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Cell Biology and Toxicology Dec 2022With the development of technology, more infants receive general anesthesia for surgery, other interventions, or clinical examination at an early stage after birth.... (Review)
Review
With the development of technology, more infants receive general anesthesia for surgery, other interventions, or clinical examination at an early stage after birth. However, whether general anesthetics can affect the function and structure of the developing infant brain remains an important, complex, and controversial issue. Sevoflurane is the most-used anesthetic in infants, but this drug is potentially neurotoxic. Short or single exposure to sevoflurane has a weak effect on cognitive function, while long or repeated exposure to general anesthetics may cause cognitive dysfunction. This review focuses on the mechanisms by which sevoflurane exposure during development may induce long-lasting undesirable effects on the brain. We review neural cell death, neural cell damage, impaired assembly and plasticity of neural circuits, tau phosphorylation, and neuroendocrine effects as important mechanisms for sevoflurane-induced developmental neurotoxicity. More advanced technologies and methods should be applied to determine the underlying mechanism(s) and guide prevention and treatment of sevoflurane-induced neurotoxicity.
Topics: Sevoflurane; Neurons; Phosphorylation; Hippocampus
PubMed: 34766256
DOI: 10.1007/s10565-021-09677-y -
BMC Medicine Jan 2023Perioperative neurocognitive disorders (PND) with a high incidence frequently occur in elderly surgical patients closely associated with prolonged anesthesia-induced...
BACKGROUND
Perioperative neurocognitive disorders (PND) with a high incidence frequently occur in elderly surgical patients closely associated with prolonged anesthesia-induced neurotoxicity. The neuromorphopathological underpinnings of anesthesia-induced neurotoxicity have remained elusive.
METHODS
Prolonged anesthesia with sevoflurane was used to establish the sevoflurane-induced neurotoxicity (SIN) animal model. Morris water maze, elevated plus maze, and open field test were employed to track SIN rats' cognitive behavior and anxiety-like behaviors. We investigated the neuropathological basis of SIN through techniques such as transcriptomic, electrophysiology, molecular biology, scanning electron microscope, Golgi staining, TUNEL assay, and morphological analysis. Our work further clarifies the pathological mechanism of SIN by depleting microglia, inhibiting neuroinflammation, and C1q neutralization.
RESULTS
This study shows that prolonged anesthesia triggers activation of the NF-κB inflammatory pathway, neuroinflammation, inhibition of neuronal excitability, cognitive dysfunction, and anxiety-like behaviors. RNA sequencing found that genes of different types of synapses were downregulated after prolonged anesthesia. Microglial migration, activation, and phagocytosis were enhanced. Microglial morphological alterations were also observed. C1qa, the initiator of the complement cascade, and C3 were increased, and C1qa tagging synapses were also elevated. Then, we found that the "Eat Me" complement pathway mediated microglial synaptic engulfment in the hippocampus after prolonged anesthesia. Afterward, synapses were remarkably lost in the hippocampus. Furthermore, dendritic spines were reduced, and their genes were also downregulated. Depleting microglia ameliorated the activation of neuroinflammation and complement and rescued synaptic loss, cognitive dysfunction, and anxiety-like behaviors. When neuroinflammatory inhibition or C1q neutralization occurred, complement was also decreased, and synaptic elimination was interrupted.
CONCLUSIONS
These findings illustrated that prolonged anesthesia triggered neuroinflammation and complement-mediated microglial synaptic engulfment that pathologically caused synaptic elimination in SIN. We have demonstrated the neuromorphopathological underpinnings of SIN, which have direct therapeutic relevance for PND patients.
Topics: Animals; Rats; Anesthesia; Anxiety; Cognitive Dysfunction; Complement C1q; Hippocampus; Microglia; Neuroinflammatory Diseases; Sevoflurane
PubMed: 36600274
DOI: 10.1186/s12916-022-02705-6 -
British Journal of Anaesthesia May 2022The choice of anaesthetic may influence regulation of renal perfusion and function. We investigated renal function in patients anaesthetised with propofol or sevoflurane... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The choice of anaesthetic may influence regulation of renal perfusion and function. We investigated renal function in patients anaesthetised with propofol or sevoflurane before surgery and postoperatively.
METHODS
Patients with ASA physical status 1-2 planned for spinal surgery were randomised to propofol or sevoflurane anaesthesia. Blood and urine were collected before anaesthesia, during anaesthesia (before surgery), during postoperative care, and the day after surgery.
