General Anesthetic Sevoflurane Research Articles

Application of remimazolam-0.6% sevoflurane anesthesia for flash visual evoked potential monitoring during pituitary adenoma resection: a non-inferiority randomized controlled trial

BackgroundFlash visual evoked potential (FVEP) is a critical method for monitoring intraoperative visual function during neurosurgery. A new benzodiazepine drug called remimazolam has recently been used for general anesthesia. However, the impact of remimazolam on FVEP remains unclear. Therefore, we aimed to investigate how remimazolam, in comparison to propofol, when combined with 0.6% sevoflurane anesthesia, affects the FVEP waveform during pituitary adenoma resection.MethodsOverall, 36 patients undergoing pituitary adenoma resection under general anesthesia were randomly assigned to either the remimazolam group (Group R) or the propofol group (Group P) in a prospective, randomized, controlled, non-inferiority trial. For anesthesia induction, a bolus of 0.2 mg/kg remimazolam or 2 mg/kg propofol was intravenously infused for approximately one minute. The anesthesia was maintained by continuous infusion of either remimazolam (0.7-1.0 mg/kg/h) or propofol (4–6 mg/kg/h), in combination with 0.6% sevoflurane, aimed at sustaining the bispectral index (BIS) within the range of 40–60. The primary outcome was the N75-P100 amplitude of FVEP recorded at approximately 20 min after intubation (T0). 10% of the amplitude at T0 in group P was defined as the non-inferiority margin (δ). Confidence interval testing was used to evaluate the non-inferiority hypothesis. The secondary outcomes covered the P100 latency of FVEP, electroretinogram (ERG) b wave amplitude, demographic characteristics, hemodynamics, and occurrence of adverse events.ResultsThe BIS index during anesthesia was comparable between the groups at the same measured time points (P > 0.05). The N75-P100 amplitude at T0 in group R was 7.64 ± 1.36 µV, while it was 6.96 ± 0.95 µV in group P (P = 0.09), with a mean difference of 0.68 µV (95% CI, -0.11 µV to 1.48 µV). The δ was set at 0.7 and the lower limit of the 95% CI exceeded the -δ. Both remimazolam and propofol had little effect on ERG b-wave amplitudes. At the designated time points, FVEP amplitude and P100 latency displayed no appreciable variation between the two groups (P > 0.05). Furthermore, there were no significant differences in the incidence of adverse events related to anesthesia, needle electrodes, or surgery between the two groups (P > 0.05).ConclusionOur findings suggest that remimazolam-0.6% sevoflurane is non-inferior to propofol-0.6% sevoflurane for general anesthesia, based on the FVEP N75-P100 amplitude. The electrophysiological data obtained in both groups indicate that reproducible and stable FVEP and ERG waveforms can be acquired at set time points. Therefore, for reliable FVEP monitoring, remimazolam-0.6% sevoflurane appears to be a safe and effective protocol in general anesthesia.Trials registrationThis study was registered on chictr.org.cn (ChiCTR2200056803, 17/02/2022).

Altered intestinal barrier contributes to cognitive impairment in old mice with constipation after sevoflurane anesthesia.

Elderly patients have a high risk of developing postoperative cognitive dysfunction (POCD). Gastrointestinal disorders, such as constipation, in the elderly population may be involved in the pathogenesis of neurological disorders by promoting inflammatory responses due to a 'leaky gut'. General anesthetic sevoflurane may impair gastrointestinal function in elderly patients to trigger neurological complications following surgery. Therefore, we hypothesized that elderly individuals with gastrointestinal dysfunction may be more vulnerable to sevoflurane and consequently develop POCD. Aged mice were randomly divided into four groups: control (CTRL), CTRL+sevoflurane (Sev), slow transit constipation (STC), and STC + Sev. Mice in the STC and STC + Sev groups were intra-gastrically administrated loperamide (3 mg/kg, twice a day for 7 days) to induce a slow transit constipation (STC) model determined with fecal water content and the time of first white fecal pellet, whereas mice in the other groups received the similar volume of saline. One week later, mice in the CTRL+Sev group and STC + Sev group received 2% sevoflurane for 2 h. The gut permeability evaluated with 4-kDa fluorescein isothiocyanate (FITC)-dextran, serum cytokines, microglia density, TLR4/NF-κB signaling expression, and POCD-like behavioral changes were determined accordingly. The loperamide-induced STC mice had decreased fecal water content and prolonged time of first white fecal pellet. Sevoflurane exposure caused significantly increased gut permeability and serum cytokines, as well as the activation of microglia and the TLR4/NF-κB signaling pathway in the prefrontal cortex of the aged STC mice. Sevoflurane also caused cognitive impairment and emotional phenotype abnormality in aged STC mice. Aged STC mice were more vulnerable to sevoflurane anesthesia and consequently developed POCD-like behavioral changes. Our data suggest that gastrointestinal disorders including constipation may contribute to the development of POCD.

