Mechanical Ventilation Impairs Glymphatic Function and Induces Delirium-Like Behavior in Mice

Delirium is a common and serious complication in critically ill patients, arising from multiple overlapping risk factors. Its pathogenesis remains poorly understood because it reflects the combined effects of interacting clinical insults, and because appropriate experimental models for mechanistic studies have been lacking. Delirium most commonly develops in patients undergoing major surgery or requiring intensive care, where inhalational anesthesia, opioid sedation, and mechanical ventilation are common clinical exposures. Here, we tested the hypothesis that these clinically relevant interventions are sufficient to induce delirium-like behavior in healthy young wild-type mice by disrupting cerebrospinal fluid (CSF) glymphatic transport. The analysis showed that inhalational anesthesia combined with mechanical ventilation increased intracranial pressure (ICP) and induced a sustained suppression and rerouting of glymphatic waste clearance, resulting in impaired waste clearance, and acute cytokine accumulation. These findings identify disruption of brain fluid dynamics as a potential mechanism contributing to delirium in perioperative and intensive care settings. Equally important, this model represents a distinct experimental platform that combines clinically relevant mechanical ventilation, inhalational anesthesia, and opioid analgesia to produce delirium-like behavioral abnormalities in otherwise healthy mice. It therefore provides a powerful tool for future mechanistic studies of delirium pathogenesis.