Validity and Repeatability Characteristics of a Non-Invasive, Infrared-Based Method Estimating Plasma Indocyanine Green Decay in Healthy Dogs.

Plasma clearance of indocyanine green (ICG-CL) is an invasive method to evaluate liver dysfunction. We aimed to investigate the practicality of a noninvasive, transcutaneous, infrared-based method estimating the disappearance rate of indocyanine green (ICG-PDR). In a randomized, cross-over study, both ICG-CL and ICG-PDR were determined in eight healthy dogs while conscious and when sedated with medetomidine and medetomidine-vatinoxan. ICG-PDR was further repeated in six of the dogs to assess its repeatability. Differences were tested with repeated-measures analysis of variance and post hoc t-tests with Bonferroni corrections, while associations were evaluated by both Spearman and Pearson correlation analyses. Furthermore, repeatability was assessed by examining calculated coefficients of variation (CV). A significant decrease in ICG-CL was observed in dogs sedated with medetomidine, while no difference between conscious and sedated states was detected with ICG-PDR. Overall, correlations between ICG-CL and ICG-PDR were poor, as was the intrasubject repeatability of ICG-PDR in conscious dogs with CV consistently above 20%. While some of the results may be explained by poor signal quality for the non-invasive method, we conclude that in healthy dogs ICG-PDR performed poorly.

Cardiovascular effects of dobutamine, norepinephrine and phenylephrine in isoflurane-anaesthetized dogs administered dexmedetomidine-vatinoxan.

OBJECTIVE: To determine whether dobutamine, norepinephrine or phenylephrine infusions alleviate hypotension in isoflurane-anaesthetized dogs administered dexmedetomidine with vatinoxan. STUDY DESIGN: Balanced, randomized crossover trial. ANIMALS: A total of eight healthy Beagle dogs. METHODS: Each dog was anaesthetized with isoflurane (end-tidal isoflurane 1.3%) and five treatments: dexmedetomidine hydrochloride (2.5 µg kg-1) bolus followed by 0.9% saline infusion (DEX-S); dexmedetomidine and vatinoxan hydrochloride (100 µg kg-1) bolus followed by an infusion of 0.9% saline (DEX-VAT-S), dobutamine (DEX-VAT-D), norepinephrine (DEX-VAT-N) or phenylephrine (DEX-VAT-P). The dexmedetomidine and vatinoxan boluses were administered at baseline (T0) and the treatment infusion was started after 15 minutes (T15) if mean arterial pressure (MAP) was < 90 mmHg. The treatment infusion rate was adjusted every 5 minutes as required. Systemic haemodynamics were recorded at T0 and 10 (T10) and 45 (T45) minutes. A repeated measures analysis of covariance model was used. RESULTS: Most dogs had a MAP < 70 mmHg at T0 before treatment. Treatments DEX-S and DEX-VAT all significantly increased MAP at T10, but systemic vascular resistance index (SVRI) was significantly higher and cardiac index (CI) lower after DEX-S than after DEX-VAT. CI did not significantly differ between DEX-S and DEX-VAT-S at T45, while SVRI remained higher with DEX-S. Normotension was achieved by all vasoactive infusions in every dog, whereas MAP was below baseline with DEX-VAT-S, and higher than baseline with DEX-S at T45. Median infusion rates were 3.75, 0.25 and 0.5 µg kg-1 minute-1 for dobutamine, norepinephrine and phenylephrine, respectively. Dobutamine and norepinephrine increased CI (mean ± standard deviation, 3.35 ± 0.70 and 3.97 ± 1.24 L minute-1 m-2, respectively) and decreased SVRI, whereas phenylephrine had the opposite effect (CI 2.13 ± 0.45 L minute-1 m-2). CONCLUSIONS AND CLINICAL RELEVANCE: Hypotension in isoflurane-anaesthetized dogs administered dexmedetomidine and vatinoxan can be treated with either dobutamine or norepinephrine.

Effects of intramuscular vatinoxan (MK-467), co-administered with medetomidine and butorphanol, on cardiopulmonary and anaesthetic effects of intravenous ketamine in dogs.

