buprenorfina y medetomidina en gatos.pdf

PAPER
Investigating medetomidine-
buprenorphine as preanaesthetic
medication in cats
OBJECTIVES: The objective of this study was to investigate
medetomidine-buprenorphine preanaesthetic medication in cats.
METHODS: Forty American Society of Anesthesiologists (ASA) I female
catswereenrolledinthisprospective,blinded,clinicalstudy.Catswere
randomised into one of four groups: group M30 were injected
intramuscularly with 30 mg/kg medetomidine, groups M101B,
M301B and M501B received 10, 30 and 50 mg/kg of medetomidine,
respectively, each in combination with 20 mg/kg buprenorphine. After
30 minutes, a sedation score was allocated. Anaesthesia was induced
using intravenous propofol and maintained using isoflurane in oxygen,
whilecatsunderwentovariohysterectomy.Heartrate,respiratoryrate,
end-tidalcarbondioxidetensionandoxygensaturationofhaemoglobin
were recorded. Atipamezole was administered intramuscularly at
volatileagentdiscontinuation.Timetakentolifttheirhead,sitinsternal
and stand were recorded along with quality of recovery.
RESULTS: M301B cats required significantly less isoflurane
compared with M30 cats. Heart rate and oxygen saturation of
haemoglobin were significantly lower in M501B cats than in M30
cats. All M1B groups experienced significantly better recoveries
compared with the medetomidine only M30 control group.
CLINICAL SIGNIFICANCE: The addition of buprenorphine to medetomidine
preanaesthetic medication in cats reduces volatile agent vaporiser
setting and improves the quality of recovery from anaesthesia.
N. J. GRINT, J. BURFORD* AND
A. H. A. DUGDALE
Journal of Small Animal Practice (2009)
50, 73–81
DOI: 10.1111/j.1748-5827.2008.00688.x
INTRODUCTION
Cats may be more difficult to restrain for
intravenous catheter placement and induc-
tion of anaesthesia than dogs because of
theirtemperament.Anidealpreanaesthetic
medicant would calm and sedate an ani-
mal, provide analgesia and muscle relaxa-
tion and reduce the dose requirements
for both anaesthetic induction and mainte-
nance agents.
Opioids are commonly utilised in prea-
naesthetic medication. Historically, opioid
use in cats has been controversialbecause of
maniacal reactions to high doses (Watts
and others 1973); however, opioids do
provide useful analgesia in this species
(Robertson and Taylor 2004b). Buprenor-
phine has been demonstrated to produce
better postoperative analgesia than mor-
phine (Stanway and others 2002) with a
prolonged duration of analgesia. A thermal
nociceptive study (Robertson and others
2003) also corroborated this longer dura-
tion of action. Slingsby and Waterman-
Pearson (1998) demonstrated a better
overall clinical assessment of the analgesia
afforded by buprenorphine compared with
pethidine in cats, and Dobbins and others
(2002) reported a higher analgesic efficacy
of buprenorphine compared with oxymor-
phone and ketoprofen.
Opioids have synergistic actions with
alpha-2-adrenergic agonists because of
their sharing of postreceptor mechanisms
of action (Sanders 2008) and similar re-
ceptor locations. Medetomidine is a com-
monly used premedicant in small animal
practice. Medetomidine is an alpha-2-
adrenergic agonist, licensed for use in cats
in the UK and is a potent analgesic (Maze
and Tranquilli 1991). It produces sedation
by acting at the locus coeruleus (Scheinin
and Schwinn 1992), while the anxiolysis
created is through suppression of the
reticular-activating system.
The aim of this study was to investigate
how different preanaesthetic drug combi-
nations affected sedation, intraoperative
and recovery from anaesthesia characteris-
tics in cats. Namely, we chose to investigate
the effect on these perioperative character-
istics of (1) combining medetomidine with
buprenorphine compared with medeto-
midine alone and (2) increasing doses
of medetomidine in the medetomidine-
buprenorphine combination groups.
METHODS
This study was conducted with the
approval of the University of Liverpool’s
ethical committee and with written
Division of Veterinary Anaesthesia and *Division
of Equine Studies, University of Liverpool,
Leahurst, Neston, Wirral CH64 7TE
Journal of Small Animal Practice Vol 50 February 2009 Ó 2009 British Small Animal Veterinary Association 73

informed owner consent. The study was
a prospective, randomised, blinded clinical
study and was conducted under Good
Clinical Practice guidelines.