A Comparative Study of Propofol and Sevoflurane for General Anesthesia in Laparoscopic Appendectomy

Introduction: Anesthesia plays a vital role in the success of surgical procedures, with the choice of anesthetic agents influencing patient recovery and postoperative complications. Propofol and sevoflurane are two commonly used anesthetic agents, each with distinct properties and implications on patient outcomes. The primary objective of this study was to compare the effects of propofol and sevoflurane on intraoperative hemodynamic parameters, recovery profiles, and postoperative complications in patients undergoing laparoscopic appendectomy. Methods: This prospective randomized trial was conducted over 2 years at Holy Family Red Crescent Medical College Hospital, Dhaka, Bangladesh, and included 180 laparoscopic appendectomy cases. Participants were randomized into two groups: 90 receiving propofol and 90 receiving sevoflurane for general anesthesia. The study received ethical approval from the hospital's review committee. Result: The mean age of patients in the Propofol group was 59.5 years (SD=2.6), while in the Sevoflurane group, it was 56.3 years (SD=7.9). Intraoperative heart rate and recovery profiles showed statistically significant differences between the two groups (p<0.05). The time to eye opening was 6.8 minutes (SD=1.5) for Propofol and 7.4 minutes (SD=1.7) for Sevoflurane. Postoperative complications were significantly higher in the Sevoflurane group: pain (35.56% vs. 24.44%), nausea and vomiting (27.78% vs. 16.67%), and analgesic requirements (44.44% vs. 30.00%). Conclusion: The findings of this study suggest that propofol may be a more favorable anesthetic agent compared to sevoflurane in laparoscopic appendectomy procedures. Propofol demonstrated better intraoperative heart rate control, faster recovery profiles, and reduced postoperative complications, potentially enhancing overall patient outcomes and satisfaction.

Intergenerational Perioperative Neurocognitive Disorder.

Accelerated neurocognitive decline after general anesthesia/surgery, also known as perioperative neurocognitive disorder (PND), is a widely recognized public health problem that may affect millions of patients each year. Advanced age, with its increasing prevalence of heightened stress, inflammation, and neurodegenerative alterations, is a consistent contributing factor to the development of PND. Although a strong homeostatic reserve in young adults makes them more resilient to PND, animal data suggest that young adults with pathophysiological conditions characterized by excessive stress and inflammation may be vulnerable to PND, and this altered phenotype may be passed to future offspring (intergenerational PND). The purpose of this narrative review of data in the literature and the authors' own experimental findings in rodents is to draw attention to the possibility of intergenerational PND, a new phenomenon which, if confirmed in humans, may unravel a big new population that may be affected by parental PND. In particular, we discuss the roles of stress, inflammation, and epigenetic alterations in the development of PND. We also discuss experimental findings that demonstrate the effects of surgery, traumatic brain injury, and the general anesthetic sevoflurane that interact to induce persistent dysregulation of the stress response system, inflammation markers, and behavior in young adult male rats and in their future offspring who have neither trauma nor anesthetic exposure (i.e., an animal model of intergenerational PND).

At-home Topical Sevoflurane Added to the Conventional Analgesic Treatment for Painful leg Ulcers Greatly Improved the Analgesic Effectiveness and Reduced Opioid Consumption in a Single-Center Retrospective Comparative Study with one-Year Follow-up.

