Comparison of three anaesthetic protocols in Bennett’s wallabies (Macropus rufogriseus)

ObjectiveInvestigate physiological and sedative/anaesthetic effects of xylazine, medetomidine or dexmedetomidine combined with ketamine in free-ranging Bennett's wallabies.Study designProspective clinical trial.AnimalsTwenty-six adult free-ranging Bennett's wallabies.MethodsAnimals were darted intramuscularly with one of three treatments: xylazine and ketamine, 2.0 and 15.0 mg kg^?1, respectively (XK): medetomidine and ketamine 0.1 and 5.0 mg kg^?1 (MK) and dexmedetomidine and ketamine 0.05 and 5.0 mg kg^?1 (DMK). Body weights were estimated. If the animal was still laterally recumbent after 45 minutes of anaesthesia, then an alpha-2 adrenoceptor antagonist, atipamezole, was administered (XK: 0.4 mg kg^?1, MK: 5 mg kg^?1, DMK: 2.5 mg kg^?1). Heart rate (HR) and respiratory rate (f_R) were recorded at 5-minute intervals and temperature at 10-minute intervals. Venous blood was taken 30 minutes after initial injection. Statistical analysis utilized anova. p < 0.05 was considered significant.ResultsAnimals became recumbent rapidly in all groups. XK animals had muscle twitches, responded to external stimuli, and three animals required additional dosing; this was not observed in the MK and DMK groups. HR (mean ± SD beats minute^?1) in XK (81 ± 4) was significantly higher than MK (74 ± 2) and DMK (67 ± 4). There were no differences in f_R, temperature, blood-gas and biochemical values between groups. More animals in MK (9/10) and DMK (5/6) needed antagonism of anaesthesia compared with XK (1/10). There were no adverse effects after anaesthesia.Conclusion and clinical relevanceCardio-respiratory effects were similar in all groups. There were fewer muscle twitches and reactions to external stimuli in MK and DMK. Duration of anaesthesia was shorter in XK; most animals in MK and DMK needed atipamezole to assist recovery. All three treatments provided satisfactory sedation/anaesthesia and are suitable for use in Bennett's wallabies.     

Effects of different doses of L-659'066 on the bispectral index and clinical sedation in dogs treated with dexmedetomidine

ObjectiveTo evaluate the effects of three doses of L-659’066 (MK-467) on the bispectral index (BIS) and clinical sedation in dexmedetomidine-sedated Beagles.Study designRandomized, experimental cross over study.AnimalsEight purpose-bred healthy laboratory Beagles.MethodsDexmedetomidine (10 μg kg^?1 IV [DEX]) was administered alone or in combination with three doses of L-659’066 (250 μg kg^?1 [DL250]; 500 μg kg^?1 [DL500] and 750 μg kg^?1 [DL750] IV) in the same syringe in a randomized crossover manner. The bispectral index (BIS), electromyography (EMG) and sedation score were recorded at baseline and 5, 10, 20, 30, 45 and 60 minutes after treatment.ResultsWhen compared to DEX, BIS and EMG were significantly higher and the sedation score significantly lower with DL500 and DL750. With DEX, BIS was significantly decreased at times 20, 30 and 60 minutes whereas the sedation scores were significantly increased at all time points after drug administration in all groups. Bioequivalence for clinical sedation was detected between DEX and all doses of L-659’066, reaching European Medicines Agency (EMA) standards.Conclusions and clinical relevanceAlthough L-659’066 interfered with dexmedetomidine induced sedation, the degree of the reduction was not clinically relevant. Despite performing better when dexmedetomidine was used alone, BIS did not reflect the clinical sedative status when the antagonist was added.     

Plasma glucose, insulin, free fatty acids, lactate and cortisol concentrations in dexmedetomidine-sedated dogs with or without MK-467: A peripheral α-2 adrenoceptor antagonist

Six healthy laboratory Beagles were treated IV with 10μg/kg dexmedetomidine (DEX) or 10μg/kg dexmedetomidine combined with 500μg/kg MK-467 in the same syringe (DMK) in a randomised cross-over design with a 14day washout. Blood was collected immediately before treatment and 35, 60 and 120min post-injection through a central venous catheter. The plasma concentrations of glucose, insulin, non-esterified free fatty acids (NEFAs), lactate and cortisol were determined. A repeated-measures ANOVA test was used to compare treatments and effects for each sample time point. Significant differences between treatments were found for plasma glucose (P=0.037) and insulin (P=0.009). DEX significantly increased plasma glucose at 120min, but reduced plasma insulin at 35 and 60min. NEFA decreased for both treatments at 35min. This reduction was transient for DMK, whereas it persisted during the follow up period for DEX. Plasma lactate concentrations increased at 35 and 60min with DEX. Neither treatment altered plasma cortisol concentrations. The addition of MK-467 to dexmedetomidine prevented or abolished most metabolic changes in healthy Beagles.     

