Volatile Anesthetic Sevoflurane Research Articles

Trends in volatile anesthetic sevoflurane and desflurane usage and its impact on carbon emissions: A six-year audit at National Taiwan University Hospital (2018–2023)

This short communication presents an audit of anesthetic gas usage at National Taiwan University Hospital from 2018 to 2023. Using descriptive statistics and trend analysis, the data reveals trends in the consumption of sevoflurane and desflurane, associated costs, and their corresponding carbon emissions. A significant decrease in desflurane usage contributed to a 42.4% reduction in carbon dioxide equivalent (CO2e) emissions per general anesthesia case from 2018 to 2023. The findings underscore the importance of sustainable practices in anesthesia to align with global efforts to reduce carbon emissions.

Sodium Leak Channel in Glutamatergic Neurons of the Lateral Parabrachial Nucleus Helps to Maintain Respiratory Frequency Under Sevoflurane Anesthesia.

The lateral parabrachial nucleus (PBL) is implicated in the regulation of respiratory activity. Sodium leak channel (NALCN) mutations disrupt the respiratory rhythm and influence anesthetic sensitivity in both rodents and humans. Here, we investigated whether the NALCN in PBL glutamatergic neurons maintains respiratory function under general anesthesia. Our results showed that chemogenetic activation of PBL glutamatergic neurons increased the respiratory frequency (RF) in mice; whereas chemogenetic inhibition suppressed RF. NALCN knockdown in PBL glutamatergic neurons but not GABAergic neurons significantly reduced RF under physiological conditions and caused more respiratory suppression under sevoflurane anesthesia. NALCN knockdown in PBL glutamatergic neurons did not further exacerbate the respiratory suppression induced by propofol or morphine. Under sevoflurane anesthesia, painful stimuli rapidly increased the RF, which was not affected by NALCN knockdown in PBL glutamatergic neurons. This study suggested that the NALCN is a key ion channel in PBL glutamatergic neurons that maintains respiratory frequency under volatile anesthetic sevoflurane but not intravenous anesthetic propofol.

Higher Brain Uptake of Gentamicin and Ceftazidime under Isoflurane Anesthesia Compared to Ketamine/Xylazine.

We have recently shown that the volatile anesthetics isoflurane and sevoflurane acutely enhance the brain uptake of the hydrophilic markers sucrose and mannitol about two-fold from an awake condition, while the combined injection of the anesthetic agents ketamine and xylazine has no effect. The present study investigated two small-molecule hydrophilic drugs with potential neurotoxicity, the antibiotic agents ceftazidime and gentamicin. Transport studies using an in vitro blood-brain barrier (BBB) model, a monolayer of induced pluripotent stem cell-derived human brain microvascular endothelial cells seeded on Transwells, and LC-MS/MS analysis demonstrated the low permeability of both drugs in the range of sucrose, with permeability coefficients of 6.62 × 10-7 ± 2.34 × 10-7 cm/s for ceftazidime and 7.38 × 10-7 ± 2.29 × 10-7 cm/s for gentamicin. In vivo brain uptake studies of ceftazidime or gentamicin after IV doses of 25 mg/kg were performed in groups of 5-6 mice anesthetized at typical doses for surgical procedures with either isoflurane (1.5-2% v/v) or ketamine/xylazine (100:10 mg/kg I.P.). The brain uptake clearance, Kin, for ceftazidime increased from 0.033 ± 0.003 μL min-1 g-1 in the ketamine/xylazine group to 0.057 ± 0.006 μL min-1 g-1 in the isoflurane group (p = 0.0001), and from 0.052 ± 0.016 μL min-1 g-1 to 0.101 ± 0.034 μL min-1 g-1 (p = 0.0005) for gentamicin. We did not test the dose dependency of the uptake, because neither ceftazidime nor gentamicin are known substrates of any active uptake or efflux transporters at the BBB. In conclusion, the present study extends our previous findings with permeability markers and suggests that inhalational anesthetic isoflurane increases the BBB permeability of hydrophilic small-molecule endobiotics or xenobiotics when compared to the injection of ketamine/xylazine. This may be of clinical relevance in the case of potential neurotoxic substances.