OBJECTIVE: To investigate the impact of intramuscular (IM) co-administration of the peripheral α2-adrenoceptor agonist vatinoxan (MK-467) with medetomidine and butorphanol prior to intravenous (IV) ketamine on the cardiopulmonary and anaesthetic effects in dogs, followed by atipamezole reversal. STUDY DESIGN: Randomized, masked crossover study. ANIMALS: A total of eight purpose-bred Beagle dogs aged 3 years. METHODS: Each dog was instrumented and administered two treatments 2 weeks apart: medetomidine (20 µg kg-1) and butorphanol (100 µg kg-1) premedication with vatinoxan (500 µg kg-1; treatment MVB) or without vatinoxan (treatment MB) IM 20 minutes before IV ketamine (4 mg kg-1). Atipamezole (100 µg kg-1) was administered IM 60 minutes after ketamine. Heart rate (HR), mean arterial (MAP) and central venous (CVP) pressures and cardiac output (CO) were measured; cardiac (CI) and systemic vascular resistance (SVRI) indices were calculated before and 10 minutes after MVB or MB, and 10, 25, 40, 55, 70 and 100 minutes after ketamine. Data were analysed with repeated measures analysis of covariance models. A p-value <0.05 was considered statistically significant. Sedation, induction, intubation and recovery scores were assessed. RESULTS: At most time points, HR and CI were significantly higher, and SVRI and CVP significantly lower with MVB than with MB. With both treatments, SVRI and MAP decreased after ketamine, whereas HR and CI increased. MAP was significantly lower with MVB than with MB; mild hypotension (57-59 mmHg) was recorded in two dogs with MVB prior to atipamezole administration. Sedation, induction, intubation and recovery scores were not different between treatments, but intolerance to the endotracheal tube was observed earlier with MVB. CONCLUSIONS AND CLINICAL RELEVANCE: Haemodynamic performance was improved by vatinoxan co-administration with medetomidine-butorphanol, before and after ketamine administration. However, vatinoxan was associated with mild hypotension after ketamine with the dose used in this study. Vatinoxan shortened the duration of anaesthesia.

Investigation of the effects of vatinoxan on somatic and visceral antinociceptive efficacy of medetomidine in dogs.

OBJECTIVE: To determine whether concurrent vatinoxan administration affects the antinociceptive efficacy of medetomidine in dogs at doses that provide circulating dexmedetomidine concentrations similar to those produced by medetomidine alone. ANIMALS: 8 healthy Beagles. PROCEDURES: Dogs received 3 IV treatments in a randomized crossover-design trial with a 2-week washout period between experiments (medetomidine [20 µg/kg], medetomidine [20 µg/kg] and vatinoxan [400 µg/kg], and medetomidine [40 µg/kg] and vatinoxan [800 µg/kg]; M20, M20V400, and M40V800, respectively). Sedation, visceral and somatic nociception, and plasma drug concentrations were assessed. Somatic and visceral nociception measurements and sedation scores were compared among treatments and over time. Sedation, visceral antinociception, and somatic antinociception effects of M20V400 and M40V800 were analyzed for noninferiority to effects of M20, and plasma drug concentration data were assessed for equivalence between treatments. RESULTS: Plasma dexmedetomidine concentrations after administration of M20 and M40V800 were equivalent. Sedation scores, visceral nociception measurements, and somatic nociception measurements did not differ significantly among treatments within time points. Overall sedative effects of M20V400 and M40V800 and visceral antinociceptive effects of M40V800 were noninferior to those produced by M20. Somatic antinociception effects of M20V400 at 10 minutes and M40V800 at 10 and 55 minutes after injection were noninferior to those produced by M20. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested coadministration with vatinoxan did not substantially diminish visceral antinociceptive effects of medetomidine when plasma dexmedetomidine concentrations were equivalent to those produced by medetomidine alone. For somatic antinociception, noninferiority of treatments was detected at some time points.

Pharmacokinetics of dexmedetomidine during administration of vatinoxan in male neutered cats anesthetized with isoflurane.

Dexmedetomidine is an alpha-2 adrenoceptor agonist, and vatinoxan is an alpha-2 antagonist believed to poorly cross the blood-brain barrier in cats. Dexmedetomidine-vatinoxan combinations are of interest in anesthetized cats because the anesthetic sparing effect of dexmedetomidine may be preserved while vatinoxan attenuates the adverse cardiovascular effects of dexmedetomidine. The aim of this study was to characterize the pharmacokinetics of dexmedetomidine in cats during administration of isoflurane and vatinoxan. Six healthy adult male castrated cats were anesthetized with isoflurane in oxygen. Vatinoxan was administered using a target-controlled infusion system intended to maintain a plasma concentration of 4 µg/ml. Dexmedetomidine, 35 µg/kg was administered intravenously over 5 min. Plasma dexmedetomidine and vatinoxan concentrations were measured at selected time points ranging from prior to 8 hr after dexmedetomidine administration using liquid chromatography/tandem mass spectrometry. Compartment models were fitted to the time-concentration data using nonlinear mixed-effect modeling. A three-compartment model best fitted the data. Typical value (% interindividual variability) for the three-compartment volumes (ml/kg), the metabolic clearance and the two intercompartment distribution clearances (ml min-1 kg-1 ) were 168 (259), 318 (35), 1,425 (18), 12.4 (31), 39.1 (18), and 29.6 (17), respectively. Mean ± standard deviation plasma vatinoxan concentration was 2.6 ± 0.6 µg/ml.

