Alpha-2 Agonist in Combination with Butorphanol and Tiletamine - Zolazepam for the Immobilization of Non-Domestic Hoofstock
A combination of compatible and complementary drugs may constitute the safest and most effective method of immobilization for selected species. Such combinations or “cocktails” have long been used by wildlife veterinarians. These mixtures of drugs consist of a primary drug, usually an opioid or cyclohexamine, with a neuroleptic or α2-agonist added, that can potentiate the primary drug and alleviate its side effects. Additive effects of drugs with complementary modes of action can more selectively induce loss of consciousness, analgesia and muscle relaxation with lower doses of each drug, than if used alone.10
Alpha-2 adrenoceptor agonists (α2-agonist) and their equipotent sedative doses, as a primary drug added to tiletamine, zolazepam and butorphanol is discussed for the immobilization of wild ungulates in a zoo situation. This combination has already been used successfully in ferrets7, wild boars3 and ratites9. The combination of low doses of α2-agonist, butorphanol and zolazepam results in a synergistic CNS depressant response, while minimizing the undesirable side effects of these three types of drugs. Each drug has specific antagonists available for their reversal, thus allowing to reverse one or more of the agonists depending on the desired response. The inclusion of low doses of tiletamine in this protocol affecting different central nervous system receptor populations, seems to aid the synergistic responses of the other drugs with lessened side effects.
Mu-opioid receptors and α2 receptors produce similar effects when activated.12 The interest in the use of α2-agonist is related to their ability to produce sedation, analgesia, muscle relaxation and anxiolysis. All α2-agonists produce decreases in heart rate and cardiac output with an increased incidence of second-degree atrioventicular block, and transient hypertension followed by hypotension. These changes are dose-dependent.12 Xylazine became the first α2-agonist to be used in veterinary medicine; in recent years others like medetomidine, detomidine, romifidine, dexmedetomidine, azepexole, milvazerol and oxymetazoline, have been introduced.12 Binding studies carried out have suggested an α2/α1 selectivity ratio of 1620, 260 and 160 for medetomidine, detomidine and xylazine, respectively. The difference in affinity is suggested to give the difference in doses inducing equipotent sedation and cardiac depression.14
A mixture of 1.2 mg/kg of tiletamine-zolazepam (Zoletil 50®, Virbac or Zelazol®, Fort Dodge), with 0.1 mg/kg of butorphanol (Torbugesic®, Fort Dodge) and an equipotent sedative dose of the α2-agonist, xylazine (Sedazine®, Fort Dodge), medetomidine (Domitor®, Pfizer or 20 mg/ml Wildlife L.) or detomidine (Dormosedan®, Pfizer) was used in 18 different species of ungulates in routine procedures at Africam Safari Park, Puebla-Mexico (Table 1). The criteria for dose selection of the α2-agonist was a comparable sedation, judged subjectively.
Table 1. Equipotent sedative doses of the α2-agonist in combination with tiletamine-zolazepam-butorphanol
Immobilization was characterized by lack of spontaneous movements and lack of response to stimuli. Induction was faster with the xylazine-tiletamine-zolazepam-butorphanol (Xtzb) combination (4–10 min) and slower with the medetomidine-tiletamine-zolazepam-butorphanol (Mtzb) combination (8–18 min). The Xtzb combination appeared to have a shorter duration of effect, as some animals arose suddenly during handling (between 25 and 45 min) without any reversal agent. The detomidine-tiletamine-zolazepam-butorphanol (Dtzb) combination had the longest duration of action.
