Contribution of sedative-hypnotic agents to delirium via modulation of the sleep pathway

PURPOSE: To review the mechanisms of sedative-hypnotic action with respect to the risk of delirium imparted by drugs that act on γ-amino-butyric-acid type A receptors or α(2) adrenoceptors. SOURCE: MEDLINE was searched for relevant articles. PRINCIPAL FINDINGS: Development of the acute confusional state of delirium is associated with longer intensive care unit (ICU) and hospital lengths of stay, significantly higher risk of functional decline, and increased mortality. Disruption of sleep is a modifiable risk factor that may contribute to delirium and cognitive dysfunction in ICU patients. Among the functions of sleep are repair of defective processes and restoration of the brain to a state in which it is ready to acquire new knowledge. It is logical that disruption of these processes may produce acute confusion. Delirium develops through a complex interaction between the patient’s baseline vulnerability (patient’s predisposing risk factors before hospitalization) and precipitating factors or insults (modifiable events that occur during hospitalization). The latter factors include both sleep disruption and sedation. We present a hypothesis that these two factors are causally linked through effects on memory. Our hypothesis explains why patients randomized to receive an α(2) adrenoceptor agonist are less likely to develop delirium (and the attendant cognitive dysfunction) than those randomized to receive benzodiazepines. CONCLUSION: Herein we present our hypothesis that alternate mechanisms of hypnotic action may differentiate the deleriogenic properties of the two classes of sedatives. Future studies should focus on whether a causal relationship can be established between sedative administration, sleep disruption, and delirium.