Advertisement

Acepromazine‐dexmedetomidine‐ketamine for injectable anaesthesia in captive European brown hares (Lepus europaeus)

      Abstract

      Objective

      To evaluate a combination of acepromazine, dexmedetomidine and ketamine (ADK) on induction and recovery from anaesthesia, and on physiological parameters in hares undergoing non‐invasive procedures.

      Study design

      Prospective clinical study.

      Animals

      Sixteen European hares (Lepus europaeus), seven males and nine females, aged (mean ± SD) 3.25 ± 0.9 months and weight 2.1 ± 0.6 kg.

      Methods

      Acepromazine 1% (A), dexmedetomidine 0.05% (D) and ketamine 5% (K) were mixed and given intramuscularly (IM) at 0.25 mL kg−1, representing 10 mg kg−1 K, 0.25 mg kg−1 A, 12.5 μg kg−1 D. If the righting reflex was present after four minutes, a second injection of 0.15 mL kg−1 (6 mg kg−1 K, 0.15 mg kg−1 A, 7.5 μg kg−1 D) was administered IM. Surgical anaesthesia was judged as present when righting, palpebral, ear‐pinch and pedal withdrawal reflexes were absent. Anaesthetized hares were tagged, and underwent blood sampling and ocular ultrasound examination. Physiological parameters were recorded every ten minutes, and were compared by Kruskal‐Wallis tests.

      Results

      A single dose induced loss of righting reflex in 11/16 (69%) hares within four minutes; the second dose was effective in the remaining hares. Ten minutes after the loss of the righting reflex, a surgical plane of anaesthesia was present in all hares. Sleep time to regaining righting reflex was 34 ± 11 (range 21–62) minutes and recovery was calm. Although there were some statistical differences over time, cardiovascular parameters remained within an acceptable range but there was respiratory depression and hares were hypoxemic.

      Conclusions and clinical relevance

      The ADK mixture produced a smooth and rapid induction of anaesthesia, a low incidence of untoward side effects and full recovery after four hours. Supplementary oxygen might be advisable if a deeper plane of anaesthesia was required. Chemical restraint was adequate to perform non‐invasive procedures.

      Keywords

      Introduction

      The European Brown Hare (Lepus europaeus) is an indigenous species to Italy. Italian regional administrations have established restocking and capture zones for brown hares, where hunting is forbidden (Nardoni et al.
      • Nardoni S
      • Papini R
      • Gallo MG
      • et al.
      Survey on the role of brown hares (Lepus europaeus, Pallas, 1778) as carriers of dermatophytes.
      ) and hares for restocking are reared in cages in specialized farms. These hares undergo a number of routine monitoring procedures. As these hares are difficult to handle, they often need chemical restraint to minimise struggling and stress during such procedures despite the fact that lagomorphs are known to be at high risk during anaesthesia (Flecknell et al.
      • Flecknell PA
      • Roughan JV
      • Hedenqvist P
      Induction of anaesthesia with sevofluorane and isofluorane in the rabbit.
      ).
      A number of injectable anaesthetic agents and their combinations have been investigated for use in the rabbit, but the reported reliability and safety in achieving anaesthesia varies and appears to depend on many conditions (Longley
      • Longley LA
      Rabbit anaesthesia.
      ). However, there are few reports about chemical restraint and anaesthesia in hares (Caillol et al.
      • Caillol M
      • Mondain-Monval M
      • Meunier M
      • et al.
      Influence of season of birth on onset of gonadotrophic and ovarian functions in young doe hares (Lepus europaeus).
      ; Noszczyk‐Nowak et al.
      • Noszczyk-Nowak A
      • Nicpoń J
      • Nowak M
      • et al.
      Preliminary reference values for electrocardiography, echocardiography and myocardial morphometry in the European brown hare (Lepus europaeus).
      ; Gerritsmann et al.
      • Gerritsmann H
      • Stalder GL
      • Seilern-Moy K
      • et al.
      Comparison of S(+)-ketamine and ketamine, with medetomidine, for field anaesthesia in the European brown hare (Lepus europaeus).
      ). In most cases anaesthetic drugs have been administered to hares on the basis of results in the rabbit. However, hares differ from rabbits not only morphologically, but also in temperament and sensibility to stress. Although inhalation anaesthesia is the most feasible approach to control the anaesthetic depth for major surgery, for procedures on the farm, or indeed in animals in the wild, facilities to provide this may well not be available, and injection techniques of anaesthesia are preferred for practical reasons. Recently, medetomidine and S(+)‐ketamine or racemic ketamine for field anaesthesia in European brown hares were compared (Gerritsmann et al.
      • Gerritsmann H
      • Stalder GL
      • Seilern-Moy K
      • et al.
      Comparison of S(+)-ketamine and ketamine, with medetomidine, for field anaesthesia in the European brown hare (Lepus europaeus).
      ), the medetomidine being antagonised with atipamezole. However at the doses used in that study, surgical anaesthesia was not produced reliably, and the quality of recovery was not ideal. Thus there is still a need to evaluate reliable injectable techniques.
      The objective of this study was to develop an effective short‐term injectable anaesthesia technique for European Hares (Lepus europaeus) that could be used in ‘the field’. The study evaluated the dose required to induce anaesthesia of an intramuscular (IM) combination of acepromazine, dexmedetomidine and ketamine (ADK) in hares undergoing tagging, blood sampling and ocular ultrasonography. In addition, the cardiorespiratory effects of the drugs, and the speed of recovery were evaluated.

