Activation in the auditory pathway of the gerbil studied with 18F-FDG PET: effects of anesthesia.

Here, we present results from an 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) study in the Mongolian gerbil, a preferred animal model in auditory research. One major issue in preclinical nuclear imaging, as well as in most of the neurophysiological methods investigating auditory processing, is the need of anesthesia. We compared the usability of two types of anesthesia which are frequently employed in electrophysiology, ketamine/xylazine (KX), and fentanyl/midazolam/medetomidine (FMM), for valid measurements of auditory activation with 18F-FDG PET. Gerbils were placed in a sound-shielding box and injected with 18F-FDG. Two acoustic free-field conditions were used: (1) baseline (no stimulation, 25 dB background noise) and (2) 90 dB frequency-modulated tones (FM). After 40 min of 18F-FDG uptake, a 30 min acquisition was performed using a small animal PET/CT system. Blood glucose levels were measured after the uptake phase before scanning. Standardized uptake value ratios for relevant regions were determined after implementing image and volume of interest templates. Scans demonstrated a significantly higher uptake in the inferior colliculus with FM stimulation compared to baseline in awake subjects (+ 12%; p = 0.02) and with FMM anesthesia (+ 13%; p = 0.0012), but not with KX anesthesia. In non-auditory brain regions, no significant difference was detected. Blood glucose levels were significantly higher under KX compared to FMM anesthesia (17.29 ± 0.42 mmol/l vs. 14.30 ± 1.91 mmol/l; p = 0.024). These results suggest that valid 18F-FDG PET measurements of auditory activation comparable to electrophysiology can be obtained from gerbils during opioid-based anesthesia due to its limited effects on interfering blood glucose levels.

Effects of a mixture of medetomidine, midazolam and butorphanol on anesthesia and blood biochemistry and the antagonizing action of atipamezole in hamsters.

Syrian golden hamsters (Mesocricetus auratus) are useful laboratory rodents for studying human infectious diseases, metabolic diseases and cancer. In other rodents, such as mice and rats, a mixture of medetomidine, midazolam and butorphanol functions as a useful anesthetic, although it alters some blood biochemical parameters. In this study, we examined the effects of this mixture on anesthesia and blood biochemical parameters, and the action of atipamezole, a medetomidine antagonist, in hamsters. Intramuscular injection of a mixture of medetomidine, midazolam and butorphanol at doses of 0.15, 2.0 and 2.5 mg/kg, respectively, had a short induction time (within 5 min) and produced an anesthetic duration of approximately 100 min in hamsters. We also demonstrated that 0.15 mg/kg of atipamezole, corresponding to the same dose as medetomidine, made hamsters recover quickly from anesthesia. The anesthetic agent markedly altered metabolic parameters, such as plasma glucose and insulin; however, 0.15 mg/kg of atipamezole returned these levels to normal range within approximately 10 min after the injection. The anesthetic also slightly altered mineral levels, such as plasma inorganic phosphorus, calcium and sodium; the latter two were also improved by atipamezole. Our results indicated that the mixture of medetomidine, midazolam, and butorphanol at doses of 0.15, 2.0 and 2.5 mg/kg, respectively, functioned as an effective anesthetic, and atipamezole was useful for antagonizing both anesthesia and biochemical alteration in hamsters.

Blood biochemical changes in mice after administration of a mixture of three anesthetic agents.

Currently, from the viewpoint of animal welfare, anesthesia or analgesia is required during experimental procedures in animals that are likely to cause pain. A part of these anesthetics have been reported to influence a blood biochemical level. It is important for us to understand the effect of the anesthetic on blood biochemistry when we choose the anesthetic agent to be used in experiments. In this study, we examined the blood biochemical changes in mice after administration of a new mixture of three anesthetic agents -medetomidine / midazolam / butorphanol (MMB). We subcutaneously administered two dose combinations of MMB (0.45 / 6 / 7.5 and 0.9 / 12 / 15 mg/kg) in mice, followed by administration of atipamezole, for reversal of anesthetic effects, after 1 hr. Thereafter, blood biochemistry was assessed at 1, 4 and 24 hr after MMB administration. We observed that MMB administration caused a transient increase in blood sugar, inorganic phosphorus, potassium and creatine kinase levels. These, however, returned to the reference range 24 hr after MMB administration. In conclusion, MMB changes the levels of some blood biochemical parameters, but not to an extent that would threaten health. However, when using laboratory animals, this effect of MMB may influence the experimental results, depending on the experimental content. Hence, the choice of anesthetic agents used in laboratory animals should be based on detailed knowledge of their pharmacological effects.

