MJ. Siegmann, S. Parry, ARS. Lark, FA. Mir, J. Choi, AH. Carpenter, EA. Crowley, CG. White, J. Kang, PL. Purdon, et al. (2025). A ketogenic diet decreases sevoflurane-induced burst suppression in rats. Brain research bulletin, 223, 111274. https://doi.org/10.1016/j.brainresbull.2025.111274

PubMed 40010575

[Abstract]
BACKGROUND: The brain requires a continuous fuel supply to support cognition and can get energy from glucose and ketones. Dysregulated brain metabolism is thought to contribute to perioperative neurocognitive disorders and anesthesia-induced burst suppression. Therefore, we investigated the relationship between brain metabolites and neurophysiology during the behavioral states of sleep and anesthesia under a standard diet (SD) or a ketogenic diet (KD).

METHODS: We measured prefrontal cortex glucose, lactate, and electroencephalogram in Fischer344 rats during spontaneous sleep/wake followed by 3 % sevoflurane anesthesia. Nine rats were fed a KD and 8 rats a SD. To assess the role of adenosine receptor-mediated ketone activity on burst suppression, 5 additional rats on the KD received an intraperitoneal injection of vehicle or the adenosine A1 receptor antagonist, DPCPX, before 3 % sevoflurane.

RESULTS: Sevoflurane induced larger fluctuations in glucose (p < 0.001) and lactate (p = 0.015) concentrations compared to sleep as measured by the standard deviation (glucose 0.085 mM and lactate 0.16 mM in sleep/wake and 0.25 mM and 0.41 mM during sevoflurane respectively). Changes in glucose and lactate were closely tied to electrophysiological oscillations. Animals on the KD had reduced burst suppression ratio (mean 10 % in KD vs 30 % in SD) (p = 0.007) as well as increased time to loss of movement (mean 14 min in KD vs 8 min in SD) (p = 0.003) compared to SD. DPCPX in KD rats showed a trend to increased burst suppression, reduced the time to start of burst suppression (45 min in KD+vehicle to 37 min KD+DPCPX) (p = 0.007), and increased duration of burst suppression (49 min in KD+vehicle to 90 min in KD+DPCPX) (p = 0.046) compared to KD+vehicle.

CONCLUSIONS: It is thought that anesthesia-induced burst suppression reflects an underlying deficiency in brain energy. Accordingly, we found that upregulating ketones, which increase available brain ATP levels, delayed anesthetic induction and decreased burst suppression consistent with the idea that the underlying metabolic state of the brain influences an anesthetic's effect on the brain. These findings suggest that metabolic interventions could be useful therapeutic targets to modulate brain activity during sleep and anesthesia. Future studies will examine whether ketones can reduce the cognitive symptoms associated with postoperative delirium.