Pharmacokinetics of vatinoxan in male neutered cats anesthetized with isoflurane.

OBJECTIVE: To characterize the pharmacokinetics of vatinoxan in isoflurane-anesthetized cats. STUDY DESIGN: Prospective experimental study. ANIMALS: A group of six adult healthy male neutered cats. METHODS: Cats were anesthetized using isoflurane in oxygen. Venous catheters were placed to administer the drug and sample blood. Vatinoxan, 1 mg kg-1, was administered intravenously over 5 minutes. Blood was sampled before and at various times during and up to 8 hours after vatinoxan administration. Plasma vatinoxan concentration was measured using liquid chromatography/tandem mass spectrometry. Compartment models were fitted to the time-concentration data using population methods and nonlinear mixed effect modeling. RESULTS: A three-compartment model best fitted the data. Typical value (% interindividual variability) for the three volumes (mL kg-1), the metabolic clearance and two distribution clearances (mL minute-1 kg-1) were 34 (55), 151 (35), 306 (18), 2.3 (34), 42.6 (25) and 5.6 (0), respectively. Hypotension increased the second distribution clearance to 10.6. CONCLUSION AND CLINICAL RELEVANCE: The pharmacokinetics of vatinoxan in anesthetized cats were characterized by a small volume of distribution and a low clearance. An intravenous bolus of 100 µg kg-1 of vatinoxan followed by constant rate infusions of 55 µg kg-1 minute-1 for 20 minutes, then 22 µg kg-1 minute-1 for 60 minutes and finally 10 µg kg-1 minute-1 for the remainder of the infusion time is expected to maintain the plasma concentration within 90%-110% of the plasma vatinoxan concentration previously shown to attenuate the cardiovascular effects of dexmedetomidine (25 µg kg-1) in conscious cats.

Concentrations of medetomidine enantiomers and vatinoxan, an α2-adrenoceptor antagonist, in plasma and central nervous tissue after intravenous coadministration in dogs.

OBJECTIVE: To quantify the peripheral selectivity of vatinoxan (L-659,066, MK-467) in dogs by comparing the concentrations of vatinoxan, dexmedetomidine and levomedetomidine in plasma and central nervous system (CNS) tissue after intravenous (IV) coadministration of vatinoxan and medetomidine. STUDY DESIGN: Experimental, observational study. ANIMALS: A group of six healthy, purpose-bred Beagle dogs (four females and two males) aged 6.5 ± 0.1 years (mean ± standard deviation). METHODS: All dogs were administered a combination of medetomidine (40 µg kg-1) and vatinoxan (800 µg kg-1) as IV bolus. After 20 minutes, the dogs were euthanized with an IV overdose of pentobarbital (140 mg kg-1) and both venous plasma and CNS tissues (brain, cervical and lumbar spinal cord) were harvested. Concentrations of dexmedetomidine, levomedetomidine and vatinoxan in all samples were quantified by liquid chromatography-tandem mass spectrometry and data were analyzed with nonparametric tests with post hoc corrections where appropriate. RESULTS: All dogs became deeply sedated after the treatment. The CNS-to-plasma ratio of vatinoxan concentration was approximately 1:50, whereas the concentrations of dexmedetomidine and levomedetomidine in the CNS were three- to seven-fold of those in plasma. CONCLUSIONS AND CLINICAL RELEVANCE: With the doses studied, these results confirm the peripheral selectivity of vatinoxan in dogs, when coadministered IV with medetomidine. Thus, it is likely that vatinoxan preferentially antagonizes α2-adrenoceptors outside the CNS.

Cardiovascular and sedation reversal effects of intramuscular administration of atipamezole in dogs treated with medetomidine hydrochloride with or without the peripheral α2-adrenoceptor antagonist vatinoxan hydrochloride.

