values [83]. Furthermore, severe pulmonary parenchymal damage was seen with substantial morphological changes, such as extensive damages to capillary endothelium and alveolar type I cells, intra‐alveolar hemorrhage, and interstitial and alveolar edema. Such changes occurred almost immediately following IV administration of 0.15 mg/kg of xylazine [84]. Bronchospasm and venospasm due to direct action of α2 adrenoceptors on the vascular and bronchial smooth muscles, transient α2‐induced platelet aggregation with pulmonary microembolism, and release of cytokines and other inflammatory mediators subsequent to α2‐induced pulmonary intravascular macrophage activation have been suggested as the contributing factors for the development of hypoxemia in sheep [85].
Caudal epidural administration of xylazine (0.07–0.1 mg/kg), with or without lidocaine, induced long‐lasting somatic analgesia for open castration in rams (8 hours, without lidocaine) and correction of vaginal prolapse in ewes (24 hours, with 0.5 mg/kg of lidocaine) [86, 87]. However, visceral analgesia induced by epidural xylazine alone may not be sufficient for ligation of the spermatic cord [86].
2.3.2.2 Detomidine
At 0.02 mg/kg IV, detomidine produced sedation which is comparable to that of 0.04 mg/kg of xylazine [88]. Increasing the dose to 0.03 mg/kg, detomidine induced recumbency in sheep with sedation that was equivalent to 0.15 mg/kg of xylazine and 0.01 mg/kg of medetomidine [89]. Effective sedation and significant but transient hypotension and bradycardia followed by tachycardia and hypoxemia were reported during sedation with 0.091 ± 0.004 mg/kg of IV detomidine. Cardiac arrhythmias (e.g. atrioventricular block, ST elevation, and premature ventricular contraction) were also observed in this study [90]. Deep sedation with hypotension of 108 ± 9.1 minutes occurred when detomidine (0.092 ± 0.006 mg/kg IV) was combined with diazepam (0.7 ± 0.2 mg/kg IV). Cardiac arrhythmias, but not hypoxemia or hypercapnia, were observed when diazepam was administered with detomidine [91]. Obviously, hypoxemia and pulmonary edema can occur with any of the α2 agonists, but the severity of hypoxemia was reported to be less with detomidine [85]. IV administration of α2 agonists normally induces a characteristic biphasic blood pressure response characterized by transient hypertension followed by longer‐lasting hypotension. The initial hypertension is the result of vasoconstriction from stimulation of peripheral (postsynaptic) α2 adrenoceptors, and the subsequent hypotension is due to activation of central (presynaptic) α2 adrenoceptors resulting in decreased sympathetic outflow and catecholamine release [33]. Celly et al. [82] reported a longer‐lasting hypertension was observed following IV administration of detomidine (0.03 mg/kg). Interestingly, in that study, mean arterial blood pressure showed the characteristic biphasic patterns for all four α2 agonists (xylazine, detomidine, medetomidine, and romifidine), but all the values were within or above normal values. In other words, hypotension, defined as below‐normal arterial blood pressure values, was not observed with any of the α2 agonists in this study [82]. Unlike xylazine, detomidine at IV doses less than 0.04 mg/kg did not produce an oxytocin‐like effect on the uterus in gravid cattle. Doses higher than 0.04 mg/kg may increase the electrical activity of the uterine muscles, but it did not induce the synchronization of the bursts of potentials that is characteristic of parturition. Therefore, detomidine at the therapeutic dose is unlikely to induce premature parturition in pregnant ruminants [56, 57].
The sedative effects of detomidine gel applied intravaginally (0.2 mg/kg) has been studied in alpacas. The onset, the time to maximal sedation, and the duration of sedation were 13.0 ± 2.5, 25 ± 4, and 65 ± 12 minutes, respectively. Four of six alpacas assumed sternal recumbency position during sedation. The result of this study showed that intravaginal detomidine produced moderate sedation which was not as profound as that of IV detomidine [92].
