equine endotoxemia: any new therapies in the horizon? - Phenix-Vet

EQUINE ENDOTOXEMIA: ANY NEW THERAPIES IN THE HORIZON?Gal Kelmer, DVM, MS, DACVS, DECVS,Department of Large Animal, Koret School of Veterinary Medicine, Faculty of Agriculture,Hebrew University of Jerusalem, Rehovot, Israel.Endotoxemia background:Endotoxemia is a leading cause of morbidity, mortality and economic loss to the equineindustry 1 . Colic is the most common cause of endotoxemia in horses 2 . Lipopolysaccharide(LPS), a component of the outer cell membrane of Gram-negative bacteria, stimulates the releaseof mediators of inflammation, including prostaglandins, histamine, serotonin, kinins, plateletactivatingfactors and others 3 . Initially LPS binds to a soluble cell membrane binding protein(LPS-BP), which transfers LPS to the macrophage cell wall receptor CD14-MD2 complex and inturn transfers the signal through transduction Toll-Like-Receptor (TLR4) into the cell. Thestimulation of TLR4 activates genes responsible for production of pro-inflammatory mediators.Massive inflammation results which in 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 endotoxemia:Initial treatment for endotoxemia in horses with colic is to treat the underlying cause inorder to eliminate the source of LPS. A strangulated intestinal segment should be removed in atimely manner. The second level of treatment intervention is to eliminate LPS prior to itsinteraction with the host’s receptors sites or block the LPS receptors. Once the inflammatorycascade has been initiated, the use of anti-inflammatory agents is indicated. After theendotoxemic cascade has been activated, the core therapy is directed at supportive fluid therapytargeted mainly to ameliorate cardiovascular deterioration.Treatment modalities:Polymyxin BPolymyxin B (PB) is a cationic cyclic polypeptide antimicrobial drug that at low dosesacts as a chelating agent by binding to the Lipid A moiety of LPS, removing endotoxin from thevascular system and by that preventing the pro-inflammatory cascade of endotoxemia 4 . TheLipid A portion of LPS is highly conserved in gram-negative bacteria and thus PB is effectiveregardless the gram-negative bacteria isolated 5 . In a study in foals administered endotoxin, PBameliorated clinical signs and decreased concentrations of TNFα and IL-6 6 . In a recent studyPB was safe and effective in treating endotoxemia in adult horses 4 .HemofiltrationOne novel treatment approach to sepsis in human medicine involves circulating thepatient blood through an external filter, thereby adsorbing the pro-inflammatory cytokines andimproving survival rates 7 . The use of hemofiltration was reported in horses and yielded nosignificant improvement in clinical and hematological response to LPS challenge 8 . A morespecific hemofiltration involves filtration of the blood through a column containing bound PB,removing LPS by adsorption. A recent systematic literature review found this method effectivein improving hemodynamic and oxygenation status and even more importantly, increasing871

endotoxemic patients is overwhelmed and dysfunctional, AB administration may protect againstopportunistic infections 1 .Summary: Many of the pharmacologic agents mentioned in this article can, to some extent, blockthe effects of endotoxin. In the clinical situation this may be the difference betweensurvival and demise in colic patients. It must be emphasized that good scientific clinicaldata is lacking on many of the treatment modalities presented in this article.Nevertheless, this review presents our current knowledge of these agents and hopefullymore information will be forthcoming soon.References:1. Sykes BW, Furr MO: Equine endotoxaemia--a state-of-the-art review of therapy. Aust Vet J 83:45-50,2005.2. Senior JM, Proudman CJ, Leuwer M, et al: Plasma endotoxin in horses presented to an equine referralhospital: correlation to selected clinical parameters and outcomes. Equine Vet J 43:585-591,2011.3. Werners AH, Bull S, Fink-Gremmels J: Endotoxaemia: a review with implications for the horse.Equine Vet J 37:371-383, 2005.4. Morresey PR, Mackay RJ: Endotoxin-neutralizing activity of polymyxin B in blood after IVadministration in horses. Am J Vet Res 67:642-647, 2006.5. Coyne CP, Fenwick BW: Inhibition of lipopolysaccharide-induced macrophage tumor necrosis factoralphasynthesis by polymyxin B sulfate. Am J Vet Res 54:305-314, 1993.6. Durando MM, MacKay RJ, Linda S, et al: Effects of polymyxin B and Salmonella typhimuriumantiserum on horses given endotoxin intravenously. Am J Vet Res 55:921-927, 1994.7. Ronco C, Ricci Z, Bellomo R: Importance of increased ultrafiltration volume and impact on mortality:sepsis and cytokine story and the role of continuous veno-venous haemofiltration. Curr OpinNephrol Hypertens 10:755-761, 2001.8. Veenman JN, Dujardint CL, Hoek A, et al: High volume continuous venovenous haemofiltration (HV-CVVH) in an equine endotoxaemic shock model. Equine Vet J 34:516-522, 2002.9. Cruz DN, Perazella MA, Bellomo R, et al: Effectiveness of polymyxin B-immobilized fiber column insepsis: a systematic review. Crit Care 11:R47, 2007.10. Bertok L: Bile acids in physico-chemical host defence. Pathophysiology 11:139-145, 2004.11. Longworth KE, Smith BL, Staub NC, et al: Use of detergent to prevent initial responses to endotoxinin horses. Am J Vet Res 57:1063-1066, 1996.12. Gordon BR, Parker TS, Levine DM, et al: Neutralization of endotoxin by a phospholipid emulsion inhealthy volunteers. J Infect Dis 191:1515-1522, 2005.13. Moore JN, Norton N, Barton MH, et al: Rapid infusion of a phospholipid emulsion attenuates theeffects of endotoxaemia in horses. Equine Vet J 39:243-248, 2007.14. Hawkins LD, Christ WJ, Rossignol DP: Inhibition of endotoxin response by synthetic TLR4antagonists. Curr Top Med Chem 4:1147-1171, 2004.15. Figueiredo MD, Moore JN, Vandenplas ML, et al: Effects of the second-generation synthetic lipid Aanalogue E5564 on responses to endotoxin in [corrected] equine whole blood and monocytes. AmJ Vet Res 69:796-803, 2008.16. Moore JN, Garner HE, Shapland JE, et al: Prevention of endotoxin-induced arterial hypoxaemia andlactic acidosis with flunixin meglumine in the conscious pony. Equine Vet J 13:95-98, 1981.17. Moore JN, Morris DD: Endotoxemia and septicemia in horses: experimental and clinical correlates. JAm Vet Med Assoc 200:1903-1914, 1992.18. Cook V, Meyer C, Campbell N, et al: Effect of firoxocib or flunixin meglumine on recovery ofischaemic-injured equine jejunum, Proceedings, 9th Interanational Equine Colic ResearchSymposium, Liverpool UK, 2008 (available from904

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