Equine Endotoxemia Flashcards
MODS
multiple organ dysfunction syndrome
- most common cause of death in the ICU
- associated with ARDS and DIC
SIRS
systemic inflammatory response syndrome criteria for Dx: 2 of the following: - leukopenia, leukocytosis, >10% bands - hyper/hypothermia - tachycardia - tachypnea - sepsis in foals (look at sclera)
Endotoxemia
endotoxin in circulation
LPS on cell wall of gram negative bacteria
pathogen recognition by host receptor –> inflammatory response that can’t be contained (endotoxic shock)
rapid proliferation - bacteria translocates from GIT and overpopulates an area
Lipid A region
most responsible for toxic effects of bacteria, well conserved among species
hydrophobic inner portion
Polysaccharide O region
accounts for serological differentiation
polar outer portion
Core acidic polysaccharide
connects lipid A region to polysaccharide O region
T/F: E. coli in the guy always causes endotoxemia
no! is normally found in the gut BUT if translocates to circulation see severe endotoxemia
4 preventative mechanisms against endotoxemia
1) mucosal epithelium = physical barrier
- restrict bacterial movement across wall
- secrete lysozyme, enzymes and antibodies to limit invasion of mucosal lining
2) In circulation
- removal of endotoxin from portal blood -> eliminated in liver
- intravascular macrophages, endothelium, platelets, lymphocytes and neutrophils
3) Monocytes
- kupffer cells = effective LPS scavengers
4) Circulating anti-endotoxin antibodies
- directed at core region
5 stages of endotoxemia
1) physical barrier breach
2) Endotoxins stimulate macrophages
3) TNF + IL-1 act on neutrophils and endothelium
4) compromised organ perfusion
5) Recovery
Colic
abdominal pain, usually pain coincides with severity
Colic and banamine/flunixin meglumine
if horse pawing with high HR, give banamine/flunixin meglumine
- if improvement, not as concerning
- if animal still showing signs of pain, worry because NSAIDs not enough to manage pain, need to sedate, keep comfortable to see what is happening, give fluids, possible Sx
What does bloat indicate in a colicy horse?
sign that therapy isn’t sufficient
Reperfusion injury
untwisting GI may lead to repercussion injury + influx of endotoxins into circulation
horse throwing itself around due to colic
prone to develop endotoxemia
Enteritis and endotoxemia
inflammation of SI, reduced motility leads to reflux, increased risk of bacteremia - no signs of pain
Tx with prophylactic antibiotics - ahminoglycosides or sulphas (but cant give sulphas if reflux bc is a PO drug)
- if you Tx a horse with banamine and not showing pain but showing reflux, is a clue to enteritis
Colitis and endotoxemia
inflammation of large colon, damage to GI walls then bacterial translocation
Potomac horse fever - neorickettsia ristcii, damages walls of LI = back easily translocates to circulation, difficult to Tx
Sand colic - sand grinds on mucosal layer - damages walls and bacteria can translocate, check diarrhea for sand
Carb overload - bacterial overgrowth in colon, degeneration of mucosa
Drug induced colitis - antibiotics, NSAIDs (Banamine and phenylbutazone)
Respiratory causes of endotoxemia
Pleuropneumonia - infection b/wn pleural space and lungs, commonly bacterial, can cause endotoxemia and laminitis
- need to drain thorax, do thoracotomy if will not drain
Choke - esophageal obstruction, can aspirate gram - and result in severe pleuropneumonia
Integument causes of endotoxemia
bacterial infections - Clostridium myositis - post banamine IM injections, tissue necrosis
gram - infection even though primary infection gram +
Reproductive causes of endotoxemia
retained placenta
- considered retained after 2 hours, 3 hours = BAD
- give oxytocin to promote passage
- will develop endotoxemia, laminitis may be first CS
Uterine rupture- leakage into abdominal cavity, not as life threatening
Severe metritis - possible but unlikely
Urinary causes of endotoxemia
uncommon, infection, obstruction, traumatized bladder
Endocrine and endotoxemia
Equine metabolic syndrome - lipotoxicity (excessive conversion of glucose to fat)
- disruption of insulin receptors –> resistance
- oxidative stress and inflammation, endotoxemia and transient resistance
Hyperglycemia = poor prognosis
Cushings - old horses in hypercortisolemic state
Bacteremia and endotoxemia
registered by innate immune system
attack LPS readily but no memory - same threat on 2nd and 3rd exposure
What does LPS bind to?
