Anesthetics fragment hippocampal network activity, alter spine dynamics, and affect memory consolidation.

General anesthesia is characterized by reversible loss of consciousness accompanied by transient amnesia. Yet, long-term memory impairment is an undesirable side effect. How different types of general anesthetics (GAs) affect the hippocampus, a brain region central to memory formation and consolidation, is poorly understood. Using extracellular recordings, chronic 2-photon imaging, and behavioral analysis, we monitor the effects of isoflurane (Iso), medetomidine/midazolam/fentanyl (MMF), and ketamine/xylazine (Keta/Xyl) on network activity and structural spine dynamics in the hippocampal CA1 area of adult mice. GAs robustly reduced spiking activity, decorrelated cellular ensembles, albeit with distinct activity signatures, and altered spine dynamics. CA1 network activity under all 3 anesthetics was different to natural sleep. Iso anesthesia most closely resembled unperturbed activity during wakefulness and sleep, and network alterations recovered more readily than with Keta/Xyl and MMF. Correspondingly, memory consolidation was impaired after exposure to Keta/Xyl and MMF, but not Iso. Thus, different anesthetics distinctly alter hippocampal network dynamics, synaptic connectivity, and memory consolidation, with implications for GA strategy appraisal in animal research and clinical settings.

Characterization of cardiovascular profile of anti-influenza drug peramivir: A reverse-translational study using the isoflurane-anesthetized dog.

An injectable anti-influenza drug peramivir has been reported to induce QT-interval prolongation in some phase III studies, although its thorough QT/QTc study was negative. We investigated the discrepancy among those clinical studies using isoflurane-anesthetized beagle dogs (n = 4). Peramivir in doses of 1 mg/kg/10 min (sub-therapeutic dose) followed by 10 mg/kg/10 min (clinically-relevant dose) was intravenously administered. Peramivir prolonged QT interval/QTcV and Tpeak-Tend, and tended to delay ventricular repolarization in a reverse-frequency dependent manner, indicating IKr inhibition in vivo. Meanwhile, peramivir did not alter P-wave duration, PR interval or QRS width, indicating a lack of impact on cardiac conduction via Na+ or Ca2+ channel inhibition in vivo. Peramivir prolonged Tpeak-Tend and tended to prolong terminal repolarization period, which would develop substrates for initiating and maintaining spiral reentry, respectively. Meanwhile, peramivir did not prolong J-Tpeakc, which could not induce early afterdepolarization, a trigger inducing torsade de pointes. Thus, our results support that clinical dose exposure of peramivir can delay the ventricular repolarization in influenza patients. Peramivir has only a small potential to induce torsade de pointes in patients with the intact hearts, but caution should be paid on its use for patients formerly having the trigger for torsade de pointes.

Effects of the orexin receptor 2 agonist danavorexton on emergence from general anaesthesia and opioid-induced sedation, respiratory depression, and analgesia in rats and monkeys.

BACKGROUND: Delayed emergence from general anaesthesia, opioid-induced sedation, and opioid-induced respiratory depression is associated with perioperative complications. We characterised the preclinical effects of the orexin receptor 2 (OX2R)-selective agonist danavorexton (TAK-925) on emergence from anaesthesia and reversal of fentanyl-induced sedation, respiratory depression, and analgesia. METHODS: Emergence from isoflurane- or propofol-induced anaesthesia and fentanyl-induced sedation were investigated by righting reflex, rotarod, and electroencephalography in rats or monkeys. Fentanyl-induced respiratory depression was assessed by arterial blood gas analysis and whole-body plethysmography in rats and monkeys. Analgesia was evaluated using formalin- and skin incision-induced pain models in rats. RESULTS: Danavorexton shortened emergence from isoflurane- or propofol-induced anaesthesia and from fentanyl-induced sedation at 1 (P=0.005), 3 (P=0.006), and 3 mg kg-1 s.c. (P=0.022), respectively, by righting reflex in rats. Danavorexton (10 mg kg-1 s.c.) accelerated recovery from isoflurane-, propofol- and fentanyl-induced motor impairment in separate rotarod tests in rats (P=0.008, P=0.007, P=0.017, respectively), and reversed anaesthesia and fentanyl-induced delta-power increases. Danavorexton shortened emergence (return of righting reflex) from isoflurane- or propofol-induced anaesthesia at 1 (P=0.002) and 3 mg kg-1 (P=0.004), respectively, in cynomolgus monkeys. Danavorexton (10 mg kg-1 s.c.) reversed fentanyl-induced increase in Pco2 (P=0.006), and decrease in Po2 (P=0.015) and pH (P<0.001) in rats, and at 3 mg kg-1 s.c. reversed fentanyl-induced increase in Pco2 (P=0.007), and decrease in Po2 (P=0.013) and SO2 (P=0.036) in monkeys. Danavorexton increased minute volume and tidal volume in fentanyl-treated animals. Danavorexton at ≤10 mg kg-1 s.c. did not compromise fentanyl analgesia in rat formalin- and skin incision-induced pain models. CONCLUSIONS: Danavorexton promoted recovery from anaesthesia and fentanyl-induced sedation, and antagonised fentanyl-induced respiratory depression without compromising fentanyl analgesia.

