- Email: [email protected]
Intratesticular and incisional line infiltration with ropivacaine for castration in medetomidine–butorphanol–midazolam sedated dogs
Accepted Manuscript Intratesticular and incisional line infiltration with ropivacaine for castration in medetomidine-butorphanol-midazolam sedated dogs Yishai Kushnir, Noa Toledano, Liat Cohen, Tali Bdolah-Abram, Yael Shilo-Benjamini PII:
S1467-2987(17)30039-9
DOI:
10.1016/j.vaa.2016.03.007
Reference:
VAA 65
To appear in:
Veterinary Anaesthesia and Analgesia
Received Date: 4 January 2016 Revised Date:
22 February 2016
Accepted Date: 6 March 2016
Please cite this article as: Kushnir Y, Toledano N, Cohen L, Bdolah-Abram T, Shilo-Benjamini Y, Intratesticular and incisional line infiltration with ropivacaine for castration in medetomidinebutorphanol-midazolam sedated dogs, Veterinary Anaesthesia and Analgesia (2017), doi: 10.1016/ j.vaa.2016.03.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
RESEARCH PAPER
2
Y Kushnir et al.
3
Intratesticular block in sedated dogs
4
Intratesticular and incisional line infiltration with ropivacaine for castration in
5
medetomidine-butorphanol-midazolam sedated dogs
6
Yishai Kushnir*, Noa Toledano*, Liat Cohen*, Tali Bdolah-Abram† & Yael Shilo-Benjamini*
7
*Koret School of Veterinary Medicine, The Robert H. Smith Faculty of Agriculture, Food and
8
Environment, The Hebrew University of Jerusalem, Israel
9
†Hadassah Medical School, The Hebrew University of Jerusalem, Israel
M AN U
SC
RI PT
1
10
Correspondence: Yishai Kushnir, Koret School of Veterinary Medicine, The Robert H. Smith
12
Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, P.O. Box
13
12, Rehovot 7610001 Israel. E-mail: [email protected]
14
TE D
11
Abstract
16
Objectives To evaluate whether intratesticular and incisional ropivacaine infiltration produces
17
sufficient intra- and postoperative analgesia for castrating dogs under sedation.
18
Study design Randomized, blinded, controlled, clinical study.
19
Animals Twenty-three healthy dogs weighing 5.8-35.6 kg admitted for castration.
20
Methods Dogs were sedated with medetomidine (0.01 mg kg-1), butorphanol (0.2 mg kg-1), and
21
midazolam (0.2 mg kg-1) intramuscularly, and were randomly assigned to 0.2-0.4 mL kg-1 of
22
ropivacaine 0.5% (group R) or an equivalent volume of saline (group S) injected intratesticularly
23
and along the incision line. If persistent motion was observed during surgery, sedation was
AC C
EP
15
ACCEPTED MANUSCRIPT
considered to be insufficient and general anaesthesia was induced. Carprofen 2.2 mg kg-1 was
25
administered postoperatively. Pain was evaluated in all dogs before sedation and postoperatively
26
following atipamezole administration at 1, 2, 4, 8 and 24 hours using an interactive visual
27
analogue scale (IVAS; 0-100), the Glasgow composite pain scale (CMPS-SF; 0-24), and a
28
mechanical algometer. Methadone 0.3 mg kg-1 IV was administered to dogs if IVAS > 30 or
29
CMPS-SF > 4.
30
Results There was no significant difference between groups for the number of dogs administered
31
general anaesthesia. The time from the beginning of surgery to induction of general anaesthesia
32
was significantly shorter [median (range)] in S [6 (3-25) minutes] than in R [56 (36-76) minutes].
33
At 8 hours IVAS was significantly higher in S (14 ± 10) than in R (6 ± 4).
34
Conclusions and clinical relevance Intratesticular and incisional ropivacaine infiltration
35
delayed the time to anaesthesia induction, and provided analgesia after castration performed
36
under deep sedation in dogs. Intratesticular local anaesthesia can be an important part of the
37
anaesthetic plan for castration.
SC
M AN U
TE D
Keywords castration, dogs, intratesticular block, local anaesthesia, sedation.
EP
39
AC C
38
RI PT
24
ACCEPTED MANUSCRIPT
Introduction
41
Orchiectomy is a common procedure in veterinary practice, and may constitute 20% of the
42
surgical caseload in a small animal practice (Dyson et al. 1998). Castration is considered a
43
painful procedure by practicing veterinarians (Lorena et al. 2014), and many studies have been
44
performed to identify techniques that will decrease perioperative pain (Kongara et al. 2012;
45
McMillan et al. 2012; Huuskonen et al. 2013; Perez et al. 2013; Stevens et al. 2013).
Local anaesthesia is an effective way to achieve analgesia with minimal systemic side effects
SC
46
RI PT
40
while decreasing anaesthetic requirement (McMillan et al. 2012) and the perioperative stress
48
response (Perez et al. 2013). Local anaesthesia has been employed during surgical castration in
49
many species (Magoha 1998; Earley & Crowe 2002; Moldal et al. 2013) including the dog
50
(Huuskonen et al. 2013; Perez et al. 2013; Stevens et al. 2013).
51
M AN U
47
In humans, ruminants and horses orchidectomy may be performed under a local anaesthetic technique, with or without sedation, avoiding use of general anaesthesia, thus decreasing cost
53
and reducing complications (Magoha 1998; Earley & Crowe 2002; Mason et al. 2005).
54
Medetomidine is a sedative commonly used in small animals that induces profound sedation,
55
recumbency and analgesia (Girard et al. 2010). The addition of butorphanol and midazolam
56
increases sedation and prolongs the sedative effects (Pypendop & Verstegen 1999; Girard et al.
57
2010).
EP
AC C
58
TE D
52
Recently published studies examining the effectiveness of intratesticular local anaesthesia on
59
perioperative pain in dogs had inconclusive results (McMillan et al. 2012; Huuskonen et al.
60
2013; Perez et al. 2013; Stevens et al. 2013). Sedation is defined as a state from which the patient
61
can be aroused with a noxious stimulus (American Society of Anesthesiologists 2005).
62
Therefore, performing castration under sedation should not be possible unless local anaesthesia
ACCEPTED MANUSCRIPT
63
provides sufficient analgesia. Thus, the goal of this study was to evaluate whether intratesticular
64
and incisional ropivacaine infiltration produces sufficient intra- and postoperative analgesia for
65
surgical castration of sedated dogs. Our hypothesis was that administration of local anaesthesia would provide sufficient
67
analgesia to perform castration without the need for general anaesthesia, and provide superior
68
postoperative analgesia when compared with a saline placebo.
SC
69
RI PT
66
Materials and methods
71
Dogs admitted to Koret School of Veterinary Medicine, Veterinary Teaching Hospital for
72
elective castration were eligible for inclusion in the study. The dogs were assessed as healthy
73
[American Society of Anesthesiologists (ASA) class I-II] based on history, physical examination
74
and complete blood count. Dogs undergoing other surgery (e.g., for brachiocephalic syndrome),
75
or castration for a medical disorder (e.g. prostatic hyperplasia) were excluded from the study.
76
The study was approved by the Internal Ethics Review Committee of the Koret School of
77
Veterinary Medicine, The Hebrew University, and written informed owner consent was obtained
78
prior to inclusion.
TE D
EP
79
M AN U
70
Before beginning the study, dogs were randomly assigned using an online randomizing software, www.random.org/lists/ , to group R that were administered an intratesticular and
81
incisional line block with ropivacaine, or to group S that were administered saline. Dogs were
82
sedated with medetomidine (0.01 mg kg-1; Domitor; Orion Pharma, Finland), butorphanol (0.2
83
mg kg-1; Morphasol; aniMedica GmbH, Ireland), and midazolam (0.2 mg kg-1; Midolam; Rafa,
84
Israel), mixed in the same syringe and injected intramuscularly (IM) into the epaxial muscles. As
85
soon as the dogs were heavily sedated (not responsive to loud stimulation, ear flick reflex, and
AC C
80
ACCEPTED MANUSCRIPT
moving the dog to a gurney), a 22-18 gauge, 2.5-4.8 cm catheter was inserted into a cephalic
87
vein appropriate to the dog’s size, and lactated Ringer’s solution (Teva Medical, Israel) was
88
administered intravenously (IV) at 5 mL kg-1 hour-1. Dogs that were not sufficiently sedated after
89
15 minutes, and moved in response to stimulus, were administered additional medetomidine
90
(0.005-0.01 mg kg-1). The dogs were placed in dorsal recumbency and oxygen 5 L minute-1 was
91
administered through a facemask using a rebreathing circuit for dogs >7 kg or a Mapleson D
92
non-rebreathing circuit for dogs weighing ≤7 kg. After clipping and aseptic preparation of the
93
surgical site, dogs in R were administered ropivacaine (1-2 mg kg-1; Naropin, 1%; AstraZeneca,
94
Sweden diluted 1:1 with saline 0.9%). Using a 25 gauge, 16 mm needle one-third of the dose was
95
injected into the center of each testicle from the ventral aspect, and one-third was injected
96
subcutaneously along the prescrotal midline. Dogs weighing < 7.5, 7.5-15 or > 15 kg were
97
administered 2.0, 1.5 or 1.0 mg kg-1 (0.4, 0.3 or 0.2 mL kg-1), respectively, of ropivacaine. Saline
98
volumes for dogs in S were calculated and administered in the same way as for R. All injections
99
were performed by the same anaesthetist (YK) who was blinded as to the injectate used.
SC
M AN U
TE D
100
RI PT
86
Veterinary students in their final year of training performed the castrations under the supervision of a surgeon or surgery resident. Dogs were monitored for heart rate (HR),
102
respiratory rate (fR), rectal temperature (RT), lead II electrocardiogram (ECG) and noninvasive
103
blood pressures (NIBP) using a Doppler technique (811-BTS; Parks Medical Electronics, OR,
104
USA) and oscillometry (Cardell 9601; Midmark Corp., OH, USA). A circulating-water heating
105
blanket (T/Pump; Gaymar Industries Inc., NY, USA) and a forced-air warming device
106
(Thermacare; Gaymar Industries Inc.) were applied to minimize heat loss. Hypotension, defined
107
as systolic arterial pressure (SAP) < 100 mmHg, was to be treated by administration of atropine
108
(0.01 mg kg-1 IV and 0.02 mg kg-1 IM; Atropine sulphate; Teva Pharmaceutical Industries Ltd,
AC C
EP
101
ACCEPTED MANUSCRIPT
Hungary) when HR < 80 beats minute-1, or by an infusion of dopamine (0.005-0.01 mg kg-1
110
minute-1; Dopamine HCl-Fresenius; Bodene Ltd, South Africa) when HR ≥ 80 beats minute-1.
111
When gross movement of the head or a limb was observed during the surgical procedure,
112
diazepam (0.5 mg kg-1; Assival; Teva Pharmaceutical Industries Ltd) was to be administered IV.
113
If motion was observed again, propofol (0.4-1.1 mg kg-1; Lipuro 1%; B. Braun Melsungen AG,
114
Germany) was administered to accomplish endotracheal intubation in dorsal recumbency and
115
anaesthesia was maintained by administration of isoflurane (Terrell Isoflurane USP; Piramal
116
Critical Care Inc., PA, USA) in oxygen. The time of propofol administration and the stage of the
117
surgical procedure were recorded.
M AN U
SC
RI PT
109
At the completion of surgery, carprofen (2 mg kg-1; Norocarp; Norbrook Laboratories,
119
Northern Ireland) was administered subcutaneously, and atipamezole (0.025-0.07 mg kg-1;
120
Antisedan; Orion Pharma) IM. The dose of atipamezole was based on the dose of medetomidine
121
administered and the time elapsed from administration. Carprofen was administered again at 12
122
and 24 hours. Monitoring and all decisions during the procedure were performed for all dogs by
123
a single anaesthetist (YK) blinded to the group.
