Early postnatal administration of intravenous amino acids to preterm, extremely low birth weight infants
Article Outline
Abbreviations: BUN, Blood urea nitrogen , ELBW, Extremely low birth weight
Over the past 25 years, dramatic improvements in neonatal medicine have resulted in regular survival of prematurely born infants as young as 24 weeks gestational age and as small as 500 to 600 g. Nowadays, these very small, immature infants are relatively common in neonatal intensive care units. Their survival creates a significant dilemma for neonatologists. How do they achieve growth of 2 to 3 kg of healthy body mass in these in preterm infants over a 12- to 16-week postnatal period? Is it possible to meet the goal of the American Academy of Pediatrics to achieve normal intrauterine growth rates in infants born preterm?1
Unfortunately, this goal remains elusive. Recent National Institute of Child Health and Development (NICHD) Neonatal Research Network data confirm that these smaller and smaller infants are taking longer and longer to initiate postnatal growth, to achieve “normal” rates of growth (commonly defined as fetal rates of growth), and to attain normal body size for adjusted gestational age after preterm birth.2 This is not surprising when one observes that early postnatal nutritional state in these very preterm, extremely low birth weight (ELBW) infants often consists of significantly higher energy intake but significantly lower protein intake than the placenta delivers to the fetus of the same gestational age. As a result, many of these very preterm infants develop a relatively greater fat mass, but decreased lean body mass, compared with fetuses growing in utero over the same gestational age period.3 This decrease in growth of lean body mass occurs despite considerable data showing that increasing amino acid and protein intakes above the relatively low values commonly delivered to these infants results in a greater net protein balance.4, 5 Recent studies also indicate that enhanced amino acid intake can be successful when started during the first day after birth.6 In this issue of The Journal of Pediatrics, Poindexter et al7 present the effects of early intravenous amino acid feeding on growth, and neurodevelopmental outcomes in a large population of preterm infants from centers in the USA that are part of the NICHD Neonatal Research Network.8 The results indicate that certain measures of growth are maintained or enhanced later in infancy among the infants that were fed earlier after birth with more amino acids. The results also show that the infants who were more aggressively fed intravenous amino acids had no greater measurable deficits in neurodevelopment than did those ELBW infants started on intravenous amino acid infusions later after birth. If confirmed, this is important information, as it provides evidence that nutrition can play an important, in fact, essential, role in improving growth without worsening the already far less than optimal neurodevelopmental outcome of extremely preterm birth. Why therefore is early postnatal amino acid nutrition of extremely preterm infants an issue at all?
There also are concerns regarding feeding preterm infants too much protein. In general, these concerns derive from early studies in which protein administration in large quantity or of poor “quality” produced metabolic acidosis, hyperammonemia, uremia, hyperaminoacidemia, growth restriction, and worse developmental outcome.9 The good news is that today even very preterm, ELBW infants are in better physiological condition when nutrition is initiated than they were 30 years ago, and protein mixtures, especially those used intravenously, also are of much higher quality. In the current era, even “high” protein intakes have been demonstrated to be efficacious in terms of enhancing protein accretion, and they are well tolerated in terms of potential side effects.6 Regarding side effects, many also have worried that higher amino acid/protein intakes in preterm infants would lead to excessive uremia and that uremia will cause harm to these infants. There is no credible evidence, however, that uremia of the degree commonly seen in preterm infants does cause harm. Also, a recent study showed that among a group of preterm infants of highly variable gestational age and birth weight, but including ELBW infants less than 1000 g birth weight and 27 weeks gestational age, there was no correlation between amino acid intake and blood urea nitrogen (BUN), and there were very few BUN values greater than 40 mg/dL.10 In fact, BUN only increased modestly (∼ 5 mg/dL) when amino acid intake was nearly tripled from ∼1 to ∼3 g/kg/d, which it should do, since amino acids are a normal oxidative substrate.11 Again, the fear of uremia likely reflects early experience when intravenous and enteral amino acid and protein mixtures were not of appropriate quality or were given in excess quantity. Of course there always is reason for caution, and infants with documented excessive uremia probably should have their energy intakes and cardiovascular and renal systems improved before being fed more than the minimum amount of amino acids (∼1.5 g/kg/d) needed to prevent protein breakdown.
