Circadian rhythms in anesthesia and critical care medicine: potential importance of circadian disruptions

Abstract

The rotation of the earth and associated alternating cycles of light and dark--the basis of our circadian rhythms--are fundamental to human biology and culture. However, it was not until 1971 that researchers first began to describe the molecular mechanisms for the circadian system. During the past few years, groundbreaking research has revealed a multitude of circadian genes affecting a variety of clinical diseases, including diabetes, obesity, sepsis, cardiac ischemia, and sudden cardiac death. Anesthesiologists, in the operating room and intensive care units, manage these diseases on a daily basis as they significantly affect patient outcomes. Intriguingly, sedatives, anesthetics, and the intensive care unit environment have all been shown to disrupt the circadian system in patients. In the current review, we will discuss how newly acquired knowledge of circadian rhythms could lead to changes in clinical practice and new therapeutic concepts.

Keywords: Per2; anesthesia; circadian rhythm; cognitive dysfunction; critical care medicine; diabetes mellitus; genetic determinants; glucose oxidation; hypertension; inflammation.

Figure 1. Regulatory mechanisms of the circadian system

The suprachiasmatic nucleus (SCN) in the brain is the central regulator of circadian rhythmicity. External stimuli such as light determine ‘Zeitgeber’ time. Light via melanopsin receptors in the retinal ganglion cells lead to the transcriptional induction of Clock and Bmal1 which leads in turn to the induction of Rev-Erb, Per1, Per2, Cry1 and Cry2. Via feedback inhibition of Clock and Bmal1 a cycle will be terminated and a new can begin. Hormonal and humoral factors are supposed to control circadian rhythms in peripheral organs.

Figure 2. Disruption of the molecular ‘clock’ and disease development

Numerous resent studies provide evidence that the circadian clock influences the development and progression of disease in an experimental setting. Non-functional circadian rhythm proteins in peripheral organs were linked to very specific disease (e.g. Clock-diabets, Cryptochrome-hypertenstion, Per2-heart attack etc.). These findings indicate that time-of-day dependent drug therapy or interventions might be imperative. However, more important seems to be the restoration of circadian rhythms to improve the function of circadian rhythm pathways such as insulin secretion, inflammation or metabolism.

Figure 3. Factors influencing the circadian system

While a regular day/night cycles with dark, quite nights are supposed to be the basis of a well synchronized circadian rhythm in humans, noise, interventions, artificial light and drugs on ICUs have proven to disrupt a functional circadian system and might lead to disease progression.

Figure 4. The link between critical illness and the circadian system

Sepsis can lead to a disrupted function of mitochondria, nonfunctional NO synthesis and deficient glycolytic pathways. Period 2 (Per2) deficiency has been associated with such metabolic alterations in mice. Therefore one could hypothesize, that restoration of a circadian rhythm with a functional Per2 protein might help to restore a nonfunctional metabolic phenotype in sepsis and thereby alleviating illness and disease progression.

Figure 5. Model of disease development

Several environmental and genetic factors can cause disruption of the circadian rhythms. This disruption could contribute to multifactorial disease such as cardiovascular disease, a metabolic syndrome or progression of critical illness.

Figure 6. Restoration of circadian rhythms – potential for treatment

Recent improvements in our understanding of how circadian rhythms impact disease development including diabetes, hypertension, heart ischemia, stroke, sepsis or delirium, exhibits the potential to discover novel therapies for critically ill patients or those undergoing general anesthesia. Restoration of circadian rhythms might be key to treat associated disease.