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Effect of Injectable Ketamine on Histopathological Changes in the Liver in Neonates Born to Pregnant Rats Subjected to Short-Term and Long-Term Anesthesia
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Afagh Zamen Ghadirli1    , Hessamedin Babaei1 , Marzieh Goodarzi1 , Soheil Shahramirad1 , Aref Arminfar1 , Alireza Avazzadeh1 , Behrooz Yahyaei *2 , Leila Khojasteh3 |
1- Medical Student, Student Research Committee, Shahrood Branch, Islamic Azad University, Shahrood, Iran.
2- Assistant Professor, Department of Medical Sciences, Shahrood Branch, Islamic Azad University, Shahrood, Iran. Assistant Professor, Biological Nanoparticles in Medicine Research Center, Shahrood Branch, Islamic Azad University, Shahrood, Iran. , behroozyahyaei@iau.ac.ir
3- Assistant Professor, Biological Nanoparticles in Medicine Research Center, Shahrood Branch, Islamic Azad University, Shahrood, Iran. |
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Keywords: Ketamine [MeSH], Anesthesia [MeSH], Histology [MeSH], Pathology [MeSH], Liver [MeSH], Rats [MeSH]
Article ID: Vol27-01 |
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Type of Study: Original Articles |
Subject:
Physiology - Pharmacology
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Abstract: (391 Views) |
KExtended Abstract
Introduction
Ketamine is an analgesic agent with notable safety features, rendering it a popular induction agent for anesthesia. Given that ketamine suppresses respiration significantly less than other available anesthetic drugs, it is utilized in medicine as an anesthetic. However, due to the hallucinations it may induce, it is not typically employed as a primary anesthetic, and it serves as the first-line anesthetic choice when reliable intubation equipment is unavailable. Ketamine is frequently utilized in severely injured individuals and appears to be safe within this population. Potential adverse effects associated with ketamine administration include transient apnea, increased salivary gland secretion, laryngospasm, partial airway constriction, hypothermia, emergence phenomenon, and neurotoxicity. Ketamine can cross the placenta and reach the fetus, potentially exerting significant effects on fetal development. Ketamine has been shown to impair learning and memory capacity in neonatal rats exposed to ketamine-induced anesthesia. Furthermore, ketamine uses in neonates has been found to result in several adverse events, such as tachycardia, hypertension, and laryngospasm. Exposure to ketamine during pregnancy can also culminate in cardiomegaly or heart enlargement, disrupted myocardial tissue, and reduced cardiac contractile function in the offspring of exposed rats. Additionally, ketamine can induce widespread apoptosis and cell death of nerve cells in the brains of premature infants. These effects can disrupt normal neuronal development and alter brain structure and function. Ketamine is extensively metabolized in the liver by microsomal enzymes into metabolites I and II and is excreted through urine. In chronic use conditions, ketamine and its metabolites cause damage to hepatocytes and other liver cells. Ketamine-induced hepatotoxicity may be dependent on mitochondrial destruction. Ketamine abuse appears to culminate in dilation of the common bile duct, microscopic damage to the bile duct, and even significant hepatic fibrosis. This study was conducted to determine the effect of injected ketamine on the histopathological changes in the livers of neonates born to pregnant rats subjected to short-term and long-term anesthesia.
Methods
This experimental study was conducted on 15 female Wistar rats, with a mean weight of 200 ± 2 g, in the Exercise Physiology Laboratory at Islamic Azad University, Shahroud Branch, Iran during 2018. The rats were divided into groups of 5 animals each. Following a one-week acclimatization period, pregnancy was induced in the animals by housing two male rats within each group of 5 females. The zero day of pregnancy was determined by vaginal smears and the observation of vaginal plugs.
The pregnant rats were randomly assigned to 3 groups of 5 as follows:
- Control Group: Received no anesthetic drug.
- Experimental Group 1 (short-term Aanesthesia): Intraperitoneal injection of ketamine at a dosage of 25 mg/kg/bw, three times per week for four weeks.
- Experimental Group 2 (long-term anesthesia): Intraperitoneal injection of ketamine at a dosage of 75 mg/kg/bw, once per week for four weeks.