Recorded times were the time from initial administration of sedative drugs to the first
EP
124
TE D
118
incision (preparation time), time from first incision to the last skin suture (surgery time), time
126
from incision to diazepam administration (time to diazepam administration), time from incision
127
to propofol administration (time to propofol administration) and time from initial administration
128
of sedatives to atipamezole administration (total sedation time).
AC C
125
129
Postoperative pain was assessed using an interactive visual analogue scale (IVAS), the
130
University of Glasgow Short Form (CMPS-SF) and an algometer before sedation to provide a
131
baseline and at 1, 2, 4, 8, and 24 hours after atipamezole administration. The IVAS was graded
ACCEPTED MANUSCRIPT
on a 100 mm strip, where 0 was non-painful and 100 was extremely painful, by observation of
133
the dog in a cage followed by interaction. The CMPS-SF (University of Glasgow 2014) was
134
scored from 0 (non-painful) to 24 (extremely painful) using 6 parameters (Kongara et al. 2012).
135
Both tests were performed simultaneously, but independently, by two assessors, that were
136
unaware of the treatment administered (YK, NT). Dogs were first observed for scoring of both
137
tests and followed by interaction required for the CMPS-SF and the IVAS. The average of the
138
score given by each examiner was used for statistical analysis, and correlation between
139
examiners was assessed. Sensitivity to pressure was measured at the surgical site by both
140
examiners together (YK, NT) using an algometer (ProdPlus; Topcat Metrology, UK). A 4 mm
141
probe was applied approximately 1 cm lateral to the incision line, with increasing pressure.
142
When responses to the pressure were observed, i.e., turning towards the incision, moving the
143
pelvic limbs, vocalizing, or aggression, the probe was removed immediately and the pressure
144
applied was recorded. This test was repeated in triplicate and the average score was used. A
145
maximal safety cut-off for mechanical nociception was not predetermined in this study.
TE D
M AN U
SC
RI PT
132
Methadone (0.3 mg kg-1; Methadone injection BP 1%; Martindale Pharmaceuticals, UK) was
147
to be administered IV as rescue analgesia if the IVAS was > 30 mm or the CMPS-SF was > 4. In
148
addition, the institution nursing staff observed the dogs continuously, and if animals appeared
149
painful between evaluation points, the investigators were contacted to re-evaluate pain and
150
administer rescue medication when necessary. Pain scores from animals that were administered
151
rescue analgesia were recorded at later points but these were excluded from statistical analysis.
AC C
152
EP
146
Sedation was scored concurrently with a 4 point simple descriptive scale (SDS; Appendix 1)
153
(Pypendop & Verstegen 1998) in order to rule out sedation as a confounding element in pain
154
evaluation.
ACCEPTED MANUSCRIPT
155
Statistical analysis
157
A sample size calculation was performed based on a pilot study in which none of the dogs in R
158
required general anaesthesia. However due to several studies claiming a failure rate of
159
approximately 20% in local anaesthetic techniques, it was assumed that up to 20% of the dogs in
160
R, and at least 80% in S would be administered general anaesthesia. Using a significance of p <
161
0.05 and a power of π = 0.80, revealed that at least eight dogs were required in each group.
SC
162
RI PT
156
Normality was evaluated using the Kolmogorov-Smirnov test, and normally distributed variables were compared between groups using the student’s t-test. The Mann-Whitney U test
164
was used for variables that were not normally distributed, or had small sample sizes. For binary
165
parameters the Pearson Chi-squared test or Fischer’s exact test were used based on sample size.
166
Bonferroni correction for repeated measures was applied for comparisons of pain scores at the
167
different time points to baseline scores. Need for rescue analgesia was evaluated using a Kaplan-
168
Meier survival curve, significance was established with Fischer’s exact test. Significance was set
169
at p < 0.05.
EP
170
TE D
M AN U
163
Results
172
Twenty-three dogs were included in the study, 11 dogs in R and 12 dogs in S. No significant
173
difference was found between the groups regarding age, weight, volume administered locally or
174
the time periods (Table 1). Two dogs in S required one additional dose of medetomidine, and
175
two other dogs were administered a third dose. Two dogs in R required one additional dose of
176
medetomidine. There were no significant differences between groups for the number of
177
medetomidine doses, total medetomidine dose or atipamezole dose.
AC C
171
ACCEPTED MANUSCRIPT
One dog in S was administered 3 doses of medetomidine, and moved on the surgery table before
179
the incision and was anaesthetized. This dog was hypotensive (the only one in the study) with a
180
SAP 89 mmHg and was administered atropine 35 minutes after propofol administration. Since
181
motion was observed despite lack of surgical stimulus, intraoperative data from this dog were
182
excluded from analyses, but postoperative assessments were included. None of the dogs required
183
dopamine administration. In one dog in R, the typical sensation of the testicle becoming larger
184
and firmer during injection of ropivacaine was not felt, possibly indicating a technical failure.
185
This dog moved 4 minutes after skin incision and diazepam was administered, and no further
186
motion was observed throughout surgery.
SC
M AN U
187
RI PT
178
The number of dogs administered diazepam or propofol was not significantly different between the groups (Table 2). However, the median time to diazepam administration was
189
significantly longer in R compared with S (p = 0.021). Time to propofol administration was also
190
significantly longer in R than in S (p = 0.01) (Table 2). The interval between diazepam and
191
propofol administrations in four dogs in R was 33 (1-54) minutes and in six dogs in S was 4 (1-
192
10) minutes. Dogs in S administered propofol were significantly smaller [9.5 (6.0-22.0) kg] than
193
dogs that were not administered propofol [24.5 (22.5–33.4) kg] (p = 0.003). This effect was not
194
significant in R [13.5 (6.4-31.5) kg and 28.0 (19.5–35.6) kg, respectively] (p = 0.109).
EP
Sedation scores did not differ significantly between groups at any time point. A significant
AC C
195
TE D
188
196
increase in postoperative pain scores compared with baseline was observed for IVAS at all time
197
points for both groups (p < 0.05; Fig. 1). Scores were significantly lower in R than in S at 8
198
hours (6 ± 4 mm and 14 ± 10, respectively) (p = 0.05). The CMPS-SF score increased
199
significantly in R only in the first hour (p = 0.02), and in S at one and two hours post-surgery
200
(both p = 0.02) (Fig. 2). Dogs were more sensitive to the algometer compared with baseline at
ACCEPTED MANUSCRIPT
one hour post-surgery in both groups (in R p = 0.04, in S p = 0.03), but at two hours only in S (p
202
= 0.04) (Fig. 3). No significant differences were found between the groups for CMPS-SF or
203
algometer values. A force over 20 N was applied with the algometer in one dog in S which did
204
not respond to a pressure of 30 N during the 3 baseline measurements, and in one dog in R which
205
responded at 23 N.
206
RI PT
201
Correlations between the two examiners were very good for both IVAS (R = 0.727) and CMPS-SF (R = 0.799). Correlations between IVAS and CMPS-SF were good (R = 0.596),
208
however correlations between algometer readings and IVAS (R = -0.444) and CMPS-SF (R = -
209
0.136) were weak.
M AN U
210
SC
207
Rescue analgesia was administered to two out of 11 (18.2%) dogs in R and to four out of 12
211
(33.3%) dogs in S. One dog in S (8.3%) was administered rescue analgesia twice (Table 3). No
212
significant difference was found between groups regarding rescue medication.
TE D
213
Discussion
215
The main finding of this study is that intratesticular and incisional line block with ropivacaine
216
delayed the need for general anaesthesia by 7-56 minutes after incision. This finding is in
217
agreement with studies showing that local anaesthesia decreases intraoperative anaesthetic
218
requirements (McMillan et al. 2012; Perez et al. 2013).
AC C
EP
214
219
In five of 11 dogs in group S, sedation with medetomidine-butorphanol-midazolam was
220
sufficient for performing castration, even without local anaesthesia. Dogs from group S that did
221
not require general anaesthesia were significantly larger (median 24.5 kg) than those that did
222
(9.5 kg). Medetomidine should preferably be dosed on a mg m-2 basis (Pypendop & Verstegen
223
1999), however, in the present study, medetomidine was dosed by mg kg-1. This may have led to
ACCEPTED MANUSCRIPT
a relatively higher dose and produced anaesthesia in the larger dogs in comparison with the
225
smaller ones. The ASA definition of general anaesthesia is “a drug-induced loss of consciousness
226
during which patients are not arousable, even by painful stimulation…” whereas deep sedation is
227
defined as “a drug-induced depression of consciousness during which patients cannot be easily
228
aroused but respond purposefully following repeated or painful stimulation…” (American
229
Society of Anesthesiologists 2005). The combination of medetomidine-butorphanol-midazolam
230
was administered in this study to provide deep sedation, however, at high doses medetomidine
231
may produce anaesthesia sufficient for minor procedures (Väha-Vähe 1989), as observed in the
232
five dogs that did not respond to the surgical stimulus.
SC
M AN U
233
RI PT
224
Medetomidine, butorphanol, and midazolam were administered IM to enable IV access since most of the dogs in the study were excited and difficult to restrain. This mode of administration
235
when compared with IV administration is considered safer and avoids sudden onset of
236
cardiovascular effects, however, it is slower and more variable and may have added variation to
237
the results.
TE D
234
The volume of ropivacaine administered to larger dogs was relatively smaller than the
239
volume administered to smaller dogs. This was based on studies that showed poor correlation
240
between body weight and testicular size, and that a 10-fold increase in body weight correlated
241
with a 5-fold increase in testicular size (Eilts et al. 1993: Roy et al. 2002).
AC C
242
EP
238
Publication of orchiectomy in dogs under sedation and local anaesthesia was not found,
243
although this technique has been published for other species (Magoha 1998; Earley & Crowe
244
2002; Mason et al. 2005). Approval of the ethical committee, and informed owner consent were
245
acquired, however, an ethical dilemma was raised regarding performing surgery on sedated dogs
246
that were not administered local anaesthesia. To accommodate this concern and decrease the
247
nociception perceived by dogs in group S, analgesia and amnesia similar to those usually provided for
ACCEPTED MANUSCRIPT
castration under general anaesthesia were administered, the animals were monitored closely and
249
additional sedation and anaesthesia were administered immediately when required. Although general
250
anaesthesia blunts the motor response to nociception, it is accepted that propofol has no
251
analgesic properties and that the analgesia provided by inhalants is minimal (Branson 2007;
252
Steffey & Mama 2007). Medetomidine and butorphanol were included in the sedation protocol
253
for dogs in this study based on current literature, in which butorphanol, medetomidine, or both,
254
were the analgesic drugs administered to dogs before surgery for castration or
255
ovariohysterectomy (Väisänen et al. 2005; Barletta et al. 2011; Vettorato & Bacco 2011;
256
Gutierrez-Blanco et al. 2015). Morphine or hydromorphone could have provided better
257
analgesia, but their sedative and analgesic effects are prolonged and could have resulted in
258
confounding the postsurgical pain assessment. This was a stated limitation in the study by
259
Stevens et al. (2013). Butorphanol was chosen because it has a short duration of action of
260
approximately 2 hours (Lamont & Mathews 2007). Carprofen was administered immediately
261
after surgery to decrease inflammatory pain. Carprofen has been used for analgesia when
262
neutering dogs at the dose used in this study (Kum et al. 2000) and when administered at 4.4 mg
263
kg-1 once daily was reported to provide analgesia equivalent to that of morphine (Dzikiti et al.
264
2006). Midazolam has been shown to cause amnesia in several species, which decreases the
265
degree of postoperative discomfort perceived by the patient (Sanday et al. 2012; Giachero et al.
266
2015; Hong et al. 2015). . The inclusion of butorphanol, midazolam and carprofen may have led
267
to a reduction in the power of this study, and the effect observed for local anaesthesia, however,
268
we considered them necessary to avoid possible suffering. Although castration was performed in
269
some dogs under sedation without local anaesthesia, this technique should not be considered
270
acceptable in clinical practice if performed without the strict guidelines stipulated in this study
271
design.