Optimal medetomidine dose when combined with ketamine and tiletamine-zolazepam to immobilize white-tailed deer.

Chemical immobilization is often needed for safe and effective capture and handling of wildlife. We evaluated medetomidine (125, 150, 175, or 200 µg/kg; for synergistic effects and relaxation) mixed with ketamine (1.5 mg/kg; for relatively shorter recovery) and tiletamine-zolazepam (1.0 mg/kg; for rapid induction) in 22 female white-tailed deer (Odocoileus virginianus) at the University of Georgia Whitehall Deer Research Facility in Athens, Georgia, USA, on 14-15 and 21 May 2009. Deer were weighed before treatment, hand-injected intramuscularly (IM) while restrained in a squeeze chute, and released into a pen for monitoring. We measured rectal temperature, respiration rate, heart rate, hemoglobin saturation (using pulse oximetry), and arterial blood gases at 0, 10, and 20 min postimmobilization. We found no differences in induction time with different doses of medetomidine. Deer became laterally recumbent for all treatments combined at a median of 4.2 (2.6-21.3) min and were approachable by a median of 4.8 (3.5-21.8) min. Twelve of the 22 deer had rectal temperatures >40 C at time 0 and were treated with a cold-water enema. Hemoglobin saturation, estimated using pulse oximetry, was 79.5, 82.0, and 82.3% at times 0, 10, and 20, respectively. We injected atipamezole (0.35 mg/kg, IM) for reversal. Recovery occurred sooner and was more consistent for 125 and 150 µg/kg medetomidine whereby deer stood with minimal sedation to moderate ataxia within 60-90 min after atipamezole administration. We recommend using 150 µg of medetomidine with ketamine (1.5 mg/kg) and tiletamine-zolazepam (1.0 mg/kg) to provide effective and safe chemical immobilization of white-tailed deer.

Evaluation of modified techniques for immobilization of wild ring-tailed lemurs (Lemur catta).

Wild ring-tailed lemurs (Lemur catta) can be anesthetized with Telazol via blow dart, but improved techniques are needed so that each lemur is reliably induced with a single dart. Medetomidine-butorphanol (MB) is a good supplemental protocol to be administered once the lemurs are captured, but other protocols may provide longer periods of sedation and immobility. One possible way of increasing the efficacy of each dart is to increase the time it is retained in the leg. In this investigation, a "double-sleeve" technique was used to try to increase the time of dart retention. This technique used a standard silicone sleeve on the needle, along with a second sleeve at the needle hub. Induction values were compared between lemurs darted with double-sleeve needles and those induced with needles that each had a single silicone sleeve. Once the lemurs were induced, supplementation with MB (0.04 mg/kg and 0.2 mg/kg) was compared with supplementation with ketamine-medetomidine (KM) (10 mg/ kg and 0.04 mg/kg). Twenty-three lemurs were darted with Telazol by using single-sleeve needles, and 24 were darted with double-sleeve needles. The number of darts per lemur and number of escapes were not different between animals darted with a single sleeve compared with a double-sleeve; thus, there were no significant improvements in induction success with the double-sleeve technique. Adequate sedation and muscle relaxation were achieved with both MB and KM; however, lemurs that received MB were more relaxed and needed fewer additional supplements that those that received KM. Single-sleeve dart needles are recommended for Telazol induction of ring-tailed lemurs via blow dart and MB is preferable to KM for supplemental sedation and muscle relaxation.