Forty female cats were enrolled on the
study when presented to Fern Grove Sur-
gery, University of Liverpool for elective
ovariohysterectomy. Exclusion criteria in-
cluded American Society of Anesthesiolo-
gists classification of .1, or pregnancy. A
sedation score was assigned before prea-
naesthetic medication (SS0). The sedation
score (Ansah and others 2000) was a com-
posite simple descriptive score, with a max-
imum score of 16 (Appendix 1). One
anaesthetist (N. J. G.), who was unaware
of the drugs allocated, performed all the
subjective scores, namely the sedation
scores and quality of recovery.
Cats were block randomised into one of
four groups using sealed envelopes, with an
initial 12 cat block and then a further 28
cat block randomised. The groups were
as follows:
d Group M30 (control): 30 lg/kg mede-
tomidine (Domitor; Pfizer).
d Group M101B: 10 lg/kg medetomi-
dine 1 20 lg/kg buprenorphine (Veter-
gesic; Alstoe Animal Health).
dine 1 20 lg/kg buprenorphine.
dine 1 20 lg/kg buprenorphine.
In the M1B groups, the medetomidine
and buprenorphine were mixedinthesame
syringe. All injections were administered
into the lumbar epaxial muscles by a qual-
ifiedveterinarynurseorveterinarysurgeon,
who was not involved in any of the subjec-
tive scoring. The drawing up and adminis-
tration of the drugs was performed out of
sight of the investigator (N. J. G.). Imme-
diately after preanaesthetic medication was
administered, a subcutaneous injection of
03 mg/kg meloxicam (Metacam; Boeh-
ringer Ingelheim) was administered to
the cat. Thereafter, the cat was left undis-
turbed but continuously monitored in
a wire basket. Any adverse effects (that is
an effect of the drug that had no therapeu-
tic, diagnostic or prophylactic value to the
animal) observed were recorded by the one
anaesthetist (N. J. G.) and categorised as
vomiting, defecation, muscle twitching,
pain on injection, urticaria or other. Their
severity (that is mild, moderate or severe)
was also graded.
After 30 minutes, the cat was removed
from the basket. A second sedation score
was assigned (SS1). After clipping and
preparation of a site over the forelimb of
the cat, a 22-G catheter (Jelco; Smith’s
Medical) was inserted percutaneously into
the cephalic vein and secured in place.
Anaesthesia was induced with propofol
(Propoflo; Abbott Animal Health) by the
same anaesthetist (N. J. G.) on all occa-
sions. A total dose of 6 mg/kg propofol
wasdrawnintoasyringe,andtheinduction
agent was administered intravenously
slowlytoeffect,byhand,toproduceadepth
of anaesthesia sufficient to allow orotra-
cheal intubation. After topical local anaes-
thetic application on the larynx (Intubeaze;
Dechra Veterinary Products), endotra-
cheal intubation was performed with an
uncuffedtube.Anaesthesiawasmaintained
with isoflurane (Isoflo; Abbott Animal
Health) delivered in oxygen through
a Mapleson D non-rebreathing system
with a fresh gas flow of 750 ml/kg/minute
oxygen.
Anaesthetic monitoring included re-
cording heart and respiratory rates. The
oxygen saturation of haemoglobin (SpO2)
was estimated by a pulse oximeter through
lingual probe, and end-tidal carbon diox-
ide tension (ETCO2) was measured with
a capnograph incorporating a paediatric
mainstream analyser (Tidal Sp; Novame-
trix).Thesameanaesthetist(N.J.G.)mon-
itored all the anaesthetics and altered
volatileagentpercenttomaintainasurgical
plane of anaesthesia (that is loose muscle
tone, slight palpebral reflex, ventrome-
dially rotated eye and stable heart rate
and respiratory rate). The dialled volatile
agent per cent on the vaporiser, SpO2,
ETCO2, heart rate and respiratory rate val-
ues were recorded every five minutes.
Each cat was then prepared for flank or
midline ovariohysterectomy surgery. The
procedure was performed by senior veteri-
nary students under the direct and contin-
uoussupervisionofaveterinarysurgeon.At
the end of surgery, the volatile agent was
discontinued. At the same time, atipame-
zole (Antisedan; Pfizer) was administered
byintramuscular injection.The dose ofati-
pamezole was related to the dose of mede-
tomidine that the cat had received in
premedication, that is:
d Group M30: 0075 mg/kg atipamezole.
d Group M101B: 0025 mg/kg atipame-
zole.
zole.
zole.
