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Assessment of ketamine and medetomidine anaesthesia in the domestic rabbit
Veterinary Anaesthesia and Analgesia, 2005, 32, 271–279
RESEARCH PAPER
Assessment of ketamine and medetomidine anaesthesia in the domestic rabbit Hannah E Orr* BVSc, CertLAS, MRCVS, Johnny V Roughan BSc, PhD & Paul A Flecknell MA, VetMB, PhD, DLAS, Diplomate ECVA, DECLAM, MRCVS
*The Rowett Research Institute, Bucksburn, Aberdeen, UK The Medical School, Comparative Biology Centre, The University of Newcastle, Newcastle upon Tyne, UK
Correspondence: Paul A Flecknell, The Medical School, Comparative Biology Centre, The University of Newcastle, Framlington Place, Newcastle upon Tyne, NE2 4H, UK. E-mail: [email protected]
Abstract Objective To study the effects of ketamine and two doses of medetomidine administered by two routes of injection in a genetically diverse population of rabbits. Study design Prospective, randomized, clinical trial. Animals One hundred and five domestic rabbits of mixed breed, sex and age. Materials and methods Rabbits undergoing orchiectomy or ovariohysterectomy received ketamine (15 mg kg)1) combined with medetomidine at 0.25 or 0.5 mg kg)1, by subcutaneous (SC) or intramuscular (IM) injection. Anaesthesia was supplemented with 1.5–2% isoflurane when signs of regular jaw movements and/or slight limb twitching indicated inadequate anaesthesia. Heart and respiratory rate, blood oxygen saturation, end-tidal carbon dioxide concentration and rectal temperature were monitored at several time points. Duration of surgical anaesthesia and anaesthesia time were measured. At completion of surgery, atipamezole (1.0 or 0.5 mg kg)1, IM or SC) was administered. Statistical analyses MANOVA was used to compare variables over time between males and females, anaesthetic doses and routes of drug administration.
Results All reflexes were lost significantly more rapidly after IM drug administration (p < 0.05). The times (in minutes) from drug injection to loss of reflexes for the respective groups were: righting reflex: 6.3 (15.0 + 0.25, SC), 5.5 (15.0 + 0.5, SC), 2.9 (15.0 + 0.25, IM) and 2.3 (15.0 + 0.5, IM); ear pinch: 9.2, 8.5, 4.8, 3.6; pedal withdrawal: 12.8, 10.4, 6.6, 5.2. Heart and respiratory rates during surgery did not differ between groups, however the highest end-tidal CO2 concentration during surgery was significantly affected by dose, with the highest concentration occurring in group 15.0 + 0.5 IM. The number of animals requiring isoflurane tended to decrease with increasing dose of anaesthetic and significantly more females required supplementation than males (p < 0.05). Recovery from anaesthesia (return of righting reflex) was not significantly different between dose groups (p > 0.1) but was more rapid in animals given IM atipamezole (13.6 ± 13 versus 21 ± 17, p ¼ 0.037). No anaesthetic-related mortality occurred and all but three animals recovered uneventfully. Five animals were killed whilst under anaesthesia because of unrelated disease. Conclusion and clinical relevance Ketamine–medetomidine combinations reliably produced surgical anaesthesia in domestic rabbits that could easily be deepened for brief periods with low concentrations of isoflurane. Subcutaneous administration was better tolerated, but the speed of induction was 271
Ketamine and medetomidine in the domestic rabbit HE Orr et al.
slower compared with IM injection. Atipamezole was an effective antagonist and produced most rapid effects when administered IM. Keywords anaesthesia, medetomidine, rabbit.
atipamezole,
ketamine,
Introduction A variety of different anaesthetic techniques have been recommended to overcome the various problems in rabbit anaesthesia, such as handling-associated stress and breath-holding during induction with volatile anaesthetic agents (Flecknell et al. 1996, 1999; Hedenqvist et al. 2001a). Apnoea is accompanied by marked bradycardia, hypercapnia and hypoxia and is not prevented by pre-anaesthetic medication (Flecknell & Liles 1996). Induction of anaesthesia using an injectable technique is therefore preferable. For some time the recommended injectable technique for use in rabbits was fentanyl/fluanasone (Hypnorm; Janssen Animal Health, High Wycombe, Bucks., UK) and midazolam. (Midazolam; Phoenix Pharma, Upton St, Gloucs., UK). This combination provides surgical anaesthesia of medium duration (Flecknell & Mitchell 1984) and can be partially antagonized using a complete opioid antagonist such as naloxone or a partial agonist/ antagonist such as buprenorphine. Using buprenorphine has the advantage of extending the period of post-operative analgesia (Flecknell et al. 1989) but recovery time, even after partial reversal of fentanyl/fluanisone, may be prolonged. In addition, the availability of ‘Hypnorm’ has varied and it is not marketed in some European states or in North America. An alternative anaesthetic technique, using the combination of ketamine and medetomidine, has been documented for use in rabbits (Flecknell 2000) although little data are available concerning optimal doses for surgical procedures. The only available data come from laboratory rabbits, where the efficacy of anaesthesia has been assessed using withdrawal reflexes, rather than surgical stimuli. In a recent study by Hedenqvist et al. (2001b)) two doses of ketamine–medetomidine that were lower than those previously proposed for rabbits (Flecknell 2000) were recommended as effective for minor and major surgical procedures in the New Zealand White rabbit. There is, however, little documented evidence demonstrating the use of the combination 272
and its reversal in a clinical setting, where it is likely to be used in rabbits of a wide range of breeds and ages and where the health status of the animals is uncertain. Domestic rabbits frequently have impaired lung function due to pre-existing diseases such as Pasteurella multocida infection. Recovery from anaesthesia can be slow, particularly when injectable anaesthetic techniques that have no option for antagonism are used. Slow recovery periods and post-operative inappetence can lead to disturbances in gastrointestinal function (Harcourt-Brown 2001). As a result of these problems an injectable technique is needed for use in rabbits that provides safe anaesthesia of adequate depth and duration for surgical procedures and which also gives a good quality and rapid recovery. The present study was undertaken using domestic pet rabbits to establish whether the doses of ketamine and medetomidine recommended for laboratory rabbits would reliably produce effective anaesthesia, of sufficient depth and duration, to enable routine neutering procedures to be performed. The study also compared the administration of ketamine–medetomidine by the intramuscular (IM) and the subcutaneous (SC) routes, and aimed at establishing whether the antagonist (atipamezole) was effective and whether significant differences arose from the route by which this agent was administered (either IM or SC). The group sizes were selected to enable a preliminary assessment of the safety of the technique and allow determination of the effects of gender and body mass on the characteristics of anaesthesia. Materials and methods Animals One hundred and five domestic rabbits of different breeds, sex and age were used for the study. The average body mass was 2.3 ± 0.8 kg (males; n ¼ 49) and 2.5 ± 0.1 (females; n ¼ 56), with a range of 1.3–4.7 kg. The animals were obtained from a rabbit rescue organization, whose policy was to neuter all rabbits before they were re-homed. Because of this, ethics committee approval was not considered necessary, so was not sought. All animals used were accepted for the study on the basis that they appeared to be healthy and had no overt clinical problems that would put them at risk from anaesthesia or complicate their recovery from
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surgery. Generally, no information regarding their previous health status or history was available. The ages of the animals were largely unknown, but estimates ranged from between 5 months to over 6 years. The rabbits were floor-housed in pens on dustfree shavings [‘Gold shavings’, Special Diets Services, Witham, Essex, UK] in a room with a 12:12 hour light:dark cycle. Room temperature was maintained in the range 20 ± 4 C, with 18 air changes per hour. The rabbits were offered a commercial pelleted diet (Rabma pellets; Special Diets Services) and the pet rabbit diet to which they were accustomed (Burgess Supa Rabbit Mix or Burgess Supa Rabbit Excel; Burgess Supafeeds, Pickering, N. Yorks., UK). They were offered water ad libitum and received supplementary hay and fresh vegetables daily. Food and water were not withdrawn before surgery. The rabbits were weighed on arrival, on the day before surgery, on the day of, and for 3 days after surgery. Food and water intake, urine and faecal production and the condition of the surgical wound were all noted daily for 5 days after surgery. Providing there were no post-operative complications, the rabbits were returned to the rabbit rescue organization for re-homing 1 week after surgery. When commencing the study, it was agreed with the referring veterinary surgeon that any animals noted to have significant dental disease, or with evidence of uterine adenocarcinoma, would be killed with an anaesthetic overdose. The body condition of each rabbit (fat score) was scored (on a scale of 1, lean, to 5, grossly obese) using a combination of the animal’s external appearance and the quantity of body fat noted during surgery. Anaesthesia Each rabbit underwent castration or ovariohysterectomy under general anaesthesia induced with ketamine (‘Ketalar’; Parke-Davis, Pontypool, Gwent, UK) and medetomidine (‘Domitor’; Pfizer Animal Health, Sandwich, Kent, UK) (Ket–Med). Rabbits were allocated to one of the four treatment groups (Table 1). The dose combinations of Ket–Med used were 15.0 + 0.25 or 15.0 + 0.5 mg kg)1, administered by the SC or IM route. The treatment that individuals received was randomized according to a blocked design, and by the order in which cases were presented for surgery. The drugs were mixed in a single syringe for injection.
