Micro Chapter 66: Sepsis
Generalized inflammatory responses of the body are organized as (from least serious to most):
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Systemic inflammatory response syndrome (SIRS) – you have SIRS if you have any 2 of:
o Fever, increased or low WBCs, increased heart rate, increased respiratory rate
Sepsis – SIRS, plus confirmed infection
Severe sepsis – SIRS, plus low blood pressure
o Fix by giving them fluids
Septic shock – SIRS, plus persistent hypotension
o Fluids won’t work, and you need drugs to increase vascular tone
Multiorgan dysfunction syndrome (MODS) – SIRS, persistent hypotension, leading to
accumulation of metabolic products that can’t be cleared (like lactic acidosis), and then clotting
problems, or failure of renal, liver, heart, or cognitive function
Bacteremia – bacteria in the blood
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Bacteremia is the most common cause of sepsis
o Other causes though are fungi, viruses, and parasites
Bacteremia most often is from spread from the skin, GU, respiratory, or GI (secondary blood
infection)
o If you don’t know the source of bacteremia, it’s called primary blood infection
Sepsis can also happen in response to massive tissue injury and necrosis (like a burn), drugs, and
chemical rxns
Not all blood infections lead to sepsis
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Asymptomatic and transient low-grade bacteremia happens in everyone on a daily basis from
minor mucosal damages, like in brushing teeth or pooping
o These organisms are rapidly removed form circulation and rarely ever cause harm
Any microbe can lead to a systemic inflammatory response if there’s enough of it in the blood, called
inoculum effect
Host defects that are major risk factors for disseminated infection and sepsis:
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Disruption or penetration of skin and mucosa
o Ex: chemotherapeutic drugs that damage rapidly dividing mucosal cells lining the mouth
and GI can cause ulcerations that allow for entry of pathogens
o Ex: necrotic tissue has no blood supply, so it’s a safe place for pathogens to hang out in
Low granulocytes (neutrophils, eosinophils, and basophils) or problems with them working right
o Neutrophils are the first line of defense against many bacteria
o Low neutrophils can allow endogenous infections from your own normal flora, which
happens more often than exogenous infection
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o Ex: diabetes - # of neutrophils is normal, but the neutrophils don’t work as well
Complement problems
o If the classical complement pathway and C3 don’t work, it can predispose to bacteremia
and sepsis
o Cirrhosis and severe burns are times when complement protein is low, because of
decreased making of it
 This messes up recruitment of neutrophils
o Premature babies don’t have enough complement developed yet, so they’re more
prone to sepsis
Problems with the immune system
Spleen’s not working or it’s not there – this especially affects antibody making, and makes it so
that you can’t screen the blood for infection as well
After infection or tissue injury starts, lots of pro-inflammatory cytokines, mainly TNF-α and Il-1, Il-6, and
Il-8, are released by innate immunity
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Other things upregulated include prostaglandins, leukotrienes, ROS, adhesion proteins, and
proteases
There’s also rapid activation of plasma proteins like complement, clotting factors, and the
kallikrein-kinin system
Page 674 – list of mediators of sepsis and what they do
If there was no inflammatory response, the person would die from overwhelming infection
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Too much inflammation though is also bad
This is why an anti-inflammatory response then follows the inflammation
The anti-inflammatory response shows increased TGF-β, and cytokines Il-4, Il-10, and Il-11
Also, the lymphocytes of septic patients become hyporesponsive to infectious stimuli, and enter
a state of immunosuppression or immunoparalysis, increasing the risk for secondary infection
Different microbes have different stuff in their cell walls that determines their ability to trigger sepsis
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Gram-negative bacilli have lipopolysaccharide (LPS, endotoxin) and lipid A, which are potent
stimulators of cytokines, and so can cause septic shock
Gram-positive bacteria have less potent stuff in their cell walls, like lipoteichoic acid and
peptidoglycan
Mycobacteria have less potent lipoarabinomannan in their cell walls
Fungi have mannan in their cell walls
Innate immunity is the first line of defense against invading microorganisms, and uses pattern
recognition receptors (PRR) to recognize common things seen in microbes
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PRR’s can be on the cell surface, or within endosomes
PRR’s initiate the innate immune response, and regulate the adaptive host response
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Toll-like receptors are pattern recognition receptors
Nucleotide-oligomerization domain leucine-rich repeat (NOD-LRR) is important in recognizing
bacterial peptidoglycan
Cytoplasmic caspase activation and recruiting domain helicases, are important in recognizing
viral DNA
Pattern-associated molecular patterns (PAMPs) – conserved molecules seen in all microbes and
not in the host
Danger-associated molecular patterns (DAMPs) – host tissue molecules that signal
noninfectious consequences of sepsis, like damage from hypoperfusion, ischemia, & reperfusion
o DAMPs include heat-shock proteins, hyaluronic acid, and fibrinogen
TLR’s allow for the innate immune system to recognize a wide variety of existing and emerging
pathogens
