Comparison of the genotoxicity of propofol and desflurane using the comet assay in the lymphocytes of patients who underwent lumbar discectomy: A randomized trial.

OBJECTIVES: To compare the genotoxic effects of desflurane and propofol using comet assay in patients undergoing elective discectomy surgery. METHODS: This was a randomized controlled study. Patients who underwent elective lumbar discectomy under general anesthesia with propofol or desflurane were included in the study. Venous blood samples were obtained at 4 different time points: 5 minutes before anesthesia induction (T1), 2 hours after the start of anesthesia (T2), the first day after surgery (T3), and the fifth day following surgery (T4). Deoxyribonucleic acid damage in lymphocytes was assessed via the comet assay. RESULTS: A total of 30 patients, 15 in each group, were included in the analysis. The groups were similar in terms of age and gender distribution. There were no significant differences in demographics, duration of surgery, total remifentanil consumption, and total rocuronium bromide consumption. The comet assay revealed that head length, head intensity, tail intensity, tail moment at T1 were similar in the desflurane and propofol groups. Head length, tail length and tail moment measured in the desflurane group at T4 were significantly higher compared to the propofol group. Tail lengths of the desflurane group at T1, T2 and T3 were significantly higher than the corresponding values in the propofol group. CONCLUSION: Propofol and desflurane do not appear to induce DNA damage in lymphocytes. However, when the quantitative data were compared, it was determined that propofol had relatively lower genotoxic potential than desflurane.ClinicalTrials.gov Reg. No.: NCT05185167.

Comparison between inhalational anesthetics in terms of DNA damage and immunological markers.

This study compared genetic damage and immunological markers between surgical patients who underwent inhalational anesthesia with isoflurane or sevoflurane. Blood samples were collected from surgical patients (n = 18 in the isoflurane group and n = 17 in the sevoflurane group) at baseline (before the anesthesia procedure) and the day after anesthesia. DNA damage was detected using an alkaline comet assay; proinflammatory interleukin (IL)-6 was detected by flow cytometry, and white blood cells were detected via an automatic hematology analyzer. The characteristics of both groups were similar, and neither of the two anesthetics induced DNA damage. Similarly, mild neutrophilia was observed after anesthesia in both groups. Increased IL-6 levels were observed 1 day after anesthesia regardless of the type of anesthetic, but this increase was greater in the isoflurane group. Our study suggested that isoflurane and sevoflurane administration may contribute to changes in the immune parameters measured, though no genotoxic hazard was identified, in healthy adult patients who undergo low-stress surgery.

Neuropsychological follow-up of isoflurane sedated intensive care patients: a substudy of a randomized trial.

BACKGROUND: Inhaled sedation of intensive care unit (ICU) patients ventilated >24 hours may have long term effects. We hypothesized that isoflurane has a better neuropsychological outcome in a one-year follow-up compared to propofol sedation. METHODS: All 66 patients included by the coordinating center of the ISOCONDA study (EudraCT#: 2016-004551-67) took part in this substudy (DRKS00020240). A delirium test (CAM-ICU) was performed 24 hours after end of sedation. Sedation-, ventilator-, ICU- and delirium-free days within 30 days were calculated. Patients were sent five questionnaires one, three and twelve months after ICU discharge: ICU-Memory-tool (ICU-MT), Short-Form-36-Health-survey (SF-36), Posttraumatic-Stress-Scale-14 (PTSS-14), WHO-Five-Well-Being-Index (WHO-5) and Hospital-Anxiety-Depression-Scale (HADS). RESULTS: CAM-ICU was positive in 17% of patients, however 68% showed signs of delirium during the ICU stay (no group differences). Mortality was lower after isoflurane (30-days: 1/33 versus 7/33, P=0.024; One-year: 9/33 versus 14/33, P=0.156). Isoflurane led to significantly more sedation- (median [IQR]: 28[25-29] versus 24[21-29], P=0.016), ventilator- (28[24-29] versus 22[4-28], P=0.011), ICU- (23[13-26] versus 11[0-25], P=0.044) and delirium-free days (25[21-29] versus 20[12-28], P=0.031). Return rate of questionnaires was high (87/128). In the ICU-MT, isoflurane patients recalled significantly more factual memories after one year. Generally, the psychological tests suggested a poor quality of life (SF-36), high rates of post-traumatic-stress-disorder (PTSS-14: 38%) and depression (WHO-5: 54%, HADS: 43%), without significant group differences. CONCLUSIONS: Isoflurane sedation leads to more delirium free days during the ICU treatment and more factual memories of the ICU stay one year after the ICU stay. However long-term outcome of ventilated ICU patients is poor, and there were no differences between isoflurane and propofol sedation.

