Objective—To identify and characterize cytochrome P450 enzymes (CYPs) responsible for the metabolism of racemic ketamine in 3 mammalian species in vitro by use of chemical inhibitors and antibodies. Sample—Human, canine, and equine liver microsomes and human single CYP3A4 and CYP2C9 and their canine orthologs. Procedures—Chemical inhibitors selective for human CYP enzymes and anti-CYP antibodies were incubated with racemic ketamine and liver microsomes or specific CYPs. Ketamine N-demethylation to norketamine was determined via enantioselective capillary electrophoresis. Results—The general CYP inhibitor 1-aminobenzotriazole almost completely blocked ketamine metabolism in human and canine liver microsomes but not in equine microsomes. Chemical inhibition of norketamine formation was dependent on inhibitor concentration in most circumstances. For all 3 species, inhibitors of CYP3A4, CYP2A6, CYP2C19, CYP2B6, and CYP2C9 diminished N-demethylation of ketamine. Anti-CYP3A4, anti-CYP2C9, and anti-CYP2B6 antibodies also inhibited ketamine N-demethylation. Chemical inhibition was strongest with inhibitors of CYP2A6 and CYP2C19 in canine and equine microsomes and with the CYP3A4 inhibitor in human microsomes. No significant contribution of CYP2D6 to ketamine biotransformation was observed. Although the human CYP2C9 inhibitor blocked ketamine N-demethylation completely in the canine ortholog CYP2C21, a strong inhibition was also obtained by the chemical inhibitors of CYP2C19 and CYP2B6. Ketamine N-demethylation was stereoselective in single human CYP3A4 and canine CYP2C21 enzymes. Conclusions and Clinical Relevance—Human-specific inhibitors of CYP2A6, CYP2C19, CYP3A4, CYP2B6, and CYP2C9 diminished ketamine N-demethylation in dogs and horses. To address drug-drug interactions in these animal species, investigations with single CYPs are needed.

Objective—To determine effects of a continuous rate infusion of lidocaine on the minimum alveolar concentration (MAC) of sevoflurane in horses. Animals—8 healthy adult horses. Procedures—Horses were anesthetized via IV administration of xylazine, ketamine, and diazepam; anesthesia was maintained with sevoflurane in oxygen. Approximately 1 hour after induction, sevoflurane MAC determination was initiated via standard techniques. Following sevoflurane MAC determination, lidocaine was administered as a bolus (1.3 mg/kg, IV, over 15 minutes), followed by constant rate infusion at 50 μg/kg/min. Determination of MAC for the lidocaine-sevoflurane combination was started 30 minutes after lidocaine infusion was initiated. Arterial blood samples were collected after the lidocaine bolus, at 30-minute intervals, and at the end of the infusion for measurement of plasma lidocaine concentrations. Results—IV administration of lidocaine decreased mean ± SD sevoflurane MAC from 2.42 ± 0.24% to 1.78 ± 0.38% (mean MAC reduction, 26.7 ± 12%). Plasma lidocaine concentrations were 2,589 ± 811 ng/mL at the end of the bolus; 2,065 ± 441 ng/mL, 2,243 ± 699 ng/mL, 2,168 ± 339 ng/mL, and 2,254 ± 215 ng/mL at 30, 60, 90, and 120 minutes of infusion, respectively; and 2,206 ± 329 ng/mL at the end of the infusion. Plasma concentrations did not differ significantly among time points. Conclusions and Clinical Relevance—Lidocaine could be useful for providing a more balanced anesthetic technique in horses. A detailed cardiovascular study on the effects of IV infusion of lidocaine during anesthesia with sevoflurane is required before this combination can be recommended.

