Proefschrift Kerklaan

General discussion

161

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

. 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

, and does not automatically reflect loss of muscle function

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.