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Bas.J.Vet.Res.Vol.19, No.2, 2020.
HISTOPATHOLOGICAL AND BIOCHEMICAL EFFECTS OF
CHRONIC PROPOFOL EXPOSURE ON DOGS
Ahmed Ali Hussein, Jihad A. Ahmed
Department of Pathology and Poultry disease, College of Veterinary Medicine,
University of Basrah, Basrah,Iraq
(Received 7 March 2020,Accepted 17 may 2020)
Key word:Propofol, chronic, histopathology.
Corresponding Author: jihad.ahmed@uobasrah.edu.iq
ABSTRACT
This study was conducted in the veterinary medical college, university of Basra.
The objective of this study was to know the histopathological effect of propofol as
anesthetic agent on dogs organs (central nervous system, heart, liver) and effect of
propofol on liver enzymes, Propofol administration for 90 days by intravenous (into
cephalic vein) into 8 adult dogs which divided into two equal groups. The control
group was injected with 0.9% normal saline (1ml/kg), while the propofol group was
injected with (10mg /kg) body weight of dog per day. The measured parameters AST,
ALT showed a significant difference in groups between zero time and after 90 days.
Also the histopathological result of brain, heart and liver showed significant changes
as atrophic neurons, nerve fibers vacuolation and gliosis and histopathological result
of heart section showed white areas of degenerate myocardial muscle cells with
presence of adipose tissue and congested blood vessels, white areas of degenerate
myocyte as infiltration of adipose tissue at pericardial region (periphery) and areas of
destruction of myocardial muscle cells while the histopathological changes of
hepatocyte showed septal fibrosis, bile duct proliferation, fine defuse vacuolation of
hepatocyte and hypertrophic of bile duct. The uses of propofol for the long term may
cause serious Histopathological injuries in many organs particularly the brain and
liver that may due to its direct interaction in these structural units.
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INTRODUCTION
Propofol, 2,6-diisopropylphenol, is an ultra-short acting anesthetic agent used
intravenously in humans(1) and animals(2). It is a non-narcotic and non-barbiturate
anesthetic agent which is usually administered for maintenance of anesthesia with
rapid induction and recovery phases(3).
Propofol has been shown to be increasingly used in veterinary practice2, especially
in dogs and cats(4). This is in part due to its low incidence of anesthesia-related side
effects and the short half-life of the drug(5, 6) .
The clinically optimal concentration of propofol in serum is 2–5 μg/mL for
operation (7). Recent studies have shown that exposure to propofol contributes to
increase mortality in a rat model (8) as well as increase mortality and pathology(9).
However, an overdose of propofol may abnormally and pathologically cause
propofol infusion syndrome (PRIS) accompanied by severe complications in patients
(10).
The Aims of Study is toxicopathology study of long term administration of
propofol (high dose) in the Brain, Heart and Liver of dogs and detection of propofol
effect on some biochemical parameters including (ALT & AST) in dogs.
MATERIALS AND METHODS
Eight adult dogs (4 males and 4 females) were used for the study. The dogs were
assigned to two groups of four animals per group (two males and two females. The
dogs aged between 6 months and 3 years old and weighed between 15 and 25 kg.
They were obtained from the local markets in Basra city and housed two dog per
cage. They were fed cereal based food with meat and chicken every day. The dogs
were allowed two weeks to acclimatize to local conditions.
Dogs were fasted for 12 hours but access to water was allowed ad libitum,( dogs
cannot vomit). Animals were quietly and gently handled, Pre-anesthetic medication
comprised 2 mg/kg ketamine (Fresenius Kabi, Germany) and 1.1mg/kg xylazine
(VMD, Belgium), combined in the same syringe and injected into the femoral biceps
muscles. After approximately 10 minutes a cannula was placed into a cephalic vein.
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The dose of propofol (10mg/kg) body weight of dog in the experiment by
using four dogs as propofol group and repeated daily for 90 days(11) . Blood was
collected from the cephalic vein at zero time and after 90 days for biochemical liver
enzymes.
RESULTS
Biochemical results
The results of biochemical study of the effect of propofol on serum AST &
ALT level showed a significant (P<0.05) increase of serum AST and ALT level in
propofol group when compared with Control group (Table 1).
Table 1: Showed the effect of propofol on serum AST enzymes level. N = 12
(Mean ± SD).
AST
Groups
ZERO time 90 Day time
Control group 13.75 ± 0.4 b 14.25 ± 0.2 b
Propofol group 13.12 ± 1.08 b 393 ± 78.7 a
*Different small letter vertically refers to presence a significant differences
Table 2: Showed the effect of propofol on serum ALT enzymes level. N = 12
(Mean ± SD).
