Mechanical Ventilation Suppresses Glymphatic Function in Parallel with Delirium-Like Symptoms in Mice

Delirium is a frequent and serious complication in intensive care patients, arising from overlapping vulnerabilities that obscure its primary causes. Using healthy mice, we tested whether mechanical ventilation combined with inhalation anesthetics and opioid sedation is sufficient to induce delirium-like behavior through disruption of cerebrospinal fluid (CSF) glymphatic dynamics. We found that ventilation acutely increased intracranial pressure and induced a long-lasting suppression of glymphatic transport, thereby re-routing and impairing brain waste clearance and promoting cytokine accumulation. These observations establish a mechanistic link between ventilator-associated alterations in brain fluid dynamics and delirium. Our findings identify glymphatic dysfunction and disturbed CSF flow as contributors to acute brain dysfunction following mechanical ventilation and suggest that therapies enhancing glymphatic flux or stabilizing intracranial pressure could reduce delirium incidence and severity in critically ill patients.