Nigel B. Campbell

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.

Anti-inflammatory effects of intravenously administered lidocaine hydrochloride on ischemia-injured jejunum in horses

OBJECTIVE To investigate effects of lidocaine hydrochloride administered IV on mucosal inflammation in ischemia-injured jejunum of horses treated with flunixin meglumine. ANIMALS 24 horses. PROCEDURES Horses received saline (0.9% NaCl) solution (SS; 1 mL/50 kg, IV [1 dose]), flunixin meglumine (1 mg/kg, IV, q 12 h), lidocaine (bolus [1.3 mg/kg] and constant rate infusion [0.05 mg/kg/min], IV, during and after recovery from surgery), or both flunixin and lidocaine (n = 6/group). During surgery, blood flow was occluded for 2 hours in 2 sections of jejunum in each horse. Uninjured and ischemia-injured jejunal specimens were collected after the ischemic period and after euthanasia 18 hours later for histologic assessment and determination of cyclooxygenase (COX) expression (via western blot procedures). Plasma samples collected prior to (baseline) and 8 hours after the ischemic period were analyzed for prostanoid concentrations. RESULTS Immediately after the ischemic period, COX-2 expression in horses treated with lidocaine alone was significantly less than expression in horses treated with SS or flunixin alone. Eighteen hours after the ischemic period, mucosal neutrophil counts in horses treated with flunixin alone were significantly higher than counts in other treatment groups. Compared with baseline plasma concentrations, postischemia prostaglandin E(2) metabolite and thromboxane B(2) concentrations increased in horses treated with SS and in horses treated with SS or lidocaine alone, respectively. CONCLUSIONS AND CLINICAL RELEVANCE In horses with ischemia-injured jejunum, lidocaine administered IV reduced plasma prostaglandin E(2) metabolite concentration and mucosal COX-2 expression. Coadministration of lidocaine with flunixin ameliorated the flunixin-induced increase in mucosal neutrophil counts.

Recovery of ischaemic injured porcine ileum: evidence for a contributory role of COX-1 and COX-2

Background: We have previously shown that the non-selective cyclooxygenase (COX) inhibitor indomethacin retards recovery of intestinal barrier function in ischaemic injured porcine ileum. However, the relative role of COX-1 and COX-2 elaborated prostaglandins in this process is unclear. Aims: To assess the role of COX-1 and COX-2 elaborated prostaglandins in the recovery of intestinal barrier function by evaluating the effects of selective COX-1 and COX-2 inhibitors on mucosal recovery and eicosanoid production. Methods: Porcine ileal mucosa subjected to 45 minutes of ischaemia was mounted in Ussing chambers, and transepithelial electrical resistance was used as an indicator of mucosal recovery. Prostaglandins E1 and E2 (PGE) and 6-keto-PGF1α (the stable metabolite of prostaglandin I2 (PGI2)) were measured using ELISA. Thromboxane B2 (TXB2, the stable metabolite of TXA2) was measured as a likely indicator of COX-1 activity. Results: Ischaemic injured tissues recovered to control levels of resistance within three hours whereas tissues treated with indomethacin (5×10−6 M) failed to fully recover, associated with inhibition of eicosanoid production. Injured tissues treated with the selective COX-1 inhibitor SC-560 (5×10−6 M) or the COX-2 inhibitor NS-398 (5×10−6 M) recovered to control levels of resistance within three hours, associated with significant elevations of PGE and 6-keto-PGF1α compared with untreated tissues. However, SC-560 significantly inhibited TXB2 production whereas NS-398 had no effect on this eicosanoid, indicating differential actions of these inhibitors related to their COX selectivity. Conclusions: The results suggest that recovery of resistance is triggered by PGE and PGI2, which may be elaborated by either COX-1 or COX-2.

A surgical tendonitis model in horses: Technique, clinical, ultrasonographic and histological characterisation

OBJECTIVE Tendon injuries are common in all athletic activities in both humans and horses. Research of treatment modalities for this disease has typically been performed on a model of collagenase-induced tendonitis. This model has several disadvantages. Our hypothesis was that a reproducible core lesion could be created surgically in superficial digital flexor tendons (SDFT), which could then be evaluated consistently using ultrasonography. MATERIALS AND METHODS Four horses free of forelimb lameness were used in this study. Each horse underwent general anaesthesia and a synovial resector was used to create a core lesion in the SDFT of each forelimb. Sonographic examination was conducted weekly using 2 cm intervals between a section 7 and 25 cm distal to the accessory carpal bone. At two, four, eight, and 12 weeks after injury, a horse was euthanatized. Histopathological evaluation of the SDFT was performed at the same levels as the sonographic examination. RESULTS Only mild clinical signs of tendonitis were observed. Ultrasonographic core lesions were 10-16 cm long and had a mean maximum cross-sectional area (CSA) of 18.25 +/- 5.91% occurring at 17-23 cm distal to the accessory carpal bone, and a mean volume of 1.86 +/- 0.26 cm(3). Mean duration taken to achieve maximum lesion CSA and lesion volume was 35 +/- 7 days. Histologically, the lesions were characterised by mild inflammation followed by fibroplasia. CONCLUSION The reported surgical technique resulted in core lesions that were consistent in size and location, were readily evaluated with ultrasonography, and showed similarities with the ultrasonographic and histological progression of naturally occurring tendonitis lesions.