Plasma drug concentrations and clinical effects of a peripheral alpha‐2‐adrenoceptor antagonist,MK‐467, in horses sedated with detomidine

ObjectiveTo investigate plasma drug concentrations and the effect of MK-467 (L-659′066) on sedation, heart rate and gut motility in horses sedated with intravenous (IV) detomidine.Study designExperimental randomized blinded crossover study.AnimalsSix healthy horses.MethodsDetomidine (10 μg kg^?1 IV) was administered alone (DET) and in combination with MK-467 (250 μg kg^?1 IV; DET + MK). The level of sedation and intestinal sounds were scored. Heart rate (HR) and central venous pressure (CVP) were measured. Blood was collected to determine plasma drug concentrations. Repeated measures anova was used for HR, CVP and intestinal sounds, and the Student's t-test for pairwise comparisons between treatments for the area under the time-sedation curve (AUC_sed) and pharmacokinetic parameters. Significance was set at p < 0.05.ResultsA significant reduction in HR was detected after DET, and HR was significantly higher after DET + MK than DET alone. No heart blocks were detected in any DET + MK treated horses. DET + MK attenuated the early increase in CVP detected after DET, but later the CVP decreased with both treatments. Detomidine-induced intestinal hypomotility was prevented by MK-467. AUC_sed was significantly higher with DET than DET + MK, but maximal sedations scores did not differ significantly between treatments. MK-467 lowered the AUC of the plasma concentration of detomidine, and increased its volume of distribution and clearance.Conclusions and clinical relevanceMK-467 prevented detomidine induced bradycardia and intestinal hypomotility. MK-467 did not affect the clinical quality of detomidine-induced sedation, but the duration of the effect was reduced, which may have been caused by the effects of MK-467 on the plasma concentration of detomidine. MK-467 may be useful clinically in the prevention of certain peripheral side effects of detomidine in horses.     

Evaluation of medetomidine-ketamine and dexmedetomidine-ketamine in Chinese water deer (Hydropotes inermis)

ObjectiveTo investigate physiological and sedative/immobilization effects of medetomidine or dexmedetomidine combined with ketamine in free-ranging Chinese water deer (CWD).Study designProspective clinical trial.Animals10 free-ranging adult Chinese water deer (11.0 ± 2.6 kg).MethodsAnimals were darted intramuscularly with 0.08 ± 0.004 mg kg^?1 medetomidine and 3.2 ± 0.2 mg kg^?1 ketamine (MK) or 0.04 ± 0.01 mg kg^?1 dexmedetomidine and 2.9 ± 0.1 mg kg^?1 ketamine (DMK) If the animal was still laterally recumbent after 60 minutes of immobilization, atipamezole was administered intravenously (MK: 0.4 ± 0.02 mg kg^?1, DMK: 0.2 ± 0.03 mg kg^?1). Heart rate (HR) respiratory rate (f_R) and temperature were recorded at 5-minute intervals. Arterial blood was taken 15 and 45 minutes after initial injection. Statistical analysis was performed using Student’s t-test or anova. p < 0.05 was considered significant.ResultsAnimals became recumbent rapidly in both groups. Most had involuntary ear twitches, but there was no response to external stimuli. There were no statistical differences in mean HR (MK: 75 ± 14 beats minute^?1; DMK: 85 ± 21 beats minute^?1), f_R (MK: 51 ± 35 breaths minute^?1; DMK; 36 ± 9 breaths minute^?1), temperature (MK: 38.1 ± 0.7 °C; DMK: 38.4 ± 0.5 °C), blood gas values (MK: PaO₂ 63 ± 6 mmHg, PaCO₂ 49.6 ± 2.6 mmHg, HCO₃^? 30.8 ± 4.5 mmol L^?1; DMK: PaO₂ 77 ± 35 mmHg, PaCO₂ 45.9 ± 11.5 mmHg, HCO₃^? 31.0 ± 4.5 mmol L^?1) and biochemical values between groups but temperature decreased in both groups. All animals needed antagonism of immobilization after 60 minutes. Recovery was quick and uneventful. There were no adverse effects after recovery.Conclusion and clinical relevanceBoth anaesthetic protocols provided satisfactory immobilisation. There was no clear preference for either protocol and both appear suitable for CWD.     