Comparative evaluation of halothane anaesthesia in medetomidine-butorphanol and midazolam-butorphanol premedicated water buffaloes (Bubalus bubalis).

Six clinically healthy male water buffaloes (Bubalus bubalis) 2-3 years of age and weighing 290-325 kg were used for 2 different treatments (H1 and H2). The animals of group H1 were premedicated with medetomidine (2.5 g/kg,i.v.) and butorphanol (0.05 mg/kg, i.v.), while in group H2 midazolam (0.25 mg/kg) and butorphanol (0.05 mg/kg) were used intravenously. Induction of anaesthesia was achieved by 5% thiopental sodium in H1 (3.85 +/- 0.63 mg/kg) and H2 (6.96 +/- 0.45 mg/kg) groups. The anaesthesia was maintained with halothane in 100 % oxygen through a large animal anaesthetic machine. Better analgesia and sedation with a significantly lower dose of thiopental for induction and significantly higher values of sternal recumbency time and standing time were recorded in group H1 than in group H2, whereas no significant (P > 0.05) difference for the halothane concentration was observed between groups H1 and H2. Significant decrease in heart rate was observed in group H1 whereas it significantly increased in group H2. In both groups, RR decreased during the preanaesthetic period, which increased significantly (P < 0.01) after halothane administration. In both groups a significant (P < 0.01) fallin RT was recorded from 20 min to the end of observation period. A significant (P < 0.05) fall in MAP was observed in group H1 from 15 min until the end, while in group H2 MAP increased nonsignificantly (P > 0.05) after premedication and a significant (P < 0.05) occurredafter thiopental administration. In both groups a significant (P < 0.01) increase in CVP and a significant (P < 0.01) decrease in SpO2 were observed after premedication which persisted up to 120 min. ECG changes included significant (P < 0.01) decrease and increase in QRS amplitudes in groups H1 and H2 respectively, a significant (P < 0.05) increase in PR interval was recorded at 15 min in group H1, a significant (P < 0.05) decrease in PR interval in group H2, a significant (P < 0.05) decrease in T wave amplitude in group H1, and a significant (P < 0.01) increase in duration of T wave in group H1 . It is concluded that both combinations can be used safely in buffaloes for surgery of 2 h duration but better sedation, analgesia and muscular relaxation and more dose sparing effect on anaesthetics and shorter recovery times were observed in group H1.

Physiologic evaluation of capture and anesthesia with medetomidine-zolazepam-tiletamine in brown bears (Ursus arctos).

Physiologic variables during anesthesia with medetomidine-zolazepam-tiletamine were evaluated in 52 free-ranging brown bears (Ursus arctos) darted from a helicopter and in six captive brown bears darted at a zoo. During anesthesia, rectal temperature, respiratory rate, heart rate, and pulse oximetry derived hemoglobin oxygen saturation were recorded. Arterial blood samples were collected and immediately analyzed for evaluation of pulmonary gas exchange, acid-base status, and selected hematologic and plasma variables. At the end of anesthesia, atipamezole was administered intramuscularly at five times the medetomidine dose. Capture-induced hyperthermia and lactic acidemia were documented in free-ranging bears. Hypoxemia during anesthesia was documented in both free-ranging and captive bears. In free-ranging bears, rectal temperature, heart rate, lactate, hematocrit, and hemoglobin decreased significantly during anesthesia, whereas partial pressure of arterial carbon dioxide, pH, potassium, and glucose increased. Yearlings had a significantly higher heart rate, pH, base excess, bicarbonate, and glucose, and had a significantly lower rectal temperature, sodium, hematocrit, and hemoglobin when compared with subadult and adult brown bears. In conclusion, alterations in pulmonary gas exchange and acid-base status in brown bears during anesthesia with medetomidine-zolazepam-tiletamine with the doses and capture methods used in this study were identified. Oxygen supplementation is recommended to counteract hypoxemia during anesthesia.

Combined cardiopulmonary assessments with implantable telemetry device in conscious freely moving cynomolgus monkeys.

