Hematological and Physiological Effects of Ketamine with and without Xylazine in Dogs- Juniper Publishers
Juniper Publishers- Journal of Cell Science
Abstract
An experimental study was conducted to evaluate the
effects of ketamine alone and with xylazine combination on anesthetic
parameters; on physiological and hematological parameters so as to
choose a suitable general anesthetic combination for use in surgical
procedures in local breed of dogs in Mekelle, Ethiopia. The experimental
study was carried out on ten local breed of dogs and were randomly
divided in to two groups with five dogs in each group. Data was
collected for analyzing physiological effects of anesthetic
combinations; anesthetic effects and hematological effects using
physical recording and laboratory analysis. The results of this study
showed duration of general anesthesia was (91±6.28min) and animal
recovered (101.2±6.5min) and was longer in xylazine-ketamine
combination, whereas duration of general anesthesia was (30±1.05min) was
shorter in ketamine alone. The result also showed that the
physiological and hematological parameters remained significantly
unchanged during the anesthesia in both groups. Therefore, relation
duration of action, xylazine and ketamine combination was a suitable
choice for undertaking of surgical operations in dogs of local breed for
longer duration of action i.e. (91±6.28min) whereas ketamine alone was a
suitable choice for shorter duration of action i.e. (30±1.05min) but
increases significantly the heart rate. Further studies on several other
anesthetic combinations i.e. (acepromazine + xylazine + ketamine and
acepromazine + diazepam + ketamine) on local breed of dogs and several
other anesthetic combinations may be conducted.
Keywords: General anesthesia; Hematological parameter; ketamine; Local breed of dogs; Mekelle; Xylazine
Abbreviations:
ANOVA: Analysis of Variance; CSA: Central Statistical Agency; DLC:
Differential Leukocyte Counts; EDTA: Ethylene Diamine Tetra Acetic Acid;
GABAA: Gamma-Amino Butyric Acid Type A Receptors; Hbc: Hemoglobin
Concentration; IM: Intramuscular; Kg: Kilogram; Mg: Milligram; PCV:
Packed Cell Volume; SD: Standard Deviation; SPSS: Statistical Package
for Social Sciences; TEC: Total Erythrocyte Count; TLC: Total Leukocyte
Count; XK: Xylazine – Ketamine
Introduction
Ketamine hydrochloride is a dissociative anesthetic
of the cyclohexylamine group used for chemical restraint and for the
induction and maintenance of anesthesia in a number of species. Unlike
many anesthetics, ketamine usually stimulates cardiovascular function in
normal animals, causing increase in heart rate (HR) and mean arterial
pressure (MAP). The use of ketamine as a sole anesthetic has been
limited by muscle hypertonicity and myoclonus, violent recovery and
occasional occurrence of convulsions [1]. Ketamine is combined with an
alpha-2-agonist (e.g. xylazine), a benzodiazepine (e.g. diazepam) or a
phenothiazine tranquillizer (e.g. acepromazine) to enhance muscle
relaxation, analgesia, to prevent seizures/convulsions and prolong the
duration of anesthetic effect. It is associated with a rapid onset, good
to excellent sedation of one to two hours duration, excellent analgesia
and smooth recovery. The analgesia and sedation are due to central
nervous system depression and the muscle relaxation is due to the
central inhibition of intraneural transmission [2].
Ketamine is poor in visceral analgesia. However, it
can be used in combination with xylazine or diazepam to provide good
visceral analgesia in case of abdominal surgery (including
ovariohysterectomy) and thoracic surgery. Pain is an unpleasant sensory
or emotional experience most commonly associated with potential tissue
damage. The sensation of pain is a consequence of the activation of
specialized receptors and neurological pathways after such pain stimuli
[3,4]. Xylazine, an alpha-2 agonist used in animal experiments,
stimulates alpha-2 adrenergic receptor in cerebral presynaptic nerve
ends, inhibits release of catecholamines and dopamine resulting in
analgesic and sedative eff ects, and hinders nerve conduction in the
central nervous system leading to relaxation of striated muscles.