Pharmacokinetics of dexmedetomidine,MK‐467, and their combination following intravenous administration in male cats

This study characterized the pharmacokinetics of dexmedetomidine, MK‐467, and their combination following intravenous bolus administration to cats. Seven 6‐ to‐year‐old male neutered cats, weighting 5.1 ± 0.7 kg, were used in a randomized, crossover design. Dexmedetomidine [12.5 (D12.5) and 25 (D25) μg/kg], MK‐467 [300 μg/kg (M300)] or dexmedetomidine (25 μg/kg) and MK‐467 [75, 150, 300 or 600 μg/kg—only the plasma concentrations in the 600 μg/kg group (D25M600) were analyzed] were administered intravenously, and blood was collected until 8 hours thereafter. Plasma drug concentrations were analyzed using liquid chromatography/mass spectrometry. A two‐compartment model best fitted the data. Median (range) volume of the central compartment (mL/kg), volume of distribution at steady state (mL/kg), clearance (mL min/kg) and terminal half‐life (min) were 342 (131–660), 829 (496–1243), 14.6 (9.6–22.7) and 48 (40–69) for D12.5; 296 (179–982), 1111 (908–2175), 18.2 (12.4–22.9) and 52 (40–76) for D25; 653 (392–927), 1595 (1094–1887), 22.7 (18.5–36.4) and 48 (35–60) for dexmedetomidine in D25M600; 117 (112–163), 491 (379–604), 3.0 (2.0‐4.5) and 122 (99‐139) for M300; and 147 (112‐173), 462 (403‐714), 2.8 (2.1–4.8) and 118 (97–172) for MK‐467 in D25M600. MK‐467 moderately but statistically significantly affected the disposition of dexmedetomidine, whereas dexmedetomidine minimally affected the disposition of MK‐467.     

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.

Detomidine and the combination of detomidine and MK‐467, a peripheral alpha‐2 adrenoceptor antagonist,as premedication in horses anaesthetized with isoflurane

ObjectiveTo investigate MK-467 as part of premedication in horses anaesthetized with isoflurane.Study designExperimental, crossover study with a 14 day wash-out period.AnimalsSeven healthy horses.MethodsThe horses received either detomidine (20 μg kg⁻¹ IV) and butorphanol (20 μg kg⁻¹ IV) alone (DET) or with MK-467 (200 μg kg⁻¹ IV; DET + MK) as premedication. Anaesthesia was induced with ketamine (2.2 mg kg⁻¹) and midazolam (0.06 mg kg⁻¹) IV and maintained with isoflurane. Heart rate (HR), mean arterial pressure (MAP), end-tidal isoflurane concentration, end-tidal carbon dioxide tension, central venous pressure, fraction of inspired oxygen (FiO₂) and cardiac output were recorded. Blood samples were taken for blood gas analysis and to determine plasma drug concentrations. The cardiac index (CI), systemic vascular resistance (SVR), ratio of arterial oxygen tension to inspired oxygen (P_aO₂/FiO₂) and tissue oxygen delivery (DO₂) were calculated. Repeated measures anova was applied for HR, CI, MAP, SVR, lactate and blood gas variables. The Student's t-test was used for pairwise comparisons of drug concentrations, induction times and the amount of dobutamine administered. Significance was set at p < 0.05.ResultsThe induction time was shorter, reduction in MAP was detected, more dobutamine was given and HR and CI were higher after DET+MK, while SVR was higher with DET. Arterial oxygen tension and P_aO₂/FiO₂ (40 minutes after induction), DO₂ and venous partial pressure of oxygen (40 and 60 minutes after induction) were higher with DET+MK. Plasma detomidine concentrations were reduced in the group receiving MK-467. After DET+MK, the area under the plasma concentration time curve of butorphanol was smaller.Conclusions and clinical relevanceMK-467 enhances cardiac function and tissue oxygen delivery in horses sedated with detomidine before isoflurane anaesthesia. This finding could improve patient safety in the perioperative period. The dosage of MK-467 needs to be investigated to minimise the effect of MK-467 on MAP.     

