Comparison of Dexmedetomidine/Morphine and Xylazine/Morphine as Premedication in Isoflurane-Anesthetized Sheep

Introduction

Premedication, commonly performed in animals, is an essential step before general anesthesia to calm the animal and provide anxiolysis, sedation, and preemptive analgesia, leading to a smoother anesthetic experience. In addition, premedication can reduce the anesthetic requirements needed during induction and maintenance. As a result, anesthetic side effects can be minimized and the overall quality of anesthesia improved.^1,2 In small ruminants, such as sheep, premedication may be used for sedation to ensure safe and effective handling. To premedicate animals, neuroleptanalgesia, a combination of a sedative with an opioid, is commonly used.^3,4 These combinations typically include an α-2 agonist or benzodiazepine with an opioid, such as xylazine or midazolam with morphine or hydromorphone.^3,4

α-2 Agonists, such as xylazine, have been widely used for chemical restraint in sheep.^1,2 As part of premedication, xylazine provides sedation, muscle relaxation, and analgesia.^5,6 Sheep are particularly sensitive to xylazine.^6–8 Recommended xylazine dosages for sheep are significantly lower than those for other species, ranging from 0.1 to 0.2 mg/kg.^6,8,9 Common cardiovascular side effects include hypertension, hypotension, respiratory depression, bradycardia, arrhythmia, and reduced cardiac output.^4,10,11 Other adverse reactions include vomiting, hypothermia, hyperglycemia, increased urine output, decreased intraocular pressure, and alterations in uterine function and endocrine activity.¹⁰ α-2 Agonists, particularly xylazine, have also been reported to cause hypoxemia.^12–14 In Suffolk crossbred sheep breathing room air, xylazine dosages of 0.15 to 0.20 mg/kg have been associated with pulmonary edema, despite no changes in mean arterial pressure or white cell count.^15,16 Despite these side effects, xylazine continues to be used in sheep.

Dexmedetomidine, another α-2 agonist, is frequently used in small animals and has become more commonly utilized in swine.^17,18 Because of its higher specificity for α-2 receptors (α-1/α-2 ratio of 1:1620) compared with xylazine (α-1/α-2 ratio of 1:140), dexmedetomidine may produce fewer side effects than xylazine.^10,19,20 Dexmedetomidine has demonstrated minimal alveolar concentration-sparing effects when used with inhalant anesthetics.^21,22 In dogs, dexmedetomidine has been used as a premedication in balanced anesthesia techniques, providing satisfactory sedation and analgesia.²³ A combination of dexmedetomidine (0.01 mg/kg) and morphine (0.3 mg/kg) as neuroleptanalgesia has been shown to provide effective analgesia for canine ovariohysterectomies.²⁴ Similarly, dexmedetomidine (0.01 mg/kg) combined with an opioid—morphine (0.5 mg/kg), meperidine (5 mg/kg), butorphanol (0.15 mg/kg), methadone (0.5 mg/kg), tramadol (5 mg/kg), or nalbuphine (0.5 mg/kg)—has been evaluated in dogs. Optimal sedation scores were observed with meperidine or methadone, while the best analgesia scores were reported with morphine, butorphanol, methadone, or nalbuphine. All agents produced similar cardiorespiratory effects.²⁵ Despite its widespread use in dogs, dexmedetomidine is rarely used in sheep.

The purpose of this study was to compare the sedative and anesthetic effects of dexmedetomidine and xylazine, each in combination with morphine, when used as premedication before anesthesia, as well as their effects on pulmonary tissues in sheep. We hypothesized that dexmedetomidine and morphine (DM) would provide profound sedation, better maintain physiologic parameters under anesthesia, and induce less lung pathology than xylazine and morphine (XM) in sheep undergoing laparoscopic surgery.

Materials and Methods

Results

Lung pathology.

Gross evaluation.

