Effects of constant rate infusions of dexmedetomidine,remifentanil and their combination on minimum alveolar concentration of sevoflurane in dogs

ObjectiveTo evaluate the effects of constant rate infusions (CRIs) of dexmedetomidine and remifentanil alone and their combination on minimum alveolar concentration (MAC) of sevoflurane in dogs.Study designRandomized crossover experimental study.AnimalsA total of six (three males, three females) healthy, adult neutered Beagle dogs weighing 12.6 ± 1.4 kg.MethodsAnesthesia was induced with sevoflurane in oxygen until endotracheal intubation was possible and anesthesia maintained with sevoflurane using positive-pressure ventilation. Each dog was anesthetized five times and was administered each of the following treatments: saline (1 mL kg^–1 hour^–1) or dexmedetomidine at 0.1, 0.5, 1.0 or 5.0 μg kg^–1 loading dose intravenously over 10 minutes followed by CRI at 0.1, 0.5, 1.0 or 5.0 μg kg^–1 hour^–1, respectively. Following 60 minutes of CRI, sevoflurane MAC was determined in duplicate using an electrical stimulus (50 V, 50 Hz, 10 ms). Then, CRI of successively increasing doses of remifentanil (0.15, 0.60 and 2.40 μg kg^–1 minute^–1) was added to each treatment. MAC was also determined after 30 minutes equilibration at each remifentanil dose. Isobolographic analysis determined interaction from the predicted doses required for a 50% MAC reduction (ED₅₀) with remifentanil, dexmedetomidine and remifentanil combined with dexmedetomidine, with the exception of dexmedetomidine 5.0 μg kg^–1 hour^–1, obtained using log-linear regression analysis.ResultsThe sevoflurane MAC decreased dose-dependently with increasing infusion rates of dexmedetomidine and remifentanil. Remifentanil ED₅₀ values were lower when combined with dexmedetomidine than those obtained during saline–remifentanil. Synergistic interactions between dexmedetomidine and remifentanil for MAC reduction occurred with dexmedetomidine at 0.5 and 1.0 μg kg^–1 hour^–1.Conclusions and clinical relevanceCombined CRIs of dexmedetomidine and remifentanil synergistically resulted in sevoflurane MAC reduction. The combination of dexmedetomidine and remifentanil effectively reduced the requirement of sevoflurane during anesthesia in dogs.     

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

ObjectiveTo 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 designExperimental, observational study.AnimalsA group of six healthy, purpose-bred Beagle dogs (four females and two males) aged 6.5 ± 0.1 years (mean ± standard deviation).MethodsAll 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.ResultsAll 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 relevanceWith 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,respiratory, electrolyte and acid–base balance during continuous dexmedetomidine infusion in anesthetized dogs

ObjectiveTo evaluate the cardiovascular, respiratory, electrolyte and acid–base effects of a continuous infusion of dexmedetomidine during propofol–isoflurane anesthesia following premedication with dexmedetomidine.Study designProspective experimental study.AnimalsFive adult male Walker Hound dogs 1–2 years of age averaging 25.4 ± 3.6 kg.MethodsDogs were sedated with dexmedetomidine 10 μg kg^?1 IM, 78 ± 2.3 minutes (mean ± SD) before general anesthesia. Anesthesia was induced with propofol (2.5 ± 0.5 mg kg^?1) IV and maintained with 1.5% isoflurane. Thirty minutes later dexmedetomidine 0.5 μg kg^?1 IV was administered over 5 minutes followed by an infusion of 0.5 μg kg^?1 hour^?1. Cardiac output (CO), heart rate (HR), ECG, direct blood pressure, body temperature, respiratory parameters, acid–base and arterial blood gases and electrolytes were measured 30 and 60 minutes after the infusion started. Data were analyzed via multiple linear regression modeling of individual variables over time, compared to anesthetized baseline values. Data are presented as mean ± SD.ResultsNo statistical difference from baseline for any parameter was measured at any time point. Baseline CO, HR and mean arterial blood pressure (MAP) before infusion were 3.11 ± 0.9 L minute^?1, 78 ± 18 beats minute^?1 and 96 ± 10 mmHg, respectively. During infusion CO, HR and MAP were 3.20 ± 0.83 L minute^?1, 78 ± 14 beats minute^?1 and 89 ± 16 mmHg, respectively. No differences were found in respiratory rates, PaO₂, PaCO₂, pH, base excess, bicarbonate, sodium, potassium, chloride, calcium or lactate measurements before or during infusion.Conclusions and clinical relevanceDexmedetomidine infusion using a loading dose of 0.5 μg kg^?1 IV followed by a constant rate infusion of 0.5 μg kg^?1 hour^?1 does not cause any significant changes beyond those associated with an IM premedication dose of 10 μg kg^?1, in propofol–isoflurane anesthetized dogs. IM dexmedetomidine given 108 ± 2 minutes before onset of infusion showed typical significant effects on cardiovascular parameters.     