Female cynomolgus monkeys were surgically implanted with telemetry transmitters recording ECG (DII), arterial pressure, physical activity, body temperature, and tidal volume. Respiratory rate (RR) and tidal volume (TV) were monitored simultaneously with the telemetry transmitter using impedance. Impedance-based monitoring of RR and TV by telemetry correlated with controlled TV and with pneumotachometer (>98%) in restrained animals. Control drugs with cardiovascular and respiratory effects, including saline, medetomidine (0.01, 0.02 and 0.04mg/kg) and cocaine (0.5, 1.0 and 1.5mg/kg) were administered intravenously. An averaging epoch of 5min was used for analysis of respiratory data. Medetomidine induced significant respiratory depression with decrease in RR and TV in freely moving animals while cocaine increased TV, RR and minute ventilation (MV) with concomitant increase in heart rate when compared with time matched values from saline-treated animals. The onset, duration and magnitude of cardiovascular and respiratory changes were correlated. This highlights the dependency of the cardiovascular and respiratory systems. The use of cardiopulmonary monitoring can allow continuous monitoring including during night time when variability of respiratory parameters is lower. Monitoring of cardiovascular and respiratory parameters in the same animals could also help to decrease the number of animals used in research.

Continuous infusion in adult females dogs submitted to ovariohysterectomy with midazolam-xylazine and/or medetomidine pre-treated with methotrimeprazine and buprenorphine

PURPOSE: To compare, by continuous infusion of ketamine or medetomidine combined to methotrimeprazine and buprenorphine, ketamine and midazolam, the degree of hypnosis, myorelaxation, anesthetic quality and surgical feasibility through evaluation of possible parametric alterations and recovery quality. METHODS: 20 healthy adult females dogs, aged 3 to 5 years, body weight between 7 and 15 kg, were assigned randomly and homogenously to 2 groups of 10 animals each (n=10), group 1 (G1) and group 2 (G2), respectively. Animals of G1 were subjected to a pre-treatment with intravenous 1.0 mg/kg methotrimeprazine and or 3ì/kg. After 15 minutes, a 5.0 mg/kg ketamine and 0.2 mg/kg midazolam were intravenously injected. Immediately after induction, an anesthetic combination of 0.4 mg/kg/h midazolam, 20 mg/kg/h ketamine and 1.0 mg/kg/h xylazine, was continuously and intravenously administered for 30 minutes. The same techniques were used in G2 except for the substitution of xylazine for 30ìg/kg/h medetomidine. RESULTS: In G1 there was a 1st and 2nd degree atrioventricular heart block, a longer recovery period and lower quality. In G2 a 1st degree atrioventricular heart block occurred but isolated and ephemeral. CONCLUSIONS: The continuous infusion method, besides reducing drugs utilization, prevented collateral effects allowing a more tranquil recovery with no excitations, both protocols permitted the surgical procedure (ovary-hysterectomy) bringing about a reduction in hypnosis and an accentuated myorelaxation. Xylazine and medetomidine showed a similar pharmacodynamic behavior but with different clinical aspects. The electrocardiographic alterations observed in G2 and in a lower degree in G1 must be well studied. Describers: dogs, ketamine, methotrimeprazine, medetomidine, midazolam and xylazine.