Rabbits received enrofloxacin (10 mg kg)1 SC, ‘Baytril’; Bayer plc, Newbury, Berkshire, UK) preoperatively, and carprofen (5 mg kg)1 SC, ‘Rimadyl’; Pfizer Animal Health) either pre-operatively or in the post-operative period. The variation in timing of administration of carprofen was to allow for comparisons of post-operative behaviour between groups, and to determine pain-related activities. These data will be reported elsewhere. Baseline recordings of heart and respiratory rate were made immediately before the anaesthetics were administered (time ¼ 0). As these were extremely high, it was not possible to make accurate measurements. Pre-anaesthesia respiratory rate was determined by observation of chest wall movements and heart rate by using a stethoscope. Estimates were made for rates between 100 and 250 beats or breaths minute)1, otherwise they were recorded as >250. The rabbit was returned to a holding container and observed. Following onset of sedation (lack of co-ordinated or directed response when touched, and pronounced ataxia) the animal was placed on a table and the depth of anaesthesia was assessed by recording the presence or absence of a righting response (the animal being able to spontaneously right itself when placed on its back), an ear pinch response (a reaction to pinching of the pinna using the fingernails) and a pedal withdrawal response (withdrawal of the pelvic limb in response to pinching one digit with the fingernails). These responses were measured approximately every 30 seconds until they were absent and were then assessed at pre-determined time points throughout the period of anaesthesia (time ¼ 5, 10, 15, 30, 45, 60, 75, 95 minutes). Data were collected by staff that were unaware of the Ket–Med dose used, but not the administration route. Heart rate, respiratory rate, oxy-haemoglobin saturation, end-tidal CO2 (FE¢CO2; side-stream sampling, flow rate 100 mL minute)1 ; Kontron Colormon Plus; Charter Kontron, Milton Keynes, Bucks., UK) and rectal temperature were also measured at each time point using the relevant Kontron modules (whenever the appropriate monitoring equipment was functioning). When the pulse oximeter signal was poor, then heart and respiratory rate were measured as for baseline readings. The pulse oximeter probe was positioned either on the ear, tongue or digit. Once the righting reflex had been lost Simple Eye Ointment (Dominion Pharma Ltd, Haslemere, Surrey, UK) was applied to both eyes to prevent corneal drying. Oxygen was administered
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Ketamine and medetomidine in the domestic rabbit HE Orr et al.
T1 T2 T3 T4
Route
Medetomidine (mg kg-1)
Ketamine (mg kg-1)
Atipamezole dose (mg kg-1)
SC IM SC IM
0.25 0.25 0.5 0.5
15 15 15 15
0.5 0.5 1 1
by face mask at 3–4 L minute)1 from the point of onset of sedation. Endotracheal intubation was performed when the animal was sufficiently anaesthetized using the ‘blind technique’ (Flecknell et al. 1996). In a minority of animals this was unsuccessful and intubation with direct observation of the larynx was performed (Flecknell et al. 1996). The rabbit was prepared for surgery and transferred to the operating theatre. Oxygen (100%, 1 L kg)1 minute)1) was then provided via an unmodified Bain circuit. Surgery was performed; ovariohysterectomy using a midline approach, orchiectomy using a closed technique (Redrobe 2000). If the depth of anaesthesia was judged inadequate at any time, as indicated by markedly increased abdominal muscle tone, or spontaneous movement in response to surgical stimuli, or by increases in heart and respiratory rate over 20%, anaesthesia was deepened by administration of isoflurane (0.5–1.5%). After completing surgery, atipamezole (Antisedan; Pfizer Animal Health) was administered at twice the medetomidine dose (0.5 or 1 mg kg)1) by the SC or IM route. The rabbit’s trachea was extubated once it had regained its swallowing reflex. The return of the righting, pedal withdrawal and ear pinch reflexes following atipamezole were recorded. Once the ear pinch response had returned the animal was placed in an incubator maintained at 30 C during the early recovery phase (approximately 30 minutes). The temperature setting was then reduced to 25 C until the rabbit assumed normal posture or was able to ambulate satisfactorily, at which point it was returned to its holding pen. Data processing and statistical analysis The effects of each treatment were compared using a MANOVA procedure, using the computer programme SPSS (Statistics Package for the Social Sciences, version 11.0; SPSS Inc., Chicago, IL, USA). 274
Table 1 Treatment groups in rabbits anaesthetized with medetomidine and ketamine
Valid n
Male
Female
12 11 11 12
13 14 14 13
This used a combination of summary measures, e.g. the duration of, or latency to loss of pedal, ear and righting reflexes, to determine significant differences depending on the factor(s) of concern, e.g. anaesthetic dose, route of administration and gender. The repeated measures option was used to compute group differences in the physiological data in tests between adjacent time periods. These comparisons were subject to post-hoc correction of probability level (Bonferroni). All values are quoted as mean ± 1 SD. The number of animals entered into analyses differed from that available for study when equipment problems and/or errors in data collection were encountered. Results Pre-anaesthetic measurements There were no significant differences either between the anaesthetic dose groups or males and females in the pre-anaesthetic measures of heart or respiratory rate. There were also no significant differences in the masses of female or male rabbits between the dose groups, although female rabbits tended overall to be marginally heavier than the males (2.3 ± 0.8 kg versus 2.5 ± 0.1, p ¼ 0.41). Mean female ‘fat score’ was 3 versus 2.45 for males. Induction of anaesthesia and preparation for surgery Ketamine and medetomidine were administered successfully to all animals, but IM injection (into the quadriceps) caused some struggling in most animals. One case resented IM injection so much that the drugs were given subcutaneously. The time for surgical preparation, i.e. shaving the surgical site, endotracheal intubation, and eye ointment application, was compared between each anaesthetic dose group and between routes of
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± ± ± ± 7 3 6 2 (13) (14) (14) (13) 44 ± 10 49 ± 9 50 ± 11 48 ± 10
(13) (14) (14) (13) 16 10 19 11 ± ± ± ± 70 70 72 68 (13) (14) (14) (13) 26 ± 9 21 ± 6 23 ± 10 20 ± 9 0.25 SC 0.25 IM 0.5 SC 0.5 IM + + + + 15.0 15.0 15.0 15.0 F
Drugs were administered subcutaneously (SC) or intramuscularly (IM). Also shown is the latency of return of each reflex from the time of administration of atipamezole.
5 4 7 2 ± ± ± ± 10 4 9 4 (13) (14) (14) (13) 3 4 3 1
3 1 2 0 ± ± ± ± 6 3 5 2 (12) (11) (11) (12) 47 ± 14 37 ± 7 40 ± 11 33 ± 7 (12) (11) (11) (12) 22 ± 11 20 ± 5 20 ± 7 17 ± 7 (12) (11) (11) (12) 8 4 4 3 ± ± ± ± 25 18 20 16 0.25 SC 0.25 IM 0.5 SC 0.5 IM + + + + 15.0 15.0 15.0 15.0 M
administration. As shown in Table 2, animals given the low SC dose tended to spend longer in the preparation room than those given either the low or the high IM dose, but the effect was not significant. Preparation time was also marginally longer for female rabbits, but again, not significantly so. The times of loss and the return of the righting reflex, pedal withdrawal and ear pinch reflexes are shown in Table 2. The times for loss of the righting reflex, and the ear and toe pinch reflexes were dependent on the route of administration rather than on the anaesthetic dose. There was, however, a non-significant tendency for reflex loss to occur earlier with the higher dose rate. The rabbits lost their reflex responses significantly more rapidly when drugs were administered IM compared with SC (p < 0.001 for loss of each reflex parameter). Gender was not a significant factor, neither were there any other significant interactions between administration route and sex or dose. These data are illustrated in Fig. 1. Supplemental anaesthesia A chi-squared test was used to determine whether there was a relationship between requirement for supplemental anaesthesia and anaesthetic dose (increasing in potency from 15.0 + 0.25 SC to 15.0 + 0.5 IM). No significant effects were apparent. However, as the dose potency increased, fewer animals tended to receive isoflurane (Fig. 2a) (Pearson chi-square, p ¼ 0.064). However, when sex was included as a factor, and ignoring dose, significantly more females required isoflurane supplementation (Fig. 2b) (p < 0.001).
