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      Comparison of the effects of ketamine and fentanyl-midazolam-medetomidine for sedation of rhesus macaques ( Macaca mulatta)

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          Abstract

          Background

          This study assessed the effects of sedation using a combination of fentanyl, midazolam and medetomidine in comparison to ketamine. Rhesus Macaques ( Macaca mulatta), ( n = 16, 5 males and 3 females randomly allocated to each treatment group) received either ketamine (KET) (10 mg.kg −1) or fentanyl-midazolam-medetomidine (FMM) (10 μg/kg −1; 0.5 mg.kg −1; 20 μg.kg −1) both IM. Oxygen (100 %) was provided by mask and heart rate, blood pressure, respiratory rate, EtCO 2 and depth of sedation were assessed every 5 min for 20 min. After the last time point, FMM monkeys were reversed with atipamezole-naloxone (0.2 mg.kg −1; 10 μg.kg −1). Recovery was scored using clinical scoring scheme. Differences in physiological parameters and quality of sedation were compared using Area Under the Curve (AUC) method and either Mann-Witney or t-student tests.

          Results

          Heart rate (beats/min) (Ket = 119 ± 18; FMM = 89 ± 17; p = 0.0066), systolic blood pressure (mmHg) (Ket = 109 ± 10; FMM = 97 ± 10; p = 0.0313), and respiratory rate (breaths/min) (Ket = 39 ± 9; FMM = 29 ± 10; p = 0.0416) were significantly lower in the FMM group. End-tidal CO 2 (mmHg) did not differ between the groups (KET = 33 ± 8; FMM = 42 ± 11; p = 0.0462) . Although some depression of physiological parameters was seen with FMM, the variables all remained within the normal ranges in both groups. Onset of a sufficient degree of sedation for safe handling was more rapid with ketamine (KET = 2.9 ± 1.4 min; FMM = 7.9 ± 1.2 min; p = 0.0009), but FMM recovery was faster (KET = 21.4 ± 13.4 min; FMM = 9.1 ± 3.6 min; p = 0.0379) and of better quality (KET = 1.3 ± 0.9; FMM = 7.4 ± 1.9; p = 0.0009) most probably because of the effectiveness of the reversal agents used.

          Conclusion

          FMM provides an easily reversible immobilization with a rapid and good recovery quality and may prove a useful alternative to ketamine.

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          Most cited references48

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          Development and psychometric evaluation of the pediatric anesthesia emergence delirium scale.

          Emergence delirium has been investigated in several clinical trials. However, no reliable and valid rating scale exists to measure this phenomenon in children. Therefore, the authors developed and evaluated the Pediatric Anesthesia Emergence Delirium (PAED) scale to measure emergence delirium in children. A list of scale items that were statements describing the emergence behavior of children was compiled, and the items were evaluated for content validity and statistical significance. Items that satisfied these evaluations comprised the PAED scale. Each item was scored from 1 to 4 (with reverse scoring where applicable), and the scores were summed to obtain a total scale score. The degree of emergence delirium varied directly with the total score. Fifty children were enrolled to determine the reliability and validity of the PAED scale. Scale validity was evaluated using five hypotheses: The PAED scale scores correlated negatively with age and time to awakening and positively with clinical judgment scores and Post Hospital Behavior Questionnaire scores, and were greater after sevoflurane than after halothane. The sensitivity of the scale was also determined. Five of 27 items that satisfied the content validity and statistical analysis became the PAED scale: (1) The child makes eye contact with the caregiver, (2) the child's actions are purposeful, (3) the child is aware of his/her surroundings, (4) the child is restless, and (5) the child is inconsolable. The internal consistency of the PAED scale was 0.89, and the reliability was 0.84 (95% confidence interval, 0.76-0.90). Three hypotheses supported the validity of the scale: The scores correlated negatively with age (r = -0.31, P <0.04) and time to awakening (r = -0.5, P <0.001) and were greater after sevoflurane anesthesia than halothane (P <0.008). The sensitivity was 0.64. These results support the reliability and validity of the PAED scale.
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            Incidence, Reversal, and Prevention of Opioid-induced Respiratory Depression.

            Opioid treatment of pain is generally safe with 0.5% or less events from respiratory depression. However, fatalities are regularly reported. The only treatment currently available to reverse opioid respiratory depression is by naloxone infusion. The efficacy of naloxone depends on its own pharmacological characteristics and on those (including receptor kinetics) of the opioid that needs reversal. Short elimination of naloxone and biophase equilibration half-lives and rapid receptor kinetics complicates reversal of high-affinity opioids. An opioid with high receptor affinity will require greater naloxone concentrations and/or a continuous infusion before reversal sets in compared with an opioid with lower receptor affinity. The clinical approach to severe opioid-induced respiratory depression is to titrate naloxone to effect and continue treatment by continuous infusion until chances for renarcotization have diminished. New approaches to prevent opioid respiratory depression without affecting analgesia have led to the experimental application of serotinine agonists, ampakines, and the antibiotic minocycline.
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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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                Author and article information

                Contributors
                +44 191 208 8646 , +44 191 208 8648 , henri.bertrand@newcastle.ac.uk
                Journal
                BMC Vet Res
                BMC Vet. Res
                BMC Veterinary Research
                BioMed Central (London )
                1746-6148
                8 June 2016
                8 June 2016
                2016
                : 12
                : 93
                Affiliations
                [ ]Comparative Biology Centre, Newcastle University, Framlington Place, Newcastle Upon Tyne, NE2 4HH UK
                [ ]Faculty of Veterinary Medicine, University of Liège, Boulevard de Colonster, Liège, 4000 Belgium
                [ ]School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington Campus, Loughborough, LE12 5RD UK
                [ ]Institute of Neuroscience, Newcastle University, Newcastle Upon Tyne, NE1 7RU UK
                Article
                721
                10.1186/s12917-016-0721-9
                4898395
                27277424
                a4067e12-f1c3-41b9-937d-43a398224cc0
                © The Author(s). 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 20 November 2015
                : 3 June 2016
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2016

                Veterinary medicine
                sedation,ketamine,fentanyl,midazolam,medetomidine,recovery macaque
                Veterinary medicine
                sedation, ketamine, fentanyl, midazolam, medetomidine, recovery macaque

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