Introduction
Medetomidine, a reliable sedative and analgesic agent, is utilized broadly across veterinary species, including small ruminant species (sheep and goats). A potent α2-adrenergic receptor agonist, medetomidine is highly selective with an α2:α1 ratio of 1,620:1. This racemic mixture is comprised of the enantiomers levomedetomidine and dexmedetomidine, of which the dextral chirality is responsible for its clinical effect.1 The α2-receptor subtypes elucidated include α2A, α2B, α2C, and α2D. The α2A, α2C, and α2D receptors are distributed primarily in the CNS, and agonism results in decreased sympathetic tone, sedation, and analgesia at the level of the spinal cord.2–4 Conversely, α2B receptors are found in the tunica media of peripheral vasculature. Alpha-2B–receptor activation causes increased systemic vascular resistance via vasoconstriction, lending to reflex bradycardia and decreased cardiac output.2,5 Dogs showed a decrease in cardiac output of up to 50% from baseline at doses of 5 to 20 µg/kg of dexmedetomidine, IV.6 Importantly, the receptor subtype distribution invites the possibility of capitalizing on the sedative and analgesic properties of medetomidine while reducing deleterious cardiovascular effects.
The cardiopulmonary effects of α2-receptor agonists in sheep, particularly regarding hypoxemia and pulmonary edema, are well described.7,8 Additionally, individual and breed predilections in both sheep and goats are documented.7,8 These effects are thought to be primarily due to peripheral α2-receptor agonist effects. While the exact mechanism leading to pulmonary edema has not been elucidated, hypotheses include bronchoconstriction, pulmonary vasospasm or micro emboli, and activation of pulmonary intravascular macrophages.7
Vatinoxan is an α2-receptor antagonist whose hydrophilic properties impede crossing of the blood brain barrier.9 The sedation potential and cardiovascular effect of vatinoxan in combination with medetomidine have been variably characterized in several domestic and wild mammals. A commercially available medetomidine (0.5 mg/mL) and vatinoxan hydrochloride (HCL; 10 mg/mL) mixture (Zenalpha [ZEN]) was approved in 2022 for IM sedation and analgesia in dogs. However, a thorough literature search did not reveal previous investigation of the commercially available drug mixture ZEN in small ruminants.
Our objective was to assess the sedation duration and quality of ZEN in healthy sheep and goats. Concurrently, we aimed to characterize the changes in cardiovascular and respiratory parameters.
Our hypothesis was that an IM injection of ZEN would produce deep sedation in healthy goats and sheep. We further hypothesized that cardiopulmonary parameters would be maintained within physiologic range for both sheep and goats.
Methods
The use of goats and sheep in this study was overseen by the Louisiana State University IACUC (IACUCAM-23-010). Zenalpha is FDA-approved in the US and labeled for use in dogs. Extralabel drug use in the present study complied with the provision of the AMDUCA and Code of Federal Regulations.10
Animals
Ten university-owned research castrated male Black Bengal mixed-breed goats all older than 5 years based on dentition were utilized in this study, along with 10 healthy university-owned research Gulf Coast native and Katahdin sheep all older than 9 months. All animals were deemed apparently healthy based on physical examination, PCV, and serum total solids. The study period was from June 27 to July 27, 2023. Animals were housed based on species in adjacent native grass pastures with access to Bahia hay (Paspalum notatum), species-appropriate concentrates, and free-choice water. All animals were acclimated to gentle restraint over a 4-week period. Animals were moved to indoor pens and kept in small groups at the study location 24 to 72 hours prior to the experiment and fasted for 12 to 18 hours prior to scheduled sedation time.
