Endotoxemia Flashcards
What is the progression of endotoxemia?
Disease -> sepsis -> endotoxemia -> systemic inflammatory response syndrome -> compensated anti-inflammatory response syndrome -> multiple organ dysfunction syndrome —> multiple organ failure
What are the primary causes multiple organ dysfunction syndrome?
Acute respiratory distress syndrome (ARDS)
Disseminated intravascular coagulation (DIC)
What are the criteria for diagnosis of systemic inflammatory response syndrome?
At least 2 of the following..
Leukopenia, leukocytosis, or >10% bands
Hyperthermia or hypothermia
Tachycardia
Tachypnea
Evidence of sepsis in foals
What is endotoxemia?
Presence of endotoxin in circulation
-LPS from the cell wall of gram negative bacteria
—> recognition of pathogen leads to inflammatory response that cannot be sufficiently controlled
What are the 3 structural domains of LPS?
Polysacchardie O region (polar) -> accounts for the serologic differentiation among bacterial species
Core acidic polysaccharide
Lipid A (hydrophobic) -> unique and well conserved
What part of LPS is most responsible for the toxic effect of endotoxemia?
Lipid A
What preventative mechanisms does the body have against endotoxemia?
Mucosal epithelial cells/ physical barrier
- restrict bacterial transmural movement across the bowel wall
- secrete lysozyme, enzymes, and antibodies
Circulation
- liver removes endotoxin from portal blood (monocytes AKA kupffer cells)
- intravascular macrophages
- anti-endotoxin antibodies bind and remove
Where can bacteria breach physical barriers leading to endotoxemia?
Digestive Respiratory Reproductive Integumentary Urinary
You do an abdominocentesis on a colic horse, what cbc and biochem results would indicate significant compromise of the GI system ?
High protein and high WBC
T/F: the larger the section of compromised bowel, the larger the chance of developing endotoxic shock
True
—> reperfusion injury due to ischemia and necrosis
How does an enteritis or colitis lead to endotoxemia?
Damage to the GI walls allowing bacterial translocation
What organism causes Potomac horse fever?
Neorickettsial
AKA equine monocytic ehrlichiosis
What pathology is associated with Potomac horse fever?
Acute entercolitis —> colic, fever, and diarrhea
Laminitis often appears due to systemic inflammation
What is a sand colic? What are methods of diagnosis?
Horse consumes sand, large amounts settle in large intestine
Auscultation of cranial abdominal cavity-> hear waves washing onto the shore
Passage of mineral oil and check for sand
How does carbohydrate overload lead to endotoxemia?
Carbohydrate overload-
> lowers pH -> bacterial overgrowth -> high amount of fermentation injury mucosa —> bacteria gains access to portal circulation
What drugs can induce a colitis?
Antibiotics
NSAIDS: Banamine (flunixin meglumine) or phenylbutazone
T/F: pleuropneumonia is most commonly viral
False
Bacterial
What is the usually the treatment for a pleuopneumonia?
Thoracotomy - provide drainage
Horse has watery green tinged nasal discharge
Dysphagia
Gagging
What is your dx?
Choke - esophageal obstruction with feed
Often leads to aspiration pneumonia -> Ecoli and Klebsiella
What gram positive organism of the skin can pass into the blood causing endotoxemia?
Clostridium myositis
What reproductive disease most commonly leads to endotoxemia?
Retained placenta
Other causes
- uterine rupture
- severe metritis
What disease of the urinary tract can lead to an endotoxemia?
Infection
Obstruction
What is the pathophysiology of equine metabolic syndrome ?
Lipotoxicity (excessive conversion of glucose to fat)
- disruption of insulin receptors progress until insulin resistance
- associated with oxidative stress and inflammation
- > increased IL6, IL8, IL10, and TNFa
- > prolonged cytokine expression in circulatory leukocytes - increased inflammatory response (also lead to laminitis )
Hyper-cortisolemic state is caused by what endocrine disease in horses?
Pituitary par intermedia dysfunction (PPID)
-> ACTH overstimulates adrenal glands —> cortisol synthesis
What is the pathophysiology of endotoxemia?
Physical barrier breach
Endotoxin stimulate macrophages
Macrophages stimulates TXA2 and vasoconstriction
Macrophages synthesize cytokines
TNF and IL1 act on neutrophils and endothelial cells —> margination of neutrophils and emptying of granular content
Endothelial damage -> hypercoagulable state
Vasodilator substances from endothelium —> shock
Compromised organ perfusion
What receptors on macrophages are responsible for binding LPS? And what pathway is activated in the macrophages?