      Materials and methods

      All procedures were carried out in accordance with the Guiding Principles in the Care and Use of Animals approved by Italian laws and were approved by the University ethics commission.
      The study was conducted on the farm where the animals were individually housed in outdoor cages (180 cm in length, 100 cm in width and 90 cm in height). The animals used were 16 clinically healthy prepubescent European hares (Lepus europaeus), seven males and nine females, aged (mean ± SD) 3.3 ± 0.9 months (range 2–5 months), and of 2.1 ± 0.6 kg (range 1.3–3.3 kg) bodyweight. They were not fasted before the experiment. The hares were transferred into smaller individual wooden boxes (70 cm in length, 50 cm in width and 50 cm in height) for the study.
      Acepromazine 1% (Prequillan, Fatro Spa, Italy) (A), dexmedetomidine 0.05% (Dexdomitor, Pfizer Italia srl, Italy) (D) and ketamine 5% (Ketavet 100, Intervet Productions srl, Italy, diluted 1:1 in sterile saline solution) (K), were mixed in the volumetric ratio of 1:1:8. Each mL of solution contained 40 mg K, 1 mg A and 50 μg D.
      The hare was removed from its box and manually restrained. The ADK mixture was injected into the Mm quadriceps femoris, at a dose of 0.25 mL kg−1 (10 mg kg−1 K, 0.25 mg kg−1 A, 12.5 μg kg−1 D). The hare then was returned to its wooden box. Two minutes later, and at 30 seconds intervals thereafter, the box was tilted gently by 90° in order to assess the time of righting reflex loss. If the righting reflex was still present after four minutes, a further dose of 0.15 mL kg−1 (6 mg kg−1K, 0.15 mg kg−1 A, 7.5 μg kg−1 D) was injected. Once the righting reflex was absent, the following reflexes were tested: righting, palpebral, ear‐pinch (the reaction to clamping the ear margin with a Halstead mosquito forceps), pedal withdrawal (pelvic limb withdrawal on clamping the inter‐digital space between third and fourth digits). Surgical anaesthesia was judged present if all the four reflexes were absent. Anaesthetized hares were tagged and an ocular ultrasound examination was performed. Room temperature was 18 °C and no methods for maintaining body temperature were used.
      Heart rate (HR), using a paediatric stethoscope, respiratory rate (fR) by counting thoracic movements, and rectal temperature (T°C) by rectal probe, were recorded 5 minutes before the injection (T0). Reflexes and physiological variables were then recorded one minute after the loss of righting reflex and removal from box (T1), and at 10 (T10), 20 (T20) and 30 (T30) minutes thereafter as long as anaesthesia was adequate for these be performed without physical restraint. In addition to HR, fR and T°C, from T1 onward additional measurements included arterial blood pressures (ABP) and arterial blood gas analysis. ABPs [mean, diastolic and systolic arterial blood pressures (MAP, SAP, DAP)] were measured by an oscillometric method (Dinamap™ XL; Critikon, Inc., Tampa, FL, USA), in which a pneumatic neonatal cuff no 2 was placed proximally to the elbow over the brachial artery. A 24 gauge catheter (Deltaven, Ohmeda, Sweden) was inserted percutaneously in the central auricular artery. Arterial samples were taken as soon as possible to T1 and at T20 and were immediately analysed for oxygen partial pressure (PaO2), carbon dioxide partial pressure (PaCO2) and pH (i‐STAT1, Abbott srl Diagnostics, Italy).
      After completion of the procedures, the hares were returned to their own wooden box and kept in a quiet area, without any stimulation, until they spontaneously sat up, which was judged as evidence of the regained righting reflex. Sleep time was measured from the loss to the return of the righting reflex. Animals were under constant observation until full recovery, i.e. ambulatory with no ataxia. Each hare was also evaluated daily until 1 month after the procedure to assess the presence or absence of any gross lesions at the injection sites.

