Impact of anesthetics on cerebral energy metabolism during light and deep anesthesia: possible implications for postoperative neurological complications

麻醉是一种药物诱导的无意识、健忘和止痛状态，可以进行手术和重症监护治疗--这无疑是现代医学的关键要素。然而，深度麻醉与术后精神错乱和持久的认知能力下降有关。这些术后并发症的潜在机制在很大程度上是未知的。麻醉深度可以根据典型的脑电模式进行分类。爆发抑制(BS)和等电是深麻醉的特征，与脑内低代谢相关。类似的脑电模式也出现在能量不匹配的情况下，如缺氧或创伤性脑损伤，这表明麻醉药对大脑新陈代谢的类似但可逆的影响。在临床常规中，使用深度麻醉来降低新陈代谢和唤起神经保护是有争议的，因为麻醉剂损害了线粒体功能。重要的是，线粒体功能障碍与麻醉深度之间的关系尚未得到系统的研究。在我们的项目中，我们的目标是研究异丙酚和异氟醚在体外(即脑片)和体内不同麻醉方式下对神经元氧化磷酸化和功能的影响。结合氧气测量、电生理学和黄素腺嘌呤二核苷酸(FAD)成像与计算机建模，我们希望预测线粒体酶系统中麻醉剂的可能靶点。为了证实我们的预测，麻醉药引起的糖酵解途径、柠檬酸循环和呼吸链(RC)酶的变化将在治疗后利用代谢组学进行测量。因此，我们想要验证这一假设，即在深度麻醉期间，异氟醚和异丙酚特异性地抑制线粒体酶降低ATP的利用率。这会导致神经代谢不匹配，并引发神经元功能障碍。首先，体外实验显示，当丙泊酚或异氟醚在高浓度时应用时，氧气消耗减少，模拟深度麻醉。对于两种麻醉药，FAD的氧化还原状态都观察到了物质特异性的变化。与实验数据相吻合的计算机模拟预测，当神经元暴露在高浓度异丙酚中时，线粒体复合体II会受到抑制。了解深麻醉期间线粒体的功能将增加我们对手术后神经并发症的病理生理学的了解。此外，比较气态麻醉剂和静脉麻醉剂对选择合适的治疗方法具有临床意义。最后，使用多参数测量和计算模型可以发现新的生物标志物，并在手术和进行深度麻醉的临床情况下(如癫痫持续状态或高颅压)改善监测。

Anesthesia is a state of pharmacologically induced unconsciousness, amnesia and analgesia that allows surgery and intensive care treatment – undoubtedly a key element of modern medicine. However, deep anesthesia is associated with postoperative delirium and lasting cognitive decline. The underlying mechanisms of these postoperative complications are largely unknown. Depth of anesthesia can be classified by typical EEG patterns. Burst suppression (BS) and isoelectricity characterize deep anesthesia and correlate with hypometabolism in the brain. Similar EEG-patterns also occur during situations with energy mismatch such as hypoxia or traumatic brain injury, suggesting similar but reversible effects of anesthetics on cerebral metabolism. In the clinical routine, the use of deep anesthesia to reduce metabolism and evoke neuroprotection is controversial as anesthetics impair mitochondrial function. Importantly, the relationship between mitochondrial dysfunction and depth of anesthesia was not yet systematically studied.In our project, we aim to characterize the effects of propofol and isoflurane on the oxidative phosphorylation and function of neurons during different anesthetic regimes in vitro (i.e. brain slices) and in vivo in rats. Combining oxygen-measurements, electrophysiology and flavin adenine dinucleotide (FAD)-imaging with computational modeling, we want to predict possible targets of anesthetics in the mitochondrial enzymatic system. To confirm our predictions, anesthetics-induced changes of enzymes of the glycolytic pathway, citric acid cycle and respiratory chain (RC) will be measured after treatment using metabolomics. We thereby want to test the hypothesis, that during deep anesthesia, isoflurane and propofol specifically inhibit mitochondrial enzymes decreasing ATP-availability. This would generate neurometabolic mismatch and trigger neuronal dysfunction.First in vitro experiments show a reduction in oxygen consumption when propofol or isoflurane were applied in high concentrations, mimicking deep anesthesia. For both anesthetics, substance-specific changes in the redox state of FAD were observed. Computational simulations fitted with experimental data predict an inhibition of the mitochondrial complex II when neurons are exposed to high concentrations of propofol. Understanding mitochondrial function during deep anesthesia will increase our knowledge on the pathophysiology of post-operative neurological complications. Furthermore, comparing gaseous and intravenous anesthetics has clinical relevance for appropriate therapeutic choice. Last, the use of multiparametric measurements and computational modeling could lead to find new biomarkers and improve monitoring during surgery and clinical situations in which deep anesthesia is performed such as status epilepticus or high intracranial pressure.