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A Technical Note on the Effect of Sedatives on Rumen Motility in Sheep Stephen J. Waite, John E. Cater, Garry C. Waghorn, Vinod Suresh
PII: S0921-4488(20)30233-9
DOI: https://doi.org/10.1016/j.smallrumres.2020.106284
Reference: RUMIN 106284
To appear in: Small Ruminant Research Received Date: 12 December 2019 Revised Date: 30 July 2020 Accepted Date: 12 November 2020
Please cite this article as: Stephen J. Waite, John E. Cater, Garry C. Waghorn, Vinod Suresh, A Technical Note on the Effect of Sedatives on Rumen Motility in Sheep,<![CDATA[Small Ruminant Research]]>(2020), doi:https://doi.org/
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A Technical Note on the Effect of Sedatives on Rumen Motility in Sheep
Stephen J. Waitea, John E. Caterb, Garry C. Waghornc, Vinod Suresha,b
aAuckland Bioengineering Institute, University of Auckland, Auckland, New Zealand.
bDepartment of Engineering Science, University of Auckland, Auckland, New Zealand.
cPresent address: 6 Berkley Avenue, Hamilton, New Zealand.
Abstract
Rumen motility is depressed by a number of anesthetic agents, making them unsuitable for the reduction of animal anxiety and distress during experimental investigations of rumen motility.
Little is known about the influence on rumen motility of chemical agents that induce sedation without unconsciousness. A pilot trial was performed to assess the effect of three commonly used ruminant sedatives on rumen motility. Xylazine, acetylpromazine and diazepam were individually administered by intravenous injection to 3 adult sheep ewes. Animal behaviour was observed and ultrasound monitoring was used to assess rumen contractions in the animals over a range of sedative doses. At low dosages0.05 mg/kg, xylazine caused motility inhibition reduced contraction frequency after 5 minutes, and at higher dosages0.125 mg/kgfull atony was observed. In contrast, neither acetylpromazine (0.02 - 0.1 mg/kg) and diazepam (0.2 - 0.5 mg/kg) depressed rumen motility. Diazepam was also observed to give greater sedative influence than acetylpromazine, both in terms of muscular and cognitive sedation. Sedative effects lasted approximately 20 - 30 minutes after administration, after which the effects diminished rapidly. We conclude that diazepam at dosages of 0.3 - 0.5 mg/kg is suitable for procedures requiring short term sedation of sheep while preserving rumen motility.
Keywords: rumen motility, rumen atony, sedation, sheep
1. Intoduction
1
To date, the motility of the reticulo-rumen (RR) has been studied through a variety of
2
invasive and non-invasive techniques, such as pressure manometrics (Dziuk and McCauley,
3
1965; Ruckebusch, 1989), fluroscopy (Akester and Titchen, 1969; Phillipson, 1939), ultra-
4
sound (Braun and Schweizer, 2014; Kaske et al., 1994), electromyography (Gregory, 1984;
5
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Ruckebusch, 1970) and direct observation through fistulation (Sellers and Stevens, 1966).
6
These methods have resulted in an in-depth understanding of the sequence of compartmen-
7
tal contractions and the subsequent movement of gas and feed particles. However, due to
8
either the point source or two dimensional nature of these methods, they cannot capture
9
the full three dimensional displacement of rumen compartments during contractions. Mod-
10
ern techniques such as x-ray computed tomography (CT) and magnetic resonance imaging
11
(MRI) have been used on humans and other mono-gastric animals to address these issues.
12
However, these methods are difficult to extend to ruminants as they require subjects to re-
13
main stationary for extended periods of time (on the order of minutes) corresponding to
14
multiple repetitions of contractile activity. In the case of humans this behaviour can be vol-
15
untarily performed, and for mono-gastric animals the use of general anesthetic agents can be
16
employed to achieve a stationary subject.