The time taken for the cat to raise its
head, assume sternal recumbency and stand
were recorded. The cat was undisturbed
during this time and was observed continu-
ously until standing. The overall quality of
the recovery period was also subjectively
assessed as excellent (score 4), good (score
3), fair (score 2) or poor (score 1). The
one anaesthetist who observed the quality
of recovery (N. J. G.) assigned scores based
on the cat’s level of calmness, its degree of
coordination when rolling into sternal
and standing, any abnormal postures or
adverse events (for example vomiting and
airway obstruction) and any signs of pain,
including paying attention to its incision
and vocalisation. Once the cat stood, all cats
ingroupM30receivedanintravenousinjec-
tion of buprenorphine (20 lg/kg).
Statistics
Heart rate, respiratory rate, SpO2 and
ETCO2 data were plotted over time for
each group (that is plots show the mean
value in that group for that time point).
The raw data for these variables were also
averaged over the anaesthetic period.
All data sets were checked for normal
distribution using visual inspection of con-
tinuous data sets and Shapiro-Wilkes test.
Where Gaussian distribution was present,
analysis was performed by analysis of var-
iance testing with Tukey’s post hoc test
unless assumptions of equal variance were
violated. Results of normally distributed
data are presented as mean (sd). If assump-
tions of equal variance were violated or if
there was non-normal distribution, analy-
sis was performed using the Kruskal-Wallis
testwithBonferronicorrectiontomaintain
a family-wise type I error rate of 005.
Results of non-normally distributed data
arepresentedasmedian(range).AWilcoxon
signed-rank test was used to compare SS0
and SS1 data for each group. Significance
74 Journal of Small Animal Practice Vol 50 February 2009 Ó 2009 British Small Animal Veterinary Association
N. J. Grint and others

wastakenasP,005.Allstatisticaltestswere
performed using SPSS v.14.0
A sample size calculation (Minitab v14)
was performed using sedation score (SS1)
data fromthe first12 cats (three cats in each
group).
RESULTS
The results of the sample size calculation
indicated that 10 cats would be needed
in each group (a level=005). This group
size would have an 80 per cent power (b
level=02) to detect a four-unit sedation
score difference between groups.
The clinical details of the cats were sim-
ilar between groups (Table 1). Data on
duration of anaesthesia and surgery and
surgical approaches are shown in Table 2.
There were similar incidences of mild
adverse effects (in the 30 minutes after pre-
anaesthetic medication) recorded in each
group (M30, 3 of 10; M101B, 4 of 10;
M301B, 4 of 10; M501B, 3 of 10). In
group M30, two cats vomited and one
cat defecated. In group M101B, four cats
vomited, and in group M301B, one cat
vomited and muscle twitches were ob-
served in further two cats. One cat in the
M301B group displayed signs suggesting
pain on injection. In group M501B, pain
on injection was observed in one cat and
muscle twitches developed in a further
two. All these adverse effects were mild,
transient and required no treatment.
Sedation scores before preanaesthetic
medication were similar across the groups
(median [range], M30: 1 [0 to 5],
M101B: 05 [0 to 2], M301B: 15 [0 to
4], M501B: 2 [0to5]). SS1 scoreswere sig-
nificantly higher than SS0 scores in all
groups (P,0005 in all groups). The SS1
scores in the medetomidine plus buprenor-
phine groups were not statistically higher
compared with the medetomidine only
group (Fig 1). The dose of propofol needed
to induce anaesthesia did not differ signifi-
cantly between groups (median [mg/kg]
[range], M30: 35 [14 to 6], M101B:
182 [1 to 4], M301B: 157 [083 to 4],
M501B: 2 [0 to 5]). However, there was
a significant reduction in the volatile agent
per cent required during anaesthesia in
group M301B compared with group
M30 (P=0002) (Fig 2). If the two outliers
in theM501B group(Fig 2)were excluded
from statistical analysis, the average volatile
agent per cent would be significantly lower
(P,0001)thantheM30controlgroupalso.
Original data (Table 3) and graphs
(Figs 3 to 6) showing how the heart rate,
respiratory rate, ETCO2 and SpO2 data
changed over time in each group are pre-
sented. The averaged cardiopulmonary
data over the anaesthetic period are shown
in Table 4. A statistically significant differ-
ence was found in averaged heart rate data
between groups M30 and M501B
(P=0001). Also SpO2 was significantly
lowerintheM501Bgroupcomparedwith
the M30 group (P=0033), although the
results were still within a clinically accept-
able range (97 to 100 per cent).
Recovery from anaesthesia times were
similar across the groups (Table 5). Qual-
ity of recovery was significantly influen-
ced (P,0001) by group, with cats in all
M1B groups experiencing significantly
better recoveries compared with cats in
the medetomidine only control group
(M30) (Fig 7).
