Intermittent fasting alleviates postoperative cognitive dysfunction by reducing neuroinflammation in aged mice.

Elderly individuals undergoing surgical procedures are often confronted with the peril of experiencing postoperative cognitive dysfunction (POCD). Prior research has demonstrated the exacerbating effect of sevoflurane anesthesia on neuroinflammation, which can further deteriorate the condition of POCD in elderly patients. Intermittent fasting (IF) restricts food consumption to a specific time window and has been demonstrated to ameliorate cognitive dysfunction induced by neuropathic inflammation. We subjected 18-month-old male mice to 16hours of fasting and 8hours of unrestricted eating over a 24-hour period for 0, 1, 2, and 4 weeks, followed by abdominal exploration under sevoflurane anesthesia. In this study, we aim to explore the potential impact of IF on postoperative cognitive function in aged mice undergoing sevoflurane surgery through the preoperative implementation of IF measures. The findings indicate two weeks of IF leads to a significant enhancement of learning and memory capabilities in mice following surgery. The cognitive performance, as determined by the novel object recognition and Morris water maze tests, as well as the synaptic plasticity, as measured by in vivo electrophysiological recordings, has demonstrated marked improvements. Furthermore, the administration of IF markedly enhances the expression of synaptic-associated proteins in hippocampal neurons, concomitant with a decreasing expression of pro-inflammatory factors and a reduced density of microglial cells within the hippocampal brain region. To summarize, the results of this study indicate that IF may mitigate inflammation in the hippocampal area of the brain. Furthermore, IF appears to provide a safeguard against cognitive impairment and synaptic plasticity impairment brought on by sevoflurane anesthesia.

The effect of remimazolam-based total intravenous anesthesia versus sevoflurane-based inhalation anesthesia on emergence delirium in children undergoing tonsillectomy and adenoidectomy: study protocol for a prospective randomized controlled trial.

Background: Remimazolam, a new ultrashort-acting benzodiazepine, is becoming increasingly applied in general anesthesia. This study is designed to investigate the effect of remimazolam-based total intravenous anesthesia and sevoflurane-based inhalation anesthesia on emergence delirium in pediatric tonsillectomy and adenoidectomy. Methods and analysis: This is a monocentric, prospective, randomized, double-blind clinical trial. A total of 90 pediatric patients will be randomized to receive remimazolam-based total intravenous anesthesia (remimazolam group, n = 45) or sevoflurane-based inhalation anesthesia (sevoflurane group, n = 45). The primary outcome will be the incidence of emergence delirium, which will be evaluated using the Pediatric Anesthesia Emergence Delirium (PAED) scale. The secondary outcomes include the extubation time, recovery time, behavior change using the post-hospitalization behavior questionnaire for ambulatory surgery (PHBQ-AS), and adverse events. Ethics and dissemination: This study has been approved by the Institutional Review Board (IRB) of the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University (2023-K-262-02). Clinical trial registration: ClinicalTrials.gov, identifier NCT06214117.

Multiple Exposures to Sevoflurane General Anesthesia During Pregnancy Inhibit CaMKII/CREB Axis by Downregulating HCN2 to Induce an Autism-Like Phenotype in Offspring Mice.

The objective of this investigation was to examine the impact of multiple exposures to general anesthesia (GA) with sevoflurane on the offspring of pregnant mice, as well as to elucidate the underlying mechanism. Neurodevelopmental assessments, including various reflexes and behavioral tests, were conducted on the offspring in the GA group to evaluate neuronal cell development. Furthermore, neonatal mouse neuronal cells were isolated and transfected with a high-expression CREB vector (pcDNA3.1-CREB), followed by treatment with sevoflurane (0.72 mol/L), ZD7288 (50 µmol/L), and KN-62 (10 µmol/L), or a combination of these compounds. The expression of relevant genes was then analyzed using qRT-PCR and western blot techniques. In comparison to the sham group, neonatal mice in the GA group exhibited significantly prolonged latencies in surface righting reflex, geotaxis test, and air righting reflex. Furthermore, there was a notable deceleration in the development of body weight and tail in the GA group. These mice also displayed impairments in social ability, reduced reciprocal social interaction behaviors, diminished learning capacity, and heightened levels of anxious behaviors. Additionally, synaptic trigger malfunction was observed, along with decreased production of c-Fos and neurotrophic factors. Sevoflurane was found to notably decrease cellular c-Fos and neurotrophic factor production, as well as the expression of HCN2 and CaMKII/CREB-related proteins. The inhibitory effects of sevoflurane on HCN2 or CaMKII channels were similar to those observed with ZD7288 or KN-62 inhibition. However, overexpression of CREB mitigated the impact of sevoflurane on neuronal cells. Repetitive exposure to sevoflurane general anesthesia while pregnant suppresses the CaMKII/CREB pathway, leading to the development of autism-like characteristics in offspring mice through the reduction of HCN2 expression.