Thermographic imaging of superficial temperature in dogs sedated with medetomidine and butorphanol with and without MK‐467 (L‐659’066)

ObjectiveTo record, with a thermal camera, peripheral temperature changes during different sedation protocols and to relate the results to changes in the rectal temperature.Study designRandomized crossover part-blinded experimental study.AnimalsEight healthy purpose-bred neutered Beagles (two females and six males) weight 14.5 ± 1.6 kg (mean ± SD) and aged 3–4 years.MethodsEach dog was sedated four times. Treatments were medetomidine 20 μg kg^?1 and butorphanol 0.1 mg kg^?1 (MB) with or without MK-467 500 μg kg^?1 (MK). Both drug combinations were administered IV and IM as separate treatments. A thermal camera (T425, FLIR) with a resolution of 320 by 240 was used for imaging.The dogs were placed in lateral recumbency on an insulated mattress. Digital (DFT) and metatarsal footpad temperatures (MFT) were measured with thermography. Thermograms and rectal temperature (RT) were taken before and at 3, 10, 20, 30, 45 and 60 minutes after treatment.ResultsAt 60 minutes after drug administration, MFT was higher (p < 0.001) after MB+MK (34.5 ± 1.1 IV, 34.8 ± 0.5 IM) than MB (31.1 ± 2.9 IV, 30.5 ± 3.6 IM), DFT was higher (p < 0.001) after MB+MK (33.6 ± 1.4 IV, 34.0 ± 0.6 IM) than MB (26.7 ± 1.4 IV, 26.7 ± 2.5 IM), and RT was lower (p < 0.001) after MB+MK (36.7 ± 0.8 IV, 36.9 ± 0.3 IM) than MB (37.5 ± 0.3 IV, 37.4 ± 0.4 IM), with both routes. The change from baseline was greater with MB+MK than MB in all variables.ConclusionsSuperficial temperature changes can be seen and detected with thermography. MK-467 used with MB resulted in increased superficial temperatures and a decline in rectal temperature compared to MB alone.Clinical relevanceThe sedation protocol may influence core temperature loss, and may also have an effect on thermographic images.     

The effects of L‐659,066, a peripheral α2‐adrenoceptor antagonist,and verapamil on the cardiovascular influences of dexmedetomidine in conscious sheep

Raekallio M. R., Honkavaara J. M., Vainio O. M. The effects of L‐659,066, a peripheral α₂‐adrenoceptor antagonist, and verapamil on the cardiovascular influences of dexmedetomidine in conscious sheep. J. vet. Pharmacol. Therap. 33 , 434–438. We investigated whether administration of L‐659,066, a peripheral α₂‐adrenoceptor antagonist, or verapamil, a calcium‐channel antagonist, would prevent the cardiovascular effects of dexmedetomidine. Eleven sheep received three intravenous treatments with a randomized, cross‐over design: dexmedetomidine (5 μg/kg, DEX); DEX with L‐659,066 (250 μg/kg, DEX + L); and verapamil (0.05 mg/kg) 10 min prior to DEX (Ver + DEX). Haemodynamics were recorded at intervals upto 40 min. Acute increases in mean arterial pressure (MAP) (106 ± 10.7 to 120.8 ± 11.7 mmHg), central venous pressure (CVP) (3.3 ± 3.2 to 14.7 ± 5.0 mmHg) and systemic vascular resistance (SVR) (1579 ± 338 to 2301 ± 523 dyne s/cm⁵), and decreases in cardiac output (CO) (5.36 ± 0.87 to 3.93 ± 1.30 L/min) and heart rate (HR) (88.6 ± 15.3 to 49.7 ± 5.5/min) were detected with DEX. The peak SVR remained lower after Ver + DEX (1835 ± 226 dyne s/cm⁵) than DEX alone, but the other parameters did not significantly differ between these treatments. 2 min after drug delivery, differences between DEX and DEX + L were statistically significant for all measured haemodynamic parameters. With DEX + L, an early decrease in MAP (99.9 ± 6.8 to 89.3 ± 6.6 mmHg) was detected, and DEX + L induced a slight but significant increase in CVP and a decrease in HR at the end of the observation period, while SVR and CO did not significantly change. All animals were assessed as deeply sedated from 2–20 min with no differences between treatments. L‐659,066 has great potential for clinical use to prevent the cardiovascular effects of dexmedetomidine mediated by peripheral α₂‐adrenoceptors, whereas the effects of verapamil were marginal.     

