So, again, locally this is a good thing,
but when it's at very high levels systemically,
it's a very bad thing.
So, septic shock is really
too much of a good thing.
So, what's going on here?
So, we have by binding of the LPS
or those other bacterial components
that are present in gram-positive cocci
or in fungus, we are activating
neutrophil and monocyte populations.
Now, if we do it locally, good.
If we do it systemically, maybe not so good.
As part of that activation cascade,
we're going to get cytokines produced,
we're going to get reactive
oxygen species produced,
we'll get various eicosanoids, arachidonic
acid, lipid mediators produced.
Again, locally good thing.
Systemically not so much.
We will also get complement activation
and we will have the production of chemokines,
so that we will get increased
inflammatory recruitment into tissues.
Remember also that LPS can act
on endothelium to activate it
and that end activation of endothelium means that,
we get more thrombosis in this case,
it tends to be a pro-thrombotic
response, which again, makes sense,
If I have a local infection, I want the
endothelium to be ready to thrombose,
in case I get vascular damage.
That increased thrombosis, is due to
increased amounts of tissue factor
and inhibitors of the plasminogen
activator pathway, okay,
and so, it's going to have
a net procoagulant effect.
Activation of the endothelium
though, also will cause vasodilation,
again, locally that's the appropriate response
that helps us to recruit inflammatory cells.
But if I vasodilate, every vessel in
my body because I have too much LPS,
oh my God, now I've got
hypotension, I have low flow.
Okay, so, a combination of all
these inflammatory mediators,
in addition to the effect
on the endothelial cells,
with hypotension and pro-coagulation,
I'm going to get microvascular occlusion
and I'm going to get severely
increased vascular permeability
and that's going to lead to multi-organ failure,
I'll have a coagulopathy, I'll have
secondary effects related to fever
and being driven by cytokines, I have
the vasodilation and capillary leak
and then all of my organs don't function properly,
because they don't have the right blood pressure
and the vessels are clogged and there are a lot of
inflammatory evil humors being made
and you end up with multi-organ failure.
So, important to recognize that we
don't have to have circulating bacteria
to get this effect of septic shock.
In fact, you can have a very
local infection, even an abscess,
but if you have too robust a
production of the or activation
of the immune response because
of the lipopolysaccharide,
then those systemic distribution of those
mediators of the various cytokines etc.,
will cause a septic shock physiology.
So, whether or not you get septic
shock depends on a number of things.
It depends on the microbial load,
the more microbes the more LPS,
the greater the effect, generally.
It will also be impacted by host comorbidity,
if there's already damage in various tissues
or there's already ongoing diminution of function,
say chronic renal failure chronic lung disease,
then a little bit of sepsis
can go a very long way,
in terms of morbidity and mortality.
And then there'll be host polymorphisms,
so, some people will not necessarily have
the same cytokine response to the LPS,
that other individuals will.
So, it's variable and not everyone who
has a bacterial infection in someplace,
is going to develop septic shock.