Proefschrift Kerklaan

Chapter 8

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In contrast with this current practice and the findings of previous observational studies

8,29

, the

PEPaNIC trial (Chapter 6 and 7) showed that withholding PN during the first week of PICU stay

is clinically superior to the early initiation of (supplemental) PN, with fewer new infections,

shorter duration of intensive care dependency and a shorter hospital stay. This trial was

conducted in 1440 critically ill children at nutritional risk (Chapter 6). Non-critically ill children

were excluded, because the lower severity of stress enabled them to be monitored without

any form of organ support and/or to be discharged from the PICU within 24 hours. This group

mainly consisted of patients after heart catheterisation, endoscopy, surgical corrections of atrial

and septum ventricular defects, inguinal hernia and craniotomy. Also children with asthma

exacerbations or congenital heart disease without cardiac failure were excluded. Children at

low nutritional risk (STRONGkids score <2) were excluded, since the need for artificial nutrition

in this population is low. By doing so, the application of the study results are reserved for at-risk

patients, with pre-existent malnourishment, increased energy requirements and/or gastro-

intestinal losses who are likely to benefit most from withholding PN.

However, underlying mechanisms for the observed benefits with late PN remain speculative.

Several aspects may have played a role:

Amplification of the acute catabolic stress response

Preservation of autophagy (fasting response)

Maintenance of muscle integrity and function

Prevention of PN-related complications

Amplification of the acute catabolic stress response

An increase in the acute inflammatory response was found with late initiation of PN, as

indicated by the plasma CRP (Chapter 7), confirming the findings of the EPaNIC trial

. It might

be speculated that this increase is caused by the expected increased use of insulin in the early

PN group, rather than by nutrient restriction in the late PN group

. An increase in CRP has been

associated with enhanced catabolism by reducing protein synthesis and increasing protein

breakdown

Also, a rise in total bilirubin was detected (Chapter 7), possibly reflecting amplification of the

metabolic component of the stress response with omitting PN up to day 8. Caloric restriction

early during critical illness might increase the redirection of conjugated bilirubin from the

hepatocyte back into the bloodstream, instead of transporting it against the concentration

gradient into the bile, resulting in preservation of energy

Inactivation of thyroid hormone, possibly also reflecting an adaptive beneficial response

32,33

is enhanced in response to nutrient restriction during the acute phase

and associated with

a better outcome

34,35

(Chapter 1). Possible alterations of the neuro-endocrine axes with late

PN, and its association with acute and long-term clinical outcomes, will be investigated in

a mechanistic study of PEPaNIC data. This will be combined with the current data and an