Macroscopically, lung tissues exhibited a range of lesions, from no changes or slight alterations (score 0) to moderate pulmonary hemorrhage and edema (scores 1.5 to 2.0) in both experimental groups (Figure 1). The macroscopic lung lesion scores are presented in Table 7. Although the lung lesion scores in the XM group appeared higher than those in the DM group, this difference was not statistically significant.

View Figure

• Download as Powerpoint
• Download Figure

Table 7. Macroscopic lung lesion score (median (IQR)) for sheep premedicated with DM or XM

Lung lobe	DM	XM	P value
Right lobe
Cranial part	0.00 (0.00–0.31)	0.50 (0.00–1.50)	0.256
Middle part	0.00 (0.00–0.31)	0.50 (0.00–1.50)	0.256
Caudal part	0.00 (0.00–0.31)	0.50 (0.00–1.50)	0.256
Total score	0.00 (0.00–0.94)	1.50 (0.00–4.50)	0.256
Left lobe
Cranial part	0.00 (0.00–0.75)	1.50 (0.25–1.75)	0.160
Caudal part	0.00 (0.00–0.75)	1.50 (0.25–1.75)	0.160
Total score	0.00 (0.00–1.55)	3.00 (0.50–3.50)	0.283

DM, combination of dexmedetomidine and morphine; XM, combination of xylazine and morphine.

View Fullscreen

Histologic evaluation.

Histologic findings revealed minimal to marked pulmonary changes (scores 1 to 4). Pulmonary congestion and hemorrhage were observed in both groups, along with mild to moderate pulmonary edema (Figure 1). Histologic scores were significantly higher in the XM group than in the DM group for both the right and left lung lobes. In addition, the XM group had a significantly higher score in the left cranial lung lobe, as well as a higher total score for the left lung lobe (P = 0.029 and P = 0.045, respectively) (Table 8). However, no significant differences were observed between the DM and XM groups for other lung lobes, including the right cranial, right middle, right caudal, and left caudal lobes.

Table 8. Histopathological lung score (median (IQR)) in sheep premedicated with DM or XM

Lung lobe	DM	XM	P value
Right lobe
Cranial part	1.00 (1.00–2.00)	2.00 (2.00–3.00)	0.103
Middle part	1.00 (1.00–2.00)	2.00 (1.00–2.00)	0.306
Caudal part	2.00 (1.00–2.00)	2.00 (2.00–3.00)	0.080
Total score	5.00 (3.00–5.00)	6.00 (6.00–7.00)	0.009*
Left lobe
Cranial part	1.00 (1.00–2.00)	2.00 (2.00–3.00)	0.029*
Caudal part	2.00 (1.00–2.00)	3.00 (2.00–3.00)	0.072
Total score	3.00 (2.00–5.00)	5.00 (4.00–5.00)	0.045*

DM, combination of dexmedetomidine and morphine; XM, combination of xylazine and morphine.

*

P < 0.05 between groups.

View Fullscreen

Discussion

Both DM and XM exhibited comparable sedation in sheep undergoing general anesthesia; required a similar amount of induction drug (tiletamine/zolazepam); did not alter physiologic parameters (except HR) or arterial blood gas parameters throughout the study (60 min), with the average HR in the DM group higher than that in the XM group; required a similar isoflurane level (∼0.5%) except at T0, at which timepoint the DM group required a lower isoflurane level; and showed no differences in gross pathology, while histologic evaluation revealed mild to moderate pulmonary edema in XM-treated sheep.

