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A comparison of medetomidine and its active enantiomer dexmedetomidine when administered with ketamine in mice

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      Abstract

      BackgroundMedetomidine-ketamine (MK) and dexmedetomidine-ketamine (DK) are widely used to provide general anaesthesia in laboratory animals, but have not been compared directly in many of these species, including rodents. This study aimed to compare the onset and depth of anaesthesia, and changes in vital signs, after intraperitoneal (IP) or subcutaneous (SC) administration of ketamine (75 mg kg-1) combined with medetomidine (1 mg kg-1) or dexmedetomidine (0.5 mg kg-1) using a randomised semi-crossover design with ≥ 48 hours between treatments in 10 male and 10 female mice. Each mouse was anaesthetised twice using the same administration route (IP or SC): once with each drug-ketamine combination. Anaesthetised mice were monitored on a heating pad without supplemental oxygen for 89 minutes; atipamezole was administered for reversal. The times that the righting reflex was lost post-injection and returned post-reversal were analysed using general linear models. Tail-pinch and pedal reflexes were examined using binomial generalized linear models. Pulse rate (PR), respiratory rate (fr), and arterial haemoglobin saturation (SpO2) were compared using generalized additive mixed models.ResultsThere were no significant differences among treatments for the times taken for loss and return of the righting reflex, or response of the tail-pinch reflex. The pedal withdrawal reflex was abolished more frequently with MK than DK over time (P = 0.021). The response of PR and SpO2 were similar among treatments, but fr was significantly higher with MK than DK (P ≤ 0.0005). Markedly low SpO2 concentrations occurred within 5 minutes post-injection (83.8 ± 6.7%) in all treatment groups and were most severe after 89 minutes lapsed (66.7 ± 7.5%). No statistical differences were detected in regards to administration route (P ≤ 0.94).ConclusionsThis study failed to demonstrate clinical advantages of the enantiomer dexmedetomidine over medetomidine when combined with ketamine to produce general anaesthesia in mice. At the doses administered, deep surgical anaesthesia was not consistently produced with either combination; therefore, anaesthetic depth must be assessed before performing surgical procedures. Supplemental oxygen should always be provided during anaesthesia to prevent hypoxaemia.

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      Most cited references 35

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      Alpha-2 adrenoceptor agonists: defining the role in clinical anesthesia.

       M Maze,  W Tranquilli (1991)
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        A review of the physiological effects of alpha2-agonists related to the clinical use of medetomidine in small animal practice.

         M Sinclair (2003)
        Medetomidine is a relatively new sedative analgesic drug that is approved for use in dogs in Canada. It is the most potent alpha2-adrenoreceptor available for clinical use in veterinary medicine and stimulates receptors centrally to produce dose-dependent sedation and analgesia. Significant dose sparing properties occur when medetomidine is combined with other anesthetic agents correlating with the high affinity of this drug to the alpha2-adrenoreceptor. Hypoventilation occurs with medetomidine sedation in dogs; however, respiratory depression becomes most significant when given in combination with other sedative or injectable agents. The typical negative cardiovascular effects produced with other alpha2-agonists (bradycardia, bradyarrhythmias, a reduction in cardiac output, hypertension +/- hypotension) are also produced with medetomidine, warranting precautions when it is used and necessitating appropriate patient selection (young, middle-aged healthy animals). While hypotension may occur, sedative doses of medetomidine typically raise the blood pressure, due to the effect on peripheral alpha2-adrenoreceptors. Anticholinergic premedication has been recommended with alpha2-agonists to prevent bradyarrhythmias and, potentially, the reduction in cardiac output produced by these agents; however, current research does not demonstrate a clear improvement in cardiovascular function. Negatively, the anticholinergic induced increase in heart rate potentiates the alpha2-agonist mediated hypertension and may increase myocardial oxygen tension, demand, and workload. Overall, reversal with the specific antagonist atipamezole is recommended when significant cardiorespiratory complications occur. Other physiological effects of medetomidine sedation include; vomiting, increased urine volumes, changes to endocrine function and uterine activity, decreased intestinal motility, decreased intraocular pressure and potentially hypothermia, muscle twitching, and cyanosis. Decreased doses of medetomidine, compared with the recommended label dose, should be considered in combination with other sedatives to enhance sedation and analgesia and lower the duration and potential severity of the negative cardiovascular side effects. The literature was searched in Pubmed, Medline, Agricola, CAB direct, and Biological Sciences.
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          Anaesthesia and post-operative analgesia following experimental surgery in laboratory rodents: are we making progress?

          Current attitudes to the use of animals in biomedical research require that any pain or distress should be minimised. This can often be achieved by the use of appropriate anaesthetic and analgesic regimens. There, is however, little information on the peri-operative regimens used. A literature review was conducted to estimate how commonly analgesics are administered to laboratory rodents, the most widely used species of laboratory animals, and to assess the anaesthetic regimens employed. Studies describing potentially painful experimental procedures involving rodents were identified from peer-reviewed journals published from 1990 to 1992 and from 2000 to 2002. In papers published between 2000 and 2002, if analgesic administration was not specified, the institutional veterinary surgeons or authors of the papers were contacted by e-mail to obtain additional information on analgesic use. From 1992 to 2002, there was an increase in the reported prevalence of analgesic administration to laboratory rodents from 2.7% to 19.8%. Although the use of analgesics has increased over the past ten years, the overall level of post-operative pain relief for laboratory rodents is still low. Anaesthetic methodology changed markedly between the two time-periods sampled. Notably, there was an increase in the use of isoflurane and of injectable anaesthetic combinations such as ketamine/xylazine, whereas the use of ether and methoxyflurane decreased.
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            Author and article information

            Affiliations
            [1 ]Comparative Biology Centre, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, United Kingdom
            [2 ]School of Veterinary Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Bearsden Road, Glasgow, G61 1QH, United Kingdom
            [3 ]Boyd Orr Centre for population and ecosystem health, Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, United Kingdom
            Contributors
            Journal
            BMC Vet Res
            BMC Vet. Res
            BMC Veterinary Research
            BioMed Central
            1746-6148
            2013
            13 March 2013
            : 9
            : 48
            23497612
            3605306
            1746-6148-9-48
            10.1186/1746-6148-9-48
            Copyright ©2013 Burnside et al.; licensee BioMed Central Ltd.

            This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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            Research Article

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