Sevoflurane General Anesthesia Research Articles

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 (0.72mol/L), ZD7288 (50μmol/L), and KN-62 (10μmol/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.

Dopamine D2-receptor neurons in nucleus accumbens regulate sevoflurane anesthesia in mice

IntroductionThe mechanism of general anesthesia remains elusive. In recent years, numerous investigations have indicated that its mode of action is closely associated with the sleep-wake pathway. As a result, this study aimed to explore the involvement of dopamine D2 receptor (D2R) expressing neurons located in the nucleus accumbens (NAc), a critical nucleus governing sleep-wake regulation, in sevoflurane anesthesia.MethodsThis exploration was carried out using calcium fiber photometry and optogenetics technology, while utilizing cortical electroencephalogram (EEG), loss of righting reflex (LORR), and recovery of righting reflex (RORR) as experimental indicators.ResultsThe findings from calcium fiber photometry revealed a decrease in the activity of NAcD2R neurons during the induction phase of sevoflurane anesthesia, with subsequent recovery observed during the anesthesia’s emergence phase. Moreover, the activation of NAcD2R neurons through optogenetics technology led to a reduction in the anesthesia induction process and an extension of the arousal process in mice. Conversely, the inhibition of these neurons resulted in the opposite effect. Furthermore, the activation of NAcD2R neurons projecting into the ventral pallidum (VP) via optogenetics demonstrated a shortened induction time for mice under sevoflurane anesthesia.DiscussionIn conclusion, our research outcomes suggest that NAcD2R neurons play a promotive role in the sevoflurane general anesthesia process in mice, and their activation can reduce the induction time of anesthesia via the ventral pallidum (VP).

Medial Septal Glutamatergic Neurons Modulate States of Consciousness during Sevoflurane Anesthesia in Mice.

Multiple neural structures involved in maintaining wakefulness have been found to promote arousal from general anesthesia. The medial septum is a critical region that modulates arousal behavior. This study hypothesized that glutamatergic neurons in the medial septum play a crucial role in regulating states of consciousness during sevoflurane general anesthesia. Adult male mice were used in this study. The effects of sevoflurane anesthesia on neuronal activity were determined by fiber photometry. Lesions and chemogenetic manipulations were used to study the effects of the altered activity of medial septal glutamatergic neurons on anesthesia induction, emergence, and sensitivity to sevoflurane. Optogenetic stimulation was used to observe the role of acute activation of medial septal glutamatergic neurons on cortical activity and behavioural changes during sevoflurane-induced continuous steady-state of general anesthesia and burst suppression state. We found that medial septal glutamatergic neuronal activity decreased during sevoflurane anesthesia induction and recovered in the early period of emergence. Chemogenetic activation of medial septal glutamatergic neurons prolonged the induction time (mean ± SD, hM3Dq-Clozapine N-oxide vs. hM3Dq-Saline, 297.5 ± 60.1 s vs. 229.4 ± 29.9 s, P < 0.001, n = 11) and decreased the emergence time (53.2 ± 11.8 s vs. 77.5 ± 33.5 s, P = 0.025, n = 11). Lesions or chemogenetic inhibition of these neurons produced the opposite effects. During steady-state of general anesthesia and deep anesthesia-induced burst suppression state, acute optogenetic activation of medial septal glutamatergic neurons induced cortical activation and behavioural emergence. Our findings reveal that activation of medial septal glutamatergic neurons has arousal-promoting effects during sevoflurane anesthesia in male mice. The activation of these neurons prolongs the induction and accelerates the emergence of anesthesia.

Changes in EEG frequency characteristics during sevoflurane general anesthesia: feature extraction by variational mode decomposition.