Exercise attenuates the perioperative neurocognitive disorder induced by hyperhomocysteinemia in mice.

The perioperative neurocognitive disorder (PND) is a severe complication that affects millions of surgical patients each year. Homocysteine (Hcy) is known to increase the risk of developing PND in both young and elderly mice. However, whether Hcy alone can induce cognitive deficits in middle-aged mice (12-month-old), whether exercise can attenuate Hcy-induced hippocampus-related cognitive deficits after surgery through suppressing neuroinflammation, synaptic elimination, and the level of Hcy remains unknown. The present study aimed to answer these questions through testing the possibility of establishing a PND model using 12-month-old mice which received homocysteine injections before exploratory laparotomy and the therapeutic mechanism of exercise. In the present study, it was found that levels of serum homocysteine were age-dependently increased in mice with a significant difference between that of 18-month-old mice and 6-week, 6-month, and 12-month-old mice. PND occurred in 18-month but not in 12-month-old mice after exploratory laparotomy under isoflurane anesthesia. Intraperitoneal injection of Hcy for 3 consecutive days before surgery rendered 12-month-old mice to develop PND after abdominal laparotomy under isoflurane anesthesia at a minimal dosage of 20 mg/kg. Neuroinflammation and synaptic elimination was present in 12-month-old preoperative Hcy-injected mice. Preoperative voluntary wheel exercise could prevent PND in 12-month-old mice that have received Hcy injection before surgery, which might be related to the decreased level of serum Hcy. Activation of glial cells, proinflammatory phenotype markers and synaptic elimination were attenuated in the hippocampus of 12-month-old preoperative Hcy-injected mice by this exercise. These results provide direct evidence that hyperhomocysteinemia can induce postoperative cognitive deficits in middle-aged mice. Pre-surgery exercise can effectively prevent Hcy-precipitated postoperative cognitive dysfunction.

Acute Intraoperative Tympanic Membrane Rupture in Patient Anesthetized With Desflurane Without Nitrous Oxide: A Case Report.

We report a case of acute intraoperative tympanic membrane (TM) rupture in a patient anesthetized with desflurane without N2O. The patient was undergoing endoscopic retrograde cholangiopancreatography (ERCP) to treat ascending cholangitis. TM rupture is known to occur with N2O but has not been reported in the literature with the use of inhaled volatile anesthetics without N2O. We suspect that several factors contributed to this complication, including prone positioning, a remote history of ear trauma, and the selection of desflurane as the maintenance anesthetic as opposed to a vapor with a higher blood-gas partition coefficient.

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.

Post-Anesthesia Cognitive Dysfunction in Mice Is Associated with an Age-Related Increase in Neuronal Intracellular [Ca2+]-Neuroprotective Effect of Reducing Intracellular [Ca2+]: In Vivo and In Vitro Studies.

Background: Postoperative cognitive dysfunction (POCD) is a common disorder after general anesthesia in elderly patients, the precise mechanisms of which remain unclear. Methods: We investigated the effect of isoflurane with or without dantrolene pretreatment on intracellular calcium concentration ([Ca2+]i), reactive oxygen species (ROS) production, cellular lactate dehydrogenase (LDH) leak, calpain activity, and cognitive function using the Morris water maze test of young (3 months), middle-aged (12-13 months), and aged (24-25 months) C57BL6/J mice. Results: Aged cortical and hippocampal neurons showed chronically elevated [Ca2+]i compared to young neurons. Furthermore, aged hippocampal neurons exhibited higher ROS production, increased LDH leak, and elevated calpain activity. Exposure to isoflurane exacerbated these markers in aged neurons, contributing to increased cognitive deficits in aged mice. Dantrolene pretreatment reduced [Ca2+]i for all age groups and prevented or significantly mitigated the effects of isoflurane on [Ca2+]i, ROS production, LDH leak, and calpain activity in aged neurons. Dantrolene also normalized or improved age-associated cognitive deficits and mitigated the cognitive deficits caused by isoflurane. Conclusions: These findings suggest that isoflurane-induced cytotoxicity and cognitive decline in aging are linked to disruptions in neuronal intracellular processes, highlighting the reduction of [Ca2+]i as a potential therapeutic intervention.

