorak MT, Khurshid A, et al. An immunogenetic and molecular basis for differences in outcomes of invasive group A streptococcal infections. Nat Med. 2002 Dec. 8(12):1398-404. [QxMD MEDLINE Link].
Nooh MM, Nookala S, Kansal R, Kotb M. Individual genetic variations directly effect polarization of cytokine responses to superantigens associated with streptococcal sepsis: implications for customized patient care. J Immunol. 2011 Mar 1. 186(5):3156-63. [QxMD MEDLINE Link].
Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008 Jan 10. 358(2):111-24. [QxMD MEDLINE Link].
Ranieri VM, Thompson BT, Barie PS, Dhainaut JF, Douglas IS, Finfer S, et al. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med. 2012 May 31. 366(22):2055-64. [QxMD MEDLINE Link].
Levy MM, Artigas A, Phillips GS, Rhodes A, Beale R, Osborn T, et al. Outcomes of the Surviving Sepsis Campaign in intensive care units in the USA and Europe: a prospective cohort study. Lancet Infect Dis. 2012 Dec. 12(12):919-24. [QxMD MEDLINE Link].
Opal SM, Laterre PF, Francois B, LaRosa SP, Angus DC, Mira JP, et al. Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial. JAMA. 2013 Mar 20. 309(11):1154-62. [QxMD MEDLINE Link].
Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001 Jul. 29(7):1303-10. [QxMD MEDLINE Link].
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 Apr 17. 348(16):1546-54. [QxMD MEDLINE Link].
Wang HE, Shapiro NI, Angus DC, Yealy DM. National estimates of severe sepsis in United States emergency departments. Crit Care Med. 2007 Aug. 35(8):1928-36. [QxMD MEDLINE Link].
Hall MJ, Williams SN, DeFrances CJ, Golosinskiy A. Inpatient care for septicemia or sepsis: a challenge for patients and hospitals. NCHS Data Brief. 2011 Jun. 1-8. [QxMD MEDLINE Link].
Gaieski DF, Edwards JM, Kallan MJ, Carr BG. Benchmarking the incidence and mortality of severe sepsis in the United States. Crit Care Med. 2013 May. 41(5):1167-74. [QxMD MEDLINE Link].
Shapiro N, Howell MD, Bates DW, Angus DC, Ngo L, Talmor D. The association of sepsis syndrome and organ dysfunction with mortality in emergency department patients with suspected infection. Ann Emerg Med. 2006 Nov. 48(5):583-90, 590.e1. [QxMD MEDLINE Link].
Mayr FB, Yende S, Linde-Zwirble WT, Peck-Palmer OM, Barnato AE, Weissfeld LA, et al. Infection Rate and Acute Organ Dysfunction Risk as Explanations for Racial Differences in Severe Sepsis. JAMA. Jun 2010. 303(24):2495-2503.
Kaukonen KM, Bailey M, Suzuki S, Pilcher D, Bellomo R. Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000-2012. JAMA. 2014 Apr 2. 311(13):1308-16. [QxMD MEDLINE Link].
Rangel-Frausto MS, Pittet D, Costigan M, Hwang T, Davis CS, Wenzel RP. The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study. JAMA. 1995 Jan 11. 273(2):117-23. [QxMD MEDLINE Link].
Brun-Buisson C. The epidemiology of the systemic inflammatory response. Intensive Care Med. 2000. 26 Suppl 1:S64-74. [QxMD MEDLINE Link].
Jung B, Nougaret S, Chanques G, et al. The Absence of Adrenal Gland Enlargement during Septic Shock Predicts Mortality: A Computed Tomography Study of 239 Patients. Anesthesiology. 2011 Aug. 115(2):334-343. [QxMD MEDLINE Link].
Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S, 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 Jun. 34(6):1589-96. [QxMD MEDLINE Link].
Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA. 2010 Oct 27. 304(16):1787-94. [QxMD MEDLINE Link].
Dennen P, Douglas IS, Anderson R. Acute kidney injury in the intensive care unit: an update and primer for the intensivist. Crit Care Med. 2010 Jan. 38(1):261-75. [QxMD MEDLINE Link].
Sepsis syndrome in urology (urosepsis). Grabe M, Bjerklund-Johansen TE, et al, eds. Guidelines on urological infections. Arnhem, The Netherlands: European Association of Urology (EAU); 2011. 33-9. [Full Text].
