Review of the Hazards and Contraindications of Etomidate

Abstract

Etomidate, an ultrashort-acting non-barbiturate sedative derived from imidazole, exerts potent inhibitory effects on the central nervous system. It is commonly employed for the induction of intravenous general anaesthesia or assisted anaesthesia. Recently, etomidate has emerged as an alternative to narcotics and novel psychoactive substances, leading to an increasing trend of abuse. Chronic overdose of etomidate can result in irreversible brain damage and various mental disorders. Severe cases may manifest as mental disturbances, behavioural disorders, self-mutilation and even death. The toxicological mechanisms of etomidate remain poorly understood. Additionally, there is limited information on the clinical symptoms and histopathological changes associated with etomidate poisoning and standardized detection methods for etomidate in blood, urine and hair are lacking. Consequently, further research on toxicological pathology and the development of reliable testing methods is crucial. This study reviews the metabolism, distribution, adverse reactions, poisoning manifestations, toxicology mechanisms and testing methods of etomidate.

Keywords

etomidate poisoning manifestations toxicological mechanisms overdose drug abuse

Introduction

Etomidate (CAS # 33125-97-2) is an ultrashort-acting non-barbiturate sedative derived from imidazole, with a chemical formula of C₁₄H₁₆N₂O₂ and a molecular mass of 244.289 (Figure 1).¹ It is widely used in endoscopy and the induction of general anaesthesia, and usually administered by intravenous injection (0.2–0.6 mg/kg).¹ Following intravenous injection, etomidate rapidly penetrates the blood–brain barrier and activates γ-aminobutyric acid A (GABAA) receptors in the prefrontal cortex by enhancing the activity of γ-aminobutyric acid (GABA) neurons in the hippocampus, thereby exerting its anaesthetic effects.^2,3 Compared to other anaesthetics, etomidate is superior in maintaining haemodynamic stability and is thus considered an optimal anaesthetic option.⁴ However, in recent years, marijuana, morphine, heroin, methamphetamine, ketamine, synthetic cannabinoids and new psychoactive substances have been classified as controlled substances, restricting their availability. Consequently, the use of etomidate as an alternative has increased, along with a trend of abuse. Additionally, some individuals have illicitly prepared etomidate into e-liquid and added it to e-cigarettes for sale, causing concern in South Korea.⁵ Due to its abuse potential and public health impact, China has classified etomidate as a class II psychotropic drug as of October 1, 2023, and implemented strict management protocols.⁶

Figure 1.

Molecular structure of etomidate.

Long-term use or overuse of etomidate can result in serious health problems, including limb tremors, dizziness and potentially irreversible brain damage.^3,5 Additionally, abuse can lead to mental disorders such as paranoia, anxiety, panic, hallucinations and persecutory delusions. In severe cases, it may cause mental disturbances, behavioural disorders, self-mutilation and even death. Therefore, it is crucial to closely monitor cases of suspected etomidate abuse or overdose deaths. However, the toxicological mechanisms of etomidate remain unclear. Furthermore, there is no standardised reference for fatal blood or urine concentration, posing significant challenges for toxicological practitioners. Therefore, this study aims to review the metabolism and distribution, adverse reactions, manifestations of overdose, toxicological mechanisms and testing methods for etomidate. Additionally, it outlines future research directions in toxicology and pathology, intending to improve understanding of its toxicological mechanisms, clinical use, diagnosis of overdose and identification of etomidate.

Metabolism and Distribution of Etomidate

Upon intravenous injection, etomidate rapidly distributes into the brain due to the rich blood supply and its high lipid solubility, facilitating rapid penetration of the blood–brain barrier.⁸ Subsequently, it gradually migrates to adipose tissues. Forman¹ SA delineated three stages of plasma etomidate concentration decline: rapid, moderate and slow decline. These stages corresponded to the distinct metabolic processes: initial distribution to highly perfused tissues like the brain and heart, subsequent distribution to peripheral tissues, primarily muscles; and finally, terminal metabolic processing.⁹ Approximately 75% of etomidate binds to plasma proteins under normal physiological conditions, significantly influencing its distribution and action.⁷ While etomidate induces sedative and hypnotic effects upon reaching the central nervous system, these effects dissipate upon redistribution to peripheral tissues.^2,11

