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

Abstract

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.

Fig. 1

Neural mechanisms of γ-aminobutyric acid (GABA)ergic and α₂ adrenoceptor agonist sedation. a Wakefulness is promoted by the release of the arousal-promoting monoamine (red) neurotransmitters, norepinephrine (NE), serotonin (5-HT), and histamine (His), from the locus ceruleus (LC), dorsal raphe nucleus (DR), and tuberomammillary nucleus (TMN), respectively, as well as acetylcholine (ACh; orange) from the pedunculopontine and laterodorsal tegmental nuclei (PPTg and LDTg) and orexin (OX; green) into the cortex, forebrain, and subcortical areas. Conversely, during the deeper stages of NREM sleep, the activity is reversed by the inhibitory action of GABA and galanin (gal; purple) released from the ventrolateral pre-optic nucleus (VLPO). b, c Activity in brain nuclei involved in sleep pathways under sedation with a (b) GABAergic agent and c α₂ adrenoceptor agonist. Abbreviations: GABA gal = neurons containing GABA and galanin; His = histamine; NA = noradrenergic; ORX = orexin; LC = locus ceruleus; PeF = perifornical nucleus; TMN = tuberomammillary nucleus; VLPO = ventrolateral pre-optic nucleus. Reproduced with permission from Nelson et al. (a) and modified with permission (intensetimes issue 9; available at www.intensetimes.eu) from Sanders et al. (b, c)

Fig. 2

Days free from complications associated with acute brain failure in septic intensive care unit patients sedated with the α₂ adrenoceptor agonist, dexmedetomidine, or the benzodiazepine, lorazepam. Data are represented in a box and whisker plot reflecting the median, lower, and upper quartiles and the lower and upper extremes of days/patient. Reproduced with permission from Pandharipande et al.

Fig. 3

Kaplan-Meier curve showing the probability of survival according to sedation group during the first 28 days following admission to the intensive care unit for sepsis. Avoidance of lorazepam sedation using dexmedetomidine decreased the probability of dying within 28 days by 70%. Reproduced with permission from Pandharipande et al.

Fig. 4

Sedation with α₂ adrenoceptor agonist produces a more “natural sleep” response than sedation with benzodiazepine. Functional magnetic resonance imaging (fMRI) was performed in volunteers tested on three separate occasions, during which they received saline, dexmedetomidine, or midazolam. Subjects were infused to achieve a target concentration that produced equivalent sedation as assessed by electroencephalography (bispectral index, BIS) and observer rating (Observer Assessment of Alertness/Sedation, OAA/S). In a single subject, sleep occurred during saline infusion while undergoing fMRI. Subtraction scans were performed yielding the difference in blood oxygen level-dependent (BOLD) activity between natural sleep and the sedated states provided by either dexmedetomidine or midazolam. There were fewer voxels of BOLD activity seen in the subtraction scan between dexmedetomidine-sedation and natural sleep (a) than seen between midazolam-sedation and natural sleep (b)