DISCUSSION
Buprenorphine has recently been licensed
in the UK for postoperative analgesia in
cats. It is a partial l-agonist opioid analge-
sic, which is a schedule III drug, and as such
is subjected to less stringent controls com-
pared with schedule II drugs such as mor-
phine and pethidine. It has been shown to
be an effective analgesic in cats after soft
tissue surgery (Slingsby and Waterman-
Pearson 1998, Dobbins and others 2002,
Stanway and others 2002) and prevents
hyperalgesia in the face of inflammation
(Taylor and others 2007). While its com-
bination with acepromazine as a premedi-
cant in cats has been investigated (Stanway
and others 2002), this is the first study to
examine its use in combination with mede-
tomidine for preanaesthetic medication in
this species.
The clinical details of the animals
enrolled were similar across all groups
and represent a typical population of cats
presented to the general practitioner for
elective neutering. Other factors, that is
surgical approach, were also recorded, as
they can affect postoperative pain (Grint
and others 2006) and thus recovery from
anaesthesia quality. Coe and others (2006)
reported that 96 per cent of veterinary sur-
geons in general practice in the UK use the
flankapproachtoperformfelineovariohys-
terectomy, with the remainder using the
midline approach. The distribution of
flank and midline approaches in this study
reflects that of general practice.
The most significant and interesting
result in this study was the very marked
difference in the quality of recovery from
Table 1. Clinical details of cats
M30 (n510) M101B (n510) M301B (n510) M501B (n510)
Age (months), median (range) 7 (6-36) 7 (5-84) 6 (6-36) 6 (6-30)
Weight (kg), median (range) 275 (23-36) 27 (19-43) 255 (25-36) 25 (21-38)
Breed
Domestic shorthair 6 7 10 8
Domestic longhair 2 2 0 2
Burmese 1 0 0 0
Siamese 1 0 0 0
Bengal 0 1 0 0
Table 2. Anaesthesia duration, surgical duration and approach data
M30 (n510) M101B (n510) M301B (n510) M501B (n510)
Surgical approach
Flank 9 9 9 10
Midline 1 1 1 0
Anaesthetic duration
(minutes), mean (SD)
54 (146) 48 (888) 38 (918) 46 (994)
Surgical duration
(minutes), mean (SD)
37 (114) 302 (784) 225 (106) 285 (106)
Medetomidine-buprenorphine as preanaesthetic medication in cats

anaesthesia between cats in the medetomi-
dine only group compared with all the
medetomidine/buprenorphine combina-
tion groups. The quality of recovery from
anaesthesia was similar in all M1B groups,
with most recoveries scored as either good
or excellent. The cats in the medetomidine
control group were rolling, hissing, scrat-
ching,bitingtheirincisionsandattempting
to escape during their recovery from anaes-
thesia, all these behaviours strongly sugges-
tive of pain (Robertson and Taylor 2004a).
Emergence delirium because of increased
inspired isoflurane per cent may have also
contributed to poorer quality recoveries in
the M30 cats.
Withholding analgesia to cats undergo-
ing ovariohysterectomy produces signifi-
cant postoperative pain (Slingsby and
Waterman-Pearson 1998). However, only
26percentofveterinarysurgeonrespondents
to a questionnaire routinely administered
analgesic to cats after ovariohysterectomy
in the UK (Lascelles and others 1999).
The anaesthetic protocol (that is whether
thedrugsincludedhaveanalgesicproperties)
chosen for any given animal will affect post-
operative pain. Slingsby and others (1998)
compared a medetomidine combination
anaesthetic with that of acepromazine/
thiopental/halothane for anaesthesia of
cats undergoing ovariohysterectomy. They
found that at every time point postopera-
tively, the medetomidine combination
group had significantly less pain compared
with the acepromazine group, highlighting
the point that there is a contribution of the
anaestheticorsedativedrugstopostoperative
analgesia. A single dose of an analgesic is
unlikely to provide adequate postoperative
analgesia; however, optimum analgesia is
more likely to be achieved by a multimoda-
l approach (Kehlet and Dahl 1993) as in
our study where an opioid, non-steroidal
anti-inflammatory drug and an alpha-2-
adrenergic agonist were used.
Meloxicam, a non-steroidal anti-
inflammatory drug, was administered to
all cats 30 minutes before anaesthetic
induction. Meloxicam will not have
affected the sedation scores in these cats
before anaesthesia and is unlikely to have
contributed to anaesthetic depth because
of the inherent lack of sedative properties.
