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what is endotoxemia?

result of massive dysregulated and general inflammatory response to the major structural component of the outer membrane layer of the gram negative bacterial cell wall. endotoxemia associated w/ gram-neg. infections may result from generalized disease such as neonatal septicemia, pleuropneuonia, peritonitis or endometritis


causes of translocation of endotoxins

translocation of the endotoxins from intestinal lumen may occur on compromise of the mucosal barrier, which is most pronounced w/ severe inflammation (colitis or strangulating intestinal lesions), severe shock states, severe trauma, malnutrition and strenuous exercise


mechanisms of gut barrier compromise

reduced intestinal blood flow resulting in ischemia, hypoxemia and increased body temperature


how does endotoxin release occur?

release occurs on cell division and cell death, but also on bacterial killings from antimicrobial treatment. In plasma, individual LPS molecules can be removed from the micellar aggregates by plasma proteins (lipopolysaccharide binding protein-LBP). LBP then transfers LPS monomers to the surface of inflammatory cells where molecules bind to a specific receptor complex and elicit cell activation. increased production and release of cytokines and other inflammatory mediators in response to this cell activation represents a crucial step in initiation and maintenance of the inflammatory cascade.


inflammatory response to endotoxins

serves to provide innate immunological response to defense against invading bacteria, and is therefore indispensable for survival. strict regulation of the inflammatory reaction normally ensures removal of offending organisms without harm to the host, and clinically significant endotoxemia and even shock states only develop when the immune response becomes dysregulated and spirals out of control


endotoxemia epidemiology

10-40% of horses presented for colic and 50% of septic neonatal foals had measurable circulating endotoxin concentrations. the number of colic patients testing positive for endotoxin was increased when only horses with conditions requiring exploratory surgery were investigated


inflammatory mediators of endoxoxemia

pathogenesis of endotoxemia primarily determined by the effects of inflammatory mediators, many of which are released AFTER inflammatory cell stimulation. important mediators=cytokines, prostaglandins, thromboxanes, leukotrienes, platelet-activating factor, nitric oxide, reactive oxygen species, histamine kinnins, complement components and growth factors
every severe insult produces a response consisting of both pro inflammatory and anti-inflammatory components, and it is the relative balance (or lack there of) of these components that determines outcome in the form of reestablishment of homeostasis or disease progression towards shock



thromboxane A2, important eicosanoid, promotes palatelet aggregation and vasoconstriction


PGE2 and PGI2

prostaglandins, important eicosanoid, cause vasodilation and have platelet anti aggregating effects. also exert anti-inflammatory effects by reducing cytokine production, inhibiting activation and proliferation of B cells, decreasing macrophage phagocytosis and inhibiting neutrophil functions


endotoxic shock

classified as distributive shock and is largely attributable to peripheral vascular dysfunction resulting in maldistribution of blood flow and perfusion deficits. Endotoin exerts peripheral vasomotor effects through release of inflammatory mediators such as prostacyclin and nitric oxide which cause widespread vasodilation and vasoplegia, leading to blood pooling in periphery and a reduction of effective circulating volume.
cardiac function is compromised by decreasing coronary blood flow and the release of myocardial depressant factors, circulating volume is reduced by increased vascular permeability


how is disease progression characterized?

development of systemic hypotension and ultimately perfusion deficits of vital organs. in addition to its role in vascular failure, endothelial dysfunction promotes development of microvascular thrombosis, thereby contributing to the development of organ failure


neutrophil activation

activation during bacterial infection generally serves to promote extravasation into infected tissues and increase the cell's bactericidal capacity. neutropenia is an early finding during experimental endotoxin administration and may be the only specific clinicopathologic evidence of acute sepsis or endotoxemia. on recovery from endotoxemia, the recovery of marginated neutrophils into circulation leads to neutrophil rebound



often develops during endotoxemia and has been described in horses with colic as well as in septic foals. disseminated intravascular coagulation (DIC) . usually clinical signs are limited to an increase in thrombotic tendency (ex. jugular vein thrombosis) or an increase in bleeding tendency following an ventipuncture or nasogastric intubation. coagulopathy has long been recognized as an important complication of endotoxemia requiring control to prevent the development of large vessel and microvascular thrombosis and bleeding episodes