o TLR4 is the TLR for LPS
 TLR4 is found on macrophage, dendritic cells, and endothelial cells
TLR’s bind PAMPs with help from accessory molecules (like MyD88, TIRAP/MAI, TRAM, and
TRIF) and initiate signaling pathways that generate NF-KB (nuclear factor kB) and activator
protein 1, causing a proinflammatory response
The initial manifestations of sepsis affect the cardiovascular system, and include hypotension and
edema – page 677
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This can cause decreased blood volume, decreasing perfusion, impaired oxygen delivery, and
accumulation of metabolites (lactic acidosis), and can lead to necrosis and organ failure
In normal inflammation, neutrophils rapidly arrive, contain and kill the infection, and then rapidly die
by apoptosis
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The inflammation triggered the apoptosis, and other anti-inflammatory effects by release of
anti-inflammatory mediators, leading to resolution of the inflammation, and minimal local tissue
damage
In sepsis, neutrophil survival is prolonged, and rates of apoptosis are reduced, leading to systemic
activation of a lots of neutrophils that add to organ failure
In sepsis, when the neutrophils promote inflammation at the endothelial cells, it activates clotting and
inhibits fibrinolysis, which uses clotting factors, and leads to deposition of fibrin and clot formation in
the microvasculature
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Lots of these little clots then impair nutrition to tissues, causing impaired organ function,
hemorrhage, and necrosis, and also makes you bleed easy
This is called disseminated intravascular coagulation (DIC) – sepsis ends in DIC
Activating the clotting cascade also triggers a positive feedback loop, stimulates
proinflammatory cytokines, and further hurts organs
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So both the proinflammatory response and the procoagulant state lead to development of
organ failure in sepsis
The impact of sepsis on the body:
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Vasculature – vasodilation of the arteries decreases resistance, and dilation of veins causes
pooling of blood in the veins (increased capacitance)
o This leads to fluid being pushed out of the vessels into the interstitial space, causing
edema
o This also decreases the blood pressure, making the heart have to work harder
Heart – sepsis decreases heart function by decreasing mitochondria function and heart
contractility
o This decreases stroke volume, which triggers reflex tachycardia
o Eventually, stroke volume decreases to the point where tachycardia can’t maintain the
cardiac output needed to maintain blood pressure
o Early in sepsis, the low blood pressure and high cardiac output (from tachycardia) is
called warm shock, because the person is vasodilated with warm or flushed skin
o Later in sepsis, cardiac output falls and peripheral vasodilation is replaced by
vasoconstriction to shunt blood to the vital organs
 This causes the skin to get pale and cold, and the hands and feet to turn bluepurple
 This is called cold shock
Brain – sepsis causes confusion, delirium, stupor, and possible coma
o These effects are from hypotension, decreased perfusion of the brain and direct effects
of the organism to the CNS
Lung – edema in the lungs can impair gas exchange, called adult respiratory distress syndrome
(ARDS)
Kidney – hypotension and infection lead to acute tubular necrosis and renal failure
o So they need dialysis in sepsis to remove dangerous metabolites that would then
accumulate
Liver – when the liver necroses and the gallbladder isn’t working right, it can lead to jaundice
and poor liver function seen as problems with drug metabolism, and lack of albumin and
clotting factors
o Lack of albumin makes edema worse, which can decrease blood pressure further
GI – hypotension can cause ischemia and necrosis of bowel mucosa and wall, leading to
hemorrhage
Endocrine and metabolism – sepsis is a catabolic state, causing massive protein, lipid, and
glycogen breakdown (proteolysis, lipolysis, and glycogenolysis)
o Sepsis causes increased making of hormones cortisol, catecholamines, and glucagon,
like in any other stress response
 Their increase can cause insulin resistance and increased blood glucose
 Hyperglycemia impairs phagocyte function
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If the adrenals are failing, then these stress hormones can’t be increased anymore,
called adrenal insufficiency
Oxygen metabolism is messed up, with a lot of the oxygen being sent to the tissues by
the heart returning to it unused
 So the tissues aren’t using the oxygen, leading to glycolysis, which converts
pyruvate to lactate, causing lactic acidosis
Treating sepsis:
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Massive amounts of fluids – correct the blood volume and improve perfusion so that the organs
can work
If fluids alone can’t work, then you turn to drugs
Drugs used should definitely include vasoconstrictors and drugs that increase heart contractility
Also you should use broad-spectrum IV antibiotics targeting the most likely bug you think is
causing the sepsis
o Then try to figure out the bug specifically and adjust treatment to that
Give them air to increase oxygen supply
Blood transfusions keep the Hgb concentration good
In renal failure, you give them dialysis
For the hyperglycemia, give them insulin
The main cytokines that cause sepsis are TNF-alpha and Il-1
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Il-1 triggers fevers, increase expression of adhesion molecules, and makes endothelial surfaces
procoagulant
Complement deficiency meningococci and H flu
Deficiency in respiratory burst staph
Anemia encapsulated bacteria
Burns pseudomonas