Effects of continuous or intermittent lipopolysaccharide administration for 48 hours on the systemic inflammatory response in horses

Objective-To determine whether the method of lipopolysaccharide (LPS) administration (intermittent vs continuous) affects the magnitude and duration of the systemic inflammatory response in horses and whether prolonged (48 hours) endotoxemia induces laminitis. Animals-12 healthy adult horses (10 mares and 2 geldings). Procedures-Horses were randomly assigned to receive LPS (total dose, 80 μg; n = 4) or saline (0.9% NaCl) solution (80 mL/h; 4) via constant rate infusion or 8 bolus IV injections of LPS (10 μg, q 6 h;4) during a 48-hour period. Physical examinations were performed every 4 hours, inflammatory cytokine gene expression was determined for blood samples obtained every 8 hours, and IV glucose tolerance tests were performed. Results-All LPS-treated horses had signs of depression and mild colic; those signs abated as the study progressed. Administration of LPS increased expression of interleukin-1β, interleukin-6, and interleukin-8, but results were not significantly different between LPS treatment groups. Cytokine expression was significantly higher on the first day versus the second day of LPS treatment. Interleukin-1β expression was positively correlated with rectal temperature and expression of other cytokines. Glucose and insulin dynamics for both LPS groups combined did not differ significantly from those of the saline solution group. Signs of laminitis were not detected in any of the horses. Conclusions and Clinical Relevance-Horses developed LPS tolerance within approximately 24 hours after administration was started, and the method of LPS administration did not affect the magnitude or duration of systemic inflammation. Laminitis was not induced in horses.     

Serum creatine kinase response to exercise during dexamethasone-induced insulin resistance in Quarter Horses with polysaccharide storage myopathy

OBJECTIVE: To determine effects of dexamethasone on insulin sensitivity, serum creatine kinase (CK) activity 4 hours after exercise, and muscle glycogen concentration in Quarter Horses with polysaccharide storage myopathy (PSSM). ANIMALS: 4 adult Quarter Horses with PSSM. PROCEDURE: A 2 x 2 crossover design was used with dexamethasone (0.08 mg/kg) or saline (0.9% NaCl) solution administered IV every 48 hours. Horses were exercised on a treadmill daily for 3 wk/treatment with a 2-week washout period between treatments. Serum CK activity was measured daily 4 hours after exercise. At the end of each treatment period, serum cortisol concentrations were measured, a hyperinsulinemic euglycemic clamp (HEC) technique was performed, and muscle glycogen content was determined. RESULTS: Mean +/- SEM serum cortisol concentration was significantly lower after 48 hours for the dexamethasone treatment (0.38 +/- 0.08 mg/dL), compared with the saline treatment (4.15 +/- 0.40 mg/dL). Dexamethasone significantly decreased the rate of glucose infusion necessary to maintain euglycemia during the HEC technique, compared with the saline treatment. Muscle glycogen concentrations and mean CK activity after exercise were not altered by dexamethasone treatment, compared with the saline treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Dexamethasone significantly reduced whole-body insulin-stimulated glucose uptake in Quarter Horses with PSSM after a 3-week period but did not diminish serum CK response to exercise or muscle glycogen concentrations in these 4 horses. Therefore, a decrease in glucose uptake for 3 weeks did not appear to alleviate exertional rhabdomyolysis in these horses. It is possible that long-term treatment may yield other results.     

Use of proxies and reference quintiles obtained from minimal model analysis for determination of insulin sensitivity and pancreatic beta-cell responsiveness in horses