Mode decomposition is a method for extracting the characteristic intrinsic mode function (IMF) from various multidimensional time-series signals. Variational mode decomposition (VMD) searches for IMFs by optimizing the bandwidth to a narrow band with the [Formula: see text] norm while preserving the online estimated central frequency. In this study, we applied VMD to the analysis of electroencephalogram (EEG) recorded during general anesthesia. Using a bispectral index monitor, EEGs were recorded from 10 adult surgical patients (the median age: 47.0, and the percentile range: 27.0-59.3years) who were anesthetized with sevoflurane. We created an application named EEG Mode Decompositor, which decomposes the recorded EEG into IMFs and displays the Hilbert spectrogram. Over the 30-min recovery from general anesthesia, the median (25-75 percentile range) bispectral index increased from 47.1 (42.2-50.4) to 97.4 (96.5-97.6), and the central frequencies of IMF-1 showed a significant change from 0.4 (0.2-0.5) Hz to 0.2 (0.1-0.3) Hz. IMF-2, IMF-3, IMF-4, IMF-5, and IMF-6 increased significantly from 1.4 (1.2-1.6) Hz to 7.5 (1.5-9.3) Hz, 6.7 (4.1-7.6) Hz to 19.4 (6.9-20.0) Hz, 10.9 (8.8-11.4) Hz to 26.4 (24.2-27.2) Hz, 13.4 (11.3-16.6) Hz to 35.6 (34.9-36.1) Hz, and 12.4 (9.7-18.1) Hz to 43.2 (42.9-43.4) Hz, respectively. The characteristic frequency component changes in specific IMFs during emergence from general anesthesia were visually captured by IMFs derived using VMD. EEG analysis by VMD is useful for extracting distinct changes during general anesthesia.

Selective Activation of NAc D1R-VP/LH Circuits Promotes Reanimation From Sevoflurane Anesthesia in Mice.

Emerging evidence has uncovered a vital role of nucleus accumbens (NAc) neurons that express the dopamine D1 receptor (D1R) and its upstream neural circuit in general anesthesia (GA) regulation. However, the underlying downstream neural basis of the modulation of GA emergence by NAc D1R neurons remains unknown. In the present study, we explored the downstream neural mechanism of NAc D1R neurons in the modulation of emergence from sevoflurane GA. We traced the axonal projections of NAc D1R neurons using a cell type-specific anterograde tracing method and immunohistochemical techniques in D1R-Cre mice. Optogenetic stimulations combined with electroencephalogram/electromyogram recordings and behavioral tests were used to determine the effects of optogenetic activation of the axonal terminals of NAc D1R neurons on sevoflurane emergence during sevoflurane-induced continuous, steady-state general anesthesia (CSSGA) or burst-suppression oscillations. Labeled efferent fibers of NAc D1R neurons were highly distributed in the ventral pallidum (VP), lateral hypothalamus (LH), and substantia nigra pars compacta. Optogenetic activation of the NAc D1R -VP circuit during CSSGA with sevoflurane induced cortical activation (mean ± standard deviation [SD]; delta power: prestimulation versus during stimulation, 48.7% ± 5.7% vs 35.1% ± 3.3%, P < .0001; beta power: 7.1% ± 2.7% vs 14.2% ± 3.3%, P = .0264) and behavioral emergence, and restored the righting reflex in 66.7% of ChR2 mice. Optogenetic stimulation of the NAc D1R -LH circuit also produced cortical activation (delta power: prestimulation versus during stimulation, 45.0% ± 6.5% vs 36.1% ± 4.6%, P = .0016) and behavioral emergence, and restored the righting reflex in 100% of the ChR2 mice during CSSGA with sevoflurane. Under a sevoflurane-induced burst-suppression state, NAc D1R -VP/LH circuit activation produced evidence of cortical activation (burst-suppression ratio [BSR]: NAc D1R -VP circuit, prestimulation versus during stimulation, 42.4% ± 4.0% vs 26.3% ± 6.0%, P = .0120; prestimulation versus poststimulation, 42.4% ± 4.0% vs 5.9% ± 5.6%, P = .0002; BSR: NAc D1R -LH circuit, prestimulation versus during stimulation, 33.3% ± 13.4% vs 5.1% ± 4.9%, P = .0177; prestimulation vs poststimulation, 33.3% ± 13.4% vs 3.2% ± 4.0%, P = .0105) and behavioral emergence. Both NAc D1R -VP and NAc D1R -LH circuits are sufficient to promote reanimation from sevoflurane GA by simultaneously inducing cortical and behavioral emergence.