Rangel-Frausto MS, Pittet D, Hwang T, Woolson RF, Wenzel RP. The dynamics of disease progression in sepsis: Markov modeling describing the natural history and the likely impact of effective antisepsis agents. Clin Infect Dis. 1998 Jul. 27(1):185-90. [QxMD MEDLINE Link].
Annane D, Aegerter P, Jars-Guincestre MC, Guidet B. Current epidemiology of septic shock: the CUB-Réa Network. Am J Respir Crit Care Med. 2003 Jul 15. 168(2):165-72. [QxMD MEDLINE Link].
Yealy DM, Kellum JA, Huang DT, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014 May 1. 370(18):1683-93. [QxMD MEDLINE Link]. [Full Text].
Peake SL, Delaney A, Bailey M, Bellomo R, Cameron PA, Cooper DJ, et al. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014 Oct 16. 371(16):1496-506. [QxMD MEDLINE Link].
Mouncey PR, Osborn TM, Power GS, Harrison DA, Sadique MZ, Grieve RD, et al. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med. 2015 Apr 2. 372(14):1301-11. [QxMD MEDLINE Link].
[Guideline] Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008 Jan. 36(1):296-327. [QxMD MEDLINE Link].
Levy B, Gibot S, Franck P, Cravoisy A, Bollaert PE. Relation between muscle Na+K+ ATPase activity and raised lactate concentrations in septic shock: a prospective study. Lancet. 2005 Mar 5-11. 365(9462):871-5. [QxMD MEDLINE Link].
Shapiro NI, Howell MD, Talmor D, Nathanson LA, Lisbon A, Wolfe RE, et al. Serum lactate as a predictor of mortality in emergency department patients with infection. Ann Emerg Med. 2005 May. 45(5):524-8. [QxMD MEDLINE Link].
Nguyen HB, Rivers EP, Knoblich BP, Jacobsen G, Muzzin A, Ressler JA, et al. Early lactate clearance is associated with improved outcome in severe sepsis and septic shock. Crit Care Med. 2004 Aug. 32(8):1637-42. [QxMD MEDLINE Link].
Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA. 2010 Feb 24. 303(8):739-46. [QxMD MEDLINE Link]. [Full Text].
Marik PE, Pastores SM, Annane D, Meduri GU, Sprung CL, Arlt W, et al. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med. 2008 Jun. 36(6):1937-49. [QxMD MEDLINE Link].
Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007 Mar 1. 44 Suppl 2:S27-72. [QxMD MEDLINE Link].
Griffee MJ, Merkel MJ, Wei KS. The role of echocardiography in hemodynamic assessment of septic shock. Crit Care Clin. 2010 Apr. 26(2):365-82, table of contents. [QxMD MEDLINE Link].
Kalil AC. Wanted: early goal-directed therapy for septic shock--dead or alive, but not critically ill!. Intensive Care Med. 2010 Jan. 36(1):1-3. [QxMD MEDLINE Link].
NIH Press Release. Sepsis study comparing three treatment methods shows same survival rate. National Institutes of Health. Available at http://www.nih.gov/news/health/mar2014/nigms-18.htm. Accessed: March 24, 2014.
A Randomized Trial of Protocol-Based Care for Early Septic Shock. N Engl J Med. 2014 Mar 18. [QxMD MEDLINE Link].
Khanna A, English SW, Wang XS, et al. Angiotensin II for the Treatment of Vasodilatory Shock. N Engl J Med. 2017 Aug 3. 377 (5):419-430. [QxMD MEDLINE Link].
Martin G. Angiotensin II: New Hope for Treating Septic Shock?. Medscape News & Perspective. Available at https://www.medscape.com/viewarticle/887520. October 27, 2017; Accessed: October 30, 2017.
Kreymann G, Grosser S, Buggisch P, Gottschall C, Matthaei S, Greten H. Oxygen consumption and resting metabolic rate in sepsis, sepsis syndrome, and septic shock. Crit Care Med. 1993 Jul. 21 (7):1012-9. [QxMD MEDLINE Link].
Sevransky JE, Levy MM, Marini JJ. Mechanical ventilation in sepsis-induced acute lung injury/acute respiratory distress syndrome: an evidence-based review. Crit Care Med. 2004 Nov. 32(11 Suppl):S548-53. [QxMD MEDLINE Link].