Etomidate undergoes primary degradation in the liver. The total plasma clearance rate of etomidate ranges from 15 to 20 ml/kg/min, with a final metabolic half-life in the human body of 2–5 hours.^1,9,11 Degradation is most rapid with the initial 30 minutes post-administration, followed by a more gradual phase.³ Experimental studies have demonstrated a close correlation between the metabolic rate of etomidate and the activity of hepatic esterase in both animals and human.^10-12 Carboxylesterases (CES) hydrolyze etomidate into 1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid and an ethanol-leaving group.⁴ Carboxylic acids are primarily excreted via the kidneys in urine, with a lesser amount excreted through bile. Previous studies suggested that within the first day post-injection, 75% of the etomidate metabolite, 1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid, is excreted in urine, increasing to 80% thereafter, with only 2% excreted as the parent compound.^1,3,9,13 In addition to intravenous injection, etomidate can be administered orally and rectally to induce sedation, and indicating good drug absorption.^9,10

The metabolic characteristics of etomidate and its main metabolite, 1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid, are crucial for understanding its potential for abuse.⁴ Etomidate’s high lipid solubility allows it to quickly cross the blood-brain barrier, exerting sedative and hypnotic effects rapidly, which may be a potential factor for abuse.^3,4,9,13 Its metabolism in the liver can be affected by other drugs or liver diseases, interfering with its clearance and increasing the risk of toxicity. Further research is needed to study the concentration and role of 1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid in the potential abuse of etomidate.

Adverse Reactions to Etomidate

Primary Adverse Reaction – Myoclonus

During anaesthesia induction with etomidate, various adverse reactions may occur, including injection-site pain, phlebitis, hemolysis and myoclonus, with myoclonus having the highest incidence.¹² Preliminary research has reported that myoclonus occurs in 10% to 65% within 30–60 seconds after bolus injection of etomidate.¹⁴ Although the use of etomidate emulsion instead of aqueous solution can reduce adverse reactions such as phlebitis, hemolysis and injection-site pain, the incidence of myoclonus remains high, ranging from 50% to 80%.¹⁵

Clinical manifestations of etomidate-induced myoclonus resemble epileptic seizures but differ fundamentally. Myoclonus seizures are not epileptic but share similarities with convulsions and certain forms of epilepsy.¹⁶ Previous studies have revealed that etomidate inhibits the brainstem ascending reticular activating system by binding to GABAA receptors, thereby inhibiting higher centres like the cerebral cortex.¹⁷ This inhibitory effect results in disinhibition in lower centres such as subcortical structures, increasing skeletal muscles’ sensitivity to movement and triggering myoclonus. While etomidate-induced myoclonus is typically transient, it can pose significant risks, particularly in patients with cardiovascular diseases such as hypertension, aneurysms and coronary heart disease.¹⁴ Moreover, evidence suggests that smoking e-cigarettes containing etomidate can lead to vertigo and drunkenness, accompanied by symptoms such as blurred eyes, bradykinesia and tremors in the hands or arms.¹⁸

Other Adverse Reactions

Etomidate injections without pretreatment can cause intense pain. Currently, etomidate is commonly used in clinical practice as a 0.2% solution of 35% propylene glycol or as a lipid emulsion prior to surgery, for the purpose of alleviating pain during the injection process.^14,15 Additionally, bradycardia and decreased oxygen saturation may occur post-injection.¹⁹ Oral administration of etomidate may induce gastrointestinal adverse reactions such as nausea and vomiting.²⁰ There are two main dosage forms of etomidate: aqueous and emulsion. The incidence of pain with etomidate injection is 50% to 70%, and incidence of nausea and vomiting is 20% to 30%.^11,20 It appears that aqueous injections of etomidate are associated with a heightened risk of injection pain and gastrointestinal adverse reactions.