Prediction models for chronic postsurgical pain in patients with breast cancer based on machine learning approaches.

This study aimed to develop prediction models for chronic postsurgical pain (CPSP) after breast cancer surgery using machine learning approaches and evaluate their performance. The study was a secondary analysis based on a high-quality dataset from a randomized controlled trial (NCT00418457), including patients with primary breast cancer undergoing mastectomy. The primary outcome was CPSP at 12 months after surgery, defined as modified Brief Pain Inventory > 0. The dataset was randomly split into a training dataset (90%) and a testing dataset (10%). Variables were selected using recursive feature elimination combined with clinical experience, and potential predictors were then incorporated into three machine learning models, including random forest, gradient boosting decision tree and extreme gradient boosting models for outcome prediction, as well as logistic regression. The performances of these four models were tested and compared. 1152 patients were finally included, of which 22.1% developed CPSP at 12 months after breast cancer surgery. The 6 leading predictors were higher numerical rating scale within 2 days after surgery, post-menopausal status, urban medical insurance, history of at least one operation, under fentanyl with sevoflurane general anesthesia, and received axillary lymph node dissection. Compared with the multivariable logistic regression model, machine learning models showed better specificity, positive likelihood ratio and positive predictive value, helping to identify high-risk patients more accurately and create opportunities for early clinical intervention. Our study developed prediction models for CPSP after breast cancer surgery based on machine learning approaches, which may help to identify high-risk patients and improve patients' management after breast cancer.

GABAergic neurons in the dorsomedial hypothalamus regulate states of consciousness in sevoflurane anesthesia

The neural inhibitory gamma-aminobutyric acid (GABA) system in the regulation of anesthetic consciousness is heterogeneous, and the medial hypothalamus (MH), consisting of ventromedial hypothalamus (VMH) and dorsomedial hypothalamus (DMH), plays an important role in sleep and circadian rhythm. However, the role of MH GABAergic neurons (MHGABA) in anesthesia remains unclear. In this study, we used righting reflex, electroencephalogram (EEG), and arousal behavioral score to evaluate the sevoflurane anesthesia. Activation of MHGABA or DMHGABA neurons prolonged the anesthesia induction time, shortened the anesthesia emergence time, and induced EEG arousal and body movement during anesthesia; meanwhile, VMHGABA neurons activated only induced EEG changes during 1.5% sevoflurane anesthesia. Furthermore, inhibition of DMHGABA neurons significantly deepened sevoflurane anesthesia. Therefore, DMHGABA neurons exert a strong emergence-promoting effect on induction, maintenance, and arousal during sevoflurane general anesthesia, which helps to reveal the mechanism of anesthesia.

Effects of ultrasound-guided brachial plexus block in combination with sevoflurane general anesthesia via laryngeal mask on upper limb tumor and fracture surgery for children based on inflammatory stress response

Sevoflurane is used successfully for general anesthesia via laryngeal mask on upper limb tumors like osteosarcoma and Ewings sarcoma and fractures in orthopedic care centers. With the advancement in interventional radiology, many procedures are now available to support surgeons to carry out such procedures without complications. In this study, we tried to evaluate the effects of ultrasound-guided brachial plexus block in combination with sevoflurane general anesthesia via laryngeal mask for upper limb tumor (osteosarcoma in the metaphysic of long bones of upper limb and Ewing sarcoma-second most malignant tumor in children) and fracture surgery in children based on inflammatory stress response. Eighty-six children who were admitted to undergo surgery for upper limb tumor and fractures from June 2018 to November 2019 were selected and divided into control and study groups according to anesthesia methods (n= 43). The control group received only sevoflurane superficial general anesthesia via laryngeal mask, besides which the study group received ultrasound-guided brachial plexus block. The surgical, anesthetic outcomes and adverse reactions were compared. Pain was assessed by the visual analogue scale (VAS) 4 h, 8 h and 12 h after surgery. The serum levels of interleukin-1β (IL-1β), IL-10, C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), epinephrine (E), norepinephrine (NE), cortisol (Cor) and insulin (Ins) were measured before surgery, on the day of surgery and 3 days after surgery, respectively. Compared with the control group, the surgical time and recovery time of the study group were shorter, the pain occurred later, the intraoperative respiration was slower, and the incidence rate of adverse reactions was significantly lower. The VAS scores of the study group were significantly lower than those of the control group 4 h, 8 h and 12 h after surgery. The IL-1β, IL-10, CRP, TNF-α, E, NE, Cor, and Ins levels of the study group were also significantly lower than those of the control group on the day of surgery and 3 days after surgery. Observations of this study suggest that sevoflurane superficial general anesthesia via laryngeal mask in combination with brachial plexus block can be used in the upper limb tumor removal and fracture surgery for children. This strategy has the advantages of short recovery time, few adverse reactions, obvious sedative and analgesic effects, and low inflammatory stress response.