AC C
EP
TE D
M AN U
SC
RI PT
248
ACCEPTED MANUSCRIPT
272
Atipamezole was administered at the end of surgery to reverse the sedation and other side effects from medetomidine, however, analgesia would also have been reversed (Pertovaara et al.
274
1994; Granholm et al. 2007). The duration of analgesia provided by IM medetomidine is
275
reported as approximately 2 hours (Lemke 2007) and would have been waning in most dogs at
276
the time of atipamezole administration. To ensure analgesia following medetomidine reversal,
277
carprofen was administered concurrently. In a clinical setting the advantages of atipamezole
278
should be weighed carefully against its disadvantages.
SC
279
RI PT
273
Previous studies found conflicting results regarding the efficacy of local anaesthesia for decreasing postoperative pain after castration. Perez et al. (2013) found decreased pain scores
281
and intra- and postoperative analgesia requirements after intratesticular or epidural anaesthesia
282
compared with a placebo, as well as decreased serum cortisol concentration in the intratesticular
283
anaesthesia group. Conversely, two studies found no benefit of intratesticular injection of local
284
anaesthetic for postoperative pain, although there was a decrease in the incidence of a cremaster
285
muscle twitch (Stevens et al. 2013), and less increase in HR and mean arterial pressure in
286
response to surgery (Huuskonen et al. 2013). The variation in results may be explained by
287
different anaesthetic techniques, or the result of inconsistencies among scoring methods for
288
assessing pain. Three pain scores were used in this study to optimize pain recognition. While
289
IVAS and CMPS-SF assess the subjective pain experience of the animal, the algometer is an
290
objective measurement of surgical site nociception and hyperalgesia (Hunt et al. 2013). The
291
poor correlation observed between the algometer and both CMPS-SF and IVAS indicates that
292
these tests measure different aspects of pain and are not interchangeable.
293 294
AC C
EP
TE D
M AN U
280
Ropivacaine onset time is approximately 15 minutes, and the duration of sensory block is expected to last approximately 6 hours (Sakonju et al. 2009). At 8 hours after surgery the effect
ACCEPTED MANUSCRIPT
of the local anaesthetic should have worn off, and yet a significant difference in IVAS scores
296
between groups was evident at this time point, and two dogs in group S required rescue
297
analgesia. This may indicate an antihyperalgesic effect that is achieved by preventing
298
intraoperative pain with ropivacaine. However, administration of ropivacaine did not abolish
299
pain postoperatively because the IVAS scores were elevated in the first 8 hours. Inflammatory
300
mediators may be elevated after surgery and may increase pain sensation. The cytokine IL-1β
301
causes mechanical allodynia that is not attenuated by local anaesthetics (Kim et al. 2014).
302
Carprofen may attenuate, but does not completely block, this inflammatory response (Kum et al.
303
2000). Despite carprofen administration, IVAS scores remained higher than baseline at 24 hours,
304
indicating that analgesia after castration should be provided for at least 24 hours.
SC
M AN U
305
RI PT
295
There was no significant difference between the groups in the number of dogs administered rescue analgesia. The score for CMPS-SF that in our opinion identified a dog requiring rescue
307
analgesia was lower than commonly used in published studies (Kongara et al. 2012). Had the
308
present study used a score of 6 as the limit, only one dog would not have been administered
309
rescue analgesia.
Saline administration constituted the control group and facilitated blinding of the evaluators
EP
310
TE D
306
and surgeons (Stevens et al. 2013). The increased intratesticular volume may cause pain that may
312
have affected our findings. However, the increase in volume was similar in both groups and none
313
of the dogs were observed to move in response to the injection. Furthermore, ropivacaine comes
314
in an acidic solution (pH of 4.0-6.0), and thus it may cause more pain on injection. Despite the
315
possibility of affecting variation in the study it was deemed necessary to use a saline control
316
group to maintain a blinded study design.
AC C
311
ACCEPTED MANUSCRIPT
Administration of atropine with an α2-agonist is controversial, as it may aggravate
318
bradycardia or cause tachycardia, accompanied by ventricular arrhythmias (Lemke 2007).
319
Regular use of atropine with medetomidine is not advocated, and administration is avoided in the
320
presence of hypertension. However, atropine was administered to one dog in this study to correct
321
bradycardia and hypotension during inhalation anaesthesia.
322
RI PT
317
Surgery times in this study were exceptionally long (up to 112 minutes) for a canine castration. Sedation from medetomidine-butorphanol-midazolam is expected to last
324
approximately 80 minutes (Verstegen & Petcho 1993), thus sedation was probably minimal in
325
some of the dogs. This likely contributed to the lack of difference between the groups in the
326
number of dogs requiring general anaesthesia because movement may be a response to
327
nociception or increasing awareness of dorsal recumbency or the surroundings. Diazepam, a mild
328
sedative in dogs with no analgesic properties, may prolong the sedation but should not be
329
efficient for dogs in pain. Diazepam was administered in this study initially to deepen sedation,
330
further movement was an indication to induce anaesthesia. An experienced surgeon will
331
complete the surgery in a much shorter time, removing the need for additional sedation. The
332
times for preparation of the surgical site were not different between the groups but were
333
prolonged. The delay in commencing surgery may have had an impact on the requirement for
334
general anaesthesia except that the preparation times were not different in dogs that were
335
anaesthetized compared with those who were not.
M AN U
TE D
EP
AC C
336
SC
323
Study limitations include the small sample size, the use of mg kg-1 basis rather than body
337
surface area for calculation of sedative drug doses, administration of carprofen and rescue
338
analgesia that may have masked the effect of ropivacaine, and that with the exception of
339
ropivacaine injection all procedures were performed by inexperienced veterinary students. The
ACCEPTED MANUSCRIPT
340
inexperience of the surgeons may also have been a factor that increased tissue trauma (Michelsen
341
et al. 2012) and variability of pain expressed by the dogs.
342
In conclusion, IM administration of medetomidine (0.01 mg kg-1), butorphanol (0.2 mg kg-1) and midazolam (0.2 mg kg-1) with subcutaneous prescrotal infiltration and intratesticular
344
injection of 0.5% ropivacaine provided satisfactory conditions for castration in seven out of 11
345
dogs [additional diazepam (0.5 mg kg-1) was administered to two of these dogs]. The remaining
346
four dogs required administration of diazepam and general anaesthesia for completion of the
347
surgery; however, the propofol was not necessary for 56 (36-76) minutes [median (range)]. More
348
than half of the control dogs required general anaesthesia, indicating that the inclusion of
349
ropivacaine in the protocol for castration provided significant analgesia, and may decrease
350
postoperative pain.
M AN U
SC
RI PT
343
351
Authors’ contributions
353
YK: conception and study design, data acquisition, data interpretation and analysis, manuscript
354
preparation and revision. NT: study design, data acquisition, data interpretation and analysis,
355
manuscript revision. LC: data acquisition, manuscript revision. TB-A: study design, data
356
interpretation and analysis, manuscript revision. YS-B: conception, study design, data
357
acquisition, data interpretation, manuscript preparation and revision. All authors approved the
358
final manuscript.
360
EP
AC C
359
TE D
352
ACCEPTED MANUSCRIPT
361
References American Society of Anesthesiologists (2005) Guidelines for ambulatory anesthesia and
363
surgery. http://www.asahq.org/quality-and-practice-management/standards-and-
364
guidelines/search=general+anesthesia+definition [Accessed December 4, 2015].
365
Barletta M, Austin BR, Ko JC et al. (2011) Evaluation of dexmedetomidine and ketamine in
366
combination with opioids as injectable anesthesia for castration in dogs. J Am Vet Med
367
Assoc 238, 1159-1167.
368
Branson KR (2007) Injectable and alternative anesthetic techniques. In: Lumb & Jones'
369
Veterinary Anesthesia and Analgesia (4th edn). Tranquilli WJ, Thurmon JC, Grimm KA
370
(eds). Blackwell Publishing, USA. pp. 273-300
371
Dyson DH, Maxie MG, Schnurr D (1998) Morbidity and mortality associated with anesthetic
372
management in small animal veterinary practice in Ontario. J Am Anim Hosp Assoc 34, 325-
373
335.
374
Dzikiti TB, Joubert KE, Venter LJ et al. (2006) Comparison of morphine and carprofen
375
administered alone or in combination for analgesia in dogs undergoing ovariohysterectomy. J
376
S Afr Vet Assoc 77, 120-126.
377
Earley B, Crowe MA (2002) Effects of ketoprofen alone or in combination with local
378
anesthesia during the castration of bull calves on plasma cortisol, immunological, and
379
inflammatory responses. J Anim Sci 80, 1044-1052.
380
Eilts BE, Williams DB, Moser EB (1993) Ultrasonic measurement of canine testes.
381
Theriogenology 40, 819-828.
AC C
EP
TE D
M AN U
SC
RI PT
362
ACCEPTED MANUSCRIPT
Giachero M, Calfa GD, Molina VA (2015) Hippocampal dendritic spines remodeling and
383
fear memory are modulated by GABAergic signaling within the basolateral amygdala
384
complex. Hippocampus 25, 545–555.
385
Girard NM, Leece EA, Cardwell J et al. (2010) The sedative effects of low-dose
386
medetomidine and butorphanol alone and in combination intravenously in dogs. Vet Anaesth
387
Analg 37, 1-6.
388
Granholm M, McKusick BC, Westerholm FC, Aspergrén JC (2007) Evaluation of the
389
clinical efficacy and safety of intramuscular and intravenous doses of dexmedetomidine and
390
medetomidine in dogs and their reversal with atipamezole. Vet Rec 160, 891-897.
391
Gutierrez-Blanco E, Victoria-Mora JM, Ibancovichi-Camarillo JA et al. (2015) Postoperative
392
analgesic effects of either a constant rate infusion of fentanyl, lidocaine, ketamine,
393
dexmedetomidine, or the combination lidocaine-ketamine-dexmedetomidine after
394
ovariohysterectomy in dogs. Vet Anaesth Analg 42, 309-318.
395
Hong YJ, Jang EH, Hwang J et al. (2015) Effect of midazolam on memory during fiberoptic
396
gastroscopy under conscious sedation. Clin Neuropharmacol 38, 47-51.
397
Hunt JR, Grint NJ, Taylor PM, Murrell JC (2013) Sedative and analgesic effects of
398
buprenorphine, combined with either acepromazine or dexmedetomidine, for premedication
399
prior to elective surgery in cats and dogs. Vet Anaesth Analg 40, 297-307.
400
Huuskonen V, Hughes JM, Estaca Bañon E, West E (2013) Intratesticular lidocaine reduces
401
the response to surgical castration in dogs. Vet Anaesth Analg 40, 74-82.
402
Kim MJ, Lee SY, Yang KY et al. (2014) Differential regulation of peripheral IL-1β-induced
403
mechanical allodynia and thermal hyperalgesia in rats. Pain 155, 723-732.
AC C
EP
TE D
M AN U
SC
RI PT
382
ACCEPTED MANUSCRIPT
Kongara K, Chambers JP, Johnson CB (2012) Effects of tramadol, morphine or their
405
combination in dogs undergoing ovariohysterectomy on peri-operative
406
electroencephalographic responses and post-operative pain. N Z Vet J 60, 129-135.
407
Kum C, Voyvoda H, Sekkin S et al. (2013) Effects of carprofen and meloxicam on C-
408
reactive protein, ceruloplasmin, and fibrinogen concentrations in dogs undergoing
409
ovariohysterectomy. Am J Vet Res 74, 1267-1273.
410
Lamont LA, Mathews KA (2007) Opioids nonsteroidal anti-inflammatories and analgesic
411
adjuvants. In: Lumb & Jones' Veterinary Anesthesia and Analgesia (4th edn). Tranquilli WJ,
412
Thurmon JC, Grimm KA (eds). Blackwell Publishing, USA. pp. 241-272
413
Lemke KA (2007) Anticholinergics and sedatives. In: Lumb & Jones' Veterinary Anesthesia
414
and Analgesia (4th edn). Tranquilli WJ, Thurmon JC, Grimm KA (eds). Blackwell
415
Publishing, USA. pp. 203-240
416
Lorena SE, Luna SP, Lascelles BD, Corrente JE (2014) Current attitudes regarding the use of
417
perioperative analgesics in dogs and cats by Brazilian veterinarians. Vet Anaesth Analg 41,
418
82-89.
