IFIX, 420 B-Braun Melsungen AG, Germany) was inserted into the epidural .... 45.2 ±4.0. 44.5 ± 3.3. 44.1 ± 2.6. 43.5 ± 1.3. 43.4 ± 2.3. HCO3 v, mmol/1. 25.1 ± 2.3.
IRTICLE O R I G I N A L
Cardiovascular and respiratory effects of epidural vs intravenous xylazine in sheep B. AMINKOV and M. PASCALEV
Department of Surgery and Radiology, Faculty of Veterinary Medicine,
Thracian University, 6000 Stara Zagora, Bulgaria
SUMMARY
RESUME
The aim of the study was to follow out the cardiovasculary and respiratory effects after the epidural and intravenous administration of xylazine in sheep. In two groups of clinically healthy sheep (n = 6), 0.2 mg/kg 2 % xylazine was applied either epidurally, diluted in 10 ml saline (group 1) or intravenously (group 2). The epidural administration of xylazine didn't induce any insignificant cardiovascular and respiratory changes. A significant decrease was observed in both mean and diastolic arterial blood pressure (p < 0.05), partial arterial oxygen pressure (p < 0.01), oxygen saturation (p < 0.05) after intravenous administration of xylazine. The respiratory rate increased (p < 0.001) as well as the actual bicarbonates (p < 0.05) after intravenous application of xylazine. In conclusion, the epidural administration of 0.2 mg/kg xylazine ensured a safe anesthesia with minimal cardiopulmonary changes, while the intravenous route of administration was related to significant respiratory changes.
Effets cardiovasculaires et respiratoires d'une injection epidurale de xylazine chez le mouton versus une injection intraveineuse. Par B. AMINKOV et M. PASCALEV.
KEY WORDS : xylazine - intravenous administration epidural administration - sheep.
MOTS-CLES : xylazine - administration intraveineuse administration epidurale - mouton.
Introduction
The aim of the present study was to compare the cardiovascular and respiratory effects of epidural versus intravenous application of 0.2 mg/kg 2 % xylazine in sheep.
Alpha -agonists are widely used in veterinary medicine for sedation and analgesia. After their administration, several side effects have been however recorded. Their degree was related to the species, dose and the route of administration. It is reported that the parenteral administration of xylazine in sheep resulted in hypoxia [ 3 , 4 , 1 5 , 2 4 ] , tachypnea [8], hypercapnea [3, 13, 14], bradycardia [3, 8], hypotension [3] and pulmonary oedema [22]. 2
The epidural administration of xylazine caused hypercapnea and metabolic alkalosis in sheep [2], bradycardia, hypotension, hypercapnea and hypoxemia in cattle [18] and bradycardia and hypotension in horses [19, 20]. Revue Med. Vet, 1998,149, 1, 69-74.
D o u z e m o u t o n s c l i n i q u e m e n t s a i n s ont ete r e p a r t i s e n d e u x g r o u p e s . 0,2 mg/kg de xylazine a 2 % ont ete administres par voie epidurale (diluee dans 10 ml de NaCl 0,9 %) (animaux du groupe 1) ou par voie intraveineuse (animaux du groupe 2). L'administration par voie epidurale ne modifie ni les parametres cardiovasculaires ni les parametres respiratoires. En revanche, apres administration par voie intraveineuse on note une diminution de la pression arterielle diastolique (p < 0,05), une diminution de la pression arterielle en oxygene (p < 0,01), une augmentation de la frequence respiratoire (p < 0,001) et une augmentation de la concentration en bicarbonates (p < 0,05). Les auteurs en deduisent que la voie epidurale est mieux toleree que la voie intraveineuse.
Material and methods Twelve clinically healthy sheep, Stara Zagora White breed, aged 2-4 years, were divided into two groups: Groupe 1 : 6 animals (4 rams and 2 ewes) weighing 50.0 ± 5.1 kg , were administered epidurally 0.2 mg/kg 2 % xylazine (Bayer, Germany), diluted in 10 ml of saline solution(EA-X). Groupe 2 : the 6 other animals (4 rams and 2 ewes) weighing 47.8 ± 5.7 kg, were administered intravenously (v. saphena) 0.2 mg/kg 2 % xylazine (Bayer, Germany) (IV-X).
70
A M I N K O V (В.) A N D P A S C A L E V (M.)
