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Review article

Development of the definition of sepsis

Dimić Nemanja1,2, Đurić Marko1,2, Nenadić Irina1,2, Boboš Marina1, Bojić Suzana1,2, Vukotić Tatjana1, Simeunović Gojgić Mirjana3, Gojgić Milan4, Stevanović Predrag1,2, Bojović Ksenija5
  • University Clinical Hospital Center Dr Dragiša Mišović – Dedinje, Belgrade, Serbia
  • University of Belgrade, Faculty of Medicine, Belgrade, Serbia
  • City Institute for Public Health, Belgrade, Serbia
  • University Hospital Medical Center Bežanijska kosa, Belgrade, Serbia
  • University of East Sarajevo, Faculty of Medicine Foča, Republic of Srpska

ABSTRACT

Sepsis is a significant health problem, considering that, annually, over 20 million people fall ill from sepsis. Despite the significant development of medicine in recent decades, the mortality rate of sepsis is exceptionally high (about 26%). The definition of sepsis developed together with the understanding of the mechanism of sepsis. At the beginning of the 1990s, the first definition of sepsis was created, according to which sepsis was defined as systemic inflammatory response syndrome (SIRS), with the presence of suspicion or evidence of infection. Due to many inadequately diagnosed patients with sepsis, another definition was created, according to which sepsis is defined as a clinical syndrome. As the result of the lack of clarity of the previous definitions and the new information on the pathophysiological process of sepsis, a third definition of sepsis was developed in 2016. According to this definition, sepsis is a life-threatening condition based on organic dysfunction resulting from the body’s inappropriate response to infection. Septic shock manifests as circulatory, cellular and metabolic instability. It is characterized by a serum lactate level higher than 2 mmol/l and hypotension, which requires vasopressor therapy after the administration of intravenous solutions. This definition of sepsis and septic shock enables early recognition and treatment of patients with sepsis, which are critical steps in reducing the incidence and mortality from this disease.


INTRODUCTION

Sepsis and septic shock are major health problems affecting millions of people worldwide, each year [1]. Namely, around 20 million people around the world fall ill with sepsis, annually. Sepsis has a high mortality rate (roughly 26%), making it potentially responsible for almost five million fatalities each year [2]. Despite the advances in medicine, the total number of deaths from sepsis continues to rise as more and more people become ill [3]. The development of the definition of sepsis is related to understanding the mechanism of sepsis. Namely, more than 100 years ago, William Osler concluded: “it seems that the patient dies from the body’s response to the infection, not from the infection itself.” Today, we know that releasing inflammatory mediators by innate immune cells after pathogen recognition leads to the activation of the coagulation cascade, vasodilation, extravasation of neutrophils and inflammatory mediators into the extravascular space and consequent organ dysfunction and hypotension during sepsis [4].

HISTORY OF THE DEFINITION OF SEPSIS

The word sepsis comes from the Greek word σήψη, which denotes the decomposition of animal, vegetable or organic matter in the presence of bacteria. The first use of this term for medical purposes was documented around 2.700years ago, in Homer’s poems, denoting putrefaction. Later, this term can be found in the writings of the great Greek physician and philosopher Hippocrates. According to Hippocrates, this term denoted dangerous and unpleasant biological decomposition, occurring in the human body, most likely in the large intestine, and potentially leading to systemic intoxication. After the ancient Greeks, the ancient Romans, most notably Galen, also attempted to define sepsis. They considered sepsis to result from the production of invisible creatures (microorganisms), which emit putrid fumes [5].

Several hundred years passed before new definitions of sepsis were formulated. At the beginning of the 19th century, with the discovery of the first microscope, the “germ theory” was developed, after which it became indisputable that sepsis occurs due to harmful microorganisms. According to this theory, germs (microorganisms) cause all infections, and any infectious disease can be cured by killing the germs causing it [6]. In 1914, Hugo Schottmüller concluded that “sepsis is present if a focus has developed from which pathogenic bacteria, constantly or periodically, enter the bloodstream in such a way that it causes subjective and objective symptoms” [7].