The general anesthetic sevoflurane is being repurposed as a topical analgesic for painful chronic wounds. This study was aimed to compare the analgesic effectiveness and safety of systemic analgesics alone or plus at-home topical sevoflurane for the management of patients with painful nonrevascularizable leg ulcers who were referred to a Pain Clinic by their attending vascular surgeons. We reviewed charts of patients treated in a single Pain Clinic with analgesic Standard of Care either alone (group SoC) or plus at-home topical sevoflurane (group SoC + Sevo), according to safety criteria. The area under the curve of pain over a year (AUC-Pain) was the primary outcome for analgesic effectiveness. Opioids were converted into Oral Morphine Milligram Equivalents. Groups SoC (n = 26) and SoC + Sevo (n = 38) were similar in baseline characteristics. Compared to SoC, median values [interquartile range] of area under the curve of pain for one-year follow-up were markedly lower for SoC + Sevo (54 [35-65] vs. 15 [11-23]; p < 0.000001, U Mann-Whitney test). Oral Morphine Milligram Equivalents were similar at baseline (SoC: 78.5 [22.5-135] vs. SoC + Sevo: 101.3 [30-160]; p = 0.753), but significantly lower for SoC + Sevo at three (120 [22.5-202.5] vs. 30 [0-80]; p = 0.005), six (120 [11.3-160] vs. 20 [0-67.5]; p = 0.004), nine (114.4 [0-154] vs. 0 [0-37]; p = 0.018), and 12 months (114.4 [0-154] vs. 0 [0-20]; p = 0.001). Multiple linear regression analysis revealed the addition of sevoflurane to be the most likely variable to explain this difference in outcome (ß:-33.408; p < 0.000001). Nine patients (24%) in SoC + Sevo had adverse effects attributed to sevoflurane, but only one patient needed to stop using sevoflurane due severe dermatitis. In conclusion, the addition of topical sevoflurane to the analgesic standard of care in patients with painful nonrevascularizable leg ulcers was a well-tolerated therapy that significantly improved pain control and allowed for a significant reduction in opioid consumption.

The Safety of Propofol Versus Sevoflurane for General Anesthesia in Children: A Meta-Analysis of Randomized Controlled Trials.

BackgroundPropofol and sevoflurane are the most used anesthetics for pediatric surgery. Emergence agitation, postoperative nausea and vomiting and postoperative pain are the primary adverse effect of these general anesthetics. Many clinical studies had compared the safety of propofol and sevoflurane in pediatric surgery, but the results were controversial.ObjectivesTo evaluate the evidence surrounding the safety of propofol versus sevoflurane for general anesthesia in children.MethodsDatabases including PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, Wanfang Data and Vip Data were searched to collect relevant articles. Trials were strictly selected according to previously defined inclusion and exclusion criteria. RevMan 5.3 software was used for meta-analyses.ResultsTwenty randomized controlled trials recruiting 1,550 children for general anesthesia were included, with overall low-moderate methodological quality. There was evidence that compared with sevoflurane anesthesia, propofol anesthesia significantly decreased the incidence of emergence agitation (OR = 4.99, 95% CI, 3.67–6.80; P < 0.00001), postoperative nausea and vomiting (OR = 1.91, 95% CI, 1.27–2.87; P = 0.002) and postoperative pain (OR = 1.72, 95% CI, 1.11–2.64; P = 0.01) in children. However, patients who received sevoflurane tended to have shorter times to eye opening (MD = −2.58, 95% CI, −2.97– −2.19; P < 0.00001) and times to extubation (MD = −1.42, 95% CI, −1.81– −1.02; P < 0.00001).ConclusionsThis review reveals that the children who received propofol anesthesia had the lower risks of emergence agitation, postoperative nausea and vomiting and postoperative pain when compared with sevoflurane anesthesia. But the children who received sevoflurane recovered slightly faster than those received propofol. Considering the limitations of the included studies, better methodological quality and large controlled trials are expected to further quantify the safety of propofol and sevoflurane for general anesthesia in children.