Furthermore, as an anaesthetic agent, the time to respiratory recovery, eye opening and extubation were all correspondingly prolonged after intravenous administration of etomidate.²¹ These delays become more pronounced with increasing etomidate dosage.²¹ This delayed recovery may be attributed to the longer desensitisation time of GABAA receptors leading to sub-neurocortical disinhibition.^21,22

Toxicological Mechanisms

Adrenocortical Dysfunction

Etomidate, a potent inhibitor of adrenal steroidogenesis, significantly impacts adrenal function in clinical applications.^23-25 Bloomfield R et al. found a significant association between the use of etomidate and the increase of critical patients’ mortality, particularly in specific patient populations, which highlighting the potential risks of etomidate in critical patients.²⁴

The increase in etomidate-related mortality is primarily linked to its inhibition of 11-β-hydroxylase, which disrupts normal adrenal steroid production.^24,25 Research indicates that etomidate not only inhibits 11-β-hydroxylase but also affects 17-α-hydroxylase activity, reducing cortisol and aldosterone production.^25,26 These hormonal changes may temporarily elevate adrenocorticotropic hormone (ACTH) levels, leading to temporary adrenal dysfunction.²⁶ Studies by Reves demonstrated that a single dose of etomidate is not universally safe.²⁷ Additionally, etomidate suppresses the normal prospective rise in cortisol and aldosterone in patients after surgery, as well as the normal adrenal response to ACTH. Adrenal suppression from a single etomidate dose lasts for 6 to 8 hours, whereas intravenous etomidate suppression can exceed 24 hours.²⁸

Administering etomidate 24 hours before a standard adrenocorticotropin test is a critical predictor of relative adrenal insufficiency; patients who do not respond to ACTH exhibit higher mortality rates.^29,30 These findings have led to differing opinions in the academic community: some researchers advocate for discontinuing etomidate use, while others believe it remains useful as a single-dose inducer in specific patients.³⁰ Some studies support using etomidate for general anaesthesia induction and short-term surgical procedures but caution against long-term infusion.³¹

Etomidate’s toxic effects on adrenocortical function are widely attributed³² to interference with the hypothalamic–pituitary–adrenocortical axis (HPA axis),^33,34 impairing adrenal function. Studies indicated that etomidate infusion decreases plasma cortisol and aldosterone concentrations, while increasing 11-deoxycorticosterone, 11-deoxycortisol, progesterone and 17-hydroxyprogesterone levels.^24,25,33,34 These hormonal changes suggest a blockage in converting these precursors during cortisol and aldosterone biosynthesis. The enzyme CYP11B1 is crucial in this pathway, and etomidate is believed to suppress CYP11B1 activity by binding through its imidazole ring. Harvey further elucidated that reduced adrenocortical steroidogenesis decreases glucocorticoid production, leading to the failure of the HPA axis’s negative feedback mechanism, increased ACTH secretion and adrenal hypertrophy³⁵ (Figure 2). Furthermore, some studies suggest that drug stress can cause adrenal hypertrophy.^35–37 Because etomidate decreases glucocorticoid levels, detecting these levels may help differentiate the cause of adrenal hypertrophy.³⁸

Figure 2.

Mechanism of etomidate causing adrenal injury.

Recent attention has focused on the abuse of etomidate. Toxicological research should further investigate adrenocortical impairment as evidence of long-term etomidate use. However, it is important to consider other potential factors contributing to adrenal impairment, including genetic predisposition, infections and autoimmune diseases. Therefore, a comprehensive assessment of the patients’ clinical and medication history, along with other risk factors, is essential for accurate judgment.

Brain Effects

The anaesthetic effects of etomidate are primarily mediated through binding to GABAA receptors.³⁸ These receptors are the predominant inhibitory neurotransmitter receptors in the mammalian brain and are key molecular targets for the anaesthetic actions of etomidate.³⁸ Although the exact mechanism of action has not been completely elucidated, it is widely accepted that intravenous anaesthetics, such as etomidate, interact with GABAA receptors and their associated chloride channels.⁴² This interaction facilitates an influx of chloride ions by activating the GABAA receptors, resulting in hyperpolarization of the cell membrane and subsequent inhibition of synaptic transmission. Additionally, etomidate modulates presynaptic calcium ion channels, further suppressing synaptic transmission and maintaining the cerebral cortex in a state of reduced excitability.⁴³

Research indicates that etomidate may cause damage to the developing brain when used for general anaesthesia.^39–41 This damage is attributed to etomidate’s potent inhibition of brain activity, which significantly reduces the excitability of developing neurons, leading to a significant increase in intracellular calcium ion concentration and resulting in neuronal injury and apoptosis.³⁹