17
However, General anesthesia is not suitable for such studies in ruminants. It is often
18
associated with complications such as the onset of bloat, due to the suppression of eructation
19
(Dunlop and Hoyt, 1997), as well as increased risk of regurgitation and aspiration of digesta.
20
A general side effect of a range of anesthetic agents is the induction of RR atony(Lin, 2015),
21
particularly for alpha2 and opioid agonists (Ruckebusch, 1983). Thus,it is usually suggested
22
to fast animals for up to 24 hours before the administration of general anesthetics in order
23
to reduce fermentation and digesta volume.
24
Although some investigators have studied rumen motility under general anesthesisa, the
25
procedures required further interventionsto preserve rumen contractions. For example, Iggo
26
and Leek (1967) observed that during halothane/oxygen anesthesia RR motility was able
27
to be stimulated by increasing intraruminal pressure by 10 mm Hg using a balloon placed
28
in the reticulum, and Leek (1969) induced contractions under halothane anesthesia through
29
electrical stimulation of the vagus nerve and physical stimulation of mechanoreceptors. Such
30
interventions increase the complexity of the procedure and may further alter the innate
31
motility patterns.
32
While designingThis work was motivated by the design of experimental protocols to study
33
rumen motility using cine-x-ray CT imaging. The procedure experimental protocols for a
34
study into the motility of the rumen through cine-x-ray CT requires the animals needed
35
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to remain relaxed and immobile for durations up to 30 minutes. Discussions with ruminant
36
veterinarians and a review of the literature indicated that general anesthesia was not suitable
37
for this purpose. We were thus led to consider the use of sedation as a means to maintain
38
the animals in a docile state without significantly depressing rumen motility while they were
39
within the confines of the CT scanner. There are a number of sedatives available for rumi-
40
nants, but little information on their influence on rumen motility in the published literature.
41
Some well known ruminant sedatives, such as xylazine (often also used in anesthetic combi-
42
nation with drugs such as ketamine) are
43
There are a number of sedative options available for ruminants, however the body of lit-
44
erature investigating their effects on rumen motility is focused primarily on xylazine, which
45
is well documented as inducing atony (Brikas et al., 1986; Hara et al., 2002) and is used in
46
treatments in which the onset of such behaviour is desirable, such as when treating trau-
47
matic reticuloperitonitis (Braun et al., 2002). Repeated administration of xylazine has been
48
shown to reduce sedative effects (Karasu and Genccelep, 2015; Genccelep and Karasu, 2017),
49
however a decrease in rumen contraction frequency is still observed.
50
Research has also examined the effects of medetomidine (Mohammad et al., 1993) di-
51
azepam, chlorpromazine and promethazine (Habib et al., 2002), as well as drugs with sec-
52
ondary sedative effects such as metoclopramide (El-Khodery and Sato, 2008), atropine, and
53
scopolamine (Braun et al., 2002; Ribeiro et al., 2014).
54
To find a suitable sedative for use in motility studies requiring animal restraint, two com-
55
monly used sedatives were identified after consultation with veterinarians for investigation,
56
acetylpromazine (ACP) and diazepam (Taylor, 1991; Hodgkinson and Dawson, 2007). This
57
technical note reports the observations ofmade during apilot trial study to test the suitabil-
58
ity of two known ruminant sedatives, on rumen motility of ACP and diazepam. Of primary
59
interest is their influence on rumen motility behaviour and their sedative effects.
60
2. Methods
61
All procedures were approved by the University of Auckland’s animal ethics committee
62
(approval number 001755).
63
Two common ruminant sedatives, ACP (Acezine 10 – Ethical Agents Veterinary Mar-
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keting – ACVM #OOA5769) and diazepam (Pamlin Injection – Ceva Animal Health Pty
65
Ltd – ACVM #A5930), were selected for trial investigation. Xylazine (Phoenic Xylazine 2%
66
Injection – Phoenix Pharmaceuticals Ltd – ACVM #A5541) was also used, as it is a known
67
motility inhibitor, and so was included to ensure that atony could correctly be identified.
