General anesthetic drugs cause cognitive deficits that persist after the drugs have been eliminated. Astrocytes may contribute to such cognition-impairing effects through the release of one or more paracrine factors that increase a tonic inhibitory conductance generated by extrasynaptic γ-aminobutyric acid type A (GABAA) receptors in hippocampal neurons. The mechanisms underlying this astrocyte-to-neuron crosstalk remain unknown. Interestingly, astrocytes express anesthetic-sensitive GABAA receptors. Here, we tested the hypothesis that anesthetic drugs activate astrocytic GABAA receptors to initiate crosstalk leading to a persistent increase in extrasynaptic GABAA receptor function in neurons. We also investigated the signaling pathways in neurons and aimed to identify the paracrine factors released from astrocytes. Astrocytes and neurons from mice were grown in primary cell cultures and studied using in vitro electrophysiological and biochemical assays. We discovered that the commonly used anesthetics etomidate (injectable) and sevoflurane (inhaled) stimulated astrocytic GABAA receptors, which in turn promoted the release paracrine factors, that increased the tonic current in neurons via a p38 MAPK-dependent signaling pathway. The increase in tonic current was mimicked by exogenous IL-1β and abolished by blocking IL-1 receptors; however, unexpectedly, IL-1β and other cytokines were not detected in astrocyte-conditioned media. In summary, we have identified a novel form of crosstalk between GABAA receptors in astrocytes and neurons that engages a p38 MAPK-dependent pathway. Brief commentary BACKGROUND: Many older patients experience cognitive deficits after surgery. Anesthetic drugs may be a contributing factor as they cause a sustained increase in the function of \"memory blocking\" extrasynaptic GABAA receptors in neurons. Interestingly, astrocytes are required for this increase; however, the mechanisms underlying the astrocyte-to-neuron crosstalk remain unknown. TRANSLATIONAL SIGNIFICANCE: We discovered that commonly used general anesthetic drugs stimulate GABAA receptors in astrocytes, which in turn release paracrine factors that trigger a persistent increase in extrasynaptic GABAA receptor function in neurons via p38 MAPK. This novel form of crosstalk may contribute to persistent cognitive deficits after general anesthesia and surgery.

Mechanical thrombectomy (MT) has become a standard treatment for acute ischemic stroke (AIS) caused by large vessel occlusion (LVO). Recent evidence suggests that general anesthesia (GA) and mechanical ventilation do not lead to inferior neurologic outcomes if compared to non-GA. However, the guidelines lack specific recommendations for ventilation targets during MT under GA. This systematic review aims to identify ventilation strategies correlating with better neurological outcomes in AIS patients undergoing MT, particularly focusing on oxygenation and carbon dioxide (CO2) targets. A systematic search of multiple databases was conducted to identify human studies reporting the correlation between ventilation strategies and neurological outcomes in MT for AIS. Eligible studies included clinical trials, observational studies, and case-control studies. Out of 157 studies assessed, 11 met the inclusion criteria. Five studies investigated oxygenation targets, while six studies explored CO2 targets. The published studies highlighted the controversial role of supplemental normobaric oxygen therapy and its potential association with worse outcomes. Regarding CO2 targets, the studies identified a potential association between end tidal CO2 levels and functional outcomes, with hypocapnia being unfavorable. This systematic review demonstrates that the current available evidence still lacks strength to suggest specific ventilation targets, but it highlights the potential risks of hyperoxia and hypocapnia in this specific cohort of patients.

Postoperative cognitive dysfunction (POCD) is a common surgical complication that causes additional pain in patients and affects their quality of life. To address this problem, emerging studies have focused on the POCD. Recent studies have shown that aging and anesthetic exposure are the two major risk factors for developing POCD. However, few reports described the exact molecular mechanisms underlying POCD in elderly patients. In the previous studies, the endoplasmic reticulum (ER) stress and neuroapoptosis in the hippocampus were associated with inducing POCD; however, no further information on the related signaling pathways could be disclosed. The PERK-eIF2α-ATF4-CHOP pathway is identified as the main regulatory pathway involved in ER stress and cell apoptosis. Therefore, we assume that the occurrence of POCD induced by sevoflurane inhalation may potentially result from ER stress and neuroapoptosis in the hippocampus of aged mice mediated by the PERK-eIF2α-ATF4-CHOP pathway. In our study, we found a relationship between sevoflurane inhalation concentration and memory decline in aged mice, with a \'ceiling effect\'. We have confirmed that POCD induced by sevoflurane results from ER stress and neuroapoptosis in the hippocampus of aged mice, which is regulated by the over-expression of PERK-eIF2α-ATF4-CHOP pathway. Furthermore, we also showed that the dephosphorylation inhibitor of eIF2α (salubrinal) could down-regulate PERK-eIF2α-ATF4-CHOP pathway expression to inhibit ER stress and enhance the cognitive function of aged mice. In general, our study has elucidated one of the molecular mechanisms of sevoflurane-related cognitive dysfunction in aged groups and provided new strategies for treating sevoflurane-induced POCD.