OBJECTIVE: To develop proxies calculated from basal plasma glucose and insulin concentrations that predict insulin sensitivity (SI; L.min(-1) x mU(-1)) and beta-cell responsiveness (ie, acute insulin response to glucose [AIRg]; mU/L x min(-1)) and to determine reference quintiles for these and minimal model variables. ANIMALS: 1 laminitic pony and 46 healthy horses. PROCEDURE: Basal plasma glucose (mg/dL) and insulin (mU/L) concentrations were determined from blood samples obtained between 8:00 AM and 9:00 AM. Minimal model results for 46 horses were compared by equivalence testing with proxies for screening SI and pancreatic beta-cell responsiveness in humans and with 2 new proxies for screening in horses (ie, reciprocal of the square root of insulin [RISQI] and modified insulin-to-glucose ratio [MIRG]). RESULTS: Best predictors of SI and AIRg were RISQI (r = 0.77) and MIRG (r = 0.75) as follows: SI = 7.93(RISQI) - 1.03 and AIRg = 70.1(MIRG) - 13.8, where RISQI equals plasma insulin concentration(-0.5) and MIRG equals [800 - 0.30(plasma insulin concentration 50)(2)]/(plasma glucose concentration - 30). Total predictive powers were 78% and 80% for RISQI and MIRG, respectively. Reference ranges and quintiles for a population of healthy horses were calculated nonparametrically. CONCLUSIONS AND CLINICAL RELEVANCE: Proxies for screening SI and pancreatic beta-cell responsiveness in horses from this study compared favorably with proxies used effectively for humans. Combined use of RISQI and MIRG will enable differentiation between compensated and uncompensated insulin resistance. The sample size of our study allowed for determination of sound reference range values and quintiles for healthy horses.     

Determination of reference range values indicative of glucose metabolism and insulin resistance by use of glucose clamp techniques in horses and ponies

OBJECTIVES: To acquire reference range values indicative of glucose metabolism by use of the hyperglycemic clamp technique in healthy horses and evaluate the usefulness of the euglycemic hyperinsulinemic clamp technique in healthy horses and ponies. ANIMALS: Dutch Warmblood horses and 4 Shetland ponies. PROCEDURE: The hyperglycemic clamp technique was used for quantification of the sensitivity of beta cells to exogenous glucose infusion in horses. The euglycemic hyperinsulinemic clamp technique was used to determine the sensitivity and responsiveness of tissues to exogenous insulin in horses and ponies. RESULTS: During the hyperglycemic clamp technique, the mean amount of glucose metabolized (M) in horses was 0.011 +/- 0.0045 mmol/kg x min(-1) (95% confidence interval [CI], 0.0018 to 0.020 mmol/kg x min(-1); range, 0.000035 to 0.021 mmol/kg x min(-1)) and the mean M value-to-plasma insulin concentration (I) ratio (ie, mmol of glucose/kg x min(-1) per pmol of insulin/L x 100) was 0.017 +/- 0.016 (95% CI, -0.014 to 0.049; range, 0.000025 to 0.055). During the euglycemic hyperinsulinemic clamp technique, the mean M value was 0.014 +/- 0.0055 mmol/kg x min(-1) (95% CI, 0.0026 to 0.025 mmol/kg x min(-1); range, 0.0042 to 0.023 mmol/kg x min(-1)) in horses and 0.0073 +/- 0.0020 mmol/kg x min(-1) (95% CI, 0.0034 to 0.011 mmol/kg x min(-1); range, 0.0049 to 0.011 mmol/kg x min(-1)) in ponies. The M value was significantly lower in ponies than in horses, whereas the M:I ratios were not significantly different between horses and ponies. CONCLUSION AND CLINICAL RELEVANCE: Glucose clamp techniques offer good methods to investigate glucose metabolism in horses and ponies. A higher degree of insulin resistance was found in ponies, compared with Dutch Warmblood horses.     

Effect of dietary fructans and dexamethasone administration on the insulin response of ponies predisposed to laminitis