15.0 + 0.25 SC
Time (minutes)
(11) (12) (13) (11)
3 4 5 1 ± ± ± ± (13) (11) (11) (12)
9 6 8 3
(13) (11) (11) (11)
(13) (14) (14) (13)
13 5 11 6
13 9 10 5
± ± ± ±
± ± ± ±
5 6 5 2
4 2 7 3
(12) (11) (11) (11)
(13) (13) (14) (13)
20 18 25 32
± ± ± ±
16 19 25 21
16 ± 19 9±6 13 ± 13 16 ± 13
(11) (9) (9) (9)
(13) (14) (13) (13)
7 4 8 8
6 5 8 5
± ± ± ±
± ± ± ±
7 4 5 6
6 4 9 4
(9) (8) (8) (9)
(9) (12) (13) (11)
4 3 4 4
3 3 6 3
± ± ± ±
± ± ± ±
6 3 3 3
3 2 9 2
(10) (10) (9) (11)
Return of pedal w’drl Return of ear pinch Return of righting Loss of pedal w’drl Loss of ear pinch Loss of righting Atipamezole time Duration of surgery Surgical prep time Ket–Med mg kg-1
Table 2 Mean surgery times and times of loss of reflexes [times in minutes from injection of anaesthetic, mean ±1SD (n)] for groups of male (M) and female (F) rabbits undergoing Ket– Med anaesthesia at different doses
Ketamine and medetomidine in the domestic rabbit HE Orr et al.
18 16 14 12 10 8 6 4 2 0
15.0 +0.25 IM 15.0 + 0.5 SC 15.0 + 0.5 IM
T loss RR
T loss EP
T loss PW
Reflex Figure 1 Mean times (±1 SD) for loss of righting reflex (RR), ear pinch (EP) and pedal withdrawal reflexes (PW) in groups of rabbits undergoing Ket–Med anaesthesia via two routes: intramuscularly (IM) or subcutaneously (SC).
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Ketamine and medetomidine in the domestic rabbit HE Orr et al.
Physiological variables
(a) Isoflurane
Number of animals (n)
The changes in respiratory rate, heart rate and body temperature are shown in Figs 3–5 respectively. Heart rate and respiratory rate fell significantly during anaesthesia in all groups. End-tidal CO2 concentrations remained stable during anaesthesia and within acceptable limits (Table 3). Oxy-haemoglobin saturation was maintained at >95%, however problems were encountered with signal detection in many animals. During the study, the probe used was changed to a reflectance probe placed on the tongue and this provided more reliable and consistent readings. Oxy-haemoglobin saturation from probes placed on the ear or using a clipprobe on the tongue were often very low (60–95%). A series of summary measures were used to evaluate the effects of anaesthesia: mean heart and respiratory rate during anaesthesia; mean oxyhaemoglobin saturation; mean FE¢CO2; mean rectal temperature; lowest heart rate; lowest respiratory rate; lowest oxygen saturation and highest FE¢CO2. Considering differences between each variable according to each factor under consideration, the analysis indicated no significant differences between the two anaesthetic doses or routes of administration, but indicated some significant differences between the sexes. Females had a significantly lower mean and a lower highest FE¢CO2 concentration (p < 0.001, p ¼ 0.004) and higher mean respiratory rate (p ¼ 0.001) during anaesthesia (Table 3).
No
20 15 10 5 0 15.0 + 0.25
15.0 + 0.25 15.0 + 0.5 Ketamine – Medetomidine
15.0 + 0.5
(b) 50 Number of animals (n)
45 40
Isoflurane required
35
No Isoflurane
30 25 20 15 10 5 0
Male
Female Sex
Figure 2 Numbers of rabbits in each Ket–Med dose group (a) and differences between the sexes (b) in animals requiring supplemental anaesthesia with isoflurane during surgery.
Intra-operative measurements Recovery from anaesthesia
The duration of surgery was not significantly different with respect to either the dose given, or administration route, but was significantly longer for females (p < 0.001).
The time (from administration of atipamezole) for return of the righting, ear and toe pinch reflexes was compared between dose groups. Righting
300 J
15.0 + 0.25 SC
Breaths minute–1
250
J
15.0 + 0.25 IM
J
200
15.0 + 0.5 SC 15.0 + 0.5 IM
150 J
100 50
J
J
J
J
J J
0 0
5
10
15
30
Time 276
45
60
75
90
Figure 3 Mean respiratory rate (breaths minute)1 ± 1 SD) for each dose/route combination of Ket–Med at each sampling time.
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J
15.0 + 0.25 SC 15.0 + 0.25 IM 15.0 + 0.5 SC
270
15.0 + 0.5 IM
Beats minute–1
J
220
J J
J
170
J
J
J
20
30
J
J
120
Figure 4 Mean heart rate (beats minute)1 ± 1 SD) for each dose/route combination of Ket–Med at each sampling time.
70 0
5
10
15
40
50
60
Time
15.0 + 0.25 SC
J
15.0 + 0.25 IM
Body temperature (degrees)
41
Figure 5 Mean body temperature (C ± 1 SD) for each dose/route combination of Ket–Med at each sampling time.
15.0 + 0.5 SC
40
15.0 + 0.5 IM
39 J J
J
38
J
J
J J
37 36 35 34 5
10
15
30
45
60
75
90
Time
Table 3 Summary measures [overall mean ± 1SD (n)] of selected physiological parameters for groups of male (M) and female (F) rabbits undergoing Ket–Med anaesthesia
Ket–Med
AVTemp
AVResp
AVO2
AV FE¢CO2
MINHeart
LOWO2
HIFE¢CO2
M 15.0 15.0 15.0 15.0
+ + + +
0.25 SC 0.25 IM 0.5 SC 0.5 IM
38 38 38 39
± ± ± ±
1 1 1 0
(12) (10) (10) (11)
63 60 66 54
± ± ± ±
26 32 17 36
(12) (11) (11) (12)
96 98 96 97
± ± ± ±
8 3 6 3
(12) (11) (10) (9)
7 7 6 7
± ± ± ±
1 1 1 1
(12) (11) (10) (10)
120 144 133 136
± ± ± ±
41 32 28 29
(12) (11) (11) (12)
93 ± 15 97 ± 4 95 ± 8 96 ± 3
(12) (11) (10) (9)
7 7 7 7
± ± ± ±
1 2 1 1
(12) (11) (10) (10)
15.0 15.0 15.0 15.0
+ + + +
0.25 SC 0.25 IM 0.5 SC 0.5 IM
38 38 38 38
± ± ± ±
1 1 1 2
(11) (14) (14) (12)
80 84 82 78
± ± ± ±
24 35 37 35
(13) (14) (14) (13)
95 97 98 99
± ± ± ±
4 4 4 3
(12) (14) (13) (13)
5 5 6 6
± ± ± ±
1 1 1 1
(12) (13) (14) (12)
121 132 124 133
± ± ± ±
31 41 28 28
(13) (14) (14) (13)
91 ± 9 94 ± 6 94 ± 10 97 ± 4
(12) (14) (13) (13)
5 6 7 7
± ± ± ±
1 1 1 1
(12) (13) (14) (12)
F
AVTemp, mean body temperature (C); AVResp, mean respiratory rate; AVO2/FE¢CO2, mean blood oxygen saturation or end-tidal CO2 conc. (%); MINHeart, minimum heart rate; LOWO2, lowest mean blood oxygen saturation; HIFE¢CO2, highest mean end-tidal CO2 conc. (%). Drugs were administered subcutaneously (SC) or intramuscularly (IM).