Minimum end‐tidal sevoflurane concentration necessary to prevent movement during a constant rate infusion of morphine,or morphine plus dexmedetomidine in ponies

ObjectiveTo compare the effects of a constant rate infusion (CRI) of dexmedetomidine and morphine to those of morphine alone on the minimum end-tidal sevoflurane concentration necessary to prevent movement (MAC_NM) in ponies.Study designProspective, randomized, crossover, ‘blinded’, experimental study.AnimalsFive healthy adult gelding ponies were anaesthetized twice with a 3-week washout period.MethodsAfter induction of anaesthesia with sevoflurane in oxygen (via nasotracheal tube), the ponies were positioned on a surgical table (T0), and anaesthesia was maintained with sevoflurane (Fe‘SEVO 2.5%) in 55% oxygen. Monitoring included pulse oximetry, electrocardiography and measurement of anaesthetic gases, arterial blood pressure and body temperature. The ponies were mechanically ventilated and randomly allocated to receive IV treatment M [morphine 0.15 mg kg^?1 (T10-T15) followed by a CRI (0.1 mg kg^?1 hour^?1)] or treatment DM [dexmedetomidine 3.5 μg kg^?1 plus morphine 0.15 mg kg^?1 (T10-T15) followed by a CRI of dexmedetomidine 1.75 μg kg^?1 hour^?1 and morphine 0.1 mg kg^?1 hour^?1]. At T60, a stepwise MAC_NM determination was initiated using constant current electrical stimuli at the skin of the lateral pastern region. Triplicate MAC_NM estimations were obtained and then averaged in each pony. Wilcoxon signed-rank test was used to detect differences in MAC between treatments (a = 0.05).ResultsSevoflurane-morphine MAC_NM values (median (range) and mean ± SD) were 2.56 (2.01–4.07) and 2.79 ± 0.73%. The addition of a continuous infusion of dexmedetomidine significantly reduced sevoflurane MAC_NM values to 0.89 (0.62–1.05) and 0.89 ± 0.22% (mean MAC_NM reduction 67 ± 11%).Conclusion and clinical relevanceCo-administration of dexmedetomidine and morphine CRIs significantly reduced the MAC_NM of sevoflurane compared with a CRI of morphine alone at the reported doses.     

Inhibition and facilitation of nociceptively evoked muscular activity by fentanyl or dexmedetomidine in isoflurane-anaesthetized pigs