Incidence of Postoperative Renal Injury after Receiving Different Exposure of Low-Flow Sevoflurane in General Anesthesia

Objective: To compare postoperative renal injury in low-flow sevoflurane anesthesia between more and less than two MAC-hours, and to determine the potential predisposing factors of postoperative renal injury. Materials and Methods: The present study was a retrospective cohort study that included 400 patients who underwent low-flow general anesthesia with sevoflurane, determining maintenance of fresh gas flow not exceeding one liter per minute. All subjects were classified into two groups, those exceeding two MAC-hours and those receiving less than two MAC-hours. The diagnosis of postoperative renal injury followed the Kidney Disease Improving Global Outcomes criteria. The multivariable logistic regression analysis was performed to identify independent risk factors for postoperative acute kidney injury. Results: The incidences of postoperative acute kidney injury among the patients received more and less than two MAC-hours groups were 20.1% and 21.5%, respectively (p=0.876). Factors found to be associated with postoperative acute kidney injury were ASA classification 2 (adjusted OR 7.82, 95% CI 1.0 to 59.2), ASA physical status 3 or higher (adjusted OR 9.85 95% CI 1.3 to 76.4), and obesity (adjusted OR 5.74, 95% CI 2.0 to 16.4). Exposure to low-flow sevoflurane for more than two MAC-hours was not associated with postoperative renal injury (adjusted odds ratio 0.89, 95% CI 0.5 to 1.5, p=0.666). Conclusion: Exposure to low-flow sevoflurane exceeding two MAC-hours did not increase the risk of postoperative acute kidney injury. Keywords: Acute kidney injury; Low flow general anesthesia; Sevoflurane

Systematic Review and Guidelines for Perioperative Management of Pediatric Patients Undergoing Major Plastic Surgery Procedures, with a Focus on Free Tissue Transfer.

Microsurgical free tissue transfer has been successfully implemented for various reconstructive applications in children. The goal of this study was to identify the best available evidence on perioperative management of pediatric patients undergoing free tissue transfer and to use it to develop evidence-based care guidelines. A systematic review was conducted in the PubMed, Embase, Scopus, and Cochrane Library databases. Because a preliminary search of the pediatric microsurgical literature yielded scant data with a low level of evidence, pediatric anesthesia guidelines for healthy children undergoing major operations were also included. Exclusion criteria included vague descriptions of perioperative care, case reports, and studies of syndromic or chronically ill children. Two hundred four articles were identified, and 53 met inclusion criteria. Management approaches specific to the pediatric population were used to formulate recommendations. High-quality data were found for anesthesia, analgesia, fluid administration/blood transfusion, and anticoagulation (Level I Evidence). Lower quality evidence was identified for patient temperature (Level III Evidence) and vasodilator use (Level IV Evidence). Key recommendations include administering sevoflurane for general anesthesia, implementing a multimodal analgesia strategy, limiting preoperative fasting, restricting blood transfusions until hemoglobin level is less than 7 g/dl unless the patient is symptomatic, and reserving chemical venous thromboembolism prophylaxis for high-risk patients. Pediatric-specific guidelines are important, as they acknowledge physiologic differences in children, which may be overlooked when extrapolating from adult studies. These evidence-based recommendations are a key first step toward standardization of perioperative care of pediatric patients undergoing plastic surgical procedures, including free tissue transfer, to improve outcomes and minimize complications.

Comparative Study of Recovery and Cognitive Dysfunction Following Desflurane versus Sevoflurane in General Anesthesia in Elderly Patient Undergoing Major Surgery

Geriatric patients (age 65 years and above) are more prone to POCD who undergo general anesthesia. Also the geriatric patients with co morbidities and substance abuse have higher chances for POCD. Objective: To compare Post-operative cognitive status and recovery (time specific) in geriatric patients undergoing general anesthesia with sevoflurane or desflurane, by MMSE score. Also to compare other side effects and recovery. Materials and Methods: This is prospective, randomized, interventional, single blind study. A study of 70 patients of either sex, ASA-I/II/III in the age group of above 65 years who were operated under general anesthesia and randomly allocated in two equal groups. Group S consisted of 35 patients who were given sevoflurane. Group D consisted of 35 patients who were given desflurane. MMSE score was taken pre-operatively and patients with score more than 27 were selected for this study. Results: Statistically significant immediate recovery from general anesthesia was noted in group D compared to group S. But difference in post-operative MMSE score at 1 hour, 3 hours and 6 hours between group S and group D was statistically insignificant. Conclusion: Patients given General Anesthesia with Desflurane showed early recovery signs, i.e. eye opening, following of verbal commands and extubation compared to patients given sevoflurane which is statistically proven. But MMSE score was lesser in desflurane than sevoflurane, which was insignificant.

