Understanding Sepsis

3rd May 2021

There has been a renaissance in Sepsis (previously referred to as Septic Shock and Septicaemia) in recent years.  It is as though things become fashionable for a time in First Aid and Medicine.

In the 90’s there was considerable interest in Spinal Injury which, 30 years on, we are only now moderating our view of spinal management and beginning to move away from the rigid doctrine of Cervical Collars.   The Millennium saw the rise of Remote First Aid in the UK as a discrete subset of Pre-Hospital Care and OPAs and NPAs became terribly popular on advanced First Aid courses.   Laterally, following events in Iraq and Afghanistan, you cannot throw a roll of Celox on a First Aid course without hitting a tourniquet.

And now Sepsis seems the big deal.

This renewed interest can be traced back to an important article published in The Lancet in 2018 (1) citing a profound increase in the number of hospital admissions and recorded deaths, 41% and 38% respectively.

What was particularly surprising was that not only other illnesses decreasing, but only two years before, the National Institute for Health and Care Excellence published its first set of guidelines on sepsis. The same year saw a new international definition of the condition (2), and in 2017 the World Health Assembly adopted a resolution on sepsis.

Yet despite the renewed interest in Sepsis, cases continued to rise.

What is Sepsis?

The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) defines sepsis as:

“Life-threatening organ dysfunction caused by a dysregulated host response to infection.”

Septic shock is defined as:

“A subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone.”

These broad definitions do not give pre-hospital care practitioners much to go on.   Unlike other conditions, sepsis in itself is a broad syndrome with uncertain pathobiology.  In short, it is not fully understood nor easy to define.

History

A 1991 consensus conference (3) developed initial definitions that focused on the prevailing view at the time that sepsis resulted from a host’s systemic inflammatory response syndrome (SIRS) stemming from infection. 

SIRS (Systemic Inflammatory Response Syndrome) was identified as the casualty presenting with two or more of the following:

• Temperature >38°C or <36°C

• Heart rate >90/min

• Respiratory rate >20/min or Paco2 <32 mm Hg (4.3 kPa)

• White blood cell count >12 000/mm3 or <4000/mm3 or >10% immature bands

The SIRS criteria do not necessarily indicate a dysregulated, life-threatening response (5) nor was it found to be particularly reliable. (6)

Recognizing the need to re-examine the current definitions (7), the European Society of Intensive Care Medicine and the Society of Critical Care Medicine convened a task force of 19 specialists in January 2014.

The Task Force concluded that the validity of SIRS as a descriptor of sepsis pathobiology should be challenged.  Sepsis is now recognized to involve early activation of both pro- and anti-inflammatory responses.

Pathophysiology

The early phase of sepsis characterized by excessive inflammation sometimes resulting in a cytokine storm - an uncontrolled and excessive release of pro-inflammatory signalling molecules called cytokines.  This may be followed by a prolonged period of decreased functioning of the immune system. (8, 9)

Upon detection of microbial antigens, the host systemic immune system is activated.  Immune cells not only recognise pathogen-associated molecular patterns but also damage-associated molecular patterns from damaged tissues.  An uncontrolled immune response is then activated because leukocytes are not recruited to the specific site of infection, but instead, they are recruited all over the body.

An immunosuppression state follows when the pro-inflammatory T helper cell 1 (TH1) is shifted to TH2.

TH1 cells mediate the activation of macrophages to phagocytose and digest intracellular bacteria and protozoa.  They also stimulate the production of nitric oxide free radicals to directly kill intracellular bacteria and protozoa.

By contrast, TH2 cells stimulate mast cells to release histamine, serotonin, and leukotriene to cause broncho-constriction, intestinal peristalsis, gastric fluid acidification.

This process is known as "compensatory anti-inflammatory response syndrome" (10).  The apoptosis (cell death) of lymphocytes further worsens the immunosuppression.