Sevoflurane augments neuroinflammation by regulating DUSP6 via YTHDF1 in postoperative cognitive dysfunction.

Background: Postoperative cognitive dysfunction (POCD) is a generally recognized complication experienced by patients who receive anesthesia during surgery. Sevoflurane, the most commonly used inhaled anesthetic, has been shown to trigger neuroinflammation that promotes to POCD. Objective: This study examined the pathological mechanism by which sevoflurane causes neuroinflammation, participating in POCD. Methods: To establish a neurocyte injury model, the human neuroblastoma cell lines SH-SY5Y and SK-N-SH were treated with sevoflurane. Cell viability was determined using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assays. The reactive oxygen species (ROS) level was evaluated by DCFH-DA assays. A lactate dehydrogenase (LDH) Cytotoxicity Assay Kit was used to measure LDH levels. Inflammatory cytokine levels were measured using enzyme-linked immunosorbent assay assays. Gene expression densities and protein abundance were evaluated using quantitative real-time polymerase chain reaction (qRT-PCR) or western blotting. The interaction between YTHDF1 and dual specific phosphatase 6 (DUSP6) was validated using RNA immunoprecipitation (RIP)-qPCR and methylated RIP (MeRIP)-qPCR assays. Flow cytometry was performed to determine apoptosis. Results: Sevoflurane promoted apoptosis, oxidative stress, and neuroinflammation and repressed the expression levels of YTHDF1 and DUSP6. Furthermore, YTHDF1 overexpression reversed sevoflurane-induced neuroinflammation in neurocytes. DUSP6 overexpression could alleviate the neuroinflammation induced by sevoflurane via regulating the extracellular signal-regulated kinase (ERK)1/2 signaling pathway. Moreover, YTHDF1 enhanced DUSP6 expression. Conclusion: Sevoflurane-stimulated neuroinflammation by regulating DUSP6 via YTHDF1. Sevoflurane promoted neuroinflammation by regulating DUSP6 via YTHDF1 in an in vitro model of POCD.

Sevoflurane impedes neuropathic pain by maintaining endoplasmic reticulum stress and oxidative stress homeostasis through inhibiting the activation of the PLCγ/CaMKII/IP3R signaling pathway.

OBJECTIVE: To investigate the effect of sevoflurane on neuropathic pain induced by chronic constriction injury (CCI) of sciatic nerve in mice, and to elucidate its mechanism by animal experiments. METHODS AND RESULTS: Thirty-two C57BL/6 mice were randomly divided into four groups: Sham group, Model group, Control group and Sevoflurane group. First, a mouse model of neuropathic pain was established. Then, the mice in each group were killed on Day 14 after operation to harvest the enlarged lumbosacral spinal cord. In contrast with the Model group, the Sevoflurane group displayed a significantly increased paw withdrawal mechanical threshold (PWMT) and significantly prolonged paw withdrawal thermal latency (PWTL) from Day 5 after operation. The morphological changes of lumbosacral spinal cord were observed by hematoxylin-eosin (HE) staining and transmission electron microscopy. Pathological results showed that sevoflurane reduced nuclear pyknosis in lumbosacral spinal cord tissue, with a large number of mitochondrial crista disappearance and mitochondrial swelling. The results of Western blotting showed that sevoflurane significantly decreased the protein expressions of phosphorylated phospholipase Cγ (p-PLCγ), phosphorylated calcium/calmodulin-dependent protein kinase II (p-CaMKII) and phosphorylated inositol 1,4,5-triphosphate receptor (p-IP3R), and reduced the protein expressions of endoplasmic reticulum (ER) stress proteins glucose-regulated protein 78 (GRP78) and GRP94, oxidative stress-related proteins P22 and P47 and inflammatory factors nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), interleukin-1 ß (IL-1ß), and tumor necrosis factor-α (TNF-α). CONCLUSIONS: Sevoflurane inhibits neuropathic pain by maintaining ER stress and oxidative stress homeostasis through inhibiting the activation of the PLCγ/CaMKII/IP3R signaling pathway.