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ability was gained significantly earlier in animals given the lower dose of Ket–Med (p ¼ 0.024) and females recovered their righting reflex significantly earlier than males; p ¼ 0.005 (13 ± 13 minutes versus 23 ± 20 minutes) (Table 2). Animals that received IM atipamezole appeared to recover their righting ability sooner than those antagonized by the SC route (19.7 ± 16 versus 12 ± 13) and this only narrowly avoided significance (p ¼ 0.052). There were no differences between effects in males and females and no significant effect of route of administration of atipamezole on the return of the ear pinch or pedal withdrawal reflexes. Three animals took longer than normal to recover their pedal withdrawal reflex following SC atipamezole administration (> 1 hour), so these were given additional atipamezole (50% of original dose by the same route). Body mass changes All except six rabbits lost mass during the postoperative days of data collection, but the extent of this was not significantly different between the treatment groups. Mean mass loss was between 1 and 3% of the pre-operative mass and occurred only during the first 2 days following surgery. This decline halted by day 3, when mean mass began to increase. Mortality Two animals had significant dental disease and two animals had a uterine adenocarcinoma. These animals were withdrawn from the study and killed with an overdose of pentobarbital before recovery from anaesthesia. Another rabbit had pre-existing trauma as a result of fighting and was killed the day after surgery. Discussion The doses that have been recommended to produce surgical anaesthesia in previous studies in laboratory rabbits range from 15 to 35 mg kg)1 ketamine, and 0.25 to 0.5 mg kg)1 medetomidine (Blum et al. 1992; Flecknell & Liles 1996; Hellebrekers et al. 1997; Hedenqvist et al. 2001b) but no controlled clinical trials of this combination have been undertaken in animals that could be considered representative of the UK companion rabbit population. The majority of previous studies have used loss 278
of the pedal withdrawal reflex as evidence of a surgical plane of anaesthesia. The present study used animals that were from a wide range of breeds, and all animals underwent surgery. Surgery (ovariohysterectomy or orchiectomy) was required in order to make the animals suitable for re-homing by a rabbit rescue centre. Both doses and routes of administration of the combination of Ket–Med provided safe and effective anaesthesia for ovariohysterectomy and orchiectomy, however, supplementation with isoflurane was required in some animals in all treatment groups. Increasing the dose rate of medetomidine from 0.25 to 0.5 mg kg)1 tended to decrease the number of animals that required supplemental anaesthesia, but the effect was not significant. More female than male animals required supplemental anaesthesia, and this almost certainly reflects the significantly longer duration and more invasive nature of surgery in females. As supplementation with isoflurane was required in all groups, we would recommend a dose of 15 mg 0.25 mg kg)1, combined with supplementation with an inhalational agent such as isoflurane, as necessary. Increasing the dose of medetomidine had a minor effect on the degree of respiratory or cardiovascular depression, and the only significant effect was an increase in the average FE¢CO2 concentration over the total period of anaesthesia. Administration by the IM route significantly increased the speed of onset of anaesthesia, as assessed by time of loss of the righting reflex, and the pedal withdrawal and ear pinch reflexes. However, this route was technically more difficult, and resented by many of the animals; as judged by movement or struggling during administration. We would therefore recommend SC administration, unless there is a particular need for a more rapid onset of action. All anaesthetic techniques available for use in rabbits depress respiration, and companion rabbits may have some degree of lung pathology as a consequence of previous infection (e.g. with P. multocida). Moderate to marked hypoxia has been noted in previously published studies of Ket–Med in rabbits, (Daunt et al. 1992; Hellebrekers et al. 1997; Hedenqvist et al. 2001b). We therefore consider it advisable to administer oxygen during anaesthesia, and preferable to intubate the animal’s trachea so that ventilation can be assisted should this prove necessary. All animals attained a sufficient depth of anaesthesia to allow endotracheal intubation. The
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respiratory rate and FE¢CO2 concentration remained within acceptable limits in all rabbits, and no animals required assisted ventilation. Pre-operative estimates of respiratory rate and heart rate were very high in most animals, and probably indicated stress. Later, the anaesthetic monitoring used was selected to represent techniques that could easily be applied in small animal practice, so invasive blood pressure monitoring was not included. Although pulse oximetry is a simple and effective means of monitoring respiratory function, a number of problems were encountered. Probe position was on the ear, tongue or digit. The digits had been used successfully in laboratory rabbits by our research group, however this site proved less reliable in pigmented rabbits and in smaller animals. Although readings were obtained from the ear in the majority of animals, values for saturation were often very low, e.g. 46% in one animal. In these, a second probe was placed in the mouth, and this invariably gave higher readings (in the range of 85–100%). Midway through the study, the pulse oximeter probe used was changed to an angled reflectance probe, which was positioned on the dorsal surface of the tongue. This probe rested securely between the tongue and hard palate, and provided more consistent data. The very low oxy-haemoglobin saturation values obtained from some animals was thought to be a consequence of the marked peripheral vasoconstriction associated with medetomidine administration. Peripheral vasoconstriction was also partly thought to be the cause of the failure to obtain pulse oximetry signals in some animals. Recovery from anaesthesia after administration of atipamezole was generally rapid. The more rapid return of the righting reflex in females was probably due to the longer duration of surgery. This would have resulted in a lesser effect of ketamine and medetomidine at the time of administration of atipamezole. Recovery from isoflurane is generally rapid, so the low concentration of this agent used to supplement anaesthesia would have had little effect on the rate of recovery. It should be noted that antagonism of medetomidine also eliminates its analgesic properties. The rabbits in this study also received carprofen as part of another study concerning pain-related behaviour. Because of this some animals received carprofen post-operatively. Small animal practitioners should be aware that additional analgesia may be necessary, and this should be administered before antagonism of medetomidine.
Acknowledgements The Medical Research Council supported Johnny Roughan. The authors thank Pfizer Animal Health for financial support for the study. References Blum JR, Daunt DA, Hamm TE et al. (1992) Cardio-respiratory effects of medetomidine in rabbits. Vet Surg 21, 158. Daunt DA, Blum JR, Hamm TE et al. (1992) Effects of medetomidine plus ketamine with and without oxygen supplementation in rabbits. Vet Surg 21, 159. Flecknell PA (ed.) (2000) Anaesthesia. In: Manual of Rabbit Medicine and Surgery. BSAVA, Quedgeley, UK, pp. 103–115. Flecknell P, Liles JH (1996) Halothane anaesthesia in the rabbit: a comparison of the effects of medetomidine, acepromazine and midazolam on breath-holding during induction. J Assoc Vet Anaes 23, 11–14. Flecknell PA, Mitchell M (1984) Midazolam and fentanylfluanisone: assessment of anaesthetic effects in laboratory rodents and rabbits. Lab Anim 18, 143–146. Flecknell PA, Liles JH, Wootton R (1989) Reversal of fentanyl/fluanisone neuroleptanalgesia in the rabbit using mixed agonist/antagonist opioids. Lab Anim 23, 147–155. Flecknell PA, Cruz IJ, Liles JH et al. (1996) Induction of anaesthesia with halothane and isoflurane in the rabbit: a comparison of the use of a face-mask or an anaesthetic chamber. Lab Anim 30, 67–74. Flecknell PA, Roughan JV, Hedenqvist P (1999) Induction of anaesthesia with sevoflurane and isoflurane in the rabbit. Lab Anim 33, 41–46. Harcourt-Brown F (2001) Textbook of Rabbit Medicine. Butterworth Heinemann, Newton, MA, USA. Hedenqvist P, Roughan JV, Antunes L et al. (2001a) Induction of anaesthesia with desflurane and isoflurane in the rabbit. Lab Anim 35, 172–179. Hedenqvist P, Roughan JV, Orr H et al. (2001b) Assessment of ketamine-medetomidine anaesthesia in the New Zealand White rabbit. Vet Anaes Analg 28, 18–25. Hellebrekers LJ, De Boer E-JW, Van Zuylen MA et al. (1997) A comparison between medetomidine-ketamine and medetomidine-propofol anaesthesia in rabbits. Lab Anim 31, 58–69. Redrobe S (2000) Surgical procedures and dental disorders. In: Manual of Rabbit Medicine and Surgery. Flecknell PA (ed.). BSAVA, Quedgeley, UK, pp. 117–133. Received 3 September 2003; accepted 2 March 2004.