In the middle of the 20th century,  sepsis  was defined as a severe generalized infectious disease caused mainly by a purulent germ, which successively enters the bloodstream from the primary focus, creating metastases [8]. At the end of the 20th century, the first contemporary definition of sepsis was formulated.

THE FIRST CONTEMPORARY DEFINITION OF SEPSIS

In the early 1990s, an international consortium of experts was established, with the aim of reducing sepsis-related mortality, through the application of a specifically designed program focused on early diagnosis and application of the appropriate therapy [9]. Namely, based on the 1992 consensus, sepsis was defined as the presence of at least two criteria of systemic inflammatory response syndrome (SIRS), with a high degree of suspicion of infection or with proven presence of infection [10]. The following SIRS criteria were established:

  1. body temperature above 38 °C or below 36 °C;
  2. heart rate of over 90 beats per minute;
  3. respiratory rate of over 20/min or carbon dioxide partial pressure below 4.3 kPa,
  4. leukocytosis (number of leukocytes above 12,000/mm3 ) or leukopenia (number of leukocytes below 4,000/mm3 , with 10% or more of unsegmented peripheral blood neutrophils), (Table 1).

Table 1. Expanded Disability Status Scale – EDSS

Table 1. Expanded Disability Status Scale – EDSS

The non-specificity of SIRS signs, which the definition of sepsis was based on, led to a significant discrepancy in the presentation of sepsis incidence and sepsis-related mortality in epidemiological studies. In addition to sepsis, the terms severe sepsis and septic shock were also defined. Severe sepsis was defined as sepsis associated with organ dysfunction, hypoperfusion, and hypotension, while septic shock was defined as the state of sepsis with arterial hypotension unresponsive to intravenous fluid replacement. This definition of sepsis was not specific enough to distinguish patients with sepsis from those with a normal inflammatory response to infection or an inflammatory condition not caused by infection [11]. Nevertheless, since the first definition of sepsis, our knowledge of the mechanisms of the host’s response to pathogens has improved significantly [12].

THE SECOND CONTEMPORARY DEFINITION OF SEPSIS

Due to a high number of undiagnosed or inadequately diagnosed patients with sepsis, in 2001, the original definition of sepsis was adapted to make the diagnosis easier for clinicians. According to this definition, sepsis is designated as a clinical syndrome. Septic patients are classified according to the severity of the clinical condition – from septicemia to severe sepsis, accompanied by the dysfunction of vital organs and septic shock as the most severe form of sepsis [13]. After this definition was introduced, the incidence of sepsis and septic shock increased significantly, and the reason for this was the presence of a large number of immunocompromised patients and patients with numerous comorbidities, but also the lack of specificity of the definition, according to which the group of patients with sepsis also included patients with uncomplicated or mild infection [14]. Nevertheless, this definition ensured the early diagnosis of sepsis and the early initiation of therapy, which are extremely important in preventing the progression of this condition to severe sepsis and septic shock, which are accompanied by significantly higher mortality rates [15].

THE THIRD CONTEMPORARY DEFINITION OF SEPSIS

For decades, sepsis was considered a systemic dissemination of infection leading to systemic clinical manifestations, including multiple organ and organ system damage, with high morbidity and mortality [16]. The greatest problem with the first and second definitions of sepsis are the narrow boundaries in defining infection and sepsis. Indeed, the SIRS criteria defining sepsis belong to the normal response to infection, such as pneumonia or urinary tract infection, and do not, in themselves, represent signs of complications in the clinical course of disease [15].

