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.

Prolonged isoflurane anesthesia-induced acidosis decreases penile intracavernous pressure in rats.

BACKGROUND: Intracavernous pressure measurement following cavernous nerve electrostimulation has been extensively adopted for the evaluation of erectile function in animals. However, the effect of measurement time and acidosis during anesthesia is still lacking. OBJECTIVE: To explore the effect of measurement time and acidosis during anesthesia. MATERIALS AND METHODS: Fifty-six male Sprague-Dawley rats were used and anesthetized by a spontaneous inhalation of isoflurane. In the first step, rats were randomly divided into four groups: a control group and three time-delayed measurement groups (intracavernous pressure measurement beginning at 15, 30, and 45 min after cavernous nerve exposure). In the second step, rats were randomly divided into three groups: a control group and two time-delayed measurement groups. Two intravenous fluid support strategies were used in time-delayed measurement groups: a normal saline solution and an isotonic Na2 CO3 solution. RESULTS: Isoflurane-anesthetized rats developed systemic acidosis that worsens with time during intracavernous pressure measurement, which results in a significant decrease in the maximum intracavernous pressure value, intracavernous pressure/mean arterial pressure ratio, and total intracavernous pressure measured. The Na2 CO3 infusion could effectively correct acidosis. The decrease in intracavernous pressure was related to the reduced nitric oxide synthase activity, decreased cyclic guanosine monophosphate concentration, and reactive oxygen species activation in rat penis under acidosis conditions. DISCUSSION AND CONCLUSION: Prolonged isoflurane anesthesia-induced acidosis markedly depresses the erectile response to cavernous nerve electrostimulation in rats. In this situation, it is recommended to supplement with a Na2 CO3 infusion to maintain a normal acid-base balance.

Green tea polyphenols improve isoflurane-induced cognitive impairment via modulating oxidative stress.

Anesthetic exposure induces learning and memory impairment and the mechanisms remain unknown. Green tea polyphenols(GTP) have been reported to be neuroprotective. The present study was performed to examine the therapeutic potential of GTP on isoflurane-induced cognitive deficits. Six-week-old male C57BL/6J mice were treated with 1.6% isoflurane for 6 hours. Multiple-dose of GTP at 25 mg/kg for 7 consecutive days and single-dose at 75 mg/kg on the 7th day were respectively administered intraperitoneally to model mice before anesthesia. Fear conditioning test and novel objection recognition were conducted to assess cognition of mice. Superoxide dismutase (SOD) was evaluated using assay kits. Protein expression levels of right hippocampus p-CaMKII, p-CREB and BDNF were examined by Western blot. Our results indicated that 6 h isoflurane anesthesia induced cognitive impairment in early 3 days. Meanwhile, the hippocampus SOD declined in step. The expression levels of p-CaMKII, p-CREB and BDNF were also downregulated. GTP 25mg/kg per day significantly attenuated cognitive dysfunction on Day 3 following isoflurane anesthesia. Moreover, GTP 25mg/kg per day effectively mitigated isodlurane-induced declines of SOD, as well as the p-CaMKII, p-CREB and BDNF levels. However, single-dose at 75 mg/kg of GTP had no significant effects. This study indicated that GTP attenuate isoflurane-induced cognition impairment and this positive effects may be related to its antioxidant properties.

Sirt1 mediates improvement of isoflurane-induced memory impairment following hyperbaric oxygen preconditioning in middle-aged mice.

Hyperbaric oxygen (HBO) preconditioning (PC) has been suggested as a feasible method to provide neuroprotection from postoperative cognitive dysfunction (POCD). However, whether HBO-PC can ameliorate cognitive deficits induced by isoflurane, and the possible mechanism by which it may exert its effect, has not yet been clarified. In the present study, middle-aged mice were exposed to isoflurane anesthesia (1.5 minimal alveolar concentration [MAC]) for 2 h to establish a POCD model. After HBO preconditioning, cognitive function and expression of hippocampal sirtuin 1 (Sirt1), nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) were evaluated 24 h following isoflurane treatment, in the presence or absence of Sirt1 knockdown by short hairpin RNA (shRNA). HBO preconditioning increased the expression of Sirt1, Nrf2, and HO-1 and ameliorated memory dysfunction. Meanwhile, Sirt1 knockdown inhibited the expression of Nrf2 and HO-1 and attenuated the HBO preconditioning-associated memory improvement. Our results suggest that the application of HBO preconditioning is a useful treatment for POCD, and that Sirt1 may be a potential molecular target for POCD therapy.