Incidence of emergence agitation in children undergoing sevoflurane anesthesia compared to isoflurane anesthesia: An updated systematic review and meta-analysis.

BACKGROUND: Emergence agitation is a complex syndrome of altered consciousness after emergence from anesthesia. It can result in injury to patients and staff and is associated with other postoperative complications. Sevoflurane has been associated with emergence agitation, potentially due to low tissue solubility and therefore speed of emergence. Prior meta-analyses comparing emergence agitation incidence between sevoflurane and isoflurane anesthetics did not demonstrate a statistically significant difference. Given the publication of additional relevant studies not included in prior meta-analyses as well as improved diagnosis of emergence agitation, we aim to perform an updated, comprehensive meta-analysis comparing emergence agitation incidence between sevoflurane and isoflurane anesthetics in children. METHODS: We conducted an updated systematic review and meta-analysis of clinical trials comparing sevoflurane to isoflurane in children <18 years of age, reporting emergence agitation as an outcome, published before July 2023 using databases and registers. Our primary outcome was the incidence of emergence agitation. Secondary outcomes were time to extubation, awakening time, and length of stay in the postanesthetic care unit. We assessed the risk of bias using the Cochrane Risk of Bias tool version 2. We pooled the effect size for the outcomes using the fixed effects model if we had low heterogeneity, otherwise, we used a random-effects model. RESULTS: Eight randomized controlled trials (523 children) were included in the final analysis. The incidence of emergence agitation after isoflurane was significantly lower compared to sevoflurane (risk ratio: 0.62 (95% CI: [0.46-0.83]; I2 = 40.01%, p < .001)). Time to extubation, awakening times, and postanesthetic care unit duration were not significantly different. The protective effect of isoflurane compared to sevoflurane remained significant in subgroups of patients who received premedication or intraoperative systemic analgesics (risk ratios: (0.48 [0.28-0.82]; I2 = 60.78%, p = .01), (0.52 [0.37-0.75]; I2 = 0.00%, p < .001), respectively). CONCLUSION: The risk of emergence agitation in children after maintenance anesthesia with sevoflurane is significantly greater than with isoflurane; we did not find evidence of prolonged emergence or postanesthetic length of stay. When possible, isoflurane should be considered for maintenance anesthesia over sevoflurane in patients at high risk of emergence agitation.

The Impact of the Combined Effect of Inhalation Anesthetics and Iron Dextran on Rats' Systemic Toxicity.

Disruption of any stage of iron homeostasis, including uptake, utilization, efflux, and storage, can cause progressive damage to peripheral organs. The health hazards associated with occupational exposure to inhalation anesthetics (IA) in combination with chronic iron overload are not well documented. This study aimed to investigate changes in the concentration of essential metals in the peripheral organs of rats after iron overload in combination with IA. The aim was also to determine how iron overload in combination with IA affects tissue metal homeostasis, hepcidin-ferritin levels, and MMP levels according to physiological, functional, and tissue features. According to the obtained results, iron accumulation was most pronounced in the liver (19×), spleen (6.7×), lungs (3.1×), and kidneys (2.5×) compared to control. Iron accumulation is associated with elevated heavy metal levels and impaired essential metal concentrations due to oxidative stress (OS). Notably, the use of IA increases the iron overload toxicity, especially after Isoflurane exposure. The results show that the regulation of iron homeostasis is based on the interaction of hepcidin, ferritin, and other proteins regulated by inflammation, OS, free iron levels, erythropoiesis, and hypoxia. Long-term exposure to IA and iron leads to the development of numerous adaptation mechanisms in response to toxicity, OS, and inflammation. These adaptive mechanisms of iron regulation lead to the inhibition of MMP activity and reduction of oxidative stress, protecting the organism from possible damage.

