Sparing the gut: COX-2 inhibitors herald a new era for treatment of horses with surgical colic.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to manage a wide variety of conditions in horses, including management of colic. Flunixin meglumine is by far the most commonly used drug in the control of colic pain and inflammation and has become a go-to for not only veterinarians but also horse-owners and nonmedical equine professionals. NSAID use, however, has always been controversial in critical cases due to a high risk of adverse effects associated with their potent cyclo-oxygenase (COX) inhibition. There are two important COX isoenzymes: COX-1 is generally beneficial for normal renal and gastrointestinal functions and COX-2 is associated with the pain and inflammation of disease. Newer selective NSAIDs can target COX-2-driven pathology while sparing important COX-1-driven physiology, which is of critical importance in horses with severe gastrointestinal disease. Emerging research suggests that firocoxib, a COX-2-selective NSAID labelled for use in horses, may be preferable for use in colic cases in spite of the decades-long dogma that flunixin saves lives.

Pharmacokinetics and pharmacodynamics of three formulations of firocoxib in healthy horses.

The objectives of this study were to compare the pharmacokinetics and COX selectivity of three commercially available formulations of firocoxib in the horse. Six healthy adult horses were administered a single dose of 57 mg intravenous, oral paste or oral tablet firocoxib in a three-way, randomized, crossover design. Blood was collected at predetermined times for PGE2 and TXB2 concentrations, as well as plasma drug concentrations. Similar to other reports, firocoxib exhibited a long elimination half-life (31.07 ± 10.64 h), a large volume of distribution (1.81 ± 0.59L/kg), and a slow clearance (42.61 ± 11.28 mL/h/kg). Comparison of the oral formulations revealed a higher Cmax , shorter Tmax , and greater AUC for the paste compared to the tablet. Bioavailability was 112% and 88% for the paste and tablet, respectively. Maximum inhibition of PGE2 was 83.76% for the I.V. formulation, 52.95% for the oral paste formulation, and 46.22% for the oral tablet formulation. Pharmacodynamic modeling suggests an IC50 of approximately 27 ng/mL and an IC80 of 108 ng/ mL for COX2 inhibition. Inhibition of TXB2 production was not detected. This study indicates a lack of bioequivalence between the oral formulations of firocoxib when administered as a single dose to healthy horses.

Distribution of enrofloxacin and its active metabolite, using an in vivo ultrafiltration sampling technique after the injection of enrofloxacin to pigs.

The objective of this study was to determine the pharmacokinetics (PK) of enrofloxacin in pigs and compare to the tissue interstitial fluid (ISF). Six healthy, young pigs were administered 7.5 mg/kg enrofloxacin subcutaneously (SC). Blood and ISF samples were collected from preplaced intravenous catheters and ultrafiltration sampling probes placed in three different tissue sites (intramuscular, subcutaneous, and intrapleural). Enrofloxacin concentrations were measured using high-pressure liquid chromatography with fluorescence detection, PK parameters were analyzed using a one-compartment model, and protein binding was determined using a microcentrifugation system. Concentrations of the active metabolite ciprofloxacin were negligible. The mean ± SD enrofloxacin plasma half-life, volume of distribution, clearance, and peak concentration were 26.6 ± 6.2 h (harmonic mean), 6.4 ± 1.2 L/kg, 0.18 ± 0.08 L/kg/h, and 1.1 ± 0.3 µg/mL, respectively. The half-life of enrofloxacin from the tissues was 23.6 h, and the maximum concentration was 1.26 µg/mL. Tissue penetration, as measured by a ratio of area-under-the-curve (AUC), was 139% (± 69%). Plasma protein binding was 31.1% and 37.13% for high and low concentrations, respectively. This study demonstrated that the concentration of biologically active enrofloxacin in tissues exceeds the concentration predicted by the unbound fraction of enrofloxacin in pig plasma. At a dose of 7.5 mg/kg SC, the high tissue concentrations and long half-life produce an AUC/MIC ratio sufficient for the pathogens that cause respiratory infections in pigs.