ATPase Inhibitory Factor 1 Is Critical for Regulating Sevoflurane-Induced Microglial Inflammatory Responses and Caspase-3 Activation.

Postoperative delirium (POD) is one of the most important complications after surgery with general anesthesia, for which the neurotoxicity of general anesthetics is a high-risk factor. However, the mechanism remains largely unknown, which also hinders the effective treatment of POD. Here, we confirmed that a clinical concentration of the general anesthetic sevoflurane increased the expression of inflammatory factors and activated the caspase-3 by upregulating ATPase inhibitory factor 1 (ATPIF1) expression in microglia. Upregulation of ATPIF1 decreased the synthesis of ATP which is an important signaling molecule secreted by microglia. Extracellular supplementation with ATP attenuated the microglial inflammatory response and caspase-3 activation caused by sevoflurane or overexpression of ATPIF1. Additionally, the microglial inflammatory response further upregulated ATPIF1 expression, resulting in a positive feedback loop. Animal experiments further indicated that intraperitoneal injection of ATP significantly alleviated sevoflurane anesthesia-induced POD-related anxiety behavior and memory damage in mice. This study reveals that ATPIF1, an important protein regulating ATP synthesis, mediates sevoflurane-induced neurotoxicity in microglia. ATP supplementation may be a potential clinical treatment to alleviate sevoflurane-induced POD.

Cost-effectiveness analysis of domiciliary topical sevoflurane for painful leg ulcers

The general anesthetic sevoflurane is being repurposed as a topical analgesic for painful chronic wounds. We conducted a Bayesian cost-effectiveness analysis (CEA) comparing the addition of domiciliary topical sevoflurane to conventional analgesics (SEVOFLURANE, n = 38) versus conventional analgesics alone (CONVENTIONAL, n = 26) for the treatment of nonrevascularizable painful leg ulcers in an outpatient Pain Clinic of a Spanish tertiary hospital. We used real-world data collected from charts to conduct this CEA from a public healthcare perspective and with a one-year time horizon. Costs of analgesics, visits and admissions were considered, expressed in €2016. Analgesic effectiveness was measured with SPID (Sum of Pain Intensity Difference). A Bayesian regression model was constructed, including "treatment" and baseline characteristics for patients ("arterial hypertension") and ulcers ("duration", "number", "depth", "pain") as covariates. The findings were summarized as a cost-effectiveness plane and a cost-effectiveness acceptability curve. One-way sensitivity analyses, a re-analysis excluding those patients who died or suffered from leg amputation, and an extreme scenario analysis were conducted to reduce uncertainty. Compared to CONVENTIONAL, SEVOFLURANE was associated with a 46% reduction in costs, and the mean incremental effectiveness (28.15±3.70 effectiveness units) was favorable to SEVOFLURANE. The estimated probability for SEVOFLURANE being dominant was 99%. The regression model showed that costs were barely influenced by any covariate, whereas effectiveness was noticeably influenced by "treatment". All sensitivity analyses showed the robustness of the model, even in the extreme scenario analysis against SEVOFLURANE. SEVOFLURANE was dominant over CONVENTIONAL as it was less expensive and much more effective.

The effects of the general anesthetic sevoflurane on neurotransmission: an experimental and computational study

