2. SHOCK
Shock is a state in which diminished cardiac output or
reduced effective circulating blood volume impairs
tissue perfusion and leads to cellular hypoxia.
3. MAJOR TYPES OF SHOCK
• It results from low cardiac output due to myocardial pump failure.
This can be due to intrinsic myocardial damage, ventricular
arrhythmias, extrinsic compression or outflow obstruction.
Cardiogenic
Shock
• It results from low cardiac output due to low blood volume, such
as an occur with massive hemorrhage or fluid loss from severe
burns.
Hypovolemic
Shock
• It may be triggered by a variety of insults, particularly microbial
infections, burns, trauma or pancreatitis. The common
pathogenic feature is a massive outpouring of inflammatory
mediators that produce arterial vasodilation, vascular leakage
and venous blood pooling. It may lead to organ dysfunction and
if severe may cause organ failure or death.
Shock
Associated with
Systemic
Inflammation
4. SEPTIC SHOCK
Septic shock is caused by the host response to
bacterial, viral or fungal infections.
It is a systemic inflammatory condition characterized
by endothelial cell activation, tissue edema,
disseminated intravascular coagulation and metabolic
derangements that often lead to organ failure and
death
5. PATHOGENESIS OF SEPTIC SHOCK
The ability of diverse microorganisms to cause
septic shock is consistent with the idea that a
variety of microbial constituents can trigger the
process.
Macrophages, neutrophils, dendritic cells,
endothelial cells and soluble components of the
innate immune system recognized and are
activated by several substances derived from
microrganisms.
Once activated, these cells and factors initiate a
number of inflammatory responses and interact in a
complex, incompletely understood fashion to
produce septic shock and multiorgan dysfunction.
6.
7. FACTORS TO PLAY A MAJOR
ROLE IN PATHOPHYSIOLOGY OF
SEPTIC SHOCK
8. 1. INFLAMMATORY AND COUNTER-
INFLAMMATORY RESPONSES
In sepsis, various microbial cell wall constituents engage receptors on
cells of the innate immune system, triggering pro-inflammatory
responses.
Likely initiators of inflammation in sepsis are signaling pathways that lie
downstream of Toll-like receptors which is a host of microbe derived
substances containing so-called pathogen-associated molecular patterns
(PAMPs), as well as G-protein coupled receptors that detect bacterial
peptides and NOD1 & NOD2.
Upon activation innate immune cells produce TNF, IL-1, IFN-γ, IL-12 and
IL-18 as well as HMGB1.
ROS and lipid mediators such as prostaglandins and PAF are also
elaborated.
These effector molecules induce endothelial cells to upregulate adhesion
molecule expression and further stimulate cytokine and chemokine
production.
The complement system is also activated resulting in the production of
anaphylotoxins, chemotactic fragments and opsonins all of which
contribute to the pro-inflammatory state.
Microbial components can activate coagulation directly through factor XII
and indirectly through endothelial function.
The activation of thrombin may further augment inflammation by
triggering PARs on inflammatory cells.
9. 2. ENDOTHELIAL ACTIVATION AND INJURY
The pro-inflammatory state and endothelial cell activation
associated with sepsis leads to widespread vascular leakage
and tissue edema, which have deleterious effects on both
nutrients delivery and waste removal.
One effect of inflammatory cytokines is to loosen endothelial
cell tight junctions, making vessels leaky and resulting in the
accumulation of protein-rich edema throughout the body.
Activated endothelium also upregulates production of nitric
oxide and other vasoactive inflammatory mediators (C3a, C5a
and PAF) which may contribute to vascular smooth muscle
relaxation and systemic hypotension.
10. 3. INDUCTION OF A PROCOAGULANT STAGE
The derangement in coagulation is sufficient to produce the
formidable complication of disseminated intravascular
coagulation in up to half of septic patients.
Sepsis alters the expression of many factors so as to favor
coagulation.
Pro-inflammatory cytokines increase tissue factor production by
monocytes and possibly endothelial cells as well, and decrease
the production of endothelial anti-coagulant factors such as
tissue factor pathway inhibitor, thrombomodulin and protein C.
They also dampen fibrinolysis by increasing pasminogen
activator inhibitor-1 expression.
The vascular leak and tissue edema decrease blood flow at the
level of small vessels producing stasis and diminishing the
washout of activated coagulation factors.
These effects lead to systemic activation of thrombin and the
deposition of fibrin-rich thrombi in small vessels often throughout
the body, further compromising tissue perfusion.
In full-blown disseminated intravascular coagulation, the
consumption of coagulation factors and platelets is so great that
deficiencies of these factors appear, leading to concomitant
bleeding and hemorrhage.
