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We previously showed that (+)-tramadol is metabolized in dog liver to (+)-M1 exclusively by CYP2D15 and to (+)-M2 by multiple CYPs, but primarily CYP2B11. However, (+)-M1 and (+)-M2 are further metabolized in dogs to (+)-M5, which is the major metabolite found in dog plasma and urine. In this study, we identified canine CYPs involved in metabolizing (+)-M1 and (+)-M2 using recombinant enzymes, untreated dog liver microsomes (DLMs), inhibitor-treated DLMs, and DLMs from CYP inducer-treated dogs. A canine P-glycoprotein expressing cell line was also used to evaluate whether (+)-tramadol, (+)-M1, (+)-M2, or (+)-M5 are substrates of canine P-glycoprotein, thereby limiting their distribution into the central nervous system. (+)-M5 was largely formed from (+)-M1 by recombinant CYP2C21 with minor contributions from CYP2C41 and CYP2B11. (+)-M5 formation in DLMs from (+)-M1 was potently inhibited by sulfaphenazole (CYP2C inhibitor) and chloramphenicol (CYP2B11 inhibitor) and was greatly increased in DLMs from phenobarbital-treated dogs. (+)-M5 was formed from (+)-M2 predominantly by CYP2D15. (+)-M5 formation from (+)-M1 in DLMs was potently inhibited by quinidine (CYP2D inhibitor) but had only a minor impact from all CYP inducers tested. Intrinsic clearance estimates showed over 50 times higher values for (+)-M5 formation from (+)-M2 compared with (+)-M1 in DLMs. This was largely attributed to the higher enzyme affinity (lower Km) for (+)-M2 compared with (+)-M1 as substrate. (+)-tramadol, (+)-M1, (+)-M2, or (+)-M5 were not p-glycoprotein substrates. This study provides a clearer picture of the role of individual CYPs in the complex metabolism of tramadol in dogs., (© 2018 John Wiley & Sons Ltd.)

Background: Point-of-care analyzers can provide a rapid turnaround time for critical blood test results. Agreement between the Enterprise Point-of-Care (EPOC) and bench-top laboratory analyzers is important to determine the clinical reliability of the EPOC., Objectives: The aim of the study was (1) to evaluate the precision (repeatability) of blood gas values measured by the EPOC and (2) to determine the level of agreement between the EPOC and Nova Critical Care Express (Nova CCX) for the assessment of arterial pH, blood gases, and electrolyte variables in canine and equine blood., Methods: Arterial blood samples from dogs were analyzed on the EPOC and Nova CCX analyzers to determine precision and agreement of pH, PaCO 2 , PaO 2 , and HCT. The same analytes plus Na + , K - , and Cl - were analyzed for agreement using equine blood. Statistical analyses included assessment of precision using the coefficient of variation (CV%), and agreement using the Deming regression, Pearson correlation, and Bland-Altman plots., Results: Both analyzers provided precise results of pH, PaCO 2 , PaO 2, and HCT, meeting CV% quality requirement values. In both species, Deming regression results were acceptable and correlation values were above 0.93 for arterial pH and blood gases, but lower for sodium and chloride. Bland-Altman plots demonstrated varying degrees of bias, but good agreement between the 2 analyzers was seen when arterial blood gases and electrolytes were measured, except for PaCO 2 and Cl -. CONCLUSION: The EPOC analyzer provides consistent, reliable results for canine arterial blood gas values and for equine arterial blood gas and electrolyte values. Cl - results could be acceptable with the application of a correction factor, but the PaCO 2 results were more variable., (© 2018 American Society for Veterinary Clinical Pathology.)

Objective: To determine the intraoperative and postoperative analgesic efficacy of intratesticular or epidural injection of analgesics for dogs undergoing castration., Design: Randomized controlled trial., Animals: 51 healthy male dogs., Procedures: Dogs were assigned to a control group that received analgesics systemically (hydromorphone [0.1 mg/kg {0.045 mg/lb}, IM] and carprofen [4.4 mg/kg {2.0 mg/lb}, SC]; n = 17), an epidural treatment group that received analgesics systemically and morphine (0.1 mg/kg) epidurally (17), or an intratesticular treatment group that received analgesics systemically and bupivacaine (0.5 mg/kg [0.23 mg/lb]/testis) intratesticularly (17). Dogs were anesthetized and castrated by veterinary students. Responses to surgical stimulation were monitored intraoperatively, and treatments were administered as required. Pain scores were assigned via a modified Glasgow composite pain scale after surgery. Serum cortisol concentrations were determined at various times. Rescue analgesia included fentanyl (intraoperatively) and hydromorphone (postoperatively)., Results: Compared with control dogs, dogs in the intratesticular bupivacaine and epidural morphine treatment groups received significantly fewer doses of fentanyl intraoperatively (11, 1, and 5 doses, respectively) and hydromorphone postoperatively (14, 7, and 3 doses, respectively) and had significantly lower postoperative pain scores (mean ± SEM score at first assessment time, 71 ± 0.5, 4.8 ± 0.2, and 4.5 ± 0.4, respectively). At 15 minutes after removal of the testes, serum cortisol concentrations were significantly higher than they were immediately prior to surgery for all groups and values for the intratesticular bupivacaine treatment group were significantly lower versus the other 2 groups., Conclusions and Clinical Relevance: Intratesticular or epidural injection of analgesics improved perioperative analgesia for dogs undergoing castration.

