Proefschrift Kerklaan

Chapter 8

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 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 30 . 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 31 . An increase in CRP has been associated with enhanced catabolism by reducing protein synthesis and increasing protein breakdown 32 . 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 33 . Inactivation of thyroid hormone, possibly also reflecting an adaptive beneficial response 32,33 , is enhanced in response to nutrient restriction during the acute phase 34 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 - Amplification of the acute catabolic stress response - Preservation of autophagy (fasting response) - Maintenance of muscle integrity and function - Prevention of PN-related complications

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