68
Three adult ewes were included in the study. Animals were housed in metabolic crates
69
for a habituation period of 7 days and the forelimbs and left flank were shaved. To min-
70
imise pain and agitation during experimentation, intravenous (IV) catheters were installed
71
in the cephalic vein of the forelimb the day before trials began. IV lines were flushed with
72
heparinised saline (35000 IU/ml – Pfizer) daily to prevent blockages due to clotting.
73
Experiments were undertaken on the sheep in their metabolic crates over the a second 7
74
day period ,with 4 trials performed per animal (one trial per drug, and an additional trial
75
to repeat key results), with a 24 hour period between successive trials. Each trial consisted
76
of three one or more administrations of one of the same three drugsedatives. first at an
77
initial low dosage, followed by two additional doses given at 30 minute intervals, resulting
78
in each trial lasting 1.5 hours. During this time, animal behaviour was observed to judge
79
the level of sedation, and motility monitoring was performed 5, 15 and 30 minutes after each
80
administration. The dosages for each drug are shown in Table 1, with the initial dosage based
81
on a standing sedation level (a level that allows for pain-relief while still free-standing), and
82
the cumulative maximum was the upper limit recommended by the suppliers. Each animal
83
received each drug in a different trial order, and there was a minimum of 24 hours between
84
successive trials to allow for drug elimination. For the first trial, a low dosage was given
85
(xylazine: 0.05 mg/kg, ACP: 0.02 mg/kg, diazepam: 0.2 mg/kg) to gauge initial effects at
86
what is considered to be a ‘standing’ sedation level (a level that allows for pain relief while
87
still free-standing (Riebold, 2015; Cooney et al., 2012)). Sedation levels and rumen motility
88
were assessed 5 and 15 minutes after the initial dose. In some instances a subsequent dose
89
was administered and the animal assessed again after 5 minutes. A maximum dose was set
90
for each of the three drugs (xylazine: 0.3 mg/kg, ACP: 0.1 mg/kg, diazepam: 0.5 mg/kg).
91
Animal behaviour (demeanour, eating, drinking, excretion, vocalisation, docility) was as-
92
sessed prior to and at the conclusion of drug administration (90 minutes), and additionally
93
one hour later. Prior to each trial, animals were checked to ensure normal eating, drinking,
94
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and excreting along with their social demeanor (vocal, inquisitiveness, docility), to assess if
95
any residual effects were present from the previous trials. Animals were given free access
96
to food (lucerne pellets) and water both prior to and during experimentation. During each
97
trial, the overall levels of sedation and agitation were determined to describe the effects of
98
the sedatives on each sheep, scored on a scale of 1-6 shown in Table 1. 1=baseline and alert;
99
5=sitting, docile, with decreased respiration and heart rate.
100
101
Table 1: Definition of Sedation Level (SL)scores
Level Respiration Heart Rate Alertness1 Posture
1 Normal Normal Normal Standing
2 Normal Normal Slightly reduced Standing 3 Normal Normal Greatly reduced Standing 4 Normal Normal Greatly reduced Sitting 5 Altered Normal Greatly reduced Sitting 6 Altered Decreased Greatly reduced Sitting
Reticulo-rumen motility was monitored using ultrasound, as it has been shown to be an
102
effective tool for non-invasive monitoring of the motion of various RR compartments in sheep
103
(Kaske et al., 1994), goats (Braun and Jacquat, 2011) and cattle (Braun et al., 2012; Braun
104
and Schweizer, 2014). Ultrasound has been used previously to investigate the behaviour
105
of atropine, scopolamine and xylazine on induction of RR atony (Braun et al., 2002) and
106
metoclopramind and neostimgmine for treatment of hypomotility (El-Khodery and Sato,
107
2008)
108
Ultrasonic monitoring was performed using a Philips SONOS 5500 with the probe placed
109
caudal to the 14ththoracic vertebrae on the shaved upper-left flank. RR motility was observed
110
through the motion of the left coronary/caudal pillar and the subsequent dorsal and ventral
111
sacs. An example of the observed motility is shown in Figure 1. Animals were first imaged to
112
1Slightly reduced: drowsiness, lowered ears, heavy lidded eyes, some trouble holding head upright; Greatly reduced: drooping head, trouble standing, loss of balance, loss of inhibition and loss of awareness of surround- ings
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determine if normal RR activity was present before each day’s trial. Ultrasound monitoring
113
was performed 5, 15 and 30 minutes after every drug administration, with monitoring periods
114
lasting 5 minutes to allow for 4-5 motility events to be observed. This resulted in 9 scans per
115
animal per trial.