Xylazine is usually used in combination with ketamine during anesthetic
applications [5].
The combination of ketamine hydrochloride and
xylazine HCl usually result in a smooth induction and recovery with
cataleptic effects of ketamine HCl get ameliorated by the sedative and
myorelaxing effects of xylazine HCl. [6,7]. Studies on acute pain
in clinical cases have most often evaluated the effects of surgical
trauma on animals, while prevention and pain management are
the key issues in anesthesia [8,9]. When pain is not appropriately
managed, it is not only an animal welfare issue, but it can also
have many detrimental effects which can impact the patient
recovery [10]. A variety of physiological changes also occur in
response to pain such as increases in heart rate, respiratory rate,
blood pressure and body temperature [9,11,12]. Ketamine is
rarely used alone because of its association with poor muscle
relaxation, tachycardia and catalepsy or muscle rigidity.
Therefore, it is commonly used in combination with xylazine,
diazepam and acepromazine to minimize the adverse effects.
Moreover, there are different breed of dogs which require
proper anesthetic medicament combination. However, there are
limited or no experiments carried out to determine a specific
anesthetic combination in relation to the local breed of dogs in
the study area. Hence, determining the effects of the ketamine
in combination with other sedative agents may help to come
out with the safest combination for surgical procedures in local
breed of dogs. Therefore, the purpose of this study is to evaluate
the hematological and physiological effects of ketamine with and
without xylazine, for use in surgical procedures in local breed of
dogs in Mekelle, Ethiopia.
Materials and Methods
Study area
The present study was conducted from November 2016 to
April 2017 in Mekelle, Tigray, Ethiopia. Mekelle is the capital
of Tigray region located about 783 kilometers north of Addis
Ababa with a total area of approximately 102,000 square kilo
meters. Its geographic location is 13° 32`N latitude and 39°33`E
longitude with human population of about 215,546. It has an
average altitude of 2200 meter above sea level with a mean
minimum and maximum monthly temperature of 8.7 degree
Celsius and 26.8 degree Celsius respectively. The annual average
rainfall of Mekelle is 600 millimeters and more than 70 percent
of it falls between the months July and August. The long dry
season extends from October to May [13].
Study population
The present study was carried out on mature and apparently
healthy local breed of dogs weighing between 10-15kg and
aged between 2-4 years. Dogs were declared healthy based on
physiologically normal parameters i.e. rectal temperature, heart
rate, respiratory rate, and capillary refill time.
Sample size
The present study was carried out on ten mature and
apparently healthy local breed of dogs (six males and four
females).
Sampling technique
Ten dogs were randomly divided in to two groups, an
experimental group with five dogs (three males and two females)
in each group and one control group with five dogs (three males
and two females) in each group.
Experimental design and procedure
Ten (10) local breed of dogs were purchased, of which
five dogs were randomly assigned to an induction regimen of
ketamine alone (control group) and the other five dogs were
assigned to ketamine with xylazine (experimental group). The
dogs were housed individually in a kennel, fed meat and bread.
Prior to anesthesia, each dog was withheld of food and water
for 12 and 6 hours respectively. These dogs were placed in a
quiet kennel and left undisturbed. Heart rate, respiratory rate
and temperature were recorded prior to premedication. Blood
samples were taken prior to premedication. All dogs were
premedicated with atropine sulphate at 0.04mg/kg body weight
subcutaneously for the reduction of salivary and bronchial
secretions fifteen minutes before induction of anesthesia with
ketamine alone and with xylazine.
Administration of Drugs
Group 1-control group (ketamine alone)
First all dogs were premedicated with atropine sulphate at
0.04mg/kg body weight subcutaneously. After fifteen minutes
of premedication, a combination of xylazine and ketamine were
administered at two different doses of ketamine at 5mg/kg and
10mg/kg IM with one-week interval between trials.
