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40 Caution should therefore be exercised in removing the effect of the α 2 agonist from a ketamine–xylazine or ketamine–dexmedetomidine anesthetic event before sufficient time has elapsed for ketamine metabolism. These ‘emergence reactions’ are commonly managed by concurrent use of an adjunct sedative, typically a benzodiazepine, phenothiazine, or, an α 2 agonist. In most species, ketamine, if administered alone, results in unacceptable excitement and agitation during awakening from anesthesia. An antagonist should not be administered until the sedative, anxiolytic, and analgesic effects of the agonist are no longer needed. 4, 6, 12, 15, 16, 17, 26, 38, 39 The anesthetist must consider several factors in the decision to administer an antagonist. Effective reversal of xylazine sedation with an antagonist results in prompt awakening of the patient, as well as normalization of most of the earlier listed side effects. 10, 17, 19, 20, 26, 38, 41ĭespite these recognized undesirable side effects, a major advantage of α 2 agonists is the availability of antagonists, which anesthetists can administer to negate these effects. Documented side effects of xylazine are transient hypertension, peripheral vasoconstriction, prolonged hypotension, 30% to 50% decrease in cardiac output, diuresis, hypothermia, hyperglycemia, cerebral hypoxia, and decreased gut motility lasting for hours. 5 These side effects, which are common to all α 2 agonists, are due primarily to the activation of α 2 receptors as well as lesser activation of α 1 and β receptors. 5, 10, 37, 42, 43 A study comparing 8 injectable anesthetic protocols for mice concluded that cocktails containing xylazine and ketamine were preferable over similar mixtures containing medetomidine in terms of both safety and surgical tolerance however even the optimal combination induced significant hypoxia, hypercapnia, and acidosis. 21, 29Īlthough the newer drugs medetomidine and dexmedetomidine have higher affinity and specificity for the α 2 receptor, xylazine continues to be used extensively in laboratory animal medicine for the anesthesia of rodents. 3- 5, 10, 11, 18, 21, 41 Xylazine has an α 2:α 1 selectivity ratio of 160, in addition to lesser affinity for β-adrenergic, dopaminergic, cholinergic, serotoninergic, H2 histamine, and opioid receptors. 23, 34, 42 Various studies across many species either compare or individually explore the relative merits of the α 2 agonists clinically available to veterinarians, including xylazine, detomidine, medetomidine, and the purified active enantiomer of medetomidine, dexmedetomidine. The sedative effects of the α 2 agonists are believed to be caused by stimulation of α 2A adrenoreceptor subtypes in the locus ceruleus of the brainstem, thus decreasing norepinephrine release. Xylazine is an α 2 agonist commonly used in veterinary medicine as a sedative and as a component in balanced anesthesia combinations. When injection of the antagonist by the technically simple intraperitoneal route is desirable, our data indicate that (at the doses evaluated) atipamezole is more effective than yohimbine. When rapid recovery of mice after xylazine–ketamine anesthesia is desirable, administration of an antagonist to reverse the effects of the xylazine is indicated. Time to return of righting reflex differed significantly among groups, with mice recovering in an average of 10.3 min after administration of atipamezole (1 mg/kg IP) as compared with 21.3 min after yohimbine (1.5 mg/kg IP) and 38.2 min after saline. Mice were anesthetized with xylazine (10 mg/kg IP) and ketamine (80 mg/kg IP), followed 15 min later by injection of an α 2 antagonist or saline (control). Time to return of righting reflex was used as the primary outcome measure.

This study is a single-dose crossover comparison of these 2 antagonist drugs, given intraperitoneally at clinically recommended doses, to determine which results in more rapid recovery of mice from xylazine–ketamine anesthesia. Although atipamezole and yohimbine dosing guidelines are available for mice, no controlled comparison has been performed to guide the lab animal community in the selection of one over the other. Xylazine's sedative effect-and its undesirable side effects of bradycardia, hypotension, and poor tissue perfusion-can be reversed by administration of α 2 antagonists, such as atipamezole or yohimbine. The α 2 adrenergic agonist xylazine produces a sedative effect and is typically combined with ketamine and used for anesthesia or chemical restraint of laboratory mice.