11. 4. METABOLIC ABNORMALITIES
Septic patients exhibit insulin resistance and hyperglycemia
Cytokines such as TNF and IL-1, stress induced hormones
and catecholamines all drive gluconeogenesis. At the same
time the pro-inflammatory cytokines suppress insulin release
while simultaneously promoting insulin resistance in the liver
and other tissues.
Hyperglycemia decreases neutrophil function- thereby
suppressing bactericidal activity-and causes increased
adhesion molecule expression on endothelial cells. Although
sepsis is initially associated with an acute surge in
glucocorticoid production, this phase may be followed by
adrenal insufficiency and a functional deficit of glucocorticoids.
This may stem from depression of the synthetic capacity of
intact adrenal glands or frank adrenal necrosis due to
disseminated intravascular dissemination.
Cellular hypoxia and diminished oxidative phosphorylation
leads to increased lactate production and lactic acidosis.
12. 5. ORGAN DYSFUNCTION
Systemic hypotension, interstitial edema, and small vessel
thrombosis all decrease the delivery of oxygen and nutrients
to the tissue, which fail to properly utilize those nutrients that
are delivered due to cellular hypoxia.
High levels of cytokines and secondary mediators diminish
myocardial contractility and cardiac output, and increased
vascular permeability and endothelial injury can lead to the
acute respiratory distress syndrome.
These factors may conspire to cause the failure of multiple
organs, particularly the kidneys, liver, lungs and heart
culminating in death.
14. THREE GENERAL PHASES
1. An initial non-progressive phase during which reflex
compensatory mechanisms are activated and perfusion of
vital organs is maintained.
2. A progressive stage characterized by tissue hypoperfusion
and onset of worsening circulatory and metabolic
imbalances, including lactic acidosis.
3. An irreversible stage that sets in after the body has
incurred cellular and tissue injury so severe that even if the
hemodynamic defects are corrected, survival is not possible.
15. CONT…
In the early non-progressive phase of shock, a variety of
neurohumoral mechanisms help to maintain cardiac output
and blood pressure. These include baroreceptor reflexes,
catecholamine release, activation of the renin-angiotensin
axis, ADH release and generalized sympathetic stimulation.
The net effect is tachycardia, peripheral vasoconstriction and
renal conservation of fluid. Coronary and cerebral vessels are
less sensitive to the sympathetic response and thus maintain
relatively normal caliber, blood flow and oxygen delivery.
If the underlying causes are not corrected, shock passes
imperceptibly to the progressive phase, during which there is
widespread tissue hypoxia.
16. CONT…
In the setting of persistent oxygen deficit, intracellular aerobic
respiration is replaced by anaerobic glycolysis with excessive
production of lactic acid. The resulting lactic acidosis lowers
the tissue pH and blunts the vasomotor response; arterioles
dilates and blood begins to pool in the microcirculation.
Peripheral pooling not only worsens the cardiac output but
also puts endothelial cells at risk for developing anoxic injury
with subsequent disseminated intravascular coagulation. With
tissue hypoxia vital organs are affected and begin to fail.
In severe cases, the process eventually enters an irreversible
stage. Widespread cell injury is reflected in lysosomal enzyme
leakage, further aggravating the shock state. If ischemic bowel
allows intestinal flora to enter the circulation, bacteremic
septic shock may be superimposed. The patient may develop
anuria as a result of acute tubular necrosis and renal failure
and despite heroic measures the downward clinical spiral
almost inevitably culminates in death.
18. In hypovolemic and cardiogenic shock the patient presents
with hypotension; a weak rapid pulse; tachypnea; and cool,
clammy, cyanotic skin.
In septic shock the skin may initially be warm and flushed
because of peripheral vasodilation. The initial threat to life
stems from the underlying catastrophe that precipitated the
shock.
Rapidly, shock begets cardiac, cerebral and pulmonary
dysfunction and eventually electrolyte disturbances and
metabolic acidosis exacerbate the dire state of the patient
further.
Individuals who survive the initial complications may enter a
second phase dominated by renal insufficiency and marked by
a progressive fall in urine output as well as severe fluid and
electrolyte imbalances.
Coagulopathy frequently complicates shock, particularly when
the cause is sepsis or trauma, or can have serious or even
fatal consequences, particularly in patients with severe with
severe disseminated intravascular coagulation.
Greater than 90% of patients with hypovolemic shock
survive with appropriate management in comparison, septic
shock or cardiogenic shock associated with extensive
myocardial infarction, are associated with low mortality rate.