Ginsenoside Rb1 Attenuates Isoflurane/surgery-induced Cognitive Dysfunction via Inhibiting Neuroinflammation and Oxidative Stress.

OBJECTIVE: Anesthetic isoflurane plus surgery has been reported to induce cognitive impairment. The underlying mechanism and targeted intervention remain largely to be determined. Ginsenoside Rb1 was reported to be neuroprotective. We therefore set out to determine whether ginsenoside Rb1 can attenuate isoflurane/surgery-induced cognitive dysfunction via inhibiting neuroinflammation and oxidative stress. METHODS: Five-months-old C57BL/6J female mice were treated with 1.4% isoflurane plus abdominal surgery for two hours. Sixty mg/kg ginsenoside Rb1 were given intraperitoneally from 7 days before surgery. Cognition of the mice were assessed by Barnes Maze. Levels of postsynaptic density-95 and synaptophysin in mice hippocampus were measured by Western blot. Levels of reactive oxygen species, tumor necrosis factor-α and interleukin-6 in mice hippocampus were measured by ELISA. RESULTS: Here we show for the first time that the ginsenoside Rb1 treatment attenuated the isoflurane/surgery-induced cognitive impairment. Moreover, ginsenoside Rb1 attenuated the isoflurane/surgery-induced synapse dysfunction. Finally, ginsenoside Rb1 mitigated the isoflurane/surgery-induced elevation levels of reactive oxygen species, tumor necrosis factor-α and interleukin-6 in the mice hippocampus. CONCLUSION: These results suggest that ginsenoside Rb1 may attenuate the isoflurane/surgery-induced cognitive impairment by inhibiting neuroinflammation and oxidative stress pending future studies.

[Electroacupuncture Intervention Inhibits the Decline of Learning-memory Ability and Overex- pression of Cleaved Caspase-3 and Bax in Hippocampus Induced by Isoflurane in APPswe/PS 1].

OBJECTIVE: To investigate the protection mechanism of electroacupuncture (EA) therapy against Alzheimer's disease (AD)-like neurotoxicity induced by Isoflurane. METHODS: Twenty-four APPswe/PS 1 dE9 double transgenic mice (one of the most extensively used transgenic mouse model of AD) and 24 littermate wild-type mice were randomly assigned into control (Con) group, isoflurane (Iso) group and EA group, respectively (n = 8 in each group). EA (2 Hz/100 Hz, 1 mA) was applied to "Baihui" (GV 20) and "Yongquan" (KI 1) for 15 min, once a day for 3 days. The transgenic mice were exposed to a closed box filled with 1.2% isoflurane + 30% O2 +70% N2 for 4 h. The animals' learning-memory ability was detected by Morris water maze test. The expression of cleaved Caspase-3 in the CA 1 area of hippocampus was detected by immunohistochemistry, and that of hippocampal Bcl-2 and Bax proteins detected by Western blot. RESULTS: Compared with the wilde-type mice, the average escape latency of place navigation test was significantly longer, while the percentage of target-quadrant stay time and the target- platform crossing times of spacial probe test were marked decreased in AD + lso mice (P < 0.05). After acupuncture intervention, the abovementioned changes were reversed (P < 0.05). Correspondingly, compared with the AD-Con group, the number of hippocampal activated Caspase-3-positive cells and the expression of Bax protein were significantly increased in the AD-Iso group (P < 0.05). After EA intervention, the increased Caspase-3-positive cell number and Bax protein expression were remarkably down-regulated in the AD-EA group, and the decreased ratio of Bcl-2/Bax in AD-Iso mice was obviously up-regulated in AD-EA mice (P < 0.05). No significant changes were found in the average escape latency, the percentage of target-quadrant stay time and the target-platofrm corssing times, and inthe number of hippocampal activated Caspase-3-positive cells, the expression levels of hippocampal Bcl-2 and Sax and the ratio of Bcl-2/Bax in the three groups of wilde-type mice (P > 0.05). CONCLUSION: EA intervention can improve the learning-memory ability in AD + Isoflurane mice, suggesting a reduction of AD-like neurotoxicity, which may be associated with its actions in inhibiting the overexpression of activated Caspase-3 and Bax proteins in the hippocampus.