Due to the above-mentioned insufficient specificity of the previous definitions of sepsis, as well as new knowledge regarding the pathophysiological mechanism of sepsis, in 2016, there was a need for a new definition that would be more specific than the previous one and would enable easier recognition of sepsis in everyday clinical practice [17]. This concept places the ‘non-homeostatic’ pathophysiological host response to infection at the core of sepsis. Namely, what distinguishes sepsis from infection is an aberrant or unregulated host response and the presence of organ dysfunction. It reflects the importance of host factors in the development of sepsis. The new definition eliminates the terms SIRS and severe sepsis, while sepsis is defined as life-threatening organ dysfunction caused by inappropriate host response to infection, and organ dysfunction is defined as an acute change in the total Sequential Organ Failure Assessment (SOFA) score by two or more points, as the result of infection [18]. Septic shock is defined as a subtype of sepsis, manifesting as circulatory, cellular, and metabolic instability and associated with mortality greater than 40%. A patient is in septic shock if, in addition to the above-mentioned organ failure associated with sepsis, their blood lactate level is above 2 mmol/l (18 mg/dl), they have hypotension, and they need vasopressor medication to raise their mean arterial pressure above 65 mmHg [19].

The main advantage of the third definition of sepsis is that the new diagnostic criteria have been tested and confirmed in extensive retrospective studies in developed countries, such as USA and Germany [20],[21]. In addition to developed countries, the effectiveness of the third definition of sepsis has also been evaluated in less developed countries. The prognostic value of this definition of sepsis was evaluated in one intensive care center, showing an increase in mortality in all three categories: infection without organ dysfunction, sepsis, and septic shock [22]. These studies have shown that this definition of sepsis facilitates the recognition of sepsis in daily clinical practice.

SEQUENTIAL ORGAN FAILURE ASSESSMENT (SOFA) SCORE

The main reasons for numerous deaths resulting from sepsis are late recognition and diagnosis and late initiation of therapy. In order to reduce mortality from sepsis, unique algorithms have been created to help diagnose this disease [23]. The most prominent among them is the SOFA score, wherein an acute change in the total SOFA score by two or more points indicates the existence of an organ dysfunction caused by infection. The initial SOFA score is considered to be 0 in a patient without previous organ dysfunction (Table 2) [24].

Table 1. Expanded Disability Status Scale – EDSS

Table 1. Expanded Disability Status Scale – EDSS

A new, simplified version of the SOFA score, i.e., the Quick SOFA score (qSOFA), was designed to rapidly diagnose sepsis in patients outside intensive care units. The qSOFA helps assess the patient’s mental, respiratory and cardiovascular status, and is used in admission units and hospital wards due to its quick and easy execution. The qSOFA criteria are, as follows:

  1. altered mental activity, GCS2 < 15
  2. hypotension, systolic blood pressure ≤ 100 mmHg
  3. tachypnea, respiratory rate ≥ 22/min.

However, the qSOFA does not define sepsis, but does allow for the rapid identification of all patients at potential risk of sepsis, because it indicates an increased risk of organ dysfunction. Thus, the presence of at least two variables suggests that the patient is at high risk of adverse outcomes, such as in-hospital death or prolonged ICU stay [25]. Studies have shown that qSOFA is more specific but less sensitive than the SIRS criteria for early identification of organ dysfunction caused by infection [26].

The application of qSOFA resulted in greater prognostic accuracy regarding in-hospital mortality than SIRS or severe sepsis [27]. The predictive validity of this test was significantly enhanced by adding lactate levels to qSOFA [28]. The main advantages of this ‘warning test’ are the simplicity of execution, the possibility of frequent repetition and monitoring, the high speed of execution (a few seconds are enough), and the fact that it does not require special equipment [29].

2 Glasgow coma scale/score (GSC)

CONCLUSION

Sepsis is a life-threatening clinical syndrome with high incidence and a high mortality rate, both in developing and developed countries. It is believed that antimicrobial resistance, which has become more pronounced since the COVID-19 pandemic, will contribute to an even higher death rate. The new definition of sepsis enables early recognition and treatment of patients with sepsis and patients at increased risk of developing sepsis. Early suspicion of sepsis and appropriate treatment in the first hours after the onset of sepsis are vital steps, as this is the only way of improving survival in sepsis patients. Despite substantial advances in medicine in the previous decades, defining, diagnosing, and treating sepsis remains a significant challenge.