Group 2- experimental group (ketamine with xylazine)
First all dogs were premedicated with atropine sulphate at
0.04mg/kg body weight subcutaneously. After fifteen minutes of
premedication, a combination of xylazine and ketamine at two
different doses diazepam and ketamine at 1mg/kg and 5mg/kg
respectively and again at 2mg/kg and 10mg/kg intramuscularly
respectively with one week interval between trials.
Monitoring of post intervention
After administration of the ketamine alone and with
xylazine, dogs of all groups were kept under close observation.
Induction period, duration of anesthesia and recovery period
were recorded. Rectal temperature, respiratory rate, and heart
rate were recorded every 5 minutes interval after administration
of the anesthetic combinations.
Hematological and physiological parameters
Three ml of blood sample were collected from cephalic
vein of each experimental dog prior to administration of the
premedication (atropine sulphate) and 30-45 minutes after
administration of the anesthetic agents; because maximum
effects occurred at 30-45 minutes. Immediately after collection,
the blood samples were transferred in a sterile test tube
containing Ethylene Diamine Tetra acetic acid (EDTA) as
anticoagulant for estimation of Packed Cell Volume, White
blood cells, Hemoglobin concentration, red blood cells and
differential leukocyte counts according to the procedures of
[14]. Physiological parameters like heart rate, respiratory rate and rectal temperature were measured every five minutes after
administration of the anesthetic combinations.
Data collection
Data were collected on physiological effects (heart rate,
respiratory rate and rectal temperature), anesthetic effects
(induction period, duration of anesthesia, recovery period,) and
hematological effects (packed cell volume, red blood cells, white
blood cells, hemoglobin concentration and differential leukocyte
counts.
Data analysis
The recorded data was entered into Microsoft excel sheet
and analyzed to Mean±SD (Standard Deviation) using Statistical
Package for Social Sciences (SPSS) version 17.0. Paired
t-test was used to compare physiological and hematological
parameters taken before and during the administration of the
drug combination for each group. One-Way Analysis of Variance
(ANOVA) at 95% confidence interval (CI) was used to determine
the level of significant difference in mean values among three
groups; to compare the means of induction time, duration of
anesthesia and recovery time between the groups. Values of
p≤0.05 were considered as statistically significant and Values of
p>0.05 was considered as non-significant.
Results
Anesthetic effects of ketamine alone and ketamine with xylazine
In this study, the duration of action ketamine alone at a
respective dose of 5mg/kg and 10mg/kg body weight given
intramuscularly were 30±1.05 minutes, 25±1.05 minutes,
respectively, whereas in ketamine with xylazine, the duration
of action was 68±6.28, 91±6.28 minutes at lower and higher
doses respectively (Table 1). So, in this study, the duration of
anesthesia was longer in ketamine with xylazine combination as
compared with ketamine alone.
Body Reflexes Activity
Rightening reflex
In the current study, the different body reflexes activities
were assessed during the anesthesia for the sake of assessing
the depth of anesthesia. The rightening reflex was elicited by
squeezing or pinching a digit of fore limb and observed whether
the dog flexes the leg or withdraws the digit from the investigator
during the examination after administration of the anesthetic
combinations. In ketamine with xylazine the rightening reflex
was lost at 8±2.12 minutes in xylazine-ketamne at dose rate of
1mg/kg and 5mg/kg, respectively, 6 ± 2.12 minutes in xylazineketamne
at 2mg/kg and 10mg/kg, respectively (Table 2). In this
study, the rightening reflex remained unchanged throughout the
anesthesia in both groups.
Palpebral reflex
The palpebral reflex was tested by lightly taping the lateral
canthus or medial canthus of the eye and observed whether the
dog blinks in response after administration of the anesthetic
combinations. In ketamine with xylazine the palpebral reflex
was lost at 8.1±2.12 minutes in xylazine-ketamne at 1mg/kg and
5mg/kg, respectively, 6.1±2.12 minutes in xylazine-ketamne at
2mg/kg and 10mg/kg, respectively (Table 2). In this study, the
palpebral reflex remained unchanged throughout the anesthesia
in both groups.
