Factors Disrupting Melatonin Secretion Rhythms During Critical Illness

Abstract

Objectives: The circadian system modulates many important physiologic processes, synchronizing tissue-specific functions throughout the body. We sought to characterize acute alterations of circadian rhythms in critically ill patients and to evaluate associations between brain dysfunction, systemic multiple organ dysfunction, environmental stimuli that entrain the circadian rhythm (zeitgebers), rest-activity rhythms, and the central circadian rhythm-controlled melatonin secretion profile.

Design: Prospective study observing a cohort for 24-48 hours beginning within the first day of ICU admission.

Setting: Multiple specialized ICUs within an academic medical center.

Patients: Patients presenting from the community with acute onset of either intracerebral hemorrhage as a representative neurologic critical illness or sepsis as a representative systemic critical illness. Healthy control patients were studied in using modified constant routine in a clinical research unit.

Interventions: None.

Measurements and main results: Light, feeding, activity, medications, and other treatment exposures were evaluated along with validated measures of encephalopathy (Glasgow Coma Scale), multiple organ system function (Sequential Organ Failure Assessment score), and circadian rhythms (profiles of serum melatonin and its urinary metabolite 6-sulphatoxymelatonin). We studied 112 critically ill patients, including 53 with sepsis and 59 with intracerebral hemorrhage. Environmental exposures were abnormal, including light (dim), nutritional intake (reduced or absent and mistimed), and arousal stimuli (increased and mistimed). Melatonin amplitude and acrophase timing were generally preserved in awake patients but dampened and delayed with increasing encephalopathy severity. Melatonin hypersecretion was observed in patients exposed to catecholamine vasopressor infusions, but unaffected by sedatives. Change in vasopressor exposure was the only factor associated with changes in melatonin rhythms between days 1 and 2.

Conclusions: Encephalopathy severity and adrenergic agonist medication exposure were the primary factors contributing to abnormal melatonin rhythms. Improvements in encephalopathy and medical stabilization did not rapidly normalize rhythms. Urinary 6-sulphatoxymelatonin is not a reliable measure of the central circadian rhythm in critically ill patients.

Figure 1

shows light exposure levels in healthy ambulatory control participants (left panel) and critically ill patients (right panel) across the day in hourly boxplots (thick line: median, box: interquartile range). Illuminescence was measured at eye level in critically ill patients and from the wrist in ambulatory patients.

Figure 2

shows melatonin levels in critically ill patients (blue) and healthy control patients (green) across the day. Critically ill patients are separated into groups by Glasgow Coma Scale scores (GCS) and vasopressor exposure. There were no patients with sepsis and coma (GCS ≤8) who did not receive vasopressors. The thick trendline is the hourly median values and the thin trendline a moving average. Note that the melatonin plot scale is reduced 50% in the middle row panels.

Figure 3

shows the timing of serum melatonin acrophase (panel A) for critically ill patients (blue) and healthy control participants (green), and a comparison of the timing of serum melatonin acrophase and urinary aMT6s acrophase (panel B) for critically ill patients. Points indicate individual measurements and the solid line is the circular kernel density estimation plot.