Recurrence-free survival after curative resection of non-small cell lung cancer between inhalational gas anesthesia and propofol-based total intravenous anesthesia: a multicenter, randomized, clinical trial (GAS TIVA trial): protocol description.

BACKGROUND: Surgery is the primary treatment for non-small cell lung cancer (NSCLC), but microscopic residual disease may be unavoidable. Preclinical studies have shown that volatile anesthetics might suppress host immunity and promote a pro-malignant environment that supports cancer cell proliferation, migration, and angiogenesis, whereas propofol may preserve cell-mediated immunity and inhibit tumor angiogenesis. However, clinical evidence that propofol-based total intravenous anesthesia (TIVA) can reduce tumor recurrence after curative resection remains inconsistent due to the retrospective observational nature of previous studies. Therefore, we will test the hypothesis that the recurrence-free survival (RFS) after curative resection of NSCLC is higher in patients who received TIVA than volatile anesthetics (GAS) in this multicenter randomized trial. METHODS: This double-blind, randomized trial will enroll patients at 22 international sites, subject to study registration, institutional review board approval, and patient written informed consent. Eligible patients are adult patients undergoing lung resection surgery with curative intent for NSCLC. Exclusion criteria will be contraindications to study drugs, American Society of Anesthesiologists physical status IV or higher, or preexisting distant metastasis or malignant tumor in other organs. At each study site, enrolled subjects will be randomly allocated into the TIVA and GAS groups with a 1:1 ratio. This pragmatic trial does not standardize any aspect of patient care. However, potential confounders will be balanced between the study arms. The primary outcome will be RFS. Secondary outcomes will be overall survival and complications within postoperative 7 days. Enrollment of 5384 patients will provide 80% power to detect a 3% treatment effect (hazard ratio of 0.83) at alpha 0.05 for RFS at 3 years. DISCUSSION: Confirmation of the study hypothesis would demonstrate that a relatively minor and low-cost alteration in anesthetic management has the potential to reduce cancer recurrence risk in NSCLC, an ultimately fatal complication. Rejection of the hypothesis would end the ongoing debate about the relationship between cancer recurrence and anesthetic management. TRIAL REGISTRATION: The study protocol was prospectively registered at the Clinical trials ( https://clinicaltrials.gov , NCT06330038, principal investigator: Hyun Joo Ahn; date of first public release: March 25, 2024) before the recruitment of the first participant.

Comparison of Propofol and Sevoflurane Anaesthesia in Terms of Postoperative Nausea-Vomiting Complication in Cardiac Surgery Patients Undergoing Enhanced Recovery After Surgery Protocol: A Prospective Randomized Study.

Objective: Postoperative nausea (PN) and vomiting (PONV) in cardiac surgery increases adrenergic stimulation, limits mobilization and oral intake, and can be distressing for patients. The primary aim of our study was to investigate the effect of sevoflurane and propofol anaesthesia on the incidence of PONV in cardiac surgery patients undergoing Enhanced Recovery After Surgery (ERAS) protocol. Methods: Following ethics committee approval, 62 patients undergoing elective coronary artery bypass surgery with ERAS protocol were included in this prospective randomized study. After standard induction of anaesthesia, Group S received 1.5-2% sevoflurane and Group P received 50-100 µg kg-1 min-1 propofol infusion as maintenance anaesthetic agent with a bispectral index of 40-50. The incidence of PN and PONV between 0-6 hours (early) and 6-24 hours (late) after extubation was compared as the primary outcome. The incidence of delirium was analyzed as a secondary outcome for similar periods. Results: In the propofol group, 3 patients were excluded due to postoperative tamponade revision and prolonged mechanical ventilation. PN in the early post-extubation period (29% vs. 7.1%, P=0.031) was significantly higher in Group S. The incidence of delirium was similar between the groups in both periods. Conclusion: Propofol may reduce the incidence of PN in the first 6 hours after extubation compared with sevoflurane. We believe that this period will be beneficial for gastrointestinal tolerance as it is the period when oral intake is initiated in patients. In conclusion, propofol maintenance in cardiac surgery patients may facilitate patient rehabilitation as part of the ERAS protocol.

Propofol total intravenous anesthesia vs. sevoflurane inhalation anesthesia: Effects on post­operative cognitive dysfunction and inflammation in geriatric patients undergoing laparoscopic surgery.