The brain functions can be reversibly modulated by the action of general anesthetics. Despite a wide number of pharmacological studies, an extensive analysis of the cellular determinants of anesthesia at the microcircuits level is still missing. Here, by combining patch-clamp recordings and mathematical modeling, we examined the impact of sevoflurane, a general anesthetic widely employed in the clinical practice, on neuronal communication. The cerebellar microcircuit was used as a benchmark to analyze the action mechanisms of sevoflurane while a biologically realistic mathematical model was employed to explore at fine grain the molecular targets of anesthetic analyzing its impact on neuronal activity. The sevoflurane altered neurotransmission by strongly increasing GABAergic inhibition while decreasing glutamatergic NMDA activity. These changes caused a notable reduction of spike discharge in cerebellar granule cells (GrCs) following repetitive activation by excitatory mossy fibers (mfs). Unexpectedly, sevoflurane altered GrCs intrinsic excitability promoting action potential generation. Computational modelling revealed that this effect was triggered by an acceleration of persistent sodium current kinetics and by an increase in voltage dependent potassium current conductance. The overall effect was a reduced variability of GrCs responses elicited by mfs supporting the idea that sevoflurane shapes neuronal communication without silencing neural circuits.

Sevoflurane modulates breast cancer cell survival via modulation of intracellular calcium homeostasis

BackgroundSome retrospective and in vitro studies suggest that general anesthetics influence breast cancer recurrence and metastasis. We compared the effects of general anesthetics sevoflurane versus propofol on breast cancer cell survival, proliferation and invasion in vitro. The investigation focused on effects in intracellular Ca2+ homeostasis as a mechanism for general anesthetic-mediated effects on breast cancer cell survival and metastasis.MethodsEstrogen receptor-positive (MCF7) and estrogen receptor-negative (MDA-MB-436) human breast cancer cell lines along with normal breast tissue (MCF10A) were used. Cells were exposed to sevoflurane or propofol at clinically relevant and extreme doses and durations for dose- and time-dependence studies. Cell survival, proliferation and migration following anesthetic exposure were assessed. Intracellular and extracellular Ca2+ concentrations were modulated using Ca2+ chelation and a TRPV1 Ca2+ channel antagonist to examine the role of Ca2+ in mediating anesthetic effects.ResultsSevoflurane affected breast cancer cell survival in dose-, time- and cell type-dependent manners. Sevoflurane, but not propofol, at equipotent and clinically relevant doses (2% vs. 2 μM) for 6 h significantly promoted breast cell survival in all three types of cells. Paradoxically, extreme exposure to sevoflurane (4%, 24 h) decreased survival in all three cell lines. Chelation of cytosolic Ca2+ dramatically decreased cell survival in both breast cancer lines but not control cells. Inhibition of TRPV1 receptors significantly reduced cell survival in all cell types, an effect that was partially reversed by equipotent sevoflurane but not propofol. Six-hour exposure to sevoflurane or propofol did not affect cell proliferation, metastasis or TRPV1 protein expression in any type of cell.ConclusionSevoflurane, but not propofol, at clinically relevant concentrations and durations, increased survival of breast cancer cells in vitro but had no effect on cell proliferation, migration or TRPV1 expression. Breast cancer cells require higher cytoplasmic Ca2+ levels for survival than normal breast tissue. Sevoflurane affects breast cancer cell survival via modulation of intracellular Ca2+ homeostasis.

Sevoflurane Induces Hippocampal Neuronal Apoptosis by Altering the Level of Neuropeptide Y in Neonatal Rats.

Numerous studies have shown that the inhaled general anesthetic sevoflurane imposes toxicity on the central nervous system during the developmental period but the underlying mechanisms remain unclear. Neuropeptide Y (NPY) was reported to have important neuroprotective effects, which can attenuate neuronal loss under pathological conditions. However, the effects of NPY on sevoflurane-induced hippocampal neuronal apoptosis have not been investigated. In this study, postnatal day 7 (PND7) Sprague-Dawley rats and primary cultured cells separated from hippocampi were exposed to sevoflurane (2.4% for 4h) and the NPY expression levels after treatment were analyzed. Furthermore, neuronal apoptosis assay was conducted via immunofluorescence staining of cleaved caspase-3 and flow cytometry after exogenous NPY administration to PND7 rats as well as cultured hippocampal neurons to elucidate the role of NPY in sevoflurane-induced neurotoxicity. Our results showed the level of NPY gradually decreased within 24h after sevoflurane exposure in both the hippocampus of PND7 rats and cultured hippocampal neurons, but not in cultured astrocytes. In the exogenous NPY pretreatment study, the proportion of cleaved caspase-3 positive cells in the CA1 region of the hippocampus was increased significantly at 24h after sevoflurane treatment, while NPY pretreatment could reduce it. Similarly, NPY could also reverse the apoptogenic effect of sevoflurane on cultured neurons. Herein, our results showed that sevoflurane caused a significant decrease in NPY expression, whereas exogenous NPY supplementation could reduce sevoflurane-induced hippocampal neuronal apoptosis both in vivo and in vitro.

