Effect of MK‐467 on organ blood flow parameters detected by contrast‐enhanced ultrasound in dogs treated with dexmedetomidine

ObjectiveTo evaluate the dexmedetomidine‐induced reduction in organ blood flow with quantitative contrast‐enhanced ultrasound (CEUS) method and to observe the influence of MK‐467 on such reduction.Study designRandomized cross‐over study.AnimalsSix adult purpose‐bred laboratory beagle dogs (mean body weight 15.3 ± 1.9 kg).MethodsContrast‐enhanced ultrasound was performed on six conscious healthy laboratory beagles. The animals on separate occasions underwent three treatments: awake without any medication (CTRL), dexmedetomidine 10 μg kg^?1 (DEX) and DEX + MK‐467 500 μg kg^?1 (DMK) intravenously (IV). The kidney (10–15 minutes post‐treatment), spleen (25–30 minutes post‐treatment), small intestine (40–45 minutes post‐treatment) and liver (50–55 minutes post‐treatment) were examined with CEUS. A time curve was generated and the following perfusion parameters were analysed: arrival time (AT), time to peak from injection (TTPinj), peak intensity (PI) and wash‐in rate (Wi). In addition to CEUS, renal glomerular filtration rate was indirectly estimated by the rate of iohexol elimination.ResultsAT and TTPinj were significantly higher for DEX than for CTRL in all studied organs. The same parameters were significantly higher for DEX than for DMK in the kidney, spleen and small intestine. PI was significantly lower for DEX than for CTRL or DMK in the kidney. Wi was significantly lower for DEX than for CTRL or DMK in the kidney and significantly lower than for CTRL only in the small intestine. Plasma concentration of iohexol was significantly higher after DEX than CTRL administration.ConclusionsContrast‐enhanced ultrasound was effective in detecting DEX‐induced changes in blood flow. MK‐467 attenuated these changes.Clinical relevanceClinicians should consider the effects of the sedation protocol when performing CEUS. Addition of MK‐467 might beneficially impact the haemodynamic function of sedation with alpha‐2 adrenoceptor agonists.     

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.     

Comparison of pulse pressure variation versus echocardiography-derived stroke volume variation for prediction of fluid responsiveness in mechanically ventilated anesthetized dogs

ObjectiveTo evaluate the ability and accuracy of aortic flow velocity–time integral variation (ΔVTI) and peak aortic velocity variation (ΔVpeak) compared with pulse pressure variation (PPV) to predict fluid responsiveness in mechanically ventilated dogs.Study designProspective clinical study.AnimalsA group of 50 mechanically ventilated dogs with spontaneous hypotension during orthopedic or oncologic surgery.MethodsInvestigations were performed in the surgery room. When mean arterial pressure (MAP) decreased to <65 mmHg, measurements were performed before and after a fluid challenge (lactated Ringer’s solution 5 mL kg⁻¹ over 15 minutes). Responders were defined as a change in stroke volume (SV; transesophageal Doppler) ≥15%. Data were analyzed using paired/unpaired t test or Mann–Whitney/Wilcoxon test when appropriate and receiver operating characteristics (ROC) curves; a p value <0.05 was considered statistically significant.ResultsAfter the fluid challenge, 35 (70%) of 50 dogs were responders with significant increases in SV and decreases in PPV; 15 dogs were nonresponders. ΔVTI and ΔVpeak correlated with a 15% increase in SV. The optimum cut-off value for PPV was 15.6% (sensitivity, 88%; specificity, 100%), for ΔVTI was 10.65% (sensitivity, 65%; specificity, 100%) and for ΔVpeak was 10.15% (sensitivity, 80%; specificity, 100%). The area under the ROC curve for PPV was (0.93 ± 0.08) and for ΔVpeak was (0.89 ± 0.09), before fluid challenge. The gray zone area spread from 6.15% to 15.6% for PPV (18 dogs), 2.45% to 10.65% for ΔVTI (22 dogs) and 0.6% to 10.15% for ΔVpeak (25 dogs).ConclusionsWhen using mechanical ventilation, ΔVTI and ΔVpeak predicted fluid responsiveness with the same ability as PPV, based on the area under the ROC curve analysis. However, PPV showed great accuracy demonstrated by a narrower gray zone that included fewer individuals.Clinical relevanceΔVTI and ΔVpeak can be used as indices of fluid responsiveness in anesthetized dogs.     

