A comparison of three combinations of injectable anesthetics in miniature donkeys

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1 Veterinary Anaesthesia and Analgesia, 2002, 29, 36^42 RESEARCH PAPER A comparison of three combinations of injectable anesthetics in miniature donkeys Nora S Matthews DVM, Dip ACVA, Tex S Taylor DVM, Dip ACVS & Jennifer A Sullivan DVM TheTexasVeterinary Medical Center, Texas A & M University, College Station, USA Correspondence: Nora Matthews, DepartmentVSAMS,Texas A & M University, College Station,TX , USA. Abstract Objective To compare three combinations of injectable anesthetics in miniature donkeys for quality of induction, recovery, muscle relaxation, cardiopulmonary changes during anesthesia and duration of recumbency. Design Prospective, randomized experimental study. Animals Six miniature donkeys (< 90 cm in height at the withers) weighing 92^127kg were used. Materials and methods The drugcombinations were: xylazine butorphanol ketamine (XBK), xylazine butorphanol tiletamine zolazepam (XBT) and xylazine propofol (XP). Each miniature donkey was anesthetized with each combination at 1-week intervals in random order. Heart and respiratory rates, indirect blood pressure and temperature were measured before and at 5-minute intervals during recumbency. Arterial blood samples were drawn for blood-gas analysis before and at 5,15 and 30 minutes of anesthesia when samples could be collected. Recumbency time to sternal and time to standing were recorded and a subjective evaluation of induction, muscle relaxation and recovery were made. Results Mean recumbency time SD was , and minutes with XBK, XBT and XP, respectively. Mean time to standing SD was , and minutes with XBK, XBT and XP, respectively. Heart and respiratory rates and blood pressures varied from baseline but were always within normal ranges. Hemoglobin saturation, ph and PaO 2 tended to be lower with these doses of XBTand XP. Conclusions and clinical relevance Overall quality of anesthesia was poor with XBK. At the doses used this combination did not provide su cient anesthesia compared with the combinations of XBT and XP, which appeared to provide acceptable anesthesia of short duration in miniature donkeys. Keywords injectable anesthesia, miniature donkeys. Introduction The number of registered miniature donkeys (donkeys <90 cm in height at the withers) in the USA appears to be growing (based on registry numbers from the American Donkey & Mule Society,1999).We were unable to nd any reports of research on injectable anesthetic techniques in miniature donkeys. Because Mammoth asses (Matthews et al. 1992a), mules (Matthews et al. 1992b) and horses (Matthews et al.1991) do not respond similarly to common intravenous anesthetic regimens, we were unsure what to expect from miniature donkeys. Our clinical experience suggests that they seem to have increased requirements for commonly used anesthetic agents when compared with horses and standard donkeys. Therefore, the objective of this study was to compare the e ects of three di erent injectable anesthetic techniques in miniature donkeys. Materials and methods Animals Six male miniature donkeys ranging in age from 18 to 30 months, weighing 92^127kg (average weight,110 kg), were used in this study. The donkeys were fairly tame; they were trained to respond to 36

2 voice commands and trained to accept harness and pull a cart. The donkeys were kept in a large paddock with access to free choice pasture and water. Food, but not water, was withheld the night before anesthesia. All procedures were approved by the Texas A & M University LaboratoryAnimal Care Committee. Experimental design Each miniature donkey was anesthetized three times; once each with the three drug combinations. Drug combinations were chosen based on doses and combinations used in prior research with standard donkeys (xylazine butorphanol ketamine, XBK) and pilot data obtained from these donkeys (xylazine propofol, XPand xylazine butorphanol tiletamine zolazepam, XBT) when they were castrated 3 weeks previously. Although butorphanol was included in