Pathogen associated molecular pattern (PAMP; LBP which binds to CD14 cell surface and activation of pathogen recognition receptors (PRR) on toll like receptors
Toll like receptor 4
-> MyD88 pathway -> TNF and IL1 production (pro inflammatory)
In the early stage of macrophage activation, it stimulates TXA2 causing ??
Vasoconstriction
—> pulmonary vasoconstriction results in increase in pulmonary arterial pressure
In the later stages of macrophage activation, they synthesize cytokines (TNF and IL1) which results in??
Amplification of endotoxin signal
Endogenous pyrogens, cortisol, epi, procoagulant activity
NO -> vasodilation
TNF and IL1 act on what cells and what response do they produce??
Neutrophils and endothelial cells
-> cytokine induced margination of neutrophils (leukopenia)
___________ cells contribute to the procoagulant activity while ______ contribute to the procoagulant effect
Endothelial; platelets
What substances produced by the endothelium are vasodilator?
Prostacyclin
NO
Endotoxemia causes abnormal vascular tone. In the initial stage there is _________ shock, in later stages there s _________ shock
Hyperdynmaic (vasoconstriction); hypodynamic (vasodilation)
What contributes to the compromised organ perfusion seen with endotoxemia?
Vasodilation Vascular leakage and injury Intravascular cellular plugging Coagulation Systemic arterial hypotension
Damaged endothelium caused by extravasation of neutrophils causes leakage of??
Proteins
In recovery from endotoxemia, LPS induces _____ which results in deactivation of mononuclear phagocytes and inhibits pro-inflammatory cytokines
IL10
What clinical signs are associated with EARLY endotoxemia?
Tachypnea and tachycardia (Associated with vasoconstriction) - depression, restlessness, inappetence, fever Pale MM colour and prolonged CRT Fever
Toxic line
At 4-6hours what clinical signs do you see associated with endotoxemia?
Tachycardia and tachypnea
Fever
Circulatory failure and coagulopathy
Dehydration
- dry MM
- skin tenting
- sunken eye
At later stages of endotoxemia what are associated clinical signs?
Decrease rectal temp Oliguria or anuria Rapid weak pulses Muscle tremors Hemostatic dysfunction -petechia, ecchymosis -hypercoagulable
At 24hrs what clinical signs are associated with endotoxemia?
Ventral edema and laminitis
T/F: horses have a higher sensitively to LPS compared to other species
True
What is the equine-specific cellular response to flagellin?
Flagellin induces pro-inflammatory responses by neutrophils (TLR5)
Physical exam shows Increased HR (>48bpm) Toxic mucus membranes Cold extremities Poor pulse Fever
You suspect endotoxemia.. what diagnostics can you do to confirm?
CBC -> leukopenia, neutropenia and left shift
Arterial blood gas: hypoxemia and metabolic acidosis
Platelet and fibrinogen low due to DIC
Limulous ameobcyte lysate assay —> direct measurement fo circulating endotoxins
When treating a horse for endotoxemia, you see on the biochem it has hyperglycemia. What is the prognosis for this animal
Poor
How can endotoxemia be prevented?
Vaccination with S. Typhimurium mutant -> partial protection and little support
LPS repeated exposure -> diminish pro inflammatory response (short duration of tolerance)
What are the goals in treatment of endotoxemia?
Circulatory support Remove causes Neutralize endotoxin Inhibit inflammation Prevent laminitis
What can you do to improve cardiovascular function in endotoxemia?
Balance polyionic solution
- LRS or Normosol
- volume and rate depend on the degree of hypovolemia
Hypertonic saline (7.5%) - always follow with balanced IV fluids
Plasma proteins
What therapies can be used to neutralize circulating endotoxin?
Hyperimmune plasma -> antiLPS IgM and IgG antibodies (very $$$$)
Polymixin B - cationic polypenptide antibiotic -> interact with lipid A forms stable molecules and decrease TNFa
Endoserum from hyper-immune horses
What therapies inhibit inflammation induced by endotoxins?
NSAIDS - flunixin meglumine prevents increase in TXA2 and PGI2
Glucocorticoids is controversial (immunosuppressive and laminitis)
Pentoxifylline: phosphodiesterase inhibition -> inhibit TNFa and IL6
DMSO -> decrease expression of TNFa, IL6, and macrophage inflammatory protein 1-a
Ketamine -> cytokine modulating activity (last choice)
Lidocaine CRI -> anti TNFa
Ethyl pyruvate -> down regulates TNFa, IL6, and COx2
T/F: flunixin meglumine is more efffective in treating hemodynamic effects off LPS when combined with pentoxifylline
True
