Circadian rhythms in critically-ill children

In health, many physiological processes depend on intrinsic timekeeping
mechanisms collectively called circadian rhythm. These synchronized variations
are important for predictive homeostasis and the temporal segregation of
conflicting processes. This rhythm is entrained by several external periodic
time cues, the so-called Zeitgebers (*timegivers*). Examples of these
Zeitgebers are daylight, social interaction, exercise, and environmental
temperature. An intensive care unit (ICU) lacks these normal synchronizing
cues, and contains several factors disturbing a patients rhythm, such as
medication, ventilation and care procedures. Additionally, a patient*s critical
illness might also contribute to circadian disturbances.
In critically-ill adults the circadian rhythm has been shown to be disturbed,
and these disturbances are associated with worse outcome. In critically ill
children, some studies also suggest a disturbed circadian rhythm in during
Pediatric Intensive Care Unit (PICU) stay, but these are only small-scale
exploratory studies.
Furthermore, these studies have only studied individual facets of the circadian
rhythm, whereas multifaceted monitoring has been proposed as the optimal method
to identify circadian rhythm in a PICU setting. This approach of circadian
rhythm monitoring of different physiological processes includes vital sign
pattern recognition, evaluation of circadian rhythm in biomarkers (cortisol and
melatonin), the registration of sleep-wake cycles using electrophysiology, and
the rhythm of gene expression. The individual facets are indirect measures of
circadian rhythmicity and controlled by more than just the circadian rhythm.
This makes the individual measures vulnerable to bias, especially in the ICU
environment with its many disturbing factors. Combining the facets reduces this
vulnerability and provides a robust way of measuring a patients circadian
rhythm.
Since these individual measures have only been described in small-scale studies
and as individual facets, we firstly aim to study their rhythm or disturbances
thereof in the PICU population, along with their correlations. We will then aim
to construct a measure of a patient*s overall circadian rhythm from the
combination of these facets and study its evaluate its determinants and
clinical consequences. Lastly, to explore whether in the future, circadian
rhythm monitoring may be performed real-time and non-invasively, we will study
the potential of algorithms based on vital signs alone.

Primary Objectives:
To evaluate the status of the circadian rhythm of critically ill children in
multiple facets and on multiple moments during their PICU stay. To describe the
distributions of rhythmic parameters in the paediatric ICU and their evolution
during PICU stay.

Secondary Objectives:
1. To identify the correlations between different circadian rhythm parameters.
2. To construct a robust combined measure of circadian rhythmicity from these
parameters, which is assumed to robustly reflect the underlying circadian
rhythm of a patient.
3. To assess the accuracy of combinations of vital signs in determining
underlying circadian rhythm with the constructed measure mentioned in secondary
objective 2 as a reference in order to explore to what extent vital signs alone
may be used to evaluate underlying circadian rhythm of a critically-ill child.
4. To determine the role of the circadian rhythm in critical illness and
recovery by studying the associations between circadian rhythms in relation
with both patient and disease characteristics on one hand and outcome on the
other.

This will be a prospective cohort study starting on admission to the PICU and
ending upon death or discharge from PICU whichever comes first. All critically
ill children (term neonates * 17 years of age) admitted to the PICU with an
expected stay of more than 48 hours will be eligible for inclusion. 165
patients will be included in total.

During the length of the study we will perform the following measurements:
- Sleep registration on days 1, 3, 7, 14 and discharge
- Cortisol 7 times a day on days 1, 3, 7, 14 and the last day before discharge
- Melatonin 13 times a day on days 1, 3, 7, 14 and the last day before discharge
- Gene expression levels twice daily on days 1, 3, 7, 14 and the last day
before discharge
- Vital signs continuously
The discharge measurements will provide a logistical challenge so will only be
performed if discharge is foreseen with more than a 24 hour period, to make
sure a full period of measurement is possible.
These measurements will only performed as long as a patient is admitted to the
ICU. Measurements will vary based on weight. Additionally, we will record
patient and disease characteristics and short-term outcomes.

Benefits and risks
During the informed consent process, it will be made clear that participation
in this study will provide no direct benefits to the patient and that refusal
to participate will have zero impact on the care received from any of the
nursing medical staff. The burden will consist of additional blood samples,
which will only be acquired during blood draws for clinical purposes as to not
impose additional draws on subjects. Also on day 3, 7 and 14 patients will
undergo EEG for 24 hours. We believe this burden to be negligible.
Group-relatedness
Biological rhythms in children are different than in adults, due to the
developing brain and body. Therefore, this study requires this specific study
group of critically ill children of a large age range.