Myocardial Protection by Desflurane: From Basic Mechanisms to Clinical Applications.

ABSTRACT: Coronary heart disease is an affliction that is common and has an adverse effect on patients' quality of life and survival while also raising the risk of intraoperative anesthesia. Mitochondria are the organelles most closely associated with the pathogenesis, development, and prognosis of coronary heart disease. Ion abnormalities, an acidic environment, the production of reactive oxygen species, and other changes during abnormal myocardial metabolism cause the opening of mitochondrial permeability transition pores, which disrupts electron transport, impairs mitochondrial function, and even causes cell death. Differences in reliability and cost-effectiveness between desflurane and other volatile anesthetics are minor, but desflurane has shown better myocardial protective benefits in the surgical management of patients with coronary artery disease. The results of myocardial protection by desflurane are briefly summarized in this review, and biological functions of the mitochondrial permeability transition pore, mitochondrial electron transport chain, reactive oxygen species, adenosine triphosphate-dependent potassium channels, G protein-coupled receptors, and protein kinase C are discussed in relation to the protective mechanism of desflurane. This article also discusses the effects of desflurane on patient hemodynamics, myocardial function, and postoperative parameters during coronary artery bypass grafting. Although there are limited and insufficient clinical investigations, they do highlight the possible advantages of desflurane and offer additional suggestions for patients.

Anesthetic effects of isoflurane and fentanyl infusion in capuchin monkeys (Sapajus sp) undergoing salpingectomy or deferentectomy, previously chemically restrained with ketamine-midazolam or ketamine-dexmedetomidine.

BACKGROUND: This study evaluated the anesthetic and cardiorespiratory effects of two anesthetic protocols for salpingectomy or deferentectomy in capuchin monkeys (Sapajus sp). MATERIALS AND METHODS: Five capuchin monkeys (5 per group) received ketamine (20 mg/kg) combined with midazolam (0.5 mg/kg; group KM) or dexmedetomidine (5 µg/kg; group KD) intramuscularly. Anesthesia is induced with propofol intravenously and maintained with isoflurane. Before the start of surgery, fentanyl 3 µg/kg was administered IV, and continuous infusion (10 µg/kg/min) IV was started. Times and quality of anesthetic recovery were evaluated postoperatively. RESULTS: KM and KD resulted in adequate chemical restraint. KD resulted in bradycardia. Intraoperative heart rate and systolic blood pressure were higher in KM than in KD. Both groups had smooth recovery. Time to standing was longer in KM than in KD. CONCLUSION: Both protocols allowed the performance of surgeries, with few cardiorespiratory effects. Anesthetic recovery was smooth and shorter in KD group.

Characterization of electropharmacological profile of an anti-atrial fibrillatory drug vernakalant along with potential risk toward torsade de pointes: Translational studies using isoflurane-anesthetized dogs and isolated rat aortic preparations.

We simultaneously assessed electropharmacological effects of anti-atrial fibrillatory drug vernakalant and its potential risk toward torsade de pointes. Vernakalant hydrochloride in doses of 0.3 and 3 mg/kg/10 min was intravenously administered to isoflurane-anesthetized beagle dogs without (n = 5) and with (n = 4) α-adrenoceptor blockade. Its vascular effect was analyzed using the rat aortae (n = 12). Vernakalant increased total peripheral vascular resistance and preload to left ventricle, leading to transient elevation of mean blood pressure indirectly via non-adrenergic pathway. Vernakalant suppressed sinus automaticity, ventricular contractility and intra-atrial/atrioventricular nodal/intraventricular conductions, and decreased cardiac output. Moreover, vernakalant prolonged atrial/ventricular effective refractory period by 53/55 ms, respectively, whereas it delayed ventricular repolarization in a reverse frequency-dependent manner. The extent of prolongation in early/late ventricular repolarization and electrically vulnerable period was 26/32 and 9 ms, respectively when QT-interval prolongation was the greatest. We compared them with those of known anti-atrial fibrillatory drugs; ranolazine, amiodarone, dronedarone, dl-sotalol and bepridil. The magnitude of vernakalant to alter those variables was the greater among those drugs except that the atrial selectivity was the lesser of those. Thus, vernakalant is expected to be efficacious against atrial fibrillation, but caution should be excised on its use for patients having labile ventricular function and repolarization.