Propofol total intravenous anesthesia (TIVA) or sevoflurane inhalation anesthesia (IA) affects post-operative cognitive dysfunction in geriatric patients undergoing laparoscopic surgery; however, relevant real-world clinical evidence on the matter is limited. The present study aimed to compare the effects of propofol TIVA and sevoflurane IA on post-operative cognitive dysfunction in the aforementioned type of patients. The present prospective study enrolled 197 geriatric patients undergoing laparoscopic surgery. Patients were assigned to the propofol TIVA group (n=97) and sevoflurane IA group (n=100) according to the actual anesthesia regimens. The mini-mental state examination (MMSE) score was assessed before surgery and on day (D)1, D3 and D7 following surgery in both groups. The MMSE score on D1 was higher in the TIVA group compared with the IA group (P=0.006). The change in the MMSE scores from before surgery to D1 (P<0.001), D3 (P=0.011) and D7 (P=0.003) was smaller in the TIVA group vs. the IA group. Multivariate linear regression analyses suggested that the anesthesia method of TIVA (vs. IA) was independently related to the increased MMSE score on D1 (b=0.803; P=0.001) and D7 (b=0.472; P=0.025). The levels of interleukin (IL)-17A, IL-6 and tumor necrosis factor-α on D1, D3 and D7 exhibited a slightly decreasing trend in the TIVA group vs. the IA group, although the difference was not statistically significant (all P>0.05). Notably, the levels of IL-17A before surgery (P=0.015), on D3 (P=0.016) and D7 (P=0.002), as well as those of IL-6 on D1 (P=0.027), were negatively associated with the MMSE score at the corresponding time points. Overall, the present study demonstrates that propofol TIVA ameliorates post-operative cognitive dysfunction on D1 compared with sevoflurane IA and exerts a potentially suppressive effect on inflammation in geriatric patients undergoing laparoscopic surgery.

Comparison of Propofol-Based Total Intravenous Anesthesia versus Volatile Anesthesia with Sevoflurane for Postoperative Delirium in Adult Coronary Artery Bypass Grafting Surgery: A Prospective Randomized Single-Blinded Study.

OBJECTIVES: To compare the incidence of delirium and early (at 1 week) postoperative cognitive dysfunction (POCD) between propofol-based total intravenous anesthesia (TIVA) and volatile anesthesia with sevoflurane in adult patients undergoing elective coronary artery bypass graft surgery (CABG) with cardiopulmonary bypass (CPB). DESIGN: This was a prospective randomized single-blinded study. SETTING: The study was conducted at a single institution, the Sree Chitra Tirunal Institute for Medical Sciences and Technology, a tertiary care institution and university-level teaching hospital. PARTICIPANTS: Seventy-two patients undergoing elective CABG under CPB participated in this study. INTERVENTIONS: This study was conducted on 72 adult patients (>18 years) undergoing elective CABG under CPB who were randomized to receive propofol or sevoflurane. Anesthetic depth was monitored to maintain the bispectral index between 40 and 60. Delirium was assessed using the Confusion Assessment Method for the Intensive Care Unit. Early POCD was diagnosed when there was a reduction of >2 points in the Montreal Cognitive Assessment score compared to baseline. Cerebral oximetry changes using near-infrared spectroscopy (NIRS), atheroma grades, and intraoperative variables were compared between the 2 groups. MEASUREMENTS & MAIN RESULTS: Seventy-two patients were randomized to receive propofol (n = 36) or sevoflurane (n = 36). The mean patient age was 59.4 ± 8.6 years. The baseline and intraoperative variables, including atheroma grades, NIRS values, hemoglobin, glycemic control, and oxygenation, were comparable in the 2 groups. Fifteen patients (21.7%) patients developed delirium, and 31 patients (44.9%) had early POCD. The incidence of delirium was higher with sevoflurane (n = 12; 34.2%) compared to propofol (n = 3; 8.8%) (odds ratio [OR], 1.72; 95% confidence interval [CI], 1.13-2.62; p = 0.027)*. POCD was higher with sevoflurane (n = 20; 57.1%) compared to propofol (n = 11; 32.3%) (OR, 1.63; 95% CI, 1.01-2.62; p = 0.038)*. In patients aged >65 years, delirium was higher with sevoflurane (7/11; 63.6%) compared to propofol (1/7; 14.2%) (p = 0.03)*. CONCLUSIONS: Propofol-based TIVA was associated with a lower incidence of delirium and POCD compared to sevoflurane in this cohort of patients undergoing CABG under CPB. Large-scale, multicenter randomized trials with longer follow-up are needed to substantiate the clinical relevance of this observation.