2.3.2.3 Medetomidine
Medetomidine induced dose‐dependent sedation and analgesia in sheep at doses of 0.001–0.007 mg/kg IV, with the level of analgesia produced by 0.005 mg/kg comparable to that of 0.015 mg/kg of fentanyl [93]. At 0.04 mg/kg IM, medetomidine induced 30–45 minutes of good analgesia and marked muscle relaxation and 58 minutes of recumbency. Full recovery usually occurred within 1½–2 hours after regaining the righting reflex [94]. When used as a preanesthetic administered 30 minutes prior to induction with propofol and maintenance with isoflurane, medetomidine (0.005 or 0.01 mg/kg IM) decreased heart rate and respiratory rate. Mean arterial blood pressure values were significantly higher following a high dose (0.01 mg/kg IM) as compared to those without preanesthetic medetomidine or those administered at a lower dose (0.005 mg/kg IM). In general, the administration of medetomidine reduced the dose requirement of propofol for induction and isoflurane for maintenance of anesthesia during surgery [95]. In sheep breathing room air that are anesthetized with medetomidine (0.02 mg/kg IV) and ketamine (2 mg/kg IV), PaO2, arterial pH, and arterial O2 saturation (SaO2) decreased and PaCO2 increased significantly. Supplementation of 100% O2 improved PaO2 and SaO2 [96]. Similar to all other α2 agonist drugs, medetomidine (0.01 mg/kg IV) caused characteristic hypoxemia in sheep breathing room air during sedation [82].
When given to produce lumbosacral analgesia in goats, medetomidine at doses of 0.01, 0.02, and 0.03 mg/kg diluted in sterile water to a total volume of 5 ml produced satisfactory analgesia in the perineum and flank regions, and the analgesia extended to the thorax, forelimbs, neck, and head for a period of at least 3 hours. Ten goats receiving 0.02 mg/kg underwent laparotomy surgery; adequate analgesia was apparent in all tissue layers (from skin to external and internal oblique muscles and transverse muscles). All 10 goats recovered uneventfully from surgery. Lateral recumbency and characteristic side effects of other α2 agonists were observed during the study, particularly with higher doses (0.02 and 0.03 mg/kg). One goat receiving 0.01 mg/kg was paralyzed following lumbosacral injection and was humanely euthanized. Because of the caudal extension of the spinal cord into the cauda equina in goats, it was speculated that the trauma to the conus medullaris and/or cauda equina resulting from struggling of the animal at the time of spinal needle insertion was responsible for the paralysis observed in this goat [97].
IM administration of medetomidine (0.01–0.03 mg/kg IM) has also been used in llamas. Sternal recumbency (5.3 ± 4.7 minutes) and mild to moderate sedation (37.3 ± 9.5 minutes) without analgesia were observed in two of three llamas receiving 0.01 mg/kg of the drug. All llamas receiving 0.02 mg/kg assumed sternal recumbency but with only slightly more profound sedation (58 ± 12.1 minutes) and analgesia (30 minutes) than that of 0.01 mg/kg. When the dose was increased to 0.03 mg/kg, medetomidine induced immobilization (91.5 ± 24.7 minutes) with profound analgesia (61.7 ± 2.9 minutes) and muscle relaxation. The only side effect observed during the period of immobilization was a significant decrease in heart rate. Atipamezole (0.125 mg/kg IM) effectively reversed the effect of medetomidine (0.03 mg/kg IM), and standing recovery occurred within 5.8 ± 3.3 minutes [98].
2.3.2.4 Romifidine
In foals, romifidine was reported to produce sedation and analgesia with greater intensity and longer duration than xylazine [99]. Celly et al. [82] reported that romifidine at 0.05 mg/kg IV produced a similar degree of hypoxemia but a significantly longer duration of initial hypertension than other α2 agonists. When xylazine (0.15 mg/kg IV), detomidine (0.03 mg/kg IV), romifidine (0.05 mg/kg IV), and medetomidine (0.01 mg/kg IV) were administered to sheep at quasiequipotent doses, similar decreases in PaO2 and increases in respiratory rate and maximum changes in transpulmonary pressure (ΔP pl) were observed with all four drugs except the duration of increase in respiratory rate, and ΔP pl were longest with romifidine [82].
When romifidine (0.05 mg/kg) was administered by lumbosacral epidural injection, it produced moderate to complete analgesia of the perineum, flank, and abdominal regions. Increasing the dose to 0.075 mg/kg did not enhance the degree of analgesia but only prolonged the duration. Khattri et al.