Neutrophils, monocytes, macrophages, dendritic cells, CD4+ T cells, and B cells all undergo apoptosis, whereas regulatory T cells are more apoptosis-resistant (9).  Subsequently, multiple organ failure ensues because tissues are unable to use oxygen efficiently due to inhibition of cytochrome c oxidase. (11)

Inflammatory responses cause multiple organ dysfunction syndrome through various mechanisms (12):

• Increased permeability of the lung vessels causes leaking of fluids into alveoli, which results in pulmonary edema and acute respiratory distress syndrome (ARDS).

• Impaired utilization of oxygen in the liver impairs bile salt transport, causing jaundice (yellowish discoloration of skin).

• In kidneys, inadequate oxygenation results in tubular epithelial cell injury (of the cells lining the kidney tubules), and causes acute kidney injury (AKI).

• Impaired calcium transport, and low production of adenosine triphosphate (ATP), can cause myocardial depression, reducing cardiac contractility and heart failure.

• Increased permeability of the mucosa alters the microflora, causing mucosal bleeding and paralytic ileus in the gastrointestinal tract.

• In the central nervous system, direct damage of the brain cells and disturbances of neurotransmissions causes altered mental status.

The low blood pressure seen in those with sepsis is the result of various processes, including excessive production of chemicals that dilate blood vessels such as nitric oxide, a deficiency of chemicals that constrict blood vessels such as vasopressin, and activation of ATP-sensitive potassium channels. (13)

The ensuing reduction in blood pressure leads to Septic Shock.

Further Reading:  Trauma Basics: Shock!

Recognition

The predominant score in current use is the Sequential Organ Failure Assessment (SOFA)  which requires laboratory variables, namely, Pao2, platelet count, creatinine level, and bilirubin level for full computation.

This combination is associated with hospital mortality rates greater than 40% - it is a specific and sensitive test. But many of these criteria are not possible to be tested in a pre-hospital setting.

For pre-hospital settings, adult patients with suspected infection can be rapidly identified as being more likely to have poor outcomes typical of sepsis if they have at least 2 of the following clinical criteria that together constitute a new bedside clinical score termed quickSOFA (qSOFA) (14-16)

Two or more of:

• Respiratory rate of 22/min or greater

• Altered mentation

• Systolic blood pressure of 100 mm Hg or less.

The qSOFA score is much easier to apply in a pre-hospital setting and can also be applied by non-registered healthcare providers, without the need for understanding complex lab values.

But when do we decide to apply this test? Should we suspect Sepsis in all medical casualties?

The Sepsis Trust have developed a rapid screening tool to identify Sepsis for different age groups.

Treatment

For those casualties with “Red Flag” sepsis, there is limited treatment for the non-registered healthcare provider.

• Contact the Emergency Services and state that the casualty has “Red Flag Sepsis”.
  
  or
  

• Transport to hospital as soon as possible - pre-alert the hospital with the phrase “Reg Flag Sepsis”.

• Provide supplemental oxygen to maintain an SpO2 >94% (88% - 91% for those with COPD)

Pre-alerting the Emergency Services or the receiving hospital that the casualty has “Red Flag Sepsis” is critical: Alerting the next echelon of care to the condition of the casualty, allows them to prepare and expedite the treatment they receive. Early administration of antibiotics is time-critical.

Current NICE Guidelines (NG51) (17) places more onus on the early transport to hospital than pre-hospital treatment.

Summary

• Sepsis requires a history of infection to begin with – your casualty cannot simply develop sepsis without initial infection.

• Sepsis is the primary cause of death from infection, especially if not recognized and treated promptly. Its recognition mandates urgent attention.

• Sepsis is a syndrome affected by both the pathogen and the host e.g. sex, race and other genetic determinants, age, comorbidities, environment. It may resent in different ways with different casualties.

• Expect the presenting characteristics to evolve over time.  Typically the inflammatory response may lead to high temperature and flushed skin but the compensatory, anti-inflammatory response may later cause a low temperature and pale, mottled skin..