      Statistical analysis

      All data were recorded using a computerized spreadsheet (Microsoft Excel 2011 for Mac; Microsoft Corporation, Redmond, WA, USA) and imported into a programme for statistical analysis (JMP 8.0.2, 2009 SAS Institute Inc., Cary, NC, USA).
      Data were checked for normality of distribution with a Shapiro‐Wilk's W test. Physiological variables at each were compared between time‐points by a Kruskal‐Wallis analysis of variance. Significant differences were analysed post hoc by using a Tukey‐Kramer's HSD test. Statistical significance was set at p ≤ 0.05. Data are reported as median (range); mean ± standard deviation (range) or number of hares as relevant.

      Results

      Induction time, sleep time and physiological variables are reported as mean ± SD (range; median) when normally distributed and otherwise as median (range) (Table 1). The first injection dose of 10 mg kg−1 K, 0.25 mg kg−1 A and 12.5 μg kg−1 D induced anaesthesia in 11/16 (69%) hares; 5/16 (31%) hares needed a the second dose of 6 mg kg−1K, 0.15 mg kg−1 A and 7.5 μg kg−1 D. All four reflexes tested were lost at T1 in 10/16 (62%), in all hares at T10, in 13/16 (81%) hares at T20, in 10/16 (62%) at T30. Three hares regained the righting reflex before T30.
      Table 1Induction time, sleep time and physiological variables in 16 hares, which had been administer a combination of 10 mg kg−1 K, 0.25 mg kg−1 A, 12.5 μg kg−1 D (0.25 mL kg−1 dose) or of 16 mg kg−1 K, 0.40 mg kg−1 A, 20 μg kg−1 D (0.25 + 0.15 mL kg−1 dose) IM
      Time points
      T0 (n = 16)T1 (n = 10)T10 (n = 16)T20 (n = 13)T30 (n = 11)
      Temp (°C)39.9A (39.3–41.1)39.8A (38.0–41.1)39.7A (38.2–40.5)38.0B (37.6–38.9)38.1B (37.1–38.4)
      Heart rate (beats minute−1)120B (88–160)150 (100–160)160A (105–200)137 (112–160)118B (100–130)
      Respiratory rate (breaths minute−1)120A (60–160)90B (54–100)78B (42–90)80B (32–98)88B (24–100)
      Systolic arterial pressure (mmHg)96 (71–120)90 (73–112)80 (73–116)78 (70–112)
      Mean arterial pressure (mmHg)70 (45–92)64 (49–88)55 (45–79)62 (48–78)
      Diastolic arterial pressure (mmHg)55 (36–75)50 (38–66)45 (36–66)50 (38–54)
      pH7.31 (7.29–7.33)7.33 (7.32–7.35)
      PaCO2 (kPa)5.6 (5.5–5.6)6.8 (6.8–6.9)
      PaCO2 (mmHg)42B (41–42)51A (51–52)
      PaO2 (kPa)8.9 (7.7–10.1)8.1 (8.0–8.7)
      PaO2 (mmHg)67 (58–76)61 (60–65)
      T0 = pre‐injection baseline, T1 = one minute after loss of righting reflex; T 10, 20 and 30 = minutes after T1; n = number of hares at this time point.
      Data are reported as median (range). Parameters with different letters differ statistically (p < 0.05).
      Induction time (in minutes; mean ± SD (median, range): total, 4 ± 1 (3, 2–7); 0.25 mL kg−1 dose, 3 ± 1 (3, 2–4 minutes); 0.25 + 0.15 mL kg−1 dose, 6 ± 1 (5, 5–7).
      Sleep time (in minutes; mean ± SD (median, range): 34 ± 11 minutes (30, 21–62).
      T°C decreased progressively with time of anaesthesia, being significantly lower than the baseline value from T1 onward (p < 0.0001). HR at T10 was higher than baseline (p = 0.034) then progressively decreased between T10 to T30 (p = 0.01). SAP, MAP and DAP progressively decreased, but the decline was not statistically significant at any time‐point.
      Respiratory rate was lower than base‐line at all anaesthetized time points. PaCO2 values increased by T20 (p = 0.01). PaO2 was low in some individual hares (range 7.7–10.1 kPa (58–76 mmHg) at T1,) but did not fall further by T20. The pH values did not differ between T1 and T20.
      Recovery was smooth and uneventful, and it was complete by 4 hours in all the hares. No gross lesions at the injection site were observed.