OBJECTIVE: To investigate the cardiovascular and sedation reversal effects of IM administration of atipamezole (AA) in dogs treated with medetomidine hydrochloride (MED) or MED and vatinoxan (MK-467). ANIMALS: 8 purpose-bred, 2-year-old Beagles. PROCEDURES: A randomized, blinded, crossover study was performed in which each dog received 2 IM treatments at a ≥ 2-week interval as follows: injection of MED (20 µg/kg) or MED mixed with 400 µg of vatinoxan/kg (MEDVAT) 30 minutes before AA (100 µg/kg). Sedation score, heart rate, mean arterial and central venous blood pressures, and cardiac output were recorded before and at various time points (up to 90 minutes) after AA. Cardiac and systemic vascular resistance indices were calculated. Venous blood samples were collected at intervals until 210 minutes after AA for drug concentration analysis. RESULTS: Heart rate following MED administration was lower, compared with findings after MEDVAT administration, prior to and at ≥ 10 minutes after AA. Mean arterial blood pressure was lower with MEDVAT than with MED at 5 minutes after AA, when its nadir was detected. Overall, cardiac index was higher and systemic vascular resistance index lower, indicating better cardiovascular function, in MEDVAT-atipamezole-treated dogs. Plasma dexmedetomidine concentrations were lower and recoveries from sedation were faster and more complete after MEDVAT treatment with AA than after MED treatment with AA. CONCLUSIONS AND CLINICAL RELEVANCE: Atipamezole failed to restore heart rate and cardiac index in medetomidine-sedated dogs, and relapses into sedation were observed. Coadministration of vatinoxan with MED helped to maintain hemodynamic function and hastened the recovery from sedation after AA in dogs.

Cardiopulmonary effects of dexmedetomidine, with and without vatinoxan, in isoflurane-anesthetized cats.

OBJECTIVE: To characterize the cardiopulmonary effects of dexmedetomidine, with or without vatinoxan, in isoflurane-anesthetized cats. STUDY DESIGN: Randomized, crossover experimental study. ANIMALS: A group of six adult healthy male neutered cats. METHODS: Cats were instrumented during anesthesia with isoflurane in oxygen. Isoflurane end-tidal concentration was set to 1.25 minimum alveolar concentration (MAC). Dexmedetomidine was administered using a target-controlled infusion system to achieve and maintain 10 target plasma concentrations ranging from 0 to 40 ng mL-1. Furthermore, vatinoxan or an equivalent volume of saline was administered using a target-controlled infusion system to achieve and maintain a target plasma concentration of 4 µg mL-1. Isoflurane concentration was adjusted after each change in dexmedetomidine concentration to maintain a concentration equivalent to 1.25 MAC. Heart rate (HR), arterial blood pressure, central venous pressure (CVP), pulmonary artery pressure (PAP), pulmonary artery occlusion pressure (PAOP), body temperature, cardiac output, arterial and mixed-venous blood gas and pH and drug concentrations were measured. Additional variables were calculated from the measurements. RESULTS: Dexmedetomidine alone resulted in decreased HR, cardiac index, stroke index and oxygen delivery, and increased systolic, mean (MAP) and diastolic arterial pressure, CVP, PAP, PAOP, systemic vascular resistance index, rate-pressure product, left ventricular stroke work index and oxygen extraction ratio. Vatinoxan resulted in severe hypotension at target plasma dexmedetomidine concentrations <10 ng mL-1. Vatinoxan attenuated the cardiovascular effects of dexmedetomidine at the 10 and 20 ng mL-1 targets, but MAP could be maintained above 60 mmHg only when isoflurane concentration was <1.25 MAC. Less improvement in cardiovascular function was seen with vatinoxan at the 40 ng mL-1 target plasma dexmedetomidine concentration. CONCLUSIONS AND CLINICAL RELEVANCE: Vatinoxan, at the plasma concentration maintained in this study, attenuated the cardiovascular effects of dexmedetomidine in isoflurane-anesthetized cats. However, its administration resulted in hypotension, which may limit its clinical usefulness.

Effect of α2-adrenoceptor antagonism on the minimum alveolar concentration of isoflurane in cats.

OBJECTIVE: To characterize the effect of α2-adrenoceptor antagonism on the minimum alveolar concentration of isoflurane (MACISO) in cats. STUDY DESIGN: Prospective experimental study. ANIMALS: A group of five healthy adult male neutered cats. METHODS: Cats were anesthetized with isoflurane in oxygen and instrumented. MACISO was determined in duplicate in five cats, before and during administration of atipamezole (250 µg kg-1 followed by 250 µg kg-1 hour-1) using the bracketing technique and tail clamping. Estimates of MACISO obtained before and during administration of atipamezole were compared using a two-tailed paired t test. RESULTS: MACISO during atipamezole administration (mean ± standard deviation 2.73% ± 0.07%) was significantly larger than before atipamezole administration (1.95% ± 0.13%; p < 0.0001). CONCLUSION AND CLINICAL RELEVANCE: The role of α2-adrenoceptors in inhaled anesthetic-induced immobility may be larger than previously thought. Antagonism of an α2-adrenoceptor agonist during inhalation anesthesia may result in an increase in MAC disproportionate to the MAC reduction induced by the agonist.

Effects of dexmedetomidine, with or without vatinoxan (MK-467), on minimum alveolar concentration of isoflurane in cats.

