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EQUINE VETERINARY EDUCATION / AE / NOVEMBER 2020
Nonselective and
Selective NSAIDs COX2
*COX1 PGE2 PGE2 PGE2
PGI2 PGI2
PGE2 Nonselective NSAIDs
*there is some constituitive COX2 signalling in the kidneys
COX1
PGE2 Nonselective NSAIDs
Fig 1: Proposed role of COX-1 and COX-2-produced prostanoids in clinical signs noted in horses with surgical colic, including abnormal gum colour and pain. In addition, the effects of COX-inhibiting nonsteroidal anti-inflammatory drugs on organ function, particularly the gastrointestinal tract and the kidneys, are depicted.
improve the clinical assessment of horses suffering from colic, very transient bursts of free LPS termed ‘LPS showers’ proved prohibitively difficult to detect during intestinal injury (Fessler et al. 1989). This likely relates to rapid clearing of LPS by LPS- binding protein, albumin and soluble CD14 (sCD14) secreted by stimulated macrophages. Very recently, Fogle et al. (2016) found that, while there were no differences in the detection of LPS, sCD14 was significantly higher in the blood of clinically endotoxaemic horses compared to clinically nonendotox- aemic horses. After initial LPS showers during intestinal injury, macrophages become activated at the onset of the sys- temic inflammatory response and remain activated, capable of continued secretion of sCD14 and reduction of detectable free LPS as the inflammatory insult persists. Therefore, researchers concluded that sCD14 may provide a more accurate and stable means of quantifying endotoxaemia than assays of LPS.
A history of NSAIDs in managing colic
In 1981, with the goal of understanding laminitis of gastrointestinal origin, researchers injected ponies intravenously with a large bolus of LPS with or without pretreatment with the potent COX-inhibitor flunixin meglumine to determine whether this drug could attenuate the peripheral
vascular effects of endotoxin. In this model, pretreatment with flunixin was reported to prevent the clinical signs seen in ponies injected with LPS alone (Moore et al. 1981b). A similar follow-up study assessed survival outcomes in ponies injected with lethal doses of LPS with pretreated with flunixin versus saline, dexamethasone or prednisolone. Flunixin pretreated animals survived slightly longer and had reduced blood derangements than control or steroid-pretreated animals, but these animals still succumbed to endotoxic shock complications (Ewert et al.
© 2019 EVJ Ltd
1985). While these findings suggest that pretreatment with an NSAID may buy a bit of time in LPS-injected ponies, the authors were careful to note that these masking effects may obscure judgement of disease severity in horses with surgical colic while failing to alleviate the underlying cause of endotoxaemia. They stressed that these cases still require early diagnosis, surgical intervention and supportive care to survive severe colic (Moore et al. 1981a). In a series of complementary studies in the mid-
1980s by Semrad et al., researchers proposed a lower dose of flunixin (0.25 mg/kg), termed an ‘anti-endotoxic’ dose, which they advised would inhibit eicosanoid production without masking clinical signs of endotoxaemia, thereby allowing more accurate assessment of colic cases for improved clinical decision-making (Semrad et al. 1985, 1987; Semrad and Moore 1987a,b). This is the origin of the reference to flunixin meglumine as an ‘anti-endotoxic’ drug. One could argue this is a dubious misnomer because flunixin does nothing to remove the source of endotoxin, nor has it been proven to reduce complication or mortality rates in severe colic, regardless of dosages. Importantly, Semrad et al. never made this assertion. It is also essential to bear in mind that intravenous administration of an LPS bolus is unlikely to fully model the complex pathology of intestinal strangulation injury, which limits direct translation of these findings to clinical colic cases. Nevertheless, flunixin has become the drug-of-choice for horse- owners and farm managers at the first hint of colic, at least in the United States, apparently with the expectation that it might save a colicking horse’s life. Because of this, flunixin can be found kept on-hand for such an emergency in just about any tack box or feed room in the USA. In 2019, Duz et al. summarised NSAID use in managing
colic in a review and survey of equine veterinarians (Duz 2019; Duz et al. 2019). NSAID therapy has become a mainstay for almost all veterinarians managing horses with
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