[Isoflurane-induced malignant hyperthermia during intensive-care treatment]. / Isofluranassoziierte maligne Hyperthermie im Rahmen der Intensivtherapie.

Malignant hyperthermia (MH), an inherited myopathia varying in severity and course, is induced by halogenated anesthetic agents and depolarizing muscle relaxants. First recognized as a distinct disease entity in 1960, MH is defined as an anesthesia-related disease due to the agents by which it is triggered. Given the wide use of these preparations in prehospital emergency medicine and intensive care treatment, physicians in other disciplines may also encounter MH.

Perinatal supplementation with omega-3 polyunsaturated fatty acids improves sevoflurane-induced neurodegeneration and memory impairment in neonatal rats.

OBJECTIVES: To investigate if perinatal Omega-3 polyunsaturated fatty acids (n-3 PUFAs) supplementation can improve sevoflurane-induced neurotoxicity and cognitive impairment in neonatal rats. METHODS: Female Sprague-Dawley rats (n = 3 each group) were treated with or without an n-3 PUFAs (fish oil) enriched diet from the second day of pregnancy to 14 days after parturition. The offspring rats (P7) were treated with six hours sevoflurane administration (one group without sevoflurane/prenatal n-3 PUFAs supplement as control). The 5-bromodeoxyuridine (Brdu) was injected intraperitoneally during and after sevoflurane anesthesia to assess dentate gyrus (DG) progenitor proliferation. Brain tissues were harvested and subjected to Western blot and immunohistochemistry respectively. Morris water maze spatial reference memory, fear conditioning, and Morris water maze memory consolidation were tested at P35, P63 and P70 (n = 9), respectively. RESULTS: Six hours 3% sevoflurane administration increased the cleaved caspase-3 in the thalamus, parietal cortex but not hippocampus of neonatal rat brain. Sevoflurane anesthesia also decreased the neuronal precursor proliferation of DG in rat hippocampus. However, perinatal n-3 PUFAs supplement could decrease the cleaved caspase-3 in the cerebral cortex of neonatal rats, and mitigate the decrease in neuronal proliferation in their hippocampus. In neurobehavioral studies, compared with control and n-3 PUFAs supplement groups, we did not find significant spatial cognitive deficit and early long-term memory impairment in sevoflurane anesthetized neonatal rats at their adulthood. However, sevoflurane could impair the immediate fear response and working memory and short-term memory. And n-3 PUFAs could improve neurocognitive function in later life after neonatal sevoflurane exposure. CONCLUSION: Our study demonstrated that neonatal exposure to prolonged sevoflurane could impair the immediate fear response, working memory and short-term memory of rats at their adulthood, which may through inducing neuronal apoptosis and decreasing neurogenesis. However, these sevoflurane-induced unfavorable neuronal effects can be mitigated by perinatal n-3 PUFAs supplementation.

Prolonged high-dose isoflurane for refractory status epilepticus: is it safe?