419
Magoha GA (1998) Local infiltration and spermatic cord block for inguinal, scrotal and
420
testicular surgery. East Afr Med J 75, 579-581.
421
Mason BJ, Newton JR, Payne RJ, Pilsworth RC (2005) Costs and complications of equine
422
castration: a UK practice-based study comparing 'standing nonsutured' and 'recumbent
423
sutured' techniques. Equine Vet J 37, 468-472.
424
McMillan MW, Seymour CJ, Brearley JC (2012) Effect of intratesticular lidocaine on
425
isoflurane requirements in dogs undergoing routine castration. J Small Anim Pract 53, 393-
426
397.
AC C
EP
TE D
M AN U
SC
RI PT
404
ACCEPTED MANUSCRIPT
Michelsen J, Heller J, Wills F, Noble GK (2012) Effect of surgeon experience on
428
postoperative plasma cortisol and C-reactive protein concentrations after ovariohysterectomy
429
in the dog: a randomised trial. Aust Vet J 90, 474-478.
430
Moldal ER, Eriksen T, Kirpensteijn J et al. (2013) Intratesticular and subcutaneous lidocaine
431
alters the intraoperative haemodynamic responses and heart rate variability in male cats
432
undergoing castration. Vet Anaesth Analg 40, 63-73.
433
Perez TE, Grubb TL, Greene SA et al. (2013) Effects of intratesticular injection of
434
bupivacaine and epidural administration of morphine in dogs undergoing castration. J Am
435
Vet Med Assoc 242, 631-642.
436
Pertovaara A, Hämäläinen MM, Kauppila T et al. (1994) Dissociation of the alpha 2-
437
adrenergic antinociception from sedation following microinjection of medetomidine into the
438
locus coeruleus in rats. Pain 57, 207-215.
439
Pypendop BH, Verstegen JP (1998) Hemodynamic effects of medetomidine in the dog: a
440
dose titration study. Vet Surg 27, 612-622.
441
Pypendop B, Verstegen J (1999) Cardiorespiratory effects of a combination of
442
medetomidine, midazolam, and butorphanol in dogs. Am J Vet Res 60, 1148-1154.
443
Roy TJ, Prieto L, Gil MC (2002) Testicular and epididymal weights in the domestic dog
444
(Canis familiaris). Vet Rec 150, 285.
445
Sakonju I, Maeda K, Maekawa R et al. (2009) Relative nerve blocking properties of
446
bupivacaine and ropivacaine in dogs undergoing brachial plexus block using a nerve
447
stimulator. J Vet Med Sci 71, 1279-1284.
AC C
EP
TE D
M AN U
SC
RI PT
427
ACCEPTED MANUSCRIPT
Sanday L, Zanin KA, Patti CL et al. (2012) Role of state-dependency in memory impairment
449
induced by acute administration of midazolam in mice. Prog Neuropsychopharmacol Biol
450
Psychiatry 37, 1-7.
451
Steffey EP, Mama KR (2007) Inhalation anesthetics. In: Lumb & Jones' Veterinary
452
Anesthesia and Analgesia (4th edn). Tranquilli WJ, Thurmon JC, Grimm KA (eds).
453
Blackwell Publishing, USA. pp. 355-394.
454
Stevens BJ, Posner LP, Jones CA, Lascelles BD (2013) Comparison of the effect of
455
intratesticular lidocaine/bupivacaine vs. saline placebo on pain scores and incision site
456
reactions in dogs undergoing routine castration. Vet J 196, 499-503.
457
University of Glasgow (2014) University of Glasgow website, SHORT FORM OF THE
458
GLASGOW COMPOSITE PAIN SCALE http://www.gla.ac.uk/media/media_61908_en.pdf
459
[accessed 4 Aug 2014].
460
Väha-Vähe T (1989) Clinical evaluation of medetomidine, a novel sedative and analgesic
461
drug for dogs and cats. Acta Vet Scand 30, 267-273.
462
Väisänen MA, Vainio OM, Raekallio MR et al. (2005) Results of 24-hour ambulatory
463
electrocardiography in dogs undergoing ovariohysterectomy following premedication with
464
medetomidine or acepromazine. J Am Vet Med Assoc 226, 738-745.
465
Verstegen J, Petcho A (1993) Medetomidine-butorphanol-midazolam for anaesthesia in dogs
466
and its reversal by atipamezole. Vet Rec 132, 353-357.
467
Vettorato E, Bacco S (2011) A comparison of the sedative and analgesic properties of
468
pethidine (meperidine) and butorphanol in dogs. J Small Anim Pract 52, 426-432.
469 470
AC C
EP
TE D
M AN U
SC
RI PT
448
ACCEPTED MANUSCRIPT
Appendix 1 Scoring sedation Score
Description No sedation
1
Mild sedation, animal still responsive to environmental stimuli
2
Moderate sedation, animal unresponsive to the majority of stimuli
3
Profound sedation, animal unresponsive to stimuli
RI PT
0
SC
472
M AN U
473 474
AC C
EP
TE D
475
ACCEPTED MANUSCRIPT
Table 1 Data of dogs administered medetomidine (0.01 mg kg-1) with butorphanol (0.2 mg kg-1)
477
and midazolam (0.2 mg kg-1) and intratesticular and incisional ropivacaine (0.2-0.4 mL kg-1
478
0.5%, group R, n = 11) or saline (group S, n = 11). Values are mean ± standard deviation for all
479
results except for age, which is presented as median and range due to lack of normal distribution. Group R
Group S
Age (months)
12 (7 - 24)
15 (6 - 36)
Weight (Kg)
23.4 ± 9.5
18.7 ± 9.0
0.247
Ropivacaine/saline volume
0.24 ± 0.07
0.24 ± 0.05
0.806
M AN U
SC
Parameter
administered locally (mL kg-1)
p-value
0.705
Preparation time (minutes)
37 ± 9
35 ± 10
0.688
Surgery time (minutes)
60 ± 19
55 ± 24
0.603
Total sedation time (minutes)
97 ± 21
90 ± 27
0.539
TE D
480
RI PT
476
Preparation time, time from medetomidine-butorphanol-midazolam administration to first
482
incision; Surgery time, time from first incision to last skin suture; Total sedation time, time from
483
medetomidine-butorphanol-midazolam administration to atipamezole administration.
485
AC C
484
EP
481
ACCEPTED MANUSCRIPT
Table 2 Administration of diazepam (0.5 mg kg-1) and propofol (0.4-1.1 mg kg-1) in response to
487
movement during orchiectomy in dogs administered medetomidine (0.01 mg kg-1) with
488
butorphanol (0.2 mg kg-1) and midazolam (0.2 mg kg-1) and intratesticular and incisional
489
ropivacaine (0.2-0.4 mL kg-1 0.5%, group R, n = 11) or saline (group S, n = 11). Times are
490
median (range).
Diazepam (number of dogs)
6 (54.5%)
Propofol (number of dogs) Time to diazepam administration (minutes)
(minutes) 491
8 (72.7%)
p-value
0.659
4 (36.4%)
6 (54.5%)
0.392
27 (4 - 42)*
6 (2 - 23)
0.021
56 (36 - 76)*
7 (3 - 25)
0.01
TE D
Time to propofol administration
Group S
SC
Group R
M AN U
Parameter
RI PT
486
Time to diazepam administration, time from skin incision to diazepam administration; Time to
493
propofol administration, time from skin incision to propofol administration. Dogs administered
494
propofol are also listed under diazepam.
495
*Significantly different from group S p < 0.05.
497 498
AC C
496
EP
492
ACCEPTED MANUSCRIPT
Table 3 Number of dogs administered methadone (0.3 mg kg-1 IV) for rescue analgesia in the
500
hours after orchiectomy. The dogs were sedated with medetomidine (0.01 mg kg-1) with
501
butorphanol (0.2 mg kg-1) and midazolam (0.2 mg kg-1) and intratesticular and incisional
502
ropivacaine (0.2-0.4 mL kg-1 0.5%, group R, n = 11) or saline (group S, n = 11) for the surgical
503
procedure.
RI PT
499
1
2
4
R
1
0
1
S
2
0
*This dog was also administered methadone at 1 hour.
AC C
EP
TE D
506 507
1*
number
8
24
0
0
2
0
4
M AN U
Group
504 505
Total
SC
Time (hours)
2
ACCEPTED MANUSCRIPT
508
Figure legends
509
Figure 1 Mean ± SD of interactive visual analogue scale (IVAS) scores of dogs before (baseline,
511
BL) and at 1, 2, 4, 8 and 24 hours after orchiectomy in dogs administered medetomidine (0.01
512
mg kg-1) with butorphanol (0.2 mg kg-1) and midazolam (0.2 mg kg-1) and intratesticular and
513
incisional ropivacaine (0.2-0.4 mL kg-1, 0.5%, group R, n = 11) or saline (group S, n = 12). Dogs
514
were excluded from analysis after administration of methadone for rescue analgesia. In group R
515
at BL and 1 hour (n = 11), at 2 and 4 hours (n = 10) and at 8 and 24 hours (n = 9). In group S at
516
BL and 1 hour (n = 12), at 2, 4 and 8 hours (n = 10) and at 24 hours (n = 8).
M AN U
SC
RI PT
510
517 518
*Significant difference between groups (p < 0.05). †Significantly different from BL (p < 0.05).
519
TE D
520
Figure 2 Mean ± SD of Glasgow short form composite measure pain scale (CMPS-SF) scores of
522
dogs before (baseline, BL) and at 1, 2, 4, 8 and 24 hours after orchiectomy in dogs administered
523
medetomidine (0.01 mg kg-1) with butorphanol (0.2 mg kg-1) and midazolam (0.2 mg kg-1) and
524
intratesticular and incisional ropivacaine (0.2-0.4 mL kg-1, 0.5%, group R, n = 11) or saline
525
(group S, n = 12). Dogs were excluded from analysis after administration of methadone for
526
rescue analgesia. In group R at BL and 1 hour (n = 11), at 2 and 4 hours (n = 10) and at 8 and 24
527
hours (n = 9). In group S at BL and 1 hour (n = 12), at 2, 4 and 8 hours (n = 10) and at 24 hours
528
(n = 8).
AC C
EP
521
529 530 531
† Significantly different from baseline value p < 0.05.
ACCEPTED MANUSCRIPT
Figure 3 Mean ± SD of mechanical algometer values (newton) of dogs before (baseline, BL) and
533
at 1, 2, 4, 8 and 24 hours after orchiectomy in dogs administered medetomidine (0.01 mg kg-1)
534
with butorphanol (0.2 mg kg-1) and midazolam (0.2 mg kg-1) and intratesticular and incisional
535
ropivacaine (0.2-0.4 mL kg-1, 0.5%, group R, n = 11) or saline (group S, n = 12). Dogs were
536
excluded from analysis after administration of methadone for rescue analgesia. In group R at BL
537
and 1 hour (n = 11), at 2 and 4 hours (n = 10) and at 8 and 24 hours (n = 9). In group S at BL and
538
1 hour (n = 12), at 2, 4 and 8 hours (n = 10) and at 24 hours (n = 8).
† Significantly different from baseline value p < 0.05.