It will have, however, contributed to anal-
gesia and antihyperalgesia in the immedi-
ate postoperative phase and for up to 24
hours thereafter (Carroll and others
2005).
Analgesia produced by medetomidine is
mediated at the level of the spinal cord
because of the activation of both presynap-
tic and postsynaptic dorsal horn alpha-2-
adrenoreceptors (Millan 1998). Ansah
FIG 1. Sedation score 30 minutes after preanaesthetic medication. The total possible sedation
score (that is maximum sedation) is 16. Shaded boxes represent the middle 50 per cent of data (that
is are bounded by the upper and lower quartiles), with the bars representing the median values.
The whiskers represent the maximum and minimum values from the data set, which fall within
a range of 153the interquartile range (IQR), below the lower quartile and 153IQR above the
upper quartile. Outliers (outwith this range) are represented by small open circles
FIG 2. Averaged volatile agent per cent over the anaesthetic period. Significant (P50002)
differences are apparent between groups M30 and M301B. If the two extreme outliers in group
M501B (denoted by circles) are excluded from analysis, the volatile agent per cent in this
group would be significantly lower (P,0001) than group M30. Shaded boxes represent the
middle 50 per cent of data (that is are bounded by the upper and lower quartiles), with the bars
representing the median values. The whiskers represent the maximum and minimum values from
the data set, which fall within a range of 153interquartile range (IQR), below the lower quartile
and 153IQR above the upper quartile. Outliers (outwith this range) are represented by small
open circles

and others (1998) studied three intramus-
cular doses of medetomidine (50, 100 and
150 lg/kg) in cats and concluded that the
analgesia produced was not very intense at
any of the dose rates and would only su-
ffice for minor surgical interventions or
mild manipulations.
The benefits of pre-emptive analgesia
have been proven in veterinary species
(Lascelles and others 1995, 1997). Woolf
and Chong (1993) advocate, however, that
the optimal form of pain prevention ‘is the
one that is applied both pre-, intra- and
postoperatively’. The medetomidine in
the preanaesthetic combinations investi-
gated in this study was antagonised with
atipamezole at the end of surgery, and by
this process, all inherent alpha-2-agonist-
mediated analgesia was lost. Therefore, in
the immediate postoperative period, the
continuing analgesia was a result oftheopi-
oid and non-steroidal anti-inflammatory
drugs.
Currently, medetomidine (as Domitor)
is licensed as a sole agent and in combina-
tion with butorphanol for sedation and
analgesia in cats (Domitor; Pfizer data
sheet). The reported antinociceptive
effects of butorphanol last for ‘less than
60 minutes’ (Robertson and others
2003) to 90 minutes (Lascelles and Rob-
ertson 2004). For the procedure in this
study, the addition of the 30 minute pre-
anaesthetic medication time, to the aver-
age anaesthetic duration (38 to 54
minutes), suggests that if butorphanol
had been the opioid used, the analgesia
provided would probably have been wan-
ing by the early recovery period. Con-
versely, buprenorphine administered
intramuscularly at 001 mg/kg signifi-
cantly increased thermal thresholds in cats
betweenfourand 12hours (Robertson and
others 2003),and clinical studies(Stanway
and others 2002) corroborated this long-
lasting effect.
The dose rate of buprenorphine chosen
for this study (20 lg/kg) was higher than
that used in previous studies (Slingsby
and Waterman-Pearson 1998, Stanway
and others 2002, Robertson and others
2003). This dose was recommended by
the distributors (Alstoe Animal Health)
and is used clinically in this hospital. The
dose rates of medetomidine used in this
study were lower than those recommended
Table
3.
Data
relating
to
heart
rate,
respiratory
rate,
SpO
2
and
end-tidal
carbon
dioxide
concentration
for
all
animals
in
the
four
study
groups.
