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

• Applicants: Privatdozent Dr. Nokolaus Berndt; Dr. Agustin Liotta
• Subject Area: Anaesthesiology ; Biochemistry ; Pharmacology
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 408355133

• Final Report Year: 2023

Final Report Abstract

Anesthesia is a state of unconsciousness, amnesia, and analgesia that enables surgery and intensive care treatments. It represents a key element of modern medicine. However, deep anesthesia is associated with postoperative neurological complications, such as delirium and long-term cognitive deficits. The underlying pathomechanisms of these complications are only partially understood. Depth of anesthesia is associated with characteristic electroencephalogram (EEG) patterns. Deep anesthesia is characterized by the burst suppression pattern or an isoelectric EEG and correlates with hypometabolism in the brain. Similar EEG patterns are also observed in metabolically compromised states, such as cerebral hypoxia or traumatic brain injury, suggesting that comparable processes occur during deep anesthesia. In clinical practice, it is controversial whether the reduction of energy metabolism by deep anesthesia can serve neuroprotection. The argument against this is that narcotics could impair mitochondrial processes and cause, among other things, an undersupply of neurons. The relationship between depth of anesthesia, lowering of metabolism, and possible mitochondrial dysfunction has hardly been investigated so far. In this research project, we investigated the effects of propofol and isoflurane on oxidative phosphorylation and neuronal function in an animal model. We combined measurements of oxygen partial pressure, flavin adenine dinucleotide autofluorescence, electrophysiological characteristics, and computational modeling of neuronal energy metabolism. Using these methods, we were able to distinguish between direct neuroprotective effects of anesthetics on neuronal energy metabolism (reduction of ATP demand) and indirect unwanted effects by inhibition of metabolic enzymes. In general, we could show that flavin adenine dinucleotide autofluorescence is a good neurometabolic marker. Our results confirmed that propofol, isoflurane, and sevoflurane can decrease oxidative metabolism at high concentrations leading to deep anesthesia. These results suggested that only deep anesthesia lowered neuronal metabolism (this assumption was confirmed by in vivo measurements with isoflurane). While propofol may induce unwanted inhibition of mitochondrial complex II [2], similar adverse effects could not be observed for isoflurane and sevoflurane. However, isoflurane could directly inhibit the Na-K-ATPase and thereby alter ion homeostasis in the brain, which is part of postoperative neurological complications. Both, mitochondrial dysfunction by propofol and disruption of ion homeostasis by isoflurane, could contribute to the development of postoperative neurologic complications.

Publications

• Flavin Adenine Dinucleotide Fluorescence as an Early Marker of Mitochondrial Impairment During Brain Hypoxia. International Journal of Molecular Sciences, 21(11), 3977.
  Berndt, Nikolaus; Kovács, Richard; Rösner, Jörg; Wallach, Iwona; Dreier, Jens P. & Liotta, Agustin
  
• Low neuronal metabolism during isoflurane-induced burst suppression is related to synaptic inhibition while neurovascular coupling and mitochondrial function remain intact. Journal of Cerebral Blood Flow & Metabolism, 41(10), 2640-2655.
  Berndt, Nikolaus; Kovács, Richard; Schoknecht, Karl; Rösner, Jörg; Reiffurth, Clemens; Maechler, Mathilde; Holzhütter, Hermann-Georg; Dreier, Jens P.; Spies, Claudia & Liotta, Agustin
  
• Sevoflurane Effects on Neuronal Energy Metabolism Correlate with Activity States While Mitochondrial Function Remains Intact. International Journal of Molecular Sciences, 23(6), 3037.
  Maechler, Mathilde; Rösner, Jörg; Wallach, Iwona; Geiger, Joerg R. P.; Spies, Claudia; Liotta, Agustin & Berndt, Nikolaus
  
• Deep Isoflurane Anesthesia Is Associated with Alterations in Ion Homeostasis and Specific Na+/K+-ATPase Impairment in the Rat Brain. Anesthesiology, 138(6), 611-623.
  Reiffurth, Clemens; Berndt, Nikolaus; Gonzalez, Lopez Adrian; Schoknecht, Karl; Kovács, Richard; Maechler, Mathilde; grote, Lambers Mirja; Dreier, Jens P.; Friedman, Alon; Spies, Claudia & Liotta, Agustin
  
• Metabolic implications of axonal demyelination and its consequences for synchronized network activity: An in silico and in vitro study. Journal of Cerebral Blood Flow & Metabolism, 43(9), 1571-1587.
  Gerevich, Zoltan; Kovács, Richard; Liotta, Agustin; Hasam-Henderson, Luisa A.; Weh, Ludwig; Wallach, Iwona & Berndt, Nikolaus