Pharmacokinetics and pharmacodynamics of intravenous medetomidine in the horse

ObjectiveTo describe the pharmacodynamics and pharmacokinetics following an intravenous (IV) bolus dose of medetomidine in the horse.Study designProspective experimental trial.AnimalsEight, mature healthy horses age 11.7 ± 4.6 (mean ± SD) years, weighing 557 ± 54 kg.MethodsMedetomidine (10 μg kg^?1) was administered IV. Blood was sampled at fixed time points from before drug administration to 48 hours post administration. Behavioral, physiological and biochemical data were obtained at predetermined time points from 0 minutes to 24 hours post administration. An algometer was also used to measure threshold responses to noxious stimuli. Medetomidine concentrations were determined by liquid chromatography-Mass Spectrometry and used for calculation of pharmacokinetic parameters using noncompartmental and compartmental analysis.ResultsPharmacokinetic analysis estimated that medetomidine peaked (8.86 ± 3.87 ng mL^?1) at 6.4 ± 2.7 minutes following administration and was last detected at 165 ± 77 minutes post administration. Medetomidine had a clearance of 39.6 ± 14.6 mL kg^?1 minute^?1 and a volume of distribution of 1854 ± 565 mL kg^?1. The elimination half-life was 29.1 ± 12.5 minutes. Glucose concentration reached a maximum of 176 ± 46 mg dL^?1 approximately 1 hour post administration. Decreased heart rate, respiratory rate, borborygmi, packed cell volume, and total protein concentration were observed following administration. Horses lowered their heads from 107 ± 12 to 20 ± 10 cm within 10 minutes of drug administration and gradually returned to normal. Horse mobility decreased after drug administration. An increased mechanical threshold was present from 10 to 45 minutes and horses were less responsive to sound.Conclusion and clinical relevance Behavioral and physiological effects following intravenous administration positively correlate with pharmacokinetic profiles from plasma medetomidine concentrations. Glucose concentration gradually transiently increased following medetomidine administration. The analgesic effect of the drug appeared to have a very short duration.     

Evaluation of the isoflurane‐sparing effects of fentanyl,lidocaine, ketamine,dexmedetomidine, or the combination lidocaine‐ketamine‐dexmedetomidine during ovariohysterectomy in dogs

ObjectiveTo evaluate the isoflurane‐sparing effects of an intravenous (IV) constant rate infusion (CRI) of fentanyl, lidocaine, ketamine, dexmedetomidine, or lidocaine‐ketamine‐dexmedetomidine (LKD) in dogs undergoing ovariohysterectomy.Study designRandomized, prospective, blinded, clinical study.AnimalsFifty four dogs.MethodsAnesthesia was induced with propofol and maintained with isoflurane with one of the following IV treatments: butorphanol/saline (butorphanol 0.4 mg kg^?1, saline 0.9% CRI, CONTROL/BUT); fentanyl (5 μg kg^?1, 10 μg kg^?1 hour^?1, FENT); ketamine (1 mg kg^?1, 40 μg kg^?1 minute^?1, KET), lidocaine (2 mg kg^?1, 100 μg kg^?1 minute^?1, LIDO); dexmedetomidine (1 μg kg^?1, 3 μg kg^?1 hour^?1, DEX); or a LKD combination. Positive pressure ventilation maintained eucapnia. An anesthetist unaware of treatment and end‐tidal isoflurane concentration (Fe′Iso) adjusted vaporizer settings to maintain surgical anesthetic depth. Cardiopulmonary variables and Fe′Iso concentrations were monitored. Data were analyzed using anova (p < 0.05).ResultsAt most time points, heart rate (HR) was lower in FENT than in other groups, except for DEX and LKD. Mean arterial blood pressure (MAP) was lower in FENT and CONTROL/BUT than in DEX. Overall mean ± SD Fe′Iso and % reduced isoflurane requirements were 1.01 ± 0.31/41.6% (range, 0.75 ± 0.31/56.6% to 1.12 ± 0.80/35.3%, FENT), 1.37 ± 0.19/20.8% (1.23 ± 0.14/28.9% to 1.51 ± 0.22/12.7%, KET), 1.34 ± 0.19/22.5% (1.24 ± 0.19/28.3% to 1.44 ± 0.21/16.8%, LIDO), 1.30 ± 0.28/24.8% (1.16 ± 0.18/32.9% to 1.43 ± 0.32/17.3%, DEX), 0.95 ± 0.19/54.9% (0.7 ± 0.16/59.5% to 1.12 ± 0.16/35.3%, LKD) and 1.73 ± 0.18/0.0% (1.64 ± 0.21 to 1.82 ± 0.14, CONTROL/BUT) during surgery. FENT and LKD significantly reduced Fe′Iso.Conclusions and clinical relevanceAt the doses administered, FENT and LKD had greater isoflurane‐sparing effect than LIDO, KET or CONTROL/BUT, but not at all times. Low HR during FENT may limit improvement in MAP expected with reduced Fe′Iso.     

