Objective: To determine the feasibility of quantitative contrast-enhanced ultrasonography (CEUS) for detection of changes in renal blood flow in dogs before and after hydrocortisone administration. Animals: 11 Beagles. Procedure: Dogs were randomly assigned to 2 treatment groups: oral administration of hydrocortisone (9.6 mg/kg; n = 6) or a placebo (5; control group) twice a day for 4 months, after which the dose was tapered until treatment cessation at 6 months. Before treatment began and at 1, 4, and 6 months after, CEUS of the left kidney was performed by IV injection of ultrasonography microbubbles. Images were digitized, and time-intensity curves were generated from regions of interest in the renal cortex and medulla. Changes in blood flow were determined as measured via contrast agent (baseline [background] intensity, peak ntensity, area under the curve, arrival time of contrast agent, time-to-peak intensity, and speed of contrast agent transport). Results: Significant increases in peak intensity, compared with that in control dogs, were observed in the renal cortex and medulla of hydrocortisone-treated dogs 1 and 4 months after treatment began. Baseline intensity changed similarly. A significant increase from control values was also apparent in area under the curve for the renal cortex 4 months after hydrocortisone treatment began and in the renal medulla 1 and 4 months after treatment began. A significant time effect with typical time course was observed, corresponding with the period during which hydrocortisone was administered. No difference was evident in the other variables between treated and control dogs. Conclusions and Clinical Relevance: Quantitative CEUS allowed detection of differences in certain markers of renal blood flow between dogs treated orally with and without hydrocortisone. Additional studies are needed to investigate the usefulness of quantitative CEUS in the diagnosis of diffuse renal lesions.

Objective: To evaluate the cardiopulmonary effects of IV fentanyl administration in dogs during isoflurane anesthesia and during anesthetic recovery with or without dexmedetomidine or acepromazine. Animals: 7 sexually intact male purpose-bred hound-type dogs aged 11 to 12 months. Procedures: Dogs received a loading dose of fentanyl (5 μg/kg, IV) followed by an IV infusion (5 μg/kg/h) for 120 minutes while anesthetized with isoflurane and for an additional 60 minutes after anesthesia was discontinued. Dogs were randomly assigned in a crossover design to receive dexmedetomidine (2.5 μg/kg), acepromazine (0.05 mg/kg), or saline (0.9% NaCl) solution (1 mL) IV after anesthesia ceased. Cardiopulmonary data were obtained during anesthesia and for 90 minutes after treatment administration during anesthetic recovery. Results: Concurrent administration of fentanyl and isoflurane resulted in significant decreases in mean arterial blood pressure, heart rate, and cardiac index and a significant increase in Paco2. All but Paco2 returned to pretreatment values before isoflurane anesthesia was discontinued. During recovery, dexmedetomidine administration resulted in significant decreases in heart rate, cardiac index, and mixed venous oxygen tension and a significant increase in arterial blood pressure, compared with values for saline solution and acepromazine treatments. Acepromazine administration resulted in significantly lower blood pressure and higher cardiac index and Po2 in mixed venous blood than did the other treatments. Dexmedetomidine treatment resulted in significantly lower values for Pao2 and arterial pH and higher Paco2 values than both other treatments. Conclusions and Clinical Relevance: Fentanyl resulted in transient pronounced cardiorespiratory effects when administered during isoflurane anesthesia. During anesthetic recovery, when administered concurrently with an IV fentanyl infusion, dexmedetomidine resulted in evidence of cardiopulmonary compromise and acepromazine transiently improved cardiopulmonary performance.

