Circadian Melatonin Rhythms in Critically Ill Patients With Delirium

Delirium is a highly prevalent neuropsychological condition in patients admitted to the ICU. Occurrence of a delirium in critically ill patients is associated with prolonged ICU stay and longer hospitalization, reduced quality of life and increased mortality. Furthermore, it is accompanied by a higher risk of cognitive disorder after ICU discharge.

Delirium is defined as an acute, usually reversible state of disturbance of consciousness with a change of perception and cognition. Its fluctuating course leads to a division in three subgroups: hyperactive, hypoactive and mixed delirium. Hyperactive delirious patients present agitated and anxious behaviour, hypoactive delirium however is characterised by withdrawal, somnolence and reduced responsiveness to stimuli. The mixed subtype shows alternating characteristics from both hyperactive and hypoactive delirium.

ICU patients especially in the post-operative setting frequently show several risk factors for delirium, including environmental changes, advanced age, alcohol abuse, dementia, demand for vasopressors, increased doses of opioids or metabolic disturbances.

Sleep and many symptoms that occur in delirium are influenced by the circadian timing system and therefore are thought to be closely related. The neurohormone melatonin plays a major role in regulating circadian rhythms. It is produced in the pineal gland and its diurnal secretion pattern is under the control of the central circadian pacemaker located in the suprachiasmatic nuclei of the anterior hypothalamus. Under normal entrained condition melatonin starts to increase one to three hours prior habitual bedtime, which often coincides with the onset of darkness outside. Thus, melatonin is often referred to as the hormone of darkness. Peak melatonin levels occur approximately two hours prior usual rise time (usually between 2 and 5 A.M.). Melatonin levels are lower during daytime independent of experienced light levels.

Delirious patients often suffer from sleep disturbances such as insomnia, sleep fragmentation, daytime somnolence, and reversal of sleep-wake rhythms. There is evidence that hyperactive as well as hypoactive and mixed delirium is connected to disturbed circadian rhythm. This leads to the question whether there is a link between delirium syndromes as well as different delirium subtypes and potential alterations in circadian melatonin plasma levels compared to non-delirious patients.

Plasma melatonin levels can be assessed in saliva, blood and urine. Due to its rapid metabolisation plasma melatonin levels represent a precise proxy of the current pineal secretion. It therefore is reasonable to collect plasma samples for melatonin assessments frequently throughout the study period to obtain an accurate time course of the circadian melatonin rhythm profile.

There is suggestive evidence that regulating melatonin levels during delirium lowers the incidence of delirium and leads to a reduction of duration and severity of the disorder.

The investigators hypothesize that the circadian melatonin profile in critically ill delirious patients measured in two-hourly intervals across 24 hours deviates significantly from non-delirious critically ill patients with similar age and SOFA (Sequential Organ Failure Assessment) score in terms of phase, width and amplitude.