Electroencephalogram (EEG) is an essential tool for assessing central nervous system activity.^41,42 Studies by Zhang found that etomidate-induced general anaesthesia increases the oscillatory activity of each EEG frequency band from the waking state to the stage of loss of consciousness.⁴³ Specifically, during the loss of consciousness, the coherence of EEG signals in θ and α waves significantly increases, and δ waves also exhibit marked coherence. These findings suggest that etomidate-induced loss of consciousness may be related to changes in hippocampal θ rhythm, with θ wave oscillations potentially indicating functional disconnection between the hippocampus and cerebral cortex.⁴²

Additionally, Alipour et al. discovered that etomidate exacerbates neuronal apoptosis in the CA1, CA2, CA3 and DG regions of the hippocampus in rats, particularly in the DG region.⁴³ Since the DG region continuously generates new neurons throughout life, which are essential for learning and memory formation, etomidate-induced neuronal apoptosis in hippocampal tissues may impair learning processes and long-term memory.⁴⁴

Recent research has further explored the effects of etomidate on the nervous system. Through apoptosis detection, neurotransmitter detection and brain tissue pathology and metabolite changes, studies have shown that long-term etomidate use can damage the nervous system of mice.⁴⁵ A study used terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end labelling in situ method to detect the apoptosis of neural cells from the striatum, hippocampus, midbrain and prefrontal cortex in mouse.⁴⁵ The results showed that high-dose etomidate could induce neuronal apoptosis in the brain tissue.⁴⁵ Additionally, high-dose etomidate induces decreases in 5-hydroxytryptamine and GABA levels, which are associated with epileptic seizures, cognitive impairment, depression and nervous hyperexcitability.^46,47

Research by Martin et al. demonstrated that etomidate blocks long-term potentiation and memory performance by increasing GABAA receptor activity.²⁷ This effect can be blocked by the selective GABAA receptor inverse agonist L-655,708 (Figure 3).²⁷ Wang proposed that etomidate might stimulate the release of paracrine factors by activating GABAA receptors in astrocytes through p38 mitogen-activated protein kinase (p38 MAPK)-dependent signalling pathways, thereby increasing neuronal electrotonic currents.⁴⁸ Research by Ding examined the effects of different doses of etomidate on mouse cerebral metabolic function through non-targeted metabolomics, identifying various differentially expressed metabolites in brain samples that correlate with specific metabolic pathways.⁴⁵

Figure 3.

Mechanism of etomidate causing brain tissue injury via inhibiting synaptic transmission.

Liver Effects

Animal experiments have demonstrated the adverse effects of etomidate on hepatic function and structure.^49,50 Bayram et al. found that male Wistar rats receiving etomidate (20 mg/kg) once every second day ten times, showed adverse effects on liver function and structure.⁴⁹ Furthermore, the levels of superoxide dismutase (SOD) and catalase (CAT), as well as malondialdehyde (MDA) in liver tissue were significantly increased, which indicated enhanced oxidative stress and lipid peroxidation.⁴⁹ Histopathological examination further identified liver injury manifestations, such as hepatocyte degeneration, vascular congestion and monocyte infiltration, confirming the potential hepatoxicity of etomidate. Djuric et al. indicated that intraperitoneal injection of etomidate (20 mg/kg) in rats, twice every 10 seconds until anaesthesia took effect, could significantly increase the serum biochemical parameters of aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and high-density lipoprotein (HDL).⁵⁰ Changes in these biochemical indicators are closely associated with liver injury, suggesting liver cell injury and dysfunction. While these findings suggest that etomidate may induce liver injury, the specific mechanism remains unclear, warranting further scientific investigation.

Detection of Etomidate and Its Metabolites

Toxicology testing is a critical component in toxicology, aiming to accurately identify if an individual has been exposed to a specific drug or its metabolites. This testing usually involves three main stages: on-site testing, laboratory testing and laboratory re-testing to ensure the accuracy and legal validity of the results. Among biological samples, blood, hair and urine are the three most commonly used materials in toxicology testing. Their results are vital for confirming drug abuse behaviour.