Corneal reflex, eye position and pupil size
Corneal reflex was tested by touching the cornea with a drop
of sterile water and noted whether the dog blinks in response
and withdraws the eye into the orbital fossa. In this observation,
the time for corneal reflex loss was the same as to the time loss
for palpebral reflex in both groups. In ketamine with zylazine the
corneal reflex was lost at 8.1±2.12 minutes in xylazine-ketamne
administered at dose rate of 1mg/kg and 5mg/kg, respectively,
6.1±2.12 minutes in xylazine-ketamne at 2mg/kg and 10mg/kg,
respectively (Table 2) In both groups the eyes remained opened,
with a central and dilated pupil during the anesthesia. In this
study, the corneal reflex remained unchanged throughout the
anesthesia in both groups.
Pedal reflex
The pedal reflex was elicited by squeezing or
pinching a
digit of hind limb and observed whether the dog flexes the leg or
withdraws the digit from the investigator during the examination
after administration of the anesthetic combinations. In group
1 the pedal reflex was lost at 8.6±2.12 minutes in xylazineketamne
at 1mg/kg and 5mg/kg, respectively, 6.6±2.12 minutes
in xylazine-ketamne at 2mg/kg and 10mg/kg, respectively
(Table 2). In this study, the pedal reflex remained unchanged
throughout the anesthesia in both groups.
Physiological Effects of Ketamine alone and ketamine with
xylazine
Heart rate, respiratory rate and rectal temperature were
recorded every 5 minutes after administration of the anesthetic
combination of xylazine and ketamine up to the time of
recovery. The recorded heart rate, respiratory rate and rectal
temperature at 60 minutes after administration of xylazine
and ketamine were the same as to the recorded values before
administration of the xylazine and ketamine so not analyzed;
only those values recorded up to 60 minutes were analyzed. In
this study, the heart rate was decreased non- significantly (P =
0.061) from 30 minutes up to 45 minutes after administration of
the combination of xylazine – ketamine (Table 3). The recorded
respiratory rate was decreased non- significantly (P = 0.065)
from 10 minutes up to 45 minutes following administration of
the combination of xylazine – ketamine (Table 3). The recorded
rectal temperature was also decreased non- significantly (P =
0.063) from 20 minutes up to 45 minutes after administration of
the combination of xylazine – ketamine on both doses (Table 3).
Ketamine alone and ketamine with xylazine
In the current study, blood samples were taken before
and during administration of ketamine alone (Table 4)
and the anesthetic combinations of xylazine-ketamine for
evaluating of hemoglobin concentration, packed cell volume,
total erythrocyte count, total leukocyte count, neutrophils,
lymphocytes, monocytes, eosinophils and basophils. In group
1 hemoglobin concentration (P = 0.066), packed cell volume
(P = 0.073), total erythrocyte count (P = 0.069), total leukocyte
count (P = 0.079), lymphocyte (P = 0.064), monocyte (P = 0.061),
eosinophil (P = 0.074) and basophils (P= 0.084) were decreased
non-significantly, Neutrophils (P = 1.000) were increased nonsignificantly
from 58.8±0.39 to 64±0.68 (Table 5).
HBC = Hemoglobin concentration, PCV = Packed cell volume, TEC = Total erythrocyte count, TLC = Total
leukocyte count, NTP = Neutrophil, LYM = Lymphocyte, MN = Monocyte, EOS = Eosinophil, BAS = Basophil
In group 2 hemoglobin concentration (P = 0.062), packed
cell volume (P = 0.065), total erythrocyte count (P = 0.067), total
leukocyte count (P = 0.078), lymphocyte (P= 0.084), monocyte
(P = 0.071), eosinophil (P = 0.0614) and basophils (P= 0.083)
were decreased non-significantly, on the other hand, neutrophils
(P = 1.0211) were increased non-significantly from 58.8±0.39 to
66.5±0.34 (Table 5).