OBJECTIVE: To determine whether pasture, and specifically the addition of fructan carbohydrate to the diet, induces exaggerated changes in serum insulin concentration in laminitispredisposed (LP) ponies, compared with ponies with no history of the condition, and also to determine insulin responses to the dexamethasone suppression test. DESIGN: Prospective study. ANIMALS: 10 LP and 11 control adult nonobese mixed-breed ponies. PROCEDURES: Insulin-modified IV glucose tolerance tests were performed (5 ponies/group). In diet studies, ponies were kept on pasture and then changed to a hay diet (10 ponies/group). Second, ponies were maintained on a basal hay diet (4 weeks) before being fed a hay diet supplemented with inulin (3 g/kg/d [1.4 g/lb/d]). Serum insulin and plasma glucose concentrations were analyzed before and after dietary changes. Serum cortisol and insulin concentrations were also measured in a standard dexamethasone suppression test. RESULTS: The LP ponies were insulin resistant (median insulin sensitivity of 0.27 x 10(4) L min(-1) mU(-1) in LP ponies, compared with 0.64 x 10(4) L min(-1) mU(-1) in control ponies). Median insulin concentration in LP ponies was significantly greater than that in control ponies at pasture, decreased in response to feeding hay, and was markedly increased (5.5-fold) following the feeding of inulin with hay. The LP ponies had a greater increase in serum insulin concentration at 19 hours after dexamethasone administration (median, 222.9 mU/L), compared with control ponies (45.6 mU/L). CONCLUSIONS AND CLINICAL RELEVANCE: Nonobese ponies predisposed to develop laminitis had compensated insulin resistance, and this phenotype was revealed by feeding plant fructan carbohydrate or by dexamethasone administration.     

Effects of long-term oral administration of levothyroxine sodium on glucose dynamics in healthy adult horses

OBJECTIVE: To determine the effects of long-term oral administration of levothyroxine sodium (L-T(4)) on glucose dynamics in adult euthyroid horses. ANIMALS: 6 healthy adult mares. PROCEDURES: Horses received L-T(4) (48 mg/d) orally for 48 weeks. Frequently sampled IV glucose tolerance test procedures were performed on 3 occasions (24-hour intervals) before and at 16, 32, and 48 weeks during the treatment period. Data were assessed via minimal model analysis. The repeatability of measurements was evaluated. RESULTS: During treatment, body weight decreased significantly from the pretreatment value; mean +/- SD weight was 49 +/- 14 kg, 43 +/- 7 kg, and 25 +/- 18 kg less than the pretreatment value at weeks 16, 32, and 48, respectively. Compared with pretreatment findings, 1.8-, 2.4-, and 1.9-fold increases in mean insulin sensitivity (SI) were detected at weeks 16, 32, and 48, respectively; SI was negatively correlated with body weight (r = -0.42; P < 0.001). During treatment, glucose effectiveness increased and the acute insulin response to glucose decreased. Overall mean within-horse coefficients of variation were 5% and 29% for plasma glucose and serum insulin concentrations, respectively, and 33%, 26%, and 23% for SI, glucose effectiveness, and the acute insulin response to glucose, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Long-term administration of L-T(4) was associated with weight loss and increased SI in adult euthyroid horses, although other factors may have confounded results. Levothyroxine sodium may be useful for the treatment of obesity and insulin resistance in horses, but further studies are required.     

Repeatability of 2 methods for assessment of insulin sensitivity and glucose dynamics in horses

Both the euglycemic-hyperinsulinemic clamp (EHC) and minimal model analysis of the frequently sampled intravenous glucose tolerance test (FSIGT) have been applied for measurement of insulin sensitivity in horses. However, no published data are available on the reproducibility of these methods. Therefore, the objective of this study was to evaluate the variation and repeatability of measures of glucose dynamics and insulin sensitivity in horses derived from minimal model analysis of the FSIGT and from the EHC method. Six healthy horses underwent both the FSIGT and EHC on 2 occasions over a 4-week period, with a minimum of 5 days between tests. Coefficient of variation (CV) and intraclass correlation coefficient (ICC) were calculated for measures of glucose metabolism and insulin sensitivity derived from each test. In the EHC, insulin sensitivity, expressed as the amount of metabolized glucose (M) per unit of serum insulin (I) (M/I ratio), averaged 0.19 +/- 0.06 x 10(-4) mmol/kg/min x (pmol/L)(-1) with an average interday CV of 14.1 +/- 5.7% (range, 7-20%) and ICC of 0.74. Minimal model analysis of the FSIGT demonstrated mean insulin sensitivity (Si) of 0.49 +/- 0.17 x 10(-4)/min x (pmol/L)(-1) with an average interday CV of 23.7 +/- 11.2% (range, 9-35%) and ICC of 0.33. Mean CV and ICC for minimal model glucose effectiveness (Sg) and acute insulin response (AIRg) were, respectively, 26.4 +/- 11.2% (range 13-40%) and 0.10 and 11.7 +/- 6.5% (range 7-21%) and 0.98. Insulin sensitivity measured by the EHC has lower interday variation when compared with the minimal model estimate derived from the FSIGT.     