The pharmacokinetics and in vitro cyclooxygenase selectivity of deracoxib in horses.

The purpose of this study was to determine the pharmacokinetics of deracoxib following oral administration to horses. In addition, in vitro equine whole blood cyclooxygenase (COX) selectivity assays were performed. Six healthy adult horses were administered deracoxib (2 mg/kg) orally. Plasma samples were collected prior to drug administration (time 0), and 10, 20, 40 min and 1, 1.5, 2, 4, 6, 8, 12, 24, and 48 h after administration for analysis with high pressure liquid chromatography using ultraviolet detection. Following PO administration, deracoxib had a long elimination half-life (t(1/2) k(10) ) of 12.49 ± 1.84 h. The average maximum plasma concentration (C(max) ) was 0.54 µg/mL, and was reached at 6.33 ± 3.44 h. Bioavailability was not determined because of the lack of an IV formulation. Results of in vitro COX selectivity assays showed that deracoxib was selective for COX-2 with a COX-1/COX-2 ratio of 25.67 and 22.06 for the IC(50) and IC(80) , respectively. Dosing simulations showed that concentrations above the IC(80) for COX-2 would be maintained following 2 mg/kg PO q12h, and above the IC(50) following 2 mg/kg PO q24h. This study showed that deracoxib is absorbed in the horse after oral administration, and may offer a useful alternative for anti-inflammatory treatment of various conditions in the horse.

Use of ultrasound to evaluate outcome following colic surgery for equine large colon volvulus.

REASONS FOR PERFORMING STUDY: The post operative response of the large colon wall after a surgically corrected large colon volvulus (LCV) has not been investigated. OBJECTIVES: To use transabdominal ultrasound to monitor the post operative change in large colon wall thickness following surgical correction of LCV. HYPOTHESIS: A prolonged period to colon wall involution is correlated with an increased rate of post operative morbidity and mortality. METHODS: A prospective clinical study including horses that presented to the North Carolina State University Veterinary Teaching Hospital for colic between September 2006 and March, 2008, had surgically diagnosed and corrected LCV (at least 360 degrees ) without resection and recovered from anaesthesia. Ultrasound of the ventral large colon was performed at the time of anaesthetic recovery and every 6-8 h until the colon wall returned to normal thickness (< or = 5 mm). Outcome was evaluated using a one-way ANOVA to compare average time to colon wall involution between: 1) survivors and nonsurvivors; and 2) horses that developed multiple organ dysfunction syndrome (MODS) during the post operative period and those that recovered without evidence of MODS. RESULTS: Sixteen horses that recovered without evidence of MODS had a significantly shorter period to colon wall involution (< or = 5 mm) compared to those diagnosed with MODS (mean +/- s.e. 19.6 h +/- 2.5 and 39.7 h +/- 6.7 respectively, P = 0.006). There was no significant difference in mean period to colon wall involution between survivors and nonsurvivors (26.2 +/- 4.9 and 33.2 +/- 7.8 h, respectively). CONCLUSIONS: A shorter time to colon wall involution was associated with decreased post operative morbidity in horses presented for surgical correction of large colon volvulus without resection. POTENTIAL RELEVANCE: Ultrasonographic monitoring of colon wall involution after surgical correction of LCV may aid in identifying those cases at risk of MODS. Further investigation of colon wall involution time using a larger number of horses is warranted.

Multicentre, blinded, randomised clinical trial comparing the use of flunixin meglumine with firocoxib in horses with small intestinal strangulating obstruction.