Instrumentation
The morning of the study, the animals were weighed and a physical examination was performed. For instrumentation, goats and sheep were anesthetized with sevoflurane in 100% oxygen delivered with a tight-fitting face mask attached to a circle breathing system at an oxygen flow rate of 2 L/min at a vaporizer setting of 7% to 9% sevoflurane until palpebral reflex was lost, then reduced to 2.5% to 3.5% after induction for maintenance. Animals were placed in right or left lateral recumbency. To reduce the risk of regurgitation, a rolled towel was placed underneath the neck. Respiratory rate and heart rate were monitored every 5 minutes throughout instrumentation. Total anesthesia time for instrumentation was also recorded. The skin over the jugular and auricular catheter insertion sites was clipped and prepared aseptically with 2% chlorhexidine and 70% isopropyl alcohol. A 16-g, 2-inch catheter was placed in either the right or left jugular vein and secured with suture. A 22-g, 1.25-inch arterial catheter was placed in the left or right auricular artery and secured with medical tape and super glue for blood gas sampling and arterial blood pressure measurement. Electrocardiographic leads were placed on the right and left metacarpi and left metatarsus. Animals were allowed to recover completely from inhalant anesthesia for a minimum of 60 minutes until a sedation score of 0 was reached. Sedation was scored on a 0-to-10 scale, as previously described.11
Experimental design
Sheep and goats received 0.06 mL of ZEN/kg (corresponding to 0.03 mg of medetomidine/kg and 0.6 mg of vatinoxan HCL/kg). Intramuscular injections were given in the right or left muscles of the neck cranial to the scapula, dorsal to the jugular furrow, and ventral to the nuchal ligament. Sedation was evaluated on a 0-to-10 scale, as previously described.11 Sedation was evaluated by 1 observer (AK). Time to sternal and lateral recumbency and return to sternal/standing, as well as loss/return of tongue tone and loss/return of palpebral reflexes, was also recorded. Loss of tongue tone was described as absent resistance to manual exteriorization of tongue through diastema for placement of the peripheral oxygen saturation (Spo2) probe. Return of tongue tone was defined as spontaneous movement of tongue or inability to tolerate Spo2 placement. Sedation score, heart rate, respiratory rate, rectal temperature, mucus membrane color, capillary refill time, invasive systolic and diastolic blood pressure, and mean arterial blood pressure (MAP) were recorded at baseline (time 0, before drug administration) and then every 5 minutes for the first 60 minutes after drug administration, followed by every 15 minutes thereafter either until sedation score returned to baseline or up to 150 minutes. For invasive blood pressure measurement, a disposable pressure transducer was used and tested at the beginning of each study day for accuracy and linearity against a mercury manometer at 0 and 150 mm Hg. The transducer was placed at the level of the heart (standing animals, point of the shoulder; animals in sternal recumbency, point of the shoulder; lateral recumbent animals, sternum) and zeroed to atmospheric pressure at baseline for each animal and with position change from standing to sternal to lateral recumbency. The transducer was maintained at the level of the heart for subsequent readings. Noncompliant tubing (91 cm in length) flushed with heparinized saline was used to connect the arterial catheter to the pressure transducer. A pressurized (300–mm Hg), 500-mL bag of heparinized 0.9% NaCl was then connected to the system. The arterial blood pressure system was visually inspected for air bubbles, and a fast-flush test was performed to evaluate the oscillating waves. Arterial blood gas samples were obtained at baseline and 5, 15, 30, and 45 minutes after administration of ZEN via a 3-way stopcock affixed to the end of the arterial catheter. Samples were analyzed immediately after acquisition with a bedside blood gas and electrolyte monitor (Element POC; Heska Corp). Peripheral oxygen saturation of hemoglobin as measured by pulse oximetry was measured as tolerated by level of sedation on the tongue or prepuce/vulva.
Atipamezole at 10 µg/kg was given IM in the event of an adverse drug reaction defined by hypoxemia unresponsive to flow-by oxygen (Pao2 < 60, Spo2 < 92%), MAP (≤ 60), and being unresponsive to a 10-mL/kg fluid bolus or if sedation score had not returned to baseline after 150 minutes. A forced-air warming unit (Bair Hugger; 3M Co) as external heat support was provided for animals under 98 °F.
Statistical analysis
All statistical analyses were performed with JMP Pro (version 17.0.0; JMP Statistical Discovery LLC). Graphs were generated with Prism, version 10.0.2 (GraphPad Software Inc). A Student t test was used to analyze the variables measured without any time point, with species as the fixed effect. A repeated-measure ANOVA with a mixed-effect model was used to analyze the variables measured over time. Species, time points, and their interactions were entered as the fixed effects, and each animal was entered as the random effect. When a fixed effect was detected, a post hoc Dunnett comparison was used against baseline. Assumptions of the parametric model, normality of residuals, and homoscedasticity were accessed by examining standardized residual and quantile plots. Data were presented as mean ± SD. Sedation scores were evaluated via the Friedman test with pairwise Dunn post hoc comparisons within each breed from baseline to 60 minutes and via the Mann-Whitney test within each time point between breeds from 5 to 90 minutes. Data were presented as median sedation score, with calculation of the interquartile range. Significance was set at P < .05.