Comparative evaluation of sedative and clinical effects of dexmedetomidine and xylazine in dromedary calves (Camelus dromedarius)

ObjectiveTo compare the sedative and clinical effects of intravenous (IV) administration of dexmedetomidine and xylazine in dromedary calves.Study designExperimental, crossover, randomized, blinded study.AnimalsA total of seven healthy male dromedary calves aged 14 ± 2 weeks and weighing 95 ± 5.5 kg.MethodsCalves were assigned three IV treatments: treatment XYL, xylazine (0.2 mg kg⁻¹); treatment DEX, dexmedetomidine (5 μg kg⁻¹); and control treatment, normal saline (0.01 mL kg⁻¹). Sedation scores, heart rate (HR), respiratory rate (f_R), rectal temperature (RT) and ruminal motility were recorded before (baseline) and after drug administration. Sedation signs were scored using a 4-point scale. One-way anova and Mann–Whitney U tests were used for data analysis.ResultsCalves in treatments XYL and DEX were sedated at 5–60 minutes. Sedation had waned in XYL calves, but not DEX calves, at 60 minutes (p = 0.037). Sedation was not present in calves of any treatment at 90 minutes. HR decreased from baseline in XYL and DEX at 5–90 minutes after drug administration and was lower in DEX than XYL at 5 minutes (p = 0.017). HR was lower in DEX (p = 0.001) and XYL (p = 0.013) than in control treatment at 90 minutes. f_R decreased from baseline in XYL and DEX at 5–60 minutes after drug administration and was lower in DEX than XYL at 5 minutes (p = 0.013). RT was unchanged in any treatment over 120 minutes. Ruminal motility was decreased in XYL at 5, 90 and 120 minutes and absent at 10–60 minutes. Motility was decreased in DEX at 5, 10 and 120 minutes and was absent at 15–90 minutes.Conclusion and clinical relevanceThe duration of sedation from dexmedetomidine (5 μg kg^–1) and xylazine (0.2 mg kg^–1) was similar in dromedary calves.     

The impact of medetomidine on the protein‐binding characteristics of MK‐467 in canine plasma

This study determined the unbound fraction of the peripheral α₂‐adrenoceptor antagonist MK‐467 alone and combined with medetomidine. MK‐467 (0.1, 1 and 10 μm ) was incubated in canine plasma with and without medetomidine (molar ratio 20:1), with human serum albumin (HSA) and with α1‐acid glycoprotein (AGP). Rapid equilibrium dialysis was used for the measurement of protein binding. All samples were analysed by liquid chromatography and tandem mass spectrometry to obtain the unbound fraction (f_u) of MK‐467. Unbound fractions (f_u) of MK‐467 in canine plasma (mean ± standard deviation) were 27.6 ± 3.5%, 26.6 ± 0.9% and 42.4 ± 1.2% at 0.1, 1.0 and 10 μm concentrations, respectively. In the presence of medetomidine, f_u were 27.5 ± 0.4%, 26.6 ± 0.9% and 41.0 ± 2.4%. The f_u of MK‐467 in HSA were 50.1 ± 2.5% at 0.1 μm , 49.4 ± 1.2% at 1.0 μm and 56.7 ± 0.5% at 10 μm . f_u of MK‐467 in AGP was 56.3 ± 3.7% at 0.1 μm , 54.6 ± 5.6% at 1.0 μm and 65.3 ± 0.4% at 10 μm . Protein binding of MK‐467 was approximately 70% between 0.1 and 1.0 μm . Medetomidine had no apparent effect on the protein binding of MK‐467.     