The animals were fasted for 24 h, but had water ad libitum.
TPR = (79.9 x MABP)/CO
A 22 gauge catheter was inserted into the auricular artery
All parameters were recorded before (baseline, 0) and at 5,
and connected via a three-way stopcock to a transducer (Bell
10, 15, 30, 45, 60 min after the epidural and intravenous
& Howell Physiological pressure Transducer, USA) and to a
administration of xylazine. The animals were in right lateral
recording system (Hellige, Germany) for determination of
recumbency for baseline cardiopulmonary measurements.
systolic (SABP), diastolic (DABP) and mean (MABP) blood
After the placement of the intravascular catheters, a resting
pressure, as well as for collecting arterial blood samples.
period of at least 30 min was allowed before baseline data
Prior to each study, all pressure transducers were calibrated
were recorded.
against a mercury manometer with zero level set at the thora cic inlet in laterally recumbent sheep.
For the epidural anesthesia, the animals were in right late ral recumbency on a table with the hind limbs extended for
An introducer (Vygon introducer for cardiac catheter) was
ward. Following subcutaneous infiltration with 3 ml 2 %
percutaneously placed in a left jugular vein. A 110 cm 7F bal
lidocaine (Pharmachim, Bulgaria), a 16-gauge 8 cm-long
loon-tipped thermodilution catheter (Swan-Ganz Flow-direc
Tuohy needle (Continuous Epidural Anaesthetic Set PER-
ted Thermodilution catheter 7F, Vygon, Germany) was direc
IFIX, 420 B-Braun Melsungen AG, Germany) was inserted
ted through the introducer into the pulmonary artery for mea
into the epidural space at the interspace between the last lum
suring core body temperature, thermodilution cardiac output
bar and first sacral vertebrae. The epidural space was identi
(CO, 1/min), and for collecting mixed venous blood samples
fied by loss of resistance to injection of 2 ml of air after pier
(for pH and blood gas measurements). Proper catheter place
cing the ligamentum flavum [7]. An attempt to aspirate cere
ment was verified before each measurement by analysis of
brospinal fluid was executed in order to show that the dura
pressure waveforms. Cardiac output was determined by the
has not been punctured. Then, a catheter with 3 lateral eyes,
standard thermodilution technique after hand-injection of 5
0 0.6 x 1.05 x 100 mm, was threaded forward through the
ml NaCl 0.9 % (at 4°C) at the rate of 1.67 ml/s through the
needle for 5 cm beyond the needle bevel; the needle was
proximal part of the catheter during expiration. Recorded CO
removed leaving the catheter in place. Solution was injected
values were the mean value of three consecutive measure
slowly into the epidural space (0.11 ml/s).
ments if they were within 10 % of each other or five measu
The results were expressed as mean ± SD and analyzed by
rements with discarding the lowest and the highest value and
means of two-way ANOVA with repeated measures to detect
calculating the average of the remaining values when the
differences (time and treatment effect). One-way ANOVA
measurements were not within 10 % of each other. The ther
was used to determine differences between treatments at each
modilution catheter was connected to a hemodynamic profile
time interval. Post-hoc comparisons of individual group
computer.
means were carried out by the Turkey's test. Differences were
The sternum was used as a zero point for all cardiovascular measurements. 1
Respiratory rate (RR, m i n ) was determined by counting visible thoracic and abdominal movements during 1 minute. For each subject, an ECG was made using an orthogonal Y
considered significant at the p < 0.05 level.
Results 1) EPIDURAL ADMINISTRATION OF XYLAZINE (EA-X)
lead. The heart rate (HR, beats/min) was determined through
During EA-X, muscle spasms in three sheep and rigidity of
counting the pulse waves on the oscillograph for one minute.
limbs were observed, but disappeared within 5-10 s. The res
2 ml-arterial and mixed venous blood samples were drawn
piratory movements were deep. Other respiratory parameters
anaerobically in heparinized syringes for determination of
didn't show any significant variation.
the following arterial (a) and mixed venous (v) parameters:
The cardiopulmonary parameters after EA-X are presented
blood p H (pH a ,pH v ); partial 0 2 and C 0 2 pressures ( P a 0 2 ,
in table I and on figures 1-4. The recorded changes were insi
P a C 0 2 , PVC>2
gnificant.