Results
Ten adult sheep (7 intact females, 3 castrated males) and 10 adult castrated male goats weighing 31.98 ± 9.28 kg and 45.31 ± 5.95 kg, respectively, were used in the study. All animals completed the study. The arterial catheter was lost in 1 sheep at time point 25 and was unable to be replaced. A drug effect outside of sedation was soft, log-formed stool observed in 1 Katahdin sheep and 2 goats, which resolved spontaneously within 24 hours of sedation.
Instrumentation time in minutes was not statistically significant (P > .05) between sheep and goats (22.40 ± 5.85 minutes and 20.80 ± 2.66 minutes, respectively). No regurgitation during instrumentation time was noticed. The total sedation time for sheep (102.80 ± 10.90 minutes) and goats (133.50 ± 32.63 minutes) was significantly different (P = .012). Recorded times are summarized in Table 1. Profound reliable sedation was achieved in 19 of 20 individuals. One goat did not achieve sternal or lateral recumbency. No noticeable error occurred with drug administration technique or accurate dosing. Sedation scores were significantly different from baseline at 15 to 45 minutes for sheep and 15 to 60 minutes for goats (P < .05). Two goats had not returned to a sedation score of 0 by 150 minutes and were given atipamezole, IM. At this time, sedation scores were 7/10 and 6/10. At 25, 30, and 35 minutes, the sedation score for sheep was significantly higher than the sedation score for goats (Figure 1). No statistically significant differences were found for time to sternal, time to lateral, time to absent tongue tone, loss and return of palpebral reflex, return to sternal, and time to standing between species (P > .05). Tongue tone was lost in 9 goats and 8 sheep. Time to return of tongue tone was 77.25 ± 28.74 minutes for goats and 47.56 ± 7.99 minutes for sheep (P < .05).
Sedation parameters presented as mean ± SD for 10 healthy sheep and 10 healthy goats after IM administration of medetomidine (0.03 mg/kg) and vatinoxan hydrochloride (0.6 mg/kg) as a single IM injection of a commercially available mixture (Zenalpha; 0.06 mL/kg) between June 27 and July 27, 2023, in a study to evaluate the mixture’s sedative and cardiopulmonary effects in the species.
| Variable | Species | No. of animals | Mean ± SD (min) |
|---|---|---|---|
| Total sedation time* | Caprine | 10 | 133.50 ± 32.63 |
| Ovine | 10 | 102.8 ± 10.90 | |
| Sternal recumbency | Caprine | 9 | 10.00 ± 8.56 |
| Ovine | 9 | 8.56 ± 5.70 | |
| Lateral recumbency | Caprine | 9 | 15.22 ± 4.94 |
| Ovine | 10 | 13.40 ± 5.50 | |
| Loss of tongue tone* | Caprine | 9 | 16.11 ± 5.23 |
| Ovine | 8 | 20.00 ±7.37 | |
| Loss of palpebral reflex | Caprine | 5 | 18.80 ± 6.42 |
| Ovine | 3 | 19.67 ± 8.39 | |
| Return of palpebral reflex | Caprine | 5 | 54.40 ± 31.79 |
| Ovine | 3 | 46.67 ± 2.89 | |
| Return of tongue tone* | Caprine | 8 | 77.25 ± 28.74 |
| Ovine | 9 | 47.56 ± 7.99 | |
| Return to sternal | Caprine | 9 | 86.78 ± 31.78 |
| Ovine | 10 | 75.50 ± 17.04 | |
| Return to standing | Caprine | 8 | 111.88 ± 37.68 |
| Ovine | 10 | 86.60 ± 14.51 |
Asterisks denote variables significantly different between species (P < .05).
Median sedation score (on a scale from 0 [standing, alert, normal behavior] to 10 [lateral recumbency, no movement]) for 10 healthy sheep (red) and 10 healthy goats (blue) at baseline immediately before (0 minutes) to 150 minutes after receiving medetomidine (0.03 mg/kg) and vatinoxan hydrochloride (0.6 mg/kg) as a single IM injection of a commercially available mixture (Zenalpha; 0.06 mL/kg) between June 27 and July 27, 2023, in a study to evaluate the mixture’s sedative and cardiopulmonary effects in the species. For each time point for each species, the x represents the median sedation score and the whiskers represent the IQR. Asterisks denote time points for which median sedation scores differed significantly (P < .05) between species.