Dellinger RP, Carlet JM, Masur H. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med. 2004 Mar. 32(3):858-73. [QxMD MEDLINE Link].
Royal College of Obstetricians and Gynaecologists (RCOG). Maternal collapse in pregnancy and the puerperium. 2011.
Vallet B, Pinsky MR, Cecconi M. Resuscitation of patients with septic shock: please "mind the gap"!. Intensive Care Med. 2013 Sep. 39(9):1653-5. [QxMD MEDLINE Link]. [Full Text].
Monnet X, Julien F, Ait-Hamou N, Lequoy M, Gosset C, Jozwiak M, et al. Lactate and venoarterial carbon dioxide difference/arterial-venous oxygen difference ratio, but not central venous oxygen saturation, predict increase in oxygen consumption in fluid responders. Crit Care Med. 2013 Jun. 41(6):1412-20. [QxMD MEDLINE Link].
Marik PE, Baram M, Vahid B. Does central venous pressure predict fluid responsiveness? A systematic review of the literature and the tale of seven mares. Chest. 2008 Jul. 134(1):172-8. [QxMD MEDLINE Link].
Nagdev AD, Merchant RC, Tirado-Gonzalez A, Sisson CA, Murphy MC. Emergency department bedside ultrasonographic measurement of the caval index for noninvasive determination of low central venous pressure. Ann Emerg Med. 2010 Mar. 55(3):290-5. [QxMD MEDLINE Link].
Asfar P, Meziani F, Hamel JF, et al. High versus low blood-pressure target in patients with septic shock. N Engl J Med. 2014 Apr 24. 370(17):1583-93. [QxMD MEDLINE Link].
Vincent JL, Gerlach H. Fluid resuscitation in severe sepsis and septic shock: an evidence-based review. Crit Care Med. 2004 Nov. 32(11 Suppl):S451-4. [QxMD MEDLINE Link].
Delaney AP, Dan A, McCaffrey J, Finfer S. The role of albumin as a resuscitation fluid for patients with sepsis: a systematic review and meta-analysis. Crit Care Med. 2011 Feb. 39(2):386-91. [QxMD MEDLINE Link].
Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton R. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. 2004 May 27. 350(22):2247-56. [QxMD MEDLINE Link].
Lira A, Pinsky MR. Choices in fluid type and volume during resuscitation: impact on patient outcomes. Ann Intensive Care. 2014. 4:38. [QxMD MEDLINE Link]. [Full Text].
Schortgen F, Clabault K, Katsahian S, Devaquet J, Mercat A, Deye N, et al. Fever control using external cooling in septic shock: a randomized controlled trial. Am J Respir Crit Care Med. 2012 May 15. 185(10):1088-95. [QxMD MEDLINE Link].
Pearse RM, Harrison DA, MacDonald N, et al. Effect of a perioperative, cardiac output-guided hemodynamic therapy algorithm on outcomes following major gastrointestinal surgery: a randomized clinical trial and systematic review. JAMA. 2014 Jun 4. 311(21):2181-90. [QxMD MEDLINE Link].
Vasu TS, Cavallazzi R, Hirani A, et al. Norephinephrine or Dopamine for Septic Shock: A Systematic Review of Randomized Clinical Trials. J Intensive Care Med. 2011 Mar 24. [QxMD MEDLINE Link].
De Backer D, Aldecoa C, Njimi H, Vincent JL. Dopamine versus norepinephrine in the treatment of septic shock: a meta-analysis*. Crit Care Med. 2012 Mar. 40(3):725-30. [QxMD MEDLINE Link].
Beale RJ, Hollenberg SM, Vincent JL, Parrillo JE. Vasopressor and inotropic support in septic shock: an evidence-based review. Crit Care Med. 2004 Nov. 32(11 Suppl):S455-65. [QxMD MEDLINE Link].
Russell JA. Vasopressin in septic shock. Crit Care Med. 2007 Sep. 35(9 Suppl):S609-15. [QxMD MEDLINE Link].
Russell JA, Walley KR, Singer J, Gordon AC, Hébert PC, Cooper DJ, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008 Feb 28. 358(9):877-87. [QxMD MEDLINE Link].
Hayes MA, Timmins AC, Yau EH, et al. Elevation of systemic oxygen delivery in the treatment of critically ill patients. N Engl J Med. 1994 Jun 16. 330(24):1717-22. [QxMD MEDLINE Link].
Pitout JD, Laupland KB. Extended-spectrum beta-lactamase-producing Enterobacteriaceae: an emerging public-health concern. Lancet Infect Dis. 2008 Mar. 8(3):159-66. [QxMD MEDLINE Link].
