Glymphatic dysfunction: a unifying hypothesis for delirium

Delirium is a common and severe neuropsychiatric syndrome with lasting cognitive consequences, yet its pathophysiology remains poorly understood. We hypothesize that impaired glymphatic flow represents a central mechanism by which delirium evolves. This hypothesis builds on recent evidence showing that major delirium risk factors, such as ageing, dementia, cardiovascular disease and renal failure, are all associated with reduced glymphatic clearance. Similarly, common delirium triggers, including infection, surgery and sleep deprivation, have been shown to impair glymphatic function. In addition, standard intensive care interventions linked to delirium, such as sedation, opioid administration and noradrenaline, are known to suppress glymphatic clearance. Collectively, these effects could lead to the accumulation of neurotoxic metabolites and pro-inflammatory cytokines, disrupting neural network activity and precipitating delirium. Recognizing glymphatic impairment as a causal contributor to delirium could open new research and therapeutic avenues aimed at preserving brain fluid clearance in critically ill patients.