Citation: Journal of the American Veterinary Medical Association 263, 1; 10.2460/javma.24.08.0497
Heart rate was decreased from baseline (P < .05) for goats at all time points while a biphasic decrease in HR was seen in sheep (Table 2). A decrease in MAP from baseline (P < .05) was seen at all time points for goats and 15 minutes onward for sheep. Three goats developed hypotension and were given a 10-mL/kg fluid bolus. None of the sheep became hypotensive. Temperature decreased over time in all animals. One goat became hypothermic and required active warming. There was a decrease in Pao2 from baseline (P < .05) at 5, 15, and 45 minutes for both species. For both species, there was also an increase in Paco2 from baseline (P < .05) at 15 minutes onward. Respiratory rate decreased from baseline (P < .05) at 55 to 90 minutes for both species. Eight goats and 3 sheep required flow-by oxygen via a facemask. One goat was given atipamezole, IM, at 55 minutes due to hypoxemia unresponsive to oxygen therapy. There was a decrease in potassium from baseline (P < .05) at all time points for both species without changes to blood glucose. Arterial blood gas results and cardiorespiratory data are summarized in Table 2 and Table 3. One sheep 12 hours after completion of the study was found unable to rise from sternal, depressed and dyspneic. A CBC, chemistry panel, and venous blood gas revealed severe neutropenia, mild hypoalbuminemia, moderate azotemia, and a mixed respiratory and metabolic acidosis. After failure to respond to supportive care, this individual was humanely euthanized. A diagnostic necropsy revealed acute moderate cranioventral bronchopneumonia secondary to Mannheimia haemolytica.
Results of blood gas analysis presented as mean ± SD for 10 healthy sheep and 10 healthy goats, as described in Table 1.
| Variable | Species | Baseline | Time after ZEN administration (min) | |||
|---|---|---|---|---|---|---|
| 5 | 15 | 30 | 45 | |||
| pH | Caprine | 7.47 ± 0.03 | 7.42 ± 0.03 | 7.39 ± 0.04* | 7.37 ± 0.07* | 7.38 ± 0.06* |
| Ovine | 7.52 ± 0.03 | 7.51 ± 0.09 | 7.48 ± 0.02* | 7.48 ± 0.03* | 7.48 ± 0.04* | |
| Paco2 (mm Hg) | Caprine | 33.87 ± 3.75 | 37.07 ± 2.95 | 39.76 ± 4.06* | 44.42 ± 11.39* | 44.02 ± 7.76* |
| Ovine | 33.86 ± 2.63 | 34.89 ± 1.58 | 35.92 ± 3.52* | 37.85 ± 2.17* | 37.97 ± 3.24* | |
| Pao2 (mm Hg) | Caprine | 88.91 ± 6.08 | 63.98 ± 11.41* | 70.52 ± 18.77* | 82.21 ± 21.45 | 75.76 ± 19.78* |
| Ovine | 82.42 ± 9.24 | 68.53 ± 9.97* | 74.49 ± 11.87* | 74.73 ± 4.27 | 73.47 ± 18.10* | |
| HCO3− (mmol/L) | Caprine | 24.54 ± 1.90 | 24.18 ± 1.53 | 24.01 ± 1.87 | 25.26 ± 2.34 | 25.95 ± 1.45* |
| Ovine | 27.54 ± 1.93 | 26.76 ± 2.20 | 26.22 ± 2.19 | 28.16 ± 1.73 | 28.58 ± 1.03* | |
| Na+(mmol/L) | Caprine | 143.20 ± 1.48 | 144.00 ± 1.63* | 143.90 ± 2.51* | 143.50 ± 1.43* | 143.60 ± 1.26 |
| Ovine | 142.40 ± 1.90 | 143.60 ± 2.32* | 144.00 ± 2.05* | 143.80 ± 2.10* | 143.33 ± 2.06 | |
| K+(mmol/L) | Caprine | 3.49 ± 0.34 | 3.24 ± 0.27* | 3.19 ± 0.27*a | 3.25 ± 0.29*a | 3.24 ± 0.24*a |
| Ovine | 3.45 ± 0.27 | 3.06 ± 0.34* | 2.86 ± 0.28*a | 2.66 ± 0.37*a | 2.46 ± 0.31*a | |
| Ca2+ (mmol/L) | Caprine | 1.17 ± 0.05 | 1.17 ± 0.06 | 1.15 ± 0.07* | 1.17 ± 0.08 | 1.16 ± 0.08* |
| Ovine | 1.14 ± 0.07 | 1.11 ± 0.05 | 1.08 ± 0.08* | 1.10 ± 0.07 | 1.09 ± 0.05* | |
| Cl− (mmol/L) | Caprine | 111.70 ± 3.09 | 112.00± 2.00 | 113.20 ± 2.53* | 112.30 ± 3.06 | 111.20 ± 2.10 |
| Ovine | 106.80 ± 2.82 | 107.90 ± 2.77 | 108.30 ± 2.98* | 106.70 ± 2.58 | 106.56 ± 2.19 | |
| Glucose (mg/dL) | Caprine | 89.90 ± 19.11 | 91.90 ± 19.17 | 92.10 ± 16.68 | 94.80 ± 18.51 | 92.40 ± 18.86 |
| Ovine | 92.60 ± 19.10 | 91.30 ± 18.03 | 90.60 ± 19.55 | 89.70 ± 21.02 | 86.56 ± 20.14 | |
ZEN = Zenalpha.
