The common inhalation anesthetic isoflurane has been shown to induce apoptosis, which then leads to accumulation of -amyloid protein, the hallmark feature of Alzheimer disease neuropathogenesis. The underlying molecular mechanism of the isoflurane-induced apoptosis is largely unknown. We, therefore, set out to assess whether isoflurane can induce apoptosis by regulating Bcl-2 family proteins, enhancing reactive oxygen species (ROS) accumulation, and activating the mitochondrial pathway of apoptosis. We performed these studies in cultured cells, primary neurons, and mice. Here we show for the first time that treatment with 2% isoflurane for 6 h can increase pro-apoptotic factor Bax levels, decrease antiapoptotic factor Bcl-2 levels, increase ROS accumulation, facilitate cytochrome c release from the mitochondria to the cytosol, induce activation of caspase-9 and caspase-3, and finally cause apoptosis as compared with the control condition. We have further found that isoflurane can increase the mRNA levels of Bax and reduce the mRNA levels of Bcl-2. The isoflurane-induced ROS accumulation can be attenuated by the intracellular calcium chelator BAPTA. Finally, the anesthetic desflurane does not induce activation of mitochondrial pathway of apoptosis. These results suggest that isoflurane may induce apoptosis through Bcl-2 family proteins-and ROS-associated mitochondrial pathway of apoptosis. These findings, which have identified at least partially the molecular mechanism by which isoflurane induces apoptosis, will promote more studies aimed at studying the potential neurotoxic effects of anesthetics.An estimated 200 million patients worldwide undergo anesthesia and surgery each year. Some clinical studies suggest that anesthesia and surgery may be associated with Alzheimer disease (AD) 3 (1-3), although different findings also exist (4, 5). Several recent studies have reported that isoflurane, one of the most commonly used inhalation anesthetics, may potentially contribute to AD neuropathogenesis by inducing apoptotic cell death and increasing -amyloid protein oligomerization and accumulation in vitro and in vivo (6 -13). However, the upstream mechanism by which isoflurane induces apoptosis remains largely to be determined.Apoptosis is a programmed cell death which can be triggered by environmental and/or developmentally associated signals (14). The central components of the apoptosis process are a group of proteolytic enzymes called caspases, which can be activated by various types of stimulation (15). The extrinsic, death receptor pathway involves activation of caspase-8, which then cleaves caspase-3, leading to apoptosis (for review, see Ref. 16). The intrinsic, mitochondrial pathway is regulated by Bcl-2 family proteins, including the anti-apoptotic factor Bcl-2 and the pro-apoptotic factor Bax (for review, see Ref. 17) and involves cytochrome c release from the mitochondria to the cytosol. The released cytochrome c then activates caspase-9, which consequently induces caspase-3 activation, leading to apoptosi...
Perioperative systemic lidocaine may be a useful adjunct for postoperative pain management by decreasing postoperative pain intensity, reducing opioid consumption, facilitating GI function, and shortening length of hospital stay.
Perioperative factors including hypoxia, hypocapnia, and certain anesthetics have been suggested to contribute to Alzheimer disease (AD) neuropathogenesis. Desflurane is one of the most commonly used inhalation anesthetics. However, the effects of desflurane on AD neuropathogenesis have not been previously determined. Here, we set out to assess the effects of desflurane and hypoxia on caspase activation, amyloid precursor protein (APP) processing, and amyloid -protein (A) generation in H4 human neuroglioma cells (H4 naïve cells) as well as those overexpressing APP (H4-APP cells). Neither 12% desflurane nor hypoxia (18% O 2 ) alone affected caspase-3 activation, APP processing, and A generation. However, treatment with a combination of 12% desflurane and hypoxia (18% O 2 ) (desflurane/hypoxia) for 6 h induced caspase-3 activation, altered APP processing, and increased A generation in H4-APP cells. Desflurane/hypoxia also increased levels of -site APP-cleaving enzyme in H4-APP cells. In addition, desflurane/hypoxia-induced A generation could be reduced by the broad caspase inhibitor benzyloxycarbonyl-VAD. Finally, the A aggregation inhibitor clioquinol and ␥-secretase inhibitor L-685,458 attenuated caspase-3 activation induced by desflurane/hypoxia. In summary, desflurane can induce A production and caspase activation, but only in the presence of hypoxia. Pending in vivo confirmation, these data may have profound implications for anesthesia care in elderly patients, and especially those with AD.
Purpose Postoperative cognitive decline in the elderly has emerged as a major health concern. In addition, there is a growing interest in the potential relationship between general anesthetic exposure and the onset and progression of Alzheimer’s disease (AD). The available evidence of a possible association between anesthesia, surgery, and long-term cognitive effects, including AD, deserves consideration. In this review, we summarize the evidence for anesthesia-induced neurotoxicity in the elderly, while highlighting the limitations of existing data, and we put the literature into perspective for the clinician. Principal findings A growing body of evidence suggests that general anesthetics may be neurotoxic to both young and aging brains. Much of the evidence originates from in vitro and in vivo studies with cells, rodents, and nonhuman primates. Despite the animal data suggesting a relationship between anesthesia and neurotoxicity in the elderly, a definitive link remains elusive in humans. Conclusions The possible relation between anesthetic neurotoxicity, postoperative cognitive dysfunction, and AD remains elusive. It remains unclear whether postoperative cognitive decline in the elderly is related more to perioperative stress and related medical co-morbidities.