Objective: To evaluate effects of racemic ketamine and S-ketamine in gazelles. Animals: 21 male gazelles (10 Rheem gazelles [Gazella subgutturosa marica] and 11 Subgutturosa gazelles [Gazella subgutturosa subgutturosa]), 6 to 67 months old and weighing (mean±SD) 19 ± 3 kg. Procedures: In a randomized, blinded crossover study, a combination of medetomidine (80 μg/kg) with racemic ketamine (5 mg/kg) or S-ketamine (3 mg/kg) was administered IM. Heart rate, blood pressure, respiratory rate, rectal temperature, and oxygen saturation (determined by means of pulse oximetry) were measured. An evaluator timed and scored induction of, maintenance of, and recovery from anesthesia. Medetomidine was reversed with atipamezole. The alternate combination was used after a 4-day interval. Comparisons between groups were performed with Wilcoxon signed rank and paired t tests. Results: Anesthesia induction was poor in 2 gazelles receiving S-ketamine, but other phases of anesthesia were uneventful. A dominant male required an additional dose of S-ketamine (0.75 mg/kg, IM). After administration of atipamezole, gazelles were uncoordinated for a significantly shorter period with S-ketamine than with racemic ketamine. Recovery quality was poor in 3 gazelles with racemic ketamine. No significant differences between treatments were found for any other variables. Time from drug administration to antagonism was similar between racemic ketamine (44.5 to 53.0 minutes) and S-ketamine (44.0 to 50.0 minutes). Conclusions and Clinical Relevance: Administration of S-ketamine at a dose 60% that of racemic ketamine resulted in poorer induction of anesthesia, an analogous degree of sedation, and better recovery from anesthesia in gazelles with unremarkable alterations in physiologic variables, compared with racemic ketamine.

Objective—To determine the analgesic and systemic effects of thoracic epidural administration of ketamine, lidocaine, or both in conscious dogs. Animals—6 adult mixed-breed dogs. Procedures—Each dog received 2% lidocaine hydrochloride without epinephrine (3.8 mg/kg), 5% ketamine hydrochloride (3.0 mg/kg), or both in randomized order with = 1 week between treatments. Drugs were administered in a total volume of 0.25 mL/kg through a thoracic epidural catheter implanted via the lumbosacral approach. Heart rate, blood pressure, respiratory rate, rectal temperature, analgesia, sedation, and ataxia were determined before treatment (baseline [time 0]) and at 5, 10, 15, 20, 30, 40, 50, 60, 90, 120, 150, and 180 minutes after administration. Results—The main areas of analgesia for the 3 treatments were the thorax and forelimbs bilaterally. Median duration of analgesia was shorter after administration of ketamine (30 minutes) than after administration of lidocaine (40 minutes) and lidocaine plus ketamine (90 minutes). All treatments caused moderate motor blockade, and only the ketamine and lidocaine plus ketamine treatments caused mild sedation. Significant decreases in systolic and mean arterial blood pressure were observed only with the lidocaine plus ketamine treatment. Conclusions and Clinical Relevance—Thoracic epidural administration of lidocaine plus ketamine resulted in longer duration of analgesia of the thorax and forelimbs bilaterally in conscious dogs, compared with administration of ketamine or lidocaine alone. Additional studies are needed to determine whether this technique adequately relieves postoperative pain after thoracic surgical procedures and whether it causes respiratory depression in dogs.

Objective—To determine the pharmacokinetic parameters of xylazine, ketamine, and butorphanol (XKB) administered IM and sodium salicylate (SAL) administered PO to calves and to compare drug effects on biomarkers of pain and distress following sham and actual castration and dehorning. Animals—40 Holstein bull calves from 3 farms. Procedures—Calves weighing 108 to 235 kg (n = 10 calves/group) received one of the following treatments prior to sham (period 1) and actual (period 2) castration and dehorning: saline (0.9% NaCl) solution IM (placebo); SAL administered PO through drinking water at concentrations from 2.5 to 5 mg/mL from 24 hours prior to period 1 to 48 hours after period 2; butorphanol (0.025 mg/kg), xylazine (0.05 mg/kg), and ketamine (0.1 mg/kg) coadministered IM immediately prior to both periods; and a combination of SAL and XKB (SAL+XKB). Plasma drug concentrations, average daily gain (ADG), chute exit velocity, serum cortisol concentrations, and electrodermal activity were evaluated. Results—ADG (days 0 to 13) was significantly greater in the SAL and SAL+XKB groups than in the other 2 groups. Calves receiving XKB had reduced chute exit velocity in both periods. Serum cortisol concentrations increased in all groups from period 1 to period 2. However, XKB attenuated the cortisol response for the first hour after castration and dehorning and oral SAL administration reduced the response from 1 to 6 hours. Administration of XKB decreased electrodermal activity scores in both periods. Conclusions and Clinical Relevance—SAL administered PO through drinking water decreased cortisol concentrations and reduced the decrease in ADG associated with castration and dehorning in calves.

