'Chronomics' in ICU: circadian aspects of immune response and therapeutic perspectives in the critically ill

Abstract

Complex interrelations exist between the master central clock, located in the suprachiasmatic nuclei of the hypothalamus, and several peripheral clocks, such as those found in different immune cells of the body. Moreover, external factors that are called 'timekeepers', such as light/dark and sleep/wake cycles, interact with internal clocks by synchronizing their different oscillation phases. Chronobiology is the science that studies biologic rhythms exhibiting recurrent cyclic behavior. Circadian rhythms have a duration of approximately 24 h and can be assessed through chronobiologic analysis of time series of melatonin, cortisol, and temperature. Critically ill patients experience severe circadian deregulation due to not only the lack of effective timekeepers in the intensive care unit (ICU) environment but also systemic inflammation. The latter has been found in both animal and human studies to disrupt circadian rhythmicity of all measured biomarkers. The aims of this article are to describe circadian physiology during acute stress and to discuss the effects of ICU milieu upon circadian rhythms, in order to emphasize the value of considering circadian-immune disturbance as a potential tool for personalized treatment. Thus, besides neoplastic processes, critical illness could be linked to what has been referred as 'chronomics': timing and rhythm. In addition, different therapeutic perspectives will be presented in association with environmental approaches that could restore circadian connection and hasten physical recovery.

Figure 1

Melatonin: the ‘master biological clock’. Non-visual effects of light are mediated through specific retinal ganglion cells which subsequently activate SCN neurons. As a result, SCN inhibits the pineal production of melatonin during daytime through a polysynaptic pathway including paraventricular nucleus (PVN), superior cervical ganglia, and preganglionic sympathetic neurons of the lateral horn of the spinal cord. The pineal melatonin is considered the master biological clock that synchronizes the circadian rhythms of different clock genes throughout the body with different external ‘timekeepers’, such as light/dark cycles. Furthermore, the SCN-PVN network is responsible for 24-h period fluctuations of both sympathetic and parasympathetic tone, estimated with heart rate variability analysis, and for circadian oscillations of immunity and endocrine function. During inflammation, circadian rhythms of different hormones are disrupted, whereas immune cells in the periphery suppress melatonin's nocturnal surge through TNF-α and produce melatonin themselves. This extrapineal melatonin acts on a paracrine manner and exhibits both pro- and anti-inflammatory properties, depending on time phase and severity of stress. SCN, suprachiasmatic nucleus; PVN, paraventricular nucleus. Figures are reproduced from the free website: ‘The brain from top to bottom’, according to its copyleft policy (http://thebrain.mcgill.ca/flash/pop/popcopy/popcopy.html).

Figure 2

Chronobiologic analysis of a time series through cosinor analysis. Schematic illustration of basic metrics derived from cosinor analysis: This method is applicable to the individual biological time series anticipated to be rhythmic with a given period. The procedure fits a cosine function (blue) to the data (red) by least squares. Midline estimating statistic of rhythm (MESOR) is the mean level of oscillation that is the average value of the rhythmic function (e.g., cosine curve) fitted to the data. Amplitude is the difference between the maximum and the MESOR. Acrophase is the time of occurrence of the maximum value.