Early-in-life isoflurane exposure alters resting-state functional connectivity in juvenile non-human primates.

BACKGROUND: Clinical studies suggest that anaesthesia exposure early in life affects neurobehavioural development. We designed a non-human primate (NHP) study to evaluate cognitive, behavioural, and brain functional and structural alterations after isoflurane exposure during infancy. These NHPs displayed decreased close social behaviour and increased astrogliosis in specific brain regions, most notably in the amygdala. Here we hypothesise that resting-state functional connectivity MRI can detect alterations in connectivity of brain areas that relate to these social behaviours and astrogliosis. METHODS: Imaging was performed in 2-yr-old NHPs under light anaesthesia, after early-in-life (postnatal days 6-12) exposure to 5 h of isoflurane either one or three times, or to room air. Brain images were segmented into 82 regions of interest; the amygdala and the posterior cingulate cortex were chosen for a seed-based resting-state functional connectivity MRI analysis. RESULTS: We found differences between groups in resting-state functional connectivity of the amygdala and the auditory cortices, medial premotor cortex, and posterior cingulate cortex. There were also alterations in resting-state functional connectivity between the posterior cingulate cortex and secondary auditory, polar prefrontal, and temporal cortices, and the anterior insula. Relationships were identified between resting-state functional connectivity alterations and the decrease in close social behaviour and increased astrogliosis. CONCLUSIONS: Early-in-life anaesthesia exposure in NHPs is associated with resting-state functional connectivity alterations of the amygdala and the posterior cingulate cortex with other brain regions, evident at the juvenile age of 2 yr. These changes in resting-state functional connectivity correlate with the decrease in close social behaviour and increased astrogliosis. Using resting-state functional connectivity MRI to study the neuronal underpinnings of early-in-life anaesthesia-induced behavioural alterations could facilitate development of a biomarker for anaesthesia-induced developmental neurotoxicity.

Anesthetic Management and Deep Sedation After Emergence From General Anesthesia: A Retrospective Cohort Study.

BACKGROUND: Residual deep sedation during anesthesia recovery may predict postoperative complications. We examined the incidence and risk factors for deep sedation after general anesthesia. METHODS: We retrospectively reviewed health records of adults who underwent procedures with general anesthesia and were admitted to the postanesthesia care unit from May 2018 to December 2020. Patients were dichotomized by Richmond Agitation-Sedation Scale (RASS) score: ≤-4 (deeply sedated/unarousable) or ≥-3 (not deeply sedated). Anesthesia risk factors for deep sedation were assessed with multivariable logistic regression. RESULTS: Of the 56,275 patients included, 2003 had a RASS ≤-4 (35.6 [95% CI, 34.1-37.2] cases per 1000 anesthetics administered). On adjusted analyses, the likelihood of a RASS ≤-4 increased when more soluble halogenated anesthetics were used. Compared with desflurane without propofol, the odds ratio (OR [95% CI]) for a RASS ≤-4 was higher with sevoflurane (1.85 [1.45-2.37]) and isoflurane (4.21 [3.29-5.38]) without propofol. Compared with desflurane without propofol, the odds of a RASS ≤-4 further increased with use of desflurane-propofol (2.61 [1.99-3.42]), sevoflurane-propofol (4.20 [3.28-5.39]), isoflurane-propofol (6.39 [4.90-8.34]), and total intravenous anesthesia (2.98 [2.22-3.98]). A RASS ≤-4 was also more likely with the use of dexmedetomidine (2.47 [2.10-2.89]), gabapentinoids (2.17 [1.90-2.48]), and midazolam (1.34 [1.21-1.49]). Deeply sedated patients discharged to general care wards had higher odds of opioid-induced respiratory complications (2.59 [1.32-5.10]) and higher odds of naloxone administration (2.93 [1.42-6.03]). CONCLUSIONS: Likelihood of deep sedation after recovery increased with intraoperative use of halogenated agents with higher solubility and increased further when propofol was concomitantly used. Patients who experience deep sedation during anesthesia recovery have an increased risk of opioid-induced respiratory complications on general care wards. These findings may be useful for tailoring anesthetic management to reduce postoperative oversedation.

Alfaxalone Alleviates Neurotoxicity and Cognitive Impairment Induced by Isoflurane Anesthesia in Offspring Rats.