Data
are
shown
graphically
in
Figs
3
to
6
Five
minutes
10
minutes
15
minutes
20
minutes
25
minutes
30
minutes
35
minutes
40
minutes
45
minutes
50
minutes
55
minutes
60
minutes
65
minutes
70
minutes
M30
n=10
n=10
n=10
n=10
n=10
n=10
n=10
n=10
n=6
n=5
n=4
n=4
n=3
n=1
Heart
rate
(beats
per
minute)
116
(125)
116
(99)
127
(197)
136
(233)
147
(208)
151
(354)
149
(263)
148
(290)
156
(252)
150
(236)
155
(307)
155
(309)
149
(25)
152
Respiratory
rate
(beats
per
minute)
33
(56)
31
(75)
32
(133)
36
(152)
28
(92)
26
(109)
27
(105)
25
(105)
24
(69)
26
(81)
31
(09)
30
(12)
30
(28)
23
SpO
2
(per
cent)
980
(10)
980
(13)
984
(15)
986
(10)
988
(07)
989
(08)
984
(09)
978
(14)
990
(06)
986
(09)
988
(05)
988
(05)
985
(07)
99
End-tidal
carbon
dioxide
(mmHg)
31
(58)
32
(42)
32
(35)
29
(59)
29
(75)
29
(77)
31
(71)
35
(48)
34
(93)
35
(76)
33
(58)
32
(65)
25
(35)
22
M10
1B
n=10
n=10
n=10
n=10
n=10
n=9
n=8
n=7
n=5
n=4
n=1
n=1
n=0
n=0
Heart
rate
(beats
per
minute)
100
(183)
106
(174)
122
(309)
137
(352)
137
(306)
141
(218)
142
(239)
135
(246)
121
(236)
113
(218)
99
78
Respiratory
rate
(beats
per
minute)
27
(69)
25
(71)
26
(113)
27
(129)
25
(105)
247
(106)
196
(103)
164
(44)
148
(32)
157
(32)
20
15
SpO
2
(per
cent)
979
(27)
970
(22)
980
(141)
983
(17)
983
(15)
983
(14)
983
(13)
976
(18)
993
(06)
990
(0)
970
980
End-tidal
carbon
dioxide
(mmHg)
33
(78)
33
(71)
34
(76)
35
(71)
35
(65)
34
(77)
33
(80)
33
(99)
35
(90)
35
(99)
30
25
M301B
n=10
n=10
n=10
n=10
n=8
n=6
n=6
n=5
n=4
n=0
n=0
n=0
n=0
n=0
Heart
rate
(beats
per
minute)
103
(219)
117
(183)
123
(233)
133
(162)
137
(218)
144
(232)
141
(242)
124
(195)
120
(207)
Respiratory
rate
(beats
per
minute)
29
(119)
31
(116)
33
(141)
31
(119)
31
(131)
28
(154)
25
(122)
28
(88)
25
(73)
SpO
2
(per
cent)
970
(18)
970
(16)
970
(19)
971
(15)
971
(19)
980
(09)
985
(05)
976
(15)
972
(25)
End-tidal
carbon
dioxide
(mmHg)
32
(88)
31
(86)
33
(71)
33
(85)
32
(49)
32
(58)
31
(70)
32
(78)
33
(80)
M501B
n=10
n=10
n=10
n=10
n=10
n=9
n=8
n=6
n=4
n=3
n=2
n=1
n=0
n=0
Heart
rate
(beats
per
minute)
89
(164)
94
(197)
102
(222)
107
(290)
117
(231)
122
(221)
117
(132)
108
(77)
101
(12)
99
(21)
97
(22)
93
Respiratory
rate
(beats
per
minute)
29
(82)
31
(69)
28
(68)
26
(64)
24
(47)
20
(54)
20
(57)
19
(61)
18
(60)
19
(62)
14
(68)
22
SpO
2
(per
cent)
971
(17)
971
(14)
969
(14)
979
(13)
975
(14)
976
(22)
974
(21)
978
(24)
955
(07)
975
(13)
960
(12)
960
End-tidal
carbon
dioxide
(mmHg)
37
(43)
37
(49)
39
(61)
36
(59)
37
(48)
38
(55)
38
(59)
37
(74)
36
(98)
37
(84)
36
(76)
40
The
values
in
brackets
are
standard
deviations

bythemanufacturers(Pfizer),withthehigh-
est doseinourstudy (that is50lg/kg) being
at the lowest limit for medetomidine seda-
tion alone and the recommended dose for
use in combination with butorphanol
(Domitor Data sheet). These doses again
are those regularly used in this hospital
for such a population of fit healthy cats.
While we included a medetomidine
control (at the middle dose level) in the
study design, we chose not to include
a buprenorphine only control group.
Buprenorphine in combination with ace-
promazine adequately sedated cats for
smooth cephalic venous catheterisation
(Stanway and others 2002), and buprenor-
phine administered intramuscularly on its
own to cats produced only mild sedation
with marked euphoria (Robertson and
others 2003). With the expected popula-
tion of cats, that is fit, healthy and young,
this level of sedation was not thought to be
appropriate.
