Sepsis

Question 1

When were the successive definitions of sepsis set?

Answer 1

• Sepsis-1: 1991
• Sepsis-2: 2001
• Sepsis-3: 2016

Question 2

What is sepsis?

Answer 2

• A highly heterogeneous syndrome caused by an imbalanced host response to an infection
• The immune response involves both sustained excessive inflammation and immune suppression, ultimately leading to a failure to return to normal homeostasis

Question 3

How did the 2001 definition of sepsis (sepsis-2) differ from the original definition set in 1991?

Answer 3

An expanded list of signs and symptoms was included

Question 4

What were the diseases identified in the original consensus definition of sepsis (1991; sepsis-1)?

Answer 4

• Sepsis: systemic inflammatory response syndrome with proven or suspected infection
• Severe sepsis: sepsis and acute organ dysfunction
• Septic shock: sepsis and persistent hypotension after fluid resuscitation

Question 5

What were the diseases identified in the third international consensus definition for sepsis and septic shock (2016; sepsis-3)?

Answer 5

• Sepsis: life threatening organ dysfunction caused by a dysregulated host response to infection (organ dysfunction identified as an acute change in total SOFA score of ≥2 points)
• Septic shock: sepsis in which the underlying circulatory and cellular and/or metabolic abnormalities are marked enough to substantially increase mortality—i.e. persisting hypotension requiring vasopressors to maintain a mean arterial pressure of ≥65 mmHg and a serum lactate concentration of >2 mmol L^–1

Question 6

According to the latest definition of sepsis (sepsis-3), how can septic shock be defined in clinical practice?

Answer 6

Sepsis with:

• persisting hypotension requiring vasopressors to maintain the mean arterial pressure at ≥65 mmHg
• serum lactate concentration of >2 mmol L^–1

Question 7

What are the diagnostic criteria for systemic inflammatory response syndrome (SIRS)?

Answer 7

At least two of the following:

• Body temperature >38ºC or <36ºC
• Heart rate >90 beats per minute
• Respiratory rate >20 breaths per minute or arterial P_CO2 <32 mmHg
• White blood cell counts >12×10⁹ l^–1 or <4×10⁹ l^–1, or >10% immature forms

Question 8

What are the main differences between sepsis-3 and the original consensus definition of sepsis from 1991?

Answer 8

• Sepsis is now no longer tied directly to systemic inflammatory response syndrome
• Severe sepsis as a category is now removed, and organ failure is now part of the definition of sepsis
• Septic shock is now tied to increased mortality and has more specific clinical diagnostic markers

Question 9

What is the sequential organ failure assessment (SOFA) score?

Answer 9

A ranking of overall organ function based on six different scores (each classified from 1 to 4 according to increasing abnormality and/or severity), one each for the respiratory, cardiovascular, hepatic, coagulation, renal, and neurological systems

Question 10

What are the cytokines implicated in the pathogenesis of sepsis?

Answer 10

• TNF
• IL-1β
• IL-12
• IL-18

Question 11

By which pathway is the complement activated in sepsis?

Answer 11

All three pathways

Question 12

How are changes in the complement used to treat sepsis?

Answer 12

• Blockade of C5a signaling may improve the outcome of sepsis (e.g. by C5a receptor antagonists)
• Blockade of C3a receptor may reduce survival

Question 13

What are the changes in specific complement factors in sepsis?

Answer 13

• There is a correlation between levels of complement activation fragments, e.g. C3b and C5a, to sepsis severity
• There is an increased level of MAC/TCC in sepsis patients (though this is not correlated to severity)

Question 14

How are blood coagulation factors and endothelial cells linked to sepsis?

Answer 14

• Increased activation of the coagulation leads to microvascular thrombosis in some places and uncontrolled hemorrhaging in other areas (due to consumption of available coagulation proteins and platelets)
• Tissue factor is the main driver of coagulation activation in sepsis
• Excessive endothelial cell activation leads to leakage of plasma proteins and edema

Question 15

What is the main factor associated with increased coagulation in sepsis patients?

Answer 15

Tissue factor

Question 16

How do NETs contribute to sepsis?

Answer 16

• Patients with sepsis have increased NET levels in their circulation
• NETs contribute to collateral tissue damage, thrombosis, and organ dysfunction
• NETs facilitate coagulation and thrombus formation by serving as a scaffold for the entrapment and aggregation of platelets and erythrocytes

Question 17

How do platelets contribute to sepsis?

Answer 17

• Excessive platelet activation is implicated in organ injury during sepsis by augmenting cell recruitment and inflammation, facilitating formation of vaso-occlusive thrombi in capillaries, and direct cell toxic effects
• Low platelet counts are independently associated with mortality in patients with sepsis

Question 18

How do B cells contribute to sepsis?

Answer 18

• Innate response activator B cells produce IL-3, which increases inflammation and the production of monocytes
• IL-3 levels in patients with sepsis correlate with increased mortality

Question 19

What is the mechanism of immune suppression in sepsis?

Answer 19

• Strong depletion of CD4⁺ and CD8⁺ T cells, B cells, and dendritic cells due to apoptosis
• Reduced expression of HLA-DR (class II MHC) on blood monocytes
• Diminished capacity of macrophages and monocytes to release pro-inflammatory cytokines upon stimulation

Question 20

What are some of the novel proposals for the treatment of sepsis?

Answer 20

• Blood purification of PAMPs and inflammatory mediators via magnetic beads covered with human MBL
• Immune stimulation by IFN-γ, IL-7, and IL-15
• Immune suppression by inhibiting the complement or coagulatory systems