Objective: To determine pharmacokinetic and pharmacodynamic properties of midazolam after IV and IM administration in alpacas. Animals: 6 healthy alpacas. Procedures: Midazolam (0.5 mg/kg) was administered IV or IM in a randomized crossover design. Twelve hours prior to administration, catheters were placed in 1 (IM trial) or both (IV trial) jugular veins for drug administration and blood sample collection for determination of serum midazolam concentrations. Blood samples were obtained at intervals up to 24 hours after IM and IV administration. Midazolam concentrations were determined by use of tandem liquid chromatography–mass spectrometry. Results: Maximum concentrations after IV administration (median, 1,394 ng/mL [range, 1,150 to 1,503 ng/mL]) and IM administration (411 ng/mL [217 to 675 ng/mL]) were measured at 3 minutes and at 5 to 30 minutes, respectively. Distribution half-life was 18.7 minutes (13 to 47 minutes) after IV administration and 41 minutes (30 to 80 minutes) after IM administration. Elimination half-life was 98 minutes (67 to 373 minutes) and 234 minutes (103 to 320 minutes) after IV and IM administration, respectively. Total clearance after IV administration was 11.3 mL/min/kg (6.7 to 13.9 mL/min/kg), and steady-state volume of distribution was 525 mL/kg (446 to 798 mL/kg). Bioavailability of midazolam after IM administration was 92%. Peak onset of sedation occurred at 0.4 minutes (IV) and 15 minutes (IM). Sedation was significantly greater after IV administration. Conclusions and Clinical Relevance: Midazolam was well absorbed after IM administration, had a short duration of action, and induced moderate levels of sedation in alpacas.

Objective-To test the hypothesis that inflammatory responses to endotoxemia differ between healthy horses and horses with equine metabolic syndrome (EMS). Animals-6 healthy horses and 6 horses with EMS. Procedures-Each horse randomly received an IV infusion of lipopolysaccharide (20 ng/kg [in 60 mL of sterile saline {0.9% NaCl} solution]) or saline solution, followed by the other treatment after a 7-day washout period. Baseline data were obtained 30 minutes before each infusion. After infusion, a physical examination was performed hourly for 9 hours and at 15 and 21 hours; a whole blood sample was collected at 30, 60, 90, 120, 180, and 240 minutes for assessment of inflammatory cytokine gene expression. Liver biopsy was performed between 240 and 360 minutes after infusion. Results-Following lipopolysaccharide infusion in healthy horses and horses with EMS, mean rectal temperature, heart rate, and respiratory rate increased, compared with baseline findings, as did whole blood gene expression of interleukin (IL)-1β, IL-6, IL-8, IL-10, and tumor necrosis factor-α. The magnitude of blood cytokine responses did not differ between groups, but increased expression of IL-6, IL-8, IL-10, and tumor necrosis factor-α persisted for longer periods in EMS-affected horses. Lipopolysaccharide infusion increased liver tissue gene expressions of IL-6 in healthy horses and IL-8 in both healthy and EMS-affected horses, but these gene expressions did not differ between groups. Conclusions and Clinical Relevance-Results supported the hypothesis that EMS affects horses’ inflammatory responses to endotoxin by prolonging cytokine expression in circulating leukocytes. These findings are relevant to the association between obesity and laminitis in horses with EMS.

Objective-To test the hypothesis that glucose and insulin dynamics during endotoxemia differ between healthy horses and horses with equine metabolic syndrome (EMS). Animals-6 healthy adult mares and 6 horses with EMS. Procedures-Each horse randomly received an IV infusion of lipopolysaccharide (20 ng/kg [in 60 mL of sterile saline {0.9% NaCl} solution]) or saline solution, followed by the other treatment after a 7-day washout period. Baseline insulin-modified frequently sampled IV glucose tolerance tests were performed 27 hours before and then repeated at 0.5 and 21 hours after infusion. Results were assessed via minimal model analysis and area under the curve values for plasma glucose and serum insulin concentrations. Results-Lipopolysaccharide infusion decreased insulin sensitivity and increased area under the serum insulin concentration curve (treatment × time) in both healthy and EMS-affected horses, compared with findings following saline solution administration. The magnitude of increase in area under the plasma glucose curve following LPS administration was greater for the EMS-affected horses than it was for the healthy horses. Horses with EMS that received LPS or saline solution infusions had decreased insulin sensitivity over time. Conclusions and Clinical Relevance-Glucose and insulin responses to endotoxemia differed between healthy horses and horses with EMS, with greater loss of glycemic control in EMS-affected horses. Horses with EMS also had greater derangements in glucose and insulin homeostasis that were potentially stress induced. It may therefore be helpful to avoid exposure of these horses to stressful situations.