LBP - lipopolysaccharide binding protein
LPS and LBP
LPS bind to LBP, LBP bind to CD14 cell surface intravascular macrophages and monocytes
Endotoxin stimulation of macrophages
PAMPs on organism bind PRR on host phagocytic cells
TLR 4 activation normally results in MyD88 (proinflammatory pathway, IL1 and TNF) and TRIF and TRAM pathway (anti inflammatory pathway)
in horses, only MyD88 is activated so no anti-inflammatory mediators produced
which pathway does TLR4 activation result in?
MyD88 - pro-inflammatory pathway
Chemical events of macrophage stimulation by endotoxins
Early: macrophages stimulate TXA2 and vasoconstrictors = vasoconstriction
Late: cytokine synthesis (IL1 and TNF) - endotoxin signal amplified, pro-coagulant activity and vasodilation
- vasoconstriction then vasodilation*
- pale mm. then hyperaemic mm.
Effect of TNF and IL-1 on neutrophils and endothelium (Stage 3)
cytokine induced margination of neutrophils = neutropenia
neutrophils empty granular content onto endothelium. –> injury –> coagulation cascade –> poor circulation –> ischemia and necrosis
endothelium damage - hyper coagulation - intravascular coagulation
Endothelium produce prostaglandin and NO = vasodilation
abnormal vascular tone dependent on stage:
initial: hyper dynamic shock = pulmonary vasoconstriction, tachypnea, hypoxia
late: hypo dynamic shock = pulmonary vasodilation
Stage 4: compromised organ perfusion
vasodilation, vascular leakage + injury, intravascular cellular plugging, coagulation, systemic arterial hypotension
protein leakage, damaged endothelium, extravasation of neutrophils
2 or more organs = multiple organ failure
Stage 5: recovery
LPS induce IL-10 which results in deactivation of mononuclear phagocytes and inhibits pro-inflammatory cytokines
Which interleukin is responsible for deactivating mononuclear phagocytes and inhibits pro-inflammatory cytokines?
IL-10
Which cytokines are pro-inflammatory?
Il-1 and TNF
Clinical endotoxemia: hyper vs hypo dynamic state
Hyperdynamic state:
- MM white or injected, CRT may be normal, strong pulses, tachycardia, tachypnea, fever
Hypodynamic state:
- MM congested, dark, toxic line, CRT >2s (long), weak pulses, tachycardia or tachypnea, cold extremities, normal or hypothermic
Experimental Endotoxemia
experimental infusion of LPS into horses
– hour 4-6 definitely have endothelial damage
all horses developed laminitis
important prevention of laminitis
cryotherapy
Equine specific cell response to flagellin
flagellin induces pro inflammatory responses of neutrophils by TLR 5, doesn’t activate monocytes
all other mammalian species –> monocytes respond strongly to flagellin via TLR 5
Diagnosis of endotoxemia
CBC: leukopenia neutropenia (toxic neutrophils), left shift
Arterial blood gas: hypoxemia and metabolic acidosis
Glc: hyperglycaemia (poor prognostic factor)
lactate: increase after supportive tx (poor prognostic facto)
platelets decrease, fibrinogen increase because DIC - prognosis is worse
limulus ameobocyte lysate assay - horseshoe crab, direct measurement of circulating endotoxins
Prevention of endotoxemia
vaccination - S. typhimurium mutant
- partial protection, no benefits on foals
LPS repeat exposure
- diminish pro-inflammatory and clinical response, decreased gene expression and TNFa production, decreased fever, tachycardia, tachypnea, pain response
- endotoxin tolerance subsides after 14-21d
General Tx of endotoxemia
CV support - maintain intravascular volume
- Hypertonic saline (follow with balanced IV fluids)
- plasma (helps w/ protein loss)
Remove primary cause (sx for retained placenta, colic, etc)
PAMPs antibody tx
hyperimmune anti LPS core antigen plasma decrease mortality rate significantly
very expensive
Antimicrobial tx of endotoxemia
can worsen clinical presentation
LPS neutralizing agent - Polymixin B
interacts directly with lipid A forming a stable molecule complex
decrease TNFa and residual LPS activity
can cause renal toxicity - must hydrate prior to treating
TREATMENT OF CHOICE
dimethyl sulfoxide :DMSO
decrease cytokine expression, good drug, also used for fever
Pentoxifylline
phosphodiesterase inhibitor
combined with flunixin meglumine - tx hemodynamic effect of LPS
Lidocaine CRI
significantly decreases severity of CS
Ketamine
cytokine modulating activity may benefit in tx of equine endotoxemia
Most important part of caring for Endotoxemia horse
AGGRESSIVE SUPPORTIVE CARE