an
d P v C 0 2 in mmHg) ; blood bicarbonates
( H C 0 3 " a , HC0 3 ~v in mmol/1), oxygen saturation (SAT a , SATV, % ) , the base excess (ABE a , ABEV in mmol/1), haemo globin (Hb a , Hb v , g/1). Blood samples were immediately ana lyzed (ABL-3, Radiometer, Denmark). All gas measure ments were corrected to body temperature [17].
blood oxygen content were calculated as follows [21]:
and 103 ± 4 mmHg for DABP). Variations in the other para
stroke volume (SV, 5
ml/beats); total periperal resistance (TPR, dyn/s/cm ) were calculated as followed [23] :
ficantly at minutes 15, 30 and 45 (p < 0.05, table II, fig.l). compared to the initial values (115 ± 5 mmHg for MABP
C v 0 2 = (0.0031 x p v 0 2 ) + (1.34 x Hb v x SATv) ml/kg/min);
cardia lasted up to min 3. MABP and DABP decreased signi They reached 99 ± 5 mmHg and 82 ± 6 mmHg respectively,
C a 0 2 = (0.0031 x p a 0 2 ) + (1.34 x Hb a x SATa)
index (CI,
One minute after the intravenous administration of xyla zine, the heart rate decreased to 40-45 beats/min. The brady
Arterial ( C a 0 2 , ml/dl) and mixed venous ( C v 0 2 , ml/dl)
Cardiac
2) INTRAVENOUS ADMINISTRATION OF XYLAZINE (IV-X)
meters were not significant. The respiratory effects after the intravenous administration of 0.2 mg/kg xylazine are presented in table II and on figures
CI = СО/body weight
1-4. In 5 sheep, apnea was observed, lasting from 25 to 50 s,
SV = CO/HR
and then the breathing was rapid, shallow and of abdominal
Revue Med. Vet.. 1998. 149, 1, 69-74.
1.)
CARDIOVASCULAR A N D R E S P I R A T O R Y E F F E C T S O F E P I D U R A L V S I N T R A V E N O U S X Y L A Z I N E I N S H E E P
71
Time after administration (min)
Baseline Variable
(time 0)
5
15
30
45
60
Heart rate, beats/min
85 ± 10
72 ± 14
71 ± 18
73 ± 17
69 ± 13
72 ± 14
Systolic arterial pressure (mmHg)
129 ± 12
126 ± 17
118 ± 17
117 ± 18
114 ± 13
111 ± 16
Diastolic arterial pressure (mmHg)
90 ± 8
84 ± 16
84 ± 17
84 ± 17
81 ± 15
81 ± 14
Mean pulmonary arterial pressure (mmHg)
22 ± 1
23 ± 1
25 ± 2
24 ± 2
23 ± 3
25 ± 3
Cardiac output, 1/min
6,5 ± 1.8
4.7 ± 1.3
4.8 ± 1.3
4.8 ± 1.0
4.9 ± 1.0
5.0 ± 1.0
Cardiac index, ml/min/kg
128 ± 5
94 ± 7
96 ± 10
97 ± 10
99 ± 4
100 ± 6
Stroke volume, ml/beat
75.3 ± 14.7
65.5 ± 11.1
68.1 ± 12.0
66.4 ± 11.9
70.5 ± 9.8
69.4 ± 11.4
Total peripheral resistance (dyn.s/cm )
1.44 ± 0.33
1.51 ± 0 . 3 6