two of the combinations, we elected to omit it when propofol was used thereby testing one drug combination which did not include a controlled substance. No additional propofol was given after the initial bolus; this protocol was chosen to characterize the e ects of a single bolus of propofol in miniature donkeys. Prior to anesthesia a 20-SWG,2-inch catheter (Abbocath, Becton Dickinson, Franklin Lakes, NJ, USA) was placed percutaneously into an external jugular vein and secured in place. All drugs were given intravenously (IV) through the catheter. The order of drug combination administered was randomized (using a random number generator table), and the donkeys were anesthetized at1-week intervals. Drug combinations The drug combinations used were: (i) xylazine (Rompun, 1.1 mg kg 1 ; Mobay Corp., Shawnee, KS, USA) combined with butorphanol (Torbugesic, mg kg 1 ; Fort Dodge Laboratories Inc., Fort Dodge, IA, USA) followed approximately 2^3 minutes later by ketamine (Ketaset, 2.2 mg kg 1 ; Fort Dodge Laboratories) (XBK). (ii) Xylazine (1.1 mg kg 1 )combined with butorphanol (0.044 mg kg 1 ) followed approximately 2^3 minutes later by tiletamine zolazepam (Telazol, 1.1 mg kg 1 ; Fort Dodge Laboratories) (XBT). (iii) Xylazine (0.8 mg kg 1 ) followed approximately 2^3 minutes later by propofol (Rapinovet, 2.2 mg kg 1 ; Schering-Plough, Corp., Union, NJ, USA) (XP). Data collection Respiratory rates and rectal temperatures were measured by observation and use of a digital thermometer, respectively, before administration of any drugs, at 5-minute intervals after the donkeys became recumbent, and until they resumed a sternal position. Heart rate, noninvasive blood pressure (systolic, diastolic and mean; cu on the tail or front limb), and electrocardiogram (leads placed in base apex position) were recorded before any drugs were given and at 5-minute intervals while the donkeys were in lateral recumbency (Protocol Propaq 106EL, Protocol Systems Inc., Beaverton, OR, USA). A pulse oximeter probe was place on the lip or tongue (Protocol Propaq 106EL) to measure hemoglobin saturation at 5-minute intervals after the donkeys were in lateral recumbency. Arterial blood samples were obtained for blood-gas analysis, from the caudal auricular artery before anesthesia or lateral metatarsal artery during recumbency at 5, 15 and 30 minutes, or as long as the donkey remained recumbent. Arterial samples were analyzed immediately (IRMA; Diametrics Medical, Saint Paul, MN, USA). Duration of recumbency was measured as the time spent in lateral recumbency (until assuming sternal recumbency). A peripheral nerve stimulator (Microstim; Neuro Technology, Houston, TX, USA), attached to the skin on the neck (one electrode a hand s breadth cranial to the scapula and the other a hand s breadth caudal to the ramus of the mandible), was used as a repeatable stimulus to di erentiate between those animals still anesthetized and those who were awake, but lying quietly. The miniature donkeys were stimulated at 5-minute intervals after becoming recumbent using a train-of-four 70 ma stimulation. Response was recorded using the following scale: no response ¼ 1; some response (e.g. stretched legs, twitched muscles, vocalization) ¼ 2; much response (e.g. sternal in response to stimuli) ¼ 3. No baseline stimulation was attempted in unanesthetized animals or after donkeys assumed sternal recumbency (NA in summary table). Quality of induction, muscle relaxation, and recovery were rated subjectively using the scheme shown below. Induction 1 ¼Satisfactory: rapid and smooth with little danger to animal or personnel. 2 ¼ Satisfactory: but slightly prolonged or with some incoordination. 3 ¼ Unsatisfactory; prolonged period of incoordination or muscle fasciculation. Muscle relaxation 1 ¼Present, excellent relaxation. 2 ¼ Absent, some muscle twitching. Veterinary Anaesthesia and Analgesia, 2002, 29, 36^42 37