aValues significantly different between species at selected time points (P < .05). Asterisks denote values significantly different from baseline (P < .05).
Results of cardiovascular variables and body temperature presented as mean ± SD for 10 healthy sheep and 10 healthy goats, as described in Table 1.
| Time after ZENadministration (min) | Species | Temp | HR | RR | SAP | DAP | MAP |
|---|---|---|---|---|---|---|---|
| Baseline (0) | Caprine | 38.6 ± 0.5a | 94 ± 19 | 37 ± 39 | 132.6 ± 10.9a | 100.2 ± 9.1 | 112.4 ± 8.3 |
| Ovine | 39.1 ± 0.4a | 95 ± 18 | 32 ± 10 | 122 ± 6.9a | 94.4 ± 5.4 | 106.2 ± 4.4 | |
| 5 | Caprine | 38.7 ± 0.7 | 79 ± 16* | 31 ± 33 | 115.2 ± 13.2* | 84.9 ± 9.7* | 97.6 ± 11.5* |
| Ovine | 39.2 ± 0.5 | 71 ± 19 | 36 ± 11* | 116.6 ± 13.3 | 88.3 ± 8.4 | 101.6 ± 9.9 | |
| 10 | Caprine | 39.1 ± 0.5 | 78 ± 16* | 31 ± 28 | 108.4 ± 21.5* | 72.7 ± 13.4*a | 87.2 ± 16.5* |
| Ovine | 39.2 ± 0.3 | 68 ± 10* | 38 ± 15 | 116.1 ± 11.7 | 87.4 ± 11.8a | 99.3 ± 10.5 | |
| 15 | Caprine | 38.9 ± 0.6 | 76 ± 12* | 27 ± 24 | 102.5 ± 16.8* | 66.1 ± 12.8*a | 81.3 ± 14.7*a |
| Ovine | 39 ± 0.4 | 77 ± 13* | 40 ± 18 | 113.8 ± 10.2 | 85.2 ± 12.2*a | 98.0 ± 11.2*a | |
| 20 | Caprine | 38.8 ± 0.5 | 75 ± 12* | 30 ± 23 | 98 ± 18.1* | 61.3 ± 16*a | 76.2 ± 17.9*a |
| Ovine | 38.8 ± 0.5 | 78 ± 12* | 38 ± 21 | 107.1 ± 13.7* | 79.9 ± 12.1*a | 91.4 ± 12.2*a | |
| 25 | Caprine | 38.7 ± 0.7 | 74 ± 11* | 28 ± 23 | 93.8 ± 14.4* | 57.8 ± 13.2*a | 71.8 ± 13.4*a |
| Ovine | 38.6 ± 0.5* | 82 ± 18 | 37 ± 22 | 103.6 ± 11.5* | 76.1 ± 10.6*a | 87.3 ± 11.5*a | |
| 30 | Caprine | 38.6 ± 0.6 | 74 ± 10* | 27 ± 22 | 92.8 ± 14.8* | 57.5 ± 11.6*a | 72.3 ± 13.6* |
| Ovine | 38.4 ± 0.5* | 85 ± 13 | 35 ± 21 | 101.6 ± 9.1* | 75.0 ± 11.4*a | 83.8 ± 9.7* | |
| 35 | Caprine | 38.5 ± 0.6 | 74 ± 11* | 25 ± 22 | 92.8 ± 15.9* | 56.7 ± 11.9*a | 71.3 ± 14.8* |
| Ovine | 38.3 ± 0.6* | 85 ± 15 | 35 ± 13 | 97 ± 11.5* | 71.0 ± 10.3*a | 81.6 ± 10.1* | |
| 40 | Caprine | 38.4 ± 0.7 | 70 ± 12* | 27 ± 22 | 92.3 ± 17.3* | 58.5 ± 13.8* | 71.4 ± 16.1* |
| Ovine | 38.2 ± 0.4* | 83 ± 14 | 33 ± 9 | 97.2 ± 11.8* | 69.1 ± 13.8* | 80.7 ± 11.6* | |
| 45 | Caprine | 38.2 ± 0.8 | 70 ± 10* | 26 ± 23 | 93.3 ± 16.5* | 58.7 ± 13.9* | 72.5 ± 15.9* |
| Ovine | 38.2 ± 0.4* | 74 ± 15* | 30 ± 9 | 98.4 ± 9.5* | 69.9 ± 11.1* | 80.9 ± 10.2* | |
| 50 | Caprine | 38.2 ± 0.8 | 67 ± 11* | 25 ± 24 | 99.3 ± 19.8* | 63.4 ± 14.1* | 77.5 ± 16.4* |
| Ovine | 38 ± 0.6* | 71 ± 12* | 31 ± 9 | 96.2 ± 10.9* | 68.8 ± 10.6* | 79.9 ± 10.5* | |