      Discussion

      Anaesthesia with a mixture of agents has potential advantages. Each component may potentiate each other's action, lower dose requirements for anaesthesia and counteract side effects (Henke et al.
      • Henke J
      • Astner S
      • Brill T
      • et al.
      Comparative study of three intramuscular anaesthetic combinations (medetomidine/ketamine, medetomidine/fentanyl/midazolam and xylazine/ketamine) in rabbits.
      ). The use of a combination of ketamine, xylazine and acepromazine mixed in the same syringe (Vachon
      • Vachon P
      Self mutilation in rabbits following intramuscular ketamine-xylazine-acepromazine injections.
      ) and various dose combinations of medetomidine/dexmedetomidine and ketamine have been reported when used in the rabbit (Longley
      • Longley LA
      Rabbit anaesthesia.
      ).
      Induction doses were chosen according to previous reports in the hares and the rabbit (Henke et al.
      • Henke J
      • Astner S
      • Brill T
      • et al.
      Comparative study of three intramuscular anaesthetic combinations (medetomidine/ketamine, medetomidine/fentanyl/midazolam and xylazine/ketamine) in rabbits.
      ; Longley
      • Longley LA
      Rabbit anaesthesia.
      ; Gerritsmann et al.
      • Gerritsmann H
      • Stalder GL
      • Seilern-Moy K
      • et al.
      Comparison of S(+)-ketamine and ketamine, with medetomidine, for field anaesthesia in the European brown hare (Lepus europaeus).
      ). Gerritsmann et al. (
      • Gerritsmann H
      • Stalder GL
      • Seilern-Moy K
      • et al.
      Comparison of S(+)-ketamine and ketamine, with medetomidine, for field anaesthesia in the European brown hare (Lepus europaeus).
      ) reported the effects of 0.2 mg kg−1 medetomidine and 30 mg kg−1 ketamine in hares, and the reversal of the medetomidine component by atipamezole. Thus Gerritsmann et al. (
      • Gerritsmann H
      • Stalder GL
      • Seilern-Moy K
      • et al.
      Comparison of S(+)-ketamine and ketamine, with medetomidine, for field anaesthesia in the European brown hare (Lepus europaeus).
      )'s doses both of ketamine and of alpha 2 agonist (assuming dexmedetomidine to be twice as potent as medetomidine) were higher than those of our study. This is the first report of administration of dexmedetomidine in hares.
      Following hind limb IM injections of ketamine, xylazine and acepromazine, self‐mutilations and sciatic enlargements have been described in the rabbit (Vachon
      • Vachon P
      Self mutilation in rabbits following intramuscular ketamine-xylazine-acepromazine injections.
      ). As also reported by Gerritsmann et al. (
      • Gerritsmann H
      • Stalder GL
      • Seilern-Moy K
      • et al.
      Comparison of S(+)-ketamine and ketamine, with medetomidine, for field anaesthesia in the European brown hare (Lepus europaeus).
      ), in the present study IM injection of volumes up to 1.6 mL in quadriceps femoris muscle was well tolerated. The choice of a site far from neural branches might explain the absence of neurological adverse effect.
      Reducing time of induction of anaesthesia is important in avoiding stress, which is paramount to successful recovery from anaesthesia in wild animals (Longley
      • Longley LA
      Rabbit anaesthesia.
      ). Induction of anaesthesia was rapid in the majority of hares, in which a dose of 10 mg kg−1 K, 0.25 mg kg−1 A and 12.5 μg kg−1 D was sufficient. Differences in induction doses might be due to individual response to the stress of handling. Dosages for adult hares should be tested in further studies.
      The absence of reaction to ear pinch and absence of pelvic limb withdrawal on clamping the inter‐digital space were taken as representative of surgical anaesthesia (Henke et al.
      • Henke J
      • Astner S
      • Brill T
      • et al.
      Comparative study of three intramuscular anaesthetic combinations (medetomidine/ketamine, medetomidine/fentanyl/midazolam and xylazine/ketamine) in rabbits.
      ). In this study, anaesthesia was adequate to perform non‐invasive procedures, but time of surgical anaesthesia was short and it was not achieved reliably in all animals. Gerritsmann et al. (
      • Gerritsmann H
      • Stalder GL
      • Seilern-Moy K
      • et al.
      Comparison of S(+)-ketamine and ketamine, with medetomidine, for field anaesthesia in the European brown hare (Lepus europaeus).
      ), despite their higher dosage regimen also found that surgical anaesthesia was unreliable.
      In our study, a significant and progressive decrease of rectal temperature was observed. It is possible that vasodilation caused by acepromazine might have enhanced temperature loss, but hypothermia was not marked. As thermoregulatory functions are depressed in anaesthesia and a controlled environmental temperature cannot be assured in field conditions, an anaesthetic technique that does not induce severe hypothermia would be preferred (Longley
      • Longley LA
