Pathophysiology of Sepsis

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Contents
• Why is sepsis so important?

• Making sense of the inflammatory response

• Making sense of pathophysiology in sepsis

• Recognition of sepsis

• Immediate treatment (Resuscitation)

Why is sepsis so important?
• Someone dies of sepsis every 3.5 seconds

• That’s the equivalent of a Boeing 747 crashing every 20 minutes killing

everyone on board

S
SEPSIS
 Why Focus on Sepsis?
• Sepsis is the leading cause of death in non- coronary care intensive care units, with a mortality rate
between 30% and 50%
• Every year in the UK there are 150,000 cases of Sepsis, resulting in a staggering 37,000 deaths – more
than bowel, breast and prostate cancer combined
• Survivors ofsepsis are opften left with serious long term conditions including amputation and
irriversable organ damage NCEPOD (2015)
• 52.4% are diagnosed in the ED
• 34.8% on the hospital wards
• 12.8% in the ICU

• Early detection and treatment increases the chances of the patient surviving and reduces ‘Failure to
Rescue’ rates.
What happens next?
 HEAT
PAIN

REDNESS
LOSS OF
FUNCTION

SWELLING
 Summary of the sequence
following injury
• Initiation of clotting cascade to arrest bleeding
• Vasodilation and increased permeability of capillaries
• redness, increased warmth
• Leakage of fluid, cells and nutrients into tissues
• swelling
• Neutrophils and Killer T cells release chemicals to destroy bacteria
• Macrophages release chemicals to promote tissue repair
 Now put those pathogens
in the bloodstream….

…. And magnify the inflammatory

response in the entire body !
What is Sepsis ?
The problem with attempting a definition of
sepsis is that sepsis is not an illness but a
syndrome that can manifest through a range of
non-specific symptoms (Singer et al 2016; Daniels 2014)
Sepsis has been called …
• Sepsis, septic shock

• SIRS (systemic inflammatory response syndrome)

• Septicaemia, Bacteraemia

• Toxic shock syndrome

• Bloodstream infection
Sepsis is…

Sepsis is defined as a life-threatening condition that

arises when the body’s response to an infection injures
its own tissues and organs (Singer et al 2016)
What causes sepsis ?
Pathogen type Cell types
gram-negative bacteria endotoxin, formyl peptides, exotoxins,
and proteases
exotoxins, superantigens (toxic shock
syndrome toxin (TSST), streptococcal
gram-positive bacteria pyrogenic exotoxin A (SpeA)),
enterotoxins, hemolysins,
peptidoglycans, lipotechoic acid
fungal cell wall material
 Pathophysiology of sepsis
• Sepsis can be simply defined as…

a spectrum of clinical conditions caused by the immune response of a patient to infection that
is characterised by systemic inflammation and coagulation, leading to multiple organ failure
and death

Immune-system activation:

• The Pathogen enters the body, often through surgery or infection, foreign body insertion (catheters),
and due to lowered immune status (immunosuppression).

• The immune system is activated by bacterial cell wall products.

 Pathophysiology of sepsis
Activation of the immune system results in
a complex series of cellular and humoral responses:

• Pro-inflammatory cytokines are released

• Reactive oxygen species, nitric oxide (NO), proteases, and pore-forming molecules are
released, to kill bacterial.
• NO is responsible for vasodilatation and increased capillary permeability.
• The complement system is activated, and mediates activation of leukocytes, attracting
them to the site of infection where they can directly attack the organism, identify it for
attack by others (antigen presenting cells, B lymphocytes).
 Pathophysiology of sepsis
The endothelium and coagulation system:

• The vascular endothelium plays a major role in the patients defence to an invading
organism, but also in the development of sepsis. Activated endothelium not only
allows the adhesion and migration of stimulated immune cells, but becomes
porous to large molecules such as proteins, resulting in the tissue oedema.