  • Conflict of interest:
    None declared.

Informations

Volume 4 No 1

March 2023

Pages 75-81
  • Keywords:
    sepsis, definition, mortality
  • Received:
    01 February 2023
  • Revised:
    04 March 2023
  • Accepted:
    17 March 2023
  • Online first:
    25 March 2023
  • DOI:
  • Cite this article:
    Dimić N, Đurić M, Nenadić I, Boboš M, Bojić S, Vukotić T, et al. Development of the definition of sepsis. Serbian Journal of the Medical Chamber. 2023;4(1):75-81. doi: 10.5937/smclk4-42608
Corresponding author

Nemanja Dimić
University Clinical Hospital Center Dr Dragiša Mišović – Dedinje, Belgrade, Serbia
Arsenija Čarnojevića Boulevard 213, 11000 Belgrade, Serbia
E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.


  • 1. Rhee C, Dantes R, Epstein L, Murphy DJ, Seymour CW, Iwashyna TJ, et al.; CDC Prevention Epicenter Program. Incidence and Trends of Sepsis in US Hospitals Using Clinical vs Claims Data, 2009-2014. JAMA. 2017 Oct 3;318(13):1241- 1249. doi: 10.1001/jama.2017.13836. [CROSSREF]

    2. Fleischmann C, Scherag A, Adhikari NK, Hartog CS, Tsaganos T, Schlattmann P, et al.; International Forum of Acute Care Trialists. Assessment of Global Incidence and Mortality of Hospital-treated Sepsis. Current Estimates and Limitations. Am J Respir Crit Care Med. 2016 Feb 1;193(3):259-72. doi: 10.1164/rccm.201504-0781OC. [CROSSREF]

    3. Srzić I, Nesek Adam V, Tunjić Pejak D. Sepsis definition: what's new in the treatment guidelines. Acta Clin Croat. 2022 Jun;61(Suppl 1):67-72. doi: 10.20471/acc.2022.61.s1.11. [CROSSREF]

    4. Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013 Aug 29;369(9):840-51. doi: 10.1056/NEJMra1208623. [CROSSREF]

    5. Funk DJ, Parrillo JE, Kumar A. Sepsis and septic shock: a history. Crit Care Clin. 2009 Jan;25(1):83-101, viii. doi: 10.1016/j.ccc.2008.12.003. [CROSSREF]

    6. Thurston AJ. Of blood, inflammation and gunshot wounds: the history of the control of sepsis. Aust N Z J Surg. 2000 Dec;70(12):855-61. doi: 10.1046/j.1440-1622.2000.01983.x. [CROSSREF]

    7. Gül F, Arslantaş MK, Cinel İ, Kumar A. Changing Definitions of Sepsis. Turk J Anaesthesiol Reanim. 2017 Jun;45(3):129-138. doi: 10.5152/TJAR.2017.93753. [CROSSREF]

    8. Kosanović Ćetković D. Sepsa. U Udžbenik akutnih infektivnih bolesti. 1981;1(C):29-33.

    9. Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, et al.; Surviving Sepsis Campaign Management Guidelines Committee. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med. 2004 Mar;32(3):858-73. doi: 10.1097/01.ccm.0000117317.18092.e4. [CROSSREF]

    10. 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.

