We do not often give thought to the factors controlling our circadian rhythm. And yet the circadian system modulates many physiologic systems, including brain arousal, cardiovascular function, sympathetic tone, appetite, metabolism and immune system function. Similar to the sinoatrial node pacing the heart, the suprachiasmatic nucleus located in the hypothalamus serves as the central pacemaker for the circadian rhythm, directing sleep, motor activity, temperature and autonomic tone. Rhythmic release of melatonin from the pineal gland helps drive this central clock in addition to other circadian biomarkers, including cortisol and core body temperature. In healthy individuals, plasma melatonin concentrations typically measure 10-fold higher at night than during the daytime. How does critical illness affect circadian rhythm, specifically melatonin secretion?

Maas et al. sought to characterize circadian rhythm disturbance in critical illness in a prospective study published this month in Critical Care Medicine. The authors enrolled 112 critically ill patients with either intracerebral hemorrhage or sepsis to investigate the primary factors affecting melatonin secretion in the presence of neurologic injury or systemic illness from sepsis. They examined multiple variables that could impact melatonin release, including sedative and vasopressor infusions and kidney injury that affects melatonin clearance. They also included external stimuli with an established impact on circadian rhythm, termed “zeitgebers,” such as light exposure, nutritional intake and physical activity. They compared melatonin levels in critically ill patients versus healthy controls by obtaining serum and urine samples every 4 hours. The median ICH score of the study participants was 2 and the median SOFA score was 7 for patients with sepsis. During the initial 24 hours of the study, 38.4% received mechanical ventilation, 28.8% developed AKI, 41% received IV sedative infusions and 31.3% required catecholamine vasopressors (specifically norepinephrine). Interestingly, 38.4% of study patients received no nutrition in the first 48 hours and 25.9% received half of their caloric needs. 

What was the impact of critical illness on melatonin secretion? Compared to healthy controls, the authors observed a rapid dysregulation of circadian rhythm in neurologically injured critically ill patients represented by a delay and dampening of the amplitude of rhythmic melatonin secretion, termed circadian singularity. A greater flattening of melatonin amplitude was observed in patients with more severe neurologic dysfunction as quantified by GCS score. In other words, melatonin dysregulation was not present uniformly in this sample critically ill population, but rather served as a marker of severe neurologic injury or multiorgan dysfunction. However, improvement in encephalopathy did not correlate with changes in melatonin amplitude. Of note, patients exposed to catecholamine vasopressors had marked augmentation of melatonin secretion to supraphysiologic levels. This is likely due to stimulation of beta-adrenergic receptors on the pineal membrane by catecholamines like norepinephrine that are known to increase melatonin synthesis. Urine and serum melatonin levels correlated weakly, presumably due to lowered urinary clearance in the presence of kidney dysfunction. 

Of the variables under study, severity of encephalopathy and exposure to catecholamine vasopressor medications had the greatest impact on secretion of melatonin in critically ill patients with ICH and sepsis. Based on their observations of supraphysiologic levels of melatonin in patients receiving catecholamine vasopressors, there is little physiologic rationale for melatonin supplementation in this subset of patients to improve sleep.  

Ultimately, we must be grateful to the authors for introducing the word “zeitgeber,” which is an external stimulus known to reinforce the central circadian rhythm, like bright light or exercise. I realized that I have 3 zeitgebers in my life, ages 2, 5 and 6 years old. While I have a hypothesis as to which one has the greatest impact on my circadian rhythm, it requires formal study.   

References: 

Maas MB et al. Factors disrupting melatonin secretion rhythms during critical illness. Critical Care Medicine 2020;48(6):854-861.