RESULTS
Twenty-seven patients completed the study protocol (average age, 51 yr; average BMI, 28 kg m) and 11 were women. Urine output and sodium excretion were lower during sevoflurane anaesthesia (n=14) than during propofol anaesthesia (n=13) (0.3 vs 1.1 ml kg h [P=0.01] and 2.6 vs 6.0 mmol h [P=0.04], respectively). Urinary potassium excretion was lower during anaesthesia than after, without intergroup difference (2.3 vs 5.7 mmol h, P<0.001). Sevoflurane anaesthesia increased plasma renin compared with baseline (138 vs 23 mIU L, P<0.001) and propofol anaesthesia (138 vs 27 mIU L, P=0.008). Plasma arginine-vasopressin did not change significantly during anaesthesia, but was elevated postoperatively compared with baseline irrespective of anaesthetic (21 vs 12 ng L, P=0.02). Sevoflurane caused higher postoperative plasma creatinine than propofol (83 vs 66 mmol L, P=0.01). Kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin did not change significantly in either group.
CONCLUSIONS
Sevoflurane anaesthesia reduced urine output and sodium excretion and increased plasma renin compared with propofol anaesthesia. The impact of this on acute kidney injury and fluid resuscitation during surgery warrants further investigation.
CLINICAL TRIAL REGISTRATION
EudraCT: 2017-001646-10; Clinicaltrials.gov: NCT0333680.
Topics: Anesthesia, General; Anesthetics, Inhalation; Anesthetics, Intravenous; Female; Humans; Kidney; Male; Methyl Ethers; Middle Aged; Propofol; Renin; Sevoflurane; Sodium
PubMed: 35279277
DOI: 10.1016/j.bja.2022.02.030 -
Turkish Neurosurgery 2020To examine whether post-treatment sevoflurane is protective against early brain injury (EBI) after subarachnoid hemorrhage (SAH) and how this neuroprotective effect...
AIM
To examine whether post-treatment sevoflurane is protective against early brain injury (EBI) after subarachnoid hemorrhage (SAH) and how this neuroprotective effect occurs at different concentrations and durations of administration in mice. Furthermore, we tested whether the neuroprotective effect of post-treatment sevoflurane is associated with inhibition of apoptosis.
MATERIAL AND METHODS
SAH was induced in mice by endovascular perforation. Animals were randomly assigned to five groups in each study. Study 1, sham-operated; SAH+vehicle-air; and SAH+1.5% sevoflurane for 30, 60, and 90 min. Study 2, SAH+3% sevoflurane for 30, 60, and 90 min. Study 3, SAH+4.5% sevoflurane for 30, 60, and 90 min. Neurobehavioral function and brain edema (brain water content) were evaluated 24 h after SAH. Neuroglial cell death was examined by terminal deoxynucleotidyl transferase-mediated uridine 5′-triphosphate-biotin nick end-labeling (TUNEL) staining.
RESULTS
Administration of 1.5% sevoflurane for 60 min and 3% sevoflurane for 30 and 60 min significantly improved neurobehavioral function, brain edema, and attenuated neuronal cell death in the basal cortex at 24 h after SAH.
CONCLUSION
Administration of 1.5% sevoflurane for 60 min and 3% for 30 and 60 min sevoflurane application attenuated the development of EBI after SAH, implying its use for anesthesia during acute aneurysm surgery or intervention.
Topics: Animals; Apoptosis; Brain; Brain Edema; Male; Mice; Mice, Inbred BALB C; Neuroprotective Agents; Platelet Aggregation Inhibitors; Random Allocation; Sevoflurane; Subarachnoid Hemorrhage
PubMed: 30901072
DOI: 10.5137/1019-5149.JTN.24788-18.1 -
Effects of propofol and sevoflurane on social and anxiety-related behaviours in sleep-deprived rats.British Journal of Anaesthesia Sep 2023Sleep disorders can profoundly affect neurological function. We investigated changes in social and anxiety-related brain functional connectivity induced by sleep...
BACKGROUND
Sleep disorders can profoundly affect neurological function. We investigated changes in social and anxiety-related brain functional connectivity induced by sleep deprivation, and the potential therapeutic effects of the general anaesthetics propofol and sevoflurane in rats.
METHODS
Twelve-week-old male Sprague-Dawley rats were subjected to sleep deprivation for 20 h per day (from 14:00 to 10:00 the next day) for 4 consecutive weeks. They were free from sleep deprivation for the remaining 4 h during which they received propofol (40 mg kg i.p.) or sevoflurane (2% for 2 h) per day or no treatment. These cohorts were instrumented for EEG/EMG recordings on days 2, 14, and 28. Different cohorts were used for open field and three-chambered social behavioural tests, functional MRI, nuclear magnetic resonance spectroscopy, and positron emission tomography imaging 48 h after 4 weeks of sleep deprivation.