The sedation score used was previously
published by Ansah and others (2000). We
considered thisscoring system to bevalid as
it was used in their study as a tool to assess
sedation in cats after either medetomidine
or dexmedetomidine administration. We
chose to score the sedation after preanaes-
thetic medication at 30 minutes as this
correlates well with the peak action of
medetomidine (Granholm and others
2006). The onset of action of buprenor-
phine is slow, approximately 35 minutes
after intramuscular injection (Johnson
and others 2007), and so while its full effect
maynothavebeenapparentby30minutes,
if the second sedation score had been
delayed further, the cats may have begun
to recover from the effects of the medeto-
midine. The inclusion of two oriental cats
in the M30 group may have affected the
sedation scores as these breeds have a
reputation of being ‘temperamental’.
The sedation scores performed before
drug administration allowed a compari-
son of baseline sedation scores, and these
were very similar across all the groups.
There was little difference in sedation
scores after premedication between the
medetomidine/buprenophine combina-
tiongroups.Furtherdifferencesmayhave
become apparent between the groups if
thesimpledescriptivescaleusedwasmore
sensitive.
Cat number 17 was an outlier in both
the volatile agent results and the SS1 score
results. This cat had been recently rescued,
wasrelativelyunhandledandappearedvery
nervous. If this anxious state produced ex-
cessive levels of catecholamines including
adrenaline in this animal, medetomidine
may have been less effective because of
the competitive nature of adrenaline and
medetomidine at the adrenoreceptors.
Cat 2 was an outlier of the volatile agent
results; however, there was no apparent
reason for this.
The addition of buprenorphine to
medetomidine appeared to have a volatile
agent sparing effect, as there was a signifi-
cant reduction in the averaged isoflurane
per cent over time in group M301B com-
pared with group M30. Buprenorphine
alone (0005 and 005 mg/kg intrave-
nously) did not produce clinically relevant
isoflurane MAC reductions in cats (Ilkiw
and others 2002). It is likely that the
apparent MAC reduction seen in this
study was as a result of the synergism
between opioid and alpha-2-adrenergic
agonist (Sanders 2008). The reduction
in volatile agentper centappears to be dose
dependent, although there were no signif-
icant differences between the three M1B
combination groups. As medetomidine
has sedative and analgesic properties, it
is not surprising that increasing the dose
of this drug further reduced the MAC of
isoflurane.
Of the cardiopulmonary data studied
over the anaesthetic period, significant
differences were found between group
M30 and group M501B in heart rate
and haemoglobin oxygen saturation. The
60
70
80
90
100
110
120
130
140
150
160
5 10 15 20 25 30 35 40 45 50 55 60 65
Time after anaesthetic induction (minutes)
Heart
rate
(beats
per
minute)
M30
M10+B
M30+B
M50+B
FIG 3. Heart rate over the duration of anaesthesia. Each plot point is the mean for the group data at
that time point
10
15
20
25
30
35
40
5 10 15 20 25 30 35 40 45 50 55 60 65
Time after induction of anaesthesia (minutes)
Respiratory
rate
(beats
per
minute)
M30
M10+B
M30+B
M50+B
FIG 4. Respiratory rate over the anaesthetic period. Each plot represents the mean respiratory rate
for each group at that time point

mean heart rates in both groups were clin-
ically acceptable, andthe lower heartratein
theM501Bgroupwaslikelybecauseofthe
combination of the buprenorphine and the
highest dose of medetomidine, although
interestingly at higher dose rates of mede-
tomidine (50, 100 and 150 lg/kg) increas-
ing dose rates did not appear to alter heart
rate (Ansah and others 1998). Medetomi-
dine has been reported to decrease PaO2 in
cats (Duke and others 1994) (which may
therefore affect SpO2). Given that the cats
in our study were breathing 100 per cent
oxygen, and that respiratory rate and
ETCO2 data did not suggest any hypoven-
tilation in any group, the desaturation we
observed was more likelyto beattributedto
poor signal detection secondary to periph-
eral vasoconstriction produced by the
medetomidine (Golden and others 1998)
at this higher dose.
Side effects reported in this study were
mild and transient. The high incidence
of vomiting (50 per cent of those reported)
is likely because of the inclusion of mede-
tomidine in the premedication rather than
the buprenorphine. The Domitor (Pfizer)
data sheet warns of the high incidence of
vomiting in cats, whereas no vomiting
has been reported in studies investigating
the use of buprenorphine in cats (Robert-
son and others 2003, Robertson and others
2005, Taylor and others 2007). The mus-
cle twitching reported in this study is also
likely because of the administration of
medetomidine (Domitor data sheet).