Effect of yohimbine on detomidine induced changes in behavior,cardiac and blood parameters in the horse

ObjectiveTo describe selected pharmacodynamic effects of detomidine and yohimbine when administered alone and in sequence.Study designRandomized crossover design.AnimalsNine healthy adult horses aged 9 ± 4 years and weighing 561 ± 56 kg.MethodsThree dose regimens were employed in the current study. 1) 0.03 mg kg^?1 detomidine IV, 2) 0.2 mg kg^?1 yohimbine IV and 3) 0.03 mg kg^?1 detomidine IV followed 15 minutes later by 0.2 mg kg^?1 yohimbine IV. Each horse received all three treatments with a minimum of 1 week between treatments. Blood samples were obtained and plasma analyzed for detomidine and yohimbine concentrations by liquid chromatography-mass spectrometry. Behavioral effects, heart rate and rhythm, glucose, packed cell volume and plasma proteins were monitored.ResultsYohimbine rapidly reversed the sedative effects of detomidine in the horse. Additionally, yohimbine effectively returned heart rate and the percent of atrio-ventricular conduction disturbances to pre-detomidine values when administered 15 minutes post-detomidine administration. Plasma glucose was significantly increased following detomidine administration. The detomidine induced hyperglycemia was effectively reduced by yohimbine administration. Effects on packed cell volume and plasma proteins were variable.Conclusions and clinical relevanceIntravenous administration of yohimbine effectively reversed detomidine induced sedation, bradycardia, atrio-ventricular heart block and hyperglycemia.     

Effects of pre‐operative administration of medetomidine on plasma insulin and glucose concentrations in healthy dogs and dogs with insulinoma

ObjectiveTo investigate the effect of medetomidine on plasma glucose and insulin concentrations in dogs with insulinoma and in healthy dogs undergoing anesthesia and surgery.AnimalsTwenty–five dogs with insulinoma and 26 healthy dogs.MethodsIn dogs with insulinoma, medetomidine (5 μg kg^?1) was randomly included (n = 12) or omitted (n = 13) from the pre–anesthetic medication protocol, which typically contained an opioid and an anticholinergic. Healthy dogs received medetomidine (5 μg kg^?1; n = 13) or acepromazine (0.04 mg kg^?1; n = 13) plus an opioid (morphine 0.5 mg kg^?1) and an anticholinergic (atropine 0.04 mg kg^?1) as pre–anesthetic medications. Pre–anesthetic medications were given intramuscularly. Plasma glucose and insulin concentrations were measured before (sample 1) and 30 minutes after pre–anesthetic medication (sample 2), and at the end of surgery in dogs with insulinoma or at 2 hours of anesthesia in healthy dogs (sample 3). Glucose requirement to maintain intra–operative normoglycemia in dogs with insulinoma was quantified and compared. Data were analyzed with anova and Bonferroni post–test, t–tests or chi–square tests as appropriate with p < 0.05 considered significant. Data are shown as mean ± SD.ResultsMedetomidine significantly decreased plasma insulin concentrations and increased plasma glucose concentrations in healthy dogs and those with insulinoma. These variables did not change significantly in the dogs not receiving medetomidine. In the dogs with insulinoma, intra–operative glucose administration rate was significantly less in the animals that received medetomidine compared to those that did not.ConclusionsPre–anesthetic administration of medetomidine significantly suppressed insulin secretion and increased plasma glucose concentration in dogs with insulinoma and in healthy dogs undergoing anesthesia and surgery.Clinical relevanceThese findings support the judicious use of medetomidine at low doses as an adjunct to the anesthetic management of dogs with insulinoma.     

Effect of dexmedetomidine and xylazine followed by MK-467 on gastrointestinal microperfusion in anaesthetized horses

Objective

To compare the effects of MK-467 during isoflurane anaesthesia combined with xylazine or dexmedetomidine on global and gastrointestinal perfusion parameters.

A possible solution to model nonlinearity in elimination and distributional clearances with α2‐adrenergic receptor agonists: Example of the intravenous detomidine and methadone combination in sedated horses

The alpha(α)₂‐agonist detomidine is used for equine sedation with opioids such as methadone. We retrieved the data from two randomized, crossover studies where detomidine and methadone were given intravenously alone or combined as boli (STUDY 1) (Gozalo‐Marcilla et al., 2017, Veterinary Anaesthesia and Analgesia, 2017, 44 , 1116) or as 2‐hr constant rate infusions (STUDY 2) (Gozalo‐Marcilla et al., 2019, Equine Veterinary Journal, 51 , 530). Plasma drug concentrations were measured with a validated tandem Mass Spectrometry assay. We used nonlinear mixed effect modelling and took pharmacokinetic (PK) data from both studies to fit simultaneously both drugs and explore their nonlinear kinetics. Two significant improvements over the classical mammillary two‐compartment model were identified. First, the inclusion of an effect of detomidine plasma concentration on the elimination clearances (Cls) of both drugs improved the fit of detomidine (Objective Function Value [OFV]: ?160) and methadone (OFV: ?132) submodels. Second, a detomidine concentration‐dependent reduction of distributional Cls of each drug further improved detomidine (OFV: ?60) and methadone (OFV: ?52) submodel fits. Using the PK data from both studies (a) helped exploring hypotheses on the nonlinearity of the elimination and distributional Cls and (b) allowed inclusion of dynamic effects of detomidine plasma concentration in the model which are compatible with the pharmacology of detomidine (vasoconstriction and reduction in cardiac output).     