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RESEARCH PAPER
Assessment of ketamine and medetomidine anaesthesia in the domestic rabbit Hannah E Orr* BVSc, CertLAS, MRCVS, Johnny V Roughan BSc, PhD & Paul A Flecknell MA, VetMB, PhD, DLAS, Diplomate ECVA, DECLAM, MRCVS
*The Rowett Research Institute, Bucksburn, Aberdeen, UK The Medical School, Comparative Biology Centre, The University of Newcastle, Newcastle upon Tyne, UK
Correspondence: Paul A Flecknell, The Medical School, Comparative Biology Centre, The University of Newcastle, Framlington Place, Newcastle upon Tyne, NE2 4H, UK. E-mail: [email protected]
Abstract Objective To study the effects of ketamine and two doses of medetomidine administered by two routes of injection in a genetically diverse population of rabbits. Study design Prospective, randomized, clinical trial. Animals One hundred and five domestic rabbits of mixed breed, sex and age. Materials and methods Rabbits undergoing orchiectomy or ovariohysterectomy received ketamine (15 mg kg)1) combined with medetomidine at 0.25 or 0.5 mg kg)1, by subcutaneous (SC) or intramuscular (IM) injection. Anaesthesia was supplemented with 1.5–2% isoflurane when signs of regular jaw movements and/or slight limb twitching indicated inadequate anaesthesia. Heart and respiratory rate, blood oxygen saturation, end-tidal carbon dioxide concentration and rectal temperature were monitored at several time points. Duration of surgical anaesthesia and anaesthesia time were measured. At completion of surgery, atipamezole (1.0 or 0.5 mg kg)1, IM or SC) was administered. Statistical analyses MANOVA was used to compare variables over time between males and females, anaesthetic doses and routes of drug administration.
Results All reflexes were lost significantly more rapidly after IM drug administration (p < 0.05). The times (in minutes) from drug injection to loss of reflexes for the respective groups were: righting reflex: 6.3 (15.0 + 0.25, SC), 5.5 (15.0 + 0.5, SC), 2.9 (15.0 + 0.25, IM) and 2.3 (15.0 + 0.5, IM); ear pinch: 9.2, 8.5, 4.8, 3.6; pedal withdrawal: 12.8, 10.4, 6.6, 5.2. Heart and respiratory rates during surgery did not differ between groups, however the highest end-tidal CO2 concentration during surgery was significantly affected by dose, with the highest concentration occurring in group 15.0 + 0.5 IM. The number of animals requiring isoflurane tended to decrease with increasing dose of anaesthetic and significantly more females required supplementation than males (p < 0.05). Recovery from anaesthesia (return of righting reflex) was not significantly different between dose groups (p > 0.1) but was more rapid in animals given IM atipamezole (13.6 ± 13 versus 21 ± 17, p ¼ 0.037). No anaesthetic-related mortality occurred and all but three animals recovered uneventfully. Five animals were killed whilst under anaesthesia because of unrelated disease. Conclusion and clinical relevance Ketamine–medetomidine combinations reliably produced surgical anaesthesia in domestic rabbits that could easily be deepened for brief periods with low concentrations of isoflurane. Subcutaneous administration was better tolerated, but the speed of induction was 271
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slower compared with IM injection. Atipamezole was an effective antagonist and produced most rapid effects when administered IM. Keywords anaesthesia, medetomidine, rabbit.
atipamezole,
ketamine,
Introduction A variety of different anaesthetic techniques have been recommended to overcome the various problems in rabbit anaesthesia, such as handling-associated stress and breath-holding during induction with volatile anaesthetic agents (Flecknell et al. 1996, 1999; Hedenqvist et al. 2001a). Apnoea is accompanied by marked bradycardia, hypercapnia and hypoxia and is not prevented by pre-anaesthetic medication (Flecknell & Liles 1996). Induction of anaesthesia using an injectable technique is therefore preferable. For some time the recommended injectable technique for use in rabbits was fentanyl/fluanasone (Hypnorm; Janssen Animal Health, High Wycombe, Bucks., UK) and midazolam. (Midazolam; Phoenix Pharma, Upton St, Gloucs., UK). This combination provides surgical anaesthesia of medium duration (Flecknell & Mitchell 1984) and can be partially antagonized using a complete opioid antagonist such as naloxone or a partial agonist/ antagonist such as buprenorphine. Using buprenorphine has the advantage of extending the period of post-operative analgesia (Flecknell et al. 1989) but recovery time, even after partial reversal of fentanyl/fluanisone, may be prolonged. In addition, the availability of ‘Hypnorm’ has varied and it is not marketed in some European states or in North America. An alternative anaesthetic technique, using the combination of ketamine and medetomidine, has been documented for use in rabbits (Flecknell 2000) although little data are available concerning optimal doses for surgical procedures. The only available data come from laboratory rabbits, where the efficacy of anaesthesia has been assessed using withdrawal reflexes, rather than surgical stimuli. In a recent study by Hedenqvist et al. (2001b)) two doses of ketamine–medetomidine that were lower than those previously proposed for rabbits (Flecknell 2000) were recommended as effective for minor and major surgical procedures in the New Zealand White rabbit. There is, however, little documented evidence demonstrating the use of the combination 272
and its reversal in a clinical setting, where it is likely to be used in rabbits of a wide range of breeds and ages and where the health status of the animals is uncertain. Domestic rabbits frequently have impaired lung function due to pre-existing diseases such as Pasteurella multocida infection. Recovery from anaesthesia can be slow, particularly when injectable anaesthetic techniques that have no option for antagonism are used. Slow recovery periods and post-operative inappetence can lead to disturbances in gastrointestinal function (Harcourt-Brown 2001). As a result of these problems an injectable technique is needed for use in rabbits that provides safe anaesthesia of adequate depth and duration for surgical procedures and which also gives a good quality and rapid recovery. The present study was undertaken using domestic pet rabbits to establish whether the doses of ketamine and medetomidine recommended for laboratory rabbits would reliably produce effective anaesthesia, of sufficient depth and duration, to enable routine neutering procedures to be performed. The study also compared the administration of ketamine–medetomidine by the intramuscular (IM) and the subcutaneous (SC) routes, and aimed at establishing whether the antagonist (atipamezole) was effective and whether significant differences arose from the route by which this agent was administered (either IM or SC). The group sizes were selected to enable a preliminary assessment of the safety of the technique and allow determination of the effects of gender and body mass on the characteristics of anaesthesia. Materials and methods Animals One hundred and five domestic rabbits of different breeds, sex and age were used for the study. The average body mass was 2.3 ± 0.8 kg (males; n ¼ 49) and 2.5 ± 0.1 (females; n ¼ 56), with a range of 1.3–4.7 kg. The animals were obtained from a rabbit rescue organization, whose policy was to neuter all rabbits before they were re-homed. Because of this, ethics committee approval was not considered necessary, so was not sought. All animals used were accepted for the study on the basis that they appeared to be healthy and had no overt clinical problems that would put them at risk from anaesthesia or complicate their recovery from
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surgery. Generally, no information regarding their previous health status or history was available. The ages of the animals were largely unknown, but estimates ranged from between 5 months to over 6 years. The rabbits were floor-housed in pens on dustfree shavings [‘Gold shavings’, Special Diets Services, Witham, Essex, UK] in a room with a 12:12 hour light:dark cycle. Room temperature was maintained in the range 20 ± 4 C, with 18 air changes per hour. The rabbits were offered a commercial pelleted diet (Rabma pellets; Special Diets Services) and the pet rabbit diet to which they were accustomed (Burgess Supa Rabbit Mix or Burgess Supa Rabbit Excel; Burgess Supafeeds, Pickering, N. Yorks., UK). They were offered water ad libitum and received supplementary hay and fresh vegetables daily. Food and water were not withdrawn before surgery. The rabbits were weighed on arrival, on the day before surgery, on the day of, and for 3 days after surgery. Food and water intake, urine and faecal production and the condition of the surgical wound were all noted daily for 5 days after surgery. Providing there were no post-operative complications, the rabbits were returned to the rabbit rescue organization for re-homing 1 week after surgery. When commencing the study, it was agreed with the referring veterinary surgeon that any animals noted to have significant dental disease, or with evidence of uterine adenocarcinoma, would be killed with an anaesthetic overdose. The body condition of each rabbit (fat score) was scored (on a scale of 1, lean, to 5, grossly obese) using a combination of the animal’s external appearance and the quantity of body fat noted during surgery. Anaesthesia Each rabbit underwent castration or ovariohysterectomy under general anaesthesia induced with ketamine (‘Ketalar’; Parke-Davis, Pontypool, Gwent, UK) and medetomidine (‘Domitor’; Pfizer Animal Health, Sandwich, Kent, UK) (Ket–Med). Rabbits were allocated to one of the four treatment groups (Table 1). The dose combinations of Ket–Med used were 15.0 + 0.25 or 15.0 + 0.5 mg kg)1, administered by the SC or IM route. The treatment that individuals received was randomized according to a blocked design, and by the order in which cases were presented for surgery. The drugs were mixed in a single syringe for injection.