early clinical signs of endotoxemia

depression, anorexia, sweating, muscle fasiculations and signs of abdominal discomfort such as yawning, pawing or recumbency. heart and respiratory rate increase, intestinal sounds are decreased or nonexistent, mucous membranes become hyperemic and the capillary refill time is accelerated, indicating hyper dynamic phase. fever is frequently observed (attributed to cytokines and prostaglandin production)


clinical signs of progressing endotoxemia

depression and anorexia typically worsen, diarrhea may develop, abdominal pain subsides after initial phase, mucus membrane color changes to brick red or purple, congestion and a periodical toxic line and prolonged capillary refill time


clinical signs of the shock phase

decreased pulse pressure and reduced venous filling, cool extremities, diffusely grey or purple mucous membranes, reduced body temperature. a muddy mucous membrane color and diffuse scleral reddening indicate vascular endothelial damage and increased vascular permeability


complications of endotoxemia

coagulation abnormalities may be identified as thrombosis at catheter placement sites, petechiae or ecchymoses and an increased bleeding tendency. spontaneous gross hemorrhage in the form of epistaxis may occur in severe cases. Clinical signs of organ failure can vary greatly because generally any body system can be affected, but renal dysfunction and laminitis tend to be the most common complication.


diagnosis of endotoxemia

made based on identification of clinical signs and supportive clinicopathologic changes as well as the recognition of risk factors or conditions known to be associated with development. In most cases, clinical signs of the primary disease are the reason for patient evaluation, but sometimes endotoxemia signs may precede the development of more distinct sings of the primary disease. in this case, diagnosis should be aimed at identification of common causes of endotoxemia


purpose of endotoxemia therapy

reduce the amount of endotoxin available for interaction with inflammatory cells and general supportive care


lipopolysaccharide scavengers

polymixin B, a vaccine for protection against endotoxemia (endovac-equi, immvac), passive immunization with plasma or serum products obtained from a hyperimmunized horse


reduction of endotoxin release

removal of infected tissues or fluids may be helpful, appropriate antimicrobial therapy is warranted b/c endotoxin is released from the bacterial cell wall upon death, combine antimicrobial therapy with endotoxin drugs during the initial treatment phase.
magnitude of endotoxin release may depend on type and dose of the antimicrobial drug. endotoxin release was inversely related to antimicrobial drug concentration, showing adequate dosing based on body weight is imperative. broad spectrum antimicrobial treatment is used before obtaining culture and sensitivity


NSAIDs used for endotoxemia treatment

flunixing meglumine is most frequently used. improves clinical signs, reduces cytokine release, improves blood pressure, maintains tissue perfusion, prevents hypoxemia and lactic acidosis, reduces endothelial damage, reduces risk of pregnancy loss and increases survival


corticosteroids used for endotoxemia treatment

dexamethasone and prednisolone were less effective than banamine in reducing cytokine production, hemoconcentration and hemodynamic changes. corticosteroid treatment cannot be recommended for use in equine cases, may also cause development of laminitis


antioxidants used for endotoxemia

DMSO, may reduce tissue damage by scavenge reactive oxygen radicals that are related from active neutrophils and other cell types


mediators for resuscitation

large volumes of isotonic solutions or hypertonic saline. inotropic and vasopressor support should be considered in patients with evidence of inadequate tissue profusion after restoration of circulatory fluid volume



treat with anticoagulants and clotting factor replacement
anticoagulents=heparin and aspirin
because of the need for adequate ATIII concentrations, administration of heparin in plasma may be useful, especially if endogenous ATIII concentration is low. Aspirin irreversibly inhibits COX activity in platelets, preventing platelet aggregation and reducing the occurrence of micro thrombosis,
fresh-frozen plasma products can be used to replenish coagulation factor and ATIII


organ dysfunction or failure

caused by severe inflammation refractory cardiovascular compromise and widespread endothelial dysfunction. acute renal failure and laminitis appear to be the most common complications of endotoxemia in horses. evaluations for organ failure include respiratory compromise, cardiac compromise, GI dysfunction and neurologic disease


prevention of endotoxemia

2 aspects=prevention of the inciting cause and prevention of the uncontrolled activation of the inflammatory cascade. early diagnosis is of utmost importance.
to prevent systemic inflammatory response, patients must be IDed early and proactive treatment must be initiated before development of clinical signs