Sustainability Standards in Pediatric Anesthesia: Quality Initiative to Reduce Costly Environmentally Harmful Volatile Anesthetics

Background: The emission and entrapment of greenhouse gases (GHG) inside the atmosphere is one of the leading causes of global warming. Commonly administered anesthetics have global warming potential up to 2,000 times greater than carbon dioxide. This Quality Improvement (QI) initiative aimed to develop a set of sustainability standards to reduce volatile anesthetic GHG emissions and costs at a children’s hospital. Methods: In January 2020, the QI project team implemented education sessions for clinical staff on the environmental impact of volatile anesthetics, bedside clinical reminders, resource guides on sustainable anesthesia practices, preset low-flow gas levels on anesthesia machines, relocated and reduced the number of available vaporizers, and implemented policies to standardize clinical practice. Using hospital pharmacy purchase order data between 2018 and 2022, GHG emissions and costs from three commonly used volatile anesthetics (Isoflurane, Sevoflurane, and Desflurane) were compared using metric ton carbon dioxide equivalents. Results: During 3 years, GHG emissions from volatile anesthetics were significantly reduced by 77%, with most of the reduction attributed to the reduced use and eventual elimination of Desflurane. Purchase costs were also significantly reduced during this period by 41%. Conclusions: This QI project successfully decreased GHG emissions over 3 years by simultaneously reducing the use of costly and environmentally harmful volatile anesthetic, Desflurane, and increasing the use of low-flow anesthesia. This study addresses our anesthesia practices and healthcare system’s impact on the pediatric population and proposes simple interventions to mitigate the negative consequences of current practices.

Sevoflurane anaesthesia induces cognitive impairment in young mice through sequential tau phosphorylation

BackgroundThe volatile anaesthetic sevoflurane induces time (single or multiple exposures)-dependent effects on tau phosphorylation and cognitive function in young mice. The underlying mechanism for this remains largely undetermined. MethodsMice received 3% sevoflurane for 0.5 h or 2 h daily for 3 days on postnatal day (P) 6, 9, and 12. Another group of mice received 3% sevoflurane for 0.5 h or 1.5 h (3 × 0.5) on P6. We investigated effects of sevoflurane anaesthesia on tau phosphorylation on P6 or P12 mice, on cognitive function from P31 to P37, and on protein interactions, using in vivo studies, in vitro phosphorylation assays, and nanobeam single-molecule level interactions in vitro. ResultsAn initial sevoflurane exposure induced CaMKIIα phosphorylation (132 [11]% vs 100 [6]%, P<0.01), leading to tau phosphorylation at serine 262 (164 [7]% vs 100 [26]%, P<0.01) and tau detachment from microtubules. Subsequent exposures to the sevoflurane induced GSK3β activation, which phosphorylated detached or free tau (tau phosphorylated at serine 262) at serine 202 and threonine 205, resulting in cognitive impairment in young mice. In vitro phosphorylation assays also demonstrated sequential tau phosphorylation. Nanobeam analysis of molecular interactions showed different interactions between tau or free tau and CaMKIIα or GSK3β, and between tau and tubulin at a single-molecule level. ConclusionsMultiple exposures to sevoflurane can induce sequential tau phosphorylation, leading to cognitive impairment in young mice, highlighting the need to investigate the underlying mechanisms of anaesthesia-induced tau phosphorylation in developing brain.

Advances in Idiosyncratic Drug-Induced Liver Injury Issues: New Clinical and Mechanistic Analysis Due to Roussel Uclaf Causality Assessment Method Use