1.49 ± 0 . 3 2
1.65 ± 0 . 3 5
1.65 ± 0 . 3 2
2.88 ± 0 . 7 1
Pulmonary artery blood temperature, °C
39.6 ± 0 . 3
39.7 ± 0.3
39.7 ± 0.2
39.7 ± 0.03
39.6 ± 0.3
39.4 ± 0.3
C 0 , ml/dl
13.4 ± 1.2
13.2 ± 1.8
12.5 ± 1.4
11.8 ± 1.4
11.7 ± 1.9
11.6 ± 1.7
H g , g/i
101 ± 9
98 ± 10
94 ± 10
90 ± 10
90 ± 13
89 ± 11
P 0 , mmHg
62.0 ± 10.1
62.1 ± 11.0
56.8 ± 11.5
50.3 ± 8.7
50.7 ± 9.4
49.4 ± 6.8
SAT , %
86.5 ± 3.7
86.7 ± 8.8
85.9 ± 7.4
76.4 ± 11.1
74.8 ± 12.4
75.3 ± 9 . 1
C 0 , ml/dl
10.9 ± 1.0
10.7 ± 1.5
10.4 ± 1.4
8.9 ± 2.2
8.9 ± 2.7
8.9 ± 1.9
H g , gn
92 ± 9
92 ± 11
89 ± 9
85 ± 11
86 ± 13
87 ± 11
PH
7.430 ± 0.038
7.416 ± 0.052
7.375 ± 0 . 1 1 3
7.439 ± 0.048
7.449 ± 0.047
7.466 ± 0.045
P C 0 , mmHg
37.3 ± 2.3
38.3 ± 1.3
39.7 ± 1.7
40.1 ± 2.0
39.9 ± 3.4
39.1 ± 2.6
H C 0 a, mmol/1
24.1 ± 2 . 2
23.6 ± 3.0
25.3 ± 3.0
26.3 ± 3.0
27.5 ± 3.1
27.9 ± 3 . 1
A B E , mmoW
0.9 ± 2.4
0.3 ± 3.1
1.7 ± 3 . 4
2.5 ± 3.0
3.2 ± 2 . 7
4.1 ± 3.1
pH
7.401 ± 0.025
7.396 ± 0.042
7.385 ± 0.047
7.395 ± 0.051
7.410 ± 0.045
7.423 ± 0.042
P C 0 , mmHg
40.0 ± 1.6
41.5 ± 2 . 6
43.4 ± 2.1
43.2 ± 1.7
42.9 ± 3.8
43.1 ± 3 . 8
HCO3 v, mmol/1
24.3 ± 1.4
23.9 ± 1.5
24.8 ± 2.6
25.4 ± 2.5
26.4 ± 2.7
27.5 ± 3.2
ABE , mmoW
0.3 ± 1.7
0.1 ± 1.8
0.8 ± 3.0
1.5 ± 2 . 8
2.5 ± 2.9
3.2 ± 3.0
5
a
2
a
v
2
V
v
2
v
a
a
2
3
a
v
v
2
V
TABLEAU I. — Cardiovascular, respiratory and acid-base parameters in sheep after epidural administration of 0.2 mg/kg xylazine hydrochloride (n : 6). Data are presented as mean ± standard deviation.
Mean arterial pressure, mmHg
70
Respiratory rate, min" 60 c
1-3
11
50 40
*** #
" -a- - . —*—
30 20 10 0
Time after administration (min)
FIGURE 1. — Mean arterial pressure (mmHg) in sheep after epidural (EA) or intravenous (IV) administration of 0.2 mg/kg xylazine hydrochloride (n = 6). Data are presented as mean ± standard deviation. *- p < 0.05 - values significantly different from baseline values.
Revue Med. Vet, 1998, 149, 1, 69-74.
Time after administration (min)
FIGURE 2. — Respiratory rate (breaths/min) in sheep after epidural (EA) or intravenous (IV) administration of 0.2 mg/kg xylazine hydrochloride (n = 6). Data are presented as mean ± standard deviation. ** - p < 0.01 ; *** - p < 0.001 - values significantly different from baseline values. # - values significantly (p < 0.05) different between groups.
A M I N K O V (В.) A N D P A S C A L E V (M.)