Following parturition and during the lactation period, when the neonatal rats reached two weeks of age, they were initially anesthetized and sacrificed for tissue sampling via intraperitoneal injection of 7 units of ketamine and 3 units of xylazine using an insulin syringe. Subsequently, their abdominal cavity was incised with a surgical blade, and the liver structure was dissected out using scissors and forceps and weighed using a digital scale. Four sections, approximately 5 micron in thickness, were taken from each of the four lobes of the liver from all neonatal rats and immediately placed in containers containing a 10% formalin solution for tissue fixation. Following a 24-hour period, the formalin solution was replaced. The collected samples were then sent to the histology laboratory for the preparation of histological sections. Afterward, the received samples underwent dehydration, clearing, embedding, and sectioning procedures for preparation. Finally, the samples were stained with hematoxylin and eosin, and the slides were examined using a light microscope (Olympus CX21, Japan) at magnifications of 100 and 400. The severity and criteria of pathological changes in the liver tissue of neonatal rats were assessed by comparing normal hepatic structures, including the centrilobular vein, sinusoidal space, hepatocyte cells, Kupffer cells, and portal space with ketamine-induced groups. The observed qualitative changes were graded from zero to 3, where grade zero indicated no observed changes, grade 1 indicated mild changes, grade 2 indicated moderate changes, and grade 3 indicated severe changes.
Results
The histological features of all sections prepared from the liver tissue of neonatal rats in the control group were completely normal. The liver structure exhibited order and integrity, with no observable changes. In the liver tissue of the control group, the centrilobular vein, sinusoidal space, and hepatocyte cells were normal. Kupffer cells, which are considered liver macrophages, were visible in the aforementioned spaces with appropriate numbers and distribution. The portal space was also well-defined around the lobules, and its components were discernible.
The histological sections prepared from the livers of all neonatal rats in the short-term dose group exhibited slight changes compared to the control group. In certain areas, the centrilobular veins showed dilation and fluid accumulation. Hyperemia was observed in the centrilobular veins and the sinusoidal spaces. Some hepatocytes displayed degenerative-necrotic changes and had acidophilic and dark cytoplasm. Kupffer cells were observed with appropriate numbers and distribution within the sinusoidal space. The portal space presented normal characteristics.
Histological sections prepared from the livers of all neonatal rats in the long-term dose group exhibited several changes, including hyperaemia in certain regions, such as the portal space, as well as increased dilation of sinusoidal spaces. The centrilobular veins also displayed varying sizes and marginal irregularities, with fluid and blood accumulation observed in some of them. Certain hepatocytes showed vacuolar and necrotic changes. Kupffer cells within the sinusoidal space were observed with appropriate number and morphology.
Conclusion
Based on the results of this study, the use of ketamine for anesthesia in pregnant rats, whether short-term and repeated or long-term, can lead to liver tissue damage in their offspring. In the long-term group, these damages were observed with greater intensity at the hepatocyte and portal levels, and in the short-term group, they were observed with greater intensity in the sinusoidal space and centrilobular vein.
In this study, the effects of ketamine administration to mothers on the liver fibrosis of their neonates were also investigated, and no apparent fibrosis was observed.
Ethical Statement
The current study was approved by the Research Ethics Committee of Islamic Azad University, Shahroud Branch (IR.IAU.SHAHROOD.REC.1397.028), and the protocol for working with laboratory animals was adhered.
Funding
This article has been extracted from Marzieh Goudarzi’s Ph.D dissertation in Medicine at Islamic Azad University, Shahroud Branch.
Conflicts of Interest
No Conflicts of interest.
Key Message: Ketamine administration to pregnant rats at varying dosages and durations can have an impact on the hepatic morphology of their neonates, potentially leading to liver damage. |
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Zamen Ghadirli A, Babaei H, Goodarzi M, Shahramirad S, Arminfar A, Avazzadeh A, et al . Effect of Injectable Ketamine on Histopathological Changes in the Liver in Neonates Born to Pregnant Rats Subjected to Short-Term and Long-Term Anesthesia. J Gorgan Univ Med Sci 2025; 27 (1) :1-8 URL: http://goums.ac.ir/journal/article-1-4473-en.html
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