Effects of dexamethasone on glucose dynamics and insulin sensitivity in healthy horses

OBJECTIVE: To determine effects of dexamethasone on glucose dynamics and insulin sensitivity in healthy horses. ANIMALS: 6 adult Standardbreds. PROCEDURES: In a balanced crossover study, horses received dexamethasone (0.08 mg/ kg, IV, q 48 h) or an equivalent volume of saline (0.9% NaCl) solution (control treatment) during a 21-day period. Horses underwent a 3-hour frequently sampled IV glucose tolerance test (FSIGT) 2 days after treatment. Minimal model analysis of glucose and insulin data from FSIGTs were used to estimate insulin sensitivity (Si), glucose effectiveness (Sg), acute insulin response to glucose (AIRg), and disposition index. Proxies for Si (reciprocal of the inverse square of basal insulin concentration [RISQI]) and beta-cell responsiveness (modified insulin-to-glucose ratio [MIRG]) were calculated from basal plasma glucose and serum insulin concentrations. RESULTS: Mean serum insulin concentration was significantly higher in dexamethasone-treated horses than control horses on days 7, 14, and 21. Similarly, mean plasma glucose concentration was higher in dexamethasone-treated horses on days 7, 14, and 21; this value differed significantly on day 14 but not on days 7 or 21. Minimal model analysis of FSIGT data revealed a significant decrease in Si and a significant increase in AIRg after dexamethasone treatment, with no change in Sg or disposition index. Mean RISQI was significantly lower, whereas MIRG was higher, in dexamethasone-treated horses than control horses on days 7, 14, and 21. CONCLUSIONS AND CLINICAL RELEVANCE: The study revealed marked insulin resistance in healthy horses after 21 days of dexamethasone administration. Because insulin resistance has been associated with a predisposition to laminitis, a glucocorticoid-induced decrease in insulin sensitivity may increase risk for development of laminitis in some horses and ponies.     

Intravenous continuous infusion of lidocaine for treatment of equine ileus

OBJECTIVE: To determine if intravenous lidocaine is useful and safe as a treatment for equine ileus. Study DESIGN: Prospective double-blinded placebo-controlled trial. STUDY POPULATION: Horses (n = 32) with a diagnosis of postoperative ileus (POI) or enteritis and that had refluxed >20 L or had been refluxing for >24 hours. METHODS: Refluxing horses were administered lidocaine (1.3 mg/kg intravenously [IV] as a bolus followed by a 0.05 mg/kg/min infusion) or saline (0.9% NaCl) solution placebo for 24 hours. Variables evaluated included volume and duration of reflux, time to 1st fecal passage, signs of pain, analgesic use, heart rate and arrhythmias, respiratory rate, temperature, days of hospitalization, outcome (survival to discharge), and complications. RESULTS: Of the lidocaine-treated horses, 65% (11/17) stopped refluxing within 30 hours (mean+/-SD, 15.2+/-2.4 hours) whereas 27% (4/15) of the saline-treated horses stopped within 30 hours. Fecal passage was significantly correlated with response to treatment; horses that responded to lidocaine passed feces within 16 hours of starting the infusion. Compared with placebo treatment, lidocaine treatment resulted in shorter hospitalization time for survivors, equivalent survival to discharge, no clinically significant changes in physical or laboratory variables, and no difference in the rate of incisional infections, jugular thrombosis, laminitis, or diarrhea. Muscle fasciculations occurred in 3 lidocaine-treated horses (18%). CONCLUSION: IV lidocaine significantly improved the clinical course in refluxing horses with minimal side effects. CLINICAL RELEVANCE: At the infusion rate studied, IV lidocaine is safe and should be considered for the treatment of equine ileus.     

