Endotoxaemia

Many treatments have been used and examined to counteract the adverse effects of endotoxin on horses. Few have evidence supporting their efficacy. This section discusses proven treatment strategies, but is not exhaustive – there are several reviews in the literature (e.g. Kelmer, 2009 (1)). Overarching treatment goals have been aimed at:

1. Counteracting the inflammatory cascade induced by endotoxin.
2. Elimination of the source of endotoxin.
3. Blocking interactions between endotoxin and the immune system.

Counteracting the inflammatory cascade is the mainstay of therapy, as almost all cases have activation of the inflammatory cascade on presentation. The main aim of treatment is to provide supportive therapy - treating cardiovascular shock with fluid therapy, preventing laminitis, and suppressing inflammation. Prevention of laminitis is not included here, but there are several reviews published (e.g. Belkap & Durham, 2017(2)).

Fluid therapy is the mainstay, non-specific, supportive therapeutic strategy to combat cardiovascular shock. All endotoxaemic patients are at least moderately, if not severely, hypovolaemic, and thus the use of balanced crystalloid solutions (i.e. Hartmann’s solution) is essential. Hypertonic saline (7% NaCl at 2-4 mL/kg) is a useful therapy to rapidly expand blood volume in adults, especially in the field, and especially in cases where drinking is not contraindicated. Even if drinking is contraindicated, isotonic IV fluid therapy can often be delayed following hypertonic saline administration, while the horse is transported to a hospital provided the trip is not too long. Hypertonic saline is usually unsuitable in foals because of its impact on electrolyte balance and acid-base abnormalities, but it is also less necessary in foals, as bolus isotonic fluids can be rapidly administered to achieve the same outcome. Commercially available plasma (2-8 L per horse) is also commonly administered to endotoxaemic patients. Hyperimmune plasma is typically used as there is some evidence of survival benefit in septic foals. While theoretically beneficial, evidence of efficacy in endotoxaemic adult horses is lacking and the cost is substantial. Synthetic colloids (such as Hetastarch) have also been administered to endotoxaemic horses with hypoproteinaemia and low colloid oncotic pressure, although evidence to support their use is lacking and they have fallen out of favour in other species because of the risk of complications.

Flunixin meglumine is a potent NSAID and the most common anti-inflammatory and antiendotoxic treatment administered other than fluid therapy. Flunixin inhibits the COX breakdown of arachidonic acid to prostaglandins, which are important mediators in the inflammatory pathway of endotoxaemia and lead to clinical features such as vasodilation and cardiovascular shock. Low doses of flunixin (0.25 mg/kg IV q 8 h) have been shown to be effective in experimental models and have been used clinically to avoid the gastrointestinal and nephrotoxic side-effects of higher doses. However, these lower doses usually do not prevent the clinical signs associated with endotoxaemia, such as colic, fever and dull mentation. In the authors’ experience, doses of 0.5 mg/kg IV q 12 h are effective for anti-inflammatory effects and combating clinical signs and are less likely to be associated with adverse effects, but this may be variable depending on the underlying cause and the severity of disease.

Most cases with endotoxaemia require antimicrobials to address the primary disease or for surgical prophylaxis. Cases associated with colitis and anterior enteritis are the exception where most do not require antimicrobial therapy. The choice of antimicrobials should be made carefully, as, theoretically, rapid killing of Gram-negative bacteria may result in release of more endotoxin and exacerbation of clinical signs. Aminoglycosides cause minimal release of LPS (3) so gentamicin is a good choice in many patients, if renal function is normal.

Dimethyl sulfoxide (DMSO) is an oxygen free-radical scavenger and anti-inflammatory agent that is widely used for treating endotoxaemia. However, evidence to support its use is lacking and there are substantial occupational health and safety risks in humans, so its use is not recommended. Where it is used, low doses (20 mg/kg IV) should be used, as higher doses have been associated with gastrointestinal mucosal damage and haemolysis.