Bochud PY, Bonten M, Marchetti O, Calandra T. Antimicrobial therapy for patients with severe sepsis and septic shock: an evidence-based review. Crit Care Med. 2004 Nov. 32(11 Suppl):S495-512. [QxMD MEDLINE Link].
Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill patients. N Engl J Med. 2003 Feb 20. 348(8):727-34. [QxMD MEDLINE Link].
Cronin L, Cook DJ, Carlet J, Heyland DK, King D, Lansang MA, et al. Corticosteroid treatment for sepsis: a critical appraisal and meta-analysis of the literature. Crit Care Med. 1995 Aug. 23(8):1430-9. [QxMD MEDLINE Link].
Kalil AC, Sun J. Low-dose steroids for septic shock and severe sepsis: the use of Bayesian statistics to resolve clinical trial controversies. Intensive Care Med. 2011 Mar. 37(3):420-9. [QxMD MEDLINE Link].
Briegel J, Forst H, Haller M. Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single-center study. Crit Care Med. 1999 Apr. 27(4):723-32. [QxMD MEDLINE Link].
Annane D, Sébille V, Charpentier C, Bollaert PE, François B, Korach JM, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002 Aug 21. 288(7):862-71. [QxMD MEDLINE Link].
Annane D, Bellissant E, Bollaert PE, Briegel J, Confalonieri M, De Gaudio R, et al. Corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review. JAMA. 2009 Jun 10. 301(22):2362-75. [QxMD MEDLINE Link].
Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008 Jan 10. 358(2):111-24. [QxMD MEDLINE Link].
Moreno R, Sprung CL, Annane D, Chevret S, Briegel J, Keh D, et al. Time course of organ failure in patients with septic shock treated with hydrocortisone: results of the Corticus study. Intensive Care Med. 2011 Nov. 37(11):1765-72. [QxMD MEDLINE Link].
van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, et al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001 Nov 8. 345(19):1359-67. [QxMD MEDLINE Link].
Arabi YM, Dabbagh OC, Tamim HM, Al-Shimemeri AA, Memish ZA, Haddad SH, et al. Intensive versus conventional insulin therapy: a randomized controlled trial in medical and surgical critically ill patients. Crit Care Med. 2008 Dec. 36(12):3190-7. [QxMD MEDLINE Link].
Preiser JC, Devos P, Ruiz-Santana S, Mélot C, Annane D, Groeneveld J, et al. A prospective randomised multi-centre controlled trial on tight glucose control by intensive insulin therapy in adult intensive care units: the Glucontrol study. Intensive Care Med. 2009 Oct. 35(10):1738-48. [QxMD MEDLINE Link].
Finfer S, Chittock DR, Su SY, Blair D, Foster D, Dhingra V, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009 Mar 26. 360(13):1283-97. [QxMD MEDLINE Link].
Finfer S, Liu B, Chittock DR, Norton R, Myburgh JA, McArthur C, et al. Hypoglycemia and risk of death in critically ill patients. N Engl J Med. 2012 Sep 20. 367(12):1108-18. [QxMD MEDLINE Link].
Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N, et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008 Jan 10. 358(2):125-39. [QxMD MEDLINE Link].
Kalfon P, Giraudeau B, Ichai C, Guerrini A, Brechot N, Cinotti R, et al. Tight computerized versus conventional glucose control in the ICU: a randomized controlled trial. Intensive Care Med. 2014 Feb. 40(2):171-81. [QxMD MEDLINE Link].
Levi M, Toh CH, Thachil J, Watson HG. Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology. Br J Haematol. 2009 Apr. 145(1):24-33. [QxMD MEDLINE Link].
Meduri GU, Headley AS, Golden E, et al. Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial. JAMA. 1998 Jul 8. 280(2):159-65. [QxMD MEDLINE Link].
Nathens AB, Rotstein OD. Selective decontamination of the digestive tract in acute severe pancreatitis--an indication whose time has come. Clin Infect Dis. 1997 Oct. 25(4):817-8. [QxMD MEDLINE Link].