To our knowledge, this is the first study to use DM and XM as sedative combinations in sheep. Because α-2 agonists have been reported to cause adverse pulmonary effects, the lowest possible dosages were selected to achieve sedation. The dexmedetomidine dosage (0.006 mg/kg, IM) was determined based on a pilot study and was significantly lower than the recommended dosage range for sheep (0.01 to 0.03 mg/kg).⁶ The pilot study demonstrated that this dosage was sufficient for handling sheep, placing intravenous catheters, collecting arterial blood samples, and administering preoxygenation via a mask. The xylazine dosage (0.1 mg/kg) was selected from the lower range of recommended dosages for sheep (0.1 to 0.3 mg/kg).⁶

Neuroleptanalgesia combines sedatives with opioids, allowing for lower doses of each drug and reducing side effects. Therefore, an opioid, morphine (0.3 mg/kg), was included.²⁹ Although the combination of morphine and α-2 agonists was expected to produce profound sedation, both DM and XM only provided mild sedation 20 min after administration. Dexmedetomidine’s sedative effects have been reported to be similar to those of medetomidine (0.006 mg/kg), producing light to moderate sedation lasting up to 60 min, while xylazine-induced sedation typically lasts 10 to 20 min.³⁰ Despite causing only mild sedation in sheep, both DM and XM sufficiently reduced the subsequent anesthetic induction dose of tiletamine/zolazepam (∼1.0 to 1.4 mg/kg). The tiletamine/zolazepam dosages required in this study were considerably lower than the recommended sheep dosage for anesthesia (12 to 24 mg/kg, IM).^31,32 Notably, the tiletamine/zolazepam dosage used in this study was intended to facilitate rapid and smooth anesthetic induction, allowing for endotracheal intubation. In addition, both DM and XM reduced the isoflurane requirement to 0.5% throughout the 60-min monitoring period. This low isoflurane level is ∼0.3-fold the minimal alveolar concentration for sheep, which ranges from 1.42% to 1.58%.³³ Similarly, dexmedetomidine (0.005 mg/kg, IV) has been shown to reduce the isoflurane requirement to ∼1% in female sheep.³⁴

The physiologic parameters (RR, SAP, MAP, DAP, and body temperature) and blood gas analysis showed no significant differences between the DM and XM groups. However, dexmedetomidine (0.002 mg/kg, IV) has been reported to initially increase MAP and systemic vascular resistance, followed by a decrease over a 90-min period in sheep.³⁵ The one physiologic parameter that differed was HR (at T10 and average HR), with DM-treated sheep exhibiting a higher mean HR than XM-treated sheep. Interestingly, in female sheep administered dexmedetomidine (0.005 mg/kg, IV), HR was not significantly affected.³⁴ This effect may be attributed to dexmedetomidine’s higher α-2 receptor selectivity, lower dose, and intramuscular (compared with intravenous) administration. Importantly, note that in other species, α-2 agonists (for example, dexmedetomidine, xylazine) can cause adverse effects such as hypertension followed by hypotension, hypothermia, and respiratory depression.^4,10,11 In this study, blood pressure remained within a normal range (∼75 mm Hg) throughout the 60-min anesthetic period, with no signs of hypertension or hypotension. In addition, body temperature (99 to 100 °F) and EtCO₂ (35 to 45 mm Hg) were maintained.