Evaluation of a dexmedetomidine–midazolam–ketamine combination administered intramuscularly in captive ornate box turtles (Terrapene ornata ornata)

ObjectiveTo characterize the effects of a combination protocol of dexmedetomidine–midazolam–ketamine (DMK) administered intramuscularly (IM) in ornate box turtles (Terrapene ornata ornata).Study designProspective experimental trial.AnimalsA total of 16 apparently clinically healthy adult ornate box turtles (eight male, eight female).MethodsEach turtle was treated with dexmedetomidine (0.1 mg kg⁻¹), midazolam (1 mg kg⁻¹) and ketamine (10 mg kg⁻¹) administered IM. Time to first response, time to maximal effect, the plateau phase and time to recovery from reversal administration were recorded. Physiologic variables, muscle tone, reflexes and the ability to perform endotracheal intubation were recorded at 5 minute intervals. Movement in response to an IM injection of 0.1 mL sterile 0.9% NaCl administered in the left pelvic limb, using a 25 gauge needle to a depth of just past the bevel of the needle, was assessed every 15 minutes. Atipamezole (0.5 mg kg⁻¹) IM and flumazenil (0.05 mg kg⁻¹) SC were administered 60 minutes after the initial DMK injections.ResultsThe mean time to first response, time to maximal effect, the plateau phase and time to recovery were 2.1, 14.9, 38.7 and 7.8 minutes, respectively. A respiratory rate was not observed in most turtles. The body temperature significantly increased over time. The palpebral reflex was persistent in 43% of turtles and the tail pinch reflex remained intact in 13% of turtles. All turtles recovered with no observed adverse effects.Conclusions and clinical relevanceIn this study, this DMK protocol administered to ornate box turtles resulted in a rapid-onset, light anesthesia lasting approximately 40 minutes and a smooth recovery with no adverse effects noted.     

The impact of MK‐467 on plasma drug concentrations,sedation and cardiopulmonary changes in sheep treated with intramuscular medetomidine and atipamezole for reversal

The effect of MK‐467, a peripheral α₂‐adrenoceptor antagonist, on plasma drug concentrations, sedation and cardiopulmonary changes induced by intramuscular (IM) medetomidine was investigated in eight sheep. Additionally, the interactions with atipamezole (ATI) used for reversal were also evaluated. Each animal was treated four times in a randomized prospective crossover design with 2‐week washout periods. Medetomidine (MED) 30 μg/kg alone or combined in the same syringe with MK‐467 300 μg/kg (MMK) was injected intramuscular, followed by ATI 150 μg/kg (MED + ATI and MMK + ATI) or saline intramuscular 30 min later. Plasma was analysed for drug concentrations, and sedation was subjectively assessed with a visual analogue scale. Systemic haemodynamics and blood gases were measured before treatments and at intervals thereafter. With MK‐467, medetomidine plasma concentrations were threefold higher prior to ATI, which was associated with more profound sedation and shorter onset. No significant differences were observed in early cardiopulmonary changes between treatments. Atipamezole reversed the medetomidine‐related cardiopulmonary changes after both treatments. Sedation scores decreased more rapidly when MK‐467 was included. In this study, MK‐467 appeared to have a pronounced effect on the plasma concentration and central effects of medetomidine, with minor cardiopulmonary improvement.     

The effects of a loading dose followed by constant rate infusion of xylazine compared with romifidine on sedation,ataxia and response to stimuli in horses

ObjectiveTo compare xylazine and romifidine constant rate infusion (CRI) protocols regarding degree of sedation, and effects on postural instability (PI), ataxia during motion (A) and reaction to different stimuli.Study designBlinded randomized experimental cross-over study.AnimalsTen adult horses.MethodsDegree of sedation was assessed by head height above ground (HHAG). Effects on PI, A and reaction to visual, tactile and acoustic stimulation were assessed by numerical rating scale (NRS) and by visual analogue scale (VAS). After baseline measurements, horses were sedated by intravenous loading doses of xylazine (1 mg kg^?1) or romifidine (80 μg kg^?1) administered over 3 minutes, immediately followed by a CRI of xylazine (0.69 mg kg^?1 hour^?1) or romifidine (30 μg kg^?1 hour^?1) which was administered for 120 minutes. Degree of sedation, PI, A and reaction to the different stimuli were measured at different time points before, during and for one hour after discontinuing drug administration. Data were analysed using two-way repeated measures anova, a Generalized Linear Model and a Wilcoxon Signed Rank Test (p < 0.05).ResultsSignificant changes over time were seen for all variables. With xylazine HHAG was significantly lower 10 minutes after the loading dose, and higher at 150 and 180 minutes (i.e. after CRI cessation) compared to romifidine. Reaction to acoustic stimulation was significantly more pronounced with xylazine. Reaction to visual stimulation was greater with xylazine at 145 and 175 minutes. PI was consistently but not significantly greater with xylazine during the first 30 minutes. Reaction to touch and A did not differ between treatments. Compared to romifidine, horses were more responsive to metallic noise with xylazine.ConclusionsTime to maximal sedation and to recovery were longer with romifidine than with xylazine.Clinical relevanceWith romifidine sufficient time should be allowed for complete sedation before manipulation.     