| 55 | Caprine | 38.1 ± 0.8* | 70 ± 12* | 26 ± 26* | 99.4 ± 19.9* | 66.2 ± 14.3* | 80.1 ± 16.8* |
| Ovine | 37.8 ± 0.6* | 66 ± 12* | 29 ± 8* | 96.4 ± 12.6* | 70.3 ± 9.9* | 80.4 ± 9.9* | |
| 60 | Caprine | 38.1 ± 0.7* | 69 ± 11* | 28 ± 25* | 103.7 ± 16.2* | 71.1 ± 13.4* | 85.2 ± 14.1* |
| Ovine | 37.8 ± 0.6* | 65 ± 19* | 27 ± 9* | 94.8 ± 9.9* | 70.7 ± 8.7* | 81.1 ± 8.8* | |
| 75 | Caprine | 37.8 ± 1* | 68 ± 12* | 26 ± 26* | 102.4 ± 15.1* | 69.1 ± 12.1* | 82.8 ± 11.8* |
| Ovine | 37.8 ± 0.6* | 65 ± 13* | 28 ± 8* | 98.9 ± 17.5* | 77.1 ± 11.5* | 87.1 ± 13.6* | |
| 90 | Caprine | 37.6 ± 1.1* | 68 ± 13* | 25 ± 30* | 106.7 ± 13.1* | 78.2 ± 11.4* | 90.3 ± 9.8* |
| Ovine | 37.7 ± 0.7* | 68 ± 14* | 25 ± 7* | 105.7 ± 10.6* | 80.7 ± 7.7* | 92.4 ± 7.8* | |
| 105 | Caprine | 37.2 ± 0.9* | 62 ± 11* | 26 ± 30 | 108.5 ± 11.9* | 76.9 ± 8.3* | 91.1 ± 7.5* |
| Ovine | 37.9 ± 0.3* | 70 ± 9* | 26 ± 8 | 104.2 ± 13.3* | 78.4 ± 6.8* | 88.0 ± 8.8* |
DAP = Diastolic arterial pressure. HR = Heart rate. MAP = Mean arterial pressure. RR = Respiratory rate. SAP = Systolic arterial pressure. Temp = Temperature.
aValues significantly different between species at selected time points (P < .05). Asterisks denote values significantly different from baseline (P < .05).
Discussion
The commercially available medetomidine (0.5 mg/mL) and vatinoxan HCL (10 mg/mL) mixture (ZEN) is FDA-approved in the US and labeled for use in dogs. Extralabel drug use in the present study complied with the provision of the AMDUCA and Code of Federal Regulations.10 The present findings disproved that with IM administration of 0.06 mL of ZEN/kg (corresponding to 0.03 mg of medetomidine/kg and 0.6 mg of vatinoxan HCL/kg), cardiopulmonary parameters would be maintained within physiologic range in goats and sheep, but confirmed that in both species, profound sedation would be achieved. Total sedation time was significantly longer in goats than sheep. In a previous study,12 the IM administration of medetomidine at 0.03 mg/kg and vatinoxan at 0.3 mg/kg produced rapid sedation compared to medetomidine alone, likely due to increased plasma concentrations of dexmedetomidine associated with the local and systemic effects of vatinoxan administration. Time to recumbency was 10 ± 3.4 minutes in the aforementioned study, whereas in the present study it was 8.56 ± 5.7 min for sheep and 10.00 ± 4.42 minutes for goats, with no statistically significant difference between species.
