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

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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.