3 Table 1 Responses to stimulation in six miniature donkeys anesthetized with injectable anesthetics Time (minutes, before or after onset of lateral recumbency) Anesthetic combination Xylazine butorphanol ketamine Xylazine butorphanol telazol Xylazine/propofol 1; n ¼ 3 1; n ¼ 1 1; n ¼ 1 3; n ¼ 1 2; n ¼ 2 2; n ¼ 1 2; n ¼ 1 NA; n ¼ 5 NA; n ¼ 1 NA; n ¼ 4 NA; n ¼ 4 1; n ¼ 6 1; n ¼ 6 1; n ¼ 6 1; n ¼ 4 2; n ¼ 1 NA; n ¼ 1 1; n ¼ 5 1; n ¼ 4 1; n ¼ 1 NA; n ¼ 6 2; n ¼ 1 2; n ¼ 1 3; n ¼ 1 3; n ¼ 1 NA; n ¼ 4 n, number of animals receiving this rating. NA, not available to stimulate (i.e. animals judged too awake to stimulate). Rating scheme used: 1¼ no response; 2 ¼ some response (i.e. stretching legs, twitching muscles); 3 ¼ much response (i.e. become sternal in response to stimuli). Table 2 Heart rate (beats minute 1 ), respiratory rate (breaths minute 1 ), systolic, diastolic, mean blood pressure (bp) (mm Hg), temperature (8F) and SpO 2 (%) in six miniature donkeys anesthetized with three drug combinations. Values are means SD. N ¼ 6 unless otherwise indicated Time (minutes, before or after onset of lateral recumbency) Anesthetic combination Variable Xylazine butorphanol ketamine n ¼ 5 n ¼ 4 n ¼ 4 Heart rate NA Respiratory rate NA Systolic bp NA Diastolic bp NA Mean bp NA Temperature NA NA SpO 2 NA NA NA NA Xylazine butorphanol tiletamine zolazepam Heart rate Respiratory rate Systolic bp Diastolic bp Mean bp Temperature SpO Xylazine/propofol Heart rate NA Respiratory rate NA Systolic bp NA Diastolic bp NA Mean bp NA Temperature NA SpO NA NA, samples were not available. 38 Veterinary Anaesthesia and Analgesia, 2002, 29, 36^42

4 3 ¼ Absent, muscle rigidity or seizure-like activity. Recovery 1 ¼ Satisfactory: no excitement or incoordination with smooth return to standing. 2 ¼ Satisfactory, but with some incoordination or excitement. 3 ¼ Unsatisfactory: dangerous to animal or personnel with excitement or marked incoordination. The number of attempts required to stand was also recorded. Statistical analysis Data were analyzed using a generalized linear model with sequence, time and drug modeled as xed e ects, and donkey modeled as a random e ect. A Duncan s multiple-range test was used for post-hoc comparisons of signi cant e ects by drug. A p < 0.05 was considered to be signi cant. Subjective data (induction, recovery and muscle relaxation) are summarized; no statistical evaluation was performed. Results Xylazine butorphanol ketamine Xylazine butorphanol ketamine produced lateral recumbency in all animals, however, duration and quality of anesthesia were quite variable. Three inductions were rated as satisfactory (1), whereas three were rated as satisfactory, but slightly prolonged (2). Three animals showed no response to stimulation at 5 minutes, but ve of six animals were in sternal or responded to stimulation by 10 minutes after induction (Table 1). Muscle relaxation with this combination was absent in four of six animals; rated as1intwodonkeys,2intwodonkeysand3intwo donkeys. Heart and respiratory rates, blood pressure, rectal temperature and SpO 2 are listed in Table 2. Blood gas data are not reported during anesthesia; only two samples were collected at 5 minutes of recumbency (Table 3). Four recoveries were satisfactory (1), whereas two were rated as satisfactory, but with some incoordination (2). Mean number of Table 3 ph, PaCO 2,PaO 2 and hemoglobin saturation (SaO 2 ) in six miniature donkeys anesthetized with three drug combinations.values are means ( SD). N ¼ 6 unless otherwise indicated Time (minutes, before or after onset of lateral recumbency) Anesthetic combination Variable Xylazine butorphanol ketamine n ¼ 5 ph NA NA NA PCO 2 (mm Hg) NA NA NA (kpa) PO 2 (mm Hg) NA NA NA (kpa) SaO 2 (%) NA NA NA Xylazine butorphanol tiletamine zolazepam n ¼ 3 ph PCO 2 (mm Hg) (kpa) PO 2 (mm Hg) (kpa) SaO 2 (%) Xylazine propofol n ¼ 4 n ¼ 3 ph NA PCO 2 (mm Hg) NA (kpa) PO 2 (mm Hg) NA (kpa) SaO 2 (%) NA NA, samples were not available. Significantly lower than baseline (p < 0.05) Veterinary Anaesthesia and Analgesia, 2002, 29, 36^42 39