Duration of sedation could not be compared to the aforementioned study, as all sheep received a reversal agent at 30 minutes. The difference in duration of sedation between species may be multifactorial. In general, goats are reportedly more sensitive than sheep to the centrally mediated sedative effects of α2-receptor agonists.13,14 No study to date has evaluated head-to-head the difference in sedation duration/depth between awake sheep and goats given an α2-receptor agonist, to our knowledge. The medetomidine dose of 0.03 mg/kg was chosen based on previous studies11,12,15 done in sheep with medetomidine. In goats, no studies are available evaluating the sedative effect of IM medetomidine at a dose of 0.03 mg/kg. The increased sedation duration and depth of sedation over time directly support the assumption of an increased sensitivity of goats to the centrally mediated effects of ZEN compared to sheep. Given the duration and depth of sedation seen in this study, the efficacy and safety of lower doses of ZEN in goats should be explored. And while there was no evidence of regurgitation and aspiration during the sedation period, given that the dose of ZEN used induced a level of sedation resulting in loss of tongue tone in 17 animals, intubation supplies and suction should be made available in a clinical setting.
A 20% decrease in MAP is documented in goats under sevoflurane anesthesia receiving a constant rate infusion of dexmedetomidine at 0.002 mg/kg/h compared to baseline; conversely, that parameter was maintained in sheep under the same conditions.14 This was suspected to be due to the interspecies difference in the centrally mediated sympatholysis of dexmedetomidine. In the present study, the mean MAP across all time points was not below 60 mm Hg for either species; however, 3 goats required a fluid bolus for treatment of hypotension. The hypotension observed in goats of the present study was likely due to the centrally mediated decrease in sympathetic tone associated with the medetomidine in conjunction with the direct peripheral effect of α2-receptor antagonism leading to vasodilation. This also could be due to species-specific α2-receptor subtype density and distribution.13,14
Vatinoxan has been shown to ameliorate the cardiopulmonary side effects of α2-receptor agonists in sheep including pulmonary edema.15–17 In sheep under sevoflurane anesthesia given 3 µg/kg of dexmedetomidine, vatinoxan prevented increased airway pressure, relative hypoxemia, and subclinical pulmonary edema compared to dexmedetomidine alone.17 Side effects associated with sheep experiencing pulmonary edema include tachypnea, dyspnea, sanguineous foaming from the upper airways, and hypoxemia. While hypoxemia did occur in both sheep and goats, no evidence of foaming from the nose or mouth was observed; therefore, pulmonary edema seems less likely to explain the observed hypoxemia. Additionally, there was no evidence of pulmonary edema on gross necropsy or histopathology of the sheep experiencing dyspnea 12 hours after sedation. Hypoxemia (defined as Pao2 < 80 mm Hg) and severe hypoxemia (< 60 mm Hg) was observed in both species within 5 minutes after ZEN administration and continued through 45 minutes after ZEN administration. Hypoxemia in conjunction and independent of hypoventilation is reported in sheep with pulmonary edema induced by α2-receptor agonists.1 All hypoxemic animals aside from 1 goat were responsive to oxygen via face mask. The sheep and goats in the present study had no obvious underlying pulmonary disease, were all allowed to breathe room air, and did not hypoventilate. During data collection, animals were allowed to be in right or left lateral recumbency after treatment injection. A study by Mitchell and Williams18 found that, in conscious sheep undergoing position change from standing to lateral to standing position, Pao2 decreased within 3 minutes when placed in lateral recumbency and increased when standing recumbency was resumed. These findings were explained with ventilation-perfusion mismatching and are similar to the results obtained in the present study, in which the arterial oxygen tension decreased in sheep after receiving ZEN within 5 minutes and stayed decreased when animals were in lateral recumbency.
All animals showed a decrease in body temperature over time. Body temperature should be monitored during sedation, and active warming should be available to animals with body temperatures below physiologic parameters.