Perioperative neurocognitive disorders (PNDs) are some of the most common postoperative complications among the elderly and susceptible individuals, which significantly worsens the clinical outcome of patients. However, the prevention and treatment strategies of PNDs are difficult to determine and implement since the pathogenesis of PNDs is not well understood. The development of living organisms is associated with active and organized cell death, which is essential for maintaining the homeostasis of life. Ferroptosis is a programmed cell death (different from apoptosis and necrosis) mainly caused by an imbalance in the generation and degradation of intracellular lipid peroxides due to iron overload. Pyroptosis is an inflammatory cell death characterized by the creation of membrane holes mediated by the gasdermin (GSDM) family, followed by cell lysis and the release of pro-inflammatory cytokines. Ferroptosis and pyroptosis are involved in the pathogenesis of various central nervous system (CNS) diseases. Furthermore, ferroptosis and pyroptosis are closely associated with the occurrence and development of PNDs. This review summarizes the main regulatory mechanisms of ferroptosis and pyroptosis and the latest related to PNDs. Based on the available evidence, potential intervention strategies that can alleviate PNDs by inhibiting ferroptosis and pyroptosis have also been provided.

UNASSIGNED: Surgery under general anesthesia leads to neural injury, especially in older patients. Sevoflurane anesthesia without surgery for 2 h does not induce neural injury, however, whether prolonger sevoflurane anesthesia without surgery has the same consequence is still unknown.
UNASSIGNED: In the present study, aged marmosets were exposed to a clinical concentration of sevoflurane (1.5-2%) for 6 h to access the effects of prolonged sevoflurane anesthesia on the levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), Caspase3 activity and myelin formation in the brain.
UNASSIGNED: Sevoflurane anesthesia did not alter the expression of IL-6 (120.1 ± 2.21 vs. 120.8 ± 2.25, p = 0.74), TNF-α (189.3 ± 31.35 vs. 218.7 ± 21.47, p = 0.25) and Caspase3 (57.35 ± 1.54 vs. 58.67 ± 1.19, p = 0.53) in the prefrontal cortex (PFC) of aged marmosets. The amount of MBP expression (60.99 ± 6.21 vs. 58.91 ± 2.71, p = 0.77) did not change following sevoflurane exposure.
UNASSIGNED: Sevoflurane anesthesia did not increase the levels of IL-6 and TNF-α, activated the the expression of Caspase3, and induced myelination deficits in the PFC of aged marmosets.

Remimazolam besylate is a novel short-acting benzodiazepine. An appropriate pharmacokinetic model of remimazolam is desirable in anesthesia practice. The aim of the study was to develop a pharmacokinetic model using plasma samples from patients anesthetized with remimazolam. Influence of patient characteristics, context-sensitive decrement-times, and dose regimens were also examined.
Data were obtained from four trials on patients, and seven trials on healthy volunteers. The characteristics of 416 male and 246 female subjects were as follows: age, 18-93 years; body weight, 34-149 kg; and American Society of Anesthesiologists physical status (ASA-PS), I-IV. 2231 arterial and 3200 venous samples were used for the final model. The equilibration rate constant between arterial plasma and effect-site was estimated using the concept of time to peak effect. The final model was used to generate context-sensitive decrement times and dose regimens for general anesthesia.
A three-compartment model plus virtual venous compartment with allometric scaling of adjusted body weight (ABW), age, sex, and ASA-PS as covariates were selected as the final model. Elimination clearance was lower in males, and in subjects with higher ABW and ASA-PS scores. Approximately 10% or 20% higher dose rate was necessary in females than in males or ASA-PS I/II than III/IV patient. The context-sensitive half-time for effect-site concentration in a 55-year-old, 70-kg, 170-cm male or female ASA-PS I/II patient after > 6-h infusion was 16.7 or 15.9 min.
Remimazolam pharmacokinetic model for general anesthesia was successfully developed. ABW, ASA-PS, and sex has a considerable impact on the remimazolam concentration.