Pharmacokinetics of enrofloxacin administered intravenously and orally to foals

OBJECTIVE: To determine the pharmacokinetics of enrofloxacin administered IV and orally to foals. ANIMALS: 5 clinically normal foals. PROCEDURE: A 2-dose cross-over trial with IV and oral administration was performed. Enrofloxacin was administered once IV (5 mg/kg of body weight) to 1-week-old foals, followed by 1 oral administration (10 mg/kg) after a 7-day washout period. Blood samples were collected for 48 hours after the single dose IV and oral administrations and analyzed for plasma enrofloxacin and ciprofloxacin concentrations by use of high-performance liquid chromatography. RESULTS: For IV administration, mean +/- SD total area under the curve (AUC0-infinity) was 48.54 +/- 10.46 microg x h/ml, clearance was 103.72 +/- 0.06 ml/kg/h, half-life (t1/2beta) was 17.10 +/- 0.09 hours, and apparent volume of distribution was 2.49 +/- 0.43 L/kg. For oral administration, AUC0-infinity was 58.47 +/- 16.37 microg x h/ml, t1/2beta was 18.39 +/- 0.06 hours, maximum concentration (Cmax) was 2.12 +/- 00.51 microg/ml, time to Cmax was 2.20 +/- 2.17 hours, mean absorption time was 2.09 +/- 0.51 hours, and bioavailability was 42 +/- 0.42%. CONCLUSIONS AND CLINICAL RELEVANCE: Compared with adult horses given 5 mg of enrofloxacin/kg IV, foals have higher AUC0-infinity, longer t1/2beta, and lower clearance. Concentration of ciprofloxacin was negligible. Using a target Cmax to minimum inhibitory concentration ratio of 1:8 to 1:10, computer modeling suggests that 2.5 to 10 mg of enrofloxacin/kg administered every 24 hours would be effective in foals, depending on minimum inhibitory concentration of the pathogen.     

Effect of general anesthesia and minor surgical trauma on urine and serum measurements in horses

OBJECTIVE: To characterize the effect of general anesthesia and minor surgery on renal function in horses. ANIMALS: 9 mares with a mean (+/- SE) age and body weight of 9+/-2 years and 492+/-17 kg, respectively. PROCEDURE: The day before anesthesia, urine was collected (catheterization) for 3 hours to quantitate baseline values, and serum biochemical analysis was performed. The following day, xylazine (1.1 mg/kg, IV) was administered, and general anesthesia was induced 5 minutes later with diazepam (0.04 mg/kg, IV) and ketamine (2.2 mg/kg, IV). During 2 hours of anesthesia with isoflurane, Paco2 was maintained between 48 and 52 mm Hg, and mean arterial blood pressure was between 70 and 80 mm Hg. Blood and urine were collected at 30, 60, and 120 minutes during and at 1 hour after anesthesia. RESULTS: Baseline urine flow was 0.92+/-0.17 ml/kg/h and significantly increased at 30 and 60 minutes after xylazine administration (2.14+/-0.59 and 2.86+/-0.97 ml/kg/h respectively) but returned to baseline values by the end of anesthesia. Serum glucose concentration increased from 12+/-4 to 167+/-8 mg/dl at 30 minutes. Glucosuria was not observed. CONCLUSIONS AND CLINICAL RELEVANCE: Transient hyperglycemia and an increase in rine production accompanies a commonly used anesthetic technique for horses. The increase in urine flow is not trivial and should be considered in anesthetic management decisions. With the exception of serum glucose concentration and urine production, the effect of general anesthesia on indices of renal function in clinically normal horses is likely of little consequence in most horses admitted for elective surgical procedures.     

Evaluation of the effects of the opioid agonist morphine on gastrointestinal tract function in horses