Within the present study population, glucose remained within normal limits and was not significantly different from baseline. Activation of α2 receptors on β islet cells of the pancreas inhibits insulin release causing hyperglycemia. Medetomidine at 0.04 mg/kg, IV, causes a biphasic increase in blood glucose in sheep. The increase in blood glucose is attenuated by the administration of atipamezole 60 minutes after medetomidine injection.19 In horses, the IV administration of romifidine in combination with vatinoxan caused a lesser increase in serum blood glucose than romifidine alone.20 It is therefore possible that vatinoxan prevented medetomidine-induced hyperglycemia in the sheep and goats used in this study.
There was a statistically significant decrease in potassium from baseline values at 5 to 45 minutes for both species, and clinically relevant hypokalemia was observed in sheep at 15 to 45 minutes (Table 2). Hypokalemia has not been a reported side effect of α2-receptor agonist administration in sheep or goats. A clinically insignificant decrease in potassium is documented in horses given romifidine and vatinoxan.20 Hypoglycemia and hypokalemia have been observed in dogs given 3 to 5 times the recommended dose of ZEN by the manufacturer.21 Redistribution of potassium between intracellular and extracellular compartments, as well as potassium loss through urine excretion, could be possible causes for the observed hypokalemia in the sheep.22,23 Even though the decrease in potassium was clinically significant, no ECG abnormalities associated with hypokalemia were observed during the sedation and immediate recovery period. Further investigation is needed to evaluate the effects of ZEN on blood potassium concentration in sheep.
Beyond the metabolic effects, gastrointestinal side effects of the peripheral α2-receptor antagonist MK-467 including increased defecation and soft stool are reported in horses, sheep, and dogs.24,25 The results of these studies are consistent with our findings. Given that all animals had normal fecal ball consistency 12 hours after study resolution, the effects appear to be short-lived and clinically insignificant.
For the animals in the current study, no withdrawal times were determined, since these animals are part of a university research/teaching herd and therefore are excluded for the use for human consumption. For the commercially available drug mixture ZEN, no withdrawal times are available. In sheep and goats, the recommended meat withdrawal time for detomidine is 3 days and for xylazine 4 to 10 days (dose dependent) after IM administration. For milk, the following withdrawal times can be found: 72 hours for detomidine and 24 to 120 hours (dose dependent) for xylazine.26 Only limited pharmacokinetic data exist on medetomidine in small ruminants. In sheep, medetomidine is rapidly cleared from plasma after IM injection.11 The combination of vatinoxan with medetomidine leads to an initially increased plasma concentration of medetomidine without influencing the overall clearance of medetomidine from the plasma.15 Contacting state diagnostic laboratories for the possibility of testing for residues in milk may be a possibility to determine individual withdrawal times for milk. For fiber-producing animals, no withdrawal time would be required, since fiber is not a food product.
There were several study limitations that should be considered. A crossover design using a medetomidine dose of 0.03 mg/kg, IM, alone would have allowed for further evaluation of the increased centrally mediated cardiovascular effects of α2-receptor agonists across species. Looking at lower doses of ZEN may have produced less cardiovascular side effects in goats with a more clinically relevant sedation time for minor procedures. A CBC prior to sedation may have helped preclude animals with subclinical disease, such as the sheep with bronchopneumonia.
In conclusion, ZEN at a dose of 0.06 mL/kg (corresponding to 0.03 mg of medetomidine/kg and 0.6 mg of vatinoxan HCL/kg) provides reliable and deep sedation in both sheep and goats. Cardiovascular parameters are maintained better in sheep than in goats. Compiled with the prolonged duration of sedation, likelihood of oxygen supplementation and possible need of blood pressure support in goats limit the utility of this product in goats at the dosage used in this study. Preexisting hypokalemia or pulmonary disease are contraindications for the use of ZEN in sheep. Zenalpha is an acceptable sedation choice for apparently healthy Gulf Coast native and Katahdin sheep in the presence of oxygen supplementation.
Acknowledgments
None reported.
Disclosures
The authors have nothing to disclose. No AI-assisted technologies were used in the generation of this manuscript.
Funding
This project was supported by the Louisiana State University Corp Grant (PG008270) and Dechra Pharmaceuticals PLC, which provided sevoflurane, crystalloid fluids, and Zenalpha.
ORCID
J. Cremer https://orcid.org/0000-0001-9644-7576
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