Rabbits received enrofloxacin (10 mg kg)1 SC, ‘Baytril’; Bayer plc, Newbury, Berkshire, UK) preoperatively, and carprofen (5 mg kg)1 SC, ‘Rimadyl’; Pfizer Animal Health) either pre-operatively or in the post-operative period. The variation in timing of administration of carprofen was to allow for comparisons of post-operative behaviour between groups, and to determine pain-related activities. These data will be reported elsewhere. Baseline recordings of heart and respiratory rate were made immediately before the anaesthetics were administered (time ¼ 0). As these were extremely high, it was not possible to make accurate measurements. Pre-anaesthesia respiratory rate was determined by observation of chest wall movements and heart rate by using a stethoscope. Estimates were made for rates between 100 and 250 beats or breaths minute)1, otherwise they were recorded as >250. The rabbit was returned to a holding container and observed. Following onset of sedation (lack of co-ordinated or directed response when touched, and pronounced ataxia) the animal was placed on a table and the depth of anaesthesia was assessed by recording the presence or absence of a righting response (the animal being able to spontaneously right itself when placed on its back), an ear pinch response (a reaction to pinching of the pinna using the fingernails) and a pedal withdrawal response (withdrawal of the pelvic limb in response to pinching one digit with the fingernails). These responses were measured approximately every 30 seconds until they were absent and were then assessed at pre-determined time points throughout the period of anaesthesia (time ¼ 5, 10, 15, 30, 45, 60, 75, 95 minutes). Data were collected by staff that were unaware of the Ket–Med dose used, but not the administration route. Heart rate, respiratory rate, oxy-haemoglobin saturation, end-tidal CO2 (FE¢CO2; side-stream sampling, flow rate 100 mL minute)1 ; Kontron Colormon Plus; Charter Kontron, Milton Keynes, Bucks., UK) and rectal temperature were also measured at each time point using the relevant Kontron modules (whenever the appropriate monitoring equipment was functioning). When the pulse oximeter signal was poor, then heart and respiratory rate were measured as for baseline readings. The pulse oximeter probe was positioned either on the ear, tongue or digit. Once the righting reflex had been lost Simple Eye Ointment (Dominion Pharma Ltd, Haslemere, Surrey, UK) was applied to both eyes to prevent corneal drying. Oxygen was administered
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T1 T2 T3 T4
Route
Medetomidine (mg kg-1)
Ketamine (mg kg-1)
Atipamezole dose (mg kg-1)
SC IM SC IM
0.25 0.25 0.5 0.5
15 15 15 15
0.5 0.5 1 1
by face mask at 3–4 L minute)1 from the point of onset of sedation. Endotracheal intubation was performed when the animal was sufficiently anaesthetized using the ‘blind technique’ (Flecknell et al. 1996). In a minority of animals this was unsuccessful and intubation with direct observation of the larynx was performed (Flecknell et al. 1996). The rabbit was prepared for surgery and transferred to the operating theatre. Oxygen (100%, 1 L kg)1 minute)1) was then provided via an unmodified Bain circuit. Surgery was performed; ovariohysterectomy using a midline approach, orchiectomy using a closed technique (Redrobe 2000). If the depth of anaesthesia was judged inadequate at any time, as indicated by markedly increased abdominal muscle tone, or spontaneous movement in response to surgical stimuli, or by increases in heart and respiratory rate over 20%, anaesthesia was deepened by administration of isoflurane (0.5–1.5%). After completing surgery, atipamezole (Antisedan; Pfizer Animal Health) was administered at twice the medetomidine dose (0.5 or 1 mg kg)1) by the SC or IM route. The rabbit’s trachea was extubated once it had regained its swallowing reflex. The return of the righting, pedal withdrawal and ear pinch reflexes following atipamezole were recorded. Once the ear pinch response had returned the animal was placed in an incubator maintained at 30 C during the early recovery phase (approximately 30 minutes). The temperature setting was then reduced to 25 C until the rabbit assumed normal posture or was able to ambulate satisfactorily, at which point it was returned to its holding pen. Data processing and statistical analysis The effects of each treatment were compared using a MANOVA procedure, using the computer programme SPSS (Statistics Package for the Social Sciences, version 11.0; SPSS Inc., Chicago, IL, USA). 274
Table 1 Treatment groups in rabbits anaesthetized with medetomidine and ketamine
Valid n
Male
Female
12 11 11 12
13 14 14 13
This used a combination of summary measures, e.g. the duration of, or latency to loss of pedal, ear and righting reflexes, to determine significant differences depending on the factor(s) of concern, e.g. anaesthetic dose, route of administration and gender. The repeated measures option was used to compute group differences in the physiological data in tests between adjacent time periods. These comparisons were subject to post-hoc correction of probability level (Bonferroni). All values are quoted as mean ± 1 SD. The number of animals entered into analyses differed from that available for study when equipment problems and/or errors in data collection were encountered. Results Pre-anaesthetic measurements There were no significant differences either between the anaesthetic dose groups or males and females in the pre-anaesthetic measures of heart or respiratory rate. There were also no significant differences in the masses of female or male rabbits between the dose groups, although female rabbits tended overall to be marginally heavier than the males (2.3 ± 0.8 kg versus 2.5 ± 0.1, p ¼ 0.41). Mean female ‘fat score’ was 3 versus 2.45 for males. Induction of anaesthesia and preparation for surgery Ketamine and medetomidine were administered successfully to all animals, but IM injection (into the quadriceps) caused some struggling in most animals. One case resented IM injection so much that the drugs were given subcutaneously. The time for surgical preparation, i.e. shaving the surgical site, endotracheal intubation, and eye ointment application, was compared between each anaesthetic dose group and between routes of
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± ± ± ± 7 3 6 2 (13) (14) (14) (13) 44 ± 10 49 ± 9 50 ± 11 48 ± 10
(13) (14) (14) (13) 16 10 19 11 ± ± ± ± 70 70 72 68 (13) (14) (14) (13) 26 ± 9 21 ± 6 23 ± 10 20 ± 9 0.25 SC 0.25 IM 0.5 SC 0.5 IM + + + + 15.0 15.0 15.0 15.0 F
Drugs were administered subcutaneously (SC) or intramuscularly (IM). Also shown is the latency of return of each reflex from the time of administration of atipamezole.
5 4 7 2 ± ± ± ± 10 4 9 4 (13) (14) (14) (13) 3 4 3 1
3 1 2 0 ± ± ± ± 6 3 5 2 (12) (11) (11) (12) 47 ± 14 37 ± 7 40 ± 11 33 ± 7 (12) (11) (11) (12) 22 ± 11 20 ± 5 20 ± 7 17 ± 7 (12) (11) (11) (12) 8 4 4 3 ± ± ± ± 25 18 20 16 0.25 SC 0.25 IM 0.5 SC 0.5 IM + + + + 15.0 15.0 15.0 15.0 M
administration. As shown in Table 2, animals given the low SC dose tended to spend longer in the preparation room than those given either the low or the high IM dose, but the effect was not significant. Preparation time was also marginally longer for female rabbits, but again, not significantly so. The times of loss and the return of the righting reflex, pedal withdrawal and ear pinch reflexes are shown in Table 2. The times for loss of the righting reflex, and the ear and toe pinch reflexes were dependent on the route of administration rather than on the anaesthetic dose. There was, however, a non-significant tendency for reflex loss to occur earlier with the higher dose rate. The rabbits lost their reflex responses significantly more rapidly when drugs were administered IM compared with SC (p < 0.001 for loss of each reflex parameter). Gender was not a significant factor, neither were there any other significant interactions between administration route and sex or dose. These data are illustrated in Fig. 1. Supplemental anaesthesia A chi-squared test was used to determine whether there was a relationship between requirement for supplemental anaesthesia and anaesthetic dose (increasing in potency from 15.0 + 0.25 SC to 15.0 + 0.5 IM). No significant effects were apparent. However, as the dose potency increased, fewer animals tended to receive isoflurane (Fig. 2a) (Pearson chi-square, p ¼ 0.064). However, when sex was included as a factor, and ignoring dose, significantly more females required isoflurane supplementation (Fig. 2b) (p < 0.001).
