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General discussion
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8
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