Circadian rhythms: from basic mechanisms to the intensive care unit

Abstract

Objective: : Circadian rhythms are intrinsic timekeeping mechanisms that allow for adaptation to cyclic environmental changes. Increasing evidence suggests that circadian rhythms may influence progression of a variety of diseases as well as effectiveness and toxicity of drugs commonly used in the intensive care unit. In this perspective, we provide a brief review of the molecular mechanisms of circadian rhythms and its relevance to critical care. DATA SOURCES, STUDY SELECTION, DATA EXTRACTION, AND DATA SYNTHESIS:: Articles related to circadian rhythms and organ systems in normal and disease conditions were searched through the PubMed library with the goal of providing a concise review.

Conclusions: : Critically ill patients may be highly vulnerable to disruption of circadian rhythms as a result of the severity of their underlying diseases as well as the intensive care unit environment where noise and frequent therapeutic/diagnostic interventions take place. Further basic and clinical research addressing the importance of circadian rhythms in the context of critical care is warranted to develop a better understanding of the complex pathophysiology of critically ill patients as well as to identify novel therapeutic approaches for these patients.

Figure 1

Molecular mechanisms of circadian rhythms in critical illness. A variety of biologic reactions are involved in the pathogenesis of critical illness, which are influenced by circadian rhythm clock of cells. Circadian locomotor output cycles kaput (CLOCK) dimerizes with brain and muscle aryl hydrocarbon receptor nuclear translocator-like (BMALI) in the nucleus and transactivates gene expression of orphan nuclear receptor (Rev-ErbA), period (PER), and cryptochrome (CRY), producing proteins that accomplish various circadian physiological actions. PER and CRY reside in the cytoplasm and form a protein complex that traffics back into the nucleus, downregulating CLOCK and BMALI expression, thus closing a negative feedback loop. Various external stimuli such as environmental disturbances and lipopolysaccharide challenge can alter circadian rhythms in critically ill patients, which may influence development and/or progression of various diseases. The number of timing on the clock face (ie., 6 hrs coincides with the onset of the light period) play a significant role in regulating the human cycle of the clock genes.