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Faster emergence behavior from ketamine/xylazine anesthesia with atipamezole versus yohimbine.

ABSTRACT: Recent interest in reversal of the hypnotic effects of anesthesia has mainly focused on overcoming a surge in GABA-mediated inhibitory signaling through activation of subcortical arousal circuits or antagonizing GABA receptors. Here we examine the reversal of anesthesia produced from non-GABA agents ketamine/xylazine and the effects of antagonists of adrenoreceptors. These antagonists vary in selectivity and produce temporally unique waking behavior post-anesthesia. We compared two antagonists with differential selectivity for ?1- vs. ?2-receptors, yohimbine (YOH, 1:40 selectivity) and atipamezole (ATI, 1:8500). Adult mice received intraperitoneal injections of either YOH (4.3 mg/kg), ATI (0.4 mg/kg), or saline after achieving sustained loss of righting following injection of ketamine/xylazine (ketamine: 65.0 mg/kg; xylazine: 9.9 mg/kg). Behaviors indicative of the post-anesthesia, re-animation sequence were carefully monitored and the timing of each behavior relative to anesthesia induction was compared. Both YOH and ATI hastened behaviors indicative of emergence, but ATI was faster than YOH to produce certain behaviors, including whisker movement (YOH: 21.9±1.5 min, ATI: 17.5±0.5 min, p = 0.004) and return of righting reflex (RORR) (YOH: 40.6±8.8 min, ATI: 26.0±1.2 min, p<0.001). Interestingly, although YOH administration hastened early behavioral markers of emergence relative to saline (whisking), the completion of the emergence sequence (time from first marker to appearance of RORR) was delayed with YOH. We attribute this effect to antagonism of ?1 receptors by yohimbine. Also notable was the failure of either antagonist to hasten the re-establishment of coordinated motor behavior (e.g., attempts to remove adhesive tape on the forepaw placed during anesthesia) relative to the end of emergence (RORR). In total, our work suggests that in addition to pharmacokinetic effects, re-establishment of normal waking behaviors after anesthesia involves neuronal circuits dependent on time and/or activity.

SUBMITTER: Mees L

PROVIDER: S-EPMC6205597 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Faster emergence behavior from ketamine/xylazine anesthesia with atipamezole versus yohimbine.

Mees Lukas L Fidler Jonathan J Kreuzer Matthias M Fu Jieming J Pardue Machelle T MT García Paul S PS

PloS one 20181029 10

Recent interest in reversal of the hypnotic effects of anesthesia has mainly focused on overcoming a surge in GABA-mediated inhibitory signaling through activation of subcortical arousal circuits or antagonizing GABA receptors. Here we examine the reversal of anesthesia produced from non-GABA agents ketamine/xylazine and the effects of antagonists of adrenoreceptors. These antagonists vary in selectivity and produce temporally unique waking behavior post-anesthesia. We compared two antagonists w ...[more]

PMID: 30372437

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Project description:ObjectivesTo explore the effect of ketamine-xylazine anesthesia on light-induced retinal degeneration in rats.MethodsRats were anesthetized with ketamine and xylazine (100 and 5 mg, respectively) for 1 h, followed by a recovery phase of 2 h before exposure to 16,000 lux of environmental illumination for 2 h. Functional assessment by electroretinography (ERG) and morphological assessment by in vivo imaging (optical coherence tomography), histology (hematoxylin/eosin staining, TUNEL assay) and immunohistochemistry (GFAP and rhodopsin staining) were performed at baseline (ERG), 36 h, 7 d and 14 d post-treatment. Non-anesthetized animals treated with light damage served as controls.ResultsKetamine-xylazine pre-treatment preserved retinal function and protected against light-induced retinal degeneration. In vivo retinal imaging demonstrated a significant increase of outer nuclear layer (ONL) thickness in the non-anesthetized group at 36 h (p<0.01) and significant reduction one week (p<0.01) after light damage. In contrast, ketamine-xylazine pre-treated animals showed no significant alteration of total retinal or ONL thickness at either time point (p>0.05), indicating a stabilizing and/or protective effect with regard to phototoxicity. Histology confirmed light-induced photoreceptor cell death and Müller cells gliosis in non-anesthetized rats, especially in the superior hemiretina, while ketamine-xylazine treated rats showed reduced photoreceptor cell death (TUNEL staining: p<0.001 after 7 d), thicker ONL and longer IS/OS. Fourteen days after light damage, a reduction of standard flash induced a-wave amplitudes and a-wave slopes (p?=?0.01) and significant alterations in parameters of the scotopic sensitivity function (e.g. Vmax of the Naka Rushton fit p?=?0.03) were observed in non-treated vs. ketamine-xylazine treated animals.ConclusionsOur results suggest that pre-treatment with ketamine-xylazine anesthesia protects retinas against light damage, reducing photoreceptor cell death. These data support the notion that anesthesia with ketamine-xylazine provides neuroprotective effects in light-induced cell damage.