    11. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, 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. doi: 10.1378/chest.101.6.1644. [CROSSREF]

    12. Salomao R, Brunialti MK, Rapozo MM, Baggio-Zappia GL, Galanos C, Freudenberg M. Bacterial sensing, cell signaling, and modulation of the immune response during sepsis. Shock. 2012 Aug;38(3):227-42. doi: 10.1097/SHK.0b013e318262c4b0. [CROSSREF]

    13. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, et al.; International Sepsis Definitions Conference. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive Care Med. 2003 Apr;29(4):530-8. doi: 10.1007/s00134-003-1662-x. [CROSSREF]

    14. Timsit JF, Perner A. Sepsis: find me, manage me, and stop me! Intensive Care Med. 2016 Dec;42(12):1851-1853. doi: 10.1007/s00134-016-4603-1. [CROSSREF]

    15. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al.; Surviving Sepsis Campaign Guidelines Committee including The Pediatric Subgroup. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013 Feb;39(2):165-228. doi: 10.1007/s00134-012-2769-8. [CROSSREF]

    16. Bone RC. The pathogenesis of sepsis. Ann Intern Med. 1991 Sep 15;115(6):457- 69. doi: 10.7326/0003-4819-115-6-457. [CROSSREF]

    17. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017 Mar;43(3):304-377. doi: 10.1007/s00134-017-4683-6. [CROSSREF]

    18. DeMerle KM, Royer SC, Mikkelsen ME, Prescott HC. Readmissions for Recurrent Sepsis: New or Relapsed Infection? Crit Care Med. 2017 Oct;45(10):1702- 1708. doi: 10.1097/CCM.0000000000002626. [CROSSREF]

    19. Carneiro AH, Póvoa P, Gomes JA. Dear Sepsis-3, we are sorry to say that we don't like you. Rev Bras Ter Intensiva. 2017 Jan-Mar;29(1):4-8. doi: 10.5935/0103-507X.20170002. [CROSSREF]

    20. Shankar-Hari M, Phillips GS, Levy ML, Seymour CW, Liu VX, Deutschman CS, et al.; Sepsis Definitions Task Force. Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):775-87. doi: 10.1001/jama.2016.0289. [CROSSREF]

    21. Seymour CW, Liu VX, Iwashyna TJ, Brunkhorst FM, Rea TD, Scherag A, et al. Assessment of Clinical Criteria for Sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):762-74. doi: 10.1001/jama.2016.0288. [CROSSREF]

    22. Besen BAMP, Romano TG, Nassar AP Jr, Taniguchi LU, Azevedo LCP, Mendes PV, Zampieri FG, Park M. Sepsis-3 definitions predict ICU mortality in a low-middle-income country. Ann Intensive Care. 2016 Dec;6(1):107. doi: 10.1186/s13613-016-0204-y. [CROSSREF]

    23. Alberto L, Marshall AP, Walker R, Aitken LM. Screening for sepsis in general hospitalized patients: a systematic review. J Hosp Infect. 2017 Aug;96(4):305- 315. doi: 10.1016/j.jhin.2017.05.005. [CROSSREF]

    24. Bumbaširević V, Veličković J, Palibrk I, Jovanović B, Avramović J. Novine u dijagnostici i lečenju sepse i septičnog šoka (Novine u lečenju sepse). Serbian Journal of Anesthesia and Intensive Therapy. 2017;39(7-8):171-80. [HTTP]

    25. 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. doi: 10.1001/ jama.2016.0287. [CROSSREF]

    26. Serafim R, Gomes JA, Salluh J, Póvoa P. A Comparison of the Quick-SOFA and Systemic Inflammatory Response Syndrome Criteria for the Diagnosis of Sepsis and Prediction of Mortality: A Systematic Review and Meta-Analysis. Chest. 2018 Mar;153(3):646-655. doi: 10.1016/j.chest.2017.12.015. [CROSSREF]

    27. Freund Y, Lemachatti N, Krastinova E, Van Laer M, Claessens YE, Avondo A, et al.; French Society of Emergency Medicine Collaborators Group. Prognostic Accuracy of Sepsis-3 Criteria for In-Hospital Mortality Among Patients With Suspected Infection Presenting to the Emergency Department. JAMA. 2017 Jan 17;317(3):301-308. doi: 10.1001/jama.2016.20329. [CROSSREF]