Clinical and mechanistic considerations in idiosyncratic drug-induced liver injury (iDILI) remain challenging topics when they are derived from mere case narratives or iDILI cases without valid diagnosis. To overcome these issues, attempts should be made on pathogenetic aspects based on published clinical iDILI cases firmly diagnosed by the original RUCAM (Roussel Uclaf Causality Assessment Method) or the RUCAM version updated in 2016. Analysis of RUCAM-based iDILI cases allowed for evaluating immune and genetic data obtained from the serum and the liver of affected patients. For instance, strong evidence for immune reactions in the liver of patients with RUCAM-based iDILI was provided by the detection of serum anti-CYP 2E1 due to drugs like volatile anesthetics sevoflurane and desflurane, partially associated with the formation of trifluoroacetyl (TFA) halide as toxic intermediates that form protein adducts and may generate reactive oxygen species (ROS). This is accompanied by production of anti-TFA antibodies detected in the serum of these patients. Other RUCAM-based studies on serum ANA (anti-nuclear antibodies) and SMA (anti-smooth muscle antibodies) associated with AIDILI (autoimmune DILI) syn DIAIH (drug-induced autoimmune hepatitis) provide additional evidence of immunological reactions with monocytes as one of several promoting immune cells. In addition, in the blood plasma of patients, mediators like the cytokines IL-22, IL-22 binding protein (IL-22BP), IL-6, IL-10, IL 12p70, IL-17A, IL-23, IP-10, or chemokines such as CD206 and sCD163 were found in DILI due to anti-tuberculosis drugs as ascertained by the prospective updated RUCAM, which scored a high causality. RUCAM-based analysis also provided compelling evidence of genetic factors such as HLA (human leucocyte antigen) alleles contributing to initiate iDILI by a few drugs. In conclusion, analysis of published RUCAM-based iDILI cases provided firm evidence of immune and genetic processes involved in iDILI caused by specific drugs.

Effects of sevoflurane and its metabolite hexafluoroisopropanol on hypoxia/reoxygenation-induced injury and mitochondrial bioenergetics in murine cardiomyocytes.

The volatile anaesthetic sevoflurane protects cardiac tissue from reoxygenation/reperfusion. Mitochondria play an essential role in conditioning. We aimed to investigate how sevoflurane and its primary metabolite hexafluoroisopropanol (HFIP) affect necrosis, apoptosis, and reactive oxygen species formation in cardiomyocytes upon hypoxia/reoxygenation injury. Moreover, we aimed to describe the similarities in the mode of action in a mitochondrial bioenergetics analysis. Murine cardiomyocytes were exposed to hypoxia (0.2% O2 for 6 h), followed by reoxygenation (air with 5% CO2 for 2 h) in the presence or absence sevoflurane 2.2% or HFIP 4 mM. Lactate dehydrogenase (LDH) release (necrosis), caspase activation (apoptosis), reactive oxygen species, mitochondrial membrane potential, and mitochondrial function (Seahorse XF analyser) were measured. Hypoxia/reoxygenation increased cell death by 44% (+31 to+55%, P<0.001). Reoxygenation in the presence of sevoflurane 2.2% or HFIP 4 mM increased LDH release only by+18% (+6 to+30%) and 20% (+7 to+32%), respectively. Apoptosis and reactive oxygen species formation were attenuated by sevoflurane and HFIP. Mitochondrial bioenergetics analysis of the two substances was profoundly different. Sevoflurane did not influence oxygen consumption rate (OCR) or extracellular acidification rate (ECAR), whereas HFIP reduced OCR and increased ECAR, an effect similar to oligomycin, an adenosine triphosphate (ATP) synthase inhibitor. When blocking the metabolism of sevoflurane into HFIP, protective effects of sevoflurane - but not of HFIP - on LDH release and caspase were mitigated. Together, our data suggest that sevoflurane metabolism into HFIP plays an essential role in cardiomyocyte postconditioning after hypoxia/reoxygenation injury.

Effects of Volatile Anesthetics versus Ketamine on Blood-Brain Barrier Permeability via Lipid-Mediated Alterations of Endothelial Cell Membranes.

