of analgesia from the tail regions to the thorax. This may be the result of a higher concentration of the injected drug solution with 0.075 mg/kg than 0.05 mg/kg since the total volume of the injected solution was maintained at the same 4 ml for both dosages in this study. Side effects resulting from spinally administered romifidine included dose‐dependent ataxia and decreased heart rate, respiratory rate, and mean arterial blood pressures [100].
In camels, the sedative and analgesic effects of romifidine were assessed at three different doses (0.04, 0.08, and 0.12 mg/kg IV). Both the sedative and analgesic effects were dose dependent with the duration of sedation (37, 51, and 65 minutes, respectively) lasting longer than the analgesic effect (21, 34, and 46 minutes, respectively). Bradycardia, ruminal tympany, increased urine output, and hyperglycemia are commonly observed side effects during romifidine sedation. Camels may not represent domestic camelids like llamas and alpacas, and they have been reported to require higher doses of xylazine to produce a similar degree of sedation. Thus, llamas and alpacas may require a lower dose of romifidine to produce desirable sedation and analgesia [101].
2.3.3 Swine
2.3.3.1 Xylazine
Compared to other domestic species, pigs are the least sensitive to xylazine. A higher dose (1.65 mg/kg IV, 2.2 mg/kg IM) is required to produce mild to moderate sedation, but still the pigs are easily aroused and able to flee when approached [8, 14]. Vomiting and bloating have been observed in pigs that were not fasted prior to anesthesia [16, 21]. When tested at doses of 1, 2, 4, 8, and 16 mg/kg IV in young pigs, xylazine alone did not produce effective sedation and analgesia. Xylazine induced a significant decrease in mean arterial blood pressure, but it gradually returned to baseline values 10 minutes after administration [102].
2.3.3.2 Detomidine
In pigs, doses of detomidine at 0.04 mg/kg IV or 0.08 mg/kg IM have been used in combination with ketamine to produce short‐term anesthesia [103]. Analgesia following lumbosacral epidural administration of detomidine was not as profound as xylazine in pigs [104]. In addition, detomidine‐ or xylazine‐induced epidural analgesia may be mediated through a different mechanism of action in that IV administration of an antagonist was capable of antagonizing epidural detomidine‐induced sedation, analgesia, and immobilization but was only able to antagonize the sedation induced by epidural xylazine but not the analgesia and immobilization [104]. This observation is supported by reports in horses and cattle [105–107]. Perhaps the difference of response to the IV administration of an antagonist lies in the fact that xylazine itself has local anesthetic effect and detomidine does not [108].
2.3.3.3 Medetomidine
In pigs, medetomidine at IM doses of 0.03–0.08 mg/kg induced dose‐dependent sedation and muscle relaxation. Increasing the dose to greater than 0.1 mg/kg did not increase the degree of sedation or muscle relaxation but did prolong the duration of activity. Compared to 2 mg/kg of xylazine, enhanced sedation, better muscle relaxation, and greater analgesia were observed with 0.03 mg/kg of medetomidine [109]. Medetomidine has been used in combination with butorphanol (0.2 mg/kg IM) and ketamine (10 mg/kg IM) (MBK) to produce anesthesia for 98.8 ± 22.5 minutes, which is significantly longer than for a xylazine (2 mg/kg IM)–butorphanol (0.2 mg/kg IM)–ketamine (10 mg/kg IM) combination (47.5 ± 16.5 minutes). The muscle relaxation was adequate for tracheal intubation, but moderate cardiovascular depression was observed during MBK anesthesia [110]. Atipamezole effectively reversed the effects produced by 0.16–0.32 mg/kg IM of medetomidine [103].