OBJECTIVE: To characterize the effects of dexmedetomidine, with or without vatinoxan, on the minimum alveolar concentration of isoflurane (MACISO) in cats. STUDY DESIGN: Randomized crossover experimental study. ANIMALS: A group of six adult healthy male neutered cats. METHODS: Cats were anesthetized with isoflurane in oxygen and instrumented. Dexmedetomidine was administered using a target-controlled infusion system to achieve 10 target plasma concentrations ranging from 0 to 40 ng mL-1. Additionally, vatinoxan or an equivalent volume of saline was administered using a target-controlled infusion system to achieve a target plasma concentration of 4 µg mL-1. Pulse rate (PR), respiratory rate, systolic arterial pressure (SAP), hemoglobin oxygen saturation, body temperature, end-tidal partial pressure of carbon dioxide and drug concentrations were measured. MACISO was determined at each target plasma dexmedetomidine concentration using the bracketing method and the tail clamp technique. Pharmacodynamic models were fitted to the plasma dexmedetomidine concentration-MACISO. Pharmacodynamic parameters were tested for equivalence, and if rejected, for difference. RESULTS: Dexmedetomidine alone decreased MACISO in a plasma concentration-dependent manner. Maximum reduction was 77 ± 4%; the dexmedetomidine concentration producing 50% of the maximum decrease (IC50) was 0.77 ng mL-1. Vatinoxan increased MACISO in the absence of dexmedetomidine, decreased the potency of dexmedetomidine for its MACISO-reducing effect (IC50 = 12 ng mL-1) and lessened the maximum MACISO reduction (60 ± 14%). PR decreased less and SAP increased less when dexmedetomidine was administered with vatinoxan compared with saline. CONCLUSION AND CLINICAL RELEVANCE: Vatinoxan altered the effect of dexmedetomidine on MACISO. A high plasma dexmedetomidine concentration in the presence of vatinoxan resulted in a large decrease in MACISO, with attenuation of dexmedetomidine-induced cardiovascular effects. The vatinoxan-dexmedetomidine combination may provide clinical benefits in isoflurane-anesthetized cats.

Effects of the peripherally acting α2-adrenoceptor antagonist MK-467 on cardiopulmonary function in sheep sedated by intramuscular administration of medetomidine and ketamine and reversed by intramuscular administration of atipamezole.

OBJECTIVE To evaluate effects of the peripherally acting α2-adrenoceptor antagonist MK-467 on cardiopulmonary function in sheep sedated with medetomidine and ketamine. ANIMALS 9 healthy adult female sheep. PROCEDURES Each animal received an IM injection of a combination of medetomidine (30 µg/kg) and ketamine (1 mg/kg; Med-Ket) alone and Med-Ket and 3 doses of MK-467 (150, 300, and 600 µg/kg) in a randomized blinded 4-way crossover study. Atipamezole (150 µg/kg, IM) was administered 60 minutes later to reverse sedation. Cardiopulmonary variables and sedation scores were recorded, and drug concentrations in plasma were analyzed. Data were analyzed with a repeated-measures ANCOVA and 1-way ANOVA. Reference limits for the equivalence of sedation scores were set at 0.8 and 1.25. RESULTS Heart rate, cardiac output, and Pao2 decreased and mean arterial blood pressure, central venous pressure, and systemic vascular resistance increased after Med-Ket alone. Administration of MK-467 significantly alleviated these effects, except for the decrease in cardiac output. After sedation was reversed with atipamezole, no significant differences were detected in cardiopulmonary variables among the treatments. Administration of MK-467 did not significantly alter plasma concentrations of medetomidine, ketamine, norketamine, or atipamezole. Sedation as determined on the basis of overall sedation scores was similar among treatments. CONCLUSIONS AND CLINICAL RELEVANCE Concurrent administration of MK-467 alleviated cardiopulmonary effects in sheep sedated with Med-Ket without affecting sedation or reversal with atipamezole.

Hemodynamic effects of MK-467 following intravenous administration to isoflurane-anesthetized cats concurrently receiving dexmedetomidine.

OBJECTIVE To evaluate the efficacy of each of 3 incremental doses of MK-467 for alleviation of dexmedetomidine-induced hemodynamic depression in isoflurane-anesthetized cats. ANIMALS 6 healthy adult domestic shorthair cats. PROCEDURES Each cat was anesthetized with isoflurane and received a target-controlled infusion of dexmedetomidine estimated to maintain the plasma dexmedetomidine concentration at 10 ng/mL throughout the experiment. Heart rate (HR) and direct arterial pressures were measured at baseline (isoflurane administration only), during dexmedetomidine infusion, and before and after IV administration of each of 3 serially increasing doses (15, 30, and 60 µg/kg) of MK-467. Cardiac index (CI) and systemic vascular resistance (SVR) were recorded at baseline, during dexmedetomidine infusion, and at the mean arterial pressure nadir after administration of the 30- and 60-µg/kg doses of MK-467. RESULTS Compared with baseline values, the dexmedetomidine infusion significantly decreased HR and increased arterial pressures. Each dose of MK-467 caused a significant decrease in arterial pressures and a significant, albeit clinically irrelevant, increase in HR (≤ 10%). Following administration of the 30- and 60-µg/kg doses of MK-467, all cats developed clinical hypotension (mean arterial pressure, < 60 mm Hg) even though CI and SVR returned to baseline values. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated administration of small doses of MK-467 to isoflurane-anesthetized cats receiving dexmedetomidine restored CI and SVR, but caused a substantial decrease in arterial pressures and only a marginal increase in HR. Therefore, caution should be used when MK-467 is administered to alleviate dexmedetomidine-induced hemodynamic depression in isoflurane-anesthetized cats.