Reversal was achieved for Xtzb with tolazoline (Tolazine®, Lloyd) (4 mg/kg BW) or atipamezole (Antisedan®, Pfizer) (1 mg/8–10 mg of xylazine1,5) for Mtzb with atipamezole (5 mg/1 mg of medetomidine5), and for Dtzb with atipamezole (3 mg/1 mg of detomidine). Naltrexone (Trexonil®, Wildlife L.) was generally used in all the combinations at 10 mg/mg of butorphanol but in some instances the effect of the butorphanol was left to provide some analgesia. Recovery times were not significantly affected by not providing naltrexone but the animals were not as alert after the recovery. Rapid reversal with atipamezole was completed as expected in all combinations with no recurrent sedation following antagonism. Despite being administered half i.m. and half s.c., atipamezole reversed the effects of Xtzb more rapidly than tolazoline administered all i.v. (1–8 min for atipamezole and 2–15 min for tolazoline). The zolazepam was not reversed.
In cases of early reversal an emergence of the cyclohexamine side effects can be expected. The effects of zolazepam were not reversed and a smooth recovery from anesthesia with no delirium or aberrant behavior was obtained. The pharmacokinetics of tiletamine and zolazepam differ; the effects of zolazepam last longer than tiletamine in some species whereas the reverse is true in others.11 This differential clearance of the two drugs can affect quality of recovery according to species.
During the anesthesia, ketamine was given i.v. (as needed) in increments of 25 mg to produce the effect desired. This produced better depth of anesthesia without interfering with the recovery quality. Using tiletamine-zolazepam as a maintenance agent is not recommended because of the side effects associated with its repeated dosing and the poor quality of recovery.11
In our experience medetomidine, detomidine and xylazine at doses that produce a similar degree of sedation produce approximately the same degree of hypoxemia, as has been previously reported.2 Animals receiving any of the combinations should receive supplemental inspired oxygen when possible. The mean heart rates observed during immobilization were slightly lower than the mean heart rate of immobilizations using potent opioids. The effects of detomidine effects included a significantly lower respiration rate, with more pronounced cardiovascular effects. Xylazine has been reported to produce milder vasoconstriction than medetomidine and detomidine.14
The addition of 0.5 mg of atropine sulfate in the same dart with a xylazine, tiletamine, zolazepam combination has been reported,6 but controversy still exists over the necessity of administering anticholinergics prior to administering α2-agonist,12 especially in wild herbivores. In this study, no premedications were administered in any of the anesthetic procedures.
The Mtzb protocol allowed a remarkably easier endotracheal intubation, presumably attributable to the antitussive property of butorphanol,8 which together with the sedative effect of medetomidine, allowed a clear endotracheal tube placement and acceptance. Other advantages of the addition of butorphanol were the enhancement of sedative and analgesic properties of the α2-agonist, the prolonged duration of the anesthesia, superior muscle relaxation, and the significant decrease in the dose of xylazine, medetomidine and detomidine used, compared to other protocols that use α2-agonist with tiletamine-zolazepam or ketamine.5,6,13
When administered isoflurane (Forane® Abbott), some individuals developed respiratory depression. The butorphanol and the zolazepam decrease the minimum alveolar concentration of inhalation anesthetic4 and therefore, the percent required for the maintenance of anesthesia. When α2-agonists are used with CNS depressants (tranquilizers, opioids, injectable general anesthetics, inhalant anesthetics) significant respiratory depression may occur.12
Species that have been successfully immobilized with these cocktails include the Addax (Addax nasomaculatus), American bison (Bison bison), eland (Taurotragus oryx), scimitar-horned oryx (Oryx dammah), impala (Aepyceros melampus), wildebeest (Connochaetes taurinus), Axis deer (Axis axis), collared peccary (Pecari tajacu), nilgai (Boselaphus tragocamelus), llama (Lama glama), wapiti (Cervus elaphus canadensis), fallow deer (Dama dama), sika deer (Cervus nippon), white-tailed deer (Odocoileus virginianus), and blackbuck antelope (Antilope cervicapra). It is important to mention that the animals used in this work were in general adults with a low excitement level. In the animals where an alarm reaction has begun, higher doses may be required. We observed that the doses recommended in this protocol were not effective in species weighing less than 30 kg, like the brocket deer (Mazama americana), and mouflon sheep (Ovis aries musimom) probably due to their elevated metabolic activity.