OBJECTIVE: To evaluate the effects of morphine administration for 6 days on gastrointestinal tract function in healthy adult horses. ANIMALS: 5 horses. PROCEDURES: Horses were randomly allocated into 2 groups in a crossover study. Horses in the treatment group received morphine sulfate at a dosage of 0.5 mg/kg, IV, every 12 hours for 6 days. Horses in the control group received saline (0.9% NaCl) solution at a dosage of 10 mL, IV, every 12 hours for 6 days. Variables assessed included defecation frequency, weight of feces produced, intestinal transit time (evaluated by use of barium-filled spheres and radiographic detection in feces), fecal moisture content, borborygmus score, and signs of CNS excitement and colic. RESULTS: Administration of morphine resulted in gastrointestinal tract dysfunction for 6 hours after each injection. During those 6 hours, mean +/- SD defecation frequency decreased from 3.1 +/- 1 bowel movements in control horses to 0.9 +/- 0.5 bowel movements in treated horses, weight of feces decreased from 4.1 +/- 0.7 kg to 1.1 +/- 0.7 kg, fecal moisture content decreased from 76 +/- 2.7% to 73.5 +/- 2.9%, and borborygmus score decreased from 13.2 +/- 2.9 to 6.3 +/- 3.9. Mean gastrointestinal transit time was also increased, compared with transit times in control horses. CONCLUSIONS AND CLINICAL RELEVANCE: Morphine administered at 0.5 mg/kg twice daily decreased propulsive motility and moisture content in the gastrointestinal tract lumen. These effects may predispose treated horses to development of ileus and constipation.     

Effects of short- and long-term recombinant equine growth hormone and short-term hydrocortisone administration on tissue sensitivity to insulin in horses

OBJECTIVE: To determine the effects of short-term IV administration of hydrocortisone or equine growth hormone (eGH) or long-term IM administration of eGH to horses on tissue sensitivity to exogenous insulin. ANIMALS: 5 Standardbreds and 4 Dutch Warmblood horses. PROCEDURE: The euglycemic-hyperinsulinemic clamp technique was used to examine sensitivity of peripheral tissues to exogenous insulin 24 hours after administration of a single dose of hydrocortisone (0.06 mg/kg), eGH (20 microg/kg), or saline (0.9% NaCl) solution and after long-term administration (11 to 15 days) of eGH to horses. The amounts of metabolized glucose (M) and plasma insulin concentration (I) were determined. RESULTS: Values for M and the M-to-I ratio were significantly higher 24 hours after administration of a single dose of hydrocortisone than after single-dose administration of eGH or saline solution. After long-term administration of eGH, basal I concentration was increased and the mean M-to-I ratio was 22% lower, compared with values for horses treated with saline solution. CONCLUSIONS AND CLINICAL RELEVANCE: Increases in M and the M-to-I ratio after a single dose of hydrocortisone imply that short-term hydrocortisone treatment increases glucose use by, and insulin sensitivity of, peripheral tissues. Assuming a single dose of hydrocortisone improves sensitivity of peripheral tissues to insulin, it may be an interesting candidate for use in reducing insulin resistance in peripheral tissues of horses with several disease states. In contrast, long-term administration of eGH decreased tissue sensitivity to exogenous insulin associated with hyperinsulinemia. Therefore, increased concentrations of growth hormone may contribute to insulin resistance in horses with various disease states.     

Diurnal variation of ghrelin, leptin, and adiponectin in Standardbred mares

Twelve Standardbred mares underwent blood sampling for 24 h to test the hypothesis that there is diurnal variation of humoral mediators of peripheral energy balance including active ghrelin, adiponectin, leptin, glucose, insulin, and cortisol. The experiment was conducted under acclimated conditions. Grass hay and pelleted grain were provided at 0730 and 1530. Plasma concentrations of active ghrelin and leptin concentrations both peaked (47.3 +/- 6.5 pg/ mL and 5.9 +/- 1.1 ng/mL, respectively; P < 0.05) at 1550, 20 min after feeding. Active ghrelin decreased (P < 0.05) to 28.9 +/- 4.5 pg/mL overnight. The nadir of leptin (4.6 +/- 0.9 ng/mL) occurred at 0650. Neither hormone showed variation (P > 0.05) after the morning feeding. Plasma glucose and insulin concentrations increased (P < 0.05) in response to feeding; however, the morning responses (glucose = 96.9 +/- 2.6 mg/dL; insulin = 40.6 +/- 7.3 uIU/mL) were greater (P < 0.05) than the afternoon responses (glucose = 89.9 +/- 1.8 mg/dL; insulin = 23.2 +/- 4.3 uIU/mL at 180 and 60 min after feeding, respectively). Cortisol concentrations increased (P < 0.05) during the morning hours, but did not respond to feeding, whereas adiponectin concentrations remained stable throughout the study. Hence, active ghrelin and leptin may be entrained to meal feeding in horses, whereas adiponectin seems unaffected. We concluded that there seems to be a diurnal variation in glucose and insulin response to a meal in horses. Furthermore, elevated glucose and insulin concentrations resulting from the morning feeding may be responsible for the increase in leptin concentration in the afternoon.     