RESULTS
Propofol protected against sleep deprivation-induced anxiety behaviours with more time (44.7 [8.9] s vs 24.2 [4.1] s for the sleep-deprivation controls; P<0.001) spent in the central area of the open field test and improved social preference index by 30% (all P<0.01). Compared with the sleep-deprived rats, propofol treatment enhanced overall functional connectivity by 74% (P<0.05) and overall glucose metabolism by 30% (P<0.01), and improved glutamate kinetics by 20% (P<0.05). In contrast, these effects were not found after sevoflurane treatment.
CONCLUSIONS
Unlike sevoflurane, propofol reduced sleep deprivation-induced social and anxiety-related behaviours. Propofol might be superior to sevoflurane for patients with sleep disorders who receive anaesthesia, which should be studied in clinical studies.
Topics: Animals; Male; Rats; Anesthetics, Inhalation; Anesthetics, Intravenous; Anxiety; Methyl Ethers; Propofol; Rats, Sprague-Dawley; Sevoflurane; Sleep; Sleep Deprivation; Social Behavior
PubMed: 37543435
DOI: 10.1016/j.bja.2023.05.025 -
Journal of Critical Care Apr 2023Volatile anesthetics are used more commonly for sedation in the intensive-care-unit (ICU). However, evidence for long-term use remains low. We therefore conducted a... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Volatile anesthetics are used more commonly for sedation in the intensive-care-unit (ICU). However, evidence for long-term use remains low. We therefore conducted a randomized-controlled trial comparing sevoflurane with intravenous sedation with particular focus on efficacy and safety.
METHODS
In this prospective, randomized-controlled phase-IIb monocentric clinical-trial ICU patients requiring at least 48 h of sedation were randomized to receive sevoflurane (S) or propofol/midazolam (P). Sedation quality was monitored using the Richmond-Agitation-Sedation-Scale. Following termination of sedation, the time to spontaneous breathing and extubation, opioid consumption, hemodynamics, ICU and hospital length of stay (LOS) and adverse events were recorded.
RESULTS
79 patients were eligible to randomization. Sedation quality was comparable between sevoflurane (n = 39) and propofol (n = 40). However, the use of sevoflurane lead to a reduction in time to spontaneous breathing (26 min vs. 375 min, P < 0.001). Patients sedated with propofol had lower opioid requirements (remifentanil:400 μg/h vs. 500 μg/h, P = 0.007; sufentanil:40 μg/h vs. 30 μg/h, P = 0.007) while hemodynamics, LOS or the occurrence of adverse events did not differ.
CONCLUSION
ICU patients sedated with sevoflurane >48 h may return to spontaneous breathing faster, while the quality of sedation is comparable to a propofol-based sedation regime. Sevoflurane might be considered to be safe for long-term sedation in this patient population, while being non-inferior compared to propofol.
Topics: Humans; Propofol; Sevoflurane; Anesthetics, Intravenous; Analgesics, Opioid; Respiration, Artificial; Prospective Studies; Critical Illness; Hypnotics and Sedatives
PubMed: 36640476
DOI: 10.1016/j.jcrc.2022.154251 -
Drug Design, Development and Therapy 2019Emergence delirium (ED) is a common neurologic complication that can not only distress children and their families in the early postanesthetic period, but can also have... (Randomized Controlled Trial)
Randomized Controlled Trial
Dexmedetomidine for the prevention of emergence delirium and postoperative behavioral changes in pediatric patients with sevoflurane anesthesia: a double-blind, randomized trial.
OBJECTIVES
Emergence delirium (ED) is a common neurologic complication that can not only distress children and their families in the early postanesthetic period, but can also have adverse effects on children in the long-term. This study aimed to investigate the effects of single-dose dexmedetomidine on ED in children with sevoflurane anesthesia and to observe postoperative behavioral changes through long-term follow-up.
METHODS
Patients aged 2-7 years, American Society of Anesthesiologists class (ASA) I or II, scheduled for tonsillectomy with and without adenoidectomy were randomized to receive dexmedetomidine 0.5 μg/kg (Group D) or volume-matched normal saline (Group C) over 10 minutes after induction of anesthesia. The primary outcome was the incidence of ED within 30 minutes after extubation. Other outcomes were the incidence of pain, extubation time, post-anesthesia care unit (PACU) length of stay after extubation, adverse events, and the incidence of negative postoperative behavioral changes (NPOBCs).
RESULTS
Ninety children completed the study. Compared with the control group (Group C), dexmedetomidine decreased the incidence of ED (31.1% vs 53.3%; =0.033) and pain (28.9% vs 57.8%; =0.006), but it prolonged extubation time (⩽0.001). PACU length of stay after extubation and the percentage of adverse events were similar between groups. The incidence of NPOBCs in Group D was significantly lower at 1 and 7 days after discharge (33.3% vs 60.0%; =0.011% and 24.4% vs 46.7%; =0.028, respectively) than it was in Group C, but no significant difference was found at the 30th day.