When equipotent sedative doses of α2-agonists are administered, they appear to act in a similar manner, with the greatest difference being related to the induction time and the duration of action. There is no anesthetic combination that applies to all situations however and this makes practice challenging, because we are in the continuous process of searching for the ‘ideal’ anesthetic combination.
1. Ancrenaz M. 1994. Use of atipamezole to reverse xylazine tranquilization in captive Arabian oryx (Oryx leucoryx). J. Wild. Dis. 30: 592–595.
2. Celly C, McDonnell W, Young S, Black W. 1997. The comparative hypoxemic effect of four alpha 2 adrenoceptor agonist (xylazine, romifidine, detomidine and medetomidine) in sheep. J. Vet. Pharmacol. Ther. 20; 464–471.
3. Enqvist K, Arnemo J, Lemel J, Truve J. 2000. Medetomidine/tiletamine-zolazepam and medetomidine/butorphanol/tiletamine-zolazepam: a comparison of two anesthetic regiments for surgical implantation of intraperitoneal radio transmitters in free-ranging juvenile European wild boras (Sus scrofa scrofa). Proceeding Am. Ass. Zoo Vet. Pp:261–263.
4. Gross M, Smith J, Tranquilli W. 1993. Cardiorespiratory effects of combined midazolam and butorphanol in isoflurane-anesthetized cats. Vet. Surg. 22;159–162.
5. Jalanka H, Roeken B. 1990. The use of medetomidine, medetomidine-ketamine combinations, and atipamezole in nondomestic mammals: a review. J. Zoo Wild. Med. 21:259–282.
6. Janovky M, Tataruch F, Amvuehl M, Giacometti M. 2000. A Zoletil-Rompun mixture as an alternative to the use of opioids for immobilization of feral red deer. J. Wild. Dis. 36;663–669.
7. Ko J, Nicklin C, Montgomery T, Kuo W. 1998. Comparison of anesthetic and cardio respiratory effects of tiletamine-zolazepam-xylazine and tiletamine-zolazepam-xylazine-butorphanol in ferrets. J. Am. Anim. Hosp. Assoc. 34;164–174.
8. Ko J, Bailey J, Pablo P, Heaton-Jones T. 1996. Comparison of sedative and cardio respiratory effects of medetomidine and medetomidine-butorphanol combination in dogs. Am. J. Vet. Res. 57: 535–540.
9. Lin H, Todhunter P, Powe T, Ruffin D. 1997 Use of xylazine, butorphanol, tiletamine-zolazepam, and isoflurane for induction and maintenance of anesthesia in ratities. J. Am Vet. Med. Assoc. 210: 244–248.
10. Nielsen L. 1996. Chemical immobilization of free-ranging terrestrial mammals. In: Lumb & Jones’. Thurmon J, Tranquilli W, Benson G, eds. Veterinary Anesthesia. Third edition. Williams & Wilkins. Pp.736–764.
11. Pablo L, Bailey. 1999 Etomidate and Telazol. Vet. Clin. North Am. Small Anim. Pract. 29; 785–792.
12. Paddleford R, Harvey R. 1999. Alpha 2 agonist and antagonists. Vet. Clin. North Am Small Anim. Pract. 29; 737–745.
13. Tsuruga H, Suzuki M, Takahashi H, Jinma K, Kaji K., 1999. Immobilization of sika deer with medetomidine and ketamine, and antagonism by atipamezole. J. Wild. Dis. 35;774–778.
14. Yamashita K, Tsubakishita S, Futaoka S, Ueda I, Hamaguchi H, Seno T, Katoh S, Izumisawa Y, Kotani T, Muir W. 2000. Cardiovascular effects of medetomidine, detomidine, and xylazine in horses J. Vet. Med. Sci. 62:1025–1032.