Isoflurane is an alternative treatment for refractory status epilepticus. Little is known regarding human toxicities caused by isoflurane. We present 2 patients with prolonged refractory status epilepticus treated with high concentrations of isoflurane who developed signal abnormalities on magnetic resonance imaging. Patient 1 was treated with isoflurane for 85 days with 1975.2% concentration-hours. Patient 2 was treated with isoflurane for 34 days with 1382.4% concentration-hours. Serial brain magnetic resonance images in both showed progressive T2 signal hyperintensity involving thalamus and cerebellum, which improved after discontinuation of isoflurane. These cases suggest that isoflurane may be neurotoxic when used in high doses for long time periods.

[A case of acute encephalitis with refractory, repetitive partial seizures requiring a high concentration of isoflurane to suppress the seizures and showing abnormal findings in the bilateral thalamus on MRI during the convalescent period].

We report a patient with acute encephalitis with refractory, repetitive partial seizures requiring a high concentration of isoflurane to suppress the seizures and showing rare abnormal findings in the bilateral thalamus on MRI during the convalescent period. A five-year-old boy was admitted to our hospital because of fever and convulsions. Shortly after admission, convulsions became frequent and disturbance of consciousness became apparent. Abnormal findings on electroencephalogram indicated encephalitis. Convulsions could not be suppressed by any intravenous anticonvulsants including barbiturates. Inhalational anticonvulsant treatment with isoflurane was performed, but it was ineffective at a low concentration. A high concentration of isoflurane was needed to suppress convulsions. Since a high concentration of isoflurane induces hypotension, various drugs to increase blood pressure were also administered. Convulsions reappeared during withdrawal of isoflurane. Finally isoflurane was withdrawn without inducing status epilepticus by administration of intravenous and oral anticonvulsants during the withdrawal process. Neurological sequelae were very severe and there are no anticonvulsants that have effectively suppressed the convulsions to date. MRI during the convalescent period showed high-intensity signal changes on fluid-attenuated inversion recovery, diffusion-weighted image and T2-weighted image in the bilateral thalamus. But it is uncertain whether these changes were the cause of this disorder.

Opening of the blood-brain barrier during isoflurane anaesthesia.

In order to produce its desired effect, anaesthesia acts upon neuronal elements by modifying membrane conductances and transmitter interactions. The effect of higher doses of isoflurane, widely used in clinical settings, on the permeability of the blood-brain barrier (BBB) is meanwhile ignored. In this study we investigated the integrity of the BBB during various levels of isoflurane anaesthesia (1% and 3%) in cats by monitoring the extravasation of Evans blue. Simultaneously we measured the electroencephalogram (EEG), with particular emphasis on its direct current (DC) component. High doses of anaesthetic (3%) broke down the BBB in the cortex and thalamus, while milder doses (1%) only opened the BBB in the thalamus. The fluorescent signal of Evans blue was visible over an extravascular length of 23 mum in the cortex and 25 mum in the thalamus, similar to the diffusion of the same dye when the BBB was disrupted with mannitol. The opening of the BBB was associated with (i) a positive DC shift in the EEG measured on the scalp and (ii) an evaluated increase in cerebral volume of 2-2.8%. The opening of the BBB by high doses of isoflurane brings into discussion hitherto unexplored effects of anaesthesia on the brain. The electrophysiological correlate provided by the DC component of the EEG constitutes a promising option for the assessment of the BBB integrity during human anaesthesia.

Acute canine model for drug-induced Torsades de Pointes in drug safety evaluation-influences of anesthesia and validation with quinidine and astemizole.