116
(a) (b)
Figure 1: Example of rumen motility imaging. Left panel shows a transverse CT image of a sheep rumen in a prone positionadapted from (Waite, 2019). The location of the ultrasound probe (U) is shown, along with C, the left longitudinal pillar and an arrow indicating direction of motion during contraction. The outer tissue A, rumen wall B and the dorsal (D) - ventral (V) axis are also shown. The coordinateX-Y axes indicate the orientation. The panels on the right show motion of the rumen as seen via ultrasound. The top frame shows the rumen wall B at rest. In the middle frame, the rumen wall B moves to the right during a contraction and in the bottom frame, the longitudinal pillar C comes into view following upward displacement as the contraction proceeds. .
Rumen motility was also scored on a 1-5 scale, based on contraction frequency and
117
‘strength or magnitude’ of contractions ranging from 1= baseline and normal to 5 = atony
118
specified in Table 2. The baseline was determined through scanning observations made before
119
the first administration in each trial.
120
Table 2: Definition of Rumen Motility (RM) scores
Score Contraction Frequency & Magnitude
1 Baseline normal motility (approximately 1 contraction per minute) 2 Frequency similar to baseline measurements, magnitude decrease 3 Contraction frequency decrease, magnitude similar to baseline 4 Contraction frequency decrease, magnitude decrease
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5 Atony
The behaviour of each animal was monitored to determine the level of sedation achieved
121
at each dosage level. Prior to each trial, animals were checked to ensure normal eating,
122
drinking, and excreting along with their social demeanor (vocal, inquisitiveness, docile). An-
123
imals were given free access to food (lucerne pellets) and water both prior to and during
124
experimentation.
125
126
3. Results
127
The sedative administration details, and the associated rumen motility (RM) and seda-
128
tion levels (SL) are presented in Table 3. Animals were assessed 5 minutes after each drug
129
administration. Additional observations were typically performed after an additional 10 min-
130
utes. Observation times are stated relative to administration of the first dose. For example,
131
for sheep #1, a xylazine dose of 0.05 mg/kg was administered at time t = 0. RM and SL
132
scores were recorded at t = 5 and 15 minutes. A second dose of xylazine (0.125 mg/kg) was
133
then administered at t = 22 minutes and RM, SL scores recorded at t= 27,37 minutes.
134
Xylazine at a dose of 0.05 mg/kg resulted in considerable sedative effects, causing an
135
observable influence on animal behaviour, with drooping ears, head and heavy breathing.
136
Reduced RR motility was also observed, both in strength and in frequency. Administration
137
of a second dose during a trial cause more pronounced sedation, with animals exhibiting
138
difficulty standing, and with increased respiration rate resulting in panting. In two out of
139
three trials, the second dose led to atony with no contractions being recorded in the scanning
140
window 5-15 minutes after administration. Xylazine effects were short lived, with animals
141
returning to normal behaviour 20-30 minutes after administration.