      Rabbit anaesthesia.
      ).
      Heart rate, fR and ABPs presumably were influenced by all the components of ADK mixture. Dexmedetomidine may produce hypothermia, bradycardia, cardiac arrhythmias and a biphasic response with a transient increase in blood pressure, followed by a long lasting hypotensive effect. Ketamine used alone increases HR and ABPs, and its use with dexmedetomidine, in rabbits, reduced the changes of HR and fR when the α2 agonist was used alone (Blake et al.
      • Blake DW
      • Ludbrook J
      • Van Leeuwen AF
      Dexmedetomidine and haemodynamic responses to acute central hypovolaemia in conscious rabbits.
      ). In our study, HR initially increased, then decreased but no cardiac arrhythmias were recorded via auscultation. Gerritsmann et al. (
      • Gerritsmann H
      • Stalder GL
      • Seilern-Moy K
      • et al.
      Comparison of S(+)-ketamine and ketamine, with medetomidine, for field anaesthesia in the European brown hare (Lepus europaeus).
      ) recorded bradycardia in two hares at the beginning of the anaesthesia, but no pulse deficit was noted during these episodes. Further studies are needed to confirm these observations by ECG monitoring.
      The ADK combination resulted in a progressive decline of fR and ABP, but severe changes were not observed in any case. Compared with Gerritsmann et al. results in adult hares (2012), the higher fR recorded in prepubescent hares might be due to differences in age and weight, to lower dosage or to a higher level of stress inducted by handling before loss of consciousness. In our study values of PaCO2 indicated mild hypercapnia; however, pH values were stable and always in normal range. Arterial oxygen values in some individual hares were low and although they did not fall further with time, it might be advisable to consider oxygen administration, when a deeper plane or a longer anaesthesia is required.
      Sleep time was short and recovery was smooth and uneventful. It is advisable to wait at least four hours, i.e. the disappearance of acepromazine effect that cannot be antagonized, before releasing animals. In Gerritsmann et al. (
      • Gerritsmann H
      • Stalder GL
      • Seilern-Moy K
      • et al.
      Comparison of S(+)-ketamine and ketamine, with medetomidine, for field anaesthesia in the European brown hare (Lepus europaeus).
      )'s experiment, hares had major ‘hangover’ signs and did not return to apparently normal behaviour for up to 180 minutes. Since they administered atipamezole to revert medetomidine effects, the poor quality of recovery they reported might be due to residual ketamine. In our experiment the effects of dexmedetomidine were not antagonized and the ketamine dose was lower (10 mg kg−1 versus 30 mg kg−1). This may have influenced recovery quality. Although the sleep time in our hares was very similar to that reported by Gerritsmann et al. (
      • Gerritsmann H
      • Stalder GL
      • Seilern-Moy K
      • et al.
      Comparison of S(+)-ketamine and ketamine, with medetomidine, for field anaesthesia in the European brown hare (Lepus europaeus).
      ) (34 ± 11 minutes versus 30 ± 25 minutes), full recovery time in our study was l longer (240 minutes versus 180 minutes), probably due to presence of acepromazine in the mixture we tested and to the lack of reversal of α2‐agonist effects.
      Perianaesthetic acepromazine use continues to be controversial; it is vasodilatory and hence hypotensive (Johnston et al.
      • Johnston GM
      • Eastment JK
      • Wood JLN
      • et al.
      The confidential enquiry into perioperative fatalities (CEPEF): mortality results of Phases 1 and 2.
      ). However, acepromazine has sedative effects and reduces the dose of other drugs, enhances the sedation by α2 agonists while counteracting their adverse haemodynamic effects. Acepromazine smooths induction and recovery and makes anaesthesia easier to manage, decreasing the likelihood of sudden bursts of catecholamine secretion in response to acute stimuli (Johnston et al.
      • Johnston GM
      • Eastment JK
      • Wood JLN
      • et al.
      The confidential enquiry into perioperative fatalities (CEPEF): mortality results of Phases 1 and 2.
      ). This might be particularly useful in animals such as hares, which are highly sensitive to stress, during the anaesthesia and the recovery, even if, as onset of action of acepromazine after IM injection can be delayed, the influence on anaesthetic induction may be limited.
      In conclusion, the results of the present study suggest that an ADK mixture at the tested doses produce a smooth and rapid induction of anaesthesia, adequate for non‐invasive procedures, few untoward side effects and no mortality in this small group of prepubescent European hares. Oxygen administration might be advisable if a deeper plane of anaesthesia was required. Further investigations are indicated into the effects of continuous or repeated boli of ADK mixture to maintain anaesthesia.