Efficacy of propofol for the prevention of emergence agitation after sevoflurane anaesthesia in children: A meta-analysis.

BackgroundEmergence agitation (EA) is a common postoperative behavioral disorder, predominantly in pediatric patients, after sevoflurane general anesthesia. This study was aimed at assessing propofol's efficacy and clinical conditions established for preventing EA in children under sevoflurane anesthesia.MethodsRandomized controlled trials (RCTs) that comparatively investigated propofol and control treatment in terms of efficacy and safety on administration at the end of surgery and examinations to prevent EA in children under sevoflurane anesthesia were searched. The sources accessed included PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov. Furthermore, manual searches were performed to identify studies; the last review was conducted on March 21, 2022. When the risk of bias assessment of trials was performed with the Cochrane Risk of Bias Tool, we calculated risk ratios (RRs) with 95% confidence intervals (CIs) for EA incidence and mean differences (MDs) with 95% CI for continuous data.ResultsWe included 12 RCTs with 1103 children. EA incidence (RR: 0.51, 95% CI: 0.39 to 0.67) and Pediatric Anesthesia Emergence Delirium scores (MD: −3.14, 95% CI: −4.37 to −1.92) were lower in the propofol group. Subgroup analyses showed lower EA incidences with 3 mg/kg propofol (RR: 0.22, 95% CI: 0.13 to 0.38) without extension of the PACU time (MD: 4.97, 95% CI: −0.84 to 10.78) in the laryngeal mask airway (LMA; RR: 0.52, 95% CI: 0.36 to 0.77) and spontaneous breathing (RR: 0.36, 95% CI: 0.21 to 0.62) groups.DiscussionWe confirmed that a prophylactic dose of propofol prevented EA and decreased its severity in children under sevoflurane anesthesia. Furthermore, several conditions such as 3 mg/kg propofol, LMA, and spontaneous breathing, potentially contributed to EA prevention. Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=274692, identifier: PROSPERO (No. CRD42021274692).

Urinary Aromatic Amino Acid Metabolites Associated With Postoperative Emergence Agitation in Paediatric Patients After General Anaesthesia: Urine Metabolomics Study.

Background: Emergence agitation (EA) is very common in paediatric patients during recovery from general anaesthesia, but underlying mechanisms remain unknown. This prospective study was designed to profile preoperative urine metabolites and identify potential biomarkers that can predict the occurrence of EA. Methods: A total of 224 patients were screened for recruitment; of those, preoperative morning urine samples from 33 paediatric patients with EA and 33 non-EA gender- and age-matched patients after being given sevoflurane general anaesthesia were analysed by ultra-high-performance liquid chromatography (UHPLC) coupled with a Q Exactive Plus mass spectrometer. Univariate analysis and orthogonal projection to latent structures squares-discriminant analysis (OPLS-DA) were used to analyse these metabolites. The least absolute shrinkage and selection operator (LASSO) regression was used to identify predictive variables. The predictive model was evaluated through the receiver operating characteristic (ROC) analysis and then further assessed with 10-fold cross-validation. Results: Seventy-seven patients completed the study, of which 33 (42.9%) patients developed EA. EA and non-EA patients had many differences in preoperative urine metabolic profiling. Sixteen metabolites including nine aromatic amino acid metabolites, acylcarnitines, pyridoxamine, porphobilinogen, 7-methylxanthine, and 5′-methylthioadenosine were found associated with an increased risk of EA, and they all exhibited higher levels in the EA group than in the non-EA group. The main metabolic pathways involved in these metabolic changes included phenylalanine, tyrosine and tryptophan metabolisms. Among these potential biomarkers, L-tyrosine had the best predictive value with an odds ratio (OR) (95% CI) of 5.27 (2.20–12.63) and the AUC value of 0.81 (0.70–0.91) and was robust with internal 10-fold cross-validation. Conclusion: Urinary aromatic amino acid metabolites are closely associated with EA in paediatric patients, and further validation with larger cohorts and mechanistic studies is needed. Clinical Trial Registration: clinicaltrials.gov, identifier NCT04807998