ObjectiveTo investigate motor and cardiovascular responses to dexmedetomidine or fentanyl in isoflurane-anaesthetized pigs.Study designExperimental, balanced, block randomized, two-group design.AnimalsA group of 16 crossbred pigs, 55 ± 8 days (mean ± standard deviation) old.MethodsDeltoid electromyography (EMG) was recorded during isoflurane anaesthesia. Electrical stimulation using 5, 10, 20 and 40 mA of the distal right thoracic limb elicited a nociceptive withdrawal reflex (NWR), quantified by the area under the curve (AUC) for the simulation intensity versus EMG amplitude response curve. Latency to movement evoked by clamping a claw for maximum 60 seconds was noted. Arterial blood pressure and pulse rate were recorded. Data were sampled at baseline and during dexmedetomidine 0.25, 0.5, 1.0, 2.0, 4.0 and 8.0 μg kg^–1 hour^–1 or fentanyl 5, 10, 20, 40, 80 and 160 μg kg^–1 hour^–1 infusions. The influence of infusion rate on NWR AUC and spontaneous EMG was analysed using a mixed model, with p < 5%.ResultsNWR AUC increased at fentanyl 5 μg kg^–1 hour^–1 but decreased at fentanyl 40, 80 and 160 μg kg^–1 hour^–1 and dexmedetomidine 4.0 and 8.0 μg kg^–1 hour^–1. All pigs at fentanyl 80 μg kg^–1 hour^–1, and three pigs at dexmedetomidine 8.0 μg kg^–1 hour^–1 had mechanical latencies greater than 60 seconds. Spontaneous EMG activity increased accompanied by visually evident ‘shivering’ at fentanyl 5, 10 and 20 μg kg^–1 hour^–1 but decreased at dexmedetomidine 2, 4 and 8 μg kg^–1 hour^–1. Clinically relevant effects of increasing infusion rates on blood pressure or pulse rate were not observed.Conclusion and clinical relevanceIf anaesthetic plane or antinociception is evaluated in pigs, response to claw clamping and NWR will not necessarily give uniform results when comparing drugs. If only one method is used, results should be interpreted cautiously.     

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

ObjectiveTo determine whether dobutamine, norepinephrine or phenylephrine infusions alleviate hypotension in isoflurane-anaesthetized dogs administered dexmedetomidine with vatinoxan.Study designBalanced, randomized crossover trial.AnimalsA total of eight healthy Beagle dogs.MethodsEach 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.ResultsMost 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 relevanceHypotension in isoflurane-anaesthetized dogs administered dexmedetomidine and vatinoxan can be treated with either dobutamine or norepinephrine.     

Effect of epidural and intravenous use of the neurokinin-1 (NK-1) receptor antagonist maropitant on the sevoflurane minimum alveolar concentration (MAC) in dogs

ObjectiveTo determine the effect of maropitant, an NK-1 receptor antagonist on the minimum alveolar concentration (MAC) of sevoflurane after intravenous and epidural administration to dogs.Study designProspective experimental study.AnimalsSeven, adult, spayed-female dogs (24.8 ± 1.9 kg).MethodsEach dog was anesthetized twice with sevoflurane in oxygen, with at least 10 days separating the anesthetic events. The minimum alveolar concentration (MAC) of sevoflurane was determined using the tail-clamp technique. During the first anesthetic event, the MAC of sevoflurane was determined initially and again after intravenous administration of maropitant (5 mg kg^?1) and an infusion (150 μg kg^?1 hour^?1). During the second anesthetic event, an epidural catheter was advanced to the 4th lumbar vertebra and MAC was determined after administration of saline and maropitant (1 mg kg^?1) epidurally. All MAC determinations were done in duplicate. The MAC values were adjusted to sea level and compared using student's t-test.ResultsThe baseline MAC for sevoflurane was 2.08 ± 0.25%. Intravenous maropitant decreased (p < 0.05) MAC by 16% (1.74 ± 0.17%). In contrast, epidural administration of either saline or maropitant did not change (p > 0.05) the MAC (2.17 ± 0.34% and 1.92 ± 0.12%, respectively).Conclusion and clinical relevanceMaropitant decreased the MAC of sevoflurane when administered intravenously to dogs but not after epidural administration.     

