Definition

Sepsis is broadly defined as a life-threatening condition caused by a hyperacute, dysregulated inflammatory response to infection, inability to restore homeostasis, and the presence of organ dysfunction (15). 

Clinical features

Clinical features for sepsis are nonspecific and are a result of the body's dysregulated response to infection. Commonly cited diagnostic features across diagnostic tests include:

1. signs and symptoms of an infection (16);
2. signs of loss of perfusion (16);
3. leukocytosis with a white blood cell count >12,000 or <4000 per cubic millimeter (15);
4. temperature <36 or >38 degrees Celsius (15);
5. hypotension (systolic <90 or mean arterial pressure <65) (16);
6. tachycardia defined as heart rate >90 (15);
7. tachypnoea defined as respiratory rate >20 or PaC0₂>32 mmHg (15); and,
8. hyperlactatemia with a serum lactate level above 4 mmol/L (16).

Historically, the accepted criteria centered around the Systemic Inflammatory Response Syndrome (SIRS) protocol, with tools including National Early Warning Score (NEWS), Sepsis-related Organ Failure Assessment (SOFA), and quick-SOFA (qSOFA); however, SIRS criteria have been criticised for focusing solely upon inflammatory excess, which is often present in non-septic patients (15).  In 2016 sepsis was redefined by international consensus under the SEPSIS-3 paper, which differentiates sepsis from septic shock (15).

The SEPSIS-3 criteria definition for sepsis is an acute change in SOFA score of two or more, with the score presumed to be zero in patients with no known pre-existing disease (15). The full SOFA score cannot be determined in the pre-hospital environment as three of the seven SOFA elements require laboratory tests unavailable to paramedics, with another two having limited applicability. 

Epidemiology

Sepsis has a high mortality rate, with estimates ranging between 10-52%, and approximately 40% for septic shock (15,16).  Studies have variously found sepsis present in five to six percent of all-causes mortality (17,18).  The SEPSIS-3 paper suggested that sepsis is the leading cause of mortality and morbidity globally, with 48.9 million cases and 11 million deaths reported in 2017 (15,19).

Classifications

Sepsis in the early stage of the pathology is classified simple as sepsis, while in the later stage of the disease is it classified as severe sepsis (also known as septic shock).  The early-stage classification of sepsis has been historically defined as infection in conjunction with SIRS (16). SIRS is a form of dysregulated inflammatory syndrome, and is itself frequently defined as two or more abnormalities in temperature, heart rate, respiration, or white blood count (15,16).  The latter-stage classification of severe sepsis is a type of distributive shock where sepsis has progressed to inadequate tissue perfusion, and is associated with higher mortality rates (16).

Pathology

Sepsis is a malignant, systemic hyper-inflammatory response to infection, characterised by an exaggerated immune response and a failure to return to homeostasis (20).  The exact mechanisms leading localised inflammation to accelerate systemically and form sepsis are unknown; however, it is believed to be a combination of four contributing factors. Firstly, there is an excessive release of inflammatory mediators.  Secondly, there is a greater activation of the complement system, which in turn attracts more leucocytes and further increases inflammation.  Thirdly, inflammation may be directly stimulated by some pathogens, as bacterial cell walls have inflammatory properties.  Finally, there may be a genetic component, as certain alleles have been linked to increased inflammation (20,21).  Pulmonary inflammation may lead to acute pulmonary oedema formation, decreasing external respiration and causing hypoxaemia (21).  Systemically, inadequate perfusion leads to multiple organ dysfunction – particularly the central nervous and renal systems.  Without correction, mortality results from shock and multiple organ failure.

Evaluation and risk assessment

Sepsis should be considered in all patients presenting with dysthermia and hypotension, and a fluid challenge immediately provided. Under the SEPSIS-3 criteria (15), sepsis has progressed to septic shock when the patient, after volume resuscitation, additionally:

• requires vasopressors to maintain a mean arterial pressure >65mmHg; and,
• has a serum lactate >2mmol/L.

Currently, only two services (ACTAS and, to a limited extent, QAS) provide serum lactate measurement (1,12).  Therefore, formal diagnosis of septic shock is not possible by practitioners from other services.  For faster and frequent assessment, the SEPSIS-3 paper recommends use of a test with lower specificity and sensitivity but increased ease of use, the qSOFA score.  Under this system the presence of any two of the following factors is sufficient to make the diagnosis of shock:

• respiratory rate >22;
• altered mentation;
• systolic blood pressure <100mmHg (15).

However, the qSOFA score has been found to have poor sensitivity (22). Any patient presenting with these three abnormalities should be treated as time critical and, where transport times over 3 hours exist, consultation for prehospital administration of antibiotics should be considered by the paramedics (23–25).

Risk factors for sepsis include a history of bacterial infections, advanced age, immunosuppression, obesity, diabetes, cancer, pneumonia, and genetic factors.  Recent hospital admission is a significant risk factor, with one study finding that 50 percent of septic intensive care admissions suffered from a nosocomial infection (16).  

