Proefschrift Kerklaan

General discussion

evaluation of functional, physical and neurocognitive outcome 2 and 4 years after admission to the PICU (Chapter 6).

Although amplification of these presumed adaptive processes appear to be beneficial during the acute phase, they may become maladaptive with prolonged critical illness 36,37 . As reflected by an early discharge (before the fourth day of PICU stay) of almost 50% of PEPaNIC patients (Chapter 7), this acute phase is likely to last only for a short period of time in the majority of critically ill children. Preservation of autophagy (fasting response) Preservation of autophagy by parenteral nutrient restriction in the acute phase may have contributed to the observed beneficial effects, given its importance for innate immunity and for quality control in cells with a long half-life 38-40 . The exact role of autophagy in the PEPaNIC study will be investigated with analyses of leukocyte samples (Chapter 6). Nutrients provided by the enteral route also affect the severity of starvation, and therefore possibly suppress autophagy as well. Long before activation of autophagy was suggested as a possible underlying mechanism for benefits of withholding artificial nutrition early in critical illness, studies showed that forced EN in septic mice decreased survival time, whereas starvation decreased mortality and promoted pathogen clearance 41,42 . Strikingly, the greatest survival was observed in mice who lost the most weight, whereas in many nutritional studies weight gain is considered a primary beneficial outcome in critically ill children. Maintenance of muscle integrity and function In the EPaNIC trial, preservation of autophagy in skeletal muscle explained the reduced ICU-acquired weakness and enhanced recovery observed with late PN 40 . Due to ethical considerations, no tissue biopsies were performed in the critically ill children participating in PEPaNIC. Alternatively, early detection of muscle mass wasting is challenging, due to unreliability of ultrasonography 43 , and does not automatically reflect loss of muscle function 44 . Muscle function can be quantified by measurements of muscle strength, most easily performed by use of a dynamometer to measure hand grip strength. This method is however not generally applicable to the PICU population, since baseline values are often lacking due to clinical instability or sedation. These factors also limit use of hand dynamometry later during PICU stay in children with prolonged critical illness that are most at risk for loss of muscle function. Investigation of the effect of late PN and critical illness on muscle function will therefore remain reserved to the long-term follow-up and will be quantified by measurements of hand grip strength, a 6-minute walk test, the timed up and go test and preferably also by use of a physical activity monitor. Results from the PEPaNIC patients at planned follow-up visits will be compared with reference values and healthy volunteers, and can be correlated to patient- and disease related factors during PICU stay, such as length of stay, duration of ventilation and nutritional data.

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