Effects of continuous intravenous infusion of morphine and morphine‐tramadol on the minimum alveolar concentration of sevoflurane and electroencephalographic entropy indices in dogs

ObjectiveTo compare the effects of continuous rate infusions (CRIs) of intravenous (IV) morphine and morphine-tramadol on the minimum alveolar concentration (MAC) of sevoflurane, and on electroencephalographic entropy indices in dogs.DesignProspective study.AnimalsEight young, healthy German shepherds, weighing 26.3 ± 3.1 kg (mean ± SD).MethodsAnaesthesia was induced and maintained with sevoflurane. A standard tail-clamp technique was used for MAC determination. Within one anaesthetic period, MAC was first determined during sevoflurane anaesthesia alone (MAC_B); then during morphine infusion (MAC_M), (loading dose 0.5 mg kg⁻¹IM; CRI, 0.2 mg kg⁻¹hour⁻¹⁾ then finally during morphine-tramadol infusion (tramadol loading dose 1.5 mg kg⁻¹IV; CRI, 2.6 mg kg⁻¹ hour⁻¹) (MAC_MT). At each change, periods of 45 minutes were allowed for equilibration. Stated entropy (SE), response entropy (RE), and RE-SE differences were measured five minutes prior to and during tail clamping.ResultsThe MAC_B was 2.1 ± 0.3vol%. The morphine and morphine-tramadol infusions reduced MAC to 1.6 ± 0.3vol% and 1.3 ± 0.3vol%, respectively. MAC was decreased below baseline more during morphine-tramadol than during morphine alone (39 ± 9% versus 25 ± 6%, respectively; p = 0.003). All SE and RE and most RE-SE differences were increased significantly (p < 0.05) over pre-stimulation in all groups when the dogs responded purposefully to noxious stimulation. When no response to noxious stimulation occurred, the entropy indices did not change.Conclusion and clinical relevanceIn dogs, combined morphine-tramadol CRI decreased sevoflurane MAC more than morphine CRI alone. Entropy indices changed during nociceptive responses in anaesthetized animals, suggesting that entropy measurements may be useful in determining anaesthetic depth in dogs.     

The cardiovascular effects of dexmedetomidine given by continuous infusion during isoflurane anesthesia in dogs

In a previous study we showed that the MAC of isoflurane was decreased by 18 ± 12% and 59 ± 7% by constant rate infusions of dexmedetomidine at 0.5 and 3 μg kg^–1 hour^–1. The purpose of this study was to document the cardiovascular changes associated with these infusions of dexmedetomidine at 1.3 MAC isoflurane/ dexmedetomidine. Dogs were anesthetized with isoflurane in oxygen given by mask. A cephalic venous catheter, a dorsal pedal arterial catheter and a balloon tipped, Swan–Ganz, pulmonary arterial catheter were placed percutaneously. After instrumentation the dogs were maintained at 1.3 MAC isoflurane for 60 minutes. At this time a set of measurements was made including, heart rate, respiratory rate, core body temperature, pulmonary and systemic arterial blood pressures (SAP, MAP, DAP, CVP, SPAP, MPAP, DPAP and PAOP), cardiac output and arterial and mixed venous blood samples were collected for the measurement of blood gases, pH, hemoglobin concentration, PCV and total protein. Calculated variables included base excess (BE), (HCO₃^?), cardiac index, systemic and pulmonary vascular resistance indices, oxygen delivery, oxygen consumption, oxygen utilization ratio and shunt fraction. After these measurements to dogs were randomly assigned to receive a loading dose of 0.5 or 3 μg kg^–1 of dexmedetomidine given over 6 minutes followed by an infusion of 0.5 (LD) or 3 μg kg^–1 hour^–1 (HD), respectively. The concentration of isoflurane was reduced by the above percentages, respectively, to maintain 1.3 MAC. Full sets of measurements were repeated at 10, 30, 60, 90, 120, 150 and 180 minutes after the start of the loading dose. Measured and calculated variables were compared with baseline using an anova and a post‐hoc Tukey's test. Significance was set at p = 0.05 and results are given as mean ± SD. The initial concentration of isoflurane was 1.73 ± 0.02% and was reduced to 1.41 ± 0.02 and 0.72 ± 0.09% for the LD and HD, respectively. Heart rate decreased with both doses but no other parameter changed significantly with the LD. With the HD there were significant changes in SAP, MAP, DAP, CVP, MPAP, PAOP, CI, SVRI, PCV, DO₂ and shunt fraction. The LD appeared to have minimal effect on the cardiopulmonary values measured, whereas the HD caused typical changes expected with an alpha‐2 agonist.     