Media Gallery

Strawberry tongue in a child with staphylococcal toxic shock syndrome. Reproduced with permission from Drage, LE. Life-threatening rashes: dermatologic signs of four infectious diseases. Mayo Clin Proc. 1999;74:68-72.
Venn diagram showing the overlap of infection, bacteremia, sepsis, systemic inflammatory response syndrome (SIRS), and multiorgan dysfunction.
A 26-year-old woman developed rapidly progressive shock associated with purpura and signs of meningitis. Her blood culture results confirmed the presence of Neisseria meningitidis. The skin manifestation seen in this image is characteristic of severe meningococcal infection and is called purpura fulminans.
Gram stain of blood showing the presence of Neisseria meningitidis.
Acute respiratory distress syndrome (ARDS), commonly observed in septic shock as a part of multiorgan failure syndrome, results in pathologically diffuse alveolar damage (DAD). This photomicrograph shows early stage (exudative stage) DAD.
Acute respiratory distress syndrome (ARDS), commonly observed in septic shock as a part of multiorgan failure syndrome, results in pathologically diffuse alveolar damage (DAD). This is a high-powered photomicrograph of early stage (exudative stage) DAD.
Photomicrograph showing delayed stage (proliferative or organizing stage) of diffuse alveolar damage (DAD). Proliferation of type II pneumocytes has occurred; hyaline membranes as well as collagen and fibroblasts are present.
Photomicrograph showing delayed stage (proliferative or organizing stage) of diffuse alveolar damage (DAD). Fibrin stain depicts collagenous tissue, which may develop into fibrotic stage of DAD.
Acute respiratory distress syndrome (ARDS) in a patient who developed septic shock secondary to toxic shock syndrome.
Bilateral airspace disease and acute respiratory failure in a patient with gram-negative septic shock. The source of the sepsis was urosepsis.
A 45-year-old woman was admitted to the intensive care unit with septic shock secondary to spontaneous biliary peritonitis. She subsequently developed acute respiratory distress syndrome (ARDS) and multiorgan failure.
An 8-year-old boy developed septic shock secondary to Blastomycosis pneumonia. Fungal infections are rare causes of septic shock.
A 28-year-old woman who was a former intravenous drug user (human immunodeficiency virus [HIV] status: negative) developed septic shock secondary to bilateral pneumococcal pneumonia.
Diagram depicting the pathogenesis of sepsis and multiorgan failure. DIC = disseminated intravascular coagulation; IL = interleukin.
Soft-tissue infection secondary to group A streptococci, leading to toxic shock syndrome.
Necrotizing cellulitis of toxic shock syndrome.
Necrosis of the little toe of the right foot and cellulitis of the foot secondary to group A streptococcal infection.
Group A streptococci cause beta hemolysis on blood agar.
Gram stain of blood showing group A streptococci that was isolated from a patient who developed toxic shock syndrome. Image courtesy of T. Matthews.
A 46-year-old man presented with nonnecrotizing cellulitis and streptococcal toxic shock syndrome. The leg was incised to exclude underlying necrotizing infection. Image courtesy of Rob Green, MD.
A 46-year-old man presented with nonnecrotizing cellulitis and streptococcal toxic shock syndrome (same patient as in previous image). This patient also had streptococcal pharyngitis. Image courtesy of Rob Green, MD.
A 46-year-old man presented with nonnecrotizing cellulitis and streptococcal toxic shock syndrome (same patient as in previous image). The patient had diffuse erythroderma, a characteristic feature of the syndrome. Image courtesy of Rob Green, MD.
A 46-year-old man presented with nonnecrotizing cellulitis and streptococcal toxic shock syndrome (same patient as in previous image). The patient had diffuse erythroderma, a characteristic feature of the syndrome. He improved with antibiotics and intravenous gammaglobulin therapy. Several days later, a characteristic desquamation of the skin occurred over his palms and soles. Image courtesy of Rob Green, MD.
Progression of soft-tissue swelling to vesicle or bullous formation is an ominous sign and suggests streptococcal shock syndrome. Image courtesy of S. Manocha.
Extensive debridement of necrotizing fasciitis of the hand.
Healing of the hand after aggressive surgical debridement of necrotizing fasciitis (same patient as in previous image).
A 58-year-old patient presented in septic shock. On physical examination, progressive swelling of the right groin was observed. On exploration, necrotizing cellulitis, but not fasciitis, was present. The wound cultures grew group A streptococci. The patient developed severe shock (toxic shock syndrome). Computed tomography (CT) scanning helped to evaluate the extent of the infection and to exclude other pathologies (eg, psoas abscess, osteomyelitis, inguinal hernia).
Computed tomography (CT) scan from a 58-year-old patient who presented in septic shock (same patient as in previous image). Progressive swelling of the right groin was noted, and necrotizing cellulitis, but not fasciitis, was present. The wound cultures grew group A streptococci. The patient developed severe shock (toxic shock syndrome). CT scanning helped in the evaluation of the extent of the infection and in the exclusion of other pathologies (eg, psoas abscess, osteomyelitis, inguinal hernia).
Computed tomography (CT) scan from a 58-year-old patient who presented in septic shock (same patient as in previous image). Progressive swelling of the right groin was noted, and necrotizing cellulitis, but not fasciitis, was present. The wound cultures grew group A streptococci. The patient developed severe shock (toxic shock syndrome). CT scanning helped in the evaluation of the extent of the infection and in the exclusion of other pathologies (eg, psoas abscess, osteomyelitis, inguinal hernia).
Space-occupying lesion correlating with left temporoparietal metastatic infiltration associated with peritumoral edema.
Space-occupying lesion correlating with left temporoparietal metastatic infiltration associated with peritumoral edema (same lesion as shown in previous computed tomography image).