M AN U
540
SC
539
RI PT
532
AC C
EP
TE D
541
ACCEPTED MANUSCRIPT
100 90
RI PT
Group R
80
Group S
60 50
†
†
†
40
†
10 0 1
2
4
TE D
Time (hours)
EP
†
†
M AN U
20
BL
†
†
†
30
SC
*
AC C
IVAS (mm)
70
8
†
24
ACCEPTED MANUSCRIPT
24 20
RI PT
Group R
12
†
†
†
SC
8
0 BL
1
2
M AN U
4
EP
TE D
Time (hours)
AC C
CMPS-SF score
Group S 16
4
8
24
ACCEPTED MANUSCRIPT
Group R
16
Group S
RI PT
18
14 12
† †
†
SC
10
6 4 2 0 BL
1
2
M AN U
8
4
EP
TE D
Time (hours)
AC C
Algometer pressure (N)
20
8
24
S1467-2987(17)30039-9
DOI:
10.1016/j.vaa.2016.03.007
Reference:
VAA 65
To appear in:
Veterinary Anaesthesia and Analgesia
Received Date: 4 January 2016 Revised Date:
22 February 2016
Accepted Date: 6 March 2016
Please cite this article as: Kushnir Y, Toledano N, Cohen L, Bdolah-Abram T, Shilo-Benjamini Y, Intratesticular and incisional line infiltration with ropivacaine for castration in medetomidinebutorphanol-midazolam sedated dogs, Veterinary Anaesthesia and Analgesia (2017), doi: 10.1016/ j.vaa.2016.03.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
RESEARCH PAPER
2
Y Kushnir et al.
3
Intratesticular block in sedated dogs
4
Intratesticular and incisional line infiltration with ropivacaine for castration in
5
medetomidine-butorphanol-midazolam sedated dogs
6
Yishai Kushnir*, Noa Toledano*, Liat Cohen*, Tali Bdolah-Abram† & Yael Shilo-Benjamini*
7
*Koret School of Veterinary Medicine, The Robert H. Smith Faculty of Agriculture, Food and
8
Environment, The Hebrew University of Jerusalem, Israel
9
†Hadassah Medical School, The Hebrew University of Jerusalem, Israel
M AN U
SC
RI PT
1
10
Correspondence: Yishai Kushnir, Koret School of Veterinary Medicine, The Robert H. Smith
12
Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, P.O. Box
13
12, Rehovot 7610001 Israel. E-mail: [email protected]
14
TE D
11
Abstract
16
Objectives To evaluate whether intratesticular and incisional ropivacaine infiltration produces
17
sufficient intra- and postoperative analgesia for castrating dogs under sedation.
18
Study design Randomized, blinded, controlled, clinical study.
19
Animals Twenty-three healthy dogs weighing 5.8-35.6 kg admitted for castration.
20
Methods Dogs were sedated with medetomidine (0.01 mg kg-1), butorphanol (0.2 mg kg-1), and
21
midazolam (0.2 mg kg-1) intramuscularly, and were randomly assigned to 0.2-0.4 mL kg-1 of
22
ropivacaine 0.5% (group R) or an equivalent volume of saline (group S) injected intratesticularly
23
and along the incision line. If persistent motion was observed during surgery, sedation was
AC C
EP
15
ACCEPTED MANUSCRIPT
considered to be insufficient and general anaesthesia was induced. Carprofen 2.2 mg kg-1 was
25
administered postoperatively. Pain was evaluated in all dogs before sedation and postoperatively
26
following atipamezole administration at 1, 2, 4, 8 and 24 hours using an interactive visual
27
analogue scale (IVAS; 0-100), the Glasgow composite pain scale (CMPS-SF; 0-24), and a
28
mechanical algometer. Methadone 0.3 mg kg-1 IV was administered to dogs if IVAS > 30 or
29
CMPS-SF > 4.
30
Results There was no significant difference between groups for the number of dogs administered
31
general anaesthesia. The time from the beginning of surgery to induction of general anaesthesia
32
was significantly shorter [median (range)] in S [6 (3-25) minutes] than in R [56 (36-76) minutes].
33
At 8 hours IVAS was significantly higher in S (14 ± 10) than in R (6 ± 4).
34
Conclusions and clinical relevance Intratesticular and incisional ropivacaine infiltration
35
delayed the time to anaesthesia induction, and provided analgesia after castration performed
36
under deep sedation in dogs. Intratesticular local anaesthesia can be an important part of the
37
anaesthetic plan for castration.
SC
M AN U
TE D
Keywords castration, dogs, intratesticular block, local anaesthesia, sedation.
EP
39
AC C
38
RI PT
24
ACCEPTED MANUSCRIPT
Introduction
41
Orchiectomy is a common procedure in veterinary practice, and may constitute 20% of the
42
surgical caseload in a small animal practice (Dyson et al. 1998). Castration is considered a
43
painful procedure by practicing veterinarians (Lorena et al. 2014), and many studies have been
44
performed to identify techniques that will decrease perioperative pain (Kongara et al. 2012;
45
McMillan et al. 2012; Huuskonen et al. 2013; Perez et al. 2013; Stevens et al. 2013).
Local anaesthesia is an effective way to achieve analgesia with minimal systemic side effects
SC
46
RI PT
40
while decreasing anaesthetic requirement (McMillan et al. 2012) and the perioperative stress
48
response (Perez et al. 2013). Local anaesthesia has been employed during surgical castration in
49
many species (Magoha 1998; Earley & Crowe 2002; Moldal et al. 2013) including the dog
50
(Huuskonen et al. 2013; Perez et al. 2013; Stevens et al. 2013).
51
M AN U
47
In humans, ruminants and horses orchidectomy may be performed under a local anaesthetic technique, with or without sedation, avoiding use of general anaesthesia, thus decreasing cost
53
and reducing complications (Magoha 1998; Earley & Crowe 2002; Mason et al. 2005).
54
Medetomidine is a sedative commonly used in small animals that induces profound sedation,
55
recumbency and analgesia (Girard et al. 2010). The addition of butorphanol and midazolam
56
increases sedation and prolongs the sedative effects (Pypendop & Verstegen 1999; Girard et al.
57
2010).
EP
AC C
58
TE D
52
Recently published studies examining the effectiveness of intratesticular local anaesthesia on
59
perioperative pain in dogs had inconclusive results (McMillan et al. 2012; Huuskonen et al.
60
2013; Perez et al. 2013; Stevens et al. 2013). Sedation is defined as a state from which the patient
61
can be aroused with a noxious stimulus (American Society of Anesthesiologists 2005).
62
Therefore, performing castration under sedation should not be possible unless local anaesthesia
ACCEPTED MANUSCRIPT
63
provides sufficient analgesia. Thus, the goal of this study was to evaluate whether intratesticular
64
and incisional ropivacaine infiltration produces sufficient intra- and postoperative analgesia for
65
surgical castration of sedated dogs. Our hypothesis was that administration of local anaesthesia would provide sufficient
67
analgesia to perform castration without the need for general anaesthesia, and provide superior
68
postoperative analgesia when compared with a saline placebo.
SC
69
RI PT
66
Materials and methods
71
Dogs admitted to Koret School of Veterinary Medicine, Veterinary Teaching Hospital for
72
elective castration were eligible for inclusion in the study. The dogs were assessed as healthy
73
[American Society of Anesthesiologists (ASA) class I-II] based on history, physical examination
74
and complete blood count. Dogs undergoing other surgery (e.g., for brachiocephalic syndrome),
75
or castration for a medical disorder (e.g. prostatic hyperplasia) were excluded from the study.
76
The study was approved by the Internal Ethics Review Committee of the Koret School of
77
Veterinary Medicine, The Hebrew University, and written informed owner consent was obtained
78
prior to inclusion.
TE D
EP
79
M AN U
70
Before beginning the study, dogs were randomly assigned using an online randomizing software, www.random.org/lists/ , to group R that were administered an intratesticular and
81
incisional line block with ropivacaine, or to group S that were administered saline. Dogs were
82
sedated with medetomidine (0.01 mg kg-1; Domitor; Orion Pharma, Finland), butorphanol (0.2
83
mg kg-1; Morphasol; aniMedica GmbH, Ireland), and midazolam (0.2 mg kg-1; Midolam; Rafa,
84
Israel), mixed in the same syringe and injected intramuscularly (IM) into the epaxial muscles. As
85
soon as the dogs were heavily sedated (not responsive to loud stimulation, ear flick reflex, and
AC C
80
ACCEPTED MANUSCRIPT
moving the dog to a gurney), a 22-18 gauge, 2.5-4.8 cm catheter was inserted into a cephalic
87
vein appropriate to the dog’s size, and lactated Ringer’s solution (Teva Medical, Israel) was
88
administered intravenously (IV) at 5 mL kg-1 hour-1. Dogs that were not sufficiently sedated after
89
15 minutes, and moved in response to stimulus, were administered additional medetomidine
90
(0.005-0.01 mg kg-1). The dogs were placed in dorsal recumbency and oxygen 5 L minute-1 was
91
administered through a facemask using a rebreathing circuit for dogs >7 kg or a Mapleson D
92
non-rebreathing circuit for dogs weighing ≤7 kg. After clipping and aseptic preparation of the
93
surgical site, dogs in R were administered ropivacaine (1-2 mg kg-1; Naropin, 1%; AstraZeneca,
94
Sweden diluted 1:1 with saline 0.9%). Using a 25 gauge, 16 mm needle one-third of the dose was
95
injected into the center of each testicle from the ventral aspect, and one-third was injected
96
subcutaneously along the prescrotal midline. Dogs weighing < 7.5, 7.5-15 or > 15 kg were
97
administered 2.0, 1.5 or 1.0 mg kg-1 (0.4, 0.3 or 0.2 mL kg-1), respectively, of ropivacaine. Saline
98
volumes for dogs in S were calculated and administered in the same way as for R. All injections
99
were performed by the same anaesthetist (YK) who was blinded as to the injectate used.
SC
M AN U
TE D
100
RI PT
86
Veterinary students in their final year of training performed the castrations under the supervision of a surgeon or surgery resident. Dogs were monitored for heart rate (HR),
102
respiratory rate (fR), rectal temperature (RT), lead II electrocardiogram (ECG) and noninvasive
103
blood pressures (NIBP) using a Doppler technique (811-BTS; Parks Medical Electronics, OR,
104
USA) and oscillometry (Cardell 9601; Midmark Corp., OH, USA). A circulating-water heating
105
blanket (T/Pump; Gaymar Industries Inc., NY, USA) and a forced-air warming device
106
(Thermacare; Gaymar Industries Inc.) were applied to minimize heat loss. Hypotension, defined
107
as systolic arterial pressure (SAP) < 100 mmHg, was to be treated by administration of atropine
108
(0.01 mg kg-1 IV and 0.02 mg kg-1 IM; Atropine sulphate; Teva Pharmaceutical Industries Ltd,
AC C
EP
101
ACCEPTED MANUSCRIPT
Hungary) when HR < 80 beats minute-1, or by an infusion of dopamine (0.005-0.01 mg kg-1
110
minute-1; Dopamine HCl-Fresenius; Bodene Ltd, South Africa) when HR ≥ 80 beats minute-1.
111
When gross movement of the head or a limb was observed during the surgical procedure,
112
diazepam (0.5 mg kg-1; Assival; Teva Pharmaceutical Industries Ltd) was to be administered IV.
113
If motion was observed again, propofol (0.4-1.1 mg kg-1; Lipuro 1%; B. Braun Melsungen AG,
114
Germany) was administered to accomplish endotracheal intubation in dorsal recumbency and
115
anaesthesia was maintained by administration of isoflurane (Terrell Isoflurane USP; Piramal
116
Critical Care Inc., PA, USA) in oxygen. The time of propofol administration and the stage of the
117
surgical procedure were recorded.
M AN U
SC
RI PT
109
At the completion of surgery, carprofen (2 mg kg-1; Norocarp; Norbrook Laboratories,
119
Northern Ireland) was administered subcutaneously, and atipamezole (0.025-0.07 mg kg-1;
120
Antisedan; Orion Pharma) IM. The dose of atipamezole was based on the dose of medetomidine
121
administered and the time elapsed from administration. Carprofen was administered again at 12
122
and 24 hours. Monitoring and all decisions during the procedure were performed for all dogs by
123
a single anaesthetist (YK) blinded to the group.
Recorded times were the time from initial administration of sedative drugs to the first
EP
124
TE D
118
incision (preparation time), time from first incision to the last skin suture (surgery time), time
126
from incision to diazepam administration (time to diazepam administration), time from incision
127
to propofol administration (time to propofol administration) and time from initial administration
128
of sedatives to atipamezole administration (total sedation time).