Use of intravenous lidocaine to treat dexmedetomidine-induced bradycardia in sedated and anesthetized dogs

ObjectiveTo assess cardiopulmonary function in sedated and anesthetized dogs administered intravenous (IV) dexmedetomidine and subsequently administered IV lidocaine to treat dexmedetomidine-induced bradycardia.Study designProspective, randomized, crossover experimental trial.AnimalsA total of six purpose-bred female Beagle dogs, weighing 9.1 ± 0.6 kg (mean ± standard deviation).MethodsDogs were randomly assigned to one of three treatments: dexmedetomidine (10 μg kg^–1 IV) administered to conscious (treatments SED1 and SED2) or isoflurane-anesthetized dogs (end-tidal isoflurane concentration 1.19 ± 0.04%; treatment ISO). After 30 minutes, a lidocaine bolus (2 mg kg^–1) IV was administered in treatments SED1 and ISO, followed 20 minutes later by a second bolus (2 mg kg^–1) and a 30 minute lidocaine constant rate infusion (L-CRI) at 50 (SED1) or 100 μg kg^–1 minute^–1 (ISO). In SED2, lidocaine bolus and L-CRI (50 μg kg^–1 minute^–1) were administered 5 minutes after dexmedetomidine. Cardiopulmonary measurements were obtained after dexmedetomidine, after lidocaine bolus, during L-CRI and 30 minutes after discontinuing L-CRI. A mixed linear model was used for comparisons within treatments (p < 0.05).ResultsWhen administered after a bolus of dexmedetomidine, lidocaine bolus and L-CRI significantly increased heart rate and cardiac index, decreased mean blood pressure, systemic vascular resistance index and oxygen extraction ratio, and did not affect stroke volume index in all treatments.Conclusion and clinical relevanceLidocaine was an effective treatment for dexmedetomidine-induced bradycardia in healthy research dogs.     

Pharmacokinetics of vatinoxan in male neutered cats anesthetized with isoflurane

ObjectiveTo characterize the pharmacokinetics of vatinoxan in isoflurane-anesthetized cats.Study designProspective experimental study.AnimalsA group of six adult healthy male neutered cats.MethodsCats 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.ResultsA 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 relevanceThe 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.     

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.     

Microcirculation assessment of dexmedetomidine constant rate infusion during anesthesia of dogs with sepsis from pyometra: a randomized clinical study

ObjectiveTo compare dexmedetomidine and fentanyl constant rate infusions in anesthetic protocols for septic dogs with pyometra, using microcirculatory, hemodynamic and metabolic variables.Study designRandomized clinical study.AnimalsA total of 33 dogs with pyometra with two or more systemic inflammatory response syndrome variables undergoing ovariohysterectomy.MethodsDogs were randomized into two groups: group DG, dexmedetomidine (3 μg kg^–1 hour^–1; 17 dogs) and group FG, fentanyl (5 μg kg^–1 hour^–1; 16 dogs) infused during isoflurane anesthesia and mechanical ventilation. Microcirculation flow index (MFI), total vessel density and De Backer score were assessed using orthogonal polarization spectral imaging at the sublingual site. Heart rate, invasive blood pressure, temperature, arterial blood gas analysis and lactate concentration were obtained at various time points. Variables were recorded at baseline (BL), immediately before (T0), 30 (T30) and 60 (T60) minutes after infusion, and 60 minutes after surgery. Data were analyzed using the Shapiro-Wilk test. To compare variables between groups, the unpaired Student t test was used. Comparison between evaluation time points was performed with two-way anova for repeated measures. Where statistical significance was detected, the Bonferroni post hoc test was used.ResultsMFI was significantly higher in group FG at T30. Mean arterial pressure at T30 was higher in group DG (89 ± 15 mmHg) than in group FG (72 ± 13 mmHg). Lactate concentrations were not significantly different between groups at each time point. Both groups had similar clinical outcomes (mortality, extubation time and occurrence of hypotension and bradyarrhythmias).Conclusions and clinical relevanceDexmedetomidine (3 μg kg^–1 hour^–1) without a loading dose can be included in the maintenance of anesthesia in dogs with pyometra and sepsis without compromising microcirculation and hemodynamic values when compared with fentanyl (5 μg kg^–1 hour^–1).     

