New horizons: disrupted brain energy metabolism as a driver of delirium.

Delirium is a highly prevalent neuropsychiatric syndrome characterised by acute inattention, altered arousal and impaired cognition. Cerebral energy insufficiency is hypothesised to drive delirium and both hypoglycaemia and hypoxia can directly precipitate functional deficits and EEG slowing. Here we review the evidence that disrupted energy metabolism may play a causative role in delirium across multiple settings. Neuromonitoring methods including near infrared resonance spectroscopy and Transcranial Doppler suggest an association between altered cerebral perfusion and delirium, albeit with a minority of studies demonstrating associations with hyperoxia or low brain oxygen extraction. Hyperglycaemia, hypoglycaemia, relative hypoglycaemia and large fluctuations in glucose show associations with delirium, dependent on the setting. Functional neuroimaging methodologies such as functional MRI and fluorodeoxyglucose-positron emission tomography, demonstrate regional rather than global changes in functional hyperaemia and hypometabolism and the networks across which these changes occur may be key drivers of the delirium phenotype. Whether those changes reflect regulated changes in activity, the development of insulin resistance or an impairment of neurovascular coupling in those circuits requires further research. Availability of glucose, the ability to take it up and use it are all important in maintaining normal brain function and the disruption of any or all of these could impair energy metabolism in the brain during acute illness and delirium. Optimising brain glucose utilisation is a rational goal towards reducing delirium. Clinical trials with intranasal insulin offer tentative indication that this might be tractable and alternative fuels also might mitigate delirium. Systematic experiments and clinical trials are necessary to assess whether restoring normal metabolism can protect against delirium in different clinical environments.