Mechanical Ventilation May Trigger Mental Decline

A new study describes a molecular pathway linking intensive care unit (ICU) ventilation to brain damage in the hippocampus.

Researchers from the University of Pennsylvania (Penn; Philadelphia, USA) and the University of Oviedo (Spain) harvested brains from mechanically ventilated mice and studied signals of apoptosis and alterations in the Akt survival pathway to identify the mechanisms that lead to brain dysfunction during mechanical ventilation. The measurements were then repeated in vagotomized or haloperidol-treated mice, and in animals injected with selective dopamine-receptor blockers. Levels of dysbindin—a regulator of the membrane availability of dopamine receptors—were also assessed in the experimental model and in brain samples from ventilated patients.

The results showed that mechanical ventilation triggers hippocampal apoptosis as a result of type 2 dopamine receptor activation, in response to vagal signaling. Activation of these receptors blocks the Akt survival pathway and activates the apoptotic cascade. Vagotomy, systemic haloperidol, or dopamine receptor blocking ameliorated this effect. The researchers also found that ventilation induced a concomitant change in the expression of dysbindin-1C, a result confirmed in hippocampal brain samples from ventilated patients. The study was published in the September 15, 2013, issue of the American Journal of Respiratory and Critical Care Medicine.

“These results prove the existence of a pathogenic mechanism of lung stretch-induced hippocampal apoptosis that could explain the neurological changes in ventilated patients,” concluded senior author Guillermo Albaiceta, MD, PhD, of the University of Oviedo, and colleagues. “Now that we have established the mouse model, we are mainly looking for therapeutic approaches aimed at avoiding the vagal activation caused by mechanical ventilation and therefore prevent the deleterious effects observed in the hippocampus.”

At least 30% of patients in ICUs suffer some form of mental dysfunction as reflected in anxiety, depression, and especially delirium. In mechanically ventilated ICU patients, the incidence of delirium is particularly high, about 80%.

Akt is a serine/threonine-specific protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, transcription, cell migration, and especially in cellular survival pathways by inhibiting apoptotic processes. Since it can block apoptosis, and thereby promote cell survival, Akt has been implicated as a major factor in many types of cancer.

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