Concentrations of vatinoxan and xylazine in plasma,cerebrospinal fluid and brain tissue following intravenous administration in sheep

ObjectivesTo investigate the extent of vatinoxan distribution into sheep brain, and whether vatinoxan influences brain concentrations of xylazine; and to examine the utility of cerebrospinal fluid (CSF) as a surrogate of brain tissue concentrations for vatinoxan and xylazine.Study designRandomised, blinded, experimental study.AnimalsA total of 14 adult female sheep.MethodsSheep were randomly allocated into two equal groups and premedicated with either intravenous (IV) vatinoxan (750 μg kg^–1, VX) or saline (SX) administered 10 minutes before IV xylazine (500 μg kg^–1). Sedation was subjectively assessed at selected intervals before and after treatments. At 10 minutes after xylazine administration, a venous blood sample was collected and the sheep were immediately euthanised with IV pentobarbital (100 mg kg^–1). Plasma, CSF and brain tissues were harvested, and concentrations of vatinoxan and xylazine were quantified using liquid chromatography–tandem mass spectrometry. Drug ratios were then calculated and the data were analysed as appropriate.ResultsThe brain-to-plasma and CSF-to-plasma ratios of vatinoxan were 0.06 ± 0.013 and 0.05 ± 0.01 (mean ± standard deviation), respectively. Xylazine brain concentrations were not significantly different (835 ± 262 versus 1029 ± 297 ng g^–1 in groups VX and SX, respectively) and were approximately 15-fold higher than those in plasma. The CSF-to-brain ratio of vatinoxan was 0.8 ± 0.2, whereas xylazine concentrations in the brain were approximately 17-fold greater than those in CSF, with and without vatinoxan.Conclusions and clinical relevanceVatinoxan did not significantly affect sedation with xylazine or the concentrations of xylazine in the brain. CSF is not a good predictor of xylazine concentrations in the brain, whereas vatinoxan concentrations were concordant between the brain and CSF, using the dosages in this study.     

Evaluation of the perioperative stress response from dexmedetomidine infusion alone,with butorphanol bolus or remifentanil infusion compared with ketamine and morphine infusions in isoflurane-anesthetized horses

ObjectiveTo evaluate perioperative stress-related hormones in isoflurane-anesthetized horses administered infusions of dexmedetomidine alone or with butorphanol or remifentanil, compared with ketamine–morphine.Study designRandomized, prospective, nonblinded clinical study.AnimalsA total of 51 horses undergoing elective surgical procedures.MethodsHorses were premedicated with xylazine, anesthesia induced with ketamine–diazepam and maintained with isoflurane and one of four intravenous infusions. Partial intravenous anesthesia (PIVA) was achieved with dexmedetomidine (1.0 μg kg^–1 hour^–1; group D; 12 horses); dexmedetomidine (1.0 μg kg^–1 hour^–1) and butorphanol bolus (0.05 mg kg^–1; group DB; 13 horses); dexmedetomidine (1.0 μg kg^–1 hour^–1) and remifentanil (3.0 μg kg^–1 hour^–1; group DR; 13 horses); or ketamine (0.6 mg kg^–1 hour^–1) and morphine (0.15 mg kg^–1, 0.1 mg kg^–1 hour^–1; group KM; 13 horses). Infusions were started postinduction; butorphanol bolus was administered 10 minutes before starting surgery. Blood was collected before drugs were administered (baseline), 10 minutes after ketamine–diazepam, every 30 minutes during surgery and 1 hour after standing. Mean arterial pressure (MAP), pulse rate, end-tidal isoflurane concentration, cortisol, nonesterified fatty acids (NEFA), glucose and insulin concentrations were compared using linear mixed models. Significance was assumed when p < 0.05.ResultsWithin D, cortisol was lower at 120–180 minutes from starting surgery compared with baseline. Cortisol was higher in KM than in D at 60 minutes from starting surgery. Within all groups, glucose was higher postinduction (except DR) and 60 minutes from starting surgery, and insulin was lower during anesthesia and higher after standing compared with baseline. After standing, NEFA were higher in KM than in DB. In KM, MAP increased at 40–60 minutes from starting surgery compared with 30 minutes postinduction.Conclusions and clinical relevanceDexmedetomidine suppressed cortisol release more than dexmedetomidine–opioid and ketamine–morphine infusions. Ketamine–morphine PIVA might increase catecholamine activity.     