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.     

Effects of intravenous terbutaline on heart rate,arterial pressure and blood gases in anesthetized horses breathing air

Objective

To investigate the effects of intravenous (IV) administration of terbutaline on PaO₂, PaCO₂, pH, heart rate (HR) and arterial pressures in healthy, laterally recumbent horses breathing ambient air under total intravenous anesthesia (TIVA).

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.     

Effects of maternal treatment with β‐hydroxy‐β‐metylbutyrate and 2‐oxoglutaric acid on femur development in offspring of minks of the standard dark brown type

The aim of the study was to evaluate the effect of the diet, mother type and sex of the offspring on the mechanical and geometric parameters of long bones as well as bone tissue density in minks. Primiparous and multiparous dams were supplemented with β‐hydroxy β‐methylbutyrate (a metabolite of leucine, at the daily dosage of 0.02 g/kg of body weight) and/or 2‐oxoglutaric acid (a precursor of glutamine, at the daily dosage of 0.4 g/kg of body weight) during gestation. The diet did not influence bone tissue density and the length of the humerus. An increase in the length of the femur was noted in male offspring delivered by multiparous dams. The diet resulted in an increase in the weight of the humerus in males from multiparous dams and a decrease in offspring from primiparous dams. Heavier femora were noted in male offspring delivered by both types of dams. The maximum elastic strength of the humerus was higher in the offspring delivered by multiparous than primiparous dams, irrespective of the offspring sex. The diet resulted in reduction in the ultimate strength of the femur in the male offspring delivered by primiparous dams. Only females born by multiparous dams, irrespective of the diet, showed a significant increase in the cross‐sectional area of the humerus, while a significant decline was noted in males delivered by multiparous dams and in all the offspring delivered by primiparous dams. An increase in the cross‐sectional area of the femur was noted in the offspring delivered by multiparous dams, while reduction was observed in the offspring delivered by primiparous dams. These results have shown for the first time that the presence of β‐hydroxy‐β‐methylbutyrate or 2‐oxoglutaric acid in the diet of pregnant primiparous or multiparous dams unambiguously affects the geometry and mechanical properties of offspring's long bones.     

Effects of three antagonists on selected pharmacodynamic effects of sublingually administered detomidine in the horse

ObjectiveTo describe the effects of alpha₂-adrenergic receptor antagonists on the pharmacodynamics of sublingual (SL) detomidine in the horse.Study designRandomized crossover design.AnimalsNine healthy adult horses with an average age of 7.6 ± 6.5 years.MethodsFour treatment groups were studied: 1) 0.04 mg kg^?1 detomidine SL; 2) 0.04 mg kg^?1 detomidine SL followed 1 hour later by 0.075 mg kg^?1 yohimbine intravenously (IV); 3) 0.04 mg kg^?1 detomidine SL followed 1 hour later by 4 mg kg^?1 tolazoline IV; and 4) 0.04 mg kg^?1 detomidine SL followed 1 hour later by 0.12 mg kg^?1 atipamezole IV. Each horse received all treatments with a minimum of 1 week between treatments. Blood samples were obtained and plasma analyzed for yohimbine, atipamezole and tolazoline concentrations by liquid chromatography-mass spectrometry. Behavioral effects, heart rate and rhythm, glucose, packed cell volume (PCV) and plasma proteins were monitored.ResultsChin-to-ground distance increased following administration of the antagonists, however, this effect was transient, with a return to pre-reversal values as early as 1 hour. Detomidine induced bradycardia and increased incidence of atrioventricular blocks were either transiently or incompletely antagonized by all antagonists. PCV and glucose concentrations increased with tolazoline administration, and atipamezole subjectively increased urination frequency but not volume.Conclusions and clinical relevanceAt the doses administered in this study, the alpha₂-adrenergic antagonistic effects of tolazoline, yohimbine and atipamezole on cardiac and behavioral effects elicited by SL administration of detomidine are transient and incomplete.