BACKGROUND: Length of hospital stay (LOS) is an important concern in all types of surgery, and the enhanced recovery after surgery (ERAS) protocol has been developed to improve perioperative management and outcomes, which require multidisciplinary management. In terms of pain control, intraoperative regional anesthesia and postoperative opioid-sparing analgesia are recommended. For open spine surgery, we aimed to combine thoracic epidural analgesia to reduce pain and opioid-related side effects, thereby hastening recovery.
OBJECTIVE: This study aimed to compare the length of hospital stay after open complete laminectomy with fusion between general anesthesia and combined general anesthesia involving a single thoracic epidural injection.
METHODS: A randomized single-blinded controlled study.
METHODS: Thirty-eight patients scheduled for elective open laminectomy with fusion between I and III levels were selected.
METHODS: LOS, postoperative pain, patient-controlled morphine consumption at 24 hours, patient satisfaction score, and other opioid-related side effects were recorded.
METHODS: Patients were randomly selected to receive standard general anesthesia (GA) or GA combined with a single-shot thoracic epidural at T11-T12 or T12-L1, a block with 10 mL of 0.25% bupivacaine, and 4 mg of morphine.
RESULTS: There were no significant differences in the demographic variables between groups. LOS was significantly lower in the combined epidural and/or GA than in the control group (3.78±0.81 [mean±standard deviation] and 4.79±1.51 days, respectively; p=.017). Numeric rating score (at rest) at the post-anesthesia care unit, 24 hours postoperative morphine consumption (mg), operating time, and blood loss were significantly lower in the epidural group. Patients who received combined epidural and/or GA were more likely to report higher patient satisfaction (p=.008). However, the incidence of intraoperative hypotension was significantly higher in the epidural group (72.2% vs. 21.1%, p=.003). The incidences of adverse events and surgical field rating scores did not differ between the 2 patient groups.
CONCLUSIONS: Combined lower thoracic epidural and/or GA in patients undergoing elective lumbar spine surgery was associated with decreased LOS.

BACKGROUND: Status epilepticus (SE) persisting despite two anti-seizures medications (ASM) and anesthetics is labeled super refractory (SRSE), correlating with important morbidity and mortality. Its treatment relies on expert opinions. Due to its pharmacological properties, ketamine (KET) has received increasing attention, but data are essentially retrospective.
OBJECTIVE: To describe an unselected cohort of adults receiving KET for SRSE.
METHODS: Analysis of a prospective registry of consecutive SE episodes, identifying SRSE patients receiving ketamine (KET). Comparison with recent adult series including more than 10 patients.
RESULTS: Eleven patients received KET after a median of 4 days (range: 2-20); median dose was 5 mg/kg/h (range: 2.5-15). KET provided permanent SE control in three (27%). Previous series, using KET administration delays and doses similar to our cohort, report KET efficacy in 28-96% of cases.
CONCLUSIONS: We found a lower SE control rate than existing literature, whose data are, however, often retrospective, potentially selecting patients with less severe SE forms or responding to KET. This might explain outcome differences, as KET administration modalities were comparable with our cohort. Since randomized controlled studies are lacking on this subject, the analysis of this prospective, unselected cohort, if confirmed, suggests a current overestimation of KET efficacy in SRSE.

Anesthetics are extensively used during cancer surgeries. The progression of cancer can be influenced by perioperative events such as exposure to general or local anesthesia. However, whether they inhibit cancer or act as a causative factor for metastasis and exert deleterious effects on cancer growth differs based on the type of cancer and the therapy administration. Recent experimental data suggested that many of the most commonly used anesthetics in surgical oncology, whether general or local agents, can alter gene expression and cause epigenetic changes via modulating miRNAs. miRNAs are single-stranded non-coding RNAs that regulate gene expression at various levels, and their dysregulation contributes to the pathogenesis of cancers. However, anesthetics via regulating miRNAs can concurrently target several effectors of cellular signaling pathways involved in cell differentiation, proliferation, and viability. This review summarized the current research about the effects of different anesthetics in regulating cancer, with a particular emphasis on the role of miRNAs. A significant number of studies conducted in this area of research illuminate the effects of anesthetics on the regulation of miRNA expression; therefore, we hope that a thorough understanding of the underlying mechanisms involved in the regulation of miRNA in the context of anesthesia-induced cancer regulation could help to define optimal anesthetic regimens and provide better perspectives for further studies.

Most surgical procedures require general anesthesia, which is a reversible deep sedation state lacking all perception. The induction of this state is possible because of complex molecular and neuronal network actions of general anesthetics (GAs) and other pharmacological agents. Laboratory and clinical studies indicate that the effects of GAs may not be completely reversible upon anesthesia withdrawal. The long-term neurocognitive effects of GAs, especially when administered at the extremes of ages, are an increasingly recognized health concern and the subject of extensive laboratory and clinical research. Initial studies in rodents suggest that the adverse effects of GAs, whose actions involve enhancement of GABA type A receptor activity (GABAergic GAs), can also extend to future unexposed offspring. Importantly, experimental findings show that GABAergic GAs may induce heritable effects when administered from the early postnatal period to at least young adulthood, covering nearly all age groups that may have children after exposure to anesthesia. More studies are needed to understand when and how the clinical use of GAs in a large and growing population of patients can result in lower resilience to diseases in the even larger population of their unexposed offspring. This minireview is focused on the authors\' published results and data in the literature supporting the notion that GABAergic GAs, in particular sevoflurane, may upregulate systemic levels of stress and sex steroids and alter expressions of genes that are essential for the functioning of these steroid systems. The authors hypothesize that stress and sex steroids are involved in the mediation of sex-specific heritable effects of sevoflurane.