BACKGROUND: Small intestinal strangulating obstruction (SISO) is associated with endotoxaemia which leads to an increased risk of death. Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to treat signs of endotoxaemia by inhibiting cyclo-oxygenases (COX). COX-1 is expressed constitutively and promotes gut barrier function, whereas COX-2 is inducible and contributes to the signs of endotoxaemia. In preclinical SISO trials, intestinal barrier recovery was more complete with reductions in endotoxin permeability in horses treated with COX-2 selective NSAIDs as compared with horses treated with flunixin meglumine. OBJECTIVES: We hypothesised that treatment of post-surgical SISO horses with firocoxib (COX-2 selective) would reduce the signs of endotoxaemia to a greater extent than flunixin meglumine (nonselective COX inhibitor) while continuing to provide similar levels of pain control. STUDY DESIGN: Blinded randomised clinical trial. METHODS: In addition to clinical monitoring, preoperative and 12-, 24- and 48-h post-operative plasma samples were assessed for prostaglandin E2 (PGE2 ), thromboxane B2 (TXB2 ), TNF⍺ and soluble CD14 (sCD14). RESULTS: In 56 recruited SISO horses, either flunixin meglumine (1.1 mg/kg, i.v., q12h) or firocoxib (0.3 mg/kg, i.v. loading dose; 0.1 mg/kg, i.v., q24h) was given in the post-operative period in three university hospitals from 2015 to 2017. COX-2 selectivity was confirmed by a relative lack of inhibition of the COX-1 prostanoid TXB2 by firocoxib and significant inhibition by flunixin meglumine (P = 0.014). Both drugs inhibited the COX-2 prostanoid PGE2 . There were no significant differences in pain scores between groups (P = 0.2). However, there was a 3.23-fold increased risk (P = 0.04) of increased plasma sCD14 in horses treated with flunixin meglumine, a validated biomarker of equine endotoxaemia. MAIN LIMITATIONS: Horses were all treated with flunixin meglumine prior to referral. In addition, many horses were treated with lidocaine, which has been shown to mitigate the deleterious effects of flunixin meglumine. CONCLUSIONS: In SISO cases, firocoxib reduced a biomarker of endotoxaemia as compared with flunixin meglumine while continuing to provide similar levels of pain control.

Attenuation of ischaemic injury in the equine jejunum by administration of systemic lidocaine.

REASONS FOR PERFORMING STUDY: Absorption of endotoxin across ischaemic-injured mucosa is a major cause of mortality after colic surgery. Recent studies have shown that flunixin meglumine retards mucosal repair. Systemic lidocaine has been used to treat post operative ileus, but it also has novel anti-inflammatory effects that could improve mucosal recovery after ischaemic injury. HYPOTHESIS: Systemic lidocaine ameliorates the deleterious negative effects of flunixin meglumine on recovery of mucosal barrier function. METHODS: Horses were treated i.v. immediately before anaesthesia with either 0.9% saline 1 ml/50 kg bwt, flunixin meglumine 1 mg/kg bwt every 12 h or lidocaine 1.3 mg/kg bwt loading dose followed by 0.05 mg/kg bwt/min constant rate infusion, or both flunixin meglumine and lidocaine, with 6 horses allocated randomly to each group. Two sections of jejunum were subjected to 2 h of ischaemia by temporary occlusion of the local blood supply, via a midline celiotomy. Horses were monitored with a behavioural pain score and were subjected to euthanasia 18 h after reversal of ischaemia. Ischaemic-injured and control jejunum was mounted in Ussing chambers for measurement of transepithelial electrical resistance (TER) and permeability to lipopolysaccharide (LPS). RESULTS: In ischaemic-injured jejunum TER was significantly higher in horses treated with saline, lidocaine or lidocaine and flunixin meglumine combined, compared to horses treated with flunixin meglumine. In ischaemic-injured jejunum LPS permeability was significantly increased in horses treated with flunixin meglumine alone. Behavioural pain scores did not increase significantly after surgery in horses treated with flunixin meglumine. CONCLUSIONS: Treatment with systemic lidocaine ameliorated the inhibitory effects of flunixin meglumine on recovery of the mucosal barrier from ischaemic injury, when the 2 treatments were combined. The mechanism of lidocaine in improving mucosal repair has not yet been elucidated.

An update on equine post-operative ileus: Definitions, pathophysiology and management.