Propofol Versus Sevoflurane General Anaesthesia for Selective Impairment of Attention Networks After Gynaecological Surgery in Middle-Aged Women: A Randomised Controlled Trial.

PurposeAttention is an essential component of cognitive function that may be impaired after surgery with anaesthesia. Propofol intravenous anaesthesia and sevoflurane inhalational anaesthesia are frequently used in gynaecological surgery. However, which type of anaesthetic has fewer cognitive effects postoperatively remains unclear. We compared the differences in attention network impairment after surgery in women receiving propofol versus sevoflurane general anaesthesia.Patients and MethodsEighty-three patients with gynaecological diseases who were 40–60 years of age were involved in the study. All patients underwent elective gynaecological surgery under either total intravenous anaesthesia or sevoflurane inhalational anaesthesia, depending on randomisation. The efficiencies of the three attention networks were captured using the attention network test preoperatively and on the 1st and 5th postoperative days.ResultsBoth groups of patients showed differences in impairments on the 1st and 5th postoperative days. Pairwise comparisons indicated that the alerting and orienting networks of patients in the propofol group were impaired to a greater extent than those of patients in the sevoflurane group on the 1st postoperative day, while the executive control network was impaired to a lesser extent. On the 5th postoperative day, the alerting networks of both groups recovered to the baseline level. Patients in the propofol group still showed impairment of the orienting network, while patients in the sevoflurane group recovered to baseline. For the executive control network, patients in the sevoflurane group still exhibited more severe impairment than those in the propofol group.ConclusionIn middle-aged women, propofol impaired orienting and alerting networks more than sevoflurane, while sevoflurane showed more residual impairment of the executive control network.

Emerging functional connectivity patterns during sevoflurane anaesthesia in the developing human brain

BackgroundSpectral-based EEG is used to monitor anaesthetic state during surgical procedures in adults. Spectral EEG features that can resemble the patterns seen in adults emerge in children after the age of 10 months and cannot distinguish wakefulness and anaesthesia in the youngest children. There is a need to explore alternative EEG measures. We hypothesise that functional connectivity is one of the measures that can help distinguish between consciousness states in children. MethodsAn EEG data set of children undergoing sevoflurane general anaesthesia (age 0–3 yr) was reanalysed using debiased weighted phase lag index as a measure of functional connectivity in wakefulness (n=38) and anaesthesia (n=73). Network topology measures were compared between states in 0- to 6-, 6- to 10-, and >10-month-old children. ResultsFunctional connectivity was reduced in anaesthesia vs wakefulness in delta band (n=cluster of 17 significant connections; P=0.013; 58% connections surviving thresholding in wakefulness and 49% in anaesthesia). Network density and node degree were lower in anaesthesia even in the youngest children (0.57 in wakefulness; 0.48 in anaesthesia; t [9]=3.39; P=0.029; G=0.98; confidence interval [CI] [0.25–1.77]). Modularity was higher in anaesthesia (0–6 months: 0.16 in wakefulness and 0.19 in anaesthesia, t [9]=–2.95, P=0.04, G=–0.85, CI [–1.60 to –0.16]; >10 months: 0.16 vs 0.21, t [13]=–6.45, P<0.001, G=–1.62, CI [–2.49 to –0.85]) and decreased with age (ρ [73]=–0.456; P<0.001). ConclusionsAnaesthesia modulates functional connectivity. Increased segregation into a more modular structure in anaesthesia decreases with age as adult-like features develop. These findings advance our understanding of the network architecture underlying the effects of anaesthesia on the developing brain.