142
ACP and diazepam both had no noticeable effect on RR motility for the dosage ranges
143
used. Diazepam had a noticeable sedative effect, with animals displaying noticeable difficulty
144
holding up their head and ears, and exhibiting a loss of balance. Animal anxiety was also
145
greatly decreased with a noticeable indifference to interaction with handlers and the ultra-
146
sound probe, along with a significant increase in appetite. Previously, animals had shown
147
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an aversion to eating and drinking when staff were present in the room. After administering
148
diazepam, animals proceeded to consume feed and water. In the case of one animal, all avail-
149
able feed and water was consumed in a 10 minute period, where upon it became agitated
150
(grunting and stomping) until more food was provided. It was found that this behaviour
151
could be minimised by removing feed from sight before diazepam was administered.
152
ACP was observed to have milder sedative effects, with signs of drowsiness (drooping
153
ears, head, eyelids, and deep breathing), however anxiety and balance were less affected,
154
with animals becoming agitated at the approach of and contact with handlers. Animals were
155
also restless during ultrasound scanning with stomping and general movement within the
156
metabolic crate.
157
The sedative effects of ACP and diazepam were observed to subside after 20-30 minutes,
158
in a similar manner to xylazine.
159
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Table 3: Sedative doses administered and effects on rumen motility (RM) and sedation levels (SL)
Drug Sheep # Dose # Dosage (mg/kg) Observation time (min) RM SL
Xylazine 1 1 0.05 5 1 2
15 3 2
2 0.125 27 5 5
37 1 2
Xylazine 2 1 0.05 5 3 3
2 0.06 38 5 2
48 5 2
63 4 1
Xylazine 3 1 0.05 5 1 2
15 1 1
2 0.125 50 3 3
60 1 2
Xylazine 3 1 0.125 5 3 4b
15 1 2
30 1 1
ACP 2 1 0.02 5 1 1
15 1 1
2 0.04 50 1 4
60 1 2
ACP 2 1 0.04 5 1 2
15 1 2
2 0.04 29 1 3
39 1 2
ACP 2 1 0.1 5 1 2
15 1 2
ACP 1 1 0.1 5 1 2
Diazepam 1 1 0.2 5 1 3
15 1a 2
Diazepam 1 1 0.3 5 1 3
15 1a 2
30 1a 2
Diazepam 1 1 0.4 5 1 3
15 1 3
Diazepam 2 1 0.5 5 1 3
Diazepam 3 1 0.2 5 1 2
15 1 2
2 0.15 22 1 3
a Animal began eating, rumen motility was observed to increase, approximately 2 contractions per minute.
b Breathing increased >60/min
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4. Discussion
160
This pilot study characterised the short term effects of three common sedative agents on
161
sedation levels and rumen motility in sheep. The results provide a basis for drug selection
162
and dosing when it is desired to sedate sheep without causing unconsciousness or inhibiting
163
rumen function.
164
Xylazine was found to provide effective sedation, but significantly inhibited rumen motil-
165
ity, up to the point of atony. These results were consistent with results reported by Braun
166
et al. (2002) in cattle, where atony occurred on average 2-3 minutes after IV administration,
167
and lasted for 12-15 minutes depending on dosage. Similar observations have been seen in
168
other reports (Brikas et al., 1986; Hara et al., 2002; Karasu and Genccelep, 2015; Genccelep
169
and Karasu, 2017).
170
Acetylpromazine and diazepam both had no noticeable effect on rumen motility for the
171
dosage ranges used. In the case of diazepam, this result is in contrast to reports by Habib
172
et al. (2002), which observed decreasing motility when diazepam was administered after a
173
12 hour fasting period. It may be attributed to the differences in feeding regimes, as fasting
174
in sheep is associated with a decrease in primary contractions (Waghorn and Reid, 1983).
175
In addition, we found that diazepam stimulated feeding behaviour which may have helped
176
protect rumen motility in this study.