15.0 + 0.25 SC
Time (minutes)
(11) (12) (13) (11)
3 4 5 1 ± ± ± ± (13) (11) (11) (12)
9 6 8 3
(13) (11) (11) (11)
(13) (14) (14) (13)
13 5 11 6
13 9 10 5
± ± ± ±
± ± ± ±
5 6 5 2
4 2 7 3
(12) (11) (11) (11)
(13) (13) (14) (13)
20 18 25 32
± ± ± ±
16 19 25 21
16 ± 19 9±6 13 ± 13 16 ± 13
(11) (9) (9) (9)
(13) (14) (13) (13)
7 4 8 8
6 5 8 5
± ± ± ±
± ± ± ±
7 4 5 6
6 4 9 4
(9) (8) (8) (9)
(9) (12) (13) (11)
4 3 4 4
3 3 6 3
± ± ± ±
± ± ± ±
6 3 3 3
3 2 9 2
(10) (10) (9) (11)
Return of pedal w’drl Return of ear pinch Return of righting Loss of pedal w’drl Loss of ear pinch Loss of righting Atipamezole time Duration of surgery Surgical prep time Ket–Med mg kg-1
Table 2 Mean surgery times and times of loss of reflexes [times in minutes from injection of anaesthetic, mean ±1SD (n)] for groups of male (M) and female (F) rabbits undergoing Ket– Med anaesthesia at different doses
Ketamine and medetomidine in the domestic rabbit HE Orr et al.
18 16 14 12 10 8 6 4 2 0
15.0 +0.25 IM 15.0 + 0.5 SC 15.0 + 0.5 IM
T loss RR
T loss EP
T loss PW
Reflex Figure 1 Mean times (±1 SD) for loss of righting reflex (RR), ear pinch (EP) and pedal withdrawal reflexes (PW) in groups of rabbits undergoing Ket–Med anaesthesia via two routes: intramuscularly (IM) or subcutaneously (SC).
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Physiological variables
(a) Isoflurane
Number of animals (n)
The changes in respiratory rate, heart rate and body temperature are shown in Figs 3–5 respectively. Heart rate and respiratory rate fell significantly during anaesthesia in all groups. End-tidal CO2 concentrations remained stable during anaesthesia and within acceptable limits (Table 3). Oxy-haemoglobin saturation was maintained at >95%, however problems were encountered with signal detection in many animals. During the study, the probe used was changed to a reflectance probe placed on the tongue and this provided more reliable and consistent readings. Oxy-haemoglobin saturation from probes placed on the ear or using a clipprobe on the tongue were often very low (60–95%). A series of summary measures were used to evaluate the effects of anaesthesia: mean heart and respiratory rate during anaesthesia; mean oxyhaemoglobin saturation; mean FE¢CO2; mean rectal temperature; lowest heart rate; lowest respiratory rate; lowest oxygen saturation and highest FE¢CO2. Considering differences between each variable according to each factor under consideration, the analysis indicated no significant differences between the two anaesthetic doses or routes of administration, but indicated some significant differences between the sexes. Females had a significantly lower mean and a lower highest FE¢CO2 concentration (p < 0.001, p ¼ 0.004) and higher mean respiratory rate (p ¼ 0.001) during anaesthesia (Table 3).
No
20 15 10 5 0 15.0 + 0.25
15.0 + 0.25 15.0 + 0.5 Ketamine – Medetomidine
15.0 + 0.5
(b) 50 Number of animals (n)
45 40
Isoflurane required
35
No Isoflurane
30 25 20 15 10 5 0
Male
Female Sex
Figure 2 Numbers of rabbits in each Ket–Med dose group (a) and differences between the sexes (b) in animals requiring supplemental anaesthesia with isoflurane during surgery.
Intra-operative measurements Recovery from anaesthesia
The duration of surgery was not significantly different with respect to either the dose given, or administration route, but was significantly longer for females (p < 0.001).
The time (from administration of atipamezole) for return of the righting, ear and toe pinch reflexes was compared between dose groups. Righting
300 J
15.0 + 0.25 SC
Breaths minute–1
250
J
15.0 + 0.25 IM
J
200
15.0 + 0.5 SC 15.0 + 0.5 IM
150 J
100 50
J
J
J
J
J J
0 0
5
10
15
30
Time 276
45
60
75
90
Figure 3 Mean respiratory rate (breaths minute)1 ± 1 SD) for each dose/route combination of Ket–Med at each sampling time.
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J
15.0 + 0.25 SC 15.0 + 0.25 IM 15.0 + 0.5 SC
270
15.0 + 0.5 IM
Beats minute–1
J
220
J J
J
170
J
J
J
20
30
J
J
120
Figure 4 Mean heart rate (beats minute)1 ± 1 SD) for each dose/route combination of Ket–Med at each sampling time.
70 0
5
10
15
40
50
60
Time
15.0 + 0.25 SC
J
15.0 + 0.25 IM
Body temperature (degrees)
41
Figure 5 Mean body temperature (C ± 1 SD) for each dose/route combination of Ket–Med at each sampling time.
15.0 + 0.5 SC
40
15.0 + 0.5 IM
39 J J
J
38
J
J
J J
37 36 35 34 5
10
15
30
45
60
75
90
Time
Table 3 Summary measures [overall mean ± 1SD (n)] of selected physiological parameters for groups of male (M) and female (F) rabbits undergoing Ket–Med anaesthesia
Ket–Med
AVTemp
AVResp
AVO2
AV FE¢CO2
MINHeart
LOWO2
HIFE¢CO2
M 15.0 15.0 15.0 15.0
+ + + +
0.25 SC 0.25 IM 0.5 SC 0.5 IM
38 38 38 39
± ± ± ±
1 1 1 0
(12) (10) (10) (11)
63 60 66 54
± ± ± ±
26 32 17 36
(12) (11) (11) (12)
96 98 96 97
± ± ± ±
8 3 6 3
(12) (11) (10) (9)
7 7 6 7
± ± ± ±
1 1 1 1
(12) (11) (10) (10)
120 144 133 136
± ± ± ±
41 32 28 29
(12) (11) (11) (12)
93 ± 15 97 ± 4 95 ± 8 96 ± 3
(12) (11) (10) (9)
7 7 7 7
± ± ± ±
1 2 1 1
(12) (11) (10) (10)
15.0 15.0 15.0 15.0
+ + + +
0.25 SC 0.25 IM 0.5 SC 0.5 IM
38 38 38 38
± ± ± ±
1 1 1 2
(11) (14) (14) (12)
80 84 82 78
± ± ± ±
24 35 37 35
(13) (14) (14) (13)
95 97 98 99
± ± ± ±
4 4 4 3
(12) (14) (13) (13)
5 5 6 6
± ± ± ±
1 1 1 1
(12) (13) (14) (12)
121 132 124 133
± ± ± ±
31 41 28 28
(13) (14) (14) (13)
91 ± 9 94 ± 6 94 ± 10 97 ± 4
(12) (14) (13) (13)
5 6 7 7
± ± ± ±
1 1 1 1
(12) (13) (14) (12)
F
AVTemp, mean body temperature (C); AVResp, mean respiratory rate; AVO2/FE¢CO2, mean blood oxygen saturation or end-tidal CO2 conc. (%); MINHeart, minimum heart rate; LOWO2, lowest mean blood oxygen saturation; HIFE¢CO2, highest mean end-tidal CO2 conc. (%). Drugs were administered subcutaneously (SC) or intramuscularly (IM).