Post-operative ileus (POI) is a serious condition which any horse undergoing abdominal surgery is at risk of developing, leading to increased hospitalisation time and resulting costs. Advances in the understanding of the development of equine POI are mainly based on human and rodent literature, where manipulation-induced inflammation has been identified as a trigger, with activation of resident muscularis externa macrophages playing a crucial role in the pathophysiology. Despite many pharmacological trials in all species, there is no single completely successful treatment for POI, highlighting that the condition is multifactorial in cause and requires a multimodal approach to minimise its incidence.

Protein biomarker of cell proliferation determines survival to discharge in cases of equine large colon volvulus.

BACKGROUND: Progenitor cells play critical roles in epithelial repair following ischaemic injury. Protein biomarkers have been used to identify intestinal progenitor cell subpopulations. This study aims to determine if a critical number of intestinal progenitor cells can predict tissue viability and survival to discharge of large colon volvulus (LCV) cases. OBJECTIVES: The objectives were to 1) identify intestinal progenitor cell subpopulations using biomarkers: proliferating cell nuclear antigen (PCNA), sex determining region Y box 9 (SOX9), phospho-histone H3 (PHH3) and Ki-67, 2) define cut-off values for critical numbers of positive cells and 3) determine if survival to discharge is associated with cut-off values. STUDY DESIGN: Retrospective cohort study. METHODS: Adult horses admitted to the Farm and Equine Veterinary Medical Center at NC State's Veterinary Hospital and Peterson and Smith Equine Hospital between 2006 and 2016 that underwent an exploratory coeliotomy with a diagnosis of LCV of ≥360 degrees, had pelvic flexure biopsy and that recovered from general anaesthesia were selected for inclusion in the study. Immunohistochemical analyses were performed and positive cells were counted. Optimal cut-off values were determined using receiver operator curves. A Fisher's exact test was used to associate cut-off values with survival to discharge. RESULTS: In this study, 23 cases of LCV ≥360° were included. Of 23 horses, 13 (57%) survived to discharge. A cut-off value of <2.1 PHH3 positive cells per crypt correctly predicted death with 100% sensitivity (95% CI; 69.15-100%) and 84.62% specificity (95% CI; 54.55-98.08%). LCV cases with <2.1 PHH3 positive cells per crypt were 96.6 times more likely to die (95% CI; 4.14-2255 and P < 0.0001). Biomarkers PCNA, SOX9 and Ki-67 did not predict short-term survival. MAIN LIMITATIONS: The population size was small. CONCLUSIONS: PHH3 immunohistochemical analysis may assist in more accurate prediction of survival to hospital discharge of LCV cases. The summary is available in Spanish - see Supporting Information.

Evaluation of digital cryotherapy using a commercially available sleeve style ice boot in healthy horses and horses receiving i.v. endotoxin.

BACKGROUND: Continuous digital cryotherapy experimentally prevents development and reduces severity of sepsis-associated laminitis. A sleeve style ice boot where ice is in direct contact with the skin, and water drains from the boot is being used clinically for distal limb cryotherapy. The degree of cooling achieved by this boot is unknown. OBJECTIVES: Evaluate skin and lamellar cooling after application of the ice sleeve in healthy horses, and the same horses during an endotoxaemia model. STUDY DESIGN: Prospective study, crossover design. METHODS: In eight healthy horses thermocouples were inserted into dorsal lamellae of both front feet, and under skin on both metacarpi. One forelimb received cryotherapy using sleeve style ice boot, with contralateral limb as control. Temperature was recorded on data logging devices at 5 min intervals during each cryotherapy session. Day 1: temperature data was collected for healthy horses. Day 2: data was collected for the same horses during i.v. administration of endotoxin. RESULTS: In healthy and endotoxaemic horses, the sleeve style ice boot significantly decreased mean skin (7.2°C and 5.8°C respectively) and lamellar (10.8°C and 9.6°C respectively) temperatures compared with control limbs (P<0.001). Skin and lamellar temperatures in endotoxaemic horses undergoing cryotherapy were significantly colder than in healthy horses (P = 0.01). MAIN LIMITATIONS: Order of treatment not randomised. CONCLUSIONS: The boot caused significant decreases in lamellar temperatures compared with untreated control limbs in all horses. Endotoxaemic horses had significantly colder lamellae and skin than healthy horses. This study is the first to show that a sleeve style boot, where ice does not cover the hoof, can cause significant decreases in lamellar temperatures through cooling of blood as it travels to the foot.

