Abstract

The red wolf (Canis rufus) is a critically endangered species that was extirpated from the southeastern United States.⁵ Over the last 2 decades, the U.S. Fish and Wildlife Service (USFWS), in cooperation with other organizations, has conducted captive propagation and reintroduction of red wolves, in an effort to restore them to a portion of their former range. In eastern North Carolina, this effort has met with some success, however, intensive management techniques are necessary for monitoring and maintaining the health of this red wolf population. Safe, effective, rapidly reversible immobilization protocols are essential for implementing these management techniques.

For several years, the USFWS has used a ketamine-xylazine combination for immobilizing captive and free-ranging red wolves; however, rough and prolonged recoveries been a concern with the use of this regime. In 1998, an investigation was conducted with captive red wolves, in order to determine the cardiopulmonary effects of xylazine-ketamine, medetomidine-ketamine, medetomidine-ketamine-acepromazine, and medetomidine-ketamine-butorphanol.⁷ Smooth, quick inductions were achieved, but the investigation also documented marked hypertension (diastolic arterial pressure [DAP] >116 mm Hg)⁶ with all four drug combinations. Recoveries using xylazine-ketamine were prolonged and several animals exhibited pronounced ataxia.⁷

The purpose of this investigation was to determine whether medetomidine and butorphanol would provide safe, effective, and reversible immobilization of red wolves without causing hypertension. This combination has been shown to induce profound sedation in domestic dogs and is fully reversible.¹ We characterized the sedative and cardiorespiratory effects of medetomidine-butorphanol in captive red wolves. Due to concerns that this combination may not provide immobilization of adequate depth or sufficient duration, two other protocols were also evaluated.

Twenty-four adult, captive red wolves were used in this investigation. Each subject was assigned to one of the following experimental groups:

• MB = medetomidine (Domitor, Pfizer Animal Health, Exton, PA 19341 USA; 0.04 mg/kg, IM) + butorphanol (Torbugesic, Fort Dodge Animal Health, Fort Dodge, IA 50501 USA; 0.4 mg/kg, IM) with atipamezole (Antisedan, Pfizer Animal Health, Exton, PA 19341 USA; 0.2 mg/kg, IM 0.2 mg/kg, IM) + naloxone (Nalxone HCl Injection, Abbott laboratories, North Chicago, IL 60064 USA; 0.02 mg/kg, IM 0.02 mg/kg, IM) reversal (n=7)
• MBD = medetomidine (0.04 mg/kg, IM) + butorphanol (0.4 mg/kg, IM), followed with diazepam (Valium, Hoffman-La Roche, Nutley, NJ 07110 USA; 0.2 mg/kg, IV) at t=0, with atipamezole (0.2 mg/kg, IM) + naloxone (0.02 mg/kg, IM) + flumazenil (Romazicon, Hoffmann-La Roche Inc, Nutley, NJ 07110 USA; 1 mg., IV 0.04 mg/kg, IV) reversal (n=9)
• MBK(30) = medetomidine (0.04 mg/kg, IM) + butorphanol (0.4 mg/kg, IM), followed with ketamine (Ketaset, Fort Dodge Animal Health, Fort Dodge, IA 50501 USA; 2 mg/kg, IV) at t=30, with atipamezole (0.2 mg/kg, IM) + naloxone (0.02 mg/kg, IM) reversal (n=8)

The initial injection of medetomidine and butorphanol was made via IM hand-injection into the caudal hindlimb. Wolves were left as undisturbed as possible for 15 min, after which an initial blood pressure measurement was taken oscillometrically. Wolves were then transported to a central processing area where other initial measurements were taken (t=0) including heart rate, respiratory rate, body temperature, end tidal carbon dioxide, and indirect hemoglobin saturation. These measurements were recorded at 10 min intervals. An initial arterial sample was taken (t=0) from the femoral artery for blood gas analysis and repeat measurements were taken at t=30 and t=50 min. An IV catheter was placed and, in most wolves, small volumes (0–8 ml/kg) of lactated Ringer’s solution were administered over 30 min. In eight wolves, higher volumes (11–26 ml/kg) of cool fluids were administered as treatment for hyperthermia. Hyperthermic wolves were also treated with cold packs. At the end of each procedure, the catheter was removed, the wolf was transported to its recovery area, and atipamezole and naloxone were administered. Flumazenil was administered IV to MBD wolves before the catheter was removed.

Complete immobilization occurred within 15 minutes in 21 wolves and within 20 minutes for 23 wolves. One wolf was not completely immobilized until administration of diazepam. At t=0, the wolves were heavily sedated and non-responsive to external stimuli with relaxed muscle tone. Wolves that received only MB generally appeared to be more lightly sedated than wolves that were administered additional agents. Four of 7 MB wolves and six of eight MBK(30) wolves were twitching and would occasionally lift their heads when stimulated by ear manipulation or dental scraping. MBK(30) wolves did not demonstrate this activity after ketamine was administered. No MBD wolves responded to manipulation, although one spontaneously recovered at t=25 minutes.

Heart rates (HR) were similar between the three groups for the first 30 minutes of the procedure (Table 1). Heart rate decreased until t=30 for all three groups. Three wolves (two MB and one MBD) had heart rates fall below 40 bpm. Median heart rate increased in the MBK(30) group after receiving ketamine and differed significantly from the MB and MBD groups at t=40 and t=50. Wolves maintained normal cardiac sinus rhythm throughout the procedure, with the exception of one MB wolf, four MBD wolves, and one MBK(30) wolf that experienced periods of second-degree heart block. Respiratory rates were similar between the three groups at all time points, were regular, and did not show substantial change over time. Body temperatures were highest at t=0, ranging from 37.6–42.2°C, but declined steadily over time.