177
Initial doses of xylazine (0.05 mg/kg were noted to result in considerable sedative effects,
178
causing an observable influence on animal behaviour, with drooping ears, head and heavy
179
breathing. Reduced RR function was also observed, both in strength and in frequency. Full
180
RR atony (no contractions recorded in the 5 minute scanning window) was observed 5-15
181
minutes after the first incremental dose (0.125mg/kg). Sedation effects also increased, with
182
animals exhibiting difficulty standing, and with increased respiration rate resulting in pant-
183
ing. Xylazine effects were short acting, with animals returning to normal behaviour 20-30
184
minutes after administration. These results were consistent with results reported by Braun
185
et al. (2002) in cattle, with atony occurring on average 2-3 minutes after IV administration,
186
and lasting for an average of 12-15 minutes depending on dosage.
187
This study involved repeated administration of sedatives to the animals. On each day of
188
the trial, one or two doses of a single sedative was administered to each of the three animals
189
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over a period of 15 - 60 minutes. Prior to each trial, animal behaviour and rumen motility
190
were assessed to check for potential carry over effects from the previous trial. A recovery
191
period of 24 hours was allowed between successive trials. This duration is sufficient to clear
192
xyalzine from the animals since the systemic half-life of intravenously administered xylazine
193
is reported to be 22 minutes in sheep (Garcia-Villar et al., 1981). Half-lives or elimination
194
times in sheep have not been reported for acetylpromazine and diazepam. However, sheep
195
sedated with intravenous diazepam and ketamine recovered to full standing position within
196
30 minutes (Walsh et al., 2012), while sedation scores of sheep administered intravenous
197
acetylpromazine returned to baseline by 2 hours post-injecction (Nishimura et al., 2017).
198
These studies, combined with the pre-trial assessment, suggest that a 24 hour recovery period
199
is sufficient to abrogate back effect of the drugs on successive trials.
200
Acetylpromazine was observed to have mild sedative effects, with signs of drowsiness
201
(drooping ears, head, eyelids, and deep breathing), however animal behaviour and physical
202
strength was less affected, with animals becoming agitated at the approach of and contact
203
with handlers. Animals were also restless during ultrasound scanning with stomping and
204
general movement within the metabolic crate.
205
Diazepam gave a much deeper level of sedation than acetylpromazine, with animals dis-
206
playing noticeable difficulty holding up their head and ears, and exhibiting a loss of balance.
207
At higher dosages (0.3-0.5 mg/kg) animals could be guided into a prone position. Animal
208
anxiety was also greatly decreased with a noticeable indifference to interaction with handlers
209
and the ultrasound probe, along with a significant increase in appetite. Previously, animals
210
had shown an aversion to eating and drinking when staff were present in the room. After
211
administering diazepam, animals proceeded to consume feed and water. In the case of one an-
212
imal, all available feed and water was consumed in a 10 minute period, where upon it became
213
agitated (grunting and stomping) until more food was provided. It was found that this be-
214
haviour could be minimised by removing feed from sight before diazepam was administered.
215
216
The sedative effects of acetylpromazine and diazepam were observed to subside after 20-30
217
minutes, in a similar manner to xylazine.
218
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5. Conclusions
219
Three common ruminant sedatives were trialled to investigate their influence on reticulo-
220
rumen motility and , as well as their level of sedation.
221
Xylazine was observed to initiate atony at low doses (0.125 mg/kg liveweight), consistent
222
with reports in the scientific literature.
223
Neither ACP or diazaepam appearedto affect motility of the rumen. The sedative influ-
224
ence of ACP was milder than that of diazepam for the dosages used.
225
A dosage of 0.3-0.5 mg/kg liveweight of diazepam was found to provide sufficient sedation
226
to allow for animal interaction (placement into a prone position, human contact or introduc-
227
tion of non-invasive measuring devices) while still maintaining normal motility of the rumen.
228
6. Acknowledgements
229
This study was funded by the Agricultural and Marketing Research and Development
230
Trust (AGMARDT, contract R1604) and DairyNZ (contract TP1602).
231
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