The purpose of this study was to investigate the effects of the volatile anesthetic agents isoflurane and sevoflurane, at clinically relevant concentrations, on the fluidity of lipid membranes and permeability of the blood-brain barrier (BBB). We analyzed the in vitro effects of isoflurane or ketamine using erythrocyte ghosts (sodium fluorescein permeability), monolayers of brain microvascular endothelial cells ([13C]sucrose and fluorescein permeability), or liposomes (fluorescence anisotropy). Additionally, we determined the effects of 30-minute exposure of mice to isoflurane on the brain tight junction proteins. Finally, we investigated in vivo brain uptake of [13C]mannitol and [13C]sucrose after intravenous administration in mice under anesthesia with isoflurane, sevoflurane, or ketamine/xylazine in addition to the awake condition. Isoflurane at 1-mM and 5-mM concentrations increased fluorescein efflux from the erythrocyte ghosts in a concentration-dependent manner. Similarly, in endothelial cell monolayers exposed to 3% (v/v) isoflurane, permeability coefficients rose by about 25% for fluorescein and 40% for [13C]sucrose, whereas transendothelial resistance and cell viability remained unaffected. Although isoflurane caused a significant decrease in liposomes anisotropy values, ketamine/xylazine did not show any effects. Brain uptake clearance (apparent Kin) of the passive permeability markers in vivo in mice approximately doubled under isoflurane or sevoflurane anesthesia compared with either ketamine/xylazine anesthesia or the awake condition. In vivo exposure of mice to isoflurane did not change any of the brain tight junction proteins. Our data support membrane permeabilization rather than loosening of intercellular tight junctions as an underlying mechanism for increased permeability of the endothelial cell monolayers and the BBB in vivo. SIGNIFICANCE STATEMENT: The blood-brain barrier controls the entry of endogenous substances and xenobiotics from the circulation into the central nervous system. Volatile anesthetic agents like isoflurane alter the lipid structure of cell membranes, transiently facilitating the brain uptake of otherwise poorly permeable, hydrophilic small molecules. Clinical implications may arise when potentially neurotoxic drugs gain enhanced access to the central nervous system under inhalational anesthetics.

Sevoflurane Ameliorates Schizophrenia in a Mouse Model and Patients: A Pre-Clinical and Clinical Feasibility Study.

GABAergic deficits have been considered to be associated with the pathophysiology of schizophrenia, and hence, GABA receptors subtype A (GABAARs) modulators, such as commonly used volatile anesthetic sevoflurane, may have therapeutic values for schizophrenia. The present study investigates the therapeutic effectiveness of low-concentration sevoflurane in MK801-induced schizophrenia-like mice and schizophrenia patients. Three weeks after MK801 administration (0.5 mg kg-1, i.p. twice a day for 5 days), mice were exposed to 1% sevoflurane 1hr/day for 5 days. Behavioral tests, immunohistochemical analysis, western blot assay, and electrophysiology assessments were performed 1-week post-exposure. Ten schizophrenia patients received 1% sevoflurane 5 hrs per day for 6 days and were assessed with the Positive and Negative Syndrome Scale (PANSS) and the 18-item Brief Psychiatric Rating Scale (BPRS-18) at week 1 and week 2. MK801 induced hypolocomotion and social deficits, downregulated expression of NMDARs subunits and postsynaptic density protein 95 (PSD95), reduced parvalbumin - and GAD67-positive neurons, altered amplitude and frequency of mEPSCs and mIPSCs, and increased the excitation/inhibition ratio. All these changes induced by MK-801 were attenuated by sevoflurane administration. Six and eight patients achieved a response defined as a reduction of at least 30% in the PANSS total score at 1st and 2nd week after treatments. The BPRS-18 total score was found to be significantly decreased by 38% at the 2nd week (p < 0.01). Low-concentration sevoflurane effectively reversed MK801-induced schizophrenialike disease in mice and alleviated schizophrenia patients' symptoms. Our work suggests sevoflurane to be a valuable therapeutic strategy for treating schizophrenia patients.

Inhibition of mitochondrial respiration by general anesthetic drugs

General anesthetic drugs have been associated with various unwanted effects including an interference with mitochondrial function. We had previously observed increases of lactate formation in the mouse brain during anesthesia with volatile anesthetic agents. In the present work, we used mitochondria that were freshly isolated from mouse brain to test mitochondrial respiration and ATP synthesis in the presence of six common anesthetic drugs. The volatile anesthetics isoflurane, halothane, and (to a lesser extent) sevoflurane caused an inhibition of complex I of the electron transport chain in a dose-dependent manner. Significant effects were seen at concentrations that are reached under clinical conditions (< 0.5 mM). Pentobarbital and propofol also inhibited complex I but at concentrations that were two-fold higher than clinical EC50 values. Only propofol caused an inhibition of complex II. Complex IV respiration was not affected by either agent. Ketamine did not affect mitochondrial respiration. Similarly, all anesthetic agents except ketamine suppressed ATP production at high concentrations. Only halothane increased cytochrome c release indicating damage of the mitochondrial membrane. In summary, volatile general anesthetic agents as well as pentobarbital and propofol dose-dependently inhibit mitochondrial respiration. This action may contribute to depressive actions of the drugs in the brain.