AC C
125
129
Postoperative pain was assessed using an interactive visual analogue scale (IVAS), the
130
University of Glasgow Short Form (CMPS-SF) and an algometer before sedation to provide a
131
baseline and at 1, 2, 4, 8, and 24 hours after atipamezole administration. The IVAS was graded
ACCEPTED MANUSCRIPT
on a 100 mm strip, where 0 was non-painful and 100 was extremely painful, by observation of
133
the dog in a cage followed by interaction. The CMPS-SF (University of Glasgow 2014) was
134
scored from 0 (non-painful) to 24 (extremely painful) using 6 parameters (Kongara et al. 2012).
135
Both tests were performed simultaneously, but independently, by two assessors, that were
136
unaware of the treatment administered (YK, NT). Dogs were first observed for scoring of both
137
tests and followed by interaction required for the CMPS-SF and the IVAS. The average of the
138
score given by each examiner was used for statistical analysis, and correlation between
139
examiners was assessed. Sensitivity to pressure was measured at the surgical site by both
140
examiners together (YK, NT) using an algometer (ProdPlus; Topcat Metrology, UK). A 4 mm
141
probe was applied approximately 1 cm lateral to the incision line, with increasing pressure.
142
When responses to the pressure were observed, i.e., turning towards the incision, moving the
143
pelvic limbs, vocalizing, or aggression, the probe was removed immediately and the pressure
144
applied was recorded. This test was repeated in triplicate and the average score was used. A
145
maximal safety cut-off for mechanical nociception was not predetermined in this study.
TE D
M AN U
SC
RI PT
132
Methadone (0.3 mg kg-1; Methadone injection BP 1%; Martindale Pharmaceuticals, UK) was
147
to be administered IV as rescue analgesia if the IVAS was > 30 mm or the CMPS-SF was > 4. In
148
addition, the institution nursing staff observed the dogs continuously, and if animals appeared
149
painful between evaluation points, the investigators were contacted to re-evaluate pain and
150
administer rescue medication when necessary. Pain scores from animals that were administered
151
rescue analgesia were recorded at later points but these were excluded from statistical analysis.
AC C
152
EP
146
Sedation was scored concurrently with a 4 point simple descriptive scale (SDS; Appendix 1)
153
(Pypendop & Verstegen 1998) in order to rule out sedation as a confounding element in pain
154
evaluation.
ACCEPTED MANUSCRIPT
155
Statistical analysis
157
A sample size calculation was performed based on a pilot study in which none of the dogs in R
158
required general anaesthesia. However due to several studies claiming a failure rate of
159
approximately 20% in local anaesthetic techniques, it was assumed that up to 20% of the dogs in
160
R, and at least 80% in S would be administered general anaesthesia. Using a significance of p <
161
0.05 and a power of π = 0.80, revealed that at least eight dogs were required in each group.
SC
162
RI PT
156
Normality was evaluated using the Kolmogorov-Smirnov test, and normally distributed variables were compared between groups using the student’s t-test. The Mann-Whitney U test
164
was used for variables that were not normally distributed, or had small sample sizes. For binary
165
parameters the Pearson Chi-squared test or Fischer’s exact test were used based on sample size.
166
Bonferroni correction for repeated measures was applied for comparisons of pain scores at the
167
different time points to baseline scores. Need for rescue analgesia was evaluated using a Kaplan-
168
Meier survival curve, significance was established with Fischer’s exact test. Significance was set
169
at p < 0.05.
EP
170
TE D
M AN U
163
Results
172
Twenty-three dogs were included in the study, 11 dogs in R and 12 dogs in S. No significant
173
difference was found between the groups regarding age, weight, volume administered locally or
174
the time periods (Table 1). Two dogs in S required one additional dose of medetomidine, and
175
two other dogs were administered a third dose. Two dogs in R required one additional dose of
176
medetomidine. There were no significant differences between groups for the number of
177
medetomidine doses, total medetomidine dose or atipamezole dose.
AC C
171
ACCEPTED MANUSCRIPT
One dog in S was administered 3 doses of medetomidine, and moved on the surgery table before
179
the incision and was anaesthetized. This dog was hypotensive (the only one in the study) with a
180
SAP 89 mmHg and was administered atropine 35 minutes after propofol administration. Since
181
motion was observed despite lack of surgical stimulus, intraoperative data from this dog were
182
excluded from analyses, but postoperative assessments were included. None of the dogs required
183
dopamine administration. In one dog in R, the typical sensation of the testicle becoming larger
184
and firmer during injection of ropivacaine was not felt, possibly indicating a technical failure.
185
This dog moved 4 minutes after skin incision and diazepam was administered, and no further
186
motion was observed throughout surgery.
SC
M AN U
187
RI PT
178
The number of dogs administered diazepam or propofol was not significantly different between the groups (Table 2). However, the median time to diazepam administration was
189
significantly longer in R compared with S (p = 0.021). Time to propofol administration was also
190
significantly longer in R than in S (p = 0.01) (Table 2). The interval between diazepam and
191
propofol administrations in four dogs in R was 33 (1-54) minutes and in six dogs in S was 4 (1-
192
10) minutes. Dogs in S administered propofol were significantly smaller [9.5 (6.0-22.0) kg] than
193
dogs that were not administered propofol [24.5 (22.5–33.4) kg] (p = 0.003). This effect was not
194
significant in R [13.5 (6.4-31.5) kg and 28.0 (19.5–35.6) kg, respectively] (p = 0.109).
EP
Sedation scores did not differ significantly between groups at any time point. A significant
AC C
195
TE D
188
196
increase in postoperative pain scores compared with baseline was observed for IVAS at all time
197
points for both groups (p < 0.05; Fig. 1). Scores were significantly lower in R than in S at 8
198
hours (6 ± 4 mm and 14 ± 10, respectively) (p = 0.05). The CMPS-SF score increased
199
significantly in R only in the first hour (p = 0.02), and in S at one and two hours post-surgery
200
(both p = 0.02) (Fig. 2). Dogs were more sensitive to the algometer compared with baseline at
ACCEPTED MANUSCRIPT
one hour post-surgery in both groups (in R p = 0.04, in S p = 0.03), but at two hours only in S (p
202
= 0.04) (Fig. 3). No significant differences were found between the groups for CMPS-SF or
203
algometer values. A force over 20 N was applied with the algometer in one dog in S which did
204
not respond to a pressure of 30 N during the 3 baseline measurements, and in one dog in R which
205
responded at 23 N.
206
RI PT
201
Correlations between the two examiners were very good for both IVAS (R = 0.727) and CMPS-SF (R = 0.799). Correlations between IVAS and CMPS-SF were good (R = 0.596),
208
however correlations between algometer readings and IVAS (R = -0.444) and CMPS-SF (R = -
209
0.136) were weak.
M AN U
210
SC
207
Rescue analgesia was administered to two out of 11 (18.2%) dogs in R and to four out of 12
211
(33.3%) dogs in S. One dog in S (8.3%) was administered rescue analgesia twice (Table 3). No
212
significant difference was found between groups regarding rescue medication.
TE D
213
Discussion
215
The main finding of this study is that intratesticular and incisional line block with ropivacaine
216
delayed the need for general anaesthesia by 7-56 minutes after incision. This finding is in
217
agreement with studies showing that local anaesthesia decreases intraoperative anaesthetic
218
requirements (McMillan et al. 2012; Perez et al. 2013).
AC C
EP
214
219
In five of 11 dogs in group S, sedation with medetomidine-butorphanol-midazolam was
220
sufficient for performing castration, even without local anaesthesia. Dogs from group S that did
221
not require general anaesthesia were significantly larger (median 24.5 kg) than those that did
222
(9.5 kg). Medetomidine should preferably be dosed on a mg m-2 basis (Pypendop & Verstegen
223
1999), however, in the present study, medetomidine was dosed by mg kg-1. This may have led to
ACCEPTED MANUSCRIPT
a relatively higher dose and produced anaesthesia in the larger dogs in comparison with the
225
smaller ones. The ASA definition of general anaesthesia is “a drug-induced loss of consciousness
226
during which patients are not arousable, even by painful stimulation…” whereas deep sedation is
227
defined as “a drug-induced depression of consciousness during which patients cannot be easily
228
aroused but respond purposefully following repeated or painful stimulation…” (American
229
Society of Anesthesiologists 2005). The combination of medetomidine-butorphanol-midazolam
230
was administered in this study to provide deep sedation, however, at high doses medetomidine
231
may produce anaesthesia sufficient for minor procedures (Väha-Vähe 1989), as observed in the
232
five dogs that did not respond to the surgical stimulus.
SC
M AN U
233
RI PT
224
Medetomidine, butorphanol, and midazolam were administered IM to enable IV access since most of the dogs in the study were excited and difficult to restrain. This mode of administration
235
when compared with IV administration is considered safer and avoids sudden onset of
236
cardiovascular effects, however, it is slower and more variable and may have added variation to
237
the results.
TE D
234
The volume of ropivacaine administered to larger dogs was relatively smaller than the
239
volume administered to smaller dogs. This was based on studies that showed poor correlation
240
between body weight and testicular size, and that a 10-fold increase in body weight correlated
241
with a 5-fold increase in testicular size (Eilts et al. 1993: Roy et al. 2002).
AC C
242
EP
238
Publication of orchiectomy in dogs under sedation and local anaesthesia was not found,
243
although this technique has been published for other species (Magoha 1998; Earley & Crowe
244
2002; Mason et al. 2005). Approval of the ethical committee, and informed owner consent were
245
acquired, however, an ethical dilemma was raised regarding performing surgery on sedated dogs
246
that were not administered local anaesthesia. To accommodate this concern and decrease the
247
nociception perceived by dogs in group S, analgesia and amnesia similar to those usually provided for
ACCEPTED MANUSCRIPT
castration under general anaesthesia were administered, the animals were monitored closely and
249
additional sedation and anaesthesia were administered immediately when required. Although general
250
anaesthesia blunts the motor response to nociception, it is accepted that propofol has no
251
analgesic properties and that the analgesia provided by inhalants is minimal (Branson 2007;
252
Steffey & Mama 2007). Medetomidine and butorphanol were included in the sedation protocol
253
for dogs in this study based on current literature, in which butorphanol, medetomidine, or both,
254
were the analgesic drugs administered to dogs before surgery for castration or
255
ovariohysterectomy (Väisänen et al. 2005; Barletta et al. 2011; Vettorato & Bacco 2011;
256
Gutierrez-Blanco et al. 2015). Morphine or hydromorphone could have provided better
257
analgesia, but their sedative and analgesic effects are prolonged and could have resulted in
258
confounding the postsurgical pain assessment. This was a stated limitation in the study by
259
Stevens et al. (2013). Butorphanol was chosen because it has a short duration of action of
260
approximately 2 hours (Lamont & Mathews 2007). Carprofen was administered immediately
261
after surgery to decrease inflammatory pain. Carprofen has been used for analgesia when
262
neutering dogs at the dose used in this study (Kum et al. 2000) and when administered at 4.4 mg
263
kg-1 once daily was reported to provide analgesia equivalent to that of morphine (Dzikiti et al.
264
2006). Midazolam has been shown to cause amnesia in several species, which decreases the
265
degree of postoperative discomfort perceived by the patient (Sanday et al. 2012; Giachero et al.
266
2015; Hong et al. 2015). . The inclusion of butorphanol, midazolam and carprofen may have led
267
to a reduction in the power of this study, and the effect observed for local anaesthesia, however,
268
we considered them necessary to avoid possible suffering. Although castration was performed in
269
some dogs under sedation without local anaesthesia, this technique should not be considered
270
acceptable in clinical practice if performed without the strict guidelines stipulated in this study
271
design.
AC C
EP
TE D
M AN U
SC
RI PT
248
ACCEPTED MANUSCRIPT
272
Atipamezole was administered at the end of surgery to reverse the sedation and other side effects from medetomidine, however, analgesia would also have been reversed (Pertovaara et al.
