Pharmacological management of equine endotoxaemia

Sepsis is a disease caused by the systemic invasion of Grampositive and/or Gram-negative bacteria. Endotoxaemia is a disease caused by the presence of endotoxin from Gramnegative bacteria (e.g. lipopolysaccharide) in the circulation. In horses, conditions such as colitis, enteritis, metritis, peritonitis, pleuropneumonia and strangulating gastrointestinal lesions can result in sepsis and/or endotoxaemia. The systemic infection of bacteria and/or their toxins act as potent inflammatory stimuli and commonly result in systemic inflammatory response syndrome (SIRS).
Systemic inflammatory response syndrome is a generalised inflammatory process that is defined as being present when inflammation is accompanied by more than one of the following systemic disturbances: tachycardia, tachypnoea, hyper/ hypothermia, coagulopathies and leukocytosis/leukopenia and it results in poor tissue perfusion which, if severe or prolonged, ultimately causes multiple organ failure and death. SIRS is a significant cause of mortality in the conditions listed above and as such has led to the utilisation of numerous drugs in attempts at managing the syndrome.
The innate immune system initiates the inflammatory response to pathogens through pattern recognition receptors (PRRs) such as toll-like receptors (TLRs) and NOD-like receptors (NLRs). PRRs detect the presence of bacteria by recognising pathogen-associated molecular patterns (PAMPs), such as components of bacteria e.g. lipoteichoic acid and peptidoglycan (Gram-positive bacteria), lipopolysaccharide (Gram-negative bacteria), and DNA (both Gram-positive and Gram-negative bacteria). There are several subtypes of both TLRs and NLRs and each sub-type recognises one or more specific ligands (e.g. TLR-4 recognises lipopolysaccharide). Activation of PRRs by the presence of their specific ligand results in the initiation of one or more intracellular signalling pathways that result in the release of potent inflammatory mediators such as TNF-α, IL-1β, IL-6, MMPs and nitric oxide leading to systemic inflammation and potentially to SIRS.
It is clear that the complexity and multiplicity of the development of the inflammatory response to bacteria is a major reason why no single ‘silver-bullet’ treatment for SIRS is available. Another major factor impeding successful management of equine SIRS in clinical practice is the delay between the start of the inflammation and treatment as well as the effect of, and need to treat, the underlying disease process that resulted in sepsis/endotoxaemia.
In this presentation I will utilise an evidence-based approach to evaluate the efficacy and safety of putative anti-SIRS drugs with the purpose of allowing clinicians to make informed treatment choices.