Effect of Volatile Anesthesia Versus Total Intravenous Anesthesia on Postoperative Pulmonary Complications in Patients Undergoing Cardiac Surgery: A Randomized Clinical Trial

The purpose of this study was to evaluate the effect of volatile anesthesia and propofol-based total intravenous anesthesia (TIVA) on postoperative pulmonary complications (PPCs) among patients undergoing cardiac surgery. Parallel-group, randomized controlled trial. Single-center tertiary care hospital. Five hundred twenty-four patients undergoing cardiac surgery with cardiopulmonary bypass. The patients were assigned randomly (1:1) to receive anesthesia maintenance with a volatile anesthetic (sevoflurane or desflurane) or propofol-based TIVA. The primary outcome was a composite of postoperative pulmonary complications within the first 7 postoperative days. The PPCs occurred in 118 of 262 patients (45.0%) in the volatile anesthesia group compared with 105 of 262 patients (40.1%) in the propofol-based intravenous anesthesia group (relative risk: 1.17 [95% CI 0.96-1.42], p=0.123). There were no significant differences in the severity of PPCs within 7 days postoperatively, the occurrence and severity grade of PPCs within 30 days, the incidence of hypoxia, and 30-day mortality. In adult patients undergoing cardiac surgery with cardiopulmonary bypass, general anesthesia with a volatile anesthetic compared with propofol-based TIVA had not reduced pulmonary complications within the first 7 days after surgery.

Effect of Volatile Anesthetics on Myocardial Infarction After Coronary Artery Surgery: A Post Hoc Analysis of a Randomized Trial

To investigate the effect of volatile anesthetics on the rates of postoperative myocardial infarction (MI) and cardiac death after coronary artery bypass graft (CABG). A post hoc analysis of a randomized trial. Cardiac surgical operating rooms. Patients undergoing elective, isolated CABG. Patients were randomized to receive a volatile anesthetic (desflurane, isoflurane, or sevoflurane) or total intravenous anesthesia (TIVA). The primary outcome was hemodynamically relevant MI (MI requiring high-dose inotropic support or prolonged intensive care unit stay) occurring within 48 hours from surgery. The secondary outcome was 1-year death due to cardiac causes. A total of 5,400 patients were enrolled between April 2014 and September 2017 (2,709 patients randomized to the volatile anesthetics group and 2,691 to TIVA). The mean age was 62 ± 8.4 years, and the median baseline ejection fraction was 57% (50-67), without differences between the 2 groups. Patients in the volatile group had a lower incidence of MI with hemodynamic complications both in the per-protocol (14 of 2,530 [0.6%] v 27 of 2,501 [1.1%] in the TIVA group; p=0.038) and as-treated analyses (16 of 2,708 [0.6%] v 29 of 2,617 [1.1%] in the TIVA group; p=0.039), but not in the intention-to-treat analysis (17 of 2,663 [0.6%] v 28 of 2,667 [1.0%] in the TIVA group; p=0.10). Overall, deaths due to cardiac causes were lower in the volatile group (23 of 2,685 [0.9%] v 40 of 2,668 [1.5%] than in the TIVA group; p=0.03). An anesthetic regimen, including volatile agents, may be associated with a lower rate of postoperative MI with hemodynamic complication in patients undergoing CABG. Furthermore, it may reduce long-term cardiac mortality.

Role of Renal Sympathetic Nerve Activity in Volatile Anesthesia's Effect on Renal Excretory Function.