5 attempts to stand was Mean time to sternal was minutes and mean time to standing was minutes. Xylazine butorphanol tiletamine zolazepam Xylazine butorphanol tiletamine zolazepam produced a signi cantly longer period of lateral recumbency than for the other combinations. All inductions were rated at 1 (satisfactory, rapid and smooth). All animals were nonresponsive to stimulation until 25 minutes of recumbency (Table 1). Muscle relaxation was excellent (rating ¼ 1) in all six donkeys. Heart and respiratory rates, temperature and blood pressures are listed in Table 2. PaO 2 was signi cantly lower at 5 minutes than baseline. Four recoveries were rated as 1 (smooth and satisfactory), whereas two were rated as 2 (satisfactory but with some incoordination). All animals stood on the rst attempt. Mean time to sternal was minutes, and mean time to standing was minutes. Xylazine propofol Five inductions were rated as 1 (excellent), whereas one induction was satisfactory, with transient paddling after recumbency (rating ¼ 2). Four animals were nonresponsive to stimulation at 10 minutes of anesthesia, but by15 minutes, ve animals were sternal or responded (Table 1). Muscle relaxation was excellent (rating ¼1) in four donkeys and absent (rating ¼ 2) in two. Heart and respiratory rates, temperature and blood pressures are shown in Table 1. All six recoveries were rated as satisfactory (1) and all animals stood on the rst attempt. Mean time to sternal was minutes, and time to standing was minutes. Discussion Xylazine butorphanol ketamine made 50% of the miniature donkeys unresponsive to electrical stimulation for 5 minutes, whereas XBT made 100% of miniature donkeys unresponsive for 15 minutes and XP made 66% of miniature donkeys unresponsive for 10 minutes. The cardiopulmonary e ects of these combinations were very similar. Comparing results from this study with previous studies on injectable anesthetics in donkeys (Matthews et al.1992a), mules (Matthews et al. 1992b) and horses (Matthews et al. 1991), seems to indicate that miniature donkeys recover from anesthesia somewhat faster than other equidae. Time to standing for XBK (28 minutes) was shorter (37minutes) and time to standing with XBT (44 minutes) was comparable with that reported with xylazine and tiletamine zolazepam without butorphanol in Mammoth asses (43 minutes) (Matthews et al. 1992a). Time to standing with XP (26 minutes) was much shorter than previously reported in donkeys (44 minutes) (Harts eld et al. 1994), although in that report, donkeys were maintained on propofol infusions for almost 2 hours. We were surprised at the short duration of anesthesia seen with XBK, as that combination appeared to provide good anesthesia in standard donkeys, mules (Matthews et al. 1997) and horses (Matthews et al.1991). This combination failed to produce su cient anesthesia for castration of two miniature donkeys (a bolus of 0.25^0.5 mg kg 1 tiletamine zolazepam was given at the time of rst incision), however, the decision was made to continue with this combination in all six miniature donkeys for the anesthesia trial. We felt that the responses of two animals might not re ect a larger group and more data were necessary before reaching a conclusion about a combination commonly used for injectable anesthesia in equidae. Miniature donkeys were chemically immobilized with XBK; animals were recumbent, but muscle relaxation was poor, four of six vocalized and appeared to be aware of procedures being performed (i.e. attaching ECG leads, blood pressure cu, etc.). The poor anesthesia seen with XBK did not appear to be produced by insu cient sedation from the xylazine and butorphanol given for premedication as all donkeys were very sedate (head at the level of the carpus or below), when the ketamine was given. There are several possible explanations for the shorter duration of e ect; metabolic rate might be higher in miniature donkeys, as they are smaller and should have a higher body surface area. However, we have been unable to nd any information about metabolic rate in donkeys or what constant would be used in the formula to calculate body surface area (Henness et al.1977; Spector1956). Although it is tempting to assume that allometric scaling would produce more accurate dosing of these smaller animals, allometric scaling does not appear to be appropriate for ketamine or xylazine (Riviere et al. 1997). An increased metabolic rate might account for increased metabolism of drugs in miniature and standard donkeys compared with horses, but does not account for why Mammoth asses (which are as large as horses) and mules have a much shorter 40 Veterinary Anaesthesia and Analgesia, 2002, 29, 36^42