Baseline
Time after administration (min)
(time 0)
5
15
30
45
60
Heart rate, beats/min
103 ± 9
104 ± 31
113 ± 2 2
101 ± 28
94 + 24
94 ± 2 4
Systolic arterial pressure (mmHg)
134 + 7
133 ± 11
125 ± 7
126 ± 6
120 ± 4
125 ± 12
Mean arterial pressure (mmHg)
115 ± 5
1 0 4 + 12
99* ± 5
99* ± 5
102* ± 4
105 ± 7
Diastolic arterial pressure (mmHg)
103 ± 4
89 ± 23
82** ± 6
85* ± 6
91*±3
94 ± 6
Cardiac output, 1/min
6.7 ± 1.8
5.7 ± 1.4
5.5 ± 1.3
5.0 ± 1.2
5.1 ± 1.0
5.3 ± 1.2
Cardiac index, ml/min/kg
142 ± 16
125 ± 3 2
120 ± 30
110 ± 33
111 ± 20
117 ± 3 4
Stroke volume, ml/beat
65.5 ± 19.6
59.4 ± 10.5
50.8 ± 13.7
51.2 ± 12.7
58.1 ± 2 0 . 0
60.7 ± 22.0
Total peripheral resistance (dyn.s/cm )
1.40 ± 0 . 3 0
1.75 ± 0 . 3 7
1.69 ± 0 . 3 4
1.65 ± 0 . 2 7
1.54 ± 0 . 2 8
1.52 ± 0 . 3 2
Pulmonary artery blood temperature, °C
39.5 ± 0.6
39.5 ± 0.6
39.3 ± 0.6
39.3 ± 0.6
39.2 ± 0.7
39.2 ± 0.6
C a 0 2 , ml/dl
14.7 ± 1.7
10.8 ± 1.8
10.8 ± 1.7
10.7 ± 1.6
11.5 ± 2 . 2
11.4 ± 1.6
Hg a , g/1
110 ± 15
100 ± 10
93 ± 3
88 ± 11
92 ± 16
90 ± 13
Pv02, mmHg
72.9 ± 15.0
40.8 ± 16.8
40.1 ± 12.3
43.9 ± 11.2
50.2 ± 11.4
49.3 ± 10.9
SATV, %
78.9 ± 10.9
48.3 ± 16.7
58.7 ± 14.0
65.1 ± 11.6
72.5 ± 10.6
73.0 ± 8.9
C v 0 2 , ml/dl
10.9 ± 1.8
6.5 ± 2.5
7.0 ± 1.9
7.4 ± 1.6
8.3 ± 1.5
8.2 ± 1.1
Hg v , g/i
94 ± 12
95 ± 7
89 ± 10
84 ± 9
85 ± 11
83 ± 7
рна
7.423 ± 0.025
7.387 ± 0.035
7.424 ± 0.067
7.448 ± 0.030
7.484 ± 0.029
7.481 ± 0.035
PaC02, mmHg
39.3 ± 1.5
46.2 ± 6.4
43.9 ± 8.0
42.9 ± 3.2
41.6 ± 3 . 4
41.2 ± 2 . 9
H C 0 3 a, mmol/1
25.1 ± 1.5
27.3 ± 2.5
28.1 ± 2.3
29.8 ± 2.8
30.8 ± 3.0
30.8 ± 2.7
ABE a , mmol/1
1.5 ± 0 . 8
3.3 ± 2 . 2
4.2 ± 2.0
5.7 ± 3 . 1
7.2* ± 2.3
7.3* ± 2.2
PHV
7.400 ± 0.013
7.390 ± 0.056
7.403 ± 0.025
7.415 ± 0.038
7.429 ± 0.033
7.427 ± 0.025
PvC02, mmHg
42.0 ± 1.5
45.2 ± 4 . 0
44.5 ± 3.3
44.1 ± 2.6
43.5 ± 1.3
43.4 ± 2.3
HCO3 v, mmol/1
25.1 ± 2.3
25.5 ± 2.6
26.2 ± 2.5
27.6 ± 2.7
29.1 ± 3.5
28.5 ± 2 . 1
ABE V , mmol/1
2.2 ± 1.7
2.3 ± 2.0
2.9 ± 2.4
4.5 ± 1.6
5.9 ± 2 . 1
5.4 ± 1.1
Variable
5
TABLEAU II. — Cardiovascular, respiratory and acid-base parameters in sheep after intravenous administration of 0.2 mg/kg xylazine hydrochloride (n = 6). Data are presented as mean ± standard deviation. * - p < 0.05 ; ** - p < 0.01
140
100
РаСЬ, mmHg
95
120
90
100
Jg
80
§
60
- values significantly different from baseline values.
85 -
тл SS
80
40
-EA
20
1
J -
75 70
-EA
65
IV
0
SATa, %
IV
60 15
30
Time after administration (min)
FIGURE 3. — P a 0 2 (mmHg) in sheep after epidural (EA) or intravenous (IV)
0
5
15
30
45
Time after administration (min)
FIGURE 4. — SAT a (%) in sheep after
epidural (EA) or intravenous (IV)
administration of 0.2 mg/kg xylazine hydrochloride (n = 6). Data are pre
administration of 0.2 mg/kg xylazine hydrochloride (n = 6). Data are pre
sented as mean ± standard deviation.
sented as mean ± standard deviation.