Regulation of fluid balance is pivotal during surgery and anesthesia and affects patient morbidity, mortality, and hospital length of stay. Retention of sodium and water is known to occur during surgery but the mechanisms are poorly defined. In this study, we explore how the volatile anesthetic sevoflurane influences renal function by affecting renal sympathetic nerve activity (RSNA). Our results demonstrate that sevoflurane induces renal sodium and water retention during pediatric anesthesia in association with elevated plasma concentration of renin but not arginine–vasopressin. The mechanisms are further explored in conscious and anesthetized ewes where we show that RSNA is increased by sevoflurane compared with when conscious. This is accompanied by renal sodium and water retention and decreased renal blood flow (RBF). Finally, we demonstrate that renal denervation normalizes renal excretory function and improves RBF during sevoflurane anesthesia in sheep. Taken together, this study describes a novel role of the renal sympathetic nerves in regulating renal function and blood flow during sevoflurane anesthesia.

Attenuation of Native Hyperpolarization-Activated, Cyclic Nucleotide-Gated Channel Function by the Volatile Anesthetic Sevoflurane in Mouse Thalamocortical Relay Neurons

As thalamocortical relay neurons are ascribed a crucial role in signal propagation and information processing, they have attracted considerable attention as potential targets for anesthetic modulation. In this study, we analyzed the effects of different concentrations of sevoflurane on the excitability of thalamocortical relay neurons and hyperpolarization-activated, cyclic-nucleotide gated (HCN) channels, which play a decisive role in regulating membrane properties and rhythmic oscillatory activity. The effects of sevoflurane on single-cell excitability and native HCN channels were investigated in acutely prepared brain slices from adult wild-type mice with the whole-cell patch-clamp technique, using voltage-clamp and current-clamp protocols. Sevoflurane dose-dependently depressed membrane biophysics and HCN-mediated parameters of neuronal excitability. Respective half-maximal inhibitory and effective concentrations ranged between 0.30 (95% CI, 0.18–0.50) mM and 0.88 (95% CI, 0.40–2.20) mM. We witnessed a pronounced reduction of HCN dependent Ih current amplitude starting at a concentration of 0.45 mM [relative change at −133 mV; 0.45 mM sevoflurane: 0.85 (interquartile range, 0.79–0.92), n = 12, p = 0.011; 1.47 mM sevoflurane: 0.37 (interquartile range, 0.34–0.62), n = 5, p < 0.001] with a half-maximal inhibitory concentration of 0.88 (95% CI, 0.40–2.20) mM. In contrast, effects on voltage-dependent channel gating were modest with significant changes only occurring at 1.47 mM [absolute change of half-maximal activation potential; 1.47 mM: −7.2 (interquartile range, −10.3 to −5.8) mV, n = 5, p = 0.020]. In this study, we demonstrate that sevoflurane inhibits the excitability of thalamocortical relay neurons in a concentration-dependent manner within a clinically relevant range. Especially concerning its effects on native HCN channel function, our findings indicate substance-specific differences in comparison to other anesthetic agents. Considering the importance of HCN channels, the observed effects might mechanistically contribute to the hypnotic properties of sevoflurane.

Cholinergic receptors play a role in the cardioprotective effects of anesthetic preconditioning: Roles of nitric oxide and the CaMKKβ/AMPK pathway.

Vagus nerve activation may have important therapeutic significance for myocardial ischemia-reperfusion (IR) injury. Nitric oxide (NO) plays a vital role in the cardioprotective effects of anesthetic preconditioning (APC). Moreover, acetylcholine (ACh) prevents cardiomyocyte damage by activating AMP-activated protein kinase (AMPK) and increasing the phosphorylation of Ca2+/calmodulin-dependent protein kinase β (CaMKKβ). The aim of the present study was to determine whether APC could protect heart function by antagonizing IR damage via the cholinergic system. It was hypothesized that the NO synthase (NOS)/CaMKKβ/AMPK pathway might be involved in the cardioprotective effects induced by cholinergic receptor activation. Isolated rat hearts were subjected to ischemia for 30 min followed by 120 min of reperfusion. Volatile anesthetic sevoflurane (3.5%) was administered for 15 min before ischemia, then rinsed for 15 min. The muscarinic acetylcholine receptor (mAChR) antagonist atropine (ATR; 100 nM) and the nicotinic acetylcholine receptor (nAChR) antagonist hexamethonium (HEM; 50 µM) were administered 10 min before APC. Both mAChR and nAChR were involved in APC-induced cardioprotection. ATR and HEM treatment both abolished the protective effects of APC on IR damage in isolated hearts, demonstrating the importance of cholinergic receptors in the protection mechanism of APC. The present study thus suggests that APC plays a cardioprotective role, in part, by regulating neurohumoral pathways. In addition, there may be functional coupling between the two cholinergic receptors, and the NOS and CaMKKβ/AMPK pathways may play roles in shared pathways that mediate the cardioprotective effects of APC. These findings may provide insight into potential new mechanisms of APC-induced cardioprotection against IR injury.