6 half-life for ketamine (12 minutes for Mammoth asses, 23 minutes for mules, compared with 42 minutes in horses) (Matthews et al. 1994). Di erences in biotransformation, protein binding and interspecies di erences in enterohepatic circulation are some of the other factors which a ect drug disposition. Differences in the pharmacokinetics of ca eine (a capacity limited drug) between donkeys and horses, suggests that there may be di erences in cytochrome P450 isoenzymes (Peck et al. 1997). Di erences in the metabolism of diprenorphine between the donkey and horse have also been reported (Dobbs & Ling 1972). We were unable, however, to nd information about the pharmacokinetics of other anesthetic drugs in donkeys, or information about protein binding or enterohepatic recycling in miniature donkeys, which might better explain why anesthetic drugs which work well in horses produce such poor results in donkeys. If miniature donkeys have a higher metabolic rate, one would expect that they would require a higher propofol dose or more frequent dosing than horses. Although the propofol dose used in this study was the same as used in horses (Nolan & Hall 1985) and ponies (Nolan & Chambers1989), the dose of xylazine premedication was higher. Longer recumbency times (36 minutes) have been reported when larger doses of xylazine (1.0 mg kg 1 )wereusedinhorses(mama et al.1996), so it is possible that the miniature donkeys did metabolize the propofol more rapidly than horses. The pharmacokinetics of tiletamine zolazepam have also not been studied in donkeys or miniature donkeys. When xylazine and butorphanol was used for premedication, tiletamine zolazepam appeared to produce very satisfactory anesthesia, and the duration of e ect was similar to that seen in horses (Matthews et al. 1991). This combination was probably more e ective than XBK because tiletamine is more potent and because of the muscle relaxation provided by zolazepam (Lin1996). Respiratory depression (decreased respiratory rate and ph, increased PaCO 2 ) was seen with anesthesia, and appeared to be most pronounced with XBT. These e ects have been reported previously with xylazine propofol in horses (Mama et al. 1996) and with tiletamine zolazepam (Hubbell et al. 1989). This respiratory depression is likely the result of a combination of sedation produced by the drugs and the e ect of recumbency. It was surprising that respiratory rates were well maintained following a bolus of propofol, because apnea (Matthews et al. 1999) and decreased respiratory rates (Mama et al. 1996) have been reported in horses. In this study, respiratory rates were higher with XP than with the other combinations, although PaO 2 tended to be decreased. The decrease in PaO 2 from baseline was most pronounced with XBT; signi cant decreases from baseline have also been reported with xylazine and tiletamine zolazepam in horses (Hubbell et al. 1989). Decreases in respiratory rate and arterial oxygenation have been reported in horses anesthetized with propofol (Nolan & Hall 1985; Mama et al. 1996; Matthews et al. 1999). We were unable to evaluate respiratory depression with XBK as few arterial blood samples could be obtained. However, the decrease in respiratory rate was similar to the decrease in respiratory rate seen with XBT. Although heart rate and blood pressure tended to decrease from baseline with all combinations, no apparent hypotension (MAP < 60 mm Hg) or bradycardia (HR < 25 beats minute 1 ) was seen at any time. Although some baseline values have been reported for donkeys (French & Patrick 1995; Zinkl et al.1990), we were unable to nd normal values for heart rate, respiratory rate and blood pressures for miniature donkeys; hence we used the same criteria as in horses, which may or