*- p < 0.05 ;
*- p < 0.05 - values significantly different from baseline values.
* * - p < 0.01 - values significantly different from baseline values
# - values significantly (p < 0.05) different between groups.
# - values significantly (p < 0.05) different between groups.
Revue Med. Vet., 1998,149, 1, 69-74.
CARDIOVASCULAR A N D R E S P I R A T O R Y E F F E C T S O F E P I D U R A L V S I N T R A V E N O U S X Y L A Z I N E I N S H E E P
type. In four sheep, cyanosis and breathing with open mouth were observed. Tachypnea was significant at minutes 5, 15 (p < 0.001) and 30 (p < 0.001). From 0 to 5 min, respiratory rate increased from 27 ± 2 to 61 ± 5 breaths/min. The arterial oxygen partial pressure decreased significantly at times 5,15, 30 and 60 min (p < 0.05). The strongest hypoxaemia was observed at min 5 after the venous administration (p < 0.01). Arterial base excess increased continuously from 1.5 ± 0.8 (control conditions) to 7.3 ± 2.2 mmol/1 (at 60 min) (p < 0.05). The variations in the other parameters were not statistically significant.
In our study, the changes in P C 0 were not significant. The reports about the effect of xylazine on P C 0 levels were contradictory. Some authors have observed significant increase in this parameter after the intravenous administration of xylazine [3, 13, 14, 24], while others reported only a slight increase [4]. a
2
a
2
Discussion
The respiratory changes in EA-X sheep were not significant. Similar results were obtained after the epidural administration of clonidine [5]. In a previous study [2], the epidural administration of 0.4 mg/kg xylazine was shown to induce hypercapnia and metabolic alkalosis. In cattle [18], epidural xylaxine resulted in a significant cardiopulmonary depression.
The results of our study demonstrated that cardiopulmonary changes in sheep induced by xylazine depended on the route of administration of the drug. In sheep with IV-X, those changes were more intense compared to sheep with EA-X.
In conclusion, the epidural administration of 0.2 mg/kg xylazine ensured a safe anesthesia with minimal cardiopulmonary changes, while the intravenous route of administration was related to significant changes in both functions.
Xylazine was shown to provoke bradycardia, due to the direct increase of the vagal tone , decreased catecholamine release in the heart, decreased sympathetic activity from the CNS [1, 16] and enhanced baroreceptor reflex activity [16]. In sheep with IV-X, variable responses were observed - i.e. tachycardia in two sheep. A similar variable response after i.v. administration of 0.15 mg/kg xylazine in sheep was also reported by others [4]. The significant decrease in MABP and DABP was from a central origin and was probably due to parasympathetic activity - by inhibiting the sympathetic and enhancing the parasympathetic nervous system activity [9]. In sheep with EA-X, the cardiovascular changes were not significant. Similar observations were reported by EISENACH et al. [5]. We [2] have previously reported bradycardia following the epidural administration of 0.4 mg/kg xylazine in sheep. The changes in heart rate depend on the dose of xylazine. A good correlation between the dose and the cardiovascular changes was observed in the horse [10,20] after epidural administration of xylazine. While higher doses (0.25 mg/kg) led to bradycardia and hypotension [20], lower doses of 0.17 mg/kg did not result in significant cardiovascular changes [10]. The respiratory changes in both groups were contradictory. In IV-X sheep, the apnea and the tachypnea were not observed in EA-X sheep. The respiratory response was not uniform in all sheep with IV-X. In four sheep, P 0 decrease could be considered as life-threatening.Tachypnea was reported by other authors [3, 8] after IV administration of high doses of xylazine. The parenteral administration of xylazine resulted in a dose-dependent hypoxaemia [3, 4, 13, 14, 24]. The causes remained still unclear. As a possible cause for the profound hypoxaemia in sheep, the increase airway tone was suggested [11]. This effect is thought to be mediated by peripheral alpha adrenoceptors. Others suggested that a transient platelet aggregation and pulmonary microembolism could be involved [6, 15]. a
2
2
An other explanation of the observed hypoxaemia in sheep could also be to the direct stimulation of alpha -adrenergic receptors in the lungs [12]. 2
Revue Med. Vet., 1998, 149, 1, 69-74.
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