Proefschrift Kerklaan

Chapter 1

Autophagy The benefits of withholding artificial nutritional support during the acute phase may also be explained by the stimulating effect on autophagy 44,45 . Autophagy is an essential survival mechanismbywhichcells breakdown their own (damaged) components to recycle intracellular nutrients and generate energy during starvation 46-49 . Besides its role as cellular housekeeper, autophagy is involved in protein quality control of tissue and organs. Additionally, it regulates both innate and adaptive immune responses, partly by efficient clearance of intracellular pathogens. Activation of autophagy by withholding parenteral nutrition during acute critical illness might result in a better, more balanced physiological response with greater protein synthesis, energy production and maintenance of cell structure 41,44,45,49 . On the other hand, when autophagy is suppressed by forced overfeeding early in critical illness, the risk of organ failure and cell death may increase, resulting in worse clinical outcome. Preservation of autophagy in skeletal muscle partially explained why parenteral nutrient restriction reduced ICU-acquired weakness and enhanced recovery 38 . Although nutrient restriction is regarded as a risk factor for muscle atrophy, increased energy intake is associated with worsened muscle function in critically ill adults and animal models 38,44 . Prolonged upregulation of autophagy may lead to increased degradation of organelles and a failure to maintain energy provision, resulting in increased apoptosis and cell death 50 . The beneficial effects of nutrient restriction are therefore likely to be limited to the acute phase of critical illness. Early enteral nutrition in critically ill children Enteral nutrition is positioned as the preferred route over parenteral nutrition in critically ill children, and guidelines recommend initiation within 48 hours 4 . It prevents gut atrophy, preserves gut integrity and immunity, and hence decreases the risk for bacterial translocation and systemic infection 51,52 . In a retrospective study of 5105 critically ill children, early enteral nutrition, defined as the provision of 25% of target calories enterally over the first 48 hours of admission, was shown to be associated with a lower mortality rate in those with a PICU length of stay of at least 96 hours 53 . However, the observational design calls for caution in assuming that this association is causal, since patients who tolerate enteral nutrition early, are likely to have a better prognosis. In children with burns, early enteral nutrition (started within 3-6 hours) was clinically superior to late enteral nutrition (after 48 hours) with a lower mortality rate, shorter hospital stay and less weight loss 54 , but data from this distinct patient group cannot automatically be applied to the general PICU population. Despite the current tendency to provide early enteral nutrition during PICU stay, initiation is often delayed and administration is frequently interrupted due to clinical procedures, gastro-intestinal intolerance and a number of misconceptions (Table 2) 55-59 .

This results in a discrepancy between the amount of prescribed and delivered calories, with overall 50-60%of the prescribed calories not being delivered when using the enteral route 2,71,72 .

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