Dysregulation of iron homeostasis and ferroptosis in sevoflurane and isoflurane associated perioperative neurocognitive disorders.

In recent years, sevoflurane and isoflurane are the most popular anesthetics in general anesthesia for their safe, rapid onset, and well tolerant. Nevertheless, many studies reported their neurotoxicity among pediatric and aged populations. This effect is usually manifested as cognitive impairment such as perioperative neurocognitive disorders. The wide application of sevoflurane and isoflurane during general anesthesia makes their safety a major health concern. Evidence indicates that iron dyshomeostasis and ferroptosis may establish a role in neurotoxicity of sevoflurane and isoflurane. However, the mechanisms of sevoflurane- and isoflurane-induced neuronal injury were not fully understood, which poses a barrier to the treatment of its neurotoxicity. We, therefore, reviewed the current knowledge on mechanisms of iron dyshomeostasis and ferroptosis and aimed to promote a better understanding of their roles in sevoflurane- and isoflurane-induced neurotoxicity.

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.

Differential effects of sevoflurane and desflurane on frontal intraoperative electroencephalogram dynamics associated with postoperative delirium.

STUDY OBJECTIVE: Intraoperative electroencephalogram (EEG) patterns associated with postoperative delirium (POD) development have been studied, but the differences in EEG recordings between sevoflurane- and desflurane-induced anesthesia have not been clarified. We aimed to distinguish the EEG characteristics of sevoflurane and desflurane in relation to POD development. DESIGN AND PATIENTS: We collected frontal four-channel EEG data during the maintenance of anesthesia from 148 elderly patients who received sevoflurane (n = 77) or desflurane (n = 71); 30 patients were diagnosed with delirium postoperatively. The patients were divided into four subgroups based on anesthetics and delirium status: sevoflurane delirium (n = 17), sevoflurane non-delirium (n = 60), desflurane delirium (n = 13), and desflurane non-delirium (n = 58). We compared spectral power, coherence, and pairwise phase consistency (PPC) between sevoflurane and desflurane, and between non-delirium and delirium groups for each anesthetic. MAIN RESULTS: In patients without POD, the sevoflurane non-delirium group exhibited higher EEG spectral power across 8.5-35 Hz (99.5% CI bootstrap analysis) and higher PPC from alpha to gamma bands (p < 0.005) compared to the desflurane non-delirium group. Conversely, in patients with POD, no significant EEG differences were observed between the sevoflurane and desflurane delirium groups. For the sevoflurane-induced patients, the sevoflurane delirium group had significantly lower power within 7.5-31.5 Hz (99.5% CI bootstrap analysis), reduced coherence over 8.9-23.8 Hz (99.5% CI bootstrap analysis), and lower PPC values in the alpha band (p < 0.005) compared with the sevoflurane non-delirium group. For the desflurane-induced patients, there were no significant differences in the EEG patterns between delirium and non-delirium groups. CONCLUSIONS: In normal patients without POD, sevoflurane demonstrates a higher power spectrum and prefrontal connectivity than desflurane. Furthermore, reduced frontal alpha power, coherence, and connectivity of intraoperative EEG could be associated with an increased risk of POD. These intraoperative EEG characteristics associated with POD are more noticeable in sevoflurane-induced anesthesia than in desflurane-induced anesthesia.

Neuroprotective potential of sevoflurane against isoflurane induced cognitive dysfunction in rats via anti-inflammatory and antioxidant effect.

PURPOSE: Intravenous anesthetics have excellent analgesic activity without inducing the side effect in the respiratory system. The aim and objective of the current experimental study was to access the neuroprotective effect of sevoflurane against isoflurane induced cognitive dysfunction in rats. METHODS: Isoflurane was used for induction the neurodysfunction in the rats, and rats received the oral administration of sevoflurane (2.5, 5 and 10 mg/kg). Morris water test was carried out for the estimation of cognitive function. Neurochemical parameters, antioxidant parameters and pro-inflammatory cytokines were also estimated. RESULTS: Sevoflurane significantly (P < 0.001) altered the neurochemical parameters such as anti-choline acetyltransferase, acetylcholine esterase, acetylcholine, protein carbonyl, choline brain-derived neurotrophic factor, and amyloid ß; antioxidant parameters such as glutathione, superoxide dismutase, and malondialdehyde; pro-inflammatory cytokines include interleukin (IL-2, IL-10, IL-4, IL-6, IL-10, IL-1ß), and tumor necrosis factor-α. Sevoflurane significantly reduced the activity of caspase-3. CONCLUSIONS: Sevoflurane exhibited the neuroprotection against the cognitive dysfunction in rats via anti-inflammatory and antioxidant mechanism.