Clinical Application of Esketamine Hydrochloride in Children with Emergence Agitation under Sevoflurane Anesthesia

Objective: To investigate the clinical effect of different doses of esketamine in preventing emergence agitation (EA) in children under sevoflurane general anesthesia.&#x0D; Methods: 80 children who underwent elective tonsillectomy or (and) adenoidectomy in our hospital were selected. The children were allocated randomly to one of four groups receiving saline(group C), esketamine hydrochloride 0.25 mg/kg (group K0.25), esketamine hydrochloride 0.5 mg/kg (group K0.5)or esketamine hydrochloride 0.75 mg/kg (group K0.75) . The children in each group were administered the study drugs 10 minutes before the end of surgery.All children were maintained anesthesia with sevoflurane. The recovery characteristics, including the time to extubation, delivery time from the PACU, postoperative nausea and vomiting, agitation and modified CHEOPS score were recorded and analyzed.&#x0D; Results: Immediately after extubation, the modified CHEOPS score and postoperative recovery agitation score of the three groups of children receiving intravenous esketamine were lower than those of group C (P&lt;0.05), but there was no statistical difference between the three groups significance (P&gt;0.05). When leaving the PACU, the postoperative awakening agitation scores of the children in the K0.25 and K0.5 groups were lower than those in the C group (P&lt;0.05), but there was no significant difference between the K0.75 and C groups (P&gt; 0.05). Compared with group C, postoperative extubation time and PACU stay time were significantly prolonged in K0.75 and K0.5 groups (P&lt;0.05).&#x0D; Conclusions: Low-dose (0.25 mg/kg) of esketamine hydrochloride can reduce the incidence of emergent agitation and postoperative pain,and has little effect on anesthesia recovery.

Effects of ultrasound-guided brachial plexus block combined with laryngeal mask sevoflurane general anesthesia on inflammation and stress response in children undergoing upper limb fracture surgery.

article: Effects of ultrasound-guided brachial plexus block combined with laryngeal mask sevoflurane general anesthesia on inflammation and stress response in children undergoing upper limb fracture surgery - Minerva Pediatrics 2021 Dec 21 - Minerva Medica - Journals

Lateralisation of subcortical functional connectivity during and after general anaesthesia

BackgroundArousal and awareness are two important components of consciousness states. Functional neuroimaging has furthered our understanding of cortical and thalamocortical mechanisms of awareness. Investigating the relationship between subcortical functional connectivity and arousal has been challenging owing to the relatively small size of brainstem structures and thalamic nuclei, and their depth in the brain. MethodsResting state functional MRI scans of 72 healthy volunteers were acquired before, during, 1 h after, and 1 day after sevoflurane general anaesthesia. Functional connectivity of subcortical regions of interest vs whole brain and homotopic functional connectivity for assessment of left–right symmetry analyses of both cortical and subcortical regions of interest were performed. Both analyses used high resolution atlases generated from deep brain stimulation applications. ResultsFunctional connectivity in subcortical loci within the thalamus and of the ascending reticular activating system was sharply restricted under anaesthesia, featuring a general lateralisation of connectivity. Similarly, left–right homology was sharply reduced under anaesthesia. Subcortical bilateral functional connectivity was not fully restored after emergence from anaesthesia, although greater restoration was seen between ascending reticular activating system loci and specific thalamic nuclei thought to be involved in promoting and maintaining arousal. Functional connectivity was fully restored to baseline by the following day. ConclusionsFunctional connectivity in the subcortex is sharply restricted and lateralised under general anaesthesia. This restriction may play a part in loss and return of consciousness. Clinical trial registrationNCT02275026.

Sevoflurane Alleviates Myocardial Ischemia Reperfusion Injury by Inhibiting P2X7-NLRP3 Mediated Pyroptosis.

