Sepsis Flashcards
What is septic shock?
sepsis with persisting hypotension requiring vasopressors to maintain a MAP>65mmHg and having serum lactate >2mmol/l despite having adequate fluid resuscitation
What are the cardiovascular effects of sepsis?
reduced blood flow to cardiac tissues which reduces oxygen available to myocytes
reduced cardiac output which reduces perfusion of organs
- caused by depression of myocyte activity by circulating cytokines
= body constricts small vessels in muscle/tissue to protect vital organs
How does sepsis affect vessels?
presence of cytokines in sepsis causes leaky vessels
- increased permeability of vessels causing water and protein loss
- reduced oxygen delivery to tissues due to oedema leading to reduced blood volume and blood pressure
How does hypercoagulability occur in sepsis?
disrupted endothelial cells lining the vasculature release tissue factor
- causes coagulation cascade activation
clots in capillaries reduce blood flow and oxygen to tissues
platelet count can drop due to being ‘used up’ in clots leading to bleeding
What is the difference between sepsis and septic shock?
sepsis
- inflammation, microvascular damage and coagulopathy, haemodynamic instability, multiple organ dysfunction and immunosuppression
septic shock
- persistent haemodynamic instability despite fluid resuscitation
- presence of inadequate oxygen delivery or utilisation reflected by anaerobic metabolism and elevated plasma lactate concentration
What is the first theory of the cause of sepsis?
- innate and adaptive
initially, pro and anti inflammatory responses occur causing release of cytokines that drive inflammation
cytokine storm can lead to early death due to the hyper inflammatory state causing fever, refractory shock, acidosis and catabolism.
if sepsis persists, both the innate and adaptive immune systems fail resulting in a marked immunosuppressive state that leads to death due to the inability of patients to clear infections
What is the second theory of sepsis?
- innate
there is an early activation of innate immunity and suppression of adaptive immunity
sepsis occurs due to the persistent activation of the innate immunity that results in intractable inflammation and organ injury
- suggest late deaths are due to persistent underlying innate immune driven inflammation
What are the 4 steps involved in sepsis?
inflammation
microsvascular dysfunction and coagulopathy
multiple organ dysfunction
sepsis associated immunosuppression
What is the mechanism behind inflammation?
innate immune system has non specific mechanisms for recognition
- PAMPs and DAMPs
cells have receptors for PAMPs and DAMPs which upon binding cause production of inflammatory cytokines and chemokines
some cytokines can cause neutrophil activation
- phagocyte cells, die by respiratory burst to release granular enzymes and neutrophil extracellular traps (NETs)
C5a amplifies inflammatory response by causing vasodilation, tissue damage and multiple organ failure
What is the mechanism behind endothelial barrier dysfunction?
cytokines bind to the endothelium causing it to become pro-coagulant
- becomes sticky and leaky leading to oedema and eventual endothelial breakdown
What is the mechanism behind coagulation?
inflammatory cytokines and platelets induce tissue factor release
damaged endothelium upregulate tissue factors causing
- thrombin generation, fibrin deposition, clot formation, bradykinin synthesis and complement activation
dendritic cells are activated
complement on RBCs triggers haemolysis and prothrombotic microvesicles
What are the different outcomes of T cell antigen recognition?
full activation
cytokine polarisation
tolerance/anergy (failure to react to antigen presence)
apoptosis
How are T regulatory cells or anergic T cells induced?
T regulatory cells are induced due to partial activation of T cells
- caused by the activation of T cells without co-stimulator help
What is the function of T regulatory cells?
inhibit autoimmune responses
- by producing cytokines like IL-10
block priming of effector T cells
prevent dendritic cell maturation
- therefore blocks co-stimulatory molecules production
kill mature dendritic cells
How does sepsis progress?
both pro and anti inflammatory responses are activated early in sepsis but the pro inflammatory response predominates
as sepsis progresses the anti inflammatory response predominates
- secondary infections and viral activation occur
early deaths during earl pro inflammatory response are due to cytokine storm mediated events
later deaths during the anti inflammatory phase are due to failure to control pathogens
