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

Chronotherapeutics: Delivering the Right Treatment at the Right Time

The ability to map an individual's circadian rhythm conveys the potential ability to personalise critical care. For example, given the typical fluctuations of physiological variables throughout the 24-h period in health, we could evaluate the benefit of different physiological targets for day and night.

Monitoring circadian rhythms will be essential for the implementation of "chronotherapeutics", the timing of an intervention or administration of a drug at the time of day where it is likely to have the optimum effect. Pharmacodynamics and pharmacokinetics show that predictable circadian oscillations manner.[96,97] Whilst we tend to prescribe certain drugs at certain times of the day, it is generally without consideration of how each drug's therapeutic profile may be affected by the time of day. Absorption, hepatic metabolism and renal excretion all follow a circadian rhythm,[97] as do the biological processes on which drugs act. Chronotherapeutic strategies have proved beneficial in cancer treatment[98] where circadian-timed chemotherapy may improve outcomes. Optimising the timing of drugs with a narrow therapeutic index and significant circadian fluctuation, such as antibiotics, steroids and anticoagulants, could lead to significant clinical benefit from improvements in efficacy and minimisation of toxicity.[97,99] Benzodiazepines phase-shift the clock according to the time of day at which they are administered,[100] and thus the circadian disruption effect could be minimised by administering the drug at the correct time of day relative to the patient's circadian phase.

Our defence from trauma and its accompanying stress response is also dependent on the time of day. Recently, it was reported that elective cardiac operations performed in the afternoon were associated with improved patient outcomes, which the authors related to changes in the oscillating gene expression of the nuclear receptor Rev-Erbα.[101] The time-of-day factor has also been implicated in the efficacy of wound healing in patients, with burn injuries incurred during the day healing up to 60% faster than those sustained at night, which may be explained by temporal patterns of fibroblast activity in a mouse model.[102]

These preliminary data point towards the improvements in outcome that may be achieved by greater understanding of the temporal nature of healing responses, and highlight the need to develop a comprehensive temporal blueprint for different tissue rhythms to allow clinicians to plan interventions to take advantage of the predictable cycling of human immune and healing responses. Such a blueprint will have to take account of differing chronotypes.

Pharmacological Adjustment of Circadian Dysrhythmia

Melatonin is thought to align the phases of peripheral clocks in different tissues with that of the central SCN.[103] In humans, melatonin is released from the pineal gland, beginning from 2100 to 2300 h, peaking between 0100 and 0300 h, and reaching its nadir between 0700 and 0900 h (virtually a mirror image of cortisol release). Taken enterally, melatonin improves the quality of sleep,[104] and there is some evidence for its effectiveness in treating jet lag.[105] A number of randomised controlled trials have investigated melatonin and melatonin receptor antagonists in critically ill patients.[106] They have shown initial success in improving sleep quality and reducing delirium in some subsets of critically ill patients.[107,108,109,110] However, no large-scale randomised controlled trials have been conducted in this area and this is clearly a priority area for future research.

In the future we may be able to target the molecular clockwork itself with pharmacological agents. Synthetic ligands are currently under investigation for Rev-Erb (α and β) and retinoic acid receptor-related orphan receptors.[111] They have a particular potential for the treatment of metabolic syndrome,[112] but as this field advances the scope of synthetic ligands may widen to include more fields of medicine, including critical care.