CONCLUSION
Dexmedetomidine 0.5 μg/kg reduced the incidence of ED after sevoflurane anesthesia and might be used to prevent NPOBCs.
CLINICAL TRIALS REGISTRATION
ChiCTR1800016828.
Topics: Anesthesia Recovery Period; Anesthesia, General; Child; Child, Preschool; Dexmedetomidine; Double-Blind Method; Emergence Delirium; Female; Humans; Injections, Intravenous; Male; Prospective Studies; Sevoflurane; Tonsillectomy
PubMed: 30936683
DOI: 10.2147/DDDT.S196075 -
British Journal of Anaesthesia Mar 2022Despite substantial advocacy for the scientific community to focus on sex-specific differences in biology, the role of sex hormones remains inadequately studied in the...
Despite substantial advocacy for the scientific community to focus on sex-specific differences in biology, the role of sex hormones remains inadequately studied in the field of anaesthesia-induced developmental neurotoxicity. A recent study by Yang and colleagues published in this journal addresses the importance of studying sex hormones during critical stages of brain development. The authors demonstrate that exogenous testosterone administered to immature mice pups around the time of sevoflurane exposure increased brain levels of testosterone, attenuated tau phosphorylation, inhibited glycogen synthase kinase-3β activation and its interaction/binding with tau, reversed sevoflurane-induced decreases in neuronal activation, and attenuated cognitive impairments. Their well-designed experiments suggest an important role that testosterone plays in balancing several important pathways crucial for neuronal protection and normal function of neuronal circuits in the male mammalian brain.
Topics: Animals; Brain; Female; Male; Mice; Phosphorylation; Sevoflurane; Testosterone; tau Proteins
PubMed: 35115156
DOI: 10.1016/j.bja.2022.01.002 -
British Journal of Anaesthesia Oct 2017Sevoflurane, a volatile anaesthetic agent well-tolerated for inhalation induction, provides a useful opportunity to elucidate the processes whereby halogenated ethers... (Review)
Review
Sevoflurane, a volatile anaesthetic agent well-tolerated for inhalation induction, provides a useful opportunity to elucidate the processes whereby halogenated ethers disrupt consciousness and cognition. Multiple molecular targets of sevoflurane have been identified, complementing imaging and electrophysiologic markers for the mechanistically obscure progression from wakefulness to unconsciousness. Recent investigations have more precisely detailed scalp EEG activity during this transition, with practical clinical implications. The relative timing of scalp potentials in frontal and parietal EEG signals suggests that sevoflurane might perturb the propagation of neural information between underlying cortical regions. Spatially distributed brain activity during general anaesthesia has been further investigated with positron emission tomography (PET) and resting-state functional magnetic resonance imaging (fMRI). Combined EEG and PET investigations have identified changes in cerebral blood flow and metabolic activity in frontal, parietal, and thalamic regions during sevoflurane-induced loss of consciousness. More recent fMRI investigations have revealed that sevoflurane weakens the signal correlations among brain regions that share functionality and specialization during wakefulness. In particular, two such resting-state networks have shown progressive breakdown in intracortical and thalamocortical connectivity with increasing anaesthetic concentrations: the Default Mode Network (introspection and episodic memory) and the Ventral Attention Network (orienting of attention to salient feature of the external world). These data support the hypotheses that perturbations in temporally correlated activity across brain regions contribute to the transition between states of sevoflurane sedation and general anaesthesia.
Topics: Anesthetics, Inhalation; Brain; Electroencephalography; Humans; Magnetic Resonance Imaging; Sevoflurane; Unconsciousness
PubMed: 29121298
DOI: 10.1093/bja/aex244 -
Advanced Science (Weinheim,... May 2023Sevoflurane has been the most widely used inhaled anesthetics with a favorable recovery profile; however, the precise mechanisms underlying its anesthetic action are...
Sevoflurane has been the most widely used inhaled anesthetics with a favorable recovery profile; however, the precise mechanisms underlying its anesthetic action are still not completely understood. Here the authors show that sevoflurane activates a cluster of urocortin 1 (UCN1 )/cocaine- and amphetamine-regulated transcript (CART ) neurons in the midbrain involved in its anesthesia. Furthermore, growth hormone secretagogue receptor (GHSR) is highly enriched in sevoflurane-activated UCN1 /CART cells and is necessary for sleep induction. Blockade of GHSR abolishes the excitatory effect of sevoflurane on UCN1 /CART neurons and attenuates its anesthetic effect. Collectively, their data suggest that anesthetic action of sevoflurane necessitates the GHSR activation in midbrain UCN1 /CART neurons, which provides a novel target including the nucleus and receptor in the field of anesthesia.
Topics: Sevoflurane; Mesencephalon; Urocortins; Sleep; Anesthesia
PubMed: 36961096
DOI: 10.1002/advs.202300189