Mechanisms underlying delirium in patients with critical illness

Abstract

Delirium is an acute, global cognitive disorder syndrome, also known as acute brain syndrome, characterized by disturbance of attention and awareness and fluctuation of symptoms. Its incidence is high among critically ill patients. Once patients develop delirium, it increases the risk of unplanned extubation, prolongs hospital stay, increases the risk of nosocomial infection, post-intensive care syndrome-cognitive impairment, and even death. Therefore, it is of great importance to understand how delirium occurs and to reduce the incidence of delirium in critically ill patients. This paper reviews the potential pathophysiological mechanisms of delirium in critically ill patients, with the aim of better understanding its pathophysiological processes, guiding the formulation of effective prevention and treatment strategies, providing a basis for clinical medication.

Keywords: cognition impairment; critical illness; delirium; mechanism; review.

Figure 1

Neuroinflammation and oxidative stress. Neuroinflammatory pathways may compromise the blood–brain barrier through systemic inflammation, leading to the activation of brain parenchymal cells such as microglia and astrocytes by inflammatory factors (e.g., IL-1β, IL-6, TNF-α). Additionally, these pathways may disrupt neurotrophic factors via inflammatory responses, resulting in synaptic dysfunction or neuronal death, which can ultimately cause delirium and impair learning and cognitive functions. Oxidative stress may further contribute to delirium by decreasing antioxidant capacity and amplifying neuroinflammatory responses. ROS, Reactive oxygen species; NO, Nitric oxide; Omi/HtrA2, Serine protease. Images created using MedPeer (www.medpeer.cn).

Figure 2

Neurotransmitter imbalance and sleep–wake cycle disturbance. Neurotransmitter imbalances may contribute to the onset of delirium. For instance, acetylcholine, dopamine, and serotonin can promote delirium through mechanisms such as reducing neural transmission, enhancing toxic responses, and decreasing melatonin secretion. Disruption of the sleep–wake cycle primarily triggers delirium by diminishing REM sleep and melatonin secretion. ACh, Acetylcholine; DA, Dopamine; 5-HT, Serotonin; CoA, Acetyl-coa; 5-HIAA, 5-hydroxyindoleacetic acid; TRP-KYN, Tryptophane-kynurenine; KP, Kynurenine pathway; QA, Quinolinic acid; KYNA, Kyinoquinolinic acid. Images created using MedPeer (www.medpeer.cn).

Figure 3

Neuroendocrine disorders and intestinal flora disorders. Both elevated and decreased cortisol levels can contribute to the development of delirium. Excessive cortisol may exacerbate neuroinflammation, resulting in neuronal damage, and it may also impair synaptic function and disrupt neurotransmitter balance, ultimately leading to delirium. In cases of severe infection, secondary CIRCI can result in decreased cortisol levels that fail to adequately control the inflammatory response, thereby inducing delirium. Additionally, an imbalance in the gut microbiome may contribute to delirium by altering microbial diversity and composition, directly affecting specific gut bacteria, and exacerbating neuroinflammation and neurotransmitter imbalances. IS, Ischemic stroke; GC, Glucocorticoid; HPA, Hypothalamic–pituitary–adrenal cortex; CIRCI, Critical illness associated corticosteroid insufficiency; DSV, Desulfovibrio Bacteria; SCFA, Short-chain fatty acids, EC, Enterochromaffin cells. Images created using MedPeer (www.medpeer.cn).