Prostaglandins I2 and E2 have a synergistic role in rescuing epithelial barrier function in porcine ileum.

Prostaglandins (PG) are cytoprotective for gastrointestinal epithelium, possibly because they enhance mucosal repair. The objective of the present studies was to assess the role of prostaglandins in intestinal repair. Intestinal mucosa from porcine ileum subjected to 1 h of ischemia was mounted in Ussing chambers. Recovery of normal transepithelial electrical resistance occurred within 2 h, and continued to increase for a further 2 h to a value twice that of control. The latter response was blocked by inhibition of prostaglandin synthesis, and restored by addition of both carbacyclin (an analog of PGI2) and PGE2, whereas the addition of each alone had little effect. Histologically, prostaglandins had no effect on epithelial restitution or villous contraction, indicating that elevations in transepithelial resistance were associated with increases in paracellular resistance. Furthermore, prostaglandin-stimulated elevations in resistance were inhibited with cytochalasin D, an agent known to stimulate cytoskeletal contraction. Synergistic elevations in transepithelial resistance, similar to those of carbacyclin and PGE2, were also noted after treatment with cAMP and A23187 (a calcium ionophore). We conclude that PGE2 and PGI2 have a synergistic role in restoration of intestinal barrier function by increasing intracellular cAMP and Ca2+, respectively, which in turn signal cytoskeletal-mediated tight junction closure.

Impaired intestinal barrier function and relapsing digestive disease: Lessons from a porcine model of early life stress.

Within this issue of Neurogastroenterology and Motility, an article by Pohl et al highlights new insights from a powerful porcine model of the link between early life adversity and relapsing functional gastrointestinal disorders. Early weaning stress closely mimics the early life psychosocial stressors that have been linked to adult onset gastrointestinal dysfunction. This early weaning model provides reproducible and highly translatable outcomes in young stress-challenged pigs. Due to the convincingly comparable neurological and gastroenterological anatomy and physiology between pigs and human beings, gastrointestinal stress and injury studies utilizing swine models will provide invaluable insights to improve our understanding and treatment of gastrointestinal disease in human beings. Future studies to examine mechanisms underlying this link between early life adversity and functional gastrointestinal disorders will explore the roles of gender and hypomaturity in gastrointestinal responses to stress.

Epiduroscopy of the lumbosacral vertebral canal in the horse: Technique and endoscopic anatomy.

REASONS FOR PERFORMING STUDY: Back pain is a common cause of gait alterations and poor performance in horses, but the available imaging modalities are frequently insufficient to isolate the underlying pathology. In human patients, epidural endoscopy (epiduroscopy) is successfully used to diagnose and treat challenging cases of lower back pain. Endoscopy of the cervical epidural space has previously been reported in anaesthetised horses. OBJECTIVES: To develop a technique for lumbosacral epiduroscopy in standing horses and to describe the endoscopic anatomy of the lumbosacral epidural space. STUDY DESIGN: Pilot study to assess the feasibility of lumbosacral epiduroscopy in 5 horse cadavers. METHODS: The cadavers of 5 horses, weighing 457-694 kg (mean, 570 kg), were suspended in an upright position. Vascular dilators of increasing size were inserted between the first 2 moveable vertebrae caudal to the sacrum to create a minimally invasive approach into the epidural space. A flexible videoendoscope was introduced and advanced as far cranially as the length of the endoscope permitted. The lumbosacral epidural space underwent gross necropsy examination following the procedure. RESULTS: The endoscope was successfully inserted into the epidural space in all horses. Saline injection through the working channel of the endoscope allowed the following anatomical structures to be seen: dura mater, left and right lumbosacral spinal nerves, cauda equina, epidural fat, connective tissue and blood vessels. Using the 60 cm working length of the endoscope, the epidural space could be examined as far cranial as L3-T18, depending on the size of the horse. No gross damage to epidural neurovascular structures was observed on necropsy examination. CONCLUSION: Lumbosacral epiduroscopy is technically feasible in standing horses and may become a valuable diagnostic tool in horses with caudal back or limb pain of unknown origin. Studies in live horses will be necessary to evaluate the safety of the procedure.