    28. Mikkelsen ME, Miltiades AN, Gaieski DF, Goyal M, Fuchs BD, Shah CV, Bellamy SL, Christie JD. Serum lactate is associated with mortality in severe sepsis independent of organ failure and shock. Crit Care Med. 2009 May;37(5):1670-7. doi: 10.1097/CCM.0b013e31819fcf68. [CROSSREF]

    29. Lamontagne F, Harrison DA, Rowan KM. qSOFA for Identifying Sepsis Among Patients With Infection. JAMA. 2017 Jan 17;317(3):267-268. doi: 10.1001/ jama.2016.19684. [CROSSREF]


REFERENCES

1. Rhee C, Dantes R, Epstein L, Murphy DJ, Seymour CW, Iwashyna TJ, et al.; CDC Prevention Epicenter Program. Incidence and Trends of Sepsis in US Hospitals Using Clinical vs Claims Data, 2009-2014. JAMA. 2017 Oct 3;318(13):1241- 1249. doi: 10.1001/jama.2017.13836. [CROSSREF]

2. Fleischmann C, Scherag A, Adhikari NK, Hartog CS, Tsaganos T, Schlattmann P, et al.; International Forum of Acute Care Trialists. Assessment of Global Incidence and Mortality of Hospital-treated Sepsis. Current Estimates and Limitations. Am J Respir Crit Care Med. 2016 Feb 1;193(3):259-72. doi: 10.1164/rccm.201504-0781OC. [CROSSREF]

3. Srzić I, Nesek Adam V, Tunjić Pejak D. Sepsis definition: what's new in the treatment guidelines. Acta Clin Croat. 2022 Jun;61(Suppl 1):67-72. doi: 10.20471/acc.2022.61.s1.11. [CROSSREF]

4. Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013 Aug 29;369(9):840-51. doi: 10.1056/NEJMra1208623. [CROSSREF]

5. Funk DJ, Parrillo JE, Kumar A. Sepsis and septic shock: a history. Crit Care Clin. 2009 Jan;25(1):83-101, viii. doi: 10.1016/j.ccc.2008.12.003. [CROSSREF]

6. Thurston AJ. Of blood, inflammation and gunshot wounds: the history of the control of sepsis. Aust N Z J Surg. 2000 Dec;70(12):855-61. doi: 10.1046/j.1440-1622.2000.01983.x. [CROSSREF]

7. Gül F, Arslantaş MK, Cinel İ, Kumar A. Changing Definitions of Sepsis. Turk J Anaesthesiol Reanim. 2017 Jun;45(3):129-138. doi: 10.5152/TJAR.2017.93753. [CROSSREF]

8. Kosanović Ćetković D. Sepsa. U Udžbenik akutnih infektivnih bolesti. 1981;1(C):29-33.

9. Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, et al.; Surviving Sepsis Campaign Management Guidelines Committee. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med. 2004 Mar;32(3):858-73. doi: 10.1097/01.ccm.0000117317.18092.e4. [CROSSREF]

10. 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.

11. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, 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. doi: 10.1378/chest.101.6.1644. [CROSSREF]

12. Salomao R, Brunialti MK, Rapozo MM, Baggio-Zappia GL, Galanos C, Freudenberg M. Bacterial sensing, cell signaling, and modulation of the immune response during sepsis. Shock. 2012 Aug;38(3):227-42. doi: 10.1097/SHK.0b013e318262c4b0. [CROSSREF]

13. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, et al.; International Sepsis Definitions Conference. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive Care Med. 2003 Apr;29(4):530-8. doi: 10.1007/s00134-003-1662-x. [CROSSREF]

14. Timsit JF, Perner A. Sepsis: find me, manage me, and stop me! Intensive Care Med. 2016 Dec;42(12):1851-1853. doi: 10.1007/s00134-016-4603-1. [CROSSREF]

15. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al.; Surviving Sepsis Campaign Guidelines Committee including The Pediatric Subgroup. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013 Feb;39(2):165-228. doi: 10.1007/s00134-012-2769-8. [CROSSREF]