Heart rate variability as a predictor of intraoperative autonomic nervous system homeostasis.

The aim of the proof-of-concept study is to investigate the level of concordance between the heart rate variability (HRV), the EEG-based Narcotrend Index as a surrogate marker for the depth of hypnosis, and the minimal alveolar concentration (MAC) of the inhalation anesthetic sevoflurane across the entire course of a surgical procedure. This non-blinded cross-sectional study recorded intraoperative HRV, Narcotrend Index, and MAC in 31 male patients during radical prostatectomy using the Da-Vinci robotic-assisted surgical system at Mannheim University Medical Center. The degree of concordance was calculated using repeated measures correlation with the R package (rmcorr) and presented using the rmcorr coefficient (rrm). The Narcotrend Index correlates significantly across all measures with the time-dependent parameter of HRV, the standard deviation of the means of RR intervals (SDNN) (rrm = 0.2; p < 0.001), the frequency-dependent parameters low frequency (LF) (rrm = 0.09; p = 0.04) and the low frequency/high frequency ratio (LF/HF ratio) (rrm = 0.11; p = 0.002). MAC correlated significantly negatively with the time-dependent parameter of heart rate variability, SDNN (rrm = -0.28; p < 0.001), the frequency-dependent parameter LF (rrm = -0.06; p < 0.001) and the LF/HF ratio (rrm = -0.18; p < 0.001) and the Narcotrend Index (rrm = -0.49; p < 0.001) across all measures. HRV mirrors the trend of the Narcotrend Index used to monitor depth of hypnosis and the inhibitory influence of the anesthetic sevoflurane on the autonomic nervous system. Therefore, HRV can provide essential information about the homeostasis of the autonomic nervous system during general anesthesia. DRKS00024696, March 9th, 2021.

Identification of differential m6A RNA methylomes and ALKBH5 as a potential prevention target in the developmental neurotoxicity induced by multiple sevoflurane exposures.

Sevoflurane, as a commonly used inhaled anesthetic for pediatric patients, has been reported that multiple sevoflurane exposures are associated with a greater risk of developing neurocognitive disorder. N6-Methyladenosine (m6A), as the most common mRNA modification in eukaryotes, has emerged as a crucial regulator of brain function in processes involving synaptic plasticity, learning and memory, and neurodevelopment. Nevertheless, the relevance of m6A RNA methylation in the multiple sevoflurane exposure-induced developmental neurotoxicity remains mostly elusive. Herein, we evaluated the genome-wide m6A RNA modification and gene expression in hippocampus of mice that received with multiple sevoflurane exposures using m6A-sequencing (m6A-seq) and RNA-sequencing (RNA-seq). We discovered 19 genes with differences in the m6A methylated modification and differential expression in the hippocampus. Among these genes, we determined that a total of nine differential expressed genes may be closely associated with the occurrence of developmental neurotoxicity induced by multiple sevoflurane exposures. We further found that the alkB homolog 5 (ALKBH5), but not methyltransferase-like 3 (METTL3) and Wilms tumor 1-associated protein (WTAP), were increased in the hippocampus of mice that received with multiple sevoflurane exposures. And the IOX1, as an inhibitor of ALKBH5, significantly improved the learning and memory defects and reduced neuronal damage in the hippocampus of mice induced by multiple sevoflurane exposures. The current study revealed the role of m6A methylated modification and m6A-related regulators in sevoflurane-induced cognitive impairment, which might provide a novel insight into identifying biomarkers and therapeutic strategies for inhaled anesthetic-induced developmental neurotoxicity.

Unraveling the signaling network between dysregulated microRNA and mRNA expression in sevoflurane-induced developmental neurotoxicity in rat.