Sevoflurane Exposure Induces Neuronal Cell Parthanatos Initiated by DNA Damage in the Developing Brain via an Increase of Intracellular Reactive Oxygen Species

The safety of volatile anesthetics in infants and young children has been drawing increasing concern due to its potential neurotoxicity in the developing brain. Neuronal death is considered a major factor associated with developmental neurotoxicity after exposure to volatile anesthetics sevoflurane, but its mechanism remains elusive. Parthanatos, a new type of programmed cell death, resulting from poly (ADP-ribose) polymerase 1 (PARP-1) hyperactivation in response to DNA damage, was found to account for the pathogenesis of multiple neurological disorders. However, the role of Parthanatos in sevoflurane-induced neonatal neuronal cell death has not been investigated. To test it, neuronal cells treated with 2, 4, and 8% sevoflurane for 6, 12, and 24 h and postnatal day 7 rats exposed to 2.5% sevoflurane for 6 h were used in the present study. Our results found sevoflurane exposure induced neuronal cell death, which was accompanied by PARP-1 hyperactivation, cytoplasmic polymerized ADP-ribose (PAR) accumulation, mitochondrial depolarization, and apoptosis-inducing factor (AIF) nuclear translocation in the neuronal cells and hippocampi of rats. Pharmacological or genetic inhibition of PAPR-1 significantly alleviated sevoflurane-induced neuronal cell death and accumulation of PAR polymer and AIF nuclear translocation, which were consistent with the features of Parthanatos. We observed in vitro and in vivo that sevoflurane exposure resulted in DNA damage, given that 8-hydroxydeoxyguanosine (8-OHdG) and phosphorylation of histone variant H2AX (γH2AX) were improved. Moreover, we detected that sevoflurane exposure was associated with an overproduction of intracellular reactive oxygen species (ROS). Inhibition of ROS with antioxidant NAC markedly alleviated DNA damage caused by sevoflurane, indicating that ROS participated in the regulation of sevoflurane-induced DNA damage. Additionally, sevoflurane exposure resulted in upregulation of Parthanatos-related proteins and neuronal cell death, which were significantly attenuated by pretreatment with NAC. Therefore, these results suggest that sevoflurane exposure induces neuronal cell Parthanatos initiated by DNA damage in the developing brain via the increase of intracellular ROS.

Probabilistic health risk assessment of occupational exposure to isoflurane and sevoflurane in the operating room

Risk assessment is an important tool in predicting the possible risk to health. It heightens awareness by estimating the probability of adverse health effects in humans who are exposed to chemicals in the course of their work. Therefore, the present work aims to determine the occupational exposure of operating room staff to the volatile anesthetic gases, isoflurane and sevoflurane, and estimates non-cancer risk using the United States Environmental Protection Agency method. Air samples from the breathing zone of staff members were collected using the Occupational Safety and Health Administration Method 103 and analyzed using gas chromatography-mass spectroscopy. The results indicate that the measured concentrations of isoflurane and sevoflurane are below the National Institute of Occupational Safety and Health standard (2 ppm) for technicians and nurses, but not for anesthesiologists and surgeons. Moreover, the estimated non-cancer risk due to isoflurane is above the acceptable value for anesthesiologists (but acceptable for other occupational categories). A sensitivity analysis indicates that exposure time has the most effect on calculated risk (53.4%). Occupational exposure to anesthetic gases may endanger the health of operating room personnel. Therefore, control measures, such as daily testing of anesthetic devices, ensuring the effectiveness of ventilation systems, advanced scavenging methods, and regular training of staff are highly recommended.

The effect of anesthetics on toll like receptor 9.