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ability was gained significantly earlier in animals given the lower dose of Ket–Med (p ¼ 0.024) and females recovered their righting reflex significantly earlier than males; p ¼ 0.005 (13 ± 13 minutes versus 23 ± 20 minutes) (Table 2). Animals that received IM atipamezole appeared to recover their righting ability sooner than those antagonized by the SC route (19.7 ± 16 versus 12 ± 13) and this only narrowly avoided significance (p ¼ 0.052). There were no differences between effects in males and females and no significant effect of route of administration of atipamezole on the return of the ear pinch or pedal withdrawal reflexes. Three animals took longer than normal to recover their pedal withdrawal reflex following SC atipamezole administration (> 1 hour), so these were given additional atipamezole (50% of original dose by the same route). Body mass changes All except six rabbits lost mass during the postoperative days of data collection, but the extent of this was not significantly different between the treatment groups. Mean mass loss was between 1 and 3% of the pre-operative mass and occurred only during the first 2 days following surgery. This decline halted by day 3, when mean mass began to increase. Mortality Two animals had significant dental disease and two animals had a uterine adenocarcinoma. These animals were withdrawn from the study and killed with an overdose of pentobarbital before recovery from anaesthesia. Another rabbit had pre-existing trauma as a result of fighting and was killed the day after surgery. Discussion The doses that have been recommended to produce surgical anaesthesia in previous studies in laboratory rabbits range from 15 to 35 mg kg)1 ketamine, and 0.25 to 0.5 mg kg)1 medetomidine (Blum et al. 1992; Flecknell & Liles 1996; Hellebrekers et al. 1997; Hedenqvist et al. 2001b) but no controlled clinical trials of this combination have been undertaken in animals that could be considered representative of the UK companion rabbit population. The majority of previous studies have used loss 278
of the pedal withdrawal reflex as evidence of a surgical plane of anaesthesia. The present study used animals that were from a wide range of breeds, and all animals underwent surgery. Surgery (ovariohysterectomy or orchiectomy) was required in order to make the animals suitable for re-homing by a rabbit rescue centre. Both doses and routes of administration of the combination of Ket–Med provided safe and effective anaesthesia for ovariohysterectomy and orchiectomy, however, supplementation with isoflurane was required in some animals in all treatment groups. Increasing the dose rate of medetomidine from 0.25 to 0.5 mg kg)1 tended to decrease the number of animals that required supplemental anaesthesia, but the effect was not significant. More female than male animals required supplemental anaesthesia, and this almost certainly reflects the significantly longer duration and more invasive nature of surgery in females. As supplementation with isoflurane was required in all groups, we would recommend a dose of 15 mg 0.25 mg kg)1, combined with supplementation with an inhalational agent such as isoflurane, as necessary. Increasing the dose of medetomidine had a minor effect on the degree of respiratory or cardiovascular depression, and the only significant effect was an increase in the average FE¢CO2 concentration over the total period of anaesthesia. Administration by the IM route significantly increased the speed of onset of anaesthesia, as assessed by time of loss of the righting reflex, and the pedal withdrawal and ear pinch reflexes. However, this route was technically more difficult, and resented by many of the animals; as judged by movement or struggling during administration. We would therefore recommend SC administration, unless there is a particular need for a more rapid onset of action. All anaesthetic techniques available for use in rabbits depress respiration, and companion rabbits may have some degree of lung pathology as a consequence of previous infection (e.g. with P. multocida). Moderate to marked hypoxia has been noted in previously published studies of Ket–Med in rabbits, (Daunt et al. 1992; Hellebrekers et al. 1997; Hedenqvist et al. 2001b). We therefore consider it advisable to administer oxygen during anaesthesia, and preferable to intubate the animal’s trachea so that ventilation can be assisted should this prove necessary. All animals attained a sufficient depth of anaesthesia to allow endotracheal intubation. The
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respiratory rate and FE¢CO2 concentration remained within acceptable limits in all rabbits, and no animals required assisted ventilation. Pre-operative estimates of respiratory rate and heart rate were very high in most animals, and probably indicated stress. Later, the anaesthetic monitoring used was selected to represent techniques that could easily be applied in small animal practice, so invasive blood pressure monitoring was not included. Although pulse oximetry is a simple and effective means of monitoring respiratory function, a number of problems were encountered. Probe position was on the ear, tongue or digit. The digits had been used successfully in laboratory rabbits by our research group, however this site proved less reliable in pigmented rabbits and in smaller animals. Although readings were obtained from the ear in the majority of animals, values for saturation were often very low, e.g. 46% in one animal. In these, a second probe was placed in the mouth, and this invariably gave higher readings (in the range of 85–100%). Midway through the study, the pulse oximeter probe used was changed to an angled reflectance probe, which was positioned on the dorsal surface of the tongue. This probe rested securely between the tongue and hard palate, and provided more consistent data. The very low oxy-haemoglobin saturation values obtained from some animals was thought to be a consequence of the marked peripheral vasoconstriction associated with medetomidine administration. Peripheral vasoconstriction was also partly thought to be the cause of the failure to obtain pulse oximetry signals in some animals. Recovery from anaesthesia after administration of atipamezole was generally rapid. The more rapid return of the righting reflex in females was probably due to the longer duration of surgery. This would have resulted in a lesser effect of ketamine and medetomidine at the time of administration of atipamezole. Recovery from isoflurane is generally rapid, so the low concentration of this agent used to supplement anaesthesia would have had little effect on the rate of recovery. It should be noted that antagonism of medetomidine also eliminates its analgesic properties. The rabbits in this study also received carprofen as part of another study concerning pain-related behaviour. Because of this some animals received carprofen post-operatively. Small animal practitioners should be aware that additional analgesia may be necessary, and this should be administered before antagonism of medetomidine.
Acknowledgements The Medical Research Council supported Johnny Roughan. The authors thank Pfizer Animal Health for financial support for the study. References Blum JR, Daunt DA, Hamm TE et al. (1992) Cardio-respiratory effects of medetomidine in rabbits. Vet Surg 21, 158. Daunt DA, Blum JR, Hamm TE et al. (1992) Effects of medetomidine plus ketamine with and without oxygen supplementation in rabbits. Vet Surg 21, 159. Flecknell PA (ed.) (2000) Anaesthesia. In: Manual of Rabbit Medicine and Surgery. BSAVA, Quedgeley, UK, pp. 103–115. Flecknell P, Liles JH (1996) Halothane anaesthesia in the rabbit: a comparison of the effects of medetomidine, acepromazine and midazolam on breath-holding during induction. J Assoc Vet Anaes 23, 11–14. Flecknell PA, Mitchell M (1984) Midazolam and fentanylfluanisone: assessment of anaesthetic effects in laboratory rodents and rabbits. Lab Anim 18, 143–146. Flecknell PA, Liles JH, Wootton R (1989) Reversal of fentanyl/fluanisone neuroleptanalgesia in the rabbit using mixed agonist/antagonist opioids. Lab Anim 23, 147–155. Flecknell PA, Cruz IJ, Liles JH et al. (1996) Induction of anaesthesia with halothane and isoflurane in the rabbit: a comparison of the use of a face-mask or an anaesthetic chamber. Lab Anim 30, 67–74. Flecknell PA, Roughan JV, Hedenqvist P (1999) Induction of anaesthesia with sevoflurane and isoflurane in the rabbit. Lab Anim 33, 41–46. Harcourt-Brown F (2001) Textbook of Rabbit Medicine. Butterworth Heinemann, Newton, MA, USA. Hedenqvist P, Roughan JV, Antunes L et al. (2001a) Induction of anaesthesia with desflurane and isoflurane in the rabbit. Lab Anim 35, 172–179. Hedenqvist P, Roughan JV, Orr H et al. (2001b) Assessment of ketamine-medetomidine anaesthesia in the New Zealand White rabbit. Vet Anaes Analg 28, 18–25. Hellebrekers LJ, De Boer E-JW, Van Zuylen MA et al. (1997) A comparison between medetomidine-ketamine and medetomidine-propofol anaesthesia in rabbits. Lab Anim 31, 58–69. Redrobe S (2000) Surgical procedures and dental disorders. In: Manual of Rabbit Medicine and Surgery. Flecknell PA (ed.). BSAVA, Quedgeley, UK, pp. 117–133. Received 3 September 2003; accepted 2 March 2004.
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