Interestingly, our study revealed pulmonary lesion differences between the 2 groups. Although gross lesion scores were higher in the XM group, these differences were not statistically significant. In contrast, XM-treated sheep exhibited significantly worse histopathologic scores, with pulmonary congestion, hemorrhage, and edema. DM-treated sheep had lower histopathologic scores, indicating fewer lesions. Similarly, in another study, xylazine (0.5 mg/kg, IV) did not cause gross lesions (macroscopic edema) in sheep.²⁸ However, xylazine has been reported to induce pulmonary edema and/or alterations in partial pressure of arterial O₂ (PaO₂) in sheep (0.15 mg/kg, IV),^9,16 calves (0.3 mg/kg, IV),³⁶ and rats.^37–39 Medetomidine (0.03 mg/kg, IV) has also been reported to lower PaO₂ in calves.³⁶ Dexmedetomidine (0.002 mg/kg, IV) has been shown to increase mean pulmonary arterial pressure, pulmonary arterial occlusion pressure, and capillary pressure within 2 min, with CT imaging revealing increased lung density.⁴⁰ The same study also reported vascular congestion followed by protein and erythrocyte extravasation into alveoli.⁴⁰ In addition, dexmedetomidine has been associated with ventilator-induced lung injury in male Sprague–Dawley rats.⁴¹ Potential mechanisms underlying these effects include bronchospasm triggered by direct stimulation of peripheral α-2 adrenergic receptors, pulmonary microembolism due to platelet aggregation associated with α-2 adrenergic receptors, and activation of pulmonary intravascular macrophages.¹⁶ These processes collectively contribute to acute lung injury and subsequent alterations in respiratory mechanics.^13,36 Our study showed no differences between left and right lung lesions; both lungs exhibited similar lesions and scores, regardless of group. All sheep were positioned in dorsal recumbency throughout the procedure, eliminating potential orthostatic effects on the lungs. These results are consistent with another study that also reported evenly distributed lung lesions.²⁸ Although XM-associated severity was histopathologically evident in our study, neither the PaO₂ (∼300 mm Hg under 100% O₂) nor %SpO₂ in either the DM or XM group indicated hypoxemia or showed significant differences. Similarly, in another study, dexmedetomidine (0.005 mg/kg, IV) resulted in PaO₂ values of ∼220 to 279 mm Hg on 100% O₂ in female sheep.^28,34 That study also concluded that histologic severity did not correlate with %SpO₂, which aligns with our findings.²⁸ Dexmedetomidine (0.002 mg/kg, IV) has been reported to significantly reduce PaO₂ for up to 10 min in anesthetized sheep.^35,42 However, the unaltered PaO₂ results in our study were consistent with another study using xylazine (0.4 mg/kg, IV) or medetomidine (0.004 mg/kg, IV) in horses.⁴³ α-2 Antagonists, including atipamezole (0.04 to 0.10 mg/kg, IV), yohimbine (0.125 mg/kg, IV), and vatinoxan (0.75 mg/kg, IV), have been shown to partially reverse these adverse effects in sheep.²⁸ Because the sheep in our study were euthanized, α-2 antagonists were not administered. Our findings suggest that dexmedetomidine may offer a more favorable pulmonary profile, potentially reducing anesthesia-associated respiratory complications. Its selective action on α-2 adrenergic receptors, sparing α-1 receptors, may mitigate the adverse pulmonary effects observed with xylazine, making dexmedetomidine a preferable choice for premedication in sheep.

Despite these promising findings, our study had several limitations. First, physiologic parameters were not measured beyond 60 min because the primary goal was to assess the use of DM and XM for premedication. Consequently, we focused on monitoring sedation effects in relation to the induction dose, isoflurane requirements, and physiologic and blood gas parameters for only 60 min following DM or XM administration. Anesthetic recovery quality was not assessed because this was a collaborative terminal study, and the sheep did not recover. Only male sheep were used, and anesthetic effects may vary by sex.^44,45 Furthermore, only single and low dosages of DM and XM were studied. Higher dosages or different combinations may have altered the results, particularly regarding lung pathology. In addition, the reversal agent atipamezole was not used. While atipamezole reportedly reverses these adverse effects, its ability to reverse α-2-induced pulmonary edema remains unknown. Lastly, although ventilatory settings were standardized across all animals, the potential influence of the laparoscopic procedure or mechanical ventilation on the observed pulmonary changes cannot be ruled out.

In conclusion, our study demonstrates that both DM and XM combinations are effective premedication protocols in sheep, providing comparable levels of sedation and maintaining stable physiologic and blood gas parameters throughout anesthesia. The DM combination was associated with fewer pulmonary complications, suggesting a potentially safer respiratory profile. In addition, the DM group exhibited a higher mean HR, which may be advantageous in minimizing bradycardia. These findings support the use of dexmedetomidine as a viable alternative to xylazine for premedication of sheep, particularly in cases where cardiopulmonary side effects are a concern.