OBJETIVO: Comparar através de infusão contínua de xilazina ou medetomidina associada à metotrimeprazina e buprenorfina, cetamina e midazolam, o grau de hipnose, miorrelaxamento e qualidade anestésica e a viabilidade cirúrgica, avaliando eventuais alterações paramétricas e qualidade de recuperação. MÉTODOS: Foram utilizados 20 cães fêmeas, adultas, hígidas (3 a 5 anos de idade) com peso corporal entre 7 e 15 quilos, escolhidas e distribuídas aleatoriamente de forma homogênea em 2 grupos de 10 animais cada, (n=10) sendo estes designados por Grupo 1 (G1), e Grupo 2 (G 2). Em G1, os animais foram submetidos a um pré-tratamento com metotrimeprazina na dose de 1,0 mg/kg e buprenorfina na dose de 0,003mg/kg ou 3 µg/kg intravenoso. Decorridos 15 minutos, administrou-se cetamina na dose de 5,0 mg/kg e midazolam na dose de 0,2 mg/kg intravenoso. Imediatamente após a indução iniciou-se administração contínua, por um período de 30 minutos, da associação anestésica de midazolam 0,4 mg/kg/h, cetamina 20mg/kg/h e xilazina 1,0 mg/kg/h IV. Em G 2 utilizou-se a mesma técnica empregada em G1 substituindo-se, a xilazina pela medetomidina na dose de 30µg/kg/h. RESULTADOS: Verificou-se em G1 bloqueio átrio-ventricular de primeiro e segundo grau, período de recuperação mais longo além de menor qualidade. Em G 2 observou-se bloqueio átrio-ventricular de primeiro grau isolado e de ação fugaz. CONCLUSÕES: Ao se aplicar o método de infusão contínua, além da redução dos fármacos aplicados, evitaram-se efeitos colaterais permitindo uma recuperação mais tranqüila e isenta de excitações, ambos os protocolos permitiram a realização do ato cirúrgico (ovário-salpingo-histerectomia), causando uma redução da hipnose e um miorrelaxamento acentuado. A xilazina e a medetomidina apresentam um comportamento farmacodinâmico semelhante, porém com aspectos clínicos diferentes, as alterações eletrocardiográficas observadas em G 2 e em menor grau em G1 devem ser melhor estudadas.

Continuous infusion in adult females dogs submitted to ovariohysterectomy with midazolam-xylazine and/or medetomidine pre-treated with methotrimeprazine and buprenorphine.

PURPOSE: To compare, by continuous infusion of ketamine or medetomidine combined to methotrimeprazine and buprenorphine, ketamine and midazolam, the degree of hypnosis, myorelaxation, anesthetic quality and surgical feasibility through evaluation of possible parametric alterations and recovery quality. METHODS: 20 healthy adult females dogs, aged 3 to 5 years, body weight between 7 and 15 kg, were assigned randomly and homogenously to 2 groups of 10 animals each (n=10), group 1 (G1) and group 2 (G2), respectively. Animals of G1 were subjected to a pre-treatment with intravenous 1.0 mg/kg methotrimeprazine and or 3ì/kg. After 15 minutes, a 5.0 mg/kg ketamine and 0.2 mg/kg midazolam were intravenously injected. Immediately after induction, an anesthetic combination of 0.4 mg/kg/h midazolam, 20 mg/kg/h ketamine and 1.0 mg/kg/h xylazine, was continuously and intravenously administered for 30 minutes. The same techniques were used in G2 except for the substitution of xylazine for 30ìg/kg/h medetomidine. RESULTS: In G1 there was a 1st and 2nd degree atrioventricular heart block, a longer recovery period and lower quality. In G2 a 1st degree atrioventricular heart block occurred but isolated and ephemeral. CONCLUSIONS: The continuous infusion method, besides reducing drugs utilization, prevented collateral effects allowing a more tranquil recovery with no excitations, both protocols permitted the surgical procedure (ovary-hysterectomy) bringing about a reduction in hypnosis and an accentuated myorelaxation. Xylazine and medetomidine showed a similar pharmacodynamic behavior but with different clinical aspects. The electrocardiographic alterations observed in G2 and in a lower degree in G1 must be well studied. Describers: dogs, ketamine, methotrimeprazine, medetomidine, midazolam and xylazine.

A cardiovascular monitoring system used in conscious cynomolgus monkeys for regulatory safety pharmacology. Part 2: Pharmacological validation.

