Proefschrift Kerklaan

General discussion

Protein Recent large prospective studies have particularly stressed the importance of a high total (but predominantly enteral) protein intake in critically ill children and adults due to its association with decreased mortality and reduced length of stay, independently of caloric intake 23,60,61 . However, co-occurrence of high protein intake and improved outcome does not imply causation. Also, as with the association between higher caloric intake and improved outcome, protein intake goals vary widely between PICUs (Chapter 2). Administration of protein enriched enteral formulas in critically ill children consistently increases total protein synthesis/balance and levels of amino acids 62-66 . However, relations between these surrogate endpoints and clinically relevant outcomes are often non-existent or weak. Sometimes surrogate endpoints even suggest a benefit whereas the clinical outcomes indicate harm (Chapter 5 and 7). Cumulative amino acid dose early during ICU stay was associated with delayed recovery in a post-hoc analysis of the EPaNIC trial 19 . Some amino acids, such as leucine, exert a primary anabolic effect in skeletal muscle and inhibit the initiating step of autophagy 67 by activation of mTOR (mammalian target of rapamycin) 68 , thereby reducing tolerance to oxidative stress, increasing risk for organ failure (especially liver and kidney) and cell death, eventually resulting in worse clinical outcome 69 . Lipids Due to a lack of evidence, the optimal amount of lipid administration in critically ill children remains unclear, reflected by a wide range in parenteral lipid targets (from below 1.5 to above 3.5 g/kg/day) (Chapter 2). Provision of saturated fatty acids is known to provoke more endoplasmatic reticulum (ER) stress and inflammation in liver and adipose tissue of rats than provision of unsaturated fatty acids 70 , resulting in catabolism and ultimately in apoptosis 71 . Intravenous lipid emulsions provided in critically ill children are traditionally rich in n-6 fatty acids impacting neural development, growth, immune function and outcome after surgery 72 . The alternative lipid emulsions, enriched with n-3 fatty acids, are safe and effective in reducing the infection rate and length of stay of adult ICU patients 73 and might promote the resolution of the inflammatory process in children post-surgically 74 . However, evidence for the use of these emulsions in critically ill children is solely based on surrogate endpoints (Chapter 5) and therefore differs between PICUs (Chapter 2). Also in the PEPaNIC study, different types of lipid emulsions were used (predominantly SMOFlipid® in Leuven and Intralipid® in Rotterdam). A more detailed analysis is needed to investigate the relation between type of lipid emulsion and clinical outcomes, such as PICU dependency and incidence of new infections. With the current lacking and conflicting evidence, the macronutrient dose dependency analysis of PEPaNIC is eagerly awaited. The optimal timing for the initiation of PN should be marked by the moment in which its benefits on clinical outcomes by providing essential

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