      Acknowledgements

      The Authors thank the ATC (Ambito Territoriale Caccia, Hunting District) of Catanzaro and Napoli for their support in this project.

      References

        • Blake DW
        • Ludbrook J
        • Van Leeuwen AF
        Dexmedetomidine and haemodynamic responses to acute central hypovolaemia in conscious rabbits.
        Clin Exp Pharmacol Physiol. 2000; 27: 801-809
        • Caillol M
        • Mondain-Monval M
        • Meunier M
        • et al.
        Influence of season of birth on onset of gonadotrophic and ovarian functions in young doe hares (Lepus europaeus).
        J Reprod Fertil. 1992; 96: 747-753
        • Flecknell PA
        • Roughan JV
        • Hedenqvist P
        Induction of anaesthesia with sevofluorane and isofluorane in the rabbit.
        Lab Anim. 1999; 33: 41-46
        • Gerritsmann H
        • Stalder GL
        • Seilern-Moy K
        • et al.
        Comparison of S(+)-ketamine and ketamine, with medetomidine, for field anaesthesia in the European brown hare (Lepus europaeus).
        Vet Anaesth Analg. 2012; 39: 511-519
        • Henke J
        • Astner S
        • Brill T
        • et al.
        Comparative study of three intramuscular anaesthetic combinations (medetomidine/ketamine, medetomidine/fentanyl/midazolam and xylazine/ketamine) in rabbits.
        Vet Anaesth Analg. 2005; 32: 261-270
        • Johnston GM
        • Eastment JK
        • Wood JLN
        • et al.
        The confidential enquiry into perioperative fatalities (CEPEF): mortality results of Phases 1 and 2.
        Vet Anaesth Analg. 2002; 29: 159-170
        • Longley LA
        Rabbit anaesthesia.
        in: Longley LA Anaesthesia of Exotic Pets. Saunders Elsevier, Philadelphia, USA2008: 36-58
        • Nardoni S
        • Papini R
        • Gallo MG
        • et al.
        Survey on the role of brown hares (Lepus europaeus, Pallas, 1778) as carriers of dermatophytes.
        J Anim Sci. 2010; 9: 126-128
        • Noszczyk-Nowak A
        • Nicpoń J
        • Nowak M
        • et al.
        Preliminary reference values for electrocardiography, echocardiography and myocardial morphometry in the European brown hare (Lepus europaeus).
        Acta Vet Scand. 2009; 51: 6https://doi.org/10.1186/1751-0147-51-6
        • Vachon P
        Self mutilation in rabbits following intramuscular ketamine-xylazine-acepromazine injections.
        Can Vet J. 1999; 40: 581-582