Research has indicated that general anesthesia may cause neuroapoptosis and long-term cognitive dysfunction in developing animals, however, the precise mechanisms orchestrating these outcomes remain inadequately elucidated within scholarly discourse. The purpose of this study was to investigate the impact of sevoflurane on the hippocampus of developing rats by analyzing the changes in microRNA and mRNA and their interactions. Rats were exposed to sevoflurane for 4 h on their seventh day after birth, and the hippocampus was collected for analysis of neuroapoptosis by Western blot and immunohistochemistry. High-throughput sequencing was conducted to analyze the variances in miRNA and mRNA expression levels, and the Morris water maze was employed to assess long-term memory in rats exposed to sevoflurane after 8 weeks. The results showed that sevoflurane exposure led to dysregulation of 5 miRNAs and 306 mRNAs in the hippocampus. Bioinformatic analysis revealed that these dysregulated miRNA-mRNA target pairs were associated with pathological neurodevelopment and developmental disorders, such as regulation of axonogenesis, regulation of neuron projection development, regulation of neuron differentiation, transmission of nerve impulse, and neuronal cell body. Further analysis showed that these miRNAs formed potential network interactions with 44 mRNAs, and two important nodes were identified, miR-130b-5p and miR-449c-5p. Overall, this study suggests that the dysregulation of the miRNA-mRNA signaling network induced by sevoflurane may contribute to neurodevelopmental toxicity in the hippocampus of rats and be associated with long-term cognitive dysfunction.

Sevoflurane-induced regulation of NKCC1/KCC2 phosphorylation through activation of Spak/OSR1 kinase and cognitive impairment in ischemia-reperfusion injury in rats.

The occurrence of excitotoxic damage caused by cerebral ischemia-reperfusion (I/R) injury is closely linked to a decrease in central inhibitory function, in which the concentration of chloride inside the cells ([Cl-]i) plays a crucial role. The outflow and inflow of [Cl-]i are controlled by KCC2 and NKCC1, which are cellular cotransporters for K+/Cl- and Na+/K+/Cl-, respectively. NKCC1/KCC2 is regulated by upstream regulators such as SPAK and OSR1, whose activity is influenced by I/R. Sevoflurane is the most commonly used and controversial general anesthetic. To elucidate the impact of sevoflurane on cerebral ischemia-reperfusion (I/R) injury and its underlying mechanism, we investigated its influence on cognitive function and the mechanism of action utilizing a rat model of I/R. By activating the kinase Spak/OSR1, we discovered that I/R damage enhanced the function of NKCC1 and inhibited the function of KCC2, which triggered an imbalance of [Cl-]i concentration, leading to neurological dysfunction and cognitive dysfunction. At the beginning of reperfusion, administration of 1.3 MAC sevoflurane for 3 h increased activation of Spak/OSR1 kinases on day 7 post-perfusion, resulting in an additional dysregulation of NKCC1 and KCC2 activity, which disappeared on day 14. Administration of Closantel, a Spak/OSR1 kinase inhibitor, to animals treated with sevoflurane reverses the additional stimulation. The research revealed that sevoflurane modified the functioning of NKCC1 and KCC2, resulting in cognitive decline by activating Spak/OSR1 kinase. However, this issue could be resolved by inhibiting Spak/OSR1. The research revealed that sevoflurane transiently alters the function of NKCC1 and KCC2, resulting in exacerbating cognitive decline. However, this can be fixed by suppressing Spak/OSR1.

Mechanism research on microRNA-669f-5p/deoxycytidylate deaminase axis mediating sevoflurane-induced cognitive dysfunction in aged mice.

OBJECTIVE: To investigate the role of the microRNA (miRNA)-669f-5p/deoxycytidylate deaminase (Dctd) axis in sevoflurane inducing cognitive dysfunction in aged mice. METHODS: Sixty-six C57BL/6J mice were used in the experiment model and were randomly divided into the sevoflurane group and the control group. The mice in the sevoflurane group were anesthetised with 3.4% sevoflurane, whereas those in the control group were air-treated for the same period. The study was then performed using bioinformatics sequencing, as well as in vitro and in vivo validation. RESULTS: The mice in the sevoflurane group showed significant cognitive impairments in terms of a decrease in both spatial learning and memory abilities. Experimental doses of miR-669f-5p agonist exhibited no obvious effect on cognitive function following sevoflurane inhalation, but inhibiting the expression of miR-669f-5p could alleviate the impairments. Based on the results of the bioinformatics sequencing, miR-669f-5p/Dctd and the toll-like receptor (TLR) signalling pathway could be the key miRNA, gene and pathway leading to postoperative cognitive dysfunction following sevoflurane inhalation. The aged mice showed significantly increased expression of miR-669f-5p in the hippocampus following sevoflurane inhalation, and upregulating/inhibiting its expression could increase/decrease TLR expression in the hippocampus. Furthermore, miR-669f-5p could reduce the expression of the Dctd gene by binding to its 3'untranslated region. CONCLUSION: The miR-669f-5p/Dctd axis plays an important role in sevoflurane inducing cognitive dysfunction in aged mice, providing a new direction for further development of therapeutic strategies concerning the prevention and treatment of cognitive dysfunction associated with sevoflurane anaesthesia.