Myocardial ischemia is common in aging population. This study investigates the protective effect of Sevoflurane on myocardial ischemia reperfusion injury (MIRI) and its underlying mechanism. A total of 87 patients with a history of myocardial ischemia who underwent abdominal surgery with Sevoflurane general anesthesia were recruited in the study. The clinical data, blood pressure, heart rate, pressure-rate quotient (PRQ) and rate-pressure product (RPP) were recorded. Serum samples were collected and heart-type fatty acid binding protein (H-FABP), ischemia modified albumin (IMA), interleukin-1β (IL-1β), and interleukin-18 (IL-18) were measured to observe whether Sevoflurane anesthesia had protective effect on myocardium. In addition, MIRI rats and hypoxia/reoxygenation (H/R) injury cell model was established using neonatal rat ventricular myocytes (NRVM). Rats or NRVM were pretreated with sevoflurane for 45min before hypoxia. The mRNA expression of purinergic receptor-7 (P2X7) and NLR family pyrin domain containing 3(NLRP3) were examined. The protein expression of P2X7, NLRP3, apoptosis-associated speck-like protein (ASC), cysteine aspartic acid specific protease-1(Caspase-1), Gasdermin-D (GSDMD), Bcl-2 Associated X Protein (Bax), B-cell lymphoma-2 (Bcl-2) in myocardial tissue and cells were evaluated. The serum contents of IL-1β, IL-18, Malondialdehyde (MDA), Superoxide dismutase (SOD), Lactate dehydrogenase (LDH), Creatine kinase (CK), and Creatine kinase isoenzymes (CK-MB) were measured. The cellular localization and fluorescence intensity of NLRP3 and ASC in cells were detected. It was found that the secretion of IL-1β and IL-18 decreased in the patients. After I45 min/R3h in SD rats and H3h/R1h in NRVM, the protein expressions of P2X7, NLRP3, ASC, Caspase-1 and GSDMD were increased, the release of IL-1β, IL-18, CK, CK-MB, LDH and MDA were increased, and SOD activity was decreased. Sevoflurane treatment inhibited the high expression of P2X7, NLRP3, ASC, Caspase-1 and GSDMD, inhibited the release of LDH, CK,CK-MB and MDA in cells, and improved the activity of SOD, indicating that Sevoflurane alleviated the damage of MIRI of rats and H/R of NRVM, and had myocardial protective effect. Taken together, our study suggests that Sevoflurane inhibited the expression of IL-1β, IL-18 and GSDMD by inhibiting the P2X7-NLRP3 signaling pathway. It reduced the H/R injury of cardiomyocytes and protected the cardiac function by regulating inflammatory reaction and pyroptosis.

Dynamic Patterns of Global Brain Communication Differentiate Conscious From Unconscious Patients After Severe Brain Injury.

The neurophysiology of the subjective sensation of being conscious is elusive; therefore, it remains controversial how consciousness can be recognized in patients who are not responsive but seemingly awake. During general anesthesia, a model for the transition between consciousness and unconsciousness, specific covariance matrices between the activity of brain regions that we call patterns of global brain communication reliably disappear when people lose consciousness. This functional magnetic imaging study investigates how patterns of global brain communication relate to consciousness and unconsciousness in a heterogeneous sample during general anesthesia and after brain injury. First, we describe specific patterns of global brain communication during wakefulness that disappear during propofol (n = 11) and sevoflurane (n = 14) general anesthesia. Second, we search for these patterns in a cohort of unresponsive wakeful patients (n = 18) and unmatched healthy controls (n = 20) in order to evaluate their potential use in clinical practice. We found that patterns of global brain communication characterized by high covariance in sensory and motor areas or low overall covariance and their dynamic change were strictly associated with intact consciousness in this cohort. In addition, we show that the occurrence of these two patterns is significantly related to activity within the frontoparietal network of the brain, a network known to play a crucial role in conscious perception. We propose that this approach potentially recognizes consciousness in the clinical routine setting.

Comparing the effect of xenon and sevoflurane anesthesia on postoperative neural injury biomarkers: a randomized controlled trial.

