• Max L Gunther, James C Jackson, and E Wesley Ely.
• Vanderbilt University, Center for Health Services Research, 6100 Medical Center East, Nashville, TN 37232-8300, United States. Max.Gunther@vanderbilt.edu
• Med. Hypotheses. 2007 Jan 1;69(6):1179-82.

AbstractCritically ill patients are at high risk of developing serious neurological dysfunctions including delirium and long-term neurocognitive impairment. Here a novel mechanism is proposed for this highly deleterious condition. A growing body of evidence has shown that critical illness and its treatment can lead to de novo cerebral atrophy including white and grey matter abnormalities, delirium, and neurocognitive decline. In healthy individuals, normal and consistent connectivity between the posterior parietal cortex (PPC), medial temporal lobe (MTL) and prefrontal cortex (PFC) maintains consciousness and normal cognitive functioning. The circuit is innervated, activated and maintained by the ascending reticular activating system (ARAS) arising from the brainstem. As elderly individuals begin to show signs of grey matter atrophy in the PPC, MTL and PFC, functional connectivity between these regions remains intact; however, the strength of the connections is no longer robust as it once was in the healthy CNS. This circuit continues to be activated and maintained via the ARAS. Individuals treated in the ICU are subject to a number of medical and pharmacological challenges which may disrupt normal CNS connectivity. Serious illnesses such as sepsis, acute respiratory distress syndrome (ARDS), and acute lung injury (ALI), as well as sedative and analgesic medications commonly prescribed in the ICU have the potential to disrupt the functional link in the circuit described above. Minor fluctuations in the ARAS (i.e. hyper or hypo activation) may be sufficient in elderly individuals to cause a disruption which surpasses the critical threshold of functional connectivity necessary to maintain normal (i.e. non-delirious) consciousness. In combination with exposure to other ICU related threats to neurocognitive function, prolonged decoupling of this circuit may lead to deleterious neurodegenerative consequences such as excitotoxicity. Over time this has the potential to result in apoptosis and long-term cognitive impairment. Delirium appears to be a good candidate for the causal mechanism of ICU related cognitive decline and may be a critical point of intervention.

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