274
1994; Granholm et al. 2007). The duration of analgesia provided by IM medetomidine is
275
reported as approximately 2 hours (Lemke 2007) and would have been waning in most dogs at
276
the time of atipamezole administration. To ensure analgesia following medetomidine reversal,
277
carprofen was administered concurrently. In a clinical setting the advantages of atipamezole
278
should be weighed carefully against its disadvantages.
SC
279
RI PT
273
Previous studies found conflicting results regarding the efficacy of local anaesthesia for decreasing postoperative pain after castration. Perez et al. (2013) found decreased pain scores
281
and intra- and postoperative analgesia requirements after intratesticular or epidural anaesthesia
282
compared with a placebo, as well as decreased serum cortisol concentration in the intratesticular
283
anaesthesia group. Conversely, two studies found no benefit of intratesticular injection of local
284
anaesthetic for postoperative pain, although there was a decrease in the incidence of a cremaster
285
muscle twitch (Stevens et al. 2013), and less increase in HR and mean arterial pressure in
286
response to surgery (Huuskonen et al. 2013). The variation in results may be explained by
287
different anaesthetic techniques, or the result of inconsistencies among scoring methods for
288
assessing pain. Three pain scores were used in this study to optimize pain recognition. While
289
IVAS and CMPS-SF assess the subjective pain experience of the animal, the algometer is an
290
objective measurement of surgical site nociception and hyperalgesia (Hunt et al. 2013). The
291
poor correlation observed between the algometer and both CMPS-SF and IVAS indicates that
292
these tests measure different aspects of pain and are not interchangeable.
293 294
AC C
EP
TE D
M AN U
280
Ropivacaine onset time is approximately 15 minutes, and the duration of sensory block is expected to last approximately 6 hours (Sakonju et al. 2009). At 8 hours after surgery the effect
ACCEPTED MANUSCRIPT
of the local anaesthetic should have worn off, and yet a significant difference in IVAS scores
296
between groups was evident at this time point, and two dogs in group S required rescue
297
analgesia. This may indicate an antihyperalgesic effect that is achieved by preventing
298
intraoperative pain with ropivacaine. However, administration of ropivacaine did not abolish
299
pain postoperatively because the IVAS scores were elevated in the first 8 hours. Inflammatory
300
mediators may be elevated after surgery and may increase pain sensation. The cytokine IL-1β
301
causes mechanical allodynia that is not attenuated by local anaesthetics (Kim et al. 2014).
302
Carprofen may attenuate, but does not completely block, this inflammatory response (Kum et al.
303
2000). Despite carprofen administration, IVAS scores remained higher than baseline at 24 hours,
304
indicating that analgesia after castration should be provided for at least 24 hours.
SC
M AN U
305
RI PT
295
There was no significant difference between the groups in the number of dogs administered rescue analgesia. The score for CMPS-SF that in our opinion identified a dog requiring rescue
307
analgesia was lower than commonly used in published studies (Kongara et al. 2012). Had the
308
present study used a score of 6 as the limit, only one dog would not have been administered
309
rescue analgesia.
Saline administration constituted the control group and facilitated blinding of the evaluators
EP
310
TE D
306
and surgeons (Stevens et al. 2013). The increased intratesticular volume may cause pain that may
312
have affected our findings. However, the increase in volume was similar in both groups and none
313
of the dogs were observed to move in response to the injection. Furthermore, ropivacaine comes
314
in an acidic solution (pH of 4.0-6.0), and thus it may cause more pain on injection. Despite the
315
possibility of affecting variation in the study it was deemed necessary to use a saline control
316
group to maintain a blinded study design.
AC C
311
ACCEPTED MANUSCRIPT
Administration of atropine with an α2-agonist is controversial, as it may aggravate
318
bradycardia or cause tachycardia, accompanied by ventricular arrhythmias (Lemke 2007).
319
Regular use of atropine with medetomidine is not advocated, and administration is avoided in the
320
presence of hypertension. However, atropine was administered to one dog in this study to correct
321
bradycardia and hypotension during inhalation anaesthesia.
322
RI PT
317
Surgery times in this study were exceptionally long (up to 112 minutes) for a canine castration. Sedation from medetomidine-butorphanol-midazolam is expected to last
324
approximately 80 minutes (Verstegen & Petcho 1993), thus sedation was probably minimal in
325
some of the dogs. This likely contributed to the lack of difference between the groups in the
326
number of dogs requiring general anaesthesia because movement may be a response to
327
nociception or increasing awareness of dorsal recumbency or the surroundings. Diazepam, a mild
328
sedative in dogs with no analgesic properties, may prolong the sedation but should not be
329
efficient for dogs in pain. Diazepam was administered in this study initially to deepen sedation,
330
further movement was an indication to induce anaesthesia. An experienced surgeon will
331
complete the surgery in a much shorter time, removing the need for additional sedation. The
332
times for preparation of the surgical site were not different between the groups but were
333
prolonged. The delay in commencing surgery may have had an impact on the requirement for
334
general anaesthesia except that the preparation times were not different in dogs that were
335
anaesthetized compared with those who were not.
M AN U
TE D
EP
AC C
336
SC
323
Study limitations include the small sample size, the use of mg kg-1 basis rather than body
337
surface area for calculation of sedative drug doses, administration of carprofen and rescue
338
analgesia that may have masked the effect of ropivacaine, and that with the exception of
339
ropivacaine injection all procedures were performed by inexperienced veterinary students. The
ACCEPTED MANUSCRIPT
340
inexperience of the surgeons may also have been a factor that increased tissue trauma (Michelsen
341
et al. 2012) and variability of pain expressed by the dogs.
342
In conclusion, IM administration of medetomidine (0.01 mg kg-1), butorphanol (0.2 mg kg-1) and midazolam (0.2 mg kg-1) with subcutaneous prescrotal infiltration and intratesticular
344
injection of 0.5% ropivacaine provided satisfactory conditions for castration in seven out of 11
345
dogs [additional diazepam (0.5 mg kg-1) was administered to two of these dogs]. The remaining
346
four dogs required administration of diazepam and general anaesthesia for completion of the
347
surgery; however, the propofol was not necessary for 56 (36-76) minutes [median (range)]. More
348
than half of the control dogs required general anaesthesia, indicating that the inclusion of
349
ropivacaine in the protocol for castration provided significant analgesia, and may decrease
350
postoperative pain.
M AN U
SC
RI PT
343
351
Authors’ contributions
353
YK: conception and study design, data acquisition, data interpretation and analysis, manuscript
354
preparation and revision. NT: study design, data acquisition, data interpretation and analysis,
355
manuscript revision. LC: data acquisition, manuscript revision. TB-A: study design, data
356
interpretation and analysis, manuscript revision. YS-B: conception, study design, data
357
acquisition, data interpretation, manuscript preparation and revision. All authors approved the
358
final manuscript.
360
EP
AC C
359
TE D
352
ACCEPTED MANUSCRIPT
361
References American Society of Anesthesiologists (2005) Guidelines for ambulatory anesthesia and
363
surgery. http://www.asahq.org/quality-and-practice-management/standards-and-
364
guidelines/search=general+anesthesia+definition [Accessed December 4, 2015].
365
Barletta M, Austin BR, Ko JC et al. (2011) Evaluation of dexmedetomidine and ketamine in
366
combination with opioids as injectable anesthesia for castration in dogs. J Am Vet Med
367
Assoc 238, 1159-1167.
368
Branson KR (2007) Injectable and alternative anesthetic techniques. In: Lumb & Jones'
369
Veterinary Anesthesia and Analgesia (4th edn). Tranquilli WJ, Thurmon JC, Grimm KA
370
(eds). Blackwell Publishing, USA. pp. 273-300
371
Dyson DH, Maxie MG, Schnurr D (1998) Morbidity and mortality associated with anesthetic
372
management in small animal veterinary practice in Ontario. J Am Anim Hosp Assoc 34, 325-
373
335.
374
Dzikiti TB, Joubert KE, Venter LJ et al. (2006) Comparison of morphine and carprofen
375
administered alone or in combination for analgesia in dogs undergoing ovariohysterectomy. J
376
S Afr Vet Assoc 77, 120-126.
377
Earley B, Crowe MA (2002) Effects of ketoprofen alone or in combination with local
378
anesthesia during the castration of bull calves on plasma cortisol, immunological, and
379
inflammatory responses. J Anim Sci 80, 1044-1052.
380
Eilts BE, Williams DB, Moser EB (1993) Ultrasonic measurement of canine testes.
381
Theriogenology 40, 819-828.
AC C
EP
TE D
M AN U
SC
RI PT
362
ACCEPTED MANUSCRIPT
Giachero M, Calfa GD, Molina VA (2015) Hippocampal dendritic spines remodeling and
383
fear memory are modulated by GABAergic signaling within the basolateral amygdala
384
complex. Hippocampus 25, 545–555.
385
Girard NM, Leece EA, Cardwell J et al. (2010) The sedative effects of low-dose
386
medetomidine and butorphanol alone and in combination intravenously in dogs. Vet Anaesth
387
Analg 37, 1-6.
388
Granholm M, McKusick BC, Westerholm FC, Aspergrén JC (2007) Evaluation of the
389
clinical efficacy and safety of intramuscular and intravenous doses of dexmedetomidine and
390
medetomidine in dogs and their reversal with atipamezole. Vet Rec 160, 891-897.
391
Gutierrez-Blanco E, Victoria-Mora JM, Ibancovichi-Camarillo JA et al. (2015) Postoperative
392
analgesic effects of either a constant rate infusion of fentanyl, lidocaine, ketamine,
393
dexmedetomidine, or the combination lidocaine-ketamine-dexmedetomidine after
394
ovariohysterectomy in dogs. Vet Anaesth Analg 42, 309-318.
395
Hong YJ, Jang EH, Hwang J et al. (2015) Effect of midazolam on memory during fiberoptic
396
gastroscopy under conscious sedation. Clin Neuropharmacol 38, 47-51.
397
Hunt JR, Grint NJ, Taylor PM, Murrell JC (2013) Sedative and analgesic effects of
398
buprenorphine, combined with either acepromazine or dexmedetomidine, for premedication
399
prior to elective surgery in cats and dogs. Vet Anaesth Analg 40, 297-307.
400
Huuskonen V, Hughes JM, Estaca Bañon E, West E (2013) Intratesticular lidocaine reduces
401
the response to surgical castration in dogs. Vet Anaesth Analg 40, 74-82.
402
Kim MJ, Lee SY, Yang KY et al. (2014) Differential regulation of peripheral IL-1β-induced
403
mechanical allodynia and thermal hyperalgesia in rats. Pain 155, 723-732.
AC C
EP
TE D
M AN U
SC
RI PT
382
ACCEPTED MANUSCRIPT
Kongara K, Chambers JP, Johnson CB (2012) Effects of tramadol, morphine or their
405
combination in dogs undergoing ovariohysterectomy on peri-operative
406
electroencephalographic responses and post-operative pain. N Z Vet J 60, 129-135.
407
Kum C, Voyvoda H, Sekkin S et al. (2013) Effects of carprofen and meloxicam on C-
408
reactive protein, ceruloplasmin, and fibrinogen concentrations in dogs undergoing
409
ovariohysterectomy. Am J Vet Res 74, 1267-1273.
410
Lamont LA, Mathews KA (2007) Opioids nonsteroidal anti-inflammatories and analgesic
411
adjuvants. In: Lumb & Jones' Veterinary Anesthesia and Analgesia (4th edn). Tranquilli WJ,
412
Thurmon JC, Grimm KA (eds). Blackwell Publishing, USA. pp. 241-272
413
Lemke KA (2007) Anticholinergics and sedatives. In: Lumb & Jones' Veterinary Anesthesia
414
and Analgesia (4th edn). Tranquilli WJ, Thurmon JC, Grimm KA (eds). Blackwell
415
Publishing, USA. pp. 203-240
416
Lorena SE, Luna SP, Lascelles BD, Corrente JE (2014) Current attitudes regarding the use of
417
perioperative analgesics in dogs and cats by Brazilian veterinarians. Vet Anaesth Analg 41,
418
82-89.
