Endotoxemia Flashcards
What is endotoxemia?
The presence of endotoxin in the ciruculation
What is endotoxin?
Heat-stable LPS component of the gram negative bacterial cell wall
What portion of the outer layer of the outer cell membrane is LPS?
75%
Why does LPS tend to form micelles in circulation?
Because it has both hydrophobic and hydrophillic regions
What is the polysaccharide O-region of LPS?
Polar antigenic region, responsible for smooth bacterial colonies in culture
What is the lipid A region of LPS?
Hydrophobic portion that is well preserved between all gram negative species
When is endotoxin produced in the highest quantities?
During death and rapid multiplication phases
Which structure of LPS is most responsible for the deleterious effects of endotoxins?
Lipid A
What does SIRS stand for?
Systemic inflammatory response syndrome
What is sepsis?
SIRS induced by infection manifested by two of more of: hyperthermia, HR>90bpm, RR >20bpm, arterial CO2
What is septic shock?
Sepsis induced by hypotension or need for vasopressors to maintain BP despite adequate fluids as well as lactic acidosis, oligura, and altered mental status
What does CARS stand for?
Compensatory anti-inflammatory response syndrome
T/F: CARS is a syndrome of immune suppresion
True
What does MODS stand for?
Multiple organ dysfunction
What does MOFS stand for?
Multiple organ failure syndrome
What is stage one endotoxemia?
Physical barriers breached and endotoxin enters the body
Where does stage one endotoxemia usually occur?
Skin and GIT (especially cecum and large intestine)
What can inhibit endotoxin from being absorbed in the GIT?
Binding of endotoxin to bile salts
What is stage two endotoxemia?
Endotoxin gains circulation and stimulates macrophages
What is LBP?
LPS binding protein that is involved in the acute phase response
What does LBP do?
Acts as a shuttle protein bringing LPS from aggregates to responding cells
What can happen after LPS binds to LBP?
- Elimination at liver
- Brought to macrophages and inactivated
- Brought to other cell types
- Transfers to high-density lipoproteins and decreases inflammatory cell interaction
- Transfers to macrophages and triggers inflammatory response
Can small amounts of endotoxin be eliminated without clinical signs?
Yes- if too large an amount it will overwhelm elimination pathways and activate inflammatory response
What receptor does the LPS-LBP complex interact with to initiate inflammatory response?
CD14
What pathway is primarily activated in equines leading to the increased pathogenesis when compared to other animals?
MyD88
What two pathways are activated when TLR-4 is activated?
MyD88 and TRIF
Is MyD88 pro- or anti-inflammatory?
Pro-inflammatory
Is TRIF pro- or anti-inflammatory?
Anti-inflammatory
What determines severity of clinical response to endotoxin?
Macrophage responsiveness
What is stage 3 endotoxemia?
Neutrophils bind to endothelial cells and become activated
What kind of cells do TNF and IL-1 act on?
Neutrophils and endothelial cells
What is the importance of cytokine induced receptor driven margination of neutrophils?
Accounts for leukopenia found in most horses with endotoxemia
What accounds to the procoagulant effects of endotoxemima
Stimulation of endothelial cells to produce procoagulant products and platelet aggregation
T/F: Once activation of neutrophils and endothelial cells occurs, the process becomes self-sustaining and malignant
True
What is stage 4 endotoxemia?
Compromised organ perfusion
What is normal organ perfusion maintained by?
- Vasodilators/constrictors
- Pro/anti-coagulants
- Proteases/ antiproteases
- Oxidants/ antioxidants
Are severely endotoxic patients prone to anti- or hypercoaguability?
Hypercoaguability
What is the vascular tone in very early endotoxemia?
Pulmonary vasoconstriction, tachypnea, and arterial hypoxia
What is the vascular tone in later endotoxemia?
Widespread vasodilation
What is the result of damage to endothelium?
Extravasation of neutrophils and leakage of protein through damaged cells
What are the clinical manifestations of compromised organ perfusion in the horse?
- GIT- ileus and colic
- Musculoskeletal- laminitis
- Renal failure
- Coagulopathies- thombosis, DIC
- CNS- stupor and incoordination
- Icterus
- Respiratory distress
What is stage 5 endotoxemia?
Recovery without treatment
Does stage 5 typically occur?
No- but can in cases of minimal endotoxin absorption or subclinical endotoxemia
What are the clinical signs of early endotoxemia?
Tachypnea, pale MM, depression, restlessness, inappetence, increasing temperature
What are the clinical signs of progressive endotoxemia?
Reduction of GIT sounds (depressed motility), HR peak ~2hr post infection, congested MM, prolonged CRT, toxic line on gingival margins
What are the clinical signs 4-6hr post infection?
Secondary phase of tachycardia and tachypnea, progressive increase in temp,
Persists for several hours
What are the clinical signs associated with high doses of endotoxin?
Dominant signs of circulatory failure and coagulopathies
Dehydration (sunken eyes, decreased turtor, dry MM), decreased rectal temp, oliguria/anuria, rapid weak pulse, cold extremities, sweating, muscle tremors/recumbency, hemostatic dysfunction (petechiae, ecchymoses)
What is an indicator of poor prognosis for high dose endotoxemia patients?
Mucosal petechia or ecchymoses
If severe cases live past 24 hours, what clinical signs may develop?