Peripheral α2-adrenoceptor antagonism affects the absorption of intramuscularly coadministered drugs.

OBJECTIVE: We determined the possible effects of a peripherally acting α2-adrenoceptor antagonist, MK-467, on the absorption of intramuscularly (IM) coadministered medetomidine, butorphanol and midazolam. STUDY DESIGN: Randomized, experimental, blinded crossover study. ANIMALS: Six healthy Beagle dogs. METHODS: Two IM treatments were administered: 1) medetomidine hydrochloride (20 µg kg-1) + butorphanol (100 µg kg-1) + midazolam (200 µg kg-1; MBM) and 2) MBM + MK-467 hydrochloride (500 µg kg-1; MBM-MK), mixed in a syringe. Heart rate was recorded at regular intervals. Sedation was assessed with visual analog scales (0-100 mm). Drug concentrations in plasma were analyzed with liquid chromatography-tandem mass spectrometry, with chiral separation of dex- and levomedetomidine. Maximum drug concentrations in plasma (Cmax) and time to Cmax (Tmax) were determined. Paired t-tests, with Bonferroni correction when appropriate, were used for comparisons between the treatments. RESULTS: Data from five dogs were analyzed. Heart rate was significantly higher from 20 to 90 minutes after MBM-MK. The Tmax values for midazolam and levomedetomidine (mean ± standard deviation) were approximately halved with coadministration of MK-467, from 23 ± 9 to 11 ± 6 minutes (p = 0.049) for midazolam and from 32 ± 15 to 18 ± 6 minutes for levomedetomidine (p = 0.036), respectively. CONCLUSIONS AND CLINICAL RELEVANCE: MK-467 accelerated the absorption of IM coadministered drugs. This is clinically relevant as it may hasten the onset of peak sedative effects.

Aberrant migration and surgical removal of a heartworm (Dirofilaria immitis) from the femoral artery of a cat.

A cat was evaluated for an acute-onset of right pelvic limb paresis. Thoracic radiographs revealed normal cardiac size and tortuous pulmonary arteries. Abdominal ultrasound identified a heartworm (HW) extending from the caudal abdominal aorta into the right external iliac artery and right femoral artery. The cat was HW-antigen positive. Echocardiography revealed a HW within the right branch of the main pulmonary artery and evidence of pulmonary hypertension. An agitated-saline contrast echocardiogram revealed a small right to left intracardiac shunt at the level of the atria. Surgical removal of the HW was performed with no substantial postoperative complications. There was return of blood flow and improved motor function to the limb. The cat remains mildly paretic on the affected limb with no other clinical signs.

Hemodynamic effects of low-dose atipamezole in isoflurane-anesthetized cats receiving an infusion of dexmedetomidine.

Objectives The objective of this study was to evaluate the cardiovascular effects of low-dose atipamezole administered intravenously to isoflurane-anesthetized cats receiving dexmedetomidine. We hypothesized that atipamezole would increase heart rate (HR) and reduce arterial blood pressure in isoflurane-anesthetized cats receiving dexmedetomidine. Methods Six healthy adult domestic shorthair cats were anesthetized with isoflurane and instrumented for direct arterial pressures and cardiac output (CO) measurements. The cats received a target-controlled infusion of dexmedetomidine (target plasma concentration 10 ng/ml) for 30 mins before administration of atipamezole. Two sequential doses of atipamezole (15 and 30 µg/kg IV) were administered at least 20 mins apart, during dexmedetomidine administration. The effects of dexmedetomidine and each dose of atipamezole on HR, mean arterial blood pressure (MAP), CO and systemic vascular resistance (SVR) were documented. Results Dexmedetomidine reduced the HR by 22%, increased MAP by 78% (both P ⩽0.01), decreased CO by 48% and increased SVR by 58% (both P ⩽0.0003). Administration of atipamezole 15 and 30 µg/kg intravenously increased HR by 8% ( P = 0.006) and 4% ( P = 0.1), respectively. MAP decreased by 39% and 47%, respectively (both P ⩽0.004). Atipamezole 30 µg/kg returned CO and SVR to baseline values. Conclusions and relevance Low doses of atipamezole (15 and 30 µg/kg) administered intravenously to anesthetized cats decreased arterial blood pressure with only marginal increases in HR. Atipamezole 30 µg/kg restored CO and SVR to baseline values before dexmedetomidine administration.