ALT
Groups
ZERO time 90 Day time
Control group 80.25 ± 6.2 b 78.97 ± 6.85 b
Propofol group 79.12 ± 1.08 b 179 ± 41.25 a
*Different small letter vertically refers to presence a significant differences
Bas.J.Vet.Res.Vol.19, No.2, 2020.
Histopathological Results
Histopathological results of brain of propofol group showed atrophic neurons
(Figure 1), : perneuronal vacuolation
(Figure 2).
Figure 1: Histopathological section of brain of propofol group showed atrophic
neurons (yellow arrow). H&E stain
Figure 2: Histopathological section of brain of propofol group showed gliosis
(proliferation of glial cells) (yellow arrow) and
arrow). H&E stain X400.
Histopathological results of heart of propofol group showed
congested blood vessels (Figure 3) and infiltration of adipose tissue at pericardial
20
esults
and gliosis (proliferation of glial
X400.
perneuronal vacuolation
fatty infiltration
cells) as in
(black
and
Bas.J.Vet.Res.Vol.19, No.2, 2020.
region (periphery) (Figure 4) and areas of
cells (Figure 5).
Figure 3: Histopathological section of Heart muscle of propofol group showed
infiltration (yellow arrow), and congested blood vessels (black arrow) . H&E stain
X100.
Figure 4: Histopathological section of Heart muscle of propofol group showed
infiltration of adipose tissue at pericardial region (periphery) (yellow arrow). H&E
stain X400.
21
focal necrosis of the myocardial muscle
Fatty
Bas.J.Vet.Res.Vol.19, No.2, 2020.
Figure 5: Histopathological section of Heart muscle of propofol group showed areas
of focal necrosis of the myocardial muscle cells
vessels (black arrow). H&E stain X
Histopathological results of liver of propofol group showed septal fibrosis and bile
duct proliferation (Figure 6)
hypertrophic of bile duct as in
Figure 6: Histopathological section of Liver of propofol group showed area of septal
fibrosis (yellow arrow), and bile duct proliferation (black arrow). H&E stain X400.
22
(yellow arrow), and congested blood
X400.
6), fine diffused vacuolation of hepatocyte (Figure 7) and
(Figure 8)
Bas.J.Vet.Res.Vol.19, No.2, 2020.
Figure 7: Histopathological section
difuse vacuolation of hepatocyte (black arrow). H&E stain X
Figure 8: Histopathological section of Liver of propofol group showed area of
hypertrophic of bile duct (yellow arrow). H&E stain
23
of Liver of propofol group
X400.
400X.
showed fine
.
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DISCUSSION
Effect of propofol on serum AST and ALT enzyme level
The current study showed a significant increase of serum AST and ALT levels in
propofol group when compared with control group. This may be due to the propofol effect on
the hepatocyte that was seen clear in histopathological section of hepatocyte (septal fibrosis,
bile duct proliferation and vacuolation of hepatocyte), This result is corresponding with
(Nguyen) who reported that propofol caused postoperative elevation of serum AST and ALT
level in patients(12).
Our results are also in agreement with (Kneiseler) who reported that an elevated serum
ALT level of pateint with developed jaundice and signs of hepatic failure one week after
surgery and propofol anesthesia(13), this result may be related to irreversible injury of
hepatocyte causes release of ALT into the circulation and their elevation.
From the results, it is noted that by increasing the dose of propofol the serum level of
hepatic AST is significantly increased when compared with the Control group, this result
may be related to the degree of hepatocytes damage caused by repeated dose of propofol.
The current result is in line with (Abdelhakiem) who observed that serum AST is released
from hepatocyte in proportion to the degree of tissue injury and disruption of
hepatocyte(14).
Histopathological effect of propofol on Brain
From the present results neuronal cells appeared to be severely affected by high dose of
propofol in which the treated groups showed atrophic neurons associated with perneuronal
vacuolation. This result may be related to the toxic effect of high dose of propofol on
neurons. The current result is in line with (Wei) who observed that propofol when
administered at clinical concentrations for prolonged time can activate toxic mechanisms
on neurons(15).
Our result of the treated group showed nerve fibers vacuolation, This result may be
related to the toxic effect of high dose of propofol, The current result is in line with (Chen)
who reported that effect of propofol that could promote Ca2+ dependent neuronal death is
inhibition of respiration therefore any impairment of mitochondrial respiration by propofol
could promote Ca2+-induced neurotoxicity(16).
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On the other hand, the current study showed gliosis (proliferation of glial cells) of
propofol treated group, our result is in line with (Weight) who found that lipid emulsion
used as a carrier for propofol may be responsible for glial activation(17). These findings
support the histopathological changes of glial cell in our results associated with propofol
treatment.