Systolic, mean, and diastolic arterial blood pressure values were elevated immediately following induction in all three groups (Table 1) but decreased over time. However, blood pressure increased in MBK(30) wolves following ketamine administration.

Table 1

Median (and range) values for red wolves immobilized with medetomidine-butorphanol (MB), medetomidine-butorphanol-diazepam (MBD), and medetomidine-butrophanol with late supplemenation of ketamine (MBK30).
^aStatistically significant difference from other groups.

Median PaO₂ values were ≥70 mm Hg throughout the procedure, although 10 wolves had PaO₂ values <70 mm Hg at t=0. PaO₂ values increased in these latter animals at subsequent time points. Median SaO₂ was ≥93% at all time points for all groups and median PaCO₂ values ranged from 25–50 mm Hg. Median arterial blood pH values were between 7.26 and 7.34.

Twenty-one wolves were fully recovered within 10 min of reversal agent administration. The remaining three wolves (one from each group) stood within 12 minutes and appeared to have fully recovered by 17 minutes. MBK(30) wolves exhibited mild ataxia for 5–10 minutes. Median time to standing for all groups was 6 minutes and to full recovery was 7 minutes. Only one spontaneous recovery (one MBD wolf at t=25 minutes) occurred.

Three wolves had periods of time when HR ≤40 beats per minute. In the subsequent year, a trial was conducted to determine whether an anticholinergic could be administered with the initial injection, in order to ameliorate bradycardia without causing hypertension or tachycardia. Glycopyrrolate was the anticholinergic chosen as it less likely than atropine to cause tachyarrhythmias. Wolves (n=6) were immobilized with medetomidine and butorphanol in the same manner as the prior year. For the first four wolves, physiologic measurements were taken for 10 minutes after induction and then incremental doses of glycopyrrolate were administered through an IV catheter, in order to try to determine an appropriate dose that could be administered with the medetomidine and butorphanol. At t=10 minutes, 0.0025 mg/kg glycopyrrolate was administered, then 0.005 mg/kg at t=20 minutes, and 0.01 mg/kg at t=30 minutes.

Median HR at t=0 was 97 bpm and had dropped to 40 bpm by t=10. Median HR was 44 bpm at t=20 but increased to 93 bpm by t=30. At t=40, median HR increased to 143 bpm. Similar changes were observed in blood pressure. Median DAP was 121 mm Hg and 115 mm Hg at t=0 and t=10, respectively. Median DAP did not increase initially, with values of 121 mm Hg at t=20 and 112 mm Hg at t=30, but then increased to 143 mm Hg at t=40.

An increase in HR was not observed until a dose of 0.005 mg/kg glycopyrrolate (total dose of 0.0075 mg/kg) had been administered, at which point HR increased moderately. When 0.01 mg/kg glycopyrrolate (total dose of 0.0175 mg/kg) was administered, there was profound tachycardia and pathologic hypertension. The glycopyrrolate appeared to have a threshold effect between 0.0075 and 0.0175 mg/kg. Therefore, in the next wolf a conservative dose of 0.008 mg/kg glycopyrrolate was administered IM with medetomidine and butorphanol. Initial HR and blood pressure values for this animal were severely elevated at t=0 (HR=130 bpm and DAP=158 mm Hg) and were sustained throughout the procedure. In light of this, the next animal was given a dose of 0.0025 mg/kg glycopyrrolate IM with medetomidine and butorphanol. While HR was not as dramatically elevated (HR=90 bpm) at t=0, this animal was severely hypertensive with SAP of 211 mm Hg and DAP of 160 mm Hg). This hypertension was sustained until the animal was reversed at t=20 min. Because of the severe hypertension that was observed with low doses of IM anticholinergics, the anticholinergic study was discontinued.

Medetomidine-butorphanol provided good sedation and immobilization for handling and transport; minor procedures could be performed. The full effects of the MB combination lasted 30–40 min and the addition of either diazepam or ketamine prolonged the combination’s effects and provided a deeper plane of sedation. However, wolves that received a low dose of ketamine had increased hypertension and post-reversal ataxia. The cardiorespiratory effects of the three drug protocols were similar and were more favorable than for previously described combinations that included ketamine administration at the onset of immobilization. Blood pressure of red wolves anesthetized with MB and MBD were lower than those reported for wolves anesthetized with regimens that included ketamine.^2,4 All three protocols provided effective immobilization with minimal adverse effects, however, the MB combination offered several advantages for short procedures, including complete reversibility (at any time), fewest drugs, and lowest cost. For longer procedures, MBD or MBK(30) could be used.

We cannot recommend the routine use of anticholinergics for preventing low HR in red wolves anesthetized with medetomidine and butorphanol. Tachycardia and hypertension were observed in animals that received glycopyrrolate and the use may create more problems than they solve. This is consistent with earlier reports of tachycardia and hypertension in medetomidine-induced dogs administered 0.04 mg/kg atropine IM.³ Tachycardia has also been noted in medetomidine-ketamine immobilized gray wolves that were administered 0.05 mg/kg atropine IM.² Of course, clinician discretion may dictate that anticholinergics are necessary in certain situations. However, in our experience, wolves with HR<40 have generally shown no signs of physiologic distress, being normotensive, with pink mucous membranes, normal capillary refill times, and excellent recoveries. If, during an immobilization, it is perceived that a wolf with a low heart rate must be treated, it may be more appropriate to administer reversal agents and discontinue the procedure, rather than risk tachyarrhythmias or hypertension that are likely to be caused by the administration of anticholinergics.

Acknowledgments

We thank E. Chittick, H. Decker, D. Hill, C. Lasher, C. Lucash, T. Mengel, M. Morse, A. Purdue, M. Randalls, M. Roetto, and B. Wolfe for assistance during this investigation.

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