419
Magoha GA (1998) Local infiltration and spermatic cord block for inguinal, scrotal and
420
testicular surgery. East Afr Med J 75, 579-581.
421
Mason BJ, Newton JR, Payne RJ, Pilsworth RC (2005) Costs and complications of equine
422
castration: a UK practice-based study comparing 'standing nonsutured' and 'recumbent
423
sutured' techniques. Equine Vet J 37, 468-472.
424
McMillan MW, Seymour CJ, Brearley JC (2012) Effect of intratesticular lidocaine on
425
isoflurane requirements in dogs undergoing routine castration. J Small Anim Pract 53, 393-
426
397.
AC C
EP
TE D
M AN U
SC
RI PT
404
ACCEPTED MANUSCRIPT
Michelsen J, Heller J, Wills F, Noble GK (2012) Effect of surgeon experience on
428
postoperative plasma cortisol and C-reactive protein concentrations after ovariohysterectomy
429
in the dog: a randomised trial. Aust Vet J 90, 474-478.
430
Moldal ER, Eriksen T, Kirpensteijn J et al. (2013) Intratesticular and subcutaneous lidocaine
431
alters the intraoperative haemodynamic responses and heart rate variability in male cats
432
undergoing castration. Vet Anaesth Analg 40, 63-73.
433
Perez TE, Grubb TL, Greene SA et al. (2013) Effects of intratesticular injection of
434
bupivacaine and epidural administration of morphine in dogs undergoing castration. J Am
435
Vet Med Assoc 242, 631-642.
436
Pertovaara A, Hämäläinen MM, Kauppila T et al. (1994) Dissociation of the alpha 2-
437
adrenergic antinociception from sedation following microinjection of medetomidine into the
438
locus coeruleus in rats. Pain 57, 207-215.
439
Pypendop BH, Verstegen JP (1998) Hemodynamic effects of medetomidine in the dog: a
440
dose titration study. Vet Surg 27, 612-622.
441
Pypendop B, Verstegen J (1999) Cardiorespiratory effects of a combination of
442
medetomidine, midazolam, and butorphanol in dogs. Am J Vet Res 60, 1148-1154.
443
Roy TJ, Prieto L, Gil MC (2002) Testicular and epididymal weights in the domestic dog
444
(Canis familiaris). Vet Rec 150, 285.
445
Sakonju I, Maeda K, Maekawa R et al. (2009) Relative nerve blocking properties of
446
bupivacaine and ropivacaine in dogs undergoing brachial plexus block using a nerve
447
stimulator. J Vet Med Sci 71, 1279-1284.
AC C
EP
TE D
M AN U
SC
RI PT
427
ACCEPTED MANUSCRIPT
Sanday L, Zanin KA, Patti CL et al. (2012) Role of state-dependency in memory impairment
449
induced by acute administration of midazolam in mice. Prog Neuropsychopharmacol Biol
450
Psychiatry 37, 1-7.
451
Steffey EP, Mama KR (2007) Inhalation anesthetics. In: Lumb & Jones' Veterinary
452
Anesthesia and Analgesia (4th edn). Tranquilli WJ, Thurmon JC, Grimm KA (eds).
453
Blackwell Publishing, USA. pp. 355-394.
454
Stevens BJ, Posner LP, Jones CA, Lascelles BD (2013) Comparison of the effect of
455
intratesticular lidocaine/bupivacaine vs. saline placebo on pain scores and incision site
456
reactions in dogs undergoing routine castration. Vet J 196, 499-503.
457
University of Glasgow (2014) University of Glasgow website, SHORT FORM OF THE
458
GLASGOW COMPOSITE PAIN SCALE http://www.gla.ac.uk/media/media_61908_en.pdf
459
[accessed 4 Aug 2014].
460
Väha-Vähe T (1989) Clinical evaluation of medetomidine, a novel sedative and analgesic
461
drug for dogs and cats. Acta Vet Scand 30, 267-273.
462
Väisänen MA, Vainio OM, Raekallio MR et al. (2005) Results of 24-hour ambulatory
463
electrocardiography in dogs undergoing ovariohysterectomy following premedication with
464
medetomidine or acepromazine. J Am Vet Med Assoc 226, 738-745.
465
Verstegen J, Petcho A (1993) Medetomidine-butorphanol-midazolam for anaesthesia in dogs
466
and its reversal by atipamezole. Vet Rec 132, 353-357.
467
Vettorato E, Bacco S (2011) A comparison of the sedative and analgesic properties of
468
pethidine (meperidine) and butorphanol in dogs. J Small Anim Pract 52, 426-432.
469 470
AC C
EP
TE D
M AN U
SC
RI PT
448
ACCEPTED MANUSCRIPT
Appendix 1 Scoring sedation Score
Description No sedation
1
Mild sedation, animal still responsive to environmental stimuli
2
Moderate sedation, animal unresponsive to the majority of stimuli
3
Profound sedation, animal unresponsive to stimuli
RI PT
0
SC
472
M AN U
473 474
AC C
EP
TE D
475
ACCEPTED MANUSCRIPT
Table 1 Data of dogs administered medetomidine (0.01 mg kg-1) with butorphanol (0.2 mg kg-1)
477
and midazolam (0.2 mg kg-1) and intratesticular and incisional ropivacaine (0.2-0.4 mL kg-1
478
0.5%, group R, n = 11) or saline (group S, n = 11). Values are mean ± standard deviation for all
479
results except for age, which is presented as median and range due to lack of normal distribution. Group R
Group S
Age (months)
12 (7 - 24)
15 (6 - 36)
Weight (Kg)
23.4 ± 9.5
18.7 ± 9.0
0.247
Ropivacaine/saline volume
0.24 ± 0.07
0.24 ± 0.05
0.806
M AN U
SC
Parameter
administered locally (mL kg-1)
p-value
0.705
Preparation time (minutes)
37 ± 9
35 ± 10
0.688
Surgery time (minutes)
60 ± 19
55 ± 24
0.603
Total sedation time (minutes)
97 ± 21
90 ± 27
0.539
TE D
480
RI PT
476
Preparation time, time from medetomidine-butorphanol-midazolam administration to first
482
incision; Surgery time, time from first incision to last skin suture; Total sedation time, time from
483
medetomidine-butorphanol-midazolam administration to atipamezole administration.
485
AC C
484
EP
481
ACCEPTED MANUSCRIPT
Table 2 Administration of diazepam (0.5 mg kg-1) and propofol (0.4-1.1 mg kg-1) in response to
487
movement during orchiectomy in dogs administered medetomidine (0.01 mg kg-1) with
488
butorphanol (0.2 mg kg-1) and midazolam (0.2 mg kg-1) and intratesticular and incisional
489
ropivacaine (0.2-0.4 mL kg-1 0.5%, group R, n = 11) or saline (group S, n = 11). Times are
490
median (range).
Diazepam (number of dogs)
6 (54.5%)
Propofol (number of dogs) Time to diazepam administration (minutes)
(minutes) 491
8 (72.7%)
p-value
0.659
4 (36.4%)
6 (54.5%)
0.392
27 (4 - 42)*
6 (2 - 23)
0.021
56 (36 - 76)*
7 (3 - 25)
0.01
TE D
Time to propofol administration
Group S
SC
Group R
M AN U
Parameter
RI PT
486
Time to diazepam administration, time from skin incision to diazepam administration; Time to
493
propofol administration, time from skin incision to propofol administration. Dogs administered
494
propofol are also listed under diazepam.
495
*Significantly different from group S p < 0.05.
497 498
AC C
496
EP
492
ACCEPTED MANUSCRIPT
Table 3 Number of dogs administered methadone (0.3 mg kg-1 IV) for rescue analgesia in the
500
hours after orchiectomy. The dogs were sedated with medetomidine (0.01 mg kg-1) with
501
butorphanol (0.2 mg kg-1) and midazolam (0.2 mg kg-1) and intratesticular and incisional
502
ropivacaine (0.2-0.4 mL kg-1 0.5%, group R, n = 11) or saline (group S, n = 11) for the surgical
503
procedure.
RI PT
499
1
2
4
R
1
0
1
S
2
0
*This dog was also administered methadone at 1 hour.
AC C
EP
TE D
506 507
1*
number
8
24
0
0
2
0
4
M AN U
Group
504 505
Total
SC
Time (hours)
2
ACCEPTED MANUSCRIPT
508
Figure legends
509
Figure 1 Mean ± SD of interactive visual analogue scale (IVAS) scores of dogs before (baseline,
511
BL) and at 1, 2, 4, 8 and 24 hours after orchiectomy in dogs administered medetomidine (0.01
512
mg kg-1) with butorphanol (0.2 mg kg-1) and midazolam (0.2 mg kg-1) and intratesticular and
513
incisional ropivacaine (0.2-0.4 mL kg-1, 0.5%, group R, n = 11) or saline (group S, n = 12). Dogs
514
were excluded from analysis after administration of methadone for rescue analgesia. In group R
515
at BL and 1 hour (n = 11), at 2 and 4 hours (n = 10) and at 8 and 24 hours (n = 9). In group S at
516
BL and 1 hour (n = 12), at 2, 4 and 8 hours (n = 10) and at 24 hours (n = 8).
M AN U
SC
RI PT
510
517 518
*Significant difference between groups (p < 0.05). †Significantly different from BL (p < 0.05).
519
TE D
520
Figure 2 Mean ± SD of Glasgow short form composite measure pain scale (CMPS-SF) scores of
522
dogs before (baseline, BL) and at 1, 2, 4, 8 and 24 hours after orchiectomy in dogs administered
523
medetomidine (0.01 mg kg-1) with butorphanol (0.2 mg kg-1) and midazolam (0.2 mg kg-1) and
524
intratesticular and incisional ropivacaine (0.2-0.4 mL kg-1, 0.5%, group R, n = 11) or saline
525
(group S, n = 12). Dogs were excluded from analysis after administration of methadone for
526
rescue analgesia. In group R at BL and 1 hour (n = 11), at 2 and 4 hours (n = 10) and at 8 and 24
527
hours (n = 9). In group S at BL and 1 hour (n = 12), at 2, 4 and 8 hours (n = 10) and at 24 hours
528
(n = 8).
AC C
EP
521
529 530 531
† Significantly different from baseline value p < 0.05.
ACCEPTED MANUSCRIPT
Figure 3 Mean ± SD of mechanical algometer values (newton) of dogs before (baseline, BL) and
533
at 1, 2, 4, 8 and 24 hours after orchiectomy in dogs administered medetomidine (0.01 mg kg-1)
534
with butorphanol (0.2 mg kg-1) and midazolam (0.2 mg kg-1) and intratesticular and incisional
535
ropivacaine (0.2-0.4 mL kg-1, 0.5%, group R, n = 11) or saline (group S, n = 12). Dogs were
536
excluded from analysis after administration of methadone for rescue analgesia. In group R at BL
537
and 1 hour (n = 11), at 2 and 4 hours (n = 10) and at 8 and 24 hours (n = 9). In group S at BL and
538
1 hour (n = 12), at 2, 4 and 8 hours (n = 10) and at 24 hours (n = 8).
† Significantly different from baseline value p < 0.05.
M AN U
540
SC
539
RI PT
532
AC C
EP
TE D
541
ACCEPTED MANUSCRIPT
100 90
RI PT
Group R
80
Group S
60 50
†
†
†
40
†
10 0 1
2
4
TE D
Time (hours)
EP
†
†
M AN U
20
BL
†
†
†
30
SC
*
AC C
IVAS (mm)
70
8
†
24
ACCEPTED MANUSCRIPT
24 20
RI PT
Group R
12
†
†
†
SC
8
0 BL
1
2
M AN U
4
EP
TE D
Time (hours)
AC C
CMPS-SF score
Group S 16
4
8
24
ACCEPTED MANUSCRIPT
Group R
16
Group S
RI PT
18
14 12
† †
†
SC
10
6 4 2 0 BL
1
2
M AN U
8
4
EP
TE D
Time (hours)
AC C
Algometer pressure (N)
20
8
24