BACKGROUND: The anesthetic isoflurane can cause neurotoxicity in fetuses and offspring of rats, affecting their neurodevelopment. However, the underlying mechanisms and therapeutic targets of isoflurane-induced neurotoxicity remain to be identified. Alfaxalone (ALF) is a steroid anesthetic. Steroids have been reported to have neuroprotective effects. This study aimed to investigate whether ALF could alleviate the isoflurane-induced neurotoxicity in fetuses and offspring of rats. METHODS: On gestation day 15 (G15), the pregnant SD rats were randomly assigned to 4 groups: control 1 (CTL1) + control 2 (CTL2), isoflurane (ISO) + CTL2, CTL1 + ALF, and ISO + ALF. To analyze the changes in the expression levels of inflammatory cytokines, apoptotic factors, and synaptophysin, the brain tissues from the G15 fetuses and offspring at postnatal day 7 (P7), postnatal day 14 (P14), and postnatal day 31 (P31) were collected. The newborn neurons in the rats' offspring at P7, P14, and P31 were counted using immunofluorescence techniques. The Morris water maze (MWM) test was performed to assess the learning and memory abilities of P31 offspring rats. RESULTS: ALF significantly alleviated the isoflurane-induced increase in the expression levels of inflammatory cytokines and apoptotic factors, such as interleukin (IL)-6 (ISO + CTL2 versus ISO + ALF: 5.133 ± 0.739 versus 1.093 ± 0.213, P < .001) and Caspase-3 (6.457 ± 0.6 versus 1.062 ± 0.1, P < .001) in the G15 fetuses. In P31 offspring rats, the expression levels of synaptophysin (0.719 ± 0.04 versus 1.068 ± 0.072, P < .001) and the number of newborn neurons in the dentate gyrus of the hippocampus were significantly lower in the ISO + CTL2 group as compared to those in the ISO + ALF group (118 ± 6 versus 140 ± 7, P < .001). These changes also occurred in the rat offspring at P7 and P14. In the MWM test, the escape latency of CTL1 + ALF group rats was significantly lower than that of ISO + ALF group rats (41 ± 6 versus 31 ± 7, P < .001) at P31. CONCLUSIONS: Based on these findings, this study suggested that isoflurane exposure during pregnancy in rats could cause neuroinflammation and death of embryos as well as impairment of cognitive function in the offspring rats. ALF can be used to counteract the negative effects of isoflurane.

Brain relaxation using desflurane anesthesia and total intravenous anesthesia in patients undergoing craniotomy for supratentorial tumors: a randomized controlled study.

BACKGROUND: Satisfactory brain relaxation is essential in neurosurgery. Desflurane anesthesia and propofol-based total intravenous anesthesia (TIVA) have different effects on cerebral hemodynamics, potentially contributing to discrepant brain relaxation. The purpose of this study was to compare the effects of desflurane and TIVA on brain relaxation in patients undergoing craniotomy for supratentorial tumors. METHODS: In this randomized, controlled study, we enrolled patients aged 18-60 years, with ASA I-III, who were scheduled to undergo elective craniotomy for supratentorial tumors. Patients were randomly assigned in a 1:1 ratio to receive desflurane anesthesia or TIVA. The primary outcome was the proportion of satisfactory brain relaxation. Secondary outcomes included emergence and extubation times, recovery of cognitive function and postoperative complications. RESULTS: Of 369 patients who were assessed for eligibility, 111 were randomized and 110 were included in the modified intention-to-treat analysis (55 in the desflurane group and 55 in the TIVA group). The proportion of satisfactory brain relaxation was similar between the two groups: 69% in the desflurane group and 73% in the TIVA group (RR: 0.950, 95% CI: 0.748-1.207; P = 0.675). Patients assigned to the desflurane group had shorter emergence (10 [8-13] min vs. 13 [10-20] min, P < 0.001) and extubation times (13 [10-18] min vs. 17 [13-23] min, P < 0.001), and better recovery of cognitive function at 15 min after extubation (16 [0-24] vs. 0 [0-20], P = 0.003), but experienced increased postoperative nausea and vomiting (PONV) (16 [29%] vs. 6 [11%] P = 0.017) and tachycardia (22 [40%] vs. 9 [16%], P = 0.006) during recovery. CONCLUSIONS: Desflurane anesthesia and TIVA provide similar brain relaxation in patients without intracranial hypertension undergoing elective craniotomy. Desflurane accelerates the recovery from anesthesia but is associated with increased PONV and tachycardia during the recovery period. TRIAL REGISTRATION: Clinicaltrial.gov (NCT04691128). Date of registration: December 31, 2020.