The effects of cyclo‐oxygenase inhibitors on bile‐injured and normal equine colon

A potential adverse effect of cyclo-oxygenase (COX) inhibitors (nonsteroidal anti-inflammatory drugs [NSAIDs]) in horses is colitis. In addition, we have previously shown an important role for COX-produced prostanoids in recovery of ischaemic-injured equine jejunum. It was hypothesised that the nonselective COX inhibitor flunixin would retard repair of bile-injured colon by preventing production of reparative prostaglandins, whereas the selective COX-2 inhibitor, etodolac would not inhibit repair as a result of continued COX-1 activity. Segments of the pelvic flexure were exposed to 1.5 mmol/l deoxycholate for 30 min, after which they were recovered for 4 h in Ussing chambers. Contrary to the proposed hypothesis, recovery of bile-injured colonic mucosa was not affected by flunixin or etodolac, despite significantly depressed prostanoid production. However, treatment of control tissue with flunixin led to increases in mucosal permeability, whereas treatment with etodolac had no significant effect. Therefore, although recovery from bile-induced colonic injury maybe independent of COX-elaborated prostanoids, treatment of control tissues with nonselective COX inhibitors may lead to marked increases in permeability. Alternatively, selective inhibition of COX-2 may reduce the incidence of adverse effects in horses requiring NSAID therapy.

Evaluation of 30- and 25-diopter intraocular lens implants in equine eyes after surgical extraction of the lens

OBJECTIVE To determine appropriate intraocular lens (IOL) implant strength to approximate emmetropia in horses. SAMPLE POPULATION 16 enucleated globes and 4 adult horses. PROCEDURES Lens diameter of 10 enucleated globes was measured. Results were used to determine the appropriate-sized IOL implant for insertion in 6 enucleated globes and 4 eyes of adult horses. Streak retinoscopy and ocular ultrasonography were performed before and after insertion of 30-diopter (D) IOL implants (enucleated globes) and insertion of 25-D IOL implants (adult horses). RESULTS In enucleated globes, mean +/- SD lens diameter was 20.14 +/- 0.75 mm. Preoperative and postoperative refractive state of enucleated globes with 30-D IOL implants was -0.46 +/- 1.03 D and -2.47 +/- 1.03 D, respectively; preoperative and postoperative difference in refraction was 2.96 +/- 0.84 D. Preoperative anterior chamber (AC) depth, crystalline lens thickness (CLT), and axial globe length (AxL) were 712 +/- 0.82 mm, 11.32 +/- 0.81 mm, and 40.52 +/- 1.26 mm, respectively; postoperative AC depth was 10.76 +/- 1.16 mm. Mean ratio of preoperative to postoperative AC depth was 0.68. In eyes receiving 25-D IOL implants, preoperative and postoperative mean refractive error was 0.08 +/- 0.68 D and -3.94 +/- 1.88 D, respectively. Preoperative AC depth, CLT, and AxL were 6.36 +/- 0.22 mm, 10.92 +/- 1.92 mm, and 38.64 +/- 2.59 mm, respectively. Postoperative AC depth was 8.99 +/- 1.68 mm. Mean ratio of preoperative to postoperative AC depth was 0.73. CONCLUSIONS AND CLINICAL RELEVANCE Insertion of 30-D (enucleated globes) and 25-D IOL implants (adult horses) resulted in overcorrection of refractive error.

The hemodynamic effects of medetomidine continuous rate infusions in the dog

OBJECTIVE To characterize the hemodynamic effects of continuous rate infusions (CRI) of medetomidine administered at doses ranging from 0 to 3 microg kg(-1) hour(-1). STUDY DESIGN Prospective, blinded, randomized experimental trial. ANIMALS Six adult purpose-bred mongrel dogs. METHODS Anesthesia was induced with sevoflurane for placement of arterial and venous catheters. Dogs recovered from anesthesia after which baseline hemodynamic measurements were obtained via lithium dilution cardiac output (CO) determination, with subsequent measurements via pulse power analysis to provide continuous CO determinations. Medetomidine, 1, 2, or 3 microg kg(-1) hour(-1) or a volume equivalent placebo, was administered via CRI for 60 minutes. Systolic, mean, and diastolic arterial pressure, heart rate (HR), CO and stroke volume were measured and stroke index (SI), cardiac index (CI), total peripheral resistance (TPR), and total peripheral resistance index (TPRI) were calculated at 3, 7, 10, 20, 30, 45, 60, 90, and 120 minutes from the start of the infusion. RESULTS Increase in dose decreased SI by 25%, 19%, and 30%, HR by 33%, 57%, and 60%, CI by 50%, 65%, 70% and increased TPRI by 109%, 235%, and 222% from baseline to the 60-minute measurement for the 1, 2, and 3 microg kg(-1) hour(-1) doses, respectively. HR, TPRI, and CI all showed significant differences over the duration of the study from the placebo treatment. CONCLUSIONS Medetomidine CRI produces clinically relevant changes in CO, TPR, and HR. The demonstrated decrease in CO is largely because of bradycardia and the degree of cardiovascular depression appears to be dose-dependent. These findings are consistent with previously described hemodynamic changes with single bolus administration of medetomidine. CLINICAL RELEVANCE Low-dose medetomidine CRIs produce clinically relevant hemodynamic depression at doses as low as 1 microg kg(-1) hour(-1) and should be used cautiously in dogs.

