Equis ISSN 2398-2977

Endotoxemia: overview

Contributor(s): Gayle Hallowell, Ruth Morgan, Graham Munroe, Jarred Williams

Introduction

  • A systemic disorder caused by the host's response to gram-negative bacteria.
  • Cause: endotoxin - a structural part of the bacteria's outer cell membrane which is released upon lysis of the cell membrane or during rapid cell growth periods.
  • Gram-negative bacteria or endotoxin in systemic circulation may → endotoxemia alongside pathology allowing this access.
  • Signs: endotoxin is a potent inflammatory stimulant which initiates inflammatory cascades → major alterations in homeostatic mechanisms and severe clinical signs.
  • Diagnosis: clinical signs, hematology, biochemistry, bacteriology - if suspect bacteremia.
  • Treatment: difficult; aimed at eliminating the source of gram-negative sepsis, binding endotoxin after its release but before inflammatory response is initiated, supportive patient care, moderation of host's inflammatory response.
  • Prognosis: guarded.

Pathogenesis

Etiology

  • Liposaccharide liberated from gram-negative bacteria upon rapid multiplication or bacteriolysis.

Endotoxin/lipopolysaccharide

  • Endotoxin is a structural component of the outer cell membrane of gram-negative bacteria.
  • Essentially a lipopolysaccharide combined with cell wall capsular polysaccharide and proteins.
  • The outer part of the endotoxin 'O-antigen' or 'O-specific' repeating polysaccharide region is very variable between bacterial species and is the antigenic stimulus for antibody production and serospecificity.
  • The remaining two components of the endotoxin are very similar among bacterial species and have been used as antigens in vaccine development:
    • The central or core oligosaccharide region.
    • The innermost lipid A region which is responsible for most of the toxic effects.
  • The endotoxin is a potent inflammatory stimulant capable of direct and indirect induction of multiple host inflammatory and immunological processes.
  • The main source of endotoxin is the gut as there are a high number of resident gram-negative organisms.

Adult

  • The main sources in the adult horse are gastrointestinal disorders, particularly where there is compromise to the intestinal wall, eg strangulating lesions or inflammatory lesions (septic peritonitis, enteritis or colitis). This is due to the large numbers of gram-negative bacteria that live in the intestine of normal horses.
  • The majority of endotoxin is restricted to the gut lumen by an efficient mucosal barrier consisting of epithelial cells, specific secretions and resident commensal bacteria.
  • Any endotoxin gaining entry is normally removed by the Kupffer cells in the liver.
  • Damage to the mucosal barrier can occur secondary to a variety of gastrointestinal problems:
    • Invasive enteric pathogens, eg Salmonella spp Salmonella spp, Clostridia spp Clostridia spp.
    • Strangulating/non-strangulating intestinal obstructions Colon: small - obstruction.
    • Toxic ingestion, eg heavy metals Toxicity: lead.
    • NSAIDs, eg phenylbutazone Phenylbutazone are anti-prostaglandin drugs and may cause ulceration and inflammation → compromised mucosal integrity - in the case of NSAIDs most commonly affects the right dorsal colon.
  • Changes in the normal commensal population of the GI tract can allow the overgrowth of pathological endotoxin organisms:
    • Rapid dietary changes, especially to high carbohydrate rations.
    • Enteral and parenteral antimicrobial agents, eg erythromycin, potentiated sulfonamides, tetracyclines, metronidazole Therapeutics: antimicrobials.
    • Surgical evacuation of the cecum/colon.
  • Other sources of endotoxin-producing bacteria in the adult horse include:
  • Liver failure can result in endotoxemia due to failure of the liver to clear the normal amount of endotoxin absorbed by the gut.

Neonate

  • Neonates much more commonly suffer from septicemia (translocation of bacteria) rather than endotoxemia (translocation of endotoxin into the blood) per se.
  • Severe bacterial infections are quite common due to failure of passive transfer and immature immune systems Foal: neonatal septicemia syndrome.
  • Exposure of the gram-negative bacteria occurs in utero or peri-parturiently via the gut, respiratory tract Lung: pneumonia - neonatal bacterial or umbilicus.
  • E. coli Escherichia coli, Salmonella spp Salmonella spp, Actinobacillus spp and other gram-negative organisms are commonly isolated in such cases.

Pathophysiology

  • Endotoxemia is caused by endotoxins - potent inflammatory stimulants which initiate inflammatory cascades → major alterations in homeostatic mechanisms and severe clinical signs.
  • If the epithelial barrier is breached the secondary host defense mechanisms come into play:
    • Phagocytic cells, ie Kupffer cells in the liver.
    • Lymphocytes.
    • Humoral factors, eg immunoglobulins, complement, acute phase reactants.
  • Endotoxin enters the circulation → binds with lipopolysaccharide-binding protein (LBP) which is rapidly synthesized by the liver (has a strong affinity to the Lipid A part of the endotoxin and a receptor on mononuclear phagocytes (CD14)) → all 3 bound together → the phagocyte becomes activated → production of pro-inflammatory mediators → overzealous inflammatory response.
  • A soluble form of CD14 when bound can activate similar cells which lack the cell-bound form.
  • The mediators include:
    • Cytokines.
    • Lipid-derived mediators.
    • Coagulation/fibrinolytic factors.
  • The main cytokines produced are tumor necrosis factor (TNF-alpha):
    • Associated with development of hypotension, hemoconcentration, acidosis, disseminated intravascular coagulation (DIC), death.
    • Induce synthesis of interleukins, prostaglandins, various tissue factors (thromboxane, leukotrienes).
    • Initiate acute phase response.
  • Interleukins:
    • Especially Interleukins 1 and 6 which regulate many of the animal's inflammatory and immunologic responses.
  • The lipid-derived mediators of inflammation:
    • Are based on arachidonic acid released from the phospholipid in the cell membrane and metabolized by cyclooxygenase/lipoxygenase.
    • Remnants of the phospholipid become the precursor for platelet activating factor (PAF).
  • Include:
    • Prostaglandins: many of the early hemodynamic, platelet and behavioral effects of endotoxemia are due to cyclooxygenase-derived metabolites, eg thromboxane A2 and prostaglandins F2-alpha, I2 and E2.
    • Thromboxanes.
    • Leukotrienes: the role of the leukotrienes are less well defined but include chemotaxis, vaso- and bronchoconstriction and increased vascular permeability.
  • PAF → thrombus formation, thrombocytopenia, microvascular permeability and hypotension.
  • Activation of nuclear factor kb (NFkB) is key in the proceeding cascade of inflammatory events.
  • Neutrophils move from the blood into the tissue in response to the inflammatory cascade.
  • Endotoxin directly activates the complement, coagulation and fibrinolytic cascades.
  • Clinical cases tend to develop a hypercoagulable state and consumptive coagulopathy.
  • Hypoxia, eicosanoid metabolism and leukocyte activity can → formation of oxygen-derived free radicals → induce oxidative damage to surrounding tissues.

