Clinical Chronobiology: A Timely Consideration in Critical Care Medicine

Helen McKenna; Gijsbertus T. J. van der Horst; Irwin Reiss; Daniel Martin


Crit Care. 2018;22(124) 

In This Article

Keeping Time

Coordination of mammalian circadian timekeeping involves an integrated system composed of a central clock in the suprachiasmatic nucleus (SCN) of the hypothalamus, and peripheral clocks in virtually all other cells and tissues. The coordinated integration of central and peripheral molecular clocks ensures that functions in different tissues occur at an appropriate time of day, such as sleeping at night and metabolising ingested nutrients during the day in the case of diurnal animals. Without these molecular clocks, there would be no temporal framework for daily processes. Although circadian clocks continue to tick indefinitely, they require careful adjusting to keep in time. The central clock in the SCN fulfils a key role in this, as it integrates input from external cues, known as Zeitgebers, to synchronise with the planetary light/dark cycle. Whereas light, perceived through the eye, is the strongest Zeitgeber for daily clock resetting (photoentrainment), other cues include temperature, feeding, exercise and social interaction. In turn, the SCN maintains synchrony of peripheral clocks through humoral and neural stimuli. Resetting the circadian clocks to alterations in Zeitgebers scheduling takes time[8] and sudden environmental changes result in cellular rhythms being temporarily out of step with demands imposed by the environment (external desynchronisation). This phase shift is experienced as jet lag when we rapidly cross longitudes and it takes approximately 1 day to adapt to each hour time zone crossed. Clocks in different tissues adapt to disturbance at different rates, leading to internal desynchrony, like the individual instruments of an orchestra playing independently.[9] The hormone melatonin appears to play a role in both external and internal synchronisation. Its secretion from the pineal gland is inhibited by bright light (detected by non-visual photosensitive retinal ganglion cells), hence circulating melatonin levels are very low during the day.[10] Melatonin was previously thought to regulate the sleep/wake cycle, but its secretion follows a similar pattern in nocturnally active animals (i.e. increasing melatonin levels at the beginning of the dark period) and may be more accurately considered the "hormone of the dark".


Whilst most humans follow a pattern of daytime wakefulness and night-time sleeping, there is natural variation in preferred time to wake and sleep. Chronotype is the behavioural expression of the set point of an individual's circadian rhythm. It describes their sleep–wake cycle in relation to time, and the two ends of the chronotype spectrum are called "morningness" and "eveningness". Morningness is characterised by early-morning waking, with mental and physical performance peaking in the first half of the day, and going to sleep relatively early; eveningness is the opposite. Chronotype can be determined by questionnaires such as the Munich Chronotype Questionnaire and the Horne–Ostberg Morningness–Eveningness Score.[11] A comprehensive and well-controlled study demonstrated that questionnaires such as these closely correlate to dim-light melatonin onset time, probably the most reliable measure of central circadian timing in humans.[12] There is a strong genetic component underlying this phenotype[13] and ignoring its influence is known to be detrimental to performance.[14] The eveningness chronotype has been associated with a predisposition to diabetes, metabolic syndrome, high body mass index and sarcopenia, as well as depressive disorders.[15,16,17] Knowledge of a patient's chronotype may be useful not just in the assessment of disease risk, but also in tailoring the timing of Zeitgebers such as light, food, exercise and sleep in order to preserve their natural circadian rhythm and optimise their biological function.