of 31

Table 1. Sepsis-Related SOFA Score (adapted from Singer et al)

System

0 Points

1 Point

2 Points

3 Points

4 Points

Respiration

PaO₂^a/FiO₂^b

≥400 mm Hg

< 400 mm Hg

< 300 mm Hg

< 200 mm Hg

(with respiratory support)

< 100 mm Hg

(with respiratory support)

Coagulation

Platelet count

≥150 x 10³/µL

< 150 x 10³/µL

< 100 x 10³/µL

< 50 x 10³/µL

< 20 x 10³/µL

Liver

Bilirubin level

< 1.2 mg/dL

1.2-1.9 mg/dL

2-5.9 mg/dL

6-11.9 mg/dL

>12 mg/dL

Cardiovascular

MAP^c ≥70 mm Hg

MAP >70 mm Hg

Dopamine < 5 or

dobutamine (any dose)^e

Dopamine 5.1-15 or

epinephrine ≤0.1 or

norepinephrine ≤0.1^e

Dopamine >15 or

epinephrine >0.1 or

norepinephrine >0.1^e

Central nervous system

GCS^d score

13-14

10-12

6-9

< 6

Renal

Creatinine

Urine output

< 1.2 mg/dL

1.2-1.9 mg/dL

2-3.4 mg/dL

3.5-4.9 mg/dL

< 500 mL/day

>5 mg/dL

< 200 mL/day

^aPaO₂=Partial pressure of oxygen.

^bFiO₂=Fraction of inspired oxygen.

^cMAP=Mean arterial pressure.

^dGCS=Glasgow Coma Scale (range, 3-15, with higher indicating better function).

^eCatecholamine doses administered as µg/kg/min for ≥1 hour.

Table 2. Surviving Sepsis Guidelines Criteria for Organ Dysfunction

Organ System	Sepsis Criteria	Severe Sepsis Criteria
Pulmonary	Arterial hypoxemia: PaO₂/FIO₂< 300	Arterial hypoxemia: PaO₂/FIO₂< 250 in absence of pneumonia and < 200 in presence of pneumonia
Hepatic	Hyperbilirubinemia: Plasma total bilirubin >4 mg/dL or 70 µmol/L	Hyperbilirubinemia: Plasma total bilirubin >2 mg/dL or 34.2 µmol/L
Renal	Creatinine increase >0.5 mg/dL or 44.2 µmol/L Acute oliguria: Urine output < 0.5 mL/kg/hr for ≥2 hr despite adequate fluid resuscitation	Creatinine >2 mg/dL or 176.8 µmol/L Acute oliguria: Urine output < 0.5mL/kg/hr for ≥2 hr despite adequate fluid resuscitation
Gastrointestinal	Ileus: Absent bowel sounds
Hematologic	INR >1.5, aPTT >60 s, or platelets < 100,000/µL	INR >1.5 or platelets < 100,000/µL
Cardiovascular	Hyperlactatemia >1 mmol/L; decreased capillary refill or mottling Hemodynamic status: SBP < 90 mm Hg, MAP < 70 mm Hg, or SBP decrease >40 mm Hg	Hyperlactatemia: Above upper limits of laboratory normal Hemodynamic status: SBP < 90 mm Hg, MAP < 70 mm Hg, or SBP decrease >40 mm Hg
Central nervous system	Confusion, lethargy, coma