Regional limb perfusion for antibiotic treatment of experimentally induced septic arthritis.

Septic arthritis was induced in one antebrachiocarpal joint of seven horses by the intra-articular injection of 1 mL Staphylococcus aureus suspension containing a mean of 10(5) colony-forming units. Twenty-four hours after inoculation, four horses were treated by regional perfusion with 1 g of gentamicin sulfate, and three horses received 2.2 mg/kg gentamicin sulfate intravenously (IV) every 6 hours. Synovial fluid was collected for culture and cytology at regular intervals, and the synovial membranes were collected for culture and histologic examination at euthanasia 24 hours after the first treatment. Gentamicin concentration in the septic synovial fluid after three successful perfusions was 221.2 +/- 71.4 (SD) micrograms/mL; after gentamicin IV, it was 7.6 +/- 1.6 (SD) micrograms/mL. The mean leukocyte count in the inoculated joints decreased significantly by hour 24 in the successfully perfused joints. Terminal bacterial cultures of synovial fluid and synovial membranes were negative in two horses with successfully perfused joints. S. aureus was isolated from the infected joints in all three horses treated with gentamicin IV.     

Glucose response to exogenous insulin and kinetics of insulin metabolism in obese and lean heifers

Changes in serum concentrations of glucose and insulin after iv injection of a low (20 mU/kg) and high (200 mU/kg) dose of bovine insulin were used to quantify insulin resistance and calculate kinetic variables of injected insulin, respectively, in four obese and four lean heifers. Serum samples from jugular venous blood were collected 60, 45, 30, 15 and 1 min before and 2.5, 5, 10, 20, 30, 40, 60, 80, 100, 120, 150, 180, 210 and 240 min after each treatment. Mean (+/- SE) pretreatment concentration of insulin (microU/ml) was higher (P less than .01) in obese (50 +/- 6.6) than lean (20 +/- 1.8) heifers, even though glucose concentrations were similar in both groups (71 +/- 2.9 mg/100 ml). Concentrations of insulin after each treatment were similar in both groups and returned to pretreatment values by 60 and 120 min after injection of the low and high doses, respectively. Glucose concentrations during the first 40 min after treatment with the low dose were lower (P less than .05) in lean than obese heifers, but were similar in both groups during the first 40 to 60 min after the high dose of insulin. The high insulin dose decreased (P less than .05) glucose concentrations below those of the low dose in each group, but the difference was greater (P less than .01) in obese than lean heifers. These results indicated that obese heifers were insensitive to the glucoregulatory effects of exogenous insulin, although the maximum responses to insulin were similar.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of fluconazole following intravenous and oral administration and body fluid concentrations of fluconazole following repeated oral dosing in horses

OBJECTIVE: To determine the pharmacokinetics of fluconazole in horses. ANIMALS: 6 clinically normal adult horses. PROCEDURE: Fluconazole (10 mg/kg of body weight) was administered intravenously or orally with 2 weeks between treatments. Plasma fluconazole concentrations were determined prior to and 10, 20, 30, 40, and 60 minutes and 2, 4, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours after administration. A long-term oral dosing regimen was designed in which all horses received a loading dose of fluconazole (14 mg/kg) followed by 5 mg/kg every 24 hours for 10 days. Fluconazole concentrations were determined in aqueous humor, plasma, CSF, synovial fluid, and urine after administration of the final dose. RESULTS: Mean (+/- SD) apparent volume of distribution of fluconazole at steady state was 1.21+/-0.01 L/kg. Systemic availability and time to maximum plasma concentration following oral administration were 101.24+/-27.50% and 1.97+/-1.68 hours, respectively. Maximum plasma concentrations and terminal half-lives after IV and oral administration were similar. Plasma, CSF, synovial fluid, aqueous humor, and urine concentrations of fluconazole after long-term oral administration of fluconazole were 30.50+/-23.88, 14.99+/-1.86, 14.19+/-5.07, 11.39+/-2.83, and 56.99+/-32.87 microg/ml, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Bioavailability of fluconazole was high after oral administration to horses. Long-term oral administration maintained plasma and body fluid concentrations of fluconazole above the mean inhibitory concentration (8.0 mg/ml) reported for fungal pathogens in horses. Fluconazole may be an appropriate agent for treatment of fungal infections in horses.     

