Delirium is 1.5 to 4.1 times as likely in intensive care unit patients when they are mechanically ventilated. While progress in treatment has occurred,
delirium is still a major problem in mechanically ventilated patients. Based on studies of a murine
mechanical ventilation model, we summarize evidence here for a novel mechanism by which such ventilation can quickly initiate brain damage likely to cause cognitive deficits expressed as
delirium. That mechanism consists of aberrant vagal sensory input driving sustained
dopamine D2 receptor (D2R) signaling in the hippocampal formation, which induces apoptosis in that brain area within 90 min without causing
hypoxia, oxidative stress, or inflammatory responses. This argues for minimizing the duration and tidal volumes of
mechanical ventilation and for more effectively reducing sustained D2R signaling than achieved with
haloperidol alone. The latter might be accomplished by reducing D2R cell surface expression and D2R-mediated Akt inhibition by elevating
protein expression of dysbindin-1C.