INTRODUCTION: This project addresses the validation study design of a test system using a telemetered non-human primate model for cardiovascular safety pharmacology evaluation. METHODS: In addition to non-pharmacological validation including installation and operation qualifications, performance qualification (locomotor activity and cardiovascular evaluations) was completed on free-moving cynomolgus monkeys by quantifying the degree of cardiovascular response measured by the telemetric device to various positive control drugs following their intravenous administration. Remifentanil (0.0005, 0.001, 0.002, 0.004, 0.008 and 0.016 mg/kg) was given to induce bradycardia and hypotension. Medetomidine (0.04 mg/kg) was used to induce an initial phase of hypertension followed by hypotension and bradycardia. Esmolol (0.5, 1.0 and 2.0 mg/kg) was used to induce bradycardia. Dopamine (0.002, 0.008, 0.01, 0.02, 0.03 and 0.05 mg/kg/min) was infused over 30 min to induce an increase in arterial and pulse pressures and tachycardia. Amiodarone (0.4, 0.8 and 1.6 mg/kg/min) was infused over 10 min to induce QT interval prolongation. Potassium chloride (0.08 mEq/kg/min) was infused for periods of less than 30 min to induce electrocardiographic (EKG) changes characteristic of hyperkalemia. Reliability was evaluated over 60 days. RESULTS: Monitoring with a reference methodology and the telemetry system was important in order to evaluate precision and accuracy of the test system. Positive control drugs produced a wide range of cardiovascular effects with different amplitudes, which were useful in identification of the limits of the test system. DISCUSSION: Reference monitoring methods and selection of a battery of positive control drugs are important to ensure proper test system validation. Drugs inducing not only QT prolongation but also positive and negative chronotropic effects, positive and negative systemic arterial pressure changes and ECG morphology alterations were useful to identify test system limitations during performance qualification. ECG data processing at significantly elevated heart rates revealed that a trained observer should review all cardiac cycles evaluated by computer.

Evaluation of sedation on electroencephalographic spectral edge frequency 95 in dogs sedated by acupuncture at GV20 or Yintang and sedative combination.

The spectral edge frequency (SEF) 95 is one of the electroencephalographic (EEG) parameters, which is a relatively simple and effective method to evaluate a sedative status. The aim of this study was to evaluate the effect of acupuncture on electroencephalographic SEF 95 in dogs (4.2 - 6.1 kg, 1-2 years old) sedated by a sedative. The acupoints used were the GV20 point and Yintang point. The sedatives used were acepromazine, butorphanol, diazepam, medetomidine, and phenobarbital, each using a different mechanism. The sedation level was assessed by a SEF 95 value under normal conditions, sedation being induced by a sedative, a combination of a sedative and acupuncture, and acupuncture release. During the sedative and acupuncture combination, the SEF 95 values significantly decreased in the butorphanol group. Although this result was just based on the changes of the brain it is suggested that acupuncture, combined with opioids, would be a useful method to produce a safe and deep sedation in clinics.

Anesthesia of wood bison with medetomidine-zolazepam/tiletamine and xylazine-zolazepam/tiletamine combinations.

This study was designed to evaluate 2 combinations for immobilization of bison. Seven wood bison received 1.5 mg/kg body weight (BW) of xylazine HCl + 1.5 mg/kg BW of zolazepam HCl and 1.5 mg/kg BW of tiletamine HCl on one occasion. The bison received 60 micrograms/kg BW of medetomidine HCl + 0.6 mg/kg BW of zolazepam HCl and 0.6 mg/kg BW of tiletamine HCL on another occasion. Xylazine was antagonized with 3 mg/kg BW of tolazoline HCl and medetomidine HCl was antagonized with 180 micrograms/kg (BW) of atipamezole HCl. Temporal characteristics of immobilization and physiological effects (acid-base status, thermoregulatory, cardiovascular, and respiratory effects) of the drug combinations were compared. Induction was significantly faster with xylazine HCl-zolazepam HCl/tiletamine HCl. Recovery following antagonist administration was significantly faster with medetomidine HCl-zolazepam HCl/tiletamine HCl. The average drug volumes required were 7.00 mL of xylazine HCl-zolazepam HCl/tiletamine HCL and 2.78 mL of medetomidine HCl-zolazepam HCl/tiletamine HCl. Hypoxemia, hypercarbia, and rumenal tympany were the major adverse effects with both drug combinations.