A 2019 meta-analysis of thirteen studies (n=33,863) showed no differences in mortality between administration of antibiotics within 60 minutes of diagnosis, and administration between 60 and 180 minutes of diagnosis; however, the quality of evidence was rates as low (23).  Delays of over 180 minutes have been associated with increased mortality (24,25).

Differential diagnoses

There are a multitude of conditions that can closely mimic a sepsis presentation, highlighting the necessity to perform extensive history taking and observations in order to differentiate and isolate likely causes of symptoms (16,26). Some of the most common imitators of sepsis include other forms of shock, hyperthyroidism, addisonian crisis, pulmonary embolism, haemorrhage, pericarditis, myocarditis, pancreatitis, and ethanol withdrawal syndromes (26,27).

References

• Wilkinson-Stokes, M. (2020), A Comparison of Australasian Jurisdictional Ambulance Services’ Paramedic Clinical Practice Guidelines Series. Paper 2: Adult Sepsis. Australian Catholic University.
• Paramedics Australasia. Paramedicine Role Descriptions [Internet]. Melbourne, Australia; 2012. Available from: http://apcollege.edu.au/pdf/media-other/paramedic-information-paramedics.org-australian-paramedical-college.apcollege.edu.au.pdf
  
• 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 [Internet]. 2016 Feb 23;315(8):801. Available from: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.0287
• Neviere R. Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis. In: Parsons PE, Finlay G, editors. UpToDate [Internet]. Waltham, MA: UpToDate; 202AD. Available from: www.uptodate.com/contents/sepsis-syndromes-in-adults-epidemiology-definitions-clinical-presentation-diagnosis-and-prognosis?search=sepsis-syndromes-in-adults-epidemiology-definitions-clinical-presentation-diagnosis
• Epstein L, Dantes R, Magill S, Fiore A. Varying Estimates of Sepsis Mortality Using Death Certificates and Administrative Codes — United States, 1999–2014. MMWR Morb Mortal Wkly Rep [Internet]. 2016 Apr 8;65(13):342–5. Available from: http://www.cdc.gov/mmwr/volumes/65/wr/mm6513a2.htm
• McPherson D, Griffiths C, Williams M, Baker A, Klodawski E, Jacobson B, et al. Sepsis-associated mortality in England: an analysis of multiple cause of death data from 2001 to 2010. BMJ Open [Internet]. 2013 Aug;3(8):e002586. Available from: http://bmjopen.bmj.com/lookup/doi/10.1136/bmjopen-2013-002586
• Rudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, et al. Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study. Lancet [Internet]. 2020 Jan;395(10219):200–11. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0140673619329897
• Stearns-Kurosawa DJ, Osuchowski MF, Valentine C, Kurosawa S, Remick DG. The Pathogenesis of Sepsis. Annu Rev Pathol Mech Dis [Internet]. 2011 Feb 28;6(1):19–48. Available from: http://www.annualreviews.org/doi/10.1146/annurev-pathol-011110-130327
• Neviere R. Pathophysiology of sepsis. In: Manaker S, Sexton DJ, Finlay G, editors. UpToDate [Internet]. Waltham, MA: UpToDate; 2020. Available from: www.uptodate.com/contents/pathophysiology-of-sepsis
• Usman OA, Usman AA, Ward MA. Comparison of SIRS, qSOFA, and NEWS for the early identification of sepsis in the Emergency Department. Am J Emerg Med [Internet]. 2019 Aug;37(8):1490–7. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0735675718308891
• Ferrer R, Martin-Loeches I, Phillips G, Osborn TM, Townsend S, Dellinger RP, et al. Empiric Antibiotic Treatment Reduces Mortality in Severe Sepsis and Septic Shock From the First Hour. Crit Care Med [Internet]. 2014 Aug;42(8):1749–55. Available from: http://journals.lww.com/00003246-201408000-00001
• Seymour CW, Gesten F, Prescott HC, Friedrich ME, Iwashyna TJ, Phillips GS, et al. Time to Treatment and Mortality during Mandated Emergency Care for Sepsis. N Engl J Med [Internet]. 2017 Jun 8;376(23):2235–44. Available from: http://www.nejm.org/doi/10.1056/NEJMoa1703058
• Whiles BB, Deis AS, Simpson SQ. Increased Time to Initial Antimicrobial Administration Is Associated With Progression to Septic Shock in Severe Sepsis Patients. Crit Care Med [Internet]. 2017 Apr;45(4):623–9. Available from: http://journals.lww.com/00003246-201704000-00008
• Schmidt GA, Mandel J. Evaluation and management of suspected sepsis and septic shock in adults. In: Parsons PE, Sexton DJ, Hockberger RS, Finlay G, editors. UpToDate [Internet]. Waltham, MA: UpToDate; 2020. Available from: www.uptodate.com/contents/evaluation-and-management-of-suspected-sepsis-and-septic-shock-in-adults
• Cecconi M, Evans L, Levy M, Rhodes A. Sepsis and septic shock. Lancet [Internet]. 2018 Jul;392(10141):75–87. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0140673618306962