• Alterations in the coagulation systems include an increase in procoagulant factors,

and reduced circulating levels of natural anticoagulants.
Pathophysiology of sepsis
• Inflammation and organ dysfunction:

• Through vasodilatation (causing reduced systemic vascular resistance) and increased

capillary permeability (causing extravasation of plasma), sepsis results in a circulating
volume reduction.
• A number of factors combine to produce multiple organ dysfunctions, hypovolaemia
leading to hypotension.
• Impaired tissue oxygen delivery is exacerbated by capillary oedema. This means that
oxygen has to diffuse a greater distance to reach target cells. There is a reduction of
capillary diameter due to oedema and the pro-coagulant state results in capillary
microthrombus formation.
Pathophysiology of sepsis
• Additional contributing factors include:
• Altered blood flow through the capillaries, resulting from a combination of shunting
of blood through different channels,
• The blood also increases its viscosity due to the loss of red cell flexibility.
• As a result, organs may become hypoxic, these abnormalities may lead to lactic
acidosis, cellular dysfunction, and multi-organ failure.
• Cellular energy levels fall as metabolic activity begins to exceed production.
• However, cell death appears to be uncommon in sepsis, implying that cells shut down
as part of the systemic response..
The continuum of sepsis
• There is a progressive imbalance between oxygen
supply and demand due to:

• intravascular volume depletion

• peripheral vasodilatation
• myocardial depression
• increased metabolism

• Global tissue hypoxia ensues.

Diagnostic criteria for sepsis

• Increase of 2 SOFA points

• General [in the absence of other disease]
• Fever > 38.3 degrees
• Tachycardia > 90 bpm
• Tachypnoea > 22 rpm
• Acute onset confusion
• Significant oedema
• Hyperglycaemia > 6.7 mmol/L
• Inflammatory parameters
• Increased White Cell Count (WCC)
• Raised C-Reactive Protein (CRP)
Diagnostic criteria for sepsis

• Haemodynamic parameters
• Decrease in systolic blood pressure < or equal to 100 mmhg
• Reduction in Oxygen saturation

• Organ dysfunction parameters [in the absence of other disease]

• Acute oliguria – urine output less than 0.5mls per kg per hr
• Coagulation abnormalities (INR / APTT)
• Arterial hypoxaemia
• Ileus
• Raised creatinine
• Tissue perfusion parameters
• High lactate levels > 2 mmol/L
• Decreased capillary refill or mottling
 Examination- signs of sepsis
General Temperature <36ºC or >38ºC

Pulmonary Tachypnoea (>20/min)

Dyspnoea
Consolidation
Cyanosis
Cardiovascular Hypotension
Tachycardia (>90 beats/min)

Central nervous system Changes in mental state

Haematological Rashes (e.g. purpura fulminans)

Gastrointestinal Abdominal rebound/tenderness

Jaundice

Renal Oliguria
Loin tenderness
Pyuria
Septic Shock
Septic Shock is a subset of sepsis where
underlying circulatory and cellular/metabolic
abnormalities are profound enough to
substantially increase mortality (Singer et al 2016)
Septic shock
• Septic shock, is sepsis with a persistent hypotension

• This requires vasopressors to maintain a mean arterial pressure of

65mmHg or more

• and having a serum lactate level of greater than 2mmol/l despite

volume resuscitation (NICE 2016)

• Persistent hypotension leads to hypoperfusion of organs

Characteristics of septic shock
• Systemic vasodilation and hypotension
• Tachycardia; depressed contractility
• Vascular leakage and oedema; hypovolaemia
• Compromised nutrient blood flow to organs
• Disseminated intravascular coagulation (DIC)
• Abnormal blood gases and acidosis
• Respiratory distress and multiple organ failure
 Previously recommended
diagnostic criteria for SIRS
• SIRS – describes the systemic inflammatory response syndrome which occurs
in response to infection or any other stimulus that activates the
inflammatory process.
• Following SIRS criteria, you need at least 2 of the following:
• Temperature >38.5ºC or <36ºC
• Heart rate >90 beats/min
• Respiratory rate >20 breaths/min or PaCO2 <32 mmHg
• WBC >12,000 cells/mm3, <4000 cells/mm3, or >10 % immature (band) forms
• SIRS is the body’s response to infection, inflammation and stress.
• Will still be used as an indication of infection in the clinical setting
 SEPSIS SIX Care Resuscitation Bundle
Study supports the SSC Resus
‘Delivery of the Bundle:
TAKE OUT PUT IN • Reduced mortality
sepsis six in the
first hour of • Simplified pathways
Blood Cultures Antibiotics
(SS bundle) &
diagnosis can
Oxygen
Lactate Levels
education can improve
significantly 15ltrs non
rebreathe mask
life-saving
improve survival’ Fluid
Urine Output
Normal Salne
interventions.
Robson (2008)
Daniels et al. (2011)
Conclusion
• It is difficult to diagnose early signs of sepsis

• Vital observations are essential to improve recognition and

responsiveness to sepsis

• If in doubt, inform someone

• Understand treatment for sepsis, i.e. the care bundle for sepsis 6 and
its underpinning evidence base