Ventral edema and laminitis
What mediators are produced in response to endotoxin?
IL-1, IL-6, IL-8, TNF, GM-CSF, eicosanoids
What is the incidence of endotoxemia in horses with colic?
30-40%
What is the incidence of endotoxemia in neonatal foals with suspected septicemia?
40-50%
What is the initial phase of endotoxemia?
Hyperdynamic state of endotoxic shock- often very short and missed, depends somewhat of degree of endotoxemia
What is the later phase of endotoxemia?
Hypodynamic state of endotoxic shock- most often the stage which is seen clinically, recognized as typical presenting signs of shock
What are the clinical signs of the hyperdynamic stage of endotoxemia?
White or injected MM, CRT normal, strong pulses, tachycardia, tachypnea, fever, warm extremities
What are the clinical signs of the hypodynamic stage of endotoxemia?
Congested dark red MM with toxic line, prolonged CRT (~3sec), weak thready pulses, tachycardia, tachypnea, cold extremities, normo- or hyperthermic
How is endotoxemia diagnosed?
Mostly based on clinical signs, history, and expectation based on disease status
What are some CBC findings in the endotoxemic patient?
Dependent on stage of disease
Lymphopenia typically only abnomality; early stages may have neutropenia with left shift and toxic cells
Are there typically distinct Chem changes in the endotoxemic patient?
No
How do you directly test for circulating endotoxin?
- Limulous amebocyte lysate assay
2. Horse side test (Etox Dx)
In which fluid will endotoxin most notably show up?
Peritoneal fluid (3x more likely than serum in academic settings)
Can specific mediators be measured in order to diagnose endotoxemia?
Not to diagnose
Can be measured to get an idea of prognosis
Can animals be vaccinated against endotoxemia?
Yes- variable protection, not readily used
Can endotoxemia be prevented with dietary manipulation?
Yes
What can be done to the diet to help prevent endotoxemia?
Adding linseed oil- alters aracidonic acid composition in cell membrane
What is the goal of treatment of endotoxemia?
Prevention of movement of endotoxin into circulation, circulatory and CVS support
Is treating endotoxemia easy?
No- widespread non-specific activation of host’s inflammatory response and immunologic processes
What can be done to treat the inciting condition?
Antimicrobials, empty the GIT, drain any infected tissue of purulent material (pleuritis), drain abscesses
Is it better to use bacteriocidal or bacteriostatic drugs in cases of endotoxemia?
Typically bacteriostatic until endotoxemia is under control
What kind of patients is the rapid death of gram negative bacteria more significant in as far as worsening the condition?
Foals
What is the primary goal of cardiovascular support treatment?
Expansion of intravascular volume
What types of fluids can be used?
Balanced polyionic solution, hypertonic saline, proteinaceous fluids
What is the dosage of balanced polyionic solution dependent on?
Degree of hypovolemia
What is the typical dose of hypertonic saline?
4mL/kg over 10 min
Should hypertonic saline always be followed with standard IV fluids?
Yes
How much protein should be administered to horses in order to make a difference?
at least 5L ($$$)
When would protein be required?
In severely endotoxemic patients
Not normally required
Are there specific antibodies to neutralize endotoxin?
Yes
Are antibodies typically used in endotoxemia patients?
No
Why does vaccination typically fail for endotoxemia?
Antigenic variation in O antigenic structure and minimal response to lipid A component of LPS
What is polymixin B?
A nonspecific binder- cationic polypeptide antibiotic that binds with lipid A
What is a concern with using polymixin B?
If animal is dehydrated/azotemic it can cause renal toxicity
What is the most widely used therapeutic modality for endotoxemia?
Inhibition of synthesis and effects of endotoxin induced mediators
What drugs are typically used to combat the pro-inflammatory response?
NSAIDS (flunixin meglumine) and controversially glucocorticoids
What is the advantage to pre-treatment with flunixin meglumine?
Blocked both early and late hypotensive responses to endotoxin and prevented increases in TXA2 and PGI2
(but how do you pre treat for something you don’t know is going to happen…..)
Why is dexamethasone use in endotoxemic patients controversial?
Helps leukocyte values return to baseline better than flunixin but hasn’t been proven to provide any significant benefit
What is the concern with glucocorticoid administration in endotoxic patients?
Potentially increases risk to develop laminits
Potential for infection to spread due to immune suppression
What is the benefit of using pentoxifylline in endotoxemic patients?
In vitro: Reduced endotoxin induced production of cytokines, thomboxane and tissue factor while increasing that of prostacycline
In vivo: nothing really useful
What is the proposed benefit of using pentoxyfylline in endotoxemic patients?
Minimize the risk of development of laminitis
T/F: Use of drugs that inhibit specific factors is largely experimental in endotoxemic patients.
True- resulted in little to no change in overall course of disease
Monoclonal antibodies, PAF receptor agonists, Alpha1 antagonist
What are the complications of endotoxemia?
The same thing as the clinical signs……
- GIT- ileus and colic (in cases where GI is not the source)
- Musculoskeletal- laminitis
- Renal failure (usually only condition that will lead to renal failure)
- Coagulopathies- thombosis, DIC
- CNS- stupor and incoordination
- Icterus
- Respiratory distress (PIVM, vascular thrombosis or permeability changes, DIC)