Immunomodulatory and pro-oncologic effects of ketamine and isoflurane anesthetics in a murine model.

INTRODUCTION: Volatile and intravenous anesthetics may worsen oncologic outcomes in basic science animal models. These effects may be related to suppressed innate and adaptive immunity, decreased immunosurveillance, and disrupted cellular signaling. We hypothesized that anesthetics would promote lung tumor growth via altered immune function in a murine model and tested this using an immunological control group of immunodeficient mice. METHODS: Lewis lung carcinoma cells were injected via tail vein into C57BL/6 immunocompetent and NSG immunodeficient mice during exposure to isoflurane and ketamine versus controls without anesthesia. Mice were imaged on days 0, 3, 10, and 14 post-tumor cell injection. On day 14, mice were euthanized and organs fixed for metastasis quantification and immunohistochemistry staining. We compared growth of tumors measured from bioluminescent imaging and tumor metastasis in ex vivo bioluminescent imaging of lung and liver. RESULTS: Metastases were significantly greater for immunocompromised NSG mice than immunocompetent C57BL/6 mice over the 14-day experiment (partial η2 = 0.67, 95% CI = 0.54, 0.76). Among immunocompetent mice, metastases were greatest for mice receiving ketamine, intermediate for those receiving isoflurane, and least for control mice (partial η2 = 0.88, 95% CI = 0.82, 0.91). In immunocompetent mice, significantly decreased T lymphocyte (partial η2 = 0.83, 95% CI = 0.29, 0.93) and monocyte (partial η2 = 0.90, 95% CI = 0.52, 0.96) infiltration was observed in anesthetic-treated mice versus controls. CONCLUSIONS: The immune system appears central to the pro-metastatic effects of isoflurane and ketamine in a murine model, with decreased T lymphocytes and monocytes likely playing a role.

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.

Effects of Isoflurane Anesthesia on C57BL/6J Pups after Cervical Dislocation of Dams.

Inhalant anesthesia is routinely used for cesarian section in many animal species, allowing the safe delivery of neonates and smooth recovery of dams. However, in mice, inhalant anesthesia in cesarean section may be avoided due to fear of negative health effects on retrieved pups. This study compared the effects of isoflurane anesthesia on pups after cervical dislocation of conscious and anesthetized dams. Time-mated C57BL/6J dams were either anesthetized with 5% isoflurane or were conscious during cervical dislocation. Rederived pups were fostered to Swiss Webster dams and weaned at 21 d. Weights of litters were recorded at birth, and individual pup weights were recorded at weaning. We found no significant difference between the two treatment groups in pup survival until weaning. We also found no significant difference when comparing the average weaning weights of all the male pups to that of all the female. Female pups from isoflurane-treated dams had significantly higher weaning weights than did those from unanesthetized dams; however, the weights of male pups from the two groups were not different at weaning. This study found no immediate negative effects of using isoflurane anesthesia prior to cervical dislocation of C57BL/6J pregnant dams for the purpose of rederivation. Isoflurane can be used for cervical dislocation of pregnant C57BL/6J dams without affecting pup survival.

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.

Establishing a health-based recommended occupational exposure limit for isoflurane using experimental animal data: a systematic review protocol.