Urine

In the research of etomidate detection, liquid chromatography-tandem mass spectrometry (LC-MS/MS) technology has been widely applied for the quantitative analysis of etomidate and its metabolite etomidate acid in urine samples due to its high sensitivity and selectivity. In 2019, Jung utilized the LC-MS/MS method to quantitatively detect etomidate and its metabolites in urine.⁵¹ They successfully established a linear testing method for etomidate and its metabolite etomidate acid within the concentration ranges of 0.4–120.0 ng/ml and 1.0–300.0 ng/ml, respectively. This was achieved by optimising chromatographic conditions, employing a Hypercarb column and preparing a 0.05% formic acid aqueous solution as mobile phase A, with a mixed solvent of 50% acetonitrile and 50% methanol as mobile phase B.

Furthermore, Wu utilised the method of methanol protein precipitation to pretreat urine samples in their study, performed via the LC-MS/MS method.⁵² Another study compared the effects of methanol and acetonitrile as solvents for urine sample pretreatment, finding that the recovery rates of etomidate and etomidate acid in LC-MS/MS of urine samples using acetonitrile for pretreatment were 82.6% and 93.4%, while the recovery rates using methanol were 78.5% and 91.0%, respectively, indicating that acetonitrile was more effective in the pretreatment process.⁵³

Although urine test offers several advantages, it has limitations. For instance, etomidate has a short metabolic half-life, undergoing rapid metabolism in the liver and blood before excretion by the kidneys. Therefore, urine test results may fail to fully reflect the actual dose taken by the individual. Therefore, when interpreting urine test results, it is essential to comprehensively consider individual metabolic rates, drug use patterns and potential metabolite effects to ensure accuracy and scientific validity.

Blood

Blood testing is essential for assessing exposure to etomidate. The primary analytical methods for this purpose include gas chromatography-mass spectrometry/mass spectrometry (GC-MS/MS) and LC-MS/MS. Both techniques require sophisticated instrumentation, but they differ in sample treatment, analysis time and sensitivity.⁵⁴ Compared to LC-MS/MS, the GC-MS/MS method has certain limitations in terms of sample requirements, sample preparation duration, sensitivity and subsequent analysis workload.^55,56 GC-MS/MS usually requires larger sample volumes and longer sample preparation time to improve analytical sensitivity, which may result in a longer analysis process. Recently, Yum developed a simple and reliable method for the analysis of etomidate content in blood samples using the liquid chromatography-tandem mass spectrometry technique. This method involves acetonitrile precipitation for human blood sample pretreatment, which were obtained from post mortem examination, followed by LC-MS/MS analysis, achieving a good linear calibration curve within the concentration range of 10–500 ng/ml. In their study, the concentration of etomidate in femoral venous blood was measured to be 110 ng/ml, and the concentration in cardiac blood was 210 ng/ml. Compared to gas GC-MS/MS, LC-MS/MS offers advantages such as short sample preparation time, low sample requirements, high sensitivity and low detection limit.⁵⁷

In addition to detecting etomidate itself, researchers have also analysed the metabolite etomidate acid in blood samples. One study analysed the contents of etomidate and etomidate acid in five blood samples from etomidate abusers.⁵⁸ Among them, blood samples from four individuals were collected within 24 hours after the use of etomidate, and one was collected within 48 hours. The results showed etomidate concentrations ranging from 17.24 to 159.32 ng/ml, while etomidate acid concentrations ranged from 28.70 to 379.93 ng/ml, indicating that the concentration of etomidate acid is usually higher than that of etomidate in the blood.⁵⁸

Hair

Hair, as a biological sample for toxicology testing, offers several significant advantages, including a long detection window, non-invasiveness, easy collection and storage and higher stability. These properties make hair tests an effective method for assessing an individual’s long-term drug exposure history. Studies by Park utilised the LC-MS/MS method to quantitatively analyse etomidate and its metabolites in rat hair. The results indicated detection calibration ranges of 0.25–50 pg/mg, for etomidate and 2–250 pg/mg for the metabolite etomidate acid. In rat hair samples, the concentrations of etomidate and etomidate acid were 2.60–8.50 pg/mg and 2.06–7.13 pg/mg, respectively.⁵⁹ Although rat hair has similar components to human hair, caution is warranted when directly extrapolating these results from animal experiments to humans. Nonetheless, this study highlights the advantages of hair testing over urine and blood tests in terms of stability and sensitivity. Notably, the pretreatment for hair tests is relatively complex and requires multiple washing and extraction procedures.