Objective-To compare effects of anesthetic induction with midazolam-propofol or midazolam-etomidate on intraocular pressure (IOP), pupillary diameter (PD), pulse rate, blood pressure, and respiratory rate in clinically normal dogs. Animals-18 dogs. Procedures-Dogs undergoing ophthalmic surgery received midazolam (0.2 mg/kg, IV) and either propofol or etomidate (IV) until intubatable. For all dogs, results of physical examinations, ophthalmic examinations of the nonoperated eye, and preanesthetic blood analyses were normal. Intraocular pressure, PD, blood pressure, pulse rate, and respiratory rate were measured in the nonoperated eye at 5 time points: just prior to the anesthetic induction sequence, after 5 minutes of preanesthetic oxygenation via face mask, after IV administration of midazolam, after IV anesthetic induction, and after endotracheal intubation. Results-PD decreased significantly from baseline by 4.4 +/- 0.4 mm (mean +/- SD) after anesthetic induction and 5.3 +/- 0.4 mm after intubation in the etomidate group and by 1. 2 +/- 0.4 mm after intubation in the propofol group. Intraocular pressure was increased significantly from baseline by 3.2 +/- 1.0 mm Hg after anesthetic induction in the etomidate group and by 4.7 +/- 1.2 mm Hg after anesthetic induction and 4.5 +/- 1. 2 mm Hg after intubation in the propofol group. Pulse rate was significantly lower by 28.6 +/- 12.6 beats/min after anesthetic induction in the etomidate group, compared with the propofol group. Conclusions and Clinical Relevance-At the studied doses, midazolam-etomidate caused clinically important miosis and increased IOP. Midazolam-propofol caused an even greater increase in IOP but had minimal effects on PD.

Objective: To describe the pharmacokinetics of N-acetylcysteine (NAC) in healthy cats after oral and IV administration. Animals: 6 healthy cats. Procedures: In a crossover study, cats received NAC (100 mg/kg) via IV and oral routes of administration; there was a 4-week washout period between treatments. Plasma samples were obtained at 0, 5, 15, 30, and 45 minutes and 1, 2, 4, 8, 12, 24, 36, and 48 hours after administration, and NAC concentrations were quantified by use of a validated high-performance liquid chromatography–mass spectrometry protocol. Data were analyzed via compartmental and noncompartmental pharmacokinetic analysis. Results: Pharmacokinetics for both routes of administration were best described by a 2-compartment model. Mean ± SD elimination half-life was 0.78 ± 0.16 hours and 1.34 ± 0.24 hours for the IV and oral routes of administration, respectively. Mean bioavailability of NAC after oral administration was 19.3 ± 4.4%. Conclusions and Clinical Relevance: The pharmacokinetics of NAC for this small population of healthy cats differed from values reported for humans. Assuming there would be similar pharmacokinetics in diseased cats, dose extrapolations from human medicine may result in underdosing of NAC in cats with acute disease. Despite the low bioavailability, plasma concentrations of NAC after oral administration at 100 mg/kg may be effective in the treatment of chronic diseases.