The effect of butorphanol on the incidence of dexmedetomidine‐induced emesis in cats

ObjectiveTo evaluate the antiemetic effect of butorphanol (BUT) when co-administered with dexmedetomidine (DEX) in cats.Study designDouble-blind, randomized controlled cross-over experimental study.AnimalsFourteen purpose-bred healthy Domestic Short Hair cats, seven females and seven males, aged median (range) 14–84 (78) months and weighing 1.7–5.5 (4.0) kg.MethodsEach cat received five different treatment protocols intramuscularly (IM): (A) 25 μg kg⁻¹ DEX; (B) 20 μg kg⁻¹ DEX and 0.2 mg kg⁻¹ BUT; (C) 20 μg kg⁻¹ DEX and 0.1 mg kg⁻¹ BUT; (D) 25 μg kg⁻¹ DEX and 0.2 mg kg⁻¹ BUT; and (E) 20 μg kg⁻¹ DEX. Episodes of emesis, incidence and severity of nausea, and time to lateral recumbency were recorded for a period of 8 minutes after treatment administration, and the sedation was scored at the end of this period. The Friedman test and the Cochran’s Q-test were used to analyse the data. Significance was evaluated at the 5% level.ResultsThe proportion of cats that vomited was significantly lower with the treatment protocols that included BUT (B, C and D) compared with the protocols that included only DEX (A and E). The proportion of cats that had nausea was significantly higher with the protocols that included only DEX (A and E) compared with protocols B and D. Time to lateral recumbency (p = 0.09) and sedation score (p = 0.07) was not statistically different between the treatment protocols.Conclusions and clinical relevanceButorphanol can be used to prevent emesis and reduce the incidence and the severity of nausea caused by DEX in cats. It seems that the combination of BUT and DEX is very useful not only when emesis could result in serious complications, but also to provide comfort and well-being in cats sedated for minor procedures.     

Effect of medetomidine-butorphanol and dexmedetomidine-butorphanol combinations on intraocular pressure in healthy dogs

ObjectiveTo assess the effects of intravenous (IV) medetomidine-butorphanol and IV dexmedetomidine-butorphanol on intraocular pressure (IOP).Study designProspective, randomized, blinded clinical study.AnimalsForty healthy dogs. Mean ± SD body mass 37.6 ± 6.6 kg and age 1.9 ± 1.3 years.MethodsDogs were allocated randomly to receive an IV combination of dexmedetomidine, 0.3 mg m^?2, combined with butorphanol, 6 mg m^?2, (group DEX) or medetomidine 0.3 mg m^?2, combined with butorphanol 6 mg m^?2, (group MED). IOP and pulse (PR) and respiratory (f_R) rates were measured prior to (baseline) and at 10 (T10), 20 (T20), 30 (T30) and 40 (T40) minutes after drug administration. Oxygen saturation of hemoglobin (SpO₂) was monitored following sedation. Data were analyzed by anova followed by Dunnett's tests for multiple comparisons. Changes were considered significant when p < 0.05.ResultsFollowing drug administration, PR and f_R were decreased significantly at all time points but did not differ significantly between groups. Baseline IOP in mmHg was 14 ± 2 for DEX and 13 ± 2 for MED. With both treatments, at T10, IOP increased significantly (p < 0.001), reaching 20 ± 3 and 17 ± 2 for DEX and MED respectively. This value for DEX was significantly higher than for MED. There were no significant differences in IOP values between groups at any other time points. At T30 and T40, IOP in both groups was below baseline (DEX, 12 ± 2 and 11 ± 2: MED 12 ± 2 and 11 ± 2) and this was statistically significant, for DEX.Conclusions and clinical relevanceAt the documented doses, both sedative combinations induced a transient increase and subsequent decrease of IOP relative to baseline, which must be taken into consideration when planning sedation of animals in which marked changes in IOP would be undesirable.