Effects of cyclooxygenase inhibitors flunixin and deracoxib on permeability of ischaemic-injured equine jejunum.

REASONS FOR PERFORMING STUDY: Recent studies have shown that flunixin prevented recovery of equine jejunum post ischaemia. However, the use of a purported cyclooxygenase (COX)-2 preferential inhibitor, etodolac, also prevented recovery. These findings may have implications for the use of nonsteroidal anti-inflammatory drugs in colic patients. OBJECTIVE: To compare the effects of deracoxib, a highly selective canine COX-2 inhibitor, with flunixin on in vitro recovery of ischaemic-injured equine jejunum. METHODS: Six horses underwent 2 h jejunal ischaemia, after which mucosa was mounted in Ussing chambers and recovered for 240 mins. Transepithelial electrical resistance (TER) and mucosal-to-serosal fluxes of 3H-mannitol were monitored as indices of barrier function in the presence of flunixin or deracoxib. RESULTS: The TER of ischaemic-injured tissue recovered significantly over 240 mins in the presence of no treatment, but not in the presence of flunixin or deracoxib. In addition, flunixin-treated ischaemic jejunum was significantly more permeable to mannitol when compared with untreated tissue by the end of the recovery period, whereas deracoxib treatment did not increase permeability. Addition of the PGE1 analogue misoprostol to flunixin-treated tissue restored recovery of TER. CONCLUSIONS AND POTENTIAL RELEVANCE: Treatment of horses with ischaemic jejunal disease with flunixin may result in a prolonged permeability defect in recovering mucosa. Addition of misoprostol or replacement of flunixin with deracoxib may ameliorate effects of COX inhibitors on recovering mucosa.

Post operative neutrophilic inflammation in equine small intestine after manipulation and ischaemia.

REASONS FOR PERFORMING STUDY: Post operative ileus (POI) remains an important cause of post operative morbidity and mortality in the horse. However, clinical progression of naturally occurring cases of POI in both horse and man does not entirely support the 'neurogenic' hypothesis as the sole mechanism of POI; and the hypothesis that inflammation plays a major role at 12-24 h after surgery requires validation. HYPOTHESIS: An inflammatory infiltrate in the muscularis externa and myenteric plexus of equine jejunum is present 18 h following a period of ischaemia. METHODS: Samples of normal jejunum, jejunum from the proximal resection margins of clinical cases and jejunum obtained 18 h after 1 or 2 h ischaemia or manipulation alone were evaluated for neutrophil infiltration. Samples obtained 18 h after surgery were additionally evaluated for leucocyte activation using calprotectin immunohistochemistry. Results were evaluated by ANOVA and P < 0.05 was considered significant. RESULTS: Significant neutrophilic inflammation was identified in the samples from the proximal resection margins of clinical cases compared to uninjured jejunum. In experimental cases, neutrophilic inflammation appeared to be increased further by 18 h and was identified through all intestinal layers, particularly in the serosa, fascial planes around circular and longitudinal muscle fibres, and myenteric plexus. This elevated level of neutrophilic inflammation was mirrored by an increased number of calprotectin-positive cells in these intestinal layers, indicating leucocyte activation. CONCLUSIONS: Significant neutrophilic inflammation occurs in equine jejunal myenteric layers 18 h after surgery. POTENTIAL RELEVANCE: This neutrophilic inflammation coincides with the clinical time point at which POI is identified and may indicate that inflammatory pathways, rather than solely neurogenic pathways, are responsible for POI in the horse.

Detection of differentially regulated genes in ischaemic equine intestinal mucosa.