Histopathological effect of propofol on Heart
The present study showed histopathological damage related to propofol administered.
There were blood vessels congestion and fatty infiltration. This may be related to the
damage of myocardial muscle cells in propofol group, this result is in agreement with
(Wolf) who suggested that propofol toxicity might be attributed to impaired fatty acid
oxidation increasing the level of malonylcarnitine and C5-acylcarnitine(18).
Our results are in line with (Kam; Krajčová) who reported that prolonged propofol
overdose lead to propofol infusion syndrome (PRIS) is a rare but lethal condition
characterized by cardiac failure, refractory arrhythmia, hyperlipidemia(19,20).
Our result of treated groups showed focal necrosis of the myocardial muscle cells and
congested blood vessels, that may be related to high dose propofol toxicity, This result
agreed with (Kam) who documented cardiovascular abnormalities with PRIS include
supraventricular arrhythmias, ventricular arrhythmias, bradycardia, hypotension, and
asystole (19). Causes of cardiovascular abnormalities may be a direct result of
myocytolysis, hypoperfusion, cytopathic hypoxia, or alterations in beta-adrenergic
receptors and calcium channel proteins.
Histopathological effect of propofol on Liver
The histopathological changes in liver tissue of propofol group showed septal fibrosis
and fine difuse vacuolation of hepatocyte and bile duct proliferation and hypertrophic of
bile duct. These changes related to toxic effect of propofol on hepatocyte as a result of
exhaustion the capacity of centrilobular hepatocytes to metabolize high dose of propofol,
this result is in consistent with (Nguyen) who found
that patient treated with propofol leads to damage of hepatocytes that related to the toxic
potential of propofol to liver cells at high dose and showed acute hepatocellular injury
with mild fibrosis(12).
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Our result of treated group may be related to metabolism impaired by hepatocytes
because of their damage by propofol, these changes occur as an adaptation of hepatocytes
to compete for metabolism of propofol. This result is matched with (13,21,22) they found
prolong treated with propofol lead to imbalance of the mitochondrial respiratory chain,
leading to disruption on cellular energy production and, consequently, compromising
Krebs cycle, metabolism of amino acids and fatty acid oxidation and consecutive cell
death.
الآثار النسیجیة المرضیة والکیموحیویة للتعرض المزمن للبروبوفول على الکلاب
احمد علی حسین، جھاد عبد الامیر احمد
فرع علم الامراض وأمراض الدواجن ، جامعة البصرة ، کلیة الطب البیطری
الخلاصة
أجریت ھذه الدراسة فی کلیة الطب البیطری بجامعة البصرة. کان الھدف من ھذه الدراسة ھو معرفة التأثیر
النسیجی للبروبوفول کعامل مخدر على أعضاء الکلاب (الجھاز العصبی المرکزی والقلب والکبد) وتأثیر البروبوفول
على إنزیمات الکبد ، وقد تم عطاء البروبوفول لمدة ٩٠ یومًا عن طریق الورید (الورید الرأسی) إلى ٨ من الکلاب
١ مل / ) ٪ البالغة التی تنقسم إلى مجموعتین متساویتین. تم حقن المجموعة الضابطة بمحلول ملحی طبیعی بنسبة ٠.٩
AST کجم) ، فی حین تم حقن مجموعة البروبوفول بجرعة ( ١٠ مجم / کجم) للکلب یومیًا. أظھرت الانزیمات المقاسة
اختلافًا کبیرًا فی المجموعات بین وقت الصفر وبعد ٩٠ یومًا. کما أظھرت النتیجة النسیجیة للدماغ والقلب ALT ،
والکبد تغیرات کبیرة مثل الخلایا العصبیة الضامرة، وأعراض إفراغ الألیاف العصبیة والزلز والنتیجة المرضیة لنسیج
القلب ، أظھرت مناطق بیضاء من خلایا عضلة القلب المتدھورة مع وجود الأنسجة الدھنیة والأوعیة الدمویة المحتقنة
، والمناطق البیضاء المتدھورة لعضلة القلب کتسلل للأنسجة الدھنیة فی منطقة التامور (المحیط) فی حین أظھرت
التغیرات النسیجیة للخلایا الکبدیة تلیف الحاجز ، وانتشار القناة الصفراویة ، ونزع فتیل الخلایا الکبدیة وتضخم القناة
الصفراویة. قد تتسبب استخدامات البروبوفول على المدى الطویل فی حدوث إصابات نسیجیة خطیرة فی العدید من
الأعضاء وخاصة الدماغ والکبد التی قد تکون بسبب تفاعلھا المباشر فی ھذه الوحدات الھیکلیة.
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