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.

Postoperative analgesic effects of either a constant rate infusion of fentanyl,lidocaine, ketamine,dexmedetomidine, or the combination lidocaine‐ketamine‐dexmedetomidine after ovariohysterectomy in dogs

ObjectiveTo evaluate the postoperative analgesic effects of a constant rate infusion (CRI) of either fentanyl (FENT), lidocaine (LIDO), ketamine (KET), dexmedetomidine (DEX), or the combination lidocaine-ketamine-dexmedetomidine (LKD) in dogs.Study designRandomized, prospective, blinded, clinical study.AnimalsFifty-four dogs.MethodsAnesthesia was induced with propofol and maintained with isoflurane. Treatments were intravenous (IV) administration of a bolus at start of anesthesia, followed by an IV CRI until the end of anesthesia, then a CRI at a decreased dose for a further 4 hours: CONTROL/BUT (butorphanol 0.4 mg kg⁻¹, infusion rate of saline 0.9% 2 mLkg⁻¹ hour⁻¹); FENT (5 μg kg⁻¹, 10 μg kg⁻¹hour⁻¹, then 2.5 μg kg⁻¹ hour⁻¹); KET (1 mgkg⁻¹, 40 μg kg⁻¹ minute⁻¹, then 10 μg kg⁻¹minute⁻¹); LIDO (2 mg kg⁻¹, 100 μg kg⁻¹ minute⁻¹, then 25 μg kg⁻¹ minute⁻¹); DEX (1 μgkg⁻¹, 3 μg kg⁻¹ hour⁻¹, then 1 μg kg⁻¹ hour⁻¹); or a combination of LKD at the aforementioned doses. Postoperative analgesia was evaluated using the Glasgow composite pain scale, University of Melbourne pain scale, and numerical rating scale. Rescue analgesia was morphine and carprofen. Data were analyzed using Friedman or Kruskal–Wallis test with appropriate post-hoc testing (p < 0.05).ResultsAnimals requiring rescue analgesia included CONTROL/BUT (n = 8), KET (n = 3), DEX (n = 2), and LIDO (n = 2); significantly higher in CONTROL/BUT than other groups. No dogs in LKD and FENT groups received rescue analgesia. CONTROL/BUT pain scores were significantly higher at 1 hour than FENT, DEX and LKD, but not than KET or LIDO. Fentanyl and LKD sedation scores were higher than CONTROL/BUT at 1 hour.Conclusions and clinical relevanceLKD and FENT resulted in adequate postoperative analgesia. LIDO, CONTROL/BUT, KET and DEX may not be effective for treatment of postoperative pain in dogs undergoing ovariohysterectomy.     