Discussion
Ketamine is rarely used alone because of its association with
poor muscle relaxation, tachycardia and catalepsy or muscle
rigidity and it is therefore commonly used in combination with
xylazine, diazepam and acepromazine to minimize the untoward
effects. The highest duration of anesthesia was observed in the
dogs of Group 2 (experimental group) as compared to group
1 (control group). This might be due to wide-distribution of
xylazine and ketamine combination in the body, because they are
highly soluble in lipid and can be redistributed into muscles and
adipose tissues [15]. The results obtained here were relatively
in line with the findings of [16] who found 8.3 minutes onset of
action after administration of xylazine at dose rate of 1mg/kg and
ketamine at dose rate of 10mg/kg body weight intramuscularly
and [17] who reported 96 minutes duration of action after
administration of xylazine at dose rate of 1mg/kg and ketamine
at dose rate of 5mg/kg body weight intramuscularly.
In this study, the onset of action of xylazine and ketamine
combination was relatively 6 minutes rapid when compared to
the studies by [18] who found 12 minutes after administration
of xylazine at dose rate of 1mg/kg and ketamine at dose rate of
15mg/kg body weight intramuscularly. The duration of action
of xylazine and ketamine combination was relatively 35.75
minutes longer when compared to the studies by Sindak et al.
[16] reported 55.25 minutes. The duration of action of xylazine
and ketamine combination was relatively 19.4 minutes longer
when compared to the studies by Emami et al. [18] found
71.60±3.07 minutes. The recovery time of xylazine and ketamine
combination in the present finding was relatively 27.85 minutes
longer when compared to the study by Sindak et al. [16] reported
73.15 minutes. This finding difference in the present study
from previous studies might be due to difference in breed and
physiological status of the dogs or might be due to difference in
dose of the anesthetic agents.
In this study, heart rate was increased significantly at
15-35 minutes after administration of ketamine alone but
decreased non- significantly at 30-45 minutes, respiratory rate
was decreased non-significantly at 10-45 minutes and rectal
temperature was decreased non- significantly at 20-45 minutes
after administration of xylazine and ketamine combination. The
decrease in heart rate, respiratory rate and rectal temperature
in this study were in agreement with the studies by Sindak et
al. [16] reported decreased heart rate at 30- 45 minutes after
administration of xylazine and ketamine combination, decrease
in respiratory rate and decrease in rectal temperature at 20-
45 minutes after administration of xylazine and ketamine;
Mwangi et al. [19] reported decreased rectal temperature at 30
minutes and Emami et al. [18] reported decreased respiratory
rate at 5-55 minutes following administration of xylazine and
ketamine combination. On the other hand, Afshar et al. [20]
reported significant decrease in heart rate at 15-60 minutes
after administration of xylazine and ketamine combination; Kul
et al. [21] reported significant decreased in respiratory rate at
15-60 minutes after administration of xylazine and ketamine
combination; Demirkan et al. [22] reported significantly
remained lower respiratory rate than the baseline throughout
the xylazine and ketamine anesthesia and rectal temperature
remained significantly decreased at 30-60 minutes after
administration of xylazine and ketamine combination.
The decreases in rectal temperature after administration
of xylazine and ketamine combination found in the present
study were in contrary with the findings of Wyatt et al. [23]
reported unchanged in rectal temperature after administration
of xylazine at 1mg/kg and ketamine at 10mg/kg body weight
intramuscularly in dogs. The decrease in body temperature
after the administration of ketamine alone and xylazineketamine,
could be explained by blocking of the hypothalamic
thermoregulatory center. The decrease in heart rate could be
attributed to inhibition of the release of the neurotransmitter
noradrenalin or depression of the sympathetic activity.