16. Bone RC. The pathogenesis of sepsis. Ann Intern Med. 1991 Sep 15;115(6):457- 69. doi: 10.7326/0003-4819-115-6-457. [CROSSREF]

17. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017 Mar;43(3):304-377. doi: 10.1007/s00134-017-4683-6. [CROSSREF]

18. DeMerle KM, Royer SC, Mikkelsen ME, Prescott HC. Readmissions for Recurrent Sepsis: New or Relapsed Infection? Crit Care Med. 2017 Oct;45(10):1702- 1708. doi: 10.1097/CCM.0000000000002626. [CROSSREF]

19. Carneiro AH, Póvoa P, Gomes JA. Dear Sepsis-3, we are sorry to say that we don't like you. Rev Bras Ter Intensiva. 2017 Jan-Mar;29(1):4-8. doi: 10.5935/0103-507X.20170002. [CROSSREF]

20. Shankar-Hari M, Phillips GS, Levy ML, Seymour CW, Liu VX, Deutschman CS, et al.; Sepsis Definitions Task Force. Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):775-87. doi: 10.1001/jama.2016.0289. [CROSSREF]

21. Seymour CW, Liu VX, Iwashyna TJ, Brunkhorst FM, Rea TD, Scherag A, et al. Assessment of Clinical Criteria for Sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):762-74. doi: 10.1001/jama.2016.0288. [CROSSREF]

22. Besen BAMP, Romano TG, Nassar AP Jr, Taniguchi LU, Azevedo LCP, Mendes PV, Zampieri FG, Park M. Sepsis-3 definitions predict ICU mortality in a low-middle-income country. Ann Intensive Care. 2016 Dec;6(1):107. doi: 10.1186/s13613-016-0204-y. [CROSSREF]

23. Alberto L, Marshall AP, Walker R, Aitken LM. Screening for sepsis in general hospitalized patients: a systematic review. J Hosp Infect. 2017 Aug;96(4):305- 315. doi: 10.1016/j.jhin.2017.05.005. [CROSSREF]

24. Bumbaširević V, Veličković J, Palibrk I, Jovanović B, Avramović J. Novine u dijagnostici i lečenju sepse i septičnog šoka (Novine u lečenju sepse). Serbian Journal of Anesthesia and Intensive Therapy. 2017;39(7-8):171-80. [HTTP]

25. 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. doi: 10.1001/ jama.2016.0287. [CROSSREF]

26. Serafim R, Gomes JA, Salluh J, Póvoa P. A Comparison of the Quick-SOFA and Systemic Inflammatory Response Syndrome Criteria for the Diagnosis of Sepsis and Prediction of Mortality: A Systematic Review and Meta-Analysis. Chest. 2018 Mar;153(3):646-655. doi: 10.1016/j.chest.2017.12.015. [CROSSREF]

27. Freund Y, Lemachatti N, Krastinova E, Van Laer M, Claessens YE, Avondo A, et al.; French Society of Emergency Medicine Collaborators Group. Prognostic Accuracy of Sepsis-3 Criteria for In-Hospital Mortality Among Patients With Suspected Infection Presenting to the Emergency Department. JAMA. 2017 Jan 17;317(3):301-308. doi: 10.1001/jama.2016.20329. [CROSSREF]

28. Mikkelsen ME, Miltiades AN, Gaieski DF, Goyal M, Fuchs BD, Shah CV, Bellamy SL, Christie JD. Serum lactate is associated with mortality in severe sepsis independent of organ failure and shock. Crit Care Med. 2009 May;37(5):1670-7. doi: 10.1097/CCM.0b013e31819fcf68. [CROSSREF]

29. Lamontagne F, Harrison DA, Rowan KM. qSOFA for Identifying Sepsis Among Patients With Infection. JAMA. 2017 Jan 17;317(3):267-268. doi: 10.1001/ jama.2016.19684. [CROSSREF]

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