equine endotoxemia: any new therapies in the horizon? - Phenix-Vet
equine endotoxemia: any new therapies in the horizon? - Phenix-Vet
equine endotoxemia: any new therapies in the horizon? - Phenix-Vet
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EQUINE ENDOTOXEMIA: ANY NEW THERAPIES IN THE HORIZON?Gal Kelmer, DVM, MS, DACVS, DECVS,Department of Large Animal, Koret School of <strong>Vet</strong>er<strong>in</strong>ary Medic<strong>in</strong>e, Faculty of Agriculture,Hebrew University of Jerusalem, Rehovot, Israel.Endotoxemia background:Endotoxemia is a lead<strong>in</strong>g cause of morbidity, mortality and economic loss to <strong>the</strong> <strong>equ<strong>in</strong>e</strong><strong>in</strong>dustry 1 . Colic is <strong>the</strong> most common cause of <strong>endotoxemia</strong> <strong>in</strong> horses 2 . Lipopolysaccharide(LPS), a component of <strong>the</strong> outer cell membrane of Gram-negative bacteria, stimulates <strong>the</strong> releaseof mediators of <strong>in</strong>flammation, <strong>in</strong>clud<strong>in</strong>g prostagland<strong>in</strong>s, histam<strong>in</strong>e, seroton<strong>in</strong>, k<strong>in</strong><strong>in</strong>s, plateletactivat<strong>in</strong>gfactors and o<strong>the</strong>rs 3 . Initially LPS b<strong>in</strong>ds to a soluble cell membrane b<strong>in</strong>d<strong>in</strong>g prote<strong>in</strong>(LPS-BP), which transfers LPS to <strong>the</strong> macrophage cell wall receptor CD14-MD2 complex and <strong>in</strong>turn transfers <strong>the</strong> signal through transduction Toll-Like-Receptor (TLR4) <strong>in</strong>to <strong>the</strong> cell. Thestimulation of TLR4 activates genes responsible for production of pro-<strong>in</strong>flammatory mediators.Massive <strong>in</strong>flammation results which <strong>in</strong> turn is responsible for cardiovascular depression,pulmonary hypertension and arterial hypoxemia that lead to decreased tissue perfusion andperipheral hypoxia and eventually, multiple organ dysfunction and death.Treatment approach for <strong>endotoxemia</strong>:Initial treatment for <strong>endotoxemia</strong> <strong>in</strong> horses with colic is to treat <strong>the</strong> underly<strong>in</strong>g cause <strong>in</strong>order to elim<strong>in</strong>ate <strong>the</strong> source of LPS. A strangulated <strong>in</strong>test<strong>in</strong>al segment should be removed <strong>in</strong> atimely manner. The second level of treatment <strong>in</strong>tervention is to elim<strong>in</strong>ate LPS prior to its<strong>in</strong>teraction with <strong>the</strong> host’s receptors sites or block <strong>the</strong> LPS receptors. Once <strong>the</strong> <strong>in</strong>flammatorycascade has been <strong>in</strong>itiated, <strong>the</strong> use of anti-<strong>in</strong>flammatory agents is <strong>in</strong>dicated. After <strong>the</strong>endotoxemic cascade has been activated, <strong>the</strong> core <strong>the</strong>rapy is directed at supportive fluid <strong>the</strong>rapytargeted ma<strong>in</strong>ly to ameliorate cardiovascular deterioration.Treatment modalities:Polymyx<strong>in</strong> BPolymyx<strong>in</strong> B (PB) is a cationic cyclic polypeptide antimicrobial drug that at low dosesacts as a chelat<strong>in</strong>g agent by b<strong>in</strong>d<strong>in</strong>g to <strong>the</strong> Lipid A moiety of LPS, remov<strong>in</strong>g endotox<strong>in</strong> from <strong>the</strong>vascular system and by that prevent<strong>in</strong>g <strong>the</strong> pro-<strong>in</strong>flammatory cascade of <strong>endotoxemia</strong> 4 . TheLipid A portion of LPS is highly conserved <strong>in</strong> gram-negative bacteria and thus PB is effectiveregardless <strong>the</strong> gram-negative bacteria isolated 5 . In a study <strong>in</strong> foals adm<strong>in</strong>istered endotox<strong>in</strong>, PBameliorated cl<strong>in</strong>ical signs and decreased concentrations of TNFα and IL-6 6 . In a recent studyPB was safe and effective <strong>in</strong> treat<strong>in</strong>g <strong>endotoxemia</strong> <strong>in</strong> adult horses 4 .HemofiltrationOne novel treatment approach to sepsis <strong>in</strong> human medic<strong>in</strong>e <strong>in</strong>volves circulat<strong>in</strong>g <strong>the</strong>patient blood through an external filter, <strong>the</strong>reby adsorb<strong>in</strong>g <strong>the</strong> pro-<strong>in</strong>flammatory cytok<strong>in</strong>es andimprov<strong>in</strong>g survival rates 7 . The use of hemofiltration was reported <strong>in</strong> horses and yielded nosignificant improvement <strong>in</strong> cl<strong>in</strong>ical and hematological response to LPS challenge 8 . A morespecific hemofiltration <strong>in</strong>volves filtration of <strong>the</strong> blood through a column conta<strong>in</strong><strong>in</strong>g bound PB,remov<strong>in</strong>g LPS by adsorption. A recent systematic literature review found this method effective<strong>in</strong> improv<strong>in</strong>g hemodynamic and oxygenation status and even more importantly, <strong>in</strong>creas<strong>in</strong>g871
endotoxemic patients is overwhelmed and dysfunctional, AB adm<strong>in</strong>istration may protect aga<strong>in</strong>stopportunistic <strong>in</strong>fections 1 .Summary: M<strong>any</strong> of <strong>the</strong> pharmacologic agents mentioned <strong>in</strong> this article can, to some extent, block<strong>the</strong> effects of endotox<strong>in</strong>. In <strong>the</strong> cl<strong>in</strong>ical situation this may be <strong>the</strong> difference betweensurvival and demise <strong>in</strong> colic patients. It must be emphasized that good scientific cl<strong>in</strong>icaldata is lack<strong>in</strong>g on m<strong>any</strong> of <strong>the</strong> treatment modalities presented <strong>in</strong> this article.Never<strong>the</strong>less, this review presents our current knowledge of <strong>the</strong>se agents and hopefullymore <strong>in</strong>formation will be forthcom<strong>in</strong>g soon.References:1. 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