The incidence of intra-operative awareness in China is approximately 0.41%, two to three times higher than that widely cited in Western countries. Inappropriately light anesthesia, and the population proportion of surgery and general anesthesia in China may account for the difference. (ClinicalTrials.gov Identifier, NCT00693875.).
BACKGROUND: The etiology of postoperative cognitive decline (POCD) remains to be determined. Anesthetic isoflurane, but not desflurane, may induce neurotoxicity. However, the functional consequences of these effects have not been assessed. We therefore performed a pilot study to determine the effects of isoflurane and desflurane on cognitive function in humans. METHODS: The subjects included patients who had lower extremity or abdominal surgery under spinal anesthesia alone (S, n = 15), spinal plus desflurane anesthesia (SD, n = 15), or spinal plus isoflurane anesthesia (SI, n = 15) by randomization. Each of the subjects received cognitive tests immediately before and 1 week after anesthesia and surgery administered by an investigator who was blinded to the anesthesia regimen. POCD was defined using the scores from each of these tests. RESULTS: We studied 45 subjects, 24 males and 21 females. The mean age of the subjects was 69.0 ± 1.9 years. There was no significant difference in age and other characteristics among the treatment arms. The mean number of cognitive function declines in the S, SD, and SI groups was 1.13, 1.07, and 1.40, respectively. POCD incidence after SI (27%), but not SD (0%), anesthesia was higher than that after S (0%), P = 0.028 (3-way comparison). CONCLUSION: These findings from our pilot study suggest that isoflurane and desflurane may have different effects on postoperative cognitive function, and additional studies with a larger sample size and longer times of follow-up testing are needed.
BackgroundThere is significant controversy regarding the influence of video laryngoscopy on the intubation outcomes in emergency and critical patients. This systematic review and meta-analysis was designed to determine whether video laryngoscopy could improve the intubation outcomes in emergency and critical patients.MethodsWe searched the Cochrane Central Register of Controlled Trials, PubMed, Embase, and Scopus databases from database inception until 15 February 2017. Only randomized controlled trials comparing video and direct laryngoscopy for tracheal intubation in emergency department, intensive care unit, and prehospital settings were selected. The primary outcome was the first-attempt success rate. Review Manager 5.3 software was used to perform the pooled analysis and assess the risk of bias for each eligible study. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) system was used to assess the quality of evidence for all outcomes.ResultsTwelve studies (2583 patients) were included in the review for data extraction. Pooled analysis did not show an improved first-attempt success rate using video laryngoscopy (relative risk [RR], 0.93; P = 0.28; low-quality evidence). There was significant heterogeneity among studies (I 2 = 91%). Subgroup analyses showed that, in the prehospital setting, video laryngoscopy decreased the first-attempt success rate (RR, 0.57; P < 0.01; high-quality evidence) and overall success rate (RR, 0.58; 95% CI, 0.48–0.69; moderate-quality evidence) by experienced operators, whereas in the in-hospital setting, no significant difference between two devices was identified for the first-attempt success rate (RR, 1.06; P = 0.14; moderate-quality evidence), regardless of the experience of the operators or the types of video laryngoscopes used (P > 0.05), although a slightly higher overall success rate was shown (RR, 1.11; P = 0.03; moderate-quality evidence). There were no differences between devices for other outcomes (P > 0.05), except for a lower rate of esophageal intubation (P = 0.01) and a higher rate of Cormack and Lehane grade 1 (P < 0.01) when using video laryngoscopy.ConclusionsOn the basis of the results of this study, we conclude that, compared with direct laryngoscopy, video laryngoscopy does not improve intubation outcomes in emergency and critical patients. Prehospital intubation is even worsened by use of video laryngoscopy when performed by experienced operators.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-017-1885-9) contains supplementary material, which is available to authorized users.
Accumulation and deposition of b-amyloid protein (Ab) are the hallmark features of Alzheimer's disease. The inhalation anesthetic isoflurane has been shown to induce caspase activation and increase Ab accumulation. In addition, recent studies suggest that isoflurane may directly promote the formation of cytotoxic soluble Ab oligomers, which are thought to be the key pathological species in AD. In contrast, propofol, the most commonly used intravenous anesthetic, has been reported to have neuroprotective effects. We therefore set out to compare the effects of isoflurane and propofol alone and in combination on caspase-3 activation and Ab oligomerization in vitro and in vivo. Naïve and stably-transfected H4 human neuroglioma cells that express human amyloid precursor protein, the precursor for Ab; neonatal mice; and conditioned cell culture media containing secreted human Ab40 or Ab42 were treated with isoflurane and/or propofol. Here we show for the first time that propofol can attenuate isoflurane-induced caspase-3 activation in cultured cells and in the brain tissues of neonatal mice. Furthermore, propofol-mediated caspase inhibition occurred when there were elevated levels of Ab. Finally, isoflurane alone induces Ab42, but not Ab40, oligomerization, and propofol can inhibit the isoflurane-mediated oligomerization of Ab42. These data suggest that propofol may mitigate the caspase-3 activation by attenuating the isoflurane-induced Ab42 oligomerization. Our findings provide novel insights into the possible mechanisms of isofluraneinduced neurotoxicity that may aid in the development of strategies to minimize potential adverse effects associated with the administration of anesthetics to patients.
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