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Journal of Pediatric Gastroenterology & Nutrition:
doi: 10.1097/MPG.0b013e3182506ee4
Invited Commentaries

Early High-dose Amino Acids for ELBW Infants: Too Early and Too Much?

Greer, Frank R.

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Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI.

Address correspondence and reprint requests to Frank R. Greer, MD, Wisconsin Perinatal Center, Meriter Hospital, 202 S Park St, Madison, WI 53715 (e-mail:

Received 7 February, 2012

Accepted 13 February, 2012

The author reports no conflicts of interest.

See “Impact of Early and High Amino Acid Supplementation on ELBW Infants at 2 Years” by Blanco et al on page 601.

In the report by Blanco et al (1) in this issue, potentially harmful effects of early high doses of intravenous amino acids (AAs) are reported for long-term outcomes on growth and neurodevelopment in extremely-low-birth-weight (ELBW) infants (birth weight <1000 g) at 18 to 24 months of age. Early administration of AA has been shown to improve nitrogen balance in the first week of life and improve weight gain (2,3). Therefore, many neonatal intensive care units have jumped on the bandwagon for early “aggressive” TPN for preterm infants, although most are unlikely to start AA infusions at 2 g · kg−1 · day−1 within the first 24 hours or rapidly advance to 4 g · kg−1 · day−1 by day 4 as was done in the present study. The control group began receiving AAs at 0.5 g · kg−1 · day−1 between 24 and 36 hours of age with increases of 0.5 g · kg−1 · day−1 every 24 hours until a maximum of 3.0 g · kg−1 · day−1 was obtained and maintained through the seventh day of life. This was the standard method of AA administration in this neonatal intensive care unit at the time. After 7 days, all of the infants were maintained on an AA dose of 3.5 g · kg−1 · day−1 until increasing enteral feedings permitted total parenteral nutrition volumes to be decreased. Alarmingly, because of the initial high mortality rate in the early/high AA group for infants <24 weeks’ gestation (4/4 infants enrolled died within 7 days), the study was stopped early by the data safety monitoring board and restarted, with the enrollment limited to infants ages 24 weeks or older. The AA solution was only discontinued if the plasma ammonia level was >91 μmol/L by day 1 of life or >79 umol/L by day 3 of life. As previously reported, the early/high AA group had a higher cumulative AA intake than the standard AA group at day 3 of life (7.6 ± 0.4 vs 1.3 ± 0.1 g · kg−1 · day−1) and day 7 of life (22.5 vs 9.9 g · kg−1 · day−1) (4,5). All 6 infants who were withdrawn from the protocol for elevated plasma ammonia were in the early/high AA group, although lack of difference in the degree of metabolic acidosis between groups was reassuring (4,5).

There are a number of problems with this preliminary study that, in all fairness, are pointed out by the authors. First, the study was small, with only 61 infants randomized and only 32 infants (54%) followed up at 18 to 24 months. Second, the study was not powered for neurodevelopmental or growth outcomes, but for the effect of AA on early serum K+ levels, as previously reported (4). The other major point is that growth is dependent on dietary intake and growth of the brain also influences neurodevelopmental outcomes. Although there were no differences in discharge weights between groups, no data were collected on dietary intakes after hospital discharge. In fact, negative growth outcomes at 18 to 24 months were unexpected and alarming in the Blanco et al study (1). The early/high AA infants had z score means for weight, length, and head circumference that were significantly lower than the standard AA group through 24 months’ corrected gestational age at most visits in this predominantly Hispanic population. The Mental Developmental Index and Psychomotor Developmental Index Bayley II developmental scores did not significantly differ between groups except for a lower Mental Developmental Index score at 18 months in the early/high AA group; however, for nearly every time point, there was a trend for a higher developmental score in the standard AA group compared with the early/high AA group.

This is the first published study looking at the effect of early and high AAs (4 g · kg−1 · day−1) in the first week of life on long-term growth and neurodevelopmental outcomes (18–24 months). These preliminary data suggest that too much protein given too early may be harmful to extremely-low-birth-weight infants. Until larger randomized controlled trials with long-term outcomes can be completed, neonatologists should proceed with caution with early administration of large amounts of AA, especially to ELBW infants.

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1. Blanco CL, Gong AK, Schoolfield J, et al. Impact of early and high amino acid supplementation on ELBW infants at 2 years. J Pediatr Gastroenterol Nutr 2012;54:601–607.

2. Thureen PJ, Melara D, Fennessey PV, et al. Effect of low versus high intravenous amino acid intake on very low birth weight infants in the early neonatal period. Pediatr Res 2003; 53:24–32.

3. Poindexter BL, Langer JC, Dusick AM, et al. National Institute of Child Health and Human Development. Early provision of parenteral amino acids in extremely low birth weight infants: relation to growth and neurodevelopmental outcomes. J Pediatr 2006; 148:300–305.

4. Blanco CL, Falck A, Green BK, et al. Metabolic response to early and high protein supplementation in a randomized trial evaluating the prevention of hyperkalemia in extremely low birth weight infants. J Pediatr 2008; 153:535–540.

5. Blanco CL, Gong AK, Green BK, et al. Early changes in plasma amino acids during aggressive nutritional therapy in extremely low birth weight infants. J Pediatr 2011; 158:543–548.

Copyright 2012 by ESPGHAN and NASPGHAN


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