General anesthesia and surgery are associated with an increase in neural injury biomarkers. Elevations of these neural injury biomarkers in the perioperative period are associated with postoperative delirium. Xenon has been shown to be protective against a range of neurological insults in animal models. It remains to be seen if xenon anesthesia is neuroprotective in the perioperative setting in humans. Twenty-four participants scheduled for lithotripsy were randomized to receive either xenon or sevoflurane general anesthesia. There was no statistically significant difference in the concentrations of postoperative neural injury biomarkers between the xenon and sevoflurane group. Following the procedure there was a significant increase in the concentration from baseline of all three biomarkers at 1 hour post-induction with a return to baseline at 5 hours. General anesthesia for lithotripsy was associated with a significant increase at 1 hour post-induction in the neural injury biomarkers total tau, neurofilament light and tau phosphorylated at threonine 181, a marker of tau phosphorylation. The protocol was approved by the St. Vincent’s Hospital Melbourne Ethics Committee (approval No. HREC/18/SVHM/221) on July 20, 2018 and was registered with the Australia New Zealand Clinical Trials Registry (registration No. ACTRN12618000916246) on May 31, 2018.

Repeated neonatal sevoflurane induced neurocognitive impairment through NF-\u03baB-mediated pyroptosis

BackgroundExposure to general anesthesia (GA) during the postnatal period is associated with neuroinflammation and long-term neurocognitive impairment in preclinical and clinical settings. Pyroptosis is a novel type of programmed cell death that, along with inflammation, has been found to play an important role in the mechanism of diverse neurological diseases. However, its roles in GA-induced neuroinflammation and neurocognitive impairment in the developing brain have not been investigated.MethodsRats at postnatal day 6 or primary hippocampal neurons at 9 days in vitro received 3% sevoflurane for 2 h daily for three consecutive days. A pharmacological inhibitor of nuclear factor (NF)-κB (BAY 11-7082) was administered to suppress NF-κB activation. Histological and biochemical analyses were performed to assess the pyroptosis as well as neuronal and synaptic damage both in vivo and in vitro. In addition, behavioral tests were performed to evaluate neurocognitive ability in rats.ResultsRepeated sevoflurane exposure activated NF-κB-mediated pyroptosis and neuroinflammation in the hippocampus in developing rats, damaged the neuronal morphology and synaptic integrity, and induced neurocognitive impairment in rats. BAY 11-7082 treatment suppressed the activation of pyroptosis, attenuated the neuronal and synaptic damage, and ameliorated the neurocognitive impairment induced by repeated sevoflurane administration to developing rats.ConclusionsRepeated sevoflurane GA may induce neuroinflammation and neurocognitive impairment in developing rats via the activation of NF-κB-mediated pyroptosis. Our findings characterize a novel role of pyroptosis as a potential therapeutic target in neuroinflammation after repeated neonatal GA.

Dissociative and analgesic properties of ketamine are independent and unaltered by sevoflurane general anesthesia.

Ketamine, an anesthetic adjunct, is routinely administered as part of a balanced general anesthetic technique. We recently showed that the acute analgesic and dissociation properties of ketamine are separable to suggest that distinct neural circuits underlie these states. We aimed to study whether this finding is robust to the substantial neural circuit alterations associated with general anesthesia. We conducted a single-site, open-label, randomized controlled, cross-over study of sevoflurane and sevoflurane-plus-ketamine (SK) general anesthesia in healthy subjects (n = 12). Before and after general anesthesia, we assessed precalibrated cuff pain intensity and nociceptive pain quality as well as dissociation using the Clinician-Administered Dissociative States Scale (CADSS). For statistical inference, we ran a variation of backward elimination repeated-measures analysis of covariance. Models with CADSS as a covariate term were used to assess whether dissociation mediated the effect of ketamine on pain intensity and quality. Sevoflurane-plus-ketamine general anesthesia was associated with a significant (P = 0.0002) pain intensity decline of 3 (SE, 0.44). There was an order effect for dissociation such that SK was associated with a significant (P = 0.0043) CADSS increase of 17.8 (3.2) when the SK treatment came first. When the pain intensity model was reanalyzed with CADSS as an additional covariate, the effect of CADSS was not significant. These results were also conserved for pain quality. Our findings suggest that the analgesic and dissociation properties of ketamine remain separable despite general anesthesia. Thus, ketamine may be used as a probe to advance our knowledge of dissociation independent pain circuits.