DYNAMISCHE IMPACT VAN KRITIEKE ZIEKTE EN HET NUTRITIONEEL BELEID OP DE LANGE-TERMIJNS UITKOMST VAN KINDEREN: ROL VAN EPIGENETISCHE VERANDERINGEN

Critical illness, caused by a variety of insults including major surgery, trauma, burn injury or severe medical illnesses, is any life-threatening medical condition that requires support of failing vital organs to avoid imminent death. As survival from critical illness improves, many patients subsequently endure devastating long-term consequences that include physical, neurocognitive and emotional/behavioural impairments. This is particularly alarming in the paediatric population since children are still developing and hopefully, have decades of life in front of them. These physical deficits, as well as learning and emotional/behavioural problems contribute to a reduced quality of life in former critically ill patients and potentially generate significant and far-reaching problems into adulthood. Theoretically, the long-term problems could be predestined by pre-admission conditions or be evoked by the acute insult itself. Importantly, also the intensive care management could induce or aggravate part of this long-term legacy. In that regard, it has been shown that avoiding hyperglycaemia, avoiding phthalates leaching from indwelling medical devices into the blood, as well as altering the nutritional strategy during paediatric intensive care unit (PICU) stay, improved the long-term outcome of children after critical illness. Regarding the nutritional management, critically ill children cannot be fed normally by mouth and also enteral nutrition via a gastric tube often fails to deliver the recommended caloric amounts. During the period of critical illness, one can supplement the insufficient enteral nutrition with PN. In the PEPaNIC RCT, a large multicentre (Leuven, Rotterdam, Edmonton) randomised controlled trial and the corresponding 2- and 4-year follow-up studies, it was shown that providing full nutritional intake early with use of PN to supplement insufficient enteral nutrition (early-PN) is clinically inferior to accepting an early macronutrient deficit by postponing any PN to beyond the first week in PICU (late-PN). Early-PN not only caused more infections and delayed recovery from the illness, it also prevented normal development of executive functions and/or caused behavioural problems as documented 2 and 4 years after PICU admission. The underlying pathophysiology and molecular mechanisms of this legacy of critical illness and the use of early-PN during critical illness remain largely unexplained, but the fact that the majority of the children are treated in the PICU during crucial developmental phases likely plays a role. It is also unclear whether these deficits increase or decrease over time when growing up. The general objective of this doctoral thesis was to gain more insights in the impaired long-term developmental outcome after critical illness and the use of early full feeding in children during PICU stay, with evaluation of the role of epigenetic alterations as a molecular basis. Epigenetic alterations may be a plausible molecular mechanism that plays a role in the emergence of the long-term legacy after critical illness and the impact hereon of early-PN use in particular. Epigenetics refers to the study of heritable changes in gene expression that do not involve changes in the underlying DNA sequence. Epigenetic alterations are known to occur after exposure to various environmental stressors such as inadequate nutrition (both undernutrition and overfeeding) and to impact long-term health and disease. The most stable epigenetic change is the methylation or de-methylation of DNA, which is the attachment to or removal of a methyl group from a nucleotide which occurs almost exclusively at the 5' carbon in the cytosine residue of a CpG (cytosine-phosphate-guanine) dinucleotide. Particularly DNA methylation changes occurring during early life may bring about long-term effects. One could thus indeed speculate that also critical illness and its nutritional management could alter the DNA methylation status of children, which could explain part of the long-term impairments. In a large genome-wide study, it was previously shown that critical illness and the administration of early-PN during critical illness altered methylation of DNA extracted from peripheral blood of these young patients. More specifically, at the day of PICU discharge, alterations in methylation of several CpG-sites were documented, changes that were not yet present upon PICU admission. Several of the affected CpG-sites were located in genes involved in a variety of relevant molecular functions, physical and neurocognitive developmental processes and in neurodegenerative and psychiatric diseases. The use of early-PN explained 23% of these de-novo changes in DNA methylation. The first three research chapters of this PhD project had a mechanistic orientation, starting from the documentation of aberrant DNA methylation changes occurring de-novo during critical illness. A first part yielded