Objective: To establish pharmacokinetics of robenacoxib after administration to cats via the IV, SC, and oral routes. Animals: 24 cats. Procedures: In a crossover design, robenacoxib was administered IV, SC, and orally (experiment 1) and orally (experiment 2) to cats with different feeding regimens. Blood robenacoxib concentrations were assayed, with a lower limit of quantification of 3 ng/mL. Results: In experiment 1, geometric mean pharmacokinetic values after IV administration of robenacoxib were as follows: blood clearance, 0.44 L/kg/h; plasma clearance, 0.29 L/kg/h; elimination half-life, 1.49 hours; and volume of distribution at steady state (determined from estimated plasma concentrations), 0.13 L/kg. Mean bioavailability was 69% and median time to maximum concentration (Cmax) was 1 hour for cats after SC administration of robenacoxib, whereas mean bioavailability was 49% and 10% and median time to Cmax was 1 hour and 30 minutes after oral administration to cats after food withholding and after cats were fed their entire ration, respectively. In experiment 2, geometric mean Cmax was 1,159, 1,201, and 692 ng/mL and area under the curve from 0 to infinity was 1,337, 1,383, and 1,069 ng × h/mL following oral administration to cats after food withholding, cats fed one-third of the daily ration, and cats fed the entire daily ration, respectively. Conclusions and Clinical Relevance: For treatment of acute conditions in cats, it is recommended to administer robenacoxib by IV or SC injection, orally after food withholding, or orally with a small amount of food to obtain optimal bioavailability and Cmax.

Objective-To determine whether dilution of blood samples from healthy dogs with 2 hydroxyethyl starch (HES) solutions, HES 130/0.4 and HES 200/0.5, would result in platelet dysfunction as measured by closure time (Ct) beyond a dilutional effect. Sample-Citrated blood samples from 10 healthy dogs with a Ct within reference limits (52 to 86 seconds). Procedures-Blood samples were diluted 1:9 and 1:3 with 6% HES 130/0.4 and 10% HES 200/0.5 solutions and saline (0.9% NaCl) solution. Dilutions at 1:9 and 1:3 mimicked 10 mL/kg and 30 mL/kg doses, respectively, ignoring in vivo redistribution. Closure time was measured with a platelet function analyzer and compared among dilutions. Results-A dilutional effect on Ct was evident for the 1:3 dilution, compared with the 1:9 dilution, but only HES 200/0.5 increased the Ct beyond the dilutional effect at the 1:3 dilution, to a median Ct of 125 seconds (interquartile range, 117.5 to 139.5 seconds). No effect of HES or dilution on Ct was identified at the 1:9 dilution. Conclusions and Clinical Relevance-1:3 dilution of blood samples from healthy dogs with HES 200/0.5 but not HES 130/0.4 significantly increased Ct beyond the dilutional effect, suggesting that IV administration of HES 200/0.5 in dogs might cause platelet dysfunction.

Objective—To determine the pharmacokinetics and hemodynamic effects of trazodone after IV and oral administration in dogs and bioavailability after oral administration. Animals—6 adult Beagles. Procedures—Dogs received trazodone HCl (8 mg/kg) orally and IV in a randomized controlled crossover design. Blood samples were collected at various times after administration. Heart rates and indirectly measured blood pressures of dogs and plasma concentrations and pharmacokinetics of trazodone were determined. Results—Following IV administration, the mean ± SD elimination half-life, apparent volume of distribution, and plasma total body clearance were 169 ± 53 minutes, 2.53 ± 0.47 L/kg, and 11.15 ± 3.56 mL/min/kg, respectively. Following oral administration, the mean ± SD elimination half-life and absolute bioavailability were 166 ± 47 minutes and 84.6 ± 13.2%, respectively. Maximum plasma concentration following oral administration was 1.3 ± 0.5 μ/mL, and time to maximum plasma concentration was 445 ± 271 minutes. After IV administration, all dogs immediately developed transient tachycardia (184.3 ± 8.0 beats/min), and 3 of 6 dogs developed aggression. Increase in heart rate was significantly associated with increase in plasma drug concentration following IV administration. Conclusions and Clinical Relevance—Results of this study indicated oral administration of trazodone resulted in acceptable absolute bioavailability, with substantial variability in time to maximum plasma concentration. Individualized approaches in dosing intervals may be necessary for dogs receiving oral trazodone. An orally administered dose of 8 mg/kg was well tolerated in dogs; IV administration of a dose of 8 mg/kg caused substantial adverse effects, including tachycardia and behavior disinhibition.