Project description:Balanced anesthesia-the use of a combination of drugs to achieve a desired anesthetic plane-offers many benefits, including smoother induction and recovery and fewer adverse effects than occur with individual drugs. Although premedication prior to inhalant anesthesia is routine in other species, mice are commonly induced with gas anesthesia alone. The hypothesis of this study was that premedication with ketamine or xylazine would safely reduce the stress of isoflurane induction and lower the minimum alveolar concentration (MAC) of isoflurane. Young adult male and female C57BL/6J mice were premedicated with ketamine (100 mg/kg), xylazine (4 mg/kg), or isotonic crystalloid (0.1 mL) and were used in 4 experiments. First, isoflurane induction was video recorded under all test conditions, and the videos were scored according to a behavioral ethogram to identify signs of distress. Mice in the ketamine group experienced tremors and ataxia before and dur- ing induction. Therefore, ketamine was given after induction with isoflurane in subsequent experiments. Second, the MAC value for each anesthetic protocol was determined by using quantal and bracketing analysis. Third, mice were anesthetized according to the 3 protocols, and vital parameters were monitored for 60 min. Finally, anesthetized mice were challenged with hypoxia and hypovolemia, and vital parameters were monitored. Premedication with xylazine significantly reduced the stress scores for isoflurane induction (control, 7.3 ± 1.5; ketamine, 6.0 ± 3.0; xylazine, 3.1 ± 1.0). Ketamine and xylazine both reduced the MAC of isoflurane (control, 1.89%; ketamine, 0.96%; xylazine, 1.20%). All mice survived 60 min of anesthesia and the hypoxia-hypovolemia challenge. Premedication with xylazine reduced the stress of induction and lowered the necessary dose of isoflurane in C57BL/6J mice to maintain a surgical plane of anesthesia. We recommend administering xylazine before isoflurane induction and anesthesia of healthy mice that are undergoing procedures in which 100% oxygen is provided and anticipated blood loss is less than 10% to 15% of the total blood volume.

Project description:BackgroundKinetic modeling in positron emission tomography (PET) requires measurement of the tracer plasma activity in the absence of a suitable reference region. To avoid invasive blood sampling, the use of an image derived input function has been proposed. However, an accurate delineation of the blood pool region in the PET image is necessary to obtain unbiased blood activity. Here, to perform brain kinetic modeling in [18F]SynVesT-1 dynamic scans, we make use of non-negative matrix factorization (NMF) to unmix the activity signal from the different tissues that can contribute to the heart region activity, and extract only the left ventricle activity in an unbiased way. This method was implemented in dynamic [18F]SynVesT-1 scans of mice anesthetized with either isoflurane or ketamine-xylazine, two anesthestics that we showed to affect differently radiotracer kinetics. The left ventricle activity (NMF-IDIF) and a manually delineated cardiac activity (IDIF) were compared with arterial blood samples (ABS), and for isoflurane anesthetized mice, arteriovenous (AV) shunt blood data were compared as well. Finally, brain regional 2 tissue compartment modeling was performed using IDIF and NMF-IDIF, and the model fit accuracy (weighted symmetrical mean absolute percentage error, wsMAPE) as well as the total volume of distribution (VT) were compared.ResultsIn isoflurane anesthetized mice, the difference between ABS and NMF-IDIF activity (+ 12.8 [Formula: see text] 11%, p = 0.0023) was smaller than with IDIF (+ 16.4 [Formula: see text] 9.8%, p = 0.0008). For ketamine-xylazine anesthetized mice the reduction in difference was larger (NMF-IDIF: 16.9 [Formula: see text] 10%, p = 0.0057, IDIF: 56.3 [Formula: see text] 14%, p < 0.0001). Correlation coefficient between isoflurane AV-shunt time activity curves and NMF-IDIF (0.97 [Formula: see text] 0.01) was higher than with IDIF (0.94 [Formula: see text] 0.03). The brain regional 2TCM wsMAPE was improved using NMF-IDIF compared with IDIF, in isoflurane (NMF-IDIF: 1.24 [Formula: see text] 0.24%, IDIF: 1.56 [Formula: see text] 0.30%) and ketamine-xylazine (NMF-IDIF: 1.40 [Formula: see text] 0.24, IDIF: 2.62 [Formula: see text] 0.27) anesthetized mice. Finally, brain VT was significantly (p < 0.0001) higher using NMF-IDIF compared with IDIF, in isoflurane (3.97 [Formula: see text] 0.13% higher) and ketamine-xylazine (32.7 [Formula: see text] 2.4% higher) anesthetized mice.ConclusionsImage derived left ventricle blood activity calculated with NMF improves absolute activity quantification, and reduces the error in the kinetic modeling fit. These improvements are more pronounced in ketamine-xylazine than in isoflurane anesthetized mice.

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Faster emergence behavior from ketamine/xylazine anesthesia with atipamezole versus yohimbine.

Publications

Faster emergence behavior from ketamine/xylazine anesthesia with atipamezole versus yohimbine.

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