the important insight that the documented de-novo changes in DNA methylation played a mediating role and statistically explained at least part of the physical, neurocognitive and emotional/behavioural impairments after paediatric critical illness and after the use of early-PN versus late-PN during critical illness. Hence, aberrant DNA methylation was identified as a plausible biological basis for the long-term developmental harm after critical illness and the early use of PN. In a second part, we showed that the aberrant DNA methylation changes occurred fast when children were critically ill, mainly within 3 days after PICU admission. Most abnormalities were at least partially maintained or got worse with longer time spent in PICU. Knowing the highly dynamic nature of epigenetics especially in children, with some marks being volatile and others durable, we expect some marks to remain present years after hospital discharge and even into adulthood and others to be gone. Temporary marks however, are not less important when it comes to development, since they might set in motion a chain of events and affect developmental trajectories, whereafter they are erased and thus no longer detectable later in life. In a third part, we also studied another epigenetic footprint of critical illness and evaluated the epigenetic ageing of former PICU patients. Altered DNA methylation has previously shown to affect biological ageing of adults and developmental processes in children. Environmental factors, such as physical activity and diet and exposure to drugs and toxins, have shown to alter the rate at which humans biologically age. Also major trauma, physical stress, chronic systemic inflammation and metabolic dysregulation affect the ageing process. We now showed that also critical illness in children affects the epigenetic changes underlying the ageing process. Indeed, with use of a previously developed "epigenetic clock" for children, we documented an epigenetic age-deceleration in former PICU patients as compared with healthy children. The epigenetic age-deceleration was most pronounced in former PICU patients aged 6 years or older at the time of critical illness. These findings had a physical correlate as former PICU patients showed stunted growth in height, particularly in those aged 6 years or older at exposure. This was not unexpected given that the physical process most correlating with chronological ageing during childhood is growth in height. The use of early-PN versus late-PN during critical illness did not affect DNA methylation ageing. The last two chapters of this PhD project had a clinically oriented focus. In a fourth part, we studied whether the age at the time of PICU admission would determine the vulnerability of the critically ill children to any long-term developmental harm by the early use of PN in the PICU. We showed that younger children were most affected by the use of early-PN during critical illness, especially those aged between one and 11 months at the time of exposure as compared with other age-subgroups. Indeed, early-PN, in comparison with late-PN resulted in worse neurocognitive outcome with the largest deficits within this specific age-subgroup. Combined with the documentation of highest vulnerability to age-deceleration and stunted growth in children aged 6 years or older at exposure to critical illness, these data showed that a metabolic insult, including critical illness and the use of early-PN, did not have a similar effect on long-term development in all critically ill children and also has effect on different domains of development. This was not unexpected given that children are exposed to several internal and external stimuli that encompasses critical illness during different time windows and developmental stages of childhood. In a final part, we evaluated whether the long-term problems of paediatric critical illness increased or decreased over time when growing up. Unfortunately, results were rather pessimistic. We showed that most long-term deficits observed in former PICU patients did not recover from 2 to 4 years after PICU admission. Especially for height, IQ and several executive functions, the gap between former PICU patients and healthy children aggravated significantly. Partial improvement over time was only observed for a few memory functions. Also, the observation that the neurocognitive harm evoked by early use of PN in the PICU only showed limited recovery was disappointing. Adjustment for risk factors largely confirmed that our findings could be attributed independently to the critical illness rather than to premorbid conditions. The observation that some memory functions recovered at least partially, despite the worsening of executive functioning and intelligence, is a positive finding. One could thus speculate that memory functions recover faster than more complex functions necessary for executive and intellectual functioning, which raises hope for future longitudinal studies evaluating post-PICU deficits beyo

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