REASONS FOR PERFORMING STUDY: Colic is a serious disease syndrome in horses. Much of the mortality is associated with ischaemic-injured intestine during strangulating obstruction, yet there is limited understanding of the associated molecular events. Identification of differentially expressed genes during ischaemic injury should expand our understanding of colic and may lead to novel targeted therapeutic approaches in the future. OBJECTIVE: To isolate and identify differentially expressed genes in equine jejunum following a 2 h ischaemic event compared to normally perfused jejunum. METHODS: Suppressive subtractive hybridisation was used to clone genes that are differentially expressed in equine jejunum injured by 2 h of complete ischaemia as compared to time-matched control jejunal tissues. Expression of selected clones was further evaluated by northern blot analysis. RESULTS: Of the 384 clones selected, 157 were confirmed to possess cDNAs corresponding differentially expressed genes by dot blot analysis. Two genes, fatty acid binding protein 2 and calcium-activated chloride channel 4 were further confirmed to be differentially expressed by northern blot analysis. CONCLUSIONS: Suppressive subtractive hybridisation can be used to detect changes in expression of a broad array of genes, as confirmed by northern blot analysis of selected genes. POTENTIAL RELEVANCE: These initial results have identified a pool of equine intestinal epithelial genes that are differentially expressed following a 2 h ischaemic event. In particular, genes indicative of deranged metabolic activity and those potentially involved in early repair events were identified and may ultimately provide clues as to the nature of epithelial ischaemic injury in horses.

Operative factors associated with short-term outcome in horses with large colon volvulus: 47 cases from 2006 to 2013.

REASONS FOR PERFORMING STUDY: There is an important need for objective parameters that accurately predict the outcome of horses with large colon volvulus. OBJECTIVES: To evaluate the predictive value of a series of histomorphometric parameters on short-term outcome, as well as the impact of colonic resection on horses with large colon volvulus. STUDY DESIGN: Retrospective cohort study. METHODS: Adult horses admitted to the Equine and Farm Animal Veterinary Center at North Carolina State University, Peterson and Smith and Chino Valley Equine Hospitals between 2006 and 2013 that underwent an exploratory coeliotomy, diagnosed with large colon volvulus of ≥360 degrees, where a pelvic flexure biopsy was obtained, and that recovered from general anaesthesia, were selected for inclusion in the study. Logistic regression was used to determine associations between signalment, histomorphometric measurements of interstitium-to-crypt ratio, degree of haemorrhage, percentage loss of luminal and glandular epithelium, as well as colonic resection with short-term outcome (discharge from the hospital). RESULTS: Pelvic flexure biopsies from 47 horses with large colon volvulus were evaluated. Factors that were significantly associated with short-term outcome on univariate logistic regression were Thoroughbred breed (P = 0.04), interstitium-to-crypt ratio >1 (P = 0.02) and haemorrhage score ≥3 (P = 0.005). Resection (P = 0.92) was not found to be associated significantly with short-term outcome. No combined factors increased the likelihood of death in forward stepwise logistic regression modelling. A digitally quantified measurement of haemorrhage area strengthened the association of haemorrhage with nonsurvival in cases of large colon volvulus. CONCLUSIONS: Histomorphometric measurements of interstitium-to-crypt ratio and degree of haemorrhage predict short-term outcome in cases of large colon volvulus. Resection was not associated with short-term outcome in horses selected for this study. Accurate quantification of mucosal haemorrhage at the time of surgery may improve veterinary surgeons' prognostic capabilities in horses with large colon volvulus.

Glutamine and transforming growth factor-alpha stimulate extracellular regulated kinases and enhance recovery of villous surface area in porcine ischemic-injured intestine.