In conclusion, increasing the dose of
medetomidine (when in combination with
buprenorphine) did not significantly in-
crease the level of sedation in cats. There
was a trend for increasing doses of
medetomidine in the medetomidine/
buprenorphine groups to further reduce
volatile agent requirement, although this
was not statistically significant. The lack
of significant increases in sedation, volatile
agent sparing effect and recovery quality in
M501B cats compared with the M301B
cats suggests that, when used in combina-
tion with buprenorphine, increasing the
dose rate of medetomidine from 30 to
50 lg/kg is not warranted in clinical
practice.
The combination of medetomidine
plus buprenorphine at all the dose ranges
investigated produced profound sedation
in this population of cats, with the level of
sedationbeing clinicallysuperiortomede-
tomidine alone. Buprenorphine appears
to have synergism with medetomidine,
in the reduction of isoflurane required.
Recovery from anaesthesia was good or
excellent in all the medetomidine/bupre-
norphinecombination groups butwas sig-
nificantly poorer in the medetomidine
only group.
96
96·5
97
97·5
98
98·5
99
5
10
15
20
25
30
35
40
45
50
55
60
65
Time after anaesthetic induction (minutes)
SpO
2
(%)
M30
M10+B
M30+B
M50+B
FIG 5. Changes in oxygen saturation of haemoglobin (SpO2) over the anaesthetic period. Points
plotted represent the mean for the group at that time point
20
25
30
35
40
5
1
5
2
5
3
5
4
5
5
5
6
5
Time after induction of anaesthesia (minutes)
ETCO
2
(mm
Hg)
M30
M10+B
M30+B
M50+B
FIG 6. End-tidal carbon dioxide concentrations over the anaesthetic period. Plot points represent
the mean value for the group at that time point
Table 4. Averaged cardiopulmonary data over the anaesthetic period
M30 M101B M301B M501B P
Heart rate
(beats per minute)
139 (167)* 122 (219) 125 (172) 105 (170)* 0001
Respiratory rate
(beats per minute)
295 (75) 231 (87) 315 (107) 254 (64)
End-tidal carbon
dioxide (mmHg)
311 (47) 336 (66) 318 (63) 375 (46)
SpO2 (per cent) 985 (067)* 979 (11) 974 (07) 972 (12)* 003
Results are presented as mean (SD)
*Significance (P,005) between groups
Table 5. Recovery from anaesthesia data. These results represent the time taken
from the discontinuation of volatile agent and the administration of atipamezole
to attaining these positions
M30 M101B M301B M501B
Head lift (minutes) 7 (3-9) 8 (3-25) 7 (4-16) 65 (5-13)
Sternal (minutes) 75 (6-11) 85 (4-25) 8 (4-41) 7 (6-20)
Standing (minutes) 9 (7-20) 125 (6-35) 11 (4-100) 9 (6-54)
Results are presented as median (total range)

Acknowledgements
The authors would like to thank the staff of
Fern Grove Clinic, the University of Liver-
pool for their assistance with this study.
This study was supported byAlstoeAnimal
Health.
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FIG 7. Quality of recovery from anaesthesia. Possible scores were poor (score 1), fair (score 2),
good (score 3) and excellent (score 4). Each of the M1B groups experienced significantly better
quality recoveries compared with the M30 control group. Application of a Bonferroni correction
indicated that these results were significant at a 1 per cent level (P,0001). There were no
significant differences between the M1B groups. Shaded boxes represent the middle 50 per cent of
data (that is are bounded by the upper and lower quartiles), with the bars representing the median
values. The whiskers represent the maximum and minimum values from the data set, which fall
within a range of 153interquartile range (IQR), below the lower quartile and 153IQR above the
upper quartile

APPENDIX 1
Posture
0=Normal
1=Laterally recumbent but occasionally
managestoriseor makes strongattemptsto
rise either spontaneously or during manip-
ulations, although with some difficulty
2=Laterally recumbent, able to lift head
up and hold it erect for a little while, occa-
sionally makes weak attempts to rise but
unable to do so.
3=Laterally recumbent, able to lift head
up slightly above the ground but can
barely hold it in place and almost imme-
diately drops it, does not make any
attempt to rise.
4=Laterally recumbent and unable to
rise or lift head up from ground.
Jaw relaxation
0=Normal tonus
1=Slightly weakened tonus
2=Moderately weakened tonus
3=No resistance to mouth opening
Hand clap
0=Strong/normal
1=Weak
2=Very weak
3=No reaction
Hindlimb stretching
0=Strong/normal
1=Weak
2=Very weak
3=No resistance
Stretching knee joint
0=Strong/normal
1=Weak
2=Very weak
3=No resistance

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