Recently, Li employed liquid chromatography coupled with triple quadrupole mass spectrometry (LC-QQQ-MS) to analyse 421 hair samples from individuals suspected of drug abuse. Among them, 115 samples tested positive for smoked etomidate, with a positivity rate of 27.3%.⁶⁰ Dai established a method for detecting etomidate and the related compound metomidate in human hair using high-performance liquid chromatography coupled with triple quadrupole mass spectrometry (HPLC-QQQ-MS). The findings suggest that in cases involving new e-cigarette smoking, attention should also be paid to metomidate testing.⁶¹ Mo optimised test conditions, replacing the C18 reverse chromatography column with a 50-mm Poroshell 120 EC-C18 chromatography column and selecting methanol as mobile phase B due to its superior chromatographic peak pattern and sensitivity compared to acetonitrile.⁶²

Additionally, research has shown that etomidate primarily exists in its prototype form in hair, while in urine, it primarily exists as the metabolite etomidate acid. This phenomenon is attributed to the short metabolic half-life of etomidate.⁵⁵ Therefore, in toxicology testing, appropriate biological samples should be selected for analysis based on the timing of etomidate intake.

Other Samples

Currently, the testing methods for etomidate are limited, primarily relying on gas chromatography (GC) and liquid chromatography (LC) techniques. These methods often require complex sample pretreatment and costly instruments. Therefore, researchers are exploring new testing methods. For example, quantitative proton nuclear magnetic resonance spectroscopy (¹H-qNMR) technology is highly accurate in quantitative analysis, capable of determining the solubility and stability of etomidate in various deuterated solvents.⁶³ This technique has been successfully applied to detecting solid samples and e-liquid samples containing etomidate. ¹H-qNMR, with its precision and reproducibility, offers analytical results comparable to those obtained with LC-MS/MS. The technology is user-friendly and swift, requiring no standards, and exhibits good tolerance and repeatability, making it highly promising for extensive application in the field of toxicology.⁶³ Additionally, the albumin-based indicator displacement assay (IDA) technology has also been employed for the rapid detection of etomidate in beverages and e-cigarette oils.⁶⁴ Etomidate exhibits high affinity for albumin, displacing the fluorescent indicators originally bound to ALB. This displacement results in a change in fluorescence intensity, which can be used to detect the presence of etomidate. The fluorescence intensity ratio of this method has a linear relationship with etomidate concentration and is suitable for rapid qualitative analysis on-site.⁶⁴

In conclusion, etomidate abuse has drawn widespread social attention, making its testing crucial in toxicology. Biological samples such as blood, urine and hair can be used for etomidate testing, each with its unique advantages and applications. Standard laboratory testing methods for etomidate have not yet been fully established, and on-site rapid testing techniques under non-laboratory settings are also in the development stage. Therefore, there is an urgent need to optimize etomidate testing methods to improve the accuracy, sensitivity and convenience.

Conclusion and Future Directions

In recent years, the tightening control over traditional narcotics and novel psychoactive substances has led to a concerning rise in the abuse of etomidate as a potential alternative. Therefore, this study recommends further evaluation of the metabolism and distribution of etomidate in the body and its toxic mechanism and identifies special postmortem and pathological changes. Moreover, it is essential to monitor changes in biochemical indicators for the continuous improvement of testing methods in biological samples. These findings can enhance the ability to identify deaths from etomidate poisoning and offer vital information for clinical treatment.

Footnotes

Author Contributions

All authors contributed to conception and design, drafted the manuscript, and critically revised manuscript. All authors gave final approval and agree to be accountable for all aspects of work ensuring integrity and accuracy.

Declarations of Conflicting Interests

The author(s) declares no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Hainan Province Clinical Medical Center; the National Natural Science Foundation of China grant number [81901922]; the Natural Science Foundation of Hainan Province, China grant numbers [821QN251, 822RC702]; the Project of the Education Department of Hainan Province, China grant number [Hnky2024-32]; and the Graduate Student Innovative Research of Hainan Medical University, China grant number [HYYB2023A12].

ORCID iD

Peng Zhang

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