Astana medical university Kazakhstan
Department of pathophysiology
Iws no - 5 = Pathophysiology of sepsis.
Submitted by = deepak yadav
Group no = 370
Submitted to =professor Аytbаеvа Zhаinа Bаidullаyеvnа
Abstract :-
The roles of inflammation and coagulation in the pathophysiology of sepsis are described. Sepsis results
when an infectious insult triggers a localized inflammatory reaction that then spills over to cause
systemic symptoms of fever or hypothermia, tachycardia, tachypnea, and either leukocytosis or
leukopenia. These clinical symptoms are called the systemic inflammatory response syndrome.
Discussion :-
Sepsis is a serious clinical condition that represents a patient's response to a severe infection and has a
very high mortality rate. Normal immune and physiologic responses eradicate pathogens, and the
pathophysiology of sepsis is due to the inappropriate regulation of these normal reactions.
Activation of inflammation in sepsis :-
During sepsis, the innate immune system activated by PAMPs and DAMPs releases multiple
inflammatory cytokines in a process known as the “cytokine storm,” which results in a severe and
persistent inflammatory response.There is a release of such pro-inflammatory mediators as tumor
necrotizing factor alpha (TNF- ) interleukins (IL-1, IL-6), platelet activating factor, prostaglandins, etc. In
parallel, anti-inflammatory mediators such as IL-4 and IL-10 are produced, which limit the body's pro-
inflammatory response. In sepsis, the regulation of the body's early response to infection is lost.
Activation of coagulation in sepsis :-
In sepsis, toxins cause direct activation of coagulation via the effect of chemical mediators on the
endothelium and monocytes as well as indirect activation through the proinflammatory cascade.
Activation of coagulation by toxins occurs directly through upregulation of tissue factor (TF) .
Inhibition of fibrinolysis in sepsis :-
Thrombin-activatable fibrinolysis inhibitor and neutrophil elastase also modulate fibrinolysis. Dynamic
changes in these molecules are deeply involved in the pathomechanisms of the impairment of
fibrinolysis, leading to MODS in DIC associated with sepsis.Fibrinolysis could be completely inhibited by
alpha(2)-antiplasmin, alpha(2)-macroglobulin and antithrombin, but not aprotinin, in the presence of
CPB, and occurred only when the irreversible inhibitor or pool of inhibitors were in excess of
plasminogen.
Microcirculatory-mitochondrial function in sepsis :-
microcirculatory and mitochondrial functions are impaired during sepsis. Mitochondrial respiration
seems to evolve during the course of sepsis, demonstrating a change from reversible to irreversible
inhibition. The spatiotemporal heterogeneity of microcirculatory and mitochondrial dysfunction
suggests that these processes may be compartmentalized. Although a causal relationship between
mitochondrial and microcirculatory dysfunction and organ failure in sepsis is supported by an increasing
number of studies, adaptive processes have also emerged as part of microcirculatory and mitochondrial
alterations.
Regional tissue distress caused by microcirculatory dysfunction and mitochondrial depression underlies
the condition in sepsis and shock where, despite correction of systemic oxygen delivery variables,
regional hypoxia and oxygen extraction deficit persist. We have termed this condition microcirculatory
and mitochondrial distress syndrome (MMDS). Orthogonal polarization spectral imaging allowed the
first clinical observation of the microcirculation in human internal organs, and has identified the pivotal
role of microcirculatory abnormalities in defining the severity of sepsis, a condition not revealed by
systemic hemodynamic or oxygen-derived variables. Recently, sublingual sidestream dark-field (SDF)
imaging has been introduced, allowing observation of the microcirculation in even greater detail.
Microcirculatory recruitment is needed to ensure adequate microcirculatory perfusion and the
oxygenation of tissue cells that follows. In sepsis, where inflammation-induced autoregulatory
dysfunction persists and oxygen need is not matched by supply, the microcirculation can be recruited by
reducing pathological shunting, promoting microcirculatory perfusion, supporting pump function, and
controlling hemorheology and coagulation. Resuscitation following MMDS must include focused
recruitment of hypoxic-shunted microcirculatory units and/or resuscitation of the mitochondria. A
combination of agents is required for successful rescue of the microcirculation. Single compounds such
as activated protein C, which acts on multiple pathways, can be expected to be beneficial in rescuing the
microcirculation in sepsis.
the cause of microcirculatory flow alteration in sepsis :-
It is associated with a decrease in capillary density and increased heterogeneity of perfusion caused by
inappropriate vasodilatation and vasoconstriction, leading to decreased oxygen delivery, tissue hypoxia
and organ dysfunction.Mechanisms of microcirculatory dysfunction in sepsis include arteriolar
hyporesponsiveness and capillary dysfunction, leading to extravasation of fluid protein and neutrophils.
The importance of microcirculatory assessment in sepsis :-
Several studies have demonstrated that: (a) improvements in the microcirculatory function in sepsis
after early resuscitation are associated with a decreased incidence of organ dysfunction and (b)
persistent microcirculatory dysfunction after resuscitation is associated with worse outcomes.However,
the microcirculation is difficult to monitor in practice and so current resuscitation goals rely on the
monitoring and restoration of macro-haemodynamic values (such as systemic arterial pressure, cardiac
output, heart rate), along with restoration of organ perfusion (inferred from normalisation of serum
lactate and ScVO2).Moreover, restoration of macro-haemodynamic variables such as arterial pressure,
especially with vasoactive agents such as noradrenaline, does not guarantee improvements in
microcirculatory flow; in fact, noradrenaline can inhibit microcirculatory function irrespective of the
presence of hypotension.
Sources =
https://ccforum.biomedcentral.com/articles/10.1186/cc3753
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5665123/#:~:text=Sepsis%20affects%20all
%20elements%20of,tissue%20hypoxia%20and%20organ%20dysfunction.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5665123/
Feedback :-
Abstract by Ashok Kumar Bairwa = he explain the topic SEPSIS very well with deep discussion.