ANGPTL2 Deletion Attenuates Neuroinflammation and Cognitive Dysfunction Induced by Isoflurane in Aged Mice through Modulating MAPK Pathway.

Postoperative cognitive dysfunction (POCD) is a well-known complication after surgery with cognitive impairments. Angiopoietin-like protein 2 (ANGPTL2) has been found to be associated with inflammation. However, the role of ANGPTL2 in inflammation of POCD is unclear. Here, mice were subjected into isoflurane anesthesia. It was demonstrated that isoflurane increased ANGPTL2 expression and promoted pathological change in brain tissues. However, downregulation of ANGPTL2 alleviated the pathological change and elevated learning and memory abilities, improving isoflurane-induced cognitive dysfunction in mice. In addition, isoflurane-induced cell apoptosis and inflammation were repressed via ANGPTL2 knockdown in mice. Downregulation of ANGPTL2 was also verified to suppress isoflurane-induced microglial activation, evidenced by a decrease of Iba1 and CD86 expressions and an increase of CD206 expression. Further, the isoflurane-induced MAPK signaling pathway was repressed through downregulation of ANGPTL2 in mice. In conclusion, this study proved that downregulation of ANGPTL2 attenuated isoflurane-induced neuroinflammation and cognitive dysfunction in mice via modulating the MAPK pathway, which provided a new therapeutic target for POCD.

Neurological Dysfunction and Serum Levels of IL-6 and IL-1ß in Patients Undergoing Isoflurane Inhalation Anesthesia: A Correlation Study.

Objective: This study aims to explore the association between neurological dysfunction and serum levels of Interleukin-6 (IL-6) and Interleukin-1ß (IL-1ß) in patients undergoing isoflurane inhalation anesthesia. Methods: This prospective observational study enrolled a total of 88 patients who underwent isoflurane anesthesia, between April 2019 and April 2020 in our hospital's operating room. The Mini-Mental State Examination scale (MMSE) was administered on the first preoperative day (T0), the 1st postoperative day (T1), the 3rd postoperative day (T2), and the 7th postoperative day (T3). Based on the MMSE score obtained on the 1st postoperative day, patients were categorized into the neurological dysfunction group (n = 23) and the normal group (n = 65). Serum levels of IL-6 and IL-1ß were measured at T0, T1, T2, and T3, and their relationship with MMSE scores was analyzed. Results: Compared to the normal group, the neurological dysfunction group exhibited significantly higher levels of serum IL-6 and IL-1ß at all time points except T0, accompanied by notably lower MMSE scores (P < .001). Combined diagnostic parameters, including area under the curve (AUC) value, sensitivity, and specificity, showed improved performance compared to individual tests. Pearson correlation analysis revealed a negative correlation between serum IL-6 and IL-1ß levels and MMSE scores (r = -0.719, -0.408, all P < .05). Conclusions: Our findings highlight a correlation between neurological dysfunction and serum IL-6 and IL-1ß levels in patients undergoing isoflurane inhalation anesthesia. These cytokines could serve as valuable indicators for the early detection of neurological dysfunction following anesthesia.

Effects of Early Exposure to Isoflurane on Susceptibility to Chronic Pain Are Mediated by Increased Neural Activity Due to Actions of the Mammalian Target of the Rapamycin Pathway.

Patients who have undergone surgery in early life may be at elevated risk for suffering neuropathic pain in later life. The risk factors for this susceptibility are not fully understood. Here, we used a mouse chronic pain model to test the hypothesis that early exposure to the general anesthetic (GA) Isoflurane causes cellular and molecular alterations in dorsal spinal cord (DSC) and dorsal root ganglion (DRG) that produces a predisposition to neuropathic pain via an upregulation of the mammalian target of the rapamycin (mTOR) signaling pathway. Mice were exposed to isoflurane at postnatal day 7 (P7) and underwent spared nerve injury at P28 which causes chronic pain. Selected groups were treated with rapamycin, an mTOR inhibitor, for eight weeks. Behavioral tests showed that early isoflurane exposure enhanced susceptibility to chronic pain, and rapamycin treatment improved outcomes. Immunohistochemistry, Western blotting, and q-PCR indicated that isoflurane upregulated mTOR expression and neural activity in DSC and DRG. Accompanying upregulation of mTOR and rapamycin-reversible changes in chronic pain-associated markers, including N-cadherin, cAMP response element-binding protein (CREB), purinergic P2Y12 receptor, glial fibrillary acidic protein (GFAP) in DSC; and connexin 43, phospho-extracellular signal-regulated kinase (p-ERK), GFAP, Iba1 in DRG, were observed. We concluded that early GA exposure, at least with isoflurane, alters the development of pain circuits such that mice are subsequently more vulnerable to chronic neuropathic pain states.

