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Abstract
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.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
Key issues
The percentage of intensive care unit (ICU) patients experiencing delirium is as much as four times greater in those who are mechanically ventilated.
Delirium in ICU patients poses serious risks apart from increased mortality, notably brain damage and what are likely to be related, long-term impairments in cognition, mood and daily living activities.
While progress has been made in its treatment, delirium remains common in mechanically ventilated patients, reflecting in part our still limited knowledge of its precipitating factors.
We recently addressed this knowledge gap by studying mechanical ventilation experimentally in mice to determine how it can cause brain damage and thereby the cognitive deficits expressed as delirium.
Just 90 min of mechanical ventilation in mice, especially at high tidal volumes, was sufficient to induce apoptosis in the hippocampal formation (HF), a brain area whose disruption is associated with cognitive impairment and delirium.
The HF apoptosis quickly induced by mechanical ventilation is not associated with hypoxia, oxidative stress or inflammatory responses in the HF, but appears to be driven instead by aberrant vagal input to dopaminergic midbrain neurons that trigger proapoptotic signaling in the HF via dopamine D2 receptors.
This hypothesis is supported by evidence that cervical vagotomy or D2R blockade by haloperidol prevents mechanical ventilation-induced apoptosis in the mouse HF.
Such HF apoptosis is followed within 4 h by an increase in HF levels of the C isoform of a protein (dysbindin-1) known to reduce cell surface D2R in neurons. A similar compensatory increase in dysbindin-1 occurs in the HF of mechanically ventilated ICU patients.
These findings provide an additional reason to minimize the tidal volume and duration of mechanical ventilation and suggest that the effectiveness of D2R antagonism in reducing delirium may be augmented by other means of reducing D2R signaling (e.g., raising levels of dysbindin-1C).
The most effective means of reducing incidence and duration of delirium, however, will probably require reducing D2R-mediated dopamine signaling along with other factors (e.g., proinflammatory cytokines) promoting delirium most comprehensively addressed in the ABCDE treatment strategy.