Efficacy and Pharmacokinetics of Pantoprazole in Alpacas

BACKGROUND Despite frequent clinical use, information about the pharmacokinetics and efficacy of pantoprazole in camelids is not available. OBJECTIVES To examine the pharmacokinetics of both IV and SC pantoprazole and to determine whether pantoprazole administration would increase 3rd compartment pH in alpacas. ANIMALS Six healthy adult alpacas. METHODS Alpacas were fitted with a 3rd compartment cannula for measuring gastric pH. After recovery, alpacas received 1 mg/kg pantoprazole IV, q24h for 3 days or 2 mg/kg SC q24h for 3 days. Alpacas received both IV and SC pantoprazole, with a minimum of 3 weeks between treatments. Third compartment pH was recorded and plasma samples were taken for pharmacokinetic analysis. RESULTS Pantoprazole induced a slow but sustained increase in 3rd compartment pH when given by both the IV and SC routes. Third compartment pH was significantly increased as compared with baseline values (1.81+/-0.7; mean+/-SD) at 24 (2.47+/-0.8), 48 (3.53+/-1.0) and 72 hours (4.03+/-1.3) after daily IV administration of pantoprazole. Third compartment pH increased from 1.73+/-0.6 at baseline to 3.05+/-1.1, 4.02+/-1.4, and 3.61+/-1.6 at 24, 48, and 72 hours after SC administration, respectively. Pharmacokinetic analysis demonstrated that pantoprazole had a short elimination half-life (0.47+0.06 h) and a high clearance rate (12.2+/-2.9 mL/kg/min) after both IV and SC administration. CONCLUSIONS AND CLINICAL RELEVANCE Based on the results of this study, pantoprazole represents a safe and effective drug for increasing 3rd compartment pH in camelids. Either IV or SC administration is likely to be an effective treatment for gastric ulcers.

Implantation of an ultrafiltration device in the ileum and spiral colon of steers to continuously collect intestinal fluid

Collection of fluid from the lumen of the gastrointestinal tract is commonly necessary for research projects, but presents challenges including intestinal motility and potential for leakage of intestinal contents. In this study, ultrafiltration collection devices were surgically implanted in the ileum and spiral colon of 12 steers for repeated collection of intestinal fluid over 48 hours. There were no significant complications associated with surgery or during the post-operative period, nor were there any significant pathologic changes found at necropsy 3 or 4 days post-surgery. Over 48 hours, we obtained 88% of the desired 212 samples. Only two devices failed to routinely collect samples. Use of ultrafiltration probes is a novel, consistent and humane method to repeatedly sample the gastrointestinal contents.

FEASIBILITY AND SAFETY OF CONTRAST-ENHANCED ULTRASOUND IN THE DISTAL LIMB OF SIX HORSES.

Vascular alterations play important roles in many orthopedic diseases such as osteoarthritis, tendonitis, and synovitis in both human and equine athletes. Understanding these alterations could enhance diagnosis, prognosis, and treatment. Contrast-enhanced ultrasound (CEUS) could be a valuable method for evaluation of blood flow and perfusion of these processes in the equine distal limb, however no reports were found describing feasibility or safety of the technique. The goal of this prospective, experimental study was to describe the feasibility and safety of distal limb CEUS in a sample of six horses. For each horse, CEUS of the distal limb was performed after intravenous injections of 5 and 10 ml, as well as intra-arterial injections of 0.5 and 1 ml contrast medium. Vital parameters were monitored and CEUS images were assessed qualitatively and quantitatively for degree of contrast enhancement. None of the horses had clinically significant changes in their vital parameters after contrast medium injection. One horse had a transient increase in respiratory rate, and several horses had mild increases of systolic blood pressure of short duration after intravenous, but not after intra-arterial injections. Intra-arterial injection was possible in all horses and resulted in significantly improved contrast enhancement both quantitatively (P = 0.027) and qualitatively (P = 0.019). Findings from this study indicated that CEUS is a feasible and safe diagnostic test for evaluation of the equine distal limb. Future studies are needed to assess the clinical utility of this test for horses with musculoskeletal diseases.