BACKGROUND: Epidermal growth factor (EGF) signals enterocyte proliferation via extracellular regulated kinases (ERKs). Because glutamine is required for EGF-stimulated proliferation and stimulates ERKs in intestinal cell culture, we hypothesized that glutamine and the EGF-related peptide transforming growth factor-alpha (TGF-alpha) would synergistically enhance repair associated with stimulation of ERKs. METHODS: Thiry-Vella loops were created in juvenile pigs. One half of the loop was subjected to 2 hours of ischemia, and the other half served as control. Loops were infused daily with Ringer's solution containing 140 mmol/L glucose, 140 mmol/L glutamine, 140 mmol/L glucose plus 60 micrograms/L TGF-alpha, or 140 mmol/L glutamine plus 60 micrograms/L TGF-alpha. RESULTS: After 2 hours of ischemia, complete villous epithelial sloughing was present. By 18 hours, villous epithelium had fully restituted, but villi remained stunted until 144 hours after injury. Glutamine + TGF-alpha triggered sustained increases in ERK activity compared with glucose-treated tissues (maximal at 18 hours), whereas glutamine alone or glucose + TGF-alpha caused only transient elevations in ERK activity. By 72 hours, villous surface area had increased to normal values with glutamine plus TGF-alpha treatment, whereas villi remained stunted with glucose alone, glutamine alone, or glucose plus TGF-alpha. CONCLUSIONS: Glutamine plus TGF-alpha treatment restored mucosal architecture within 72 hours of severe ischemic injury associated with sustained elevations in ERK activity.

Is reperfusion injury an important cause of mucosal damage after porcine intestinal ischemia?

BACKGROUND: Intestinal ischemic injury is exacerbated by reperfusion in rodent and feline models because of xanthine oxidase-initiated reactive oxygen metabolite formation and neutrophil infiltration. Studies were conducted to determine the relevance of reperfusion injury in the juvenile pig, whose low levels of xanthine oxidase are similar to those of the human being. METHODS: Ischemia was induced by means of complete mesenteric arterial occlusion, volvulus, or hemorrhagic shock. Injury was assessed by means of histologic examination and measurement of lipid peroxidation. In addition, myeloperoxidase, as a marker of neutrophil infiltration, and xanthine oxidase-xanthine dehydrogenase were measured. RESULTS: Significant ischemic injury was evident after 0.5 to 3 hours of complete mesenteric occlusion or 2 hours of shock or volvulus. In none of these models was the ischemic injury worsened by reperfusion. To maximize superoxide production, pigs were ventilated on 100% O2, but only limited reperfusion injury (1.2-fold increase in histologic grade) was noted. Xanthine oxidase-xanthine dehydrogenase levels were negligible (0.4 +/- 0.4 mU/gm). CONCLUSIONS: Reperfusion injury may not play an important role in intestinal injury under conditions of complete mesenteric ischemia and low-flow states in the pig. This may result from low xanthine oxidase-xanthine dehydrogenase levels, which are similar to those found in the human being.

Surgical and postoperative factors influencing short-term survival of horses following small intestinal resection: 92 cases (1994-2001).

Although short-term survival rates following small intestinal resection reportedly range from 48-88%, there is little information on predicting which horse may or may not survive small intestinal (SI) resection and anastomosis. The aim of this study was to identify factors that contribute to nonsurvival in horses following small intestinal resection. Medical records of horses which recovered from anaesthesia following SI resection were reviewed. Clinical and surgical variables were evaluated for their association with short-term survival using logistic regression and were reported as odds ratios (OR), including the 95% confidence interval (CI), indicating the likelihood of horses not surviving to hospital discharge. Ninety-two records met the criteria for inclusion. Thirty-six (81.8%) of the horses that underwent jejunojejunostomy (JJ) and 34 (70.8%) of the horses that underwent jejunocaecostomy (JC) survived to discharge. Multiple logistic analysis indicated that postoperative ileus (OR = 29.7; 95% CI 2.5-354.6), repeat celiotomy (OR = 18; CI 1.7-187.6), and an elevated heart rate of > or = 60 beats/min (OR = 5.6; CI 1.5-20.6) were the principal factors associated with nonsurvival. A low total plasma protein of <55 g/l (OR = 1.8; CI 0.-7.6) was incorporated in the final model because its inclusion improved the overall validity of the model, Clinicians should be aware of the factors associated with the greatest likelihood of nonsurvival following small intestinal resection, so that they can institute aggressive treatment and accurately inform owners on the likelihood of survival.