Toll like receptors (TLRs) are critical receptors to respond to danger signals, and their functions are relevant in the perioperative period. We previously reported that volatile anesthetics directly bound to TLR2 and TLR4 and attenuated their functions. Given that TLR9 can respond to mitochondrial DNA, a danger signal that is released upon tissue injury, we examined the role of anesthetics on TLR9 function. Our reporter assay showed that volatile anesthetics isoflurane and sevoflurane increased the activation of TLR9, while propofol attenuated it. TLR9 activation occurs via its dimerization. The dimerization is facilitated by unmethylated cytosine-phosphate-guanine (CpG) DNA as well as DNA containing cytosine at the second position from 5'-end (5'-xCx DNA). Our structural analysis using photoactivable anesthetics and rigid docking simulation showed that isoflurane and sevoflurane bound to both TLR9 dimer interface and 5'-xCx DNA binding site. Propofol bound to the TLR9 antagonist binding site. This is the first illustration that anesthetics can affect the binding of nucleic acids to their receptor. This study sets the foundation for the effect of anesthetics on TLR9 and will pave the way for future studies to determine the significance of such interactions in the clinical setting.

Enrichment of surface oxygen functionalities on activated carbon for adsorptive removal of sevoflurane

Activated carbons have been reported to be useful for adsorptive removal of the volatile anaesthetic sevoflurane from a vapour stream. The surface functionalities on activated carbons could be modified through aqueous oxidation using oxidising solutions to enhance the sevoflurane adsorption. In this study, an attempt to oxidise the surface of a commercial activated carbon to improve its adsorption capacity for sevoflurane was conducted using 6 mol/L nitric acid, 2 mol/L ammonium persulfate, and 30 wt per cent (wt%) of hydrogen peroxide (H2O2). The adsorption tests at fixed conditions (bed depth: 10 cm, inlet concentration: 528 mg/L, and flow rate: 3 L/min) revealed that H2O2 oxidation gave desirable sevoflurane adsorption (0.510 ± 0.005 mg/m2). A parametric study was conducted with H2O2 to investigate the effect of oxidation conditions to the changes in surface oxygen functionalities by varying the concentration, oxidation duration, and temperature, and the Conductor-like Screening Model for Real Solvents (COSMO-RS) was applied to predict the interactions between oxygen functionalities and sevoflurane. The H2O2 oxidation incorporated varying degrees of both surface oxygen functionalities with hydrogen bond (HB) acceptor and HB donor characters under the studied conditions. Oxidised samples with enriched oxygen functionalities with HB acceptor character and fewer HB donor character exhibited better adsorption capacity for sevoflurane. The presence of a high amount of oxygen functional groups with HB donor character adversely affected the sevoflurane adsorption despite the enrichment of oxygen functional groups with HB acceptor character that have a higher tendency to adsorb sevoflurane.

Sevoflurane inhibits migration and invasion of glioma cells via regulating miR-34a-5p/MMP-2 axis

Glioma is the most common brain malignancy and surgical resection is the primary option for patient with glioma. Anesthetics could be used to inhibit cancer dissemination and metastasis during surgery. This study aims to assess the function of volatile anesthetic sevoflurane in glioma migration and invasion and explore the potential mechanism. Twenty-five patients with glioma were recruited in this study. LN229 and U251 cells were used in vitro experiments. Cell viability was analyzed by MTT analysis. Cell migration and invasion were examined via transwell analysis. microRNA-34a-5p (miR-34a-5p) and matrix metalloproteinase-2 (MMP-2) levels were measured via quantitative real-time polymerase chain reaction. The relationship of miR-34a-5p and MMP-2 was tested via bioinformatics analysis, luciferase reporter analysis, RNA immunoprecipitation and RNA pull-down. Sevoflurane decreased glioma cell migration and invasion. In glioma cells, sevoflurane up-regulated miR-34a-5p abundance and down-regulated MMP-2 level. Overexpression of miR-34a-5p contributed to sevoflurane-caused suppression of migration and invasion, while its knockdown played an opposite effect. MMP-2 was targeted via miR-34a-5p and MMP-2 silence reversed the influence of miR-34a-5p knockdown under sevoflurane. Sevoflurane exposure represses cell migration and invasion, which might be related to inhibition of MMP-2 by up-regulating miR-34a-5p. This study provides a novel mechanism for understanding the pharmacological effects of sevoflurane on glioma.