2.4 Atipamezole, Tolazoline, Yohimbine, and Vatinoxan (α2 Antagonists)
The pharmacologic effects induced by any one of the α2 agonists can be antagonized effectively with an α2 antagonist, such as yohimbine, tolazoline, or atipamezole. These antagonists can be used to shorten the time of recovery to standing, to treat severe α2 agonist‐induced bradycardia, and to minimize adverse effects associated with accidental overdose. The α2 agonists are known to cause bloating and ruminal tympany by decreasing gastrointestinal (GI) motility. Administration of any of the α2 antagonists effectively reversed the decrease in GI motility [88, 111]. However, administration of these antagonists is not without risk. Sudden awareness of pain, significant peripheral vasodilation, and CNS excitement have occurred following rapid IV administration of an antagonist. The death of a sheep after administration of a large dose of yohimbine (0.8 mg/kg IV) has been reported [75]. Rapid IV injection of tolazoline has also been reported to cause significant cardiac stimulation, tachycardia, increased cardiac output, vasodilation, and GI distress [112]. Ruminants and camelids are more sensitive to tolazoline than other species, and death has been reported after its use [113, 114]. When administered alone at 1.5 mg/kg IV to Holstein calves, tolazoline caused coughing, an increased frequency of defecation, and a mild increase in breathing effort. At higher doses (2–10 mg/kg IV), adverse effects including bright red conjunctival mucous membranes, coughing, nasal discharge, salivation, labored breathing, CNS depression, signs of abdominal pain, straining, head pressing, restlessness, and severe diarrhea were observed. All calves in the study recovered uneventfully [114]. Currently, lower doses of tolazoline (0.5–1.5 mg/kg IV) are recommended for use in all ruminants including camelids. Others have suggested that, except in emergency situations, IV administration of tolazoline should be avoided to prevent adverse effects such as cardiac asystole [115]. When atipamezole (0.1 mg/kg IV) was administered to six goats to antagonize medetomidine (0.02 mg/kg IV)‐induced sedation and recumbency, all goats stood within 2 minutes. Four goats developed piloerection and all appeared to be agitated and vocalized [116]. When given to reverse IM xylazine‐ or medetomidine‐induced sedation in free‐ranging cattle, atipamezole (0.04–0.09 mg/kg) induced a brief period of excitement following IV administration. Relapse into medetomidine (0.04 mg/kg IV)‐induced sedation 1–2 hours after the administration of atipamezole (0.2 mg/kg IV) as a result of the shorter half‐life (t½) of the drug has been observed in dairy calves. In free‐ranging cattle, atipamezole (0.057 ± 0.017 mg/kg IV) has been administered to reverse xylazine‐induced immobilization. Eight cows receiving xylazine in this report were in the last 2 months of pregnancy and all cows calved normally and no premature parturition occurred [70]. Administration of a reversal agent (atipamezole) may have shortened the duration of xylazine‐induced increases in uterine contraction, thus preventing the adverse effect of xylazine on pregnant cows. Slow injection is recommended when administering an antagonist to avoid sudden awareness of pain and excitement. The undesirable effects of α2 antagonists are extremely rare in healthy animals when the drugs are administered at appropriate dosages and by slow IV injection.
Vatinoxan, also known as MK‐467, is a peripherally acting α2 antagonist. The drug is incapable of entering the CNS to act on the central α2 receptors due to its low lipophilicity and inability to penetrate the blood–brain barrier [117]. Studies in dogs [118–121], cats [122], horses [123, 124], and sheep [125] have shown that concurrent administration with an α2 agonist, vatinoxan, was able to attenuated the adverse cardiovascular effects that are often associated with the α2 agonists. Studies in dogs and horses also showed that vatinoxan enhanced the absorption and volume of distribution of an α2 agonist following IV or IM administration [123, 124, 126, 127]. In sheep, concurrent IM administration of vatinoxan (0.15, 0.3, or 0.6 mg/kg) with medetomidine (0.03 mg/kg IM) and ketamine (1 mg/kg IM) showed that the drug did not completely prevent early vasoconstriction‐related cardiopulmonary effects of medetomidine, but it accelerated, in a dose‐dependent manner, the return of certain physiologic variables to baseline values [128]. It appeared that the absorption of IM vatinoxan was slower than that of the IM medetomidine and hence the presence of the initial cardiopulmonary effects of medetomidine. When vatinoxan (0.25 mg/kg) was administered prior to medetomidine, it was able to attenuate medetomidine‐induced reduction in heart rate and changes in mean arterial blood pressure in sheep [125]. α2 agonist‐induced hypoxemia was believed to be the result of