Objective—To compare cardiovascular effects of sevoflurane alone and sevoflurane plus an IV infusion of lidocaine in horses. Animals—8 adult horses. Procedures—Each horse was anesthetized twice via IV administration of xylazine, diazepam, and ketamine. During 1 anesthetic episode, anesthesia was maintained by administration of sevoflurane in oxygen at 1.0 and 1.5 times the minimum alveolar concentration (MAC). During the other episode, anesthesia was maintained at the same MAC multiples via a reduced concentration of sevoflurane plus an IV infusion of lidocaine. Heart rate, arterial blood pressures, blood gas analyses, and cardiac output were measured during mechanical (controlled) ventilation at both 1.0 and 1.5 MAC for each anesthetic protocol and during spontaneous ventilation at 1 of the 2 MAC multiples. Results—Cardiorespiratory variables did not differ significantly between anesthetic protocols. Blood pressures were highest at 1.0 MAC during spontaneous ventilation and lowest at 1.5 MAC during controlled ventilation for either anesthetic protocol. Cardiac output was significantly higher during 1.0 MAC than during 1.5 MAC for sevoflurane plus lidocaine but was not affected by anesthetic protocol or mode of ventilation. Clinically important hypotension was detected at 1.5 MAC for both anesthetic protocols. Conclusions and Clinical Relevance—Lidocaine infusion did not alter cardiorespiratory variables during anesthesia in horses, provided anesthetic depth was maintained constant. The IV administration of lidocaine to anesthetized nonstimulated horses should be used for reasons other than to improve cardiovascular performance. Severe hypotension can be expected in nonstimulated horses at 1.5 MAC sevoflurane, regardless of whether lidocaine is administered.

Objective: To evaluate the effect of several sedation protocols on glomerular filtration rate (GFR) in cats as measured by use of quantitative renal scintigraphy and to analyze interobserver differences in GFR calculation. Animals: 5 cats (1 sexually intact male, 1 neutered male, and 3 sexually intact females). Procedures: Effects on GFR of 3 sedation protocols commonly used at the Iowa State University College of Veterinary Medicine were evaluated. The protocols were medetomidine (11 μg/kg) and butorphanol tartrate (0.22 mg/kg) administered IM; ketamine hydrochloride (10 mg/kg) and midazolam (0.5 mg/kg) administered IV; and ketamine (10 mg/kg), midazolam (0.5 mg/kg), and acepromazine maleate (0.05 mg/kg) administered IM. Results for the 3 protocols were compared with results of GFR measurements obtained in these same cats without sedation (control protocol). Results: No significant difference between GFR measurements was associated with the 3 sedation protocols, compared with GFR measurements for the control protocol. The greatest mean GFR values were for the medetomidine-butorphanol and ketamine-midazolam protocols. There were no significant differences between observers for calculation of GFR. Conclusions and Clinical Relevance: Results suggested that none of the 3 sedation protocols had significant effects on GFR calculated by use of quantitative renal scintigraphy, compared with results for GFR evaluations performed in the cats when they were not sedated. No significant interobserver error was evident. However, the statistical power of this study was low, and the probability of a type II error was high.