Effects of dopamine,norepinephrine or phenylephrine on the prevention of hypotension in isoflurane-anesthetized cats administered vatinoxan or vatinoxan and dexmedetomidine

ObjectiveTo determine the dose of phenylephrine, norepinephrine and dopamine necessary to maintain mean arterial pressure (MAP) within 70–80 mmHg during administration of isoflurane, isoflurane and vatinoxan and isoflurane, vatinoxan and dexmedetomidine at three plasma concentrations.Study designRandomized crossover experimental study.AnimalsA group of five adult healthy neutered male cats.MethodsInstrumentation occurred during anesthesia with isoflurane in oxygen. Isoflurane end-tidal concentration was set to 1.25 × minimum alveolar concentration (MAC). Phenylephrine, norepinephrine or dopamine was administered to maintain MAP 70–80 mmHg. A target-controlled infusion system was used to administer vatinoxan at a target plasma concentration of 1 μg mL^–1 and three dexmedetomidine concentrations (5, 10 and 20 ng mL^–1). Isoflurane concentration was altered to maintain an equivalent 1.25 MAC. Heart rate, arterial blood pressure, central venous pressure, pulmonary artery pressure, pulmonary artery occlusion pressure, body temperature, arterial and mixed venous blood gas, cardiac output and drug concentrations were measured at baseline (isoflurane alone), during vatinoxan administration, and during administration of vatinoxan and dexmedetomidine at the three target concentrations.ResultsMAP < 70 mmHg was observed with vatinoxan alone and in the dopamine treatment with dexmedetomidine concentrations ≤ 10 ng mL^–1. Norepinephrine and phenylephrine maintained MAP 70–80 mmHg during vatinoxan and dexmedetomidine ≤ 10 ng mL^–1. As the target dexmedetomidine concentration increased, the dose of norepinephrine and phenylephrine needed to maintain MAP 70–80 mmHg decreased; no treatment was necessary to maintain MAP > 70 mmHg at the 20 ng mL^–1 target dexmedetomidine concentration in most cats.Conclusions and clinical relevanceNorepinephrine and phenylephrine, but not dopamine, are effective to prevent hypotension in isoflurane-anesthetized cats administered dexmedetomidine and vatinoxan.     

The effect of fentanyl on the end‐tidal sevoflurane concentration needed to prevent motor movement in dogs

ObjectiveThe objectives of this study were to determine the effects of fentanyl on the end-tidal concentration of sevoflurane needed to prevent motor movement (MAC_NM) in response to noxious stimulation, and to evaluate if acute tolerance develops.Study designRandomized cross-over experimental study.AnimalsSix healthy, adult (2–3 years old), intact male, mixed-breed dogs weighing 16.2 ± 1.1 kg.MethodsSix dogs were randomly assigned to receive one of three separate treatments over a 3 week period. After baseline sevoflurane MAC_NM (MAC_NM-B) determination, fentanyl treatments (T) were administered as a loading dose (Ld) and constant rate infusion (CRI) as follows: T1-Ld of 7.5 μg kg^?1 and CRI at 3 μg kg^?1 hour^?1; T2-Ld of 15 μg kg^?1 and CRI at 6.0 μg kg ^?1 hour^?1; T3-Ld of 30 μg kg^?1 and CRI at 12 μg kg^?1 hour^?1. The MAC_NM was defined as the minimum end-tidal sevoflurane concentration preventing motor movement. The first post-treatment MAC_NM (MAC_NM-I) determination was initiated 90 minutes after the start of the CRI, and a second MAC_NM (MAC_NM-II) determination was initiated 3 hours after MAC_NM-I was established.ResultsThe overall least square mean MAC_NM-B for all groups was 2.66%. All treatments decreased (p < 0.05) MAC_NM, and the decrease from baseline was 22%, 35% and 41% for T1, T2 and T3, respectively. Percentage change in T1 differed (p < 0.05) from T2 and T3; however, T2 did not differ from T3. MAC_NM-I was not significantly different from MAC_NM-II within treatments.Conclusions and clinical relevanceFentanyl doses in the range of 3–12 μg kg^?1 hour^?1 significantly decreased the sevoflurane MAC_NM. Clinically significant tolerance to fentanyl did not occur under the study conditions.     

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

ObjectiveTo 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 designRandomized, masked crossover study.AnimalsA total of eight purpose-bred Beagle dogs aged 3 years.MethodsEach 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.ResultsAt 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 relevanceHaemodynamic 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.