• As such, temperature alone should not be used solely to rule in or out Sepsis.

• qSOFA is the preferred diagnostic tool in a pre-hospital setting.

• The Sepsis Trust Screening Tools may better target potential casualties through questioning and undertaking a History, prior to a qSOFA score.

• Expedite your casualty to hospital as soon as possible. Transport to definitive care is more important than pre-hospital treatment.

• Pre-alert the next echelon of care with the phrase “Red Flag Sepsis”.

References

1. Burki TK.  (2018)  “Sharp rise in sepsis deaths in the UK”. Lancet Respir Med.  6(11):826.

2. Singer M, Deutschman CS, Seymour CW, et al.  (2016).  “The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)”.  Journal of the American Medical Association.  315(8):801–810.

3. Bone  RC, Balk  RA, Cerra  FB,  et al.  (1992)  “American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis”.  Critical Care Medicine.  20(6):864-874.

4. Levy  MM, Fink  MP, Marshall  JC,  et al.  (2003)  “International Sepsis Definitions Conference”.  2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference.  Intensive Care Medicine.  29(4):530-538.

5. Churpek  MM, Zadravecz  FJ, Winslow  C, Howell  MD, Edelson  DP.  (2015)  “Incidence and prognostic value of the systemic inflammatory response syndrome and organ dysfunctions in ward patients”.  American Journal of Respiratory and Critical Care Medicine. 192(8):958-964.

6. Kaukonen  K-M, Bailey  M, Pilcher  D, Cooper  DJ, Bellomo  R.  (2015)  “Systemic inflammatory response syndrome criteria in defining severe sepsis”.   New England Journal of Medicine.  372(17):1629-1638.

7. Vincent  J-L, Opal  SM, Marshall  JC, Tracey  KJ.  (2013)  “Sepsis definitions: time for change”.  Lancet.  381(9868):774-775.

8. Shukla P, Rao GM, Pandey G, Sharma S, Mittapelly N, Shegokar R. and Mishra PR.  (2014)  “Advances in therapeutic intervention of sepsis”.  British Journal of Pharmacology.  171: 5011-5031

9. Cao C, Yu M and Chai Y.  (2019)  “Pathological alteration and therapeutic implications of sepsis-induced immune cell apoptosis”.  Cell Death and Disease.  10. 782.

10. Polat G, Ugan RA, et al. (2017)  "Sepsis and septic shock: Current treatment strategies and new approaches".  The Eurasian Journal of Medicine. 49 (1): 53–8.

11. Yuki K, Murakami N (2016)  "Sepsis pathophysiology and anesthetic consideration". Cardiovascular & Hematological Disorders Drug Targets. 15 (1): 57–69

12. Fujishima, S.  (2016)  “Organ dysfunction as a new standard for defining sepsis”.  Inflammation and Regeneration.  36, 24 (2016).

13. Marik, P.E.  (2014)  “Iatrogenic salt water drowning and the hazards of a high central venous pressure”.  Annals of Intensive Care.  4, 21.

14. Singer M, Deutschman CS, Seymour CW, et al. (2016) “The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)”. Journal of the American Medical Association. 315(8):801–810

15. Seymour CW, Liu VX, Iwashyna TJ, et al. (2016) “Assessment of Clinical Criteria for Sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)”. Journal of the American Medical Association. 315(8):762–774.

16. Seymour CW, Coopersmith CM, Deutschman, CS et al. (2016) “Application of a Framework to Assess the Usefulness of Alternative Sepsis Criteria”. Critical Care Medicine. 44(3). e122-e13

17. Nice Guidelines NG51. (2016) “Sepsis: recognition, diagnosis and early management”. National Institute for Health and Care Excellence. Published: 13 July 2016 Last updated: 13 September 2017 https://www.nice.org.uk/guidance/ng51 Accessed 27th April 2021.