Level of Consciousness Is Dissociable from Electroencephalographic Measures of Cortical Connectivity, Slow Oscillations, and Complexity.

Leading neuroscientific theories posit a central role for the functional integration of cortical areas in conscious states. Considerable evidence supporting this hypothesis is based on network changes during anesthesia, but it is unclear whether these changes represent state-related (conscious vs unconscious) or drug-related (anesthetic vs no anesthetic) effects. We recently demonstrated that carbachol delivery to prefrontal cortex (PFC) restored wakefulness despite continuous administration of the general anesthetic sevoflurane. By contrast, carbachol delivery to parietal cortex, or noradrenaline delivery to either prefrontal or parietal cortices, failed to restore wakefulness. Thus, carbachol-induced reversal of sevoflurane anesthesia represents a unique state that combines wakefulness with clinically relevant anesthetic concentrations in the brain. To differentiate the state-related and drug-related associations of cortical connectivity and dynamics, we analyzed the electroencephalographic data gathered from adult male Sprague Dawley rats during the aforementioned experiments for changes in functional cortical gamma connectivity (25–155 Hz), slow oscillations (0.5–1 Hz), and complexity (<175 Hz). We show that higher gamma (85–155 Hz) connectivity is decreased (p ≤ 0.02) during sevoflurane anesthesia, an expected finding, but was not restored during wakefulness induced by carbachol delivery to PFC. Conversely, for rats in which wakefulness was not restored, the functional gamma connectivity remained reduced, but there was a significant decrease (p < 0.001) in the power of slow oscillations and increase (p < 0.001) in cortical complexity, which was similar to that observed during wakefulness induced after carbachol delivery to PFC. We conclude that the level of consciousness can be dissociated from cortical connectivity, oscillations, and dynamics.SIGNIFICANCE STATEMENT Numerous theories of consciousness suggest that functional connectivity across the cortex is characteristic of the conscious state and is reduced during anesthesia. However, it is unknown whether the observed changes are state-related (conscious vs unconscious) or drug-related (drug vs no drug). We used a novel rat model in which cholinergic stimulation of PFC produced wakefulness despite continuous exposure to a general anesthetic. We demonstrate that, as expected, general anesthesia reduces connectivity. Surprisingly, the connectivity remains suppressed despite pharmacologically induced wakefulness in the presence of anesthetic, with restoration occurring only after the anesthetic is discontinued. Thus, whether an animal exhibits wakefulness or not can be dissociated from cortical connectivity, prompting a reevaluation of the role of connectivity in level of consciousness.

Delta oscillations phase limit neural activity during sevoflurane anesthesia

Understanding anesthetic mechanisms with the goal of producing anesthetic states with limited systemic side effects is a major objective of neuroscience research in anesthesiology. Coherent frontal alpha oscillations have been postulated as a mechanism of sevoflurane general anesthesia. This postulate remains unproven. Therefore, we performed a single-site, randomized, cross-over, high-density electroencephalogram study of sevoflurane and sevoflurane-plus-ketamine general anesthesia in 12 healthy subjects. Data were analyzed with multitaper spectral, global coherence, cross-frequency coupling, and phase-dependent methods. Our results suggest that coherent alpha oscillations are not fundamental for maintaining sevoflurane general anesthesia. Taken together, our results suggest that subanesthetic and general anesthetic sevoflurane brain states emerge from impaired information processing instantiated by a delta-higher frequency phase-amplitude coupling syntax. These results provide fundamental new insights into the neural circuit mechanisms of sevoflurane anesthesia and suggest that anesthetic states may be produced by extracranial perturbations that cause delta-higher frequency phase-amplitude interactions.

Binding of the general anesthetic sevoflurane to ion channels.