It has been questioned whether current intravenous amino acid solutions are “optimal” for very preterm neonates. Current intravenous amino acid solutions that are commonly used in preterm infants were developed from studies in infants who were older and more mature than today’s ELBW infant population. These solutions were manipulated to produce plasma aminograms similar to those found in term to 1-month-old, breast-fed infants. The major change in their composition was an increase in the total amount of essential amino acids, as well as their relative fraction versus non-essential amino acids. There also were specific reductions in certain amino acids (eg, glycine, phenylalanine, and methionine) that were considered to be potentially toxic and that might, at higher amino acid infusion rates, produce dangerously high plasma concentrations. Fortunately, clinical trials have shown improved nitrogen balance, growth rates, and lower plasma concentrations of the worrisome amino acids in preterm infants fed current parenteral nutrition solutions compared with those found in infants who were fed the original intravenous amino acid mixtures that were based on egg albumin and which had much lower relative amounts of the essential amino acids.12 Nevertheless, there still is room for improvement, as concentrations of some essential amino acids (eg, lysine and threonine) are lower than found in normally growing, healthy human fetuses in both the second and third trimesters from umbilical vein samples.6 It is possible therefore that even further improvement in amino acid quality of intravenous amino acid mixtures will promote better amino acid balance and improved growth.13
There is a misconception that increased amino acid/protein intakes must be accompanied by increasing energy intakes or the amino acids/protein will not adequately be incorporated into net protein growth. This is true only at very low nonprotein caloric intakes, below 60 kcal/kg/d. Above that level, increased protein intake is the primary determinant of protein gain, whereas increased non-protein intake, alone or with amino acids and protein, primarily enhances growth of body fat.13
There is increasing concern for over growth leading to long-term, later-life disorders of metabolism. This is a reasonable concern, and more and more evidence is accumulating that overgrowth is detrimental.14 One must distinguish clearly, however, “aggressive” nutrition after birth of very preterm, ELBW infants that is aimed simply at providing the nutrients that they need to achieve normal growth rates and body compositions (more amino acids/protein vs energy) from aggressive nutrition later in the neonatal period that leads to rapid catch-up growth (usually provided as more energy than protein). In fact, providing what the preterm infant needs right after birth, thereby continuing normal in utero nutrition, very likely might prevent much of the growth failure that these infants develop during their neonatal intensive care unit hospitalization and thereby limit or even prevent the need for catch-up growth. This particularly should apply to amino acid and protein nutrition leading to increased lean body mass and normal cellular development rather than increased energy leading to increased fat body mass.15
There are several aspects of the Poindexter study that limit generalization of its results.7 First, the study was post hoc rather than a prospective trial. It is not clear therefore whether the earlier fed infants represented a healthier group of infants that would have been expected to tolerate intravenous amino acid feeding better, grow sooner, and grow at a faster rate, probably with greater amounts of lean body mass. Second, there were no measures of lean body mass versus fat mass to indicate which of these were affected by the increased nutrient intake in the “early” group. Third, there also was no independent measure of brain size separate from head circumference to determine if the fewer cases of lower head circumference in the earlier fed group indicated that brain growth was possibly enhanced in the earlier fed group. The latter is important since recent imaging studies of adolescents who were born preterm indicate significant deficits in brain volume.16 Fourth, the fewer cases of lower head circumference in the earlier fed group occurred significantly in males, not females, indicating that some of the positive results of the study might be due to sex differences and not nutrition.
What should we do then to optimize growth rates and developmental outcomes of very preterm, ELBW infants?17 First, these infants need to be fed enough amino acids and protein, starting right after birth, to prevent protein breakdown, to promote the growth of cells, tissues, and organs and to produce the body composition that mimics the growth and body composition of healthy fetuses growing in utero. This means providing amino acids and protein earlier and in greater amounts after birth than customarily are provided. Further studies are needed to determine the optimal mixtures of amino acids for intravenous feeding. Glucose and lipid intakes need to meet the requirements of energy expenditure, but in general this will mean providing less of these substrates than these infants usually receive. For glucose, maintaining normal glucose concentrations that match those of the normally growing fetus (>50 mg/dL, <90 mg/dL) might be important for neurodevelopment.17 Polyunsaturated fatty acids of the n-3 variety are likely beneficial for neurodevelopment as well.18, 19 Determining which and how much of these two energy substrates optimize protein growth should be a major focus of research.20
The article by Poindexter et al in this issue,7 while limited in several ways, provides an important entrée into future studies and the exciting potential to develop nutritional products and practices that will not just make preterm infants grow bigger, but grow bigger at appropriate rates. Future studies are needed to determine the effect of various nutritional strategies on long-term outcomes of growth of body components (adipose tissue, muscle, bone, water), on the rate of development of obesity, insulin resistance, and diabetes, and on brain growth (cellular as well as overall volume), neuronal, neurologic, developmental, and cognitive outcomes.
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PII: S0022-3476(05)01171-6
doi:10.1016/j.jpeds.2005.12.011
© 2006 Elsevier Inc. All rights reserved.
Refers to article:
- Early provision of parenteral amino acids in extremely low birth weight infants: Relation to growth and neurodevelopmental outcome