Timecourse

  • SIRS can progress very rapidly and result in death within a short time if not detected early.

Diagnosis

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Treatment

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Prevention

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Outcomes

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Further Reading

Publications

Refereed papers

  • Recent references from PubMed and VetMedResource.
  • Fogle J, Jacob M & Blickslager A et al (2017) Comparison of lipopolysaccharides and soluble CD14 measurement between clinically endotoxaemic and nonendotoxaemic horses. Equine Vet J 49 (2), 155–159 PubMed.
  • Senior J M et al (2011) Plasma endotoxin in horses presented to an equine referral hospital: Correlation to selected clinical parameters and outcomes. Equine Vet J 43 (5), 585-591 PubMed.
  • Nieto J E et al (2009) Effect of lipopolysaccharide infusion on gene expression of inflammatory cytokines in normal horses in vivo. Equine Vet J 41 (7), 717-719 PubMed.
  • Toth F, Frank N, Chameroy K A & Boston R C (2009) Effects of endotoxaemia and carbohydrate overload on glucose and insulin dynamics and the development of laminitis in horses. Equine Vet J 41 (9), 852-858 PubMed.
  • Pantaleon L G et al (2007) Effects of small- and large-volume resuscitation on coagulation and electrolytes during experimental endotoxemia in anesthetized horses. J Vet Intern Med 21 (6), 1374-1379 PubMed.
  • Moore J N et al (2007) Rapid infusion of a phospholipid emulsion attenuates the effects of endotoxaemia in horses. Equine Vet J 39 (3), 243-248 PubMed.
  • Hallowell G D & Korley K T T (2006) Preoperative administration of hydroxyethyl starch or hypertonic saline to horses with colic. J Vet Intern Med 20 (4), 980-986 PubMed.
  • Toribio R E et al (2005) Alterations in serum parathyroid hormone and electrolyte concentrations and urinary excretion of electrolytes in horses with induced endotoxemia. J Vet Intern Med 19 (2), 223-231 PubMed
  • Barton M H (1998) Effect of cisapride on gastric emptying in horses following endotoxin treatment. Equine Vet J 30 (4), 344-348 PubMed.
  • Ingle-Fehr J E et al (1998) Evaluation of digital and laminar blood flow in horses given low dose of endotoxin. Am J Vet Res 59 (2), 192-196 PubMed.
  • Barton M H et al (1997) Effects of pentoxifylline infusion on response of horses to in vivo challenge exposure with endotoxin. Am J Vet Res 58 (11), 1300-1307 PubMed.
  • Baskett A et al (1997) Effects of pentoxifylline, flunixin meglumine, and their combination on a model of endotoxemia in horses. Am J Vet Res 58 (11), 1291-1299 PubMed.
  • Harkins J D et al (1997) Effect on alpha-phenyl-tert-butylnitrone on endotoxin toxemia in horses. Vet Hum Toxicol 39 (5), 268-271 PubMed.
  • Shuster R et al (1997) Survey of diplomates of the American college of Veterinary Internal Medicine and the american College of Veterinary surgeons regarding clinical aspects and treatment of endotoxemia in horses. JAVMA 210 (1), 87-92 PubMed.
  • Moore J N (1991) Rethinking endotoxemia in 1991. Equine Vet J 23 (1), 3-4 PubMed.
  • Kindahl H et al (1991) Experimental models of endotoxemia related to abortion in the mare. J Reprod Fertil Suppl 44, 509-516 PubMed.
  • Stabenfeldt G H et al (1991) An estrogen conjugate enzyme immunoassay for monitoring pregnancy in the mare - limitations of the assay between days 40 and 70 of gestation. J Reprod Fertil Suppl 44, 37-44 PubMed.
  • Lavoie J P et al (1990) Hemodynamic, pathologic, hematologic and behavioral changes during endotoxin infusion in equine neonates. Equine Vet J 22 (1), 23-29 PubMed.
  • Fessler J F et al (1989) Plasma endotoxin concentrations in experimental and clinical equine subjects. Equine Vet J Suppl 7 24-28 PubMed.
  • Baker B et al (1988) Endotoxemia in racehorses following exertion. J S Afr Vet Assoc 59 (2), 63-66 PubMed.

Other sources of information

  • Corley K T T & Hallowell G D (In Press) Treatment of Endotoxemia. In: Equine Acute Abdomen. 2nd edn.


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