Avoiding kidney damage in ICU sedation with sevoflurane: use isoflurane instead.

Intensive care unit (ICU) sedation with sevoflurane is associated with nephrogenic diabetes insipidus. Given that isoflurane is now licenced (in Europe) for ICU sedation and has Investigational New Drug status in the USA, evidence indicates that clinicians should stop using sevoflurane in this indication except in the context of clinical trials.

Desflurane improves lung collapse more than propofol during one-lung ventilation and reduces operation time in lobectomy by video-assisted thoracic surgery: a randomized controlled trial.

BACKGROUND: This study evaluated whether desflurane improved lung collapse during one-lung ventilation (OLV) more than propofol, and whether it could reduce the operation time of video-assisted thoracic surgery. METHODS: Sixty patients undergoing lobectomy by video-assisted thoracic surgery (VATS) were randomly assigned to general anesthesia with desflurane or propofol. Lungs were inspected by thoracoscope at 10, 30, and 60 min after initiation of OLV. After surgery, the Lung Collapse Score, a composite of lung color and volume assessments, was assigned by two clinicians blinded to the anesthetic regimen. The primary outcome was operation time. The secondary outcome included the complication rate. RESULTS: Of the 60 participants, 50 completed the study, 26 in Desflurane group and 24 in Propofol group. The Lung Collapse Scores at 30 and 60 min after OLV initiation were significantly better in Desflurane group than in Propofol group, and operation time was significantly shorter in Desflurane group (214 (57) min vs. 262 (72) min [mean (SD)], difference in means, -48; 95% CI, -85 to -11; P = 0.01). The incidence of multiple complications was 1/26 (3%) and 6/24 (25%) in Desflurane and Propofol group, respectively (relative risk, 0.1; 95% CI, 0.02 to 1.18; P = 0.04). CONCLUSIONS: Desflurane improved lung collapse during OLV and significantly shortened VATS lobectomy operation time compared to propofol in our studied patients. Desflurane resulted in fewer postoperative complications. Thus, desflurane may be an appropriate anesthetic during lobectomy by VATS requiring OLV. TRIAL REGISTRATION: The study was registered with the University Hospital Medical Information Network ( UMIN000009412 ). The date of disclosure of this study information is 27/11/2012. On this date, we registered the study into UMIN; patients were included from 2013 to 2014. However, on 11/27/2015, the UMIN system administrator suggested a detailed description. Thereafter, we added it to the Randomization Unit. Despite being prospective, it was retrospectively registered on UMIN for the above reasons.

Late post-natal neurometabolic development in healthy male rats using 1 H and 31 P magnetic resonance spectroscopy.

Brain metabolism evolves rapidly during early post-natal development in the rat. While changes in amino acids, energy metabolites, antioxidants or metabolites involved in phospholipid metabolism have been reported in the early stages, neurometabolic changes during the later post-natal period are less well characterized. Therefore, we aimed to assess the neurometabolic changes in male Wistar rats between post-natal days 29 and 77 (p29-p77) using longitudinal magnetic resonance spectroscopy (MRS) in vivo at 9.4 Tesla. 1 H MRS was performed in the hippocampus between p29 and p77 at 1-week intervals (n = 7) and in the cerebellum between p35 and p77 at 2-week intervals (n = 7) using the SPECIAL sequence at ultra-short echo-time. NOE enhanced and 1 H decoupled 31 P MR spectra were acquired at p35, p48 and p63 (n = 7) in a larger voxel covering cortex, hippocampus and part of the striatum. The hippocampus showed a decrease in taurine concentration and an increase in glutamate (with more pronounced changes until p49), seemingly a continuation of their well-described changes in the early post-natal period. A constant increase in myo-inositol and choline-containing compounds in the hippocampus (in particular glycero-phosphocholine as shown by 31 P MRS) was measured throughout the observation period, probably related to membrane metabolism and myelination. The cerebellum showed only a significant increase in myo-inositol between p35 and p77. In conclusion, this study showed important changes in brain metabolites in both the hippocampus and cerebellum in the later post-natal period (p29/p35-p77) of male rats, something previously unreported. Based on these novel data, changes in some neurometabolites beyond p28-35, conventionally accepted as the cut off for adulthood, should be taken into account in both experimental design and data interpretation in this animal model.