Pentoxifylline has been widely used as an adjunctive therapy for equine endotoxaemia based on experimental evidence of inhibition of inflammatory cytokine and tissue factor activity. However, absorption following oral administration is poor and erratic, and an intravenous formulation is not commercially available. In addition, responses after exposure to endotoxin have been less promising than administration before endotoxin exposure. Clinical trials are needed before its use can be recommended.

Low doses of corticosteroids have been shown to be beneficial in experimental endotoxaemia in horses and foals, but their use is controversial in clinical cases. Physiological doses of corticosteroids may provide benefit in some cases where there is dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis and inadequate cortisol release in response to illness – a syndrome called critical illness-related corticosteroid insufficiency (CIRCI). Hypotensive animals that are unresponsive to fluid therapy and vasopressors may have CIRCI and might benefit from corticosteroid administration, but in cases with hypotension that do respond to fluid therapy or vasopressors, corticosteroids are probably contraindicated. Hydrocortisone doses of 1.3 mg/kg/day IV divided and administered every 4 hours have been recommended for use in foals. For adults, the dose is 0.16-0.3 mg/kg IV q 4 h (4). A dose of 0.3 mg/kg did not have an impact on clinical signs or proinflammatory cytokine production, but did appear to protect against LPS-induced neutrophil depletion in an experimental model of endotoxaemia (5). As for many other adjunctive therapies, clinical trials are lacking and are needed before this therapy can be recommended.

Elimination of the source of endotoxin involves treatment of the primary disease – strangulating intestinal lesions should be treated surgically without delay. Similarly, antimicrobial therapy should be implemented promptly where the primary disease is likely to be bacterial infection (for example, retained foetal membranes, foal sepsis or pleuropneumonia) but preferably following collection of samples for culture and susceptibility testing, if possible.

Blocking or eliminating endotoxin before it interacts with the horse’s immune system can be achieved by neutralising LPS with plasma rich in anti-LPS antibodies (hyperimmune plasma) (Equiplas E) or, potentially, polymyxin B. In a clinical trial of septic foals, foals treated with anti-LPS enriched plasma were more likely to survive than foals treated with regular plasma (6). However, other studies have only shown a small difference, and some have found no difference at all. A randomised controlled clinical trial is needed, but difficult to perform.

Polymyxin B has been shown to be effective in reducing the clinical signs associated with endotoxaemia in experimental scenarios, but it is nephrotoxic and the reduced perfusion and dehydration present in clinical cases means it is often contraindicated. In this author’s experience there is no benefit to the administration of polymyxin B in clinical cases. In addition, the availability of this drug in Australia is variable.

• Kelmer G. Update on Treatments for Endotoxemia. The Veterinary clinics of North America Equine practice. 2009;25(2):259-70.
• Belknap JK, Durham AE, Belknap JK, Geor RJ. Overview of Laminitis Prevention. Hoboken, NJ, USA: John Wiley & Sons, Inc; 2017. p. 421-6.
• Kusser WC, Ishiguro EE. Effects of aminoglycosides and spectinomycin on the synthesis and release of lipopolysaccharide by Escherichia coli. Antimicrobial Agents and Chemotherapy. 1988;32(8):1247-50.
• Hart KA, Barton MH. Adrenocortical Insufficiency in Horses and Foals. The Veterinary clinics of North America Equine practice. 2011;27(1):19-34.
• Anderson MJ, Ibrahim AS, Cooper BR, Woolcock AD, Moore GE, Taylor SD. Effects of administration of ascorbic acid and low‐dose hydrocortisone after infusion of sublethal doses of lipopolysaccharide to horses. Journal of veterinary internal medicine. 2020;34(6):2710-8.
• Peek SF, Semrad S, McGuirk SM, Riseberg A, Slack JA, Marques F, et al. Prognostic value of clinicopathologic variables obtained at admission and effect of antiendotoxin plasma on survival in septic and critically ill foals. J Vet Intern Med. 2006;20(3):569-74.