Commentary on “Higher versus Lower Amino Acid Intake in Parenteral Nutrition for Newborn Infants”

Parenteral nutrition (PN) solutions consist of water, electrolytes, carbohydrate (dextrose), vitamins, micronutrients, and amino acids (AA) and are usually accompanied by intravenous lipid solutions. They were first given to newborn infants more than 50 years ago and are now considered a key component of neonatal intensive care. Whilst infants born at term with surgical complications or other reasons preventing enteral feeding need PN, the commonest patient group receiving PN are preterm infants. In these infants, protein requirements can be more than twice those at term as nitrogen losses in the urine are around 1–1.5 g/kg protein equivalent each day. Without early use of PN, very-preterm infants become malnourished. In many neonatal intensive care units, PN is routinely started on admission for most infants born <32 weeks’ gestation and/or <1,500 g birthweight. PN has important risks, including those associated with composition such as solution quality control, microbiological safety, solubility, and AA balance as well as risks associated with delivery such as use of central lines, sepsis, and line misplacement [1]. Most preterm infants take several days or weeks to achieve full milk feeds and so determining the optimal AA intake is an important issue in neonatal medicine [2].

AA requirements have been calculated using fetal nitrogen accretion as a reference. The so-called factorial method estimates that infants born at 24–28 weeks’ gestation require an AA intake of around 3.5–4 g/kg/day if fetal protein accretion rates of approximately 2 g/kg are to be enabled [3]. However, even relatively well preterm neonates are metabolically unstable, and hyperglycemia and hyperlipidemia are common. The ability to metabolize parenterally delivered AA may also be compromised, but there is no practical means of assessing this in clinical practice. The question this Cochrane Review aimed to determine is whether providing higher amounts of AA in the first few days improves important outcomes [4]. Osborn et al. [4] identified 32 studies of which 21 reported on clinical outcomes in preterm infants. Higher AA intakes (starting at 2–3 g/kg and increasing to 3–4 g/kg, compared to lower doses at commencement or lower maximal amounts) had no impact on survival (Fig. 1), chronic lung disease, sepsis, necrotising enterocolitis, head circumference at hospital discharge (Fig. 2), brain injury, or later neurodevelopment but did demonstrate small benefits on weight gain, measures of protein accretion, and glucose control. An apparent reduction in retinopathy of prematurity was seen from meta-analyses of data from four studies, but the quality of evidence was very low, and an effect on severe retinopathy of prematurity was not observed.

It is not possible to determine the optimal regimen from the studies included in these meta-analyses. Higher intake may be beneficial or harmful. Populations of preterm infants vary markedly – it is plausible that a relatively stable 24-weeks’-gestation infant may benefit from an AA intake closer to 4 g/kg while an unstable 30-weeks’-gestation infant with severe sepsis may be harmed by an intake >2 g/kg. We urgently need adequately powered trials with long-term functional outcomes to determine optimal AA intake [5].

Cochrane Neonatal Reviews are produced with support from Vermont Oxford Network, a worldwide collaboration of health professionals dedicated to providing evidence-based care of the highest quality for newborn infants and their families. Editorial support for Cochrane Neonatal has come from a UK National Institute of Health Research (NIHR) Cochrane Programme Grant (16/114/03).