Histone Deacetylase 2-Mediated Epigenetic Regulation is Involved in the Early Isoflurane Exposure-Related Increase in Susceptibility to Anxiety-Like Behaviour Evoked by Chronic Variable Stress in Mice.

Increasing studies report that prolonged or multiple anaesthetic exposures early in life are associated with detrimental effects on brain function. Although studies have evaluated the detrimental effects on neurocognitive function, few have focused on long-term neuropsychiatric effects. In the present study, C57BL/6 mice received either three neonatal isoflurane exposures or control exposure. Starting on postnatal day 45, the mice were either exposed or not to a chronic variable stress (CVS) paradigm, and CVS-related neuropsychiatric performance was evaluated using a series of behavioural tests. The expression levels of histone 3 lysine 9 acetylation (acetyl-H3K9), brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein-binding protein, and histone deacetylases 1-4 in the amygdala were measured by immunoblotting or immunohistochemistry analysis. In mice with neonatal isoflurane exposure, the effects of sodium butyrate (NaB), a commonly used HDAC inhibitor, were examined on CVS-related behavioural and molecular alterations. The results showed that repeated neonatal isoflurane exposure did not affect innate depression-like and anxiety-like behaviours under non-stress conditions but facilitated the CVS-induced anxiety-like behavioural phenotype. Increased HDAC2 expression in the amygdala was associated with an increase in the CVS-induced repression of acetyl-H3K9 and BDNF expression and an enhanced CVS-evoked anxiety-like behavioural phenotype in mice neonatal isoflurane exposure. NaB significantly decreased the CVS-induced anxiety level by elevating acetyl-H3K9 and BDNF expression. These results suggested that early anaesthesia exposure facilitated chronic stress-induced neuropsychiatric outcomes, and the HDAC2-related epigenetic dysregulation of BDNF gene expression is involved in the underlying mechanism.

Role of Unfolded Protein Response and Endoplasmic Reticulum-Associated Degradation by Repeated Exposure to Inhalation Anesthetics in Caenorhabditis elegans.

Background: When an imbalance occurs between the demand and capacity for protein folding, unfolded proteins accumulate in the endoplasmic reticulum (ER) lumen and activate the unfolded protein response (UPR). In addition, unfolded proteins are cleared from the ER lumen for ubiquitination and subsequent cytosolic proteasomal degradation, which is termed as the ER-associated degradation (ERAD) pathway. This study focused on changes in the UPR and ERAD pathways induced by the repeated inhalation anesthetic exposure in Caenorhabditis elegans. Methods: Depending on repeated isoflurane exposure, C. elegans was classified into the control or isoflurane group. To evaluate the expression of a specific gene, RNA was extracted from adult worms in each group and real-time polymerase chain reaction was performed. Ubiquitinated protein levels were measured using western blotting, and behavioral changes were evaluated by chemotaxis assay using various mutant strains. Results: Isoflurane upregulated the expression of ire-1 and pek-1 whereas the expression of atf-6 was unaffected. The expression of both sel-1 and sel-11 was decreased by isoflurane exposure, possibly indicating the inhibition of retro-translocation. The expression of cdc-48.1 and cdc-48.2 was decreased and higher ubiquitinated protein levels were observed in the isoflurane group than in the control, suggesting that deubiquitination and degradation of misfolded proteins were interrupted. The chemotaxis indices of ire-1, pek-1, sel-1, and sel-11 mutants decreased significantly compared to N2, and they were not suppressed further even after the repeated isoflurane exposure. Conclusion: Repeated isoflurane exposure caused significant ER stress in C. elegans. Following the increase in UPR, the ERAD pathway was disrupted by repeated isoflurane exposure and ubiquitinated proteins was accumulated subsequently. UPR and ERAD pathways are potential modifiable neuroprotection targets against anesthesia-induced neurotoxicity.