Pharmacokinetics and toxic effects of lithium chloride after intravenous adminstration in conscious horses

OBJECTIVE: To determine the pharmacokinetics and toxic effects associated with IV administration of lithium chloride (LiCl) to conscious healthy horses. ANIMALS: 6 healthy Standardbred horses. PROCEDURE: Twenty 3-mmol boluses of LiCl (0.15 mmol/L) were injected IV at 3-minute intervals (total dose, 60 mmol) during a 1-hour period. Blood samples for measurement of serum lithium concentrations were collected before injection and up to 24 hours after injection. Behavioral and systemic toxic effects of LiCl were also assessed. RESULTS: Lithium elimination could best be described by a 3-compartment model for 5 of the 6 horses. Mean peak serum concentration was 0.561 mmol/L (range, 0.529 to 0.613 mmol/L), with actual measured mean serum value of 0.575 mmol/L (range, 0.52 to 0.67 mmol/L) at 2.5 minutes after administration of the last bolus. Half-life was 43.5 hours (range, 32 to 84 hours), and after 24 hours, mean serum lithium concentration was 0.13+/-0.05 mmol/L (range, 0.07 to 0.21 mmol/L). The 60-mmol dose of LiCl did not produce significant differences in any measured hematologic or biochemical variables, gastrointestinal motility, or ECG variables evaluated during the study period. CONCLUSIONS AND CLINICAL RELEVANCE: Distribution of lithium best fit a 3-compartment model, and clearance of the electrolyte was slow. Healthy horses remained unaffected by LiCl at doses that exceeded those required for determination of cardiac output. Peak serum concentrations were less than steady-state serum concentrations that reportedly cause toxic effects in other species.     

Effects of endotoxaemia and carbohydrate overload on glucose and insulin dynamics and the development of laminitis in horses

Reasons for performing study: Insulin resistance (IR) is a risk factor for pasture‐associated laminitis in equids and alimentary carbohydrate overload may trigger laminitis. Whether glucose metabolism responses to carbohydrate overload are more pronounced in insulin‐resistant horses requires further study. Hypothesis: Horses pretreated with endotoxin to alter insulin sensitivity differ significantly in their glucose and insulin responses to carbohydrate overload. Methods: Horses (n = 24) were divided into 3 groups. A lipopolysaccharide (LPS; n = 8) group that received endotoxin as an 8 h 7.5 ng/kg bwt/h i.v. continuous rate infusion, an oligofructose (OF; n = 8) group that received an infusion of saline followed by 5 g/kg bwt OF via nasogastric intubation, and a LPS/OF (n = 8) group that received LPS followed 16 h later by OF. Glucose and insulin dynamics were evaluated at ‐24 h and 48 h using the frequently sampled i.v. glucose tolerance test and minimal model analysis. Physical examinations and haematology were performed and the severity of laminitis assessed. Results: Horses receiving LPS developed leucopenia and both LPS and OF induced clinical signs consistent with systemic inflammation. Insulin sensitivity significantly decreased (P<0.001) over time, but responses did not differ significantly among groups. Time (P<0.001) and treatment × time (P = 0.038) effects were detected for the acute insulin response to glucose, with mean values significantly increasing in LPS and LPS/OF groups, but not the OF group. Five horses in the LPS/OF group developed clinical laminitis compared with 0 and 2 horses in the LPS and OF groups, respectively. Conclusions: Endotoxaemia and carbohydrate overload reduce insulin sensitivity in horses. Endotoxin pretreatment does not affect the alterations in glucose metabolism induced by carbohydrate overload. Potential relevance: Insulin sensitivity decreases after carbohydrate overload in horses, which may be relevant to the development of pasture‐associated laminitis.