may not be appropriate for miniature donkeys. Baseline values might also provide some insight about the metabolic rate of miniature donkeys. The changes seen with all combinations appear to be similar to those reported with these drug combinations in other equidae. In conclusion, XBT appeared to produce good anesthesia of short duration in miniature donkeys. Xylazine propofol reliably produced good anesthesia but the duration was quite short (< 10 minutes); however, based on pilot data from two donkeys, it appears that anesthesia can be maintained with additional propofol (0.2 mg kg 1 minute 1 ). The choice of which combination to use might depend on availability of controlled drugs (butorphanol, tiletamine zolazepam) and expected length of the procedure. Xylazine butorphanol ketamine, at the doses used in this study, cannot be recommended for providing adequate anesthesia in miniature donkeys. Acknowledgements We would like to thank the American Donkey and Mule Society, Denton, TX, USA and the Canadian Donkey and Mule Association, Alberta, Canada for nancial support of this project. We would also like Veterinary Anaesthesia and Analgesia, 2002, 29, 36^42 41

7 to thank Dr Noah Cohen for assistance with the statistical analysis. References Dobbs HE, Ling CM (1972) The use of etorphine/acepromazine in the horse and donkey.vet Rec 91,40^41. French JM, PatrickVH (1995) Reference values for physiological, haematological and biochemical parameters in domestic donkeys (Equus asinus). Equine Vet Educ 7, 33^35. Harts eld SM, Matthews NS,TaylorTS et al. (1994) Detomidine propofol anesthesia for carotid artery translocation in donkeys.vet Surg 23,75^76. Henness AM, Theilen GH, Madewell BR et al. (1977) Use of drugs based on square meters of body surface area. J Am Vet Med Assoc171, 1076^1077. Hubbell JAE, Bednarski RM, Muir WW (1989) Xylazine and tiletamine zolazepam anesthesia in horses. Am J Vet Res 50,737^742. Lin HC (1996) Dissociative anesthetics. In: Lumb and Jones VeterinaryAnesthesia, 3rd edn. Thurmon J,Tranquilli W, Benson G (eds). Williams & Wilkins, Philadelphia, PA, USA, pp. 241^296. Mama KR, Ste ey EP, Pascoe PJ (1996) Evaluationof propofol for general anesthesia in premedicated horses. Am J Vet Res 57, 512^516. Matthews NS, Harts eld SM, Cornick JL et al. (1991) A comparison of injectable anesthetic combinations in horses. Vet Surg 20, 268^273. Matthews NS,Taylor TS, Harts eld SM et al. (1992a) A comparison of injectable anaesthetic regimens in mammoth asses. EquineVet J S11,37^40. Matthews NS,Taylor TS, Harts eld SM et al. (1992b) A comparison of injectable anaesthetic regimens in mules. EquineVetJ S11,41^44. Matthews NS,Taylor TS, Harts eld SM et al. (1994) Pharmacokinetics of ketamine in mules and mammoth asses premedicated with xylazine. EquineVet J 26, 241^243. Matthews NS,Taylor TS, Harts eld SM (1997) Anaesthesia of donkeys and mules. EquineVet Ed 9,198^202. Matthews NS, Harts eld SM, Hague B et al. (1999) Detomidine propofol anesthesia for abdominal surgery in horses. Vet Surg 28, 196^201. Nolan AM, Chambers JP (1989) The use of propofol as an induction agent after detomidine premedication in ponies. JAssVet Anaesth16,30^32. Nolan AM, Hall LW (1985) Intravenous anaesthesia in the horse with propofol. EquineVet J17,394^398. Peck KE, Mealey KL, Matthews NS et al. (1997) Comparative pharmacokinetics of ca eine and three metabolites in clinically normal horses and donkeys. Am J Vet Res 58, 881^884. Riviere JE, Martin-Jimenez T, Sundlof SF et al. (1997) Interspecies allometric analysis of the comparative pharmacokinetics of 44 drugs across veterinary and laboratory animal species. J Vet Pharmacol Ther 20, 453^463. Spector WS (1956) Constants for estimating surface area: mammals. In: Handbook of Biological Data. Spector WS (ed.).w.b. Saunders Co, Philadelphia, PA, pp.175^176. Zinkl JG, Mae D, Merid GPet al. (1990) Reference ranges and the in uence of age and sex on hematologic and serum biochemical values in donkeys (Equus asinus) Am J Vet Res 51, 408^412. Received 30 May 2000; accepted 28 June Veterinary Anaesthesia and Analgesia, 2002, 29, 36^42