Hemodynamic effects of dexmedetomidine, with and without MK-467, following intramuscular administration in cats anesthetized with isoflurane.

OBJECTIVE: To characterize the hemodynamic effects of dexmedetomidine, with or without MK-467, following intramuscular (IM) administration in cats. STUDY DESIGN: Randomized, crossover, experimental study. ANIMALS: Six healthy adult male castrated purpose-bred cats. METHODS: Cats were anesthetized with isoflurane in oxygen and instrumented. Cats were administered dexmedetomidine (25 µg kg-1), with (DM) or without (D) MK-467 (600 µg kg-1), IM in the epaxial muscles. Cardiovascular variables, respiratory variables, temperature, and arterial and mixed-venous pH, blood gases and electrolytes were measured prior to drug administration and at various time points for 6 hours thereafter, during anesthesia with isoflurane. Additional variables were calculated from the measurements, using standard equations. Results were analyzed with a two-way repeated-measures analysis of variance, followed by Dunnett's and paired t tests where appropriate. RESULTS: Dexmedetomidine resulted in a significant decrease in cardiac index (CI) and significant increases in mean arterial pressure (MAP) and systemic vascular resistance index (SVRI). The addition of MK-467 failed to prevent most of the early cardiovascular effects of dexmedetomidine, but the duration of systemic vasoconstriction was shorter and CI did not decrease. The lowest and highest post-treatment values in each treatment were 0.1 ± 0.03 and 0.13 ± 0.03 L minute-1 BW-0.67 (D) versus 0.14 ± 0.01 and 0.19 ± 0.03 L minute-1 BW-0.67 (DM) for CI, 87 ± 13 and 181 ± 21 mmHg (D) versus 70 ± 11 and 153 ± 18 mmHg (DM) for MAP and 58,948 ± 17,754 and 119,432 ± 40,423 dynes second cm-5 BW-0.67 (D) versus 25,870 ± 3782 and 76,498 ± 17,258 dynes second cm-5 BW-0.67 (DM) for SVRI, respectively. CONCLUSION AND CLINICAL RELEVANCE: IM coadministration of MK-467 and dexmedetomidine in isoflurane-anesthetized cats shortened dexmedetomidine-induced cardiovascular effects. This drug combination may be useful in cats in which longer-lasting hypertension and hemodynamic depression is of concern.

The impact of MK-467 on sedation, heart rate and arterial blood pressure after intramuscular coadministration with dexmedetomidine in conscious cats.

OBJECTIVE: To study the effects of MK-467, a peripheral α2-adrenoceptor antagonist, on sedation, heart rate and blood pressure after intramuscular (IM) coadministration with 25 µg kg-1 of dexmedetomidine in cats. STUDY DESIGN: Prospective, randomized, controlled, blinded, cross-over, experimental study. ANIMALS: A total of eight healthy, adult, neutered male cats. METHODS: Cats were administered five IM treatments at least 2 weeks apart, consisting of dexmedetomidine 25 µg kg-1 (D25), MK-467 600 µg kg-1 (M600) and D25 combined with 300, 600 and 1200 µg kg-1 of MK-467 (D25M300, D25M600 and D25M1200, respectively). Heart rate and direct arterial blood pressure were recorded via telemetry and sedation assessed prior to treatments and at intervals for 8 hours thereafter. RESULTS: Heart rate decreased significantly after all treatments with dexmedetomidine and remained below baseline up to 240 (D25), 20 (D25M300) and 3 minutes (D25M600 and D25M1200). Mean arterial pressure (MAP) increased with D25, remained unchanged with M600 and decreased over time with all combination treatments. The highest and lowest MAP after each treatment were 168±17 and 100±14 (D25), 157±18 and 79±11 (D25M300), 153±11 and 74±10 (D25M600), 144±12 and 69±7 (D25M1200) and 136±9 and 104±13 mmHg (M600). All treatments with dexmedetomidine produced sedation although its duration was significantly reduced by the addition of MK-467. CONCLUSIONS AND CLINICAL RELEVANCE: Dexmedetomidine induced bradycardia and hypertension, which were attenuated by all three doses of MK-467. The duration of sedation was reduced by MK-467. MK-467 may improve the cardiovascular tolerance of IM dexmedetomidine in cats.