Objective: To compare effects of isoflurane and sevoflurane on intracranial pressure and cardiovascular variables at 1.0, 1.5, and 2.0 times the minimum alveolar concentration (MAC) in mechanically ventilated normocapnic dogs., Animals: 6 healthy male Beagles., Procedures: The individual MAC was determined for each agent with an electrical stimulus. After a minimum of 1 week, anesthetic induction by use of a mask with one of the inhalation anesthetics selected randomly was followed by mechanical ventilation and instrumentation for measurement of intracranial pressure and cardiovascular variables. Heart rate; systolic, mean, and diastolic arterial blood pressures; central venous pressure; mean pulmonary arterial pressure; pulmonary artery occlusion pressure; cardiac output; intracranial pressure (ICP); core body temperature; end-tidal inhalation anesthetic and carbon dioxide concentration; and arterial blood gas values were measured after attaining equilibrium at 1.0, 1.5, and 2.0 MAC of each inhalation anesthetic. Cardiac index, systemic vascular resistance, pulmonary vascular resistance, and cerebral perfusion pressure (CPP) were calculated., Results: Mean ICP did not differ within and between anesthetics at any MAC. Compared with equipotent concentrations of isoflurane, the CPP and mean values for systolic, mean, and diastolic arterial blood pressures were increased at 2.0 MAC for sevoflurane, whereas mean values for mean and diastolic arterial blood pressures and systemic vascular resistance were increased at 1.5 MAC for sevoflurane., Conclusions and Clinical Relevance: Although ICP was similar in healthy normocapnic dogs, CPP was better maintained during 2.0 MAC for sevoflurane, compared with isoflurane.

The objective of this study was to evaluate glomerular filtration rate (GFR) and the cardiovascular effects of the combination of tepoxalin (TPX) and medetomidine (MED) in dogs. Six healthy dogs of either sex (5 males and 1 female), aged 2.5 ± 2.2 years and weighing 14.7 ± 4.4 kg, were studied. Each dog received four randomized treatments with a minimum of 1 week between treatments: no medication as the control group (C); MED (750 μg/m(2), intravenously [IV]); TPX (10 mg/kg orally for 3 days); and MT (TPX 10 mg/kg orally for 3 days plus MED 750 μg/m(2), IV). Iohexol (300 mg iodine/kg, IV) was injected in all dogs in each treatment as an indicator of GFR. Blood samples for serum iohexol clearance analysis were collected before and 1, 2, 5, 10, 15, 20, 60, 120, 240 and 360 min after the iohexol administration. Rectal temperature, heart rate, respiratory rate and direct arterial pressure (AP) were obtained before and 5, 10, 15, 20, 60, 120, 240 and 360 min after the iohexol injection. GFR did not differ between treatments. Heart rate was significantly lower in the MED and MT groups than in C or TPX. Mean AP was significantly higher with MT than TPX, but only at 5 min after the iohexol injection. TPX, MED and the combination of these two drugs do not alter GFR. The combination has minimal effect on cardiovascular variables at these doses in healthy dogs.

Objective: To evaluate and compare hemostatic variables and clinical bleeding following the administration of 6% hetastarch (600/0.75) or lactated Ringer's solution (LRS) to dogs anesthetized for orthopedic surgery., Study Design: Randomized blinded prospective study., Animals: Fourteen, healthy adult mixed-breed hound dogs of either sex, aged 11-13 months, and weighing 20.8±1.2 kg., Methods: The dogs were randomly assigned to receive a 10 mL kg(-1) intravenous (i.v.) bolus of either 6% hetastarch (600/0.75) or LRS over 20 minutes followed by a maintenance infusion of LRS (10 mL kg(-1)  hour(-1)) during anesthesia. Before (Baseline) and at 1 and 24 hours after bolus administration, packed cell volume (PCV), total protein concentration (TP), prothrombin time (PT), activated partial thromboplastin time (APTT), von Willebrand's factor antigen concentration (vWF:Ag), factor VIII coagulant activity (F VIII:C), platelet count, platelet aggregation, colloid osmotic pressure (COP) and buccal mucosal bleeding time (BMBT) were measured. In addition a surgeon who was blinded to the treatments assessed bleeding from the incision site during the procedure and at 1 and 24 hours after the bolus administration., Results: Following hetastarch or LRS administration, the PCV and TP decreased significantly 1-hour post-infusion. APTT did not change significantly compared to baseline in either treatment group, but the PT was significantly longer at 1-hour post-infusion than at 24 hours in both groups. No significant change was detected for vWF:Ag, FVIII:C, platelet aggregation or clinical bleeding in either group. The BMBT increased while platelet count decreased significantly at 1-hour post-infusion in both groups. The COP decreased significantly in both treatment groups 1-hour post-infusion but was significantly higher 1-hour post-infusion in the hetastarch group compared to the LRS group., Conclusions and Clinical Relevance: At the doses administered, both hetastarch and LRS can alter hemostatic variables in healthy dogs. However, in these dogs undergoing orthopedic surgery, neither fluid was associated with increased clinical bleeding., (© 2011 The Authors. Veterinary Anaesthesia and Analgesia © 2011 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesiologists.)