Efficiency of passive activated carbon anaesthetic gas capturing systems during simulated ventilation.

BACKGROUND: Interest in passive flow filter systems to remove sevoflurane from anaesthetic machine exhaust have increased recently to mitigate the environmental impact of volatile anaesthetics. These filter systems consist of chemically activated carbon, with limited evidence on their performance characteristics. We hypothesised that their efficiency depends on filter material. METHODS: Binding capacity was tested for three carbon filter materials (CONTRAfluran®, FlurAbsorb®, and Anaesthetic Agent Filter AAF633). Adsorption efficiency and resistive pressure were determined during simulated ventilation at different stages of filter saturation and fresh gas flow. In addition, sevoflurane concentration in filtered gas was measured at randomly selected anaesthesia workstations. RESULTS: Sevoflurane concentration in filtered gas exceeded 10 ppm when saturated with 184 ml sevoflurane each for CONTRAfluran and FlurAbsorb and 276 ml for AAF633. During simulated ventilation, sevoflurane concentration >10 ppm passed through CONTRAfluran and AAF633 at fresh gas flow 10 L min-1 only at maximum saturation, but through FlurAbsorb at all stages of saturation. The resistance pressure of all filters was negligible during simulated ventilation, but increased up to 5.2 (0.2) cm H2O during simulated coughing. At two of seven anaesthesia workstations, sevoflurane concentration in filtered exhaust gas was >10 ppm. CONCLUSIONS: Depending on the filter material and saturation, the likelihood of sevoflurane passing through passive flow carbon filters depends on the filter material and fresh gas flow. Combining the filter systems with anaesthetic gas scavenging systems could protect from pollution of ambient air with sevoflurane.

Effects of mid­gestational sevoflurane and magnesium sulfate on maternal oxidative stress, inflammation and fetal brain histopathology.

Models of inflammation, oxidative stress, hyperoxia and hypoxia have demonstrated that magnesium sulfate (MgSO4), a commonly used drug in obstetrics, has neuroprotective potential. In the present study, the effects of MgSO4 treatment on inflammation, oxidative stress and fetal brain histopathology were evaluated in an experimental rat model following sevoflurane (Sv) exposure during the mid-gestational period. Rats were randomly divided into groups: C (control; no injections or anesthesia), Sv (exposure to 2.5% Sv for 2 h), MgSO4 (administered 270 mg/kg MgSO4 intraperitoneally) and Sv + MgSO4 (Sv administered 30 min after MgSO4 injection). Inflammatory and oxidative stress markers were measured in the serum and neurotoxicity was investigated histopathologically in fetal brain tissue. Short-term mid-gestational exposure to a 1.1 minimum alveolar concentration of Sv did not significantly increase the levels of any of the measured biochemical markers, except for TNF-α. Histopathological evaluations demonstrated no findings suggestive of pathological apoptosis, neuroinflammation or oxidative stress-induced cell damage. MgSO4 injection prior to anesthesia caused no significant differences in biochemical or histopathological marker levels compared to the C and Sv groups. The present study indicated that short-term exposure to Sv could potentially be considered a harmless external stimulus to the fetal brain.

Effects of different anesthetic regimens on postoperative cognitive function of elderly patients undergoing thoracic surgery: a double-blinded randomized controlled trial.