Effects of constant rate infusions of dexmedetomidine or MK-467 on the minimum alveolar concentration of sevoflurane in dogs.

OBJECTIVE: To determine the effects of low and high dose infusions of dexmedetomidine and a peripheral α2-adrenoceptor antagonist, MK-467, on sevoflurane minimum alveolar concentration (MAC) in dogs. STUDY DESIGN: Crossover experimental study. ANIMALS: Six healthy, adult Beagle dogs weighing 12.6±0.9 kg (mean±standard deviation). METHODS: Dogs were anesthetized with sevoflurane in oxygen. After a 60-minute instrumentation and equilibration period, the MAC of sevoflurane was determined in triplicate using the tail clamp technique. PaCO2 and temperature were maintained at 40±5 mmHg (5.3±0.7 kPa) and 38±0.5 ºC, respectively. After baseline MAC determination, dogs were administered two incremental loading and infusion doses of either dexmedetomidine (1.5 µg kg-1 then 1.5 µg kg-1 hour-1 and 4.5 µg kg-1 then 4.5 µg kg-1 hour-1) or MK-467 (90 µg kg-1 then 90 µg kg-1 hour-1 and 180 µg kg-1 then 180 µg kg-1 hour-1); loading doses were administered over 10 minutes. MAC was redetermined in duplicate starting 30 minutes after the start of drug administration at each dose. End-tidal sevoflurane concentrations were corrected for calibration and adjusted to sea level. A repeated-measures analysis was performed and comparisons between doses were conducted using Tukey's method. Statistical significance was considered at p<0.05. RESULTS: Sevoflurane MAC decreased significantly from 1.86±0.3% to 1.04±0.1% and 0.57±0.1% with incremental doses of dexmedetomidine. Sevoflurane MAC significantly increased with high dose MK-467, from 1.93±0.3% to 2.29±0.5%. CONCLUSIONS AND CLINICAL RELEVANCE: Dexmedetomidine caused a dose-dependent decrease in sevoflurane MAC, whereas MK-467 caused an increase in MAC at the higher infusion dose. Further studies evaluating the combined effects of dexmedetomidine and MK-467 on MAC and cardiovascular function may elucidate potential benefits of the addition of a peripheral α2-adrenergic antagonist to inhalation anesthesia in dogs.

Pharmacokinetics of dexmedetomidine, MK-467 and their combination following intramuscular administration in male cats.

OBJECTIVE: To characterize the pharmacokinetics of dexmedetomidine, MK-467 and their combination following intramuscular (IM) administration to cats. STUDY DESIGN: Prospective randomized crossover experimental study. ANIMALS: A total of eight healthy adult male castrated cats aged 1-2 years. METHODS: Cats were administered dexmedetomidine (25 µg kg-1) IM (treatment D25IM) or intravenously (IV; treatment D25IV); MK-467 (600 µg kg-1) IM (treatment MK600IM) or IV (treatment MK600IV); or dexmedetomidine (25 µg kg-1) IM with 300, 600 or 1200 µg kg-1 MK-467 IM (treatments D25MK300IM, D25MK600IM and D25MK1200IM). D25MK600IM was the only combination treatment analyzed. Blood samples were obtained prior to drug administration and at various times for 5 hours (D25IV) or 8 hours (all other treatments) thereafter. Plasma dexmedetomidine and MK-467 concentrations were measured using liquid chromatography/mass spectrometry. Compartment models were fitted to the time-concentration data. RESULTS: A one-compartment model best fitted the time-plasma dexmedetomidine concentration data in cats administered D25IM, and the time-plasma MK-467 concentration data in cats administered MK600IM and D25MK600IM. A two-compartment model best fitted the time-plasma dexmedetomidine concentration data in cats administered D25IV and D25MK600IM, and the time-plasma MK-467 concentration data in cats administered MK600IV. Median (range) area under the time-concentration curve, absorption rate half-life, maximum concentration, time to maximum concentration and terminal half-life for dexmedetomidine in D25IM and D25MK600IM were 1129 (792-1890) and 924 (596-1649) ng minute mL-1, 4.4 (0.4-15.7) and 2.3 (0.2-8.0) minutes, 10.2 (4.8-16.9) and 17.8 (15.8-73.5) ng mL-1, 17.8 (2.6-44.9) and 5.2 (1.2-15.1) minutes and 62 (52-139) and 50 (31-125) minutes, respectively. Rate of absorption but not systemic exposure was significantly influenced by treatment. No significant differences were observed in MK-467 pharmacokinetic parameters in MK600IM and D25MK600IM. CONCLUSIONS AND CLINICAL RELEVANCE: MK-467 significantly influenced the disposition of dexmedetomidine, whereas dexmedetomidine did not significantly affect the disposition of MK-467 when the drugs were coadministered IM.