BACKGROUND: Isoflurane is used as an inhalation anesthetic in medical, paramedical, and veterinary practice. Epidemiological studies suggest an increased risk of miscarriages and malformations at birth related to maternal exposure to isoflurane and other inhalation anesthetics. However, these studies cannot be used to derive an occupational exposure level (OEL), because exposure was not determined quantitatively and other risk factors such as co-exposures to other inhalation anesthetics and other work-related factors may also have contributed to the observed adverse outcomes. The aim of this systematic review project is to assess all available evidence on the effects of isoflurane in studies of controlled exposures in laboratory animals to derive a health-based recommended OEL. METHODS: A comprehensive search strategy was developed to retrieve all animal studies addressing isoflurane exposure from PubMed, EMBASE, and Web of Science. Title-abstract screening will be performed by machine learning, and full-text screening by one reviewer. Discrepancies will be resolved by discussion. We will include primary research in healthy, sexually mature (non human) vertebrates of single exposure to isoflurane. Studies describing combined exposure and treatments with > = 1 vol% isoflurane will be excluded. Subsequently, details regarding study identification, study design, animal model, and intervention will be summarized. All relevant exposure characteristics and outcomes will be extracted. The risk of bias will be assessed by two independent reviewers using an adapted version of the SYRCLE's risk of bias tool and an addition of the OHAT tool. For all outcomes for which dose-response curves can be derived, the benchmark dose (BMD) approach will be used to establish a point of departure for deriving a recommended health-based recommended OEL for 8 h (workshift exposure) and for 15 min (short-term exposure). DISCUSSION: Included studies should be sufficiently sensitive to detect the adverse health outcomes of interest. Uncertainties in the extrapolation from animals to humans will be addressed using assessment factor. These factors are justified in accordance with current practice in chemical risk assessment. A panel of experts will be involved to reach consensus decisions regarding significant steps in this project, such as determination of the critical effects and how to extrapolate from animals to humans. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022308978.

Intracardiac Induced Ventricular Fibrillation for the Euthanasia of Sheep.

Euthanasia is the humane termination of an animal's life and an important consideration for scientists, veterinarians, regulators, and others contemplating investigations involving animals. Techniques for euthanasia must induce the most rapid, painless, and distress-free death possible. This study investigated the effectiveness of direct current induction of ventricular fibrillation for the euthanasia of sheep after a primary study in which artifacts or chemical contamination from injectable euthanasia agents were undesirable. Female crossbred adult sheep (Ovis aries; n = 12) under deep isoflurane general anesthesia were instrumented with electrophysiology catheters to induce ventricular fibrillation for euthanasia. Data regarding invasive arterial blood pressure, expired airway gases, limb lead electrocardiograms, and pulse oximetry were collected and assessed just prior to, immediately after, and at 5, 10, 15, and 20min after energy delivery. In all animals, a single 10-s application of 9V of direct current to the right ventricular endocardium via the electrophysiology catheter induced persistent ventricular fibrillation. Arterial blood pressure (mean ± 1 SD) immediately after fibrillation induction was 22.9±4.5mmHg, with negligible difference between systolic and diastolic pressures. The lack of differential pressure continued through the end of the monitoring period. Arterial blood pressure reached an initial nadir at 1??0.5min after fibrillation induction, peaked (40.8±11.1mmHg) due to a vasoconstrictive reflex at 3min after induction, and returned to a static uniform pressure (20.4±17.8mmHg) with mildly increased variability due to reflexive diaphragmatic contractions at 10min after induction. The use of 9V direct current for the induction of ventricular fibrillation via an electrophysiology catheter is a reliable method of euthanasia in sheep.

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.

Anaesthesia by intravenous propofol reduces the incidence of intra-operative gastric electrical slow-wave dysrhythmias compared to isoflurane.

Gastric motility is coordinated by bioelectrical slow-wave activity, and abnormal electrical dysrhythmias have been associated with nausea and vomiting. Studies have often been conducted under general anaesthesia, while the impact of general anaesthesia on slow-wave activity has not been studied. Clinical studies have shown that propofol anaesthesia reduces postoperative nausea and vomiting (PONV) compared with isoflurane, while the underlying mechanisms remain unclear. In this study, we investigated the effects of two anaesthetic drugs, intravenous (IV) propofol and volatile isoflurane, on slow-wave activity. In vivo experiments were performed in female weaner pigs (n = 24). Zolazepam and tiletamine were used to induce general anaesthesia, which was maintained using either IV propofol (n = 12) or isoflurane (n = 12). High-resolution electrical mapping of slow-wave activity was performed. Slow-wave dysrhythmias occurred less often in the propofol group, both in the duration of the recorded period that was dysrhythmic (propofol 14 ± 26%, isoflurane 43 ± 39%, P = 0.043 (Mann-Whitney U test)), and in a case-by-case basis (propofol 3/12, isoflurane 8/12, P = 0.015 (Chi-squared test)). Slow-wave amplitude was similar, while velocity and frequency were higher in the propofol group than the isoflurane group (P < 0.001 (Student's t-test)). This study presents a potential physiological biomarker linked to recent observations of reduced PONV with IV propofol. The results suggest that propofol is a more suitable anaesthetic for studying slow-wave patterns in vivo.