The decrease in respiratory rate could be attributed to
depression of the respiratory center by the ketamine alone,
xylazine-ketamine, [24]. The non-significant decrease in heart
rate, respiratory rate and rectal temperature in the present study
when compared to other studies might be due to difference in
breed and physiological status of the dogs or might be due to
difference in dose of the sedative agents. After administration
of ketamine alone, and xylazine - ketamine combinations, the
hemoglobin concentration, packed cell volume, total erythrocyte
count, total leukocyte count, lymphocyte, monocyte, eosinophil
and basophils were decreased non-significantly, but neutrophils
were increased non-significantly. Pooling of circulating blood
cells in the spleen and other reservoirs secondary to decreased
sympathetic activity could be the reason for a decrease in
hemoglobin concentration, packed cell volume, total erythrocyte
count, total leukocyte count, lymphocyte, monocyte, eosinophil
and basophils [25]. The decrease in hemoglobin concentration,
packed cell volume, total erythrocyte count, total leukocyte
count, lymphocyte, monocyte, eosinophil and basophils after
administration of ketamine alone, xylazine and ketamine
combination might be attributed to the shifting of fluid from
extravascular compartment to intravascular compartment in
order to maintain normal cardiac output in the dogs [26].
This finding is in agreement with the findings of Mahmud
et al. [27] who had reported decreased the hemoglobin
concentration, packed cell volume, total erythrocyte count,
total leukocyte count, lymphocyte, monocyte, eosinophil and basophils and increased neutrophils after administration of
xylazine at 0.4mg/kg and ketamine at 10mg/kg combination
in dogs. In the current study, heart rate was decreased nonsignificantly
at 30-45 minutes, respiratory rate decreased nonsignificantly
at 10-45 minutes after administration of ketamine
alone, the xylazine-ketamine, intramuscularly and rectal
temperature decreased non-significantly at 20-45 minutes
after administration of ketamine alone, and xylazine-ketamine,
combinations intramuscularly [28-30].
Conclusion
Ketamine is rarely used alone because of its association
with poor muscle relaxation, visceral analgesia, tachycardia
and catalepsy or muscle rigidity. Therefore, it is commonly used
in combination with xylazine, diazepam and acepromazine to
enhance muscle relaxation, to provide good visceral analgesia in
case of abdominal surgery (including ovariohysterectomy) and
thoracic surgery, to prevent seizures/convulsions and to prolong
the duration of anesthetic effect. The study was conducted on
10 mature and apparently healthy local breed of dogs which
were randomly grouped in to Group I and Group II. All dogs were
premedicated using atropine (0.04mg/kg BW, S.C). After 15
mints premedication, anesthesia induced with ketamine a lone,
and xylazine-ketamine (1.0mg /kg/BW+10.0mg/kg BW, I.M) for
Group I, and Group II respectively. The anesthetic parameters;
induction time, duration of anesthesia recovery period, the
physiological parameters; temperature, heart rate, respiratory
rate, and the hematological parameters; packed cell volume,
total erythrocyte count, total leukocyte count, hemoglobin
determination were recorded and analyzed in all both groups
and all the anesthetic parameters were found statistically
significant but the physiological and hematological parameters
were statistically non-significant in both groups. The results of
the present study concluded that xylazine-ketamine combination
is useful anesthetic protocol for rapid induction, prolonged
duration of anesthesia; diazepam-ketamine combination is useful
anesthetic protocol for short duration of anesthesia and rapid
recovery. All drug combinations do not affect the physiological
and hematological parameters of the animals during the study
time and all of them can be safe for surgical procedures if used
safely and appropriately. However, further studies on several
other anesthetic combinations i.e. (acepromazine + xylazine +
ketamine and acepromazine + diazepam + ketamine) on local
breed of dogs and several other anesthetic combinations may be
conducted.
Acknowledgements
A special gratitude goes to Mekelle University, without its
support; the study would not have been possible. Great thanks
go to Dr. H. for all his help in analyzing the research data and Mr.
Yisehak, T. the surgery technician for his help and cooperation
rendered during the experimental study. I never forget to say
thanks to Mr. Kane, W. the pathology laboratory staff worker for
his help, patience, permission and full information during my
working period.
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