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what are the 3 components of lipopolysaccharide molecule? which imbeds in the cell wall? which controls virulence?
- lipid-A: toxic principle, buried in cell wall, conserved/same in all bacteria
- O-chain: controls virulence/Ag that leads to host specific Abs
- core glycolipid region: mediates toxic effects
Horses have a lot of Gram negative bacteria in GI/colon. How is kept away from circulation in health?
- enterocyte mucosal cells (tight junctions/endothelial lining)
- mucous layer produced by prostaglandins
- immune cells like Kupffer cells in liver and macrophages
what clinical signs are consistent with endotoxemia?
fever, *leukopenia* or leukocytosis, hypotension, shock, death
Once LPS accessed blood stream, what does it bind to? Then where does this complex go?
- lipopolysaccharide binding protein (an acute phase protein made in liver)
- complex goes to immune cells like macrophage/neutrophil/lymphocyte and endothelial cells
Once presented to the immune cell/endothelial cell, what other components must be involved for LPS-LBP complex to enter the cell?
CD14 and TLR4 signal the immune cells then MD2 (transmembrane protein) signals in the cell to upregulate transcription factors
when the whole LPS-LBP + TLR4/CD14 + MD2 complex results in upregulation of transcription factors in nucleus of the cell, what are the two most famous signaling pathways that lead to immune cell production (IL1, 6,8, TNF, etc)?
- mitogen-activated protein kinase (MAPK)
- and nuclear factor KB (NF-kappa beta)
which inflammatory cytokines are primarily responsible for mediation of clinical signs of endotoxemia?
- TNF (primary responder to entoxin)
- IL1 (cytokine that signals between cells)
endotoxin also interacts with complement proteins and which clotting factor that then activates the intrinsic pathway?
Hageman Fact (Factor 12)
what is result of cleavage of phospholipid bilyaer of cells?
arachidonic acid pathway starts and Platelet activating factor activated
Arachidonic pathway results in LOX and COX pathways. What is product of LOX pathway and what is its function?
leukotrienes: vasoconstriction, bronchospasm, incr. vascular permeability
Arachidonic pathway results in LOX and COX pathways.
- what is product of COX pathway and what are the functions of these products?
- Prostaglandins like PGI2, PGF2alpha, PGE2: potent vasodilators that promote edema formation
- Thromboxane A2 as vasoconstrictor
What is result when PMNs and endothelial cells express selectins?
- allows PMNs to roll along endothelial cells and interact with adhesion molecules ("marginate")
- less responsive to chemotaxis/less extravasion
- *result is neutropenia*
which cell causes respiratory bursts that create reactive oxygen species (ROS)?
PMNs --> damages endothelium (along with nitric oxide and histamine)
when endothelium gets damaged, it exposes tissue factor. Does this activate intrinsic or extrinsic pathway?
extrinsic pathway of coagulation
what are the 2 hallmarks of endotoxemia?
systemic hypotension and inadequate tissue perfusion
How long does hyperdynamic state last? does vasculature constrict or dilate? how does this effect CRT?
- 15-45 minutes
- dilates (in response to complement, prostacycline, histamine)
- fast CRT
what is cause of fever? what is cause of colic/pain?
- *fever* from *TNF* at thermoregulatory center and *IL1* induces production of PGE2 near hypothalmus to incr. temp
- *colic* from *prostaglandins* incr. pain perception
when does hypodynamic state set in? how do mucous membranes look now and what is CRT?
- ~90 minutes from exposure to endotoxin
- prolonged CRT with purple/dark red mm
What is the 3rd space accumulation that happens in hypOdynamic state?
Na rich fluid pumped into GI, water follows --> diarrhea may be seen and worsens distributive shock
In hypOdynamic state, how is body temp affected? urine output? oncotic pressure? lactate level?
- temp decreases (cold extremities)
- urine can cease
- very decr. oncotic pressure
- elevated lactate
Hemostasis is disordered. what are signs of hypercoagulable state? what are expected platelet count and clotting time results
- hypercoagulable -thrombosis from venipunture site
- decr. plt count and prolonged ApTT times; vascular damage evident w/petechia
What is fibrin count like with endotoxemia?
low count (normally high in face of inflammation so this is noteworthy)
what are key therapies to institute within first 6 hours of hospitalizing septic patient?
oxygen + IV fluids + pressor therapy + inotropes + packed RBCs
what are the 5 priorities when approaching an equine septic case?
- 1: cardiovascular resuscitation
- 2. laminitis prevention
- 3. remove cause of endotoxemia
- 4. neutralize free circulating endotoxin
- 5. inhibit inflammation
what are some options for monitoring cardiovascular resuscitation efforts?
- blood gas for saturation of venous oxygen and lactate
if partial pressure of oxygen in arteries is below what value should you provide oxygen? what range do you want CVP between?
Patient needs packed RBCs if PCV is below what?
which fluid choice is first line of defense in these patients? why?
- hypertonic saline (7% NaCl at 4mg/kg)
- expands plasma volume by 2-3 times amount administered (recruits from ICF)
- and suppresses PMNs from causing oxidative damage or tethering to endothelial cells
- and blocks transcription of cytokines
why is colloid therapy also important in septic patients? what are the colloid options and dose?
- hypoproteinemia is common sequela
- hetastarch at 10ml/kg
- plasma at 20ml/kg
in addition to cryotherapy, why is flunixin meglumine often administered?
may reduce small vessel thrombosis by preventing release of Thromboxane A2/PG inflammatory agents
what is the purpose of administering pentoxifylline?
- encourages vasodilation by stim. PGE
- suppresses TNF and promotes deformability of RBCs
What are appropriate circumstances for giving Abs to septic patient with diarrhea?
- horse less than 3 months old
- suspicion of Clostridial or antimicrobial-associated enteritis
- degenerative left shift (or PMN/lymph count <1,000)
- evidence of dyhemostasis (jug. thrombosis, clinical bleeds)
what are therapy options for neutralizing endotoxin?
- hyperimmune plasma
- polymyxin B (beware of nephrotoxic, respiratory failure side effects if dose too high)
Flunixin meglumine is often given for its anti-inflammatory properties but what is unwanted SE directly related to sepsis? What other medication can we combine to avoid this problem?
- delays mucosal healing of small intestine (also renal/GI concerns)
- combine with Lidocain 2% CRI
what are 3 reasons lidocaine helps a septic patient?
- somatic analgesia
- decr. risk of reperfusion injury
Are steroid indicated in equine septic patients?
no, contraindicated at this time
what is the most widely used reactive oxygen species (ROS) scavenger?
DMSO (only proven in mouse model but cheap and safe, so we use it anyway)