The direct-site hypothesis assumes general anesthetics bind ion channels to impact protein equilibrium and function, inducing anesthesia. Despite advancements in the field, a first principle all-atom demonstration of this structure-function premise is still missing. We focus on the clinically used sevoflurane interaction to anesthetic-sensitive Kv1.2 mammalian channel to resolve if sevoflurane binds protein’s well-characterized open and closed structures in a conformation-dependent manner to shift channel equilibrium. We employ an innovative approach relying on extensive docking calculations and free-energy perturbation of all potential binding sites revealed by the latter, and find sevoflurane binds open and closed structures at multiple sites under complex saturation and concentration effects. Results point to a non-trivial interplay of site and conformation-dependent modes of action involving distinct binding sites that increase channel open-probability at diluted ligand concentrations. Given the challenge in exploring more complex processes potentially impacting channel-anesthetic interaction, the result is revealing as it demonstrates the process of multiple anesthetic binding events alone may account for open-probability shifts recorded in measurements.

Mechanisms of hysteresis in human brain networks during transitions of consciousness and unconsciousness: Theoretical principles and empirical evidence.

Hysteresis, the discrepancy in forward and reverse pathways of state transitions, is observed during changing levels of consciousness. Identifying the underlying mechanism of hysteresis phenomena in the brain will enhance the ability to understand, monitor, and control state transitions related to consciousness. We hypothesized that hysteresis in brain networks shares the same underlying mechanism of hysteresis as other biological and non-biological networks. In particular, we hypothesized that the principle of explosive synchronization, which can mediate abrupt state transitions, would be critical to explaining hysteresis in the brain during conscious state transitions. We analyzed high-density electroencephalogram (EEG) that was acquired in healthy human volunteers during conscious state transitions induced by the general anesthetics sevoflurane or ketamine. We developed a novel method to monitor the temporal evolution of EEG networks in a parameter space, which consists of the strength and topography of EEG-based networks. Furthermore, we studied conditions of explosive synchronization in anatomically informed human brain network models. We identified hysteresis in the trajectory of functional brain networks during state transitions. The model study and empirical data analysis explained various hysteresis phenomena during the loss and recovery of consciousness in a principled way: (1) more potent anesthetics induce a larger hysteresis; (2) a larger range of EEG frequencies facilitates transitions into unconsciousness and impedes the return of consciousness; (3) hysteresis of connectivity is larger than that of EEG power; and (4) the structure and strength of functional brain networks reconfigure differently during the loss vs. recovery of consciousness. We conclude that the hysteresis phenomena observed during the loss and recovery of consciousness are generic network features. Furthermore, the state transitions are grounded in the same principle as state transitions in complex non-biological networks, especially during perturbation. These findings suggest the possibility of predicting and modulating hysteresis of conscious state transitions in large-scale brain networks.

Evaluation of Dopamine Receptor Integrity after Sevofl urane Exposure in Neonatal Rat Brain Using Positron Emission Tomography

Aims: The volatile general anesthetic sevofl urane is commonly used across all ages in the clinic. Sevofl urane-induced neurotoxic effects on the developing dopaminergic system are still unclear. The aim of this study was to evaluate the integrity of the D2/D3 receptor in developing rat brain utilizing molecular imaging techniques.

Concentration-Dependent Binding of Small Ligands to Multiple Saturable Sites in Membrane Proteins

Membrane proteins are primary targets for most therapeutic indications in cancer and neurological diseases, binding over 50% of all known small molecule drugs. Understanding how such ligands impact membrane proteins requires knowledge on the molecular structure of ligand binding, a reasoning that has driven relentless efforts in drug discovery and translational research. Binding of small ligands appears however highly complex involving interaction to multiple transmembrane protein sites featuring single or multiple occupancy states. Within this scenario, looking for new developments in the field, we investigate the concentration-dependent binding of ligands to multiple saturable sites in membrane proteins. The study relying on docking and free-energy perturbation provides us with an extensive description of the probability density of protein-ligand states that allows for computation of thermodynamic properties of interest. It also provides one- and three-dimensional spatial descriptions for the ligand density across the protein-membrane system which can be of interest for structural purposes. Illustration and discussion of the results are shown for binding of the general anesthetic sevoflurane against Kv1.2, a mammalian ion channel for which experimental data are available.