OBJECTIVE: Postoperative cognitive dysfunction (POCD) is a serious surgical complication. We assessed the different POCD incidences between anesthesia using sevoflurane and sevoflurane combined with dexmedetomidine, with propofol-based sedation in elderly patients who underwent a thoracic surgical procedure. METHODS: A total of 90 patients aged 65 to 80 years old who underwent a thoracic surgical procedure at our hospital and 15 nonsurgical participants as controls, were enrolled in this study. Patients were divided in a randomized 1:1:1 ratio into 3 groups. All participants were randomized into a trial with three anesthesia groups (P, PS, PSD) or a control group (C) of healthy matches. All trial groups received distinct anesthetic combinations during surgery, while controls mirrored patient criteria.Group P (propofol and remifentanil were maintained during the surgery), Group PS (propofol, remifentanil, and sevoflurane were maintained during the surgery), and Group PSD (propofol, remifentanil, sevoflurane, and dexmedetomidine were maintained during the surgery).All participants were rated using a series of cognitive assessment scales before and three days after surgery. All participants were interviewed over the telephone, 7 days, 30 days, and 90 days postoperatively. RESULTS: POCD incidences in the PSD (combined anesthetization with propofol, sevoflurane, and dexmedetomidine) group was significantly lower than that in the PS (combined anesthetization with propofol and sevoflurane) group, 1 day post-surgery (10.0% vs. 40.0%, P = 0.008), and the results were consistent at 3 days post-surgery. When the patients were assessed 7 days, 30 days, and 90 days postoperatively, there was no significant difference in POCD incidence among the three groups. Multivariate logistic regression analysis of POCD one day after surgery showed that education level was negatively correlated with incidence of POCD (P = 0.018) and single lung ventilation time was positively correlated with incidence of POCD (P = 0.001). CONCLUSION: For elderly patients who underwent a thoracic surgical procedure, dexmedetomidine sedation shows an obvious advantage on improving short-term POCD incidence, which is caused by sevoflurane.

The Impact of the Combined Effect of Inhalation Anesthetics and Iron Dextran on Rats' Systemic Toxicity.

Disruption of any stage of iron homeostasis, including uptake, utilization, efflux, and storage, can cause progressive damage to peripheral organs. The health hazards associated with occupational exposure to inhalation anesthetics (IA) in combination with chronic iron overload are not well documented. This study aimed to investigate changes in the concentration of essential metals in the peripheral organs of rats after iron overload in combination with IA. The aim was also to determine how iron overload in combination with IA affects tissue metal homeostasis, hepcidin-ferritin levels, and MMP levels according to physiological, functional, and tissue features. According to the obtained results, iron accumulation was most pronounced in the liver (19×), spleen (6.7×), lungs (3.1×), and kidneys (2.5×) compared to control. Iron accumulation is associated with elevated heavy metal levels and impaired essential metal concentrations due to oxidative stress (OS). Notably, the use of IA increases the iron overload toxicity, especially after Isoflurane exposure. The results show that the regulation of iron homeostasis is based on the interaction of hepcidin, ferritin, and other proteins regulated by inflammation, OS, free iron levels, erythropoiesis, and hypoxia. Long-term exposure to IA and iron leads to the development of numerous adaptation mechanisms in response to toxicity, OS, and inflammation. These adaptive mechanisms of iron regulation lead to the inhibition of MMP activity and reduction of oxidative stress, protecting the organism from possible damage.

The miR-182-5p/GPX4 Pathway Contributes to Sevoflurane-Induced Ototoxicity via Ferroptosis.

Our study aimed to investigate the role of ferroptosis in sevoflurane-induced hearing impairment and explore the mechanism of the microRNA-182-5p (miR-182-5p)/Glutathione Peroxidase 4 (GPX4) pathway in sevoflurane-induced ototoxicity. Immunofluorescence staining was performed using myosin 7a and CtBP2. Cell viability was assessed using the CCK-8 kit. Fe2+ concentration was measured using FerroOrange and Mi-to-FerroGreen fluorescent probes. The lipid peroxide level was assessed using BODIPY 581/591 C11 and MitoSOX fluorescent probes. The auditory brainstem response (ABR) test was conducted to evaluate the hearing status. Bioinformatics tools and dual luciferase gene reporter analysis were used to confirm the direct targeting of miR-182-5p on GPX4 mRNA. GPX4 and miR-182-5p expression in cells was assessed by qRT-PCR and Western blot. Ferrostatin-1 (Fer-1) pretreatment significantly improved hearing impairment and damage to ribbon synapses in mice caused by sevoflurane exposure. Immunofluorescence staining revealed that Fer-1 pretreatment reduced intracellular and mitochondrial iron overload, as well as lipid peroxide accumulation. Our findings indicated that miR-182-5p was upregulated in sevoflurane-exposed HEI-OC1 cells, and miR-182-5p regulated GPX4 expression by binding to the 3'UTR of GPX4 mRNA. The inhibition of miR-182-5p attenuated sevoflurane-induced iron overload and lipid peroxide accumulation. Our study elucidated that the miR-182-5p/GPX4 pathway was implicated in sevoflurane-induced ototoxicity by promoting ferroptosis.