An acute in vivo model for drug-induced torsades de pointes (TdP) for use in safety evaluation of drugs was developed using dogs with acute complete atrioventricular (AV) block. In order to study the effects of anesthetic agents on the inducibility of TdP, arrhythmias were induced by programmed electrical stimulation (PES) before and after cumulative intravenous administration of quinidine under anesthesia with sodium pentobarbital, halothane, or isoflurane. Both prolongation of the QTc and the incidence of TdP were greatest in dogs anesthetized with halothane and were smallest in those given pentobarbital, suggesting that halothane is the most suitable anesthetic for this TdP model. To further validate this model, astemizole was administered intravenously to other dogs under halothane anesthesia. Astemizole at 0.3 mg/kg caused slight prolongation of the QT interval but did not induce any arrhythmias. At 1 mg/kg, however, TdP were induced in 5 of 10 animals and in an additional 2 animals at 3 mg/kg. Single and multiple ectopic beats preceded the induction of TdP, and the ectopic beats were observed in a dose-dependent manner. The plasma concentrations of quinidine in dogs with TdP were equivalent to or less than quinidine levels in humans with TdP, while those of astemizole were higher in dogs. In conclusion, this acute canine model of TdP with halothane anesthesia, complete AV block, PES, and simultaneous measurements of plasma drug concentration would be valuable for assessing the risk of drugs, especially I(Kr) blockers, to induce TdP in humans.

Effects of general anaesthetic procedures on mitochondrial function of human skeletal muscle.

BACKGROUND: General anaesthetics inhibit mitochondrial function in animal models. However, very few studies have been performed in humans, and the results have not been conclusive. METHODS: We prospectively studied the oxygen consumption and the individual enzyme activity of each complex of the mitochondrial respiratory chain of skeletal muscle mitochondria in 54 healthy individuals who underwent general anaesthesia for orthopaedic surgery. The control group (n = 54) was made up of individuals submitted to the same orthopaedic procedure under regional anaesthesia (n = 31), and patients who underwent muscle biopsies for diagnostic purposes by local anaesthesia (n = 23). RESULTS: We found a significant decrease in the oxidation of glutamate (-36%), succinate (-25%) and ascorbate (-29%) in the general anaesthetic group compared with the controls (P < 0.001 for all substrates). The level of such inhibition was similar for volatile anaesthetics with strong (halothane) or weak (isoflurane) negative inotropic effect. By contrast, the enzymatic activity of all individual complexes and the coupling of oxidative phosphorylation did not differ between the two groups. CONCLUSION: We conclude that during general anaesthetic procedures there is an extensive inhibition of substrate oxidation in human muscle mitochondria, and that it is not caused by a direct effect on complexes of the mitochondrial respiratory chain or through uncoupling oxidative phosphorylation.

Effect of nebulized lignocaine on airway irritation and haemodynamic changes during induction of anaesthesia with desflurane.

This study was designed to assess the effect of nebulized lignocaine or saline given before induction on the quality of induction of anaesthesia with desflurane in unpremedicated, young, adult males. Of the first six patients, five developed laryngospasm, breath-holding, coughing and increased secretions. In four patients oxygen saturation decreased to 92% or less. Significant tachycardia and hypertension occurred in four patients, and bradyarrhythmia after induction occurred in three patients. Hiccups and bronchospasm occurred in one patient. Because of the unacceptably high incidence of complications, the study was discontinued. The incidence and severity of complications were not decreased by administration of nebulized lignocaine and were higher than those reported by other workers. We conclude that in unpremedicated, young, adult males, induction of anaesthesia with desflurane and nitrous oxide in oxygen was associated with a high incidence of respiratory irritant effects, tachycardia, hypertension and post-induction bradyarrhythmia. We also found that lignocaine, as used in this study, did not appear to obtund the cardiovascular and respiratory complications during inhalation induction using desflurane.

A prospective study of liver function in infants and children exposed to daily isoflurane for several weeks.

Eleven infants and children presenting for daily radiotherapy for a period of at least 2 weeks were anaesthetised with isoflurane in 33% oxygen and nitrous oxide. They were unpremedicated and given no other agents to supplement anaesthesia. The average number of exposures was 24 (SD 11; range 10-39) and the total anaesthetic time per exposure varied between 15 and 30 minutes. Liver function was assessed by determining serum total bilirubin, aspartate amino transferase, gamma glutamyl transferase and alkaline phosphatase before the start of treatment and at 5-daily intervals thereafter. There was no measurable change in any of these determinants of liver function. All children accepted daily induction of anaesthesia with isoflurane. Induction, maintenance and recovery from anaesthesia were uncomplicated.