aPTT = activated partial thromboplastin time; FIO₂ = fraction of inspired oxygen; INR = international normalized ratio; MAP = mean arterial pressure; PaO₂ = partial pressure of oxygen; PEEP = positive end-expiratory pressure; PT = prothrombin time; SBP = systolic blood pressure. Source: Dellinger RP, Levy MM, Rhodes A, et al, for the Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013 Feb;41(2):580-637.^[11]

Table 3. Mediators of Sepsis

Type	Mediator	Activity
Cellular mediators	LPS	Activation of macrophages, neutrophils, platelets, and endothelium releases various cytokines and other mediators
	Lipoteichoic acid
	Peptidoglycan
	Superantigens
	Endotoxin
Humoral mediators	Cytokines	Activate inflammatory pathways
	TNF-α and IL-1β	Potent proinflammatory effect
	IL-6	Acts as pyrogen, stimulates B- and T-cell proliferation
	IL-8	Neutrophil chemotactic factor, activation and degranulation of neutrophils
	IL-10	Inhibits cytokine production, induces immunosuppression
	MIF	Activates macrophages and T cells
	G-CSF	Promotes neutrophil and macrophage, platelet activation
	Complement	Promotes neutrophil and macrophage, platelet activation and chemotaxis, other proinflammatory effects
	Nitric oxide	Involved in hemodynamic alterations of septic shock; cytotoxic, augments vascular permeability, contributes to shock
	Lipid mediators	Enhance vascular permeability and contribute to lung injury
	Phospholipase A2
	PAF
	Eicosanoids
	Arachidonic acid metabolites	Augment vascular permeability
	Adhesion molecules	Enhance neutrophil-endothelial cell interaction, regulate leukocyte migration and adhesion, and play a role in pathogenesis of sepsis; increased levels of VAP-1 activity and anchor protein SDC-1 content have been found in critically ill patients with septic shock^[12]
	Selectins
	Leukocyte integrins
	High mobility box–1	Late mediator of endotoxin-induced lethality and tissue repair
G-CSF = granulocyte colony-stimulating factor; IL = interleukin; LPS = lipopolysaccharide; MIF = macrophage inhibitory factor; PAF = platelet-activating factor; SDC-1 = syndecan-1; TNF = tumor necrosis factor; VAP-1 = vascular adhesion protein–1. Source: Cinel I, Opal SM. Molecular biology of inflammation and sepsis: a primer. Crit Care Med. 2009 Jan;37(1):291-304.^[13]

Back to List

Author

Andre Kalil, MD, MPH Professor of Medicine, Department of Medicine, Section of Infectious Diseases, University of Nebraska College of Medicine; Director, Transplant ID Program, University of Nebraska Medical Center

Disclosure: Nothing to disclose.

Coauthor(s)

Kristina L Bailey, MD Assistant Professor, Department of Medicine, Section of Pulmonary, Critical Care, Sleep and Allergy, University of Nebraska Medical Center

Kristina L Bailey, MD is a member of the following medical societies: American College of Chest Physicians, American Thoracic Society, Research Society on Alcoholism

Disclosure: Nothing to disclose.

Chief Editor

Michael R Pinsky, MD, CM, Dr(HC), FCCP, FAPS, MCCM Professor of Critical Care Medicine, Bioengineering, Cardiovascular Disease, Clinical and Translational Science and Anesthesiology, Vice-Chair of Academic Affairs, Department of Critical Care Medicine, University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine

Michael R Pinsky, MD, CM, Dr(HC), FCCP, FAPS, MCCM is a member of the following medical societies: American College of Chest Physicians, American College of Critical Care Medicine, American Thoracic Society, European Society of Intensive Care Medicine, Society of Critical Care Medicine

Disclosure: Received income in an amount equal to or greater than $250 from: Baxter Medical, Exostat, LiDCO<br/>Received honoraria from LiDCO Ltd for consulting; Received intellectual property rights from iNTELOMED.

Acknowledgements

Fatima Al Faresi, MD Dermatologist, Tawam Hospital, Al Ain, UAE