Currently blood urea nitrogen (BUN) is commonly used as a marker of protein intolerance in very preterm infants. The purpose of this study was to evaluate the relationship between amino-acid intakes and BUN concentrations during the early neonatal period in preterm neonates.
Retrospective review of BUN concentration data from 121 infants with birthweight ≤1250 g receiving exclusive parenteral nutrition over the first 72 hours of life.
There were 136 separate BUN concentration values. Amino-acid intake range was 0 to 3.7 g kg−1 day−1 and nonprotein calorie intake range was 15 to 45 kcal kg−1 d−1. There was no correlation between BUN concentration and amino-acid intake (p=0.2 and r2=0.01).
In parenterally nourished preterm neonates amino-acid intake is not correlated with BUN concentration in the first days of life. Therefore, limiting amino-acid intake based on BUN concentration is not warranted in this patient population.
Nutritional practices vary dramatically among neonatal intensive care units in this country. In many institutions nutrition is only gradually introduced over the first weeks of life because of concerns of nutrient intolerance. Many clinicians are reluctant to provide higher amino-acid intakes to preterm infants, especially over the first days of life. This reluctance is often based on the report of azotemia, hyperammonemia, and metabolic acidosis seen in infants who received the early protein hydrolysate solutions.1 The current goal of nutritional management of preterm infants recommended by the American Academy of Pediatrics is to achieve a postnatal growth approximating that of a normally grown fetus of the same postconceptional age.2 We recently evaluated neonatal amino-acid intakes at higher rates than commonly used in clinical practice but estimated to replicate fetal protein growth, and demonstrated improved protein accretion rates compared to those seen at more conventional parenteral amino-acid delivery rates.3 Nevertheless, many clinicians continue to limit the amino-acid intake provided to preterm and sick neonates due to continued concern over amino-acid intolerance. Elevated BUN concentrations are often cited as the reason for limiting amino-acid intake. For this reason, we chose to evaluate the relationship between amino-acid intakes and BUN concentrations over the first 72 hours of life in a population of neonates with birthweights ≤1250 g.
Infants whose results are reported here were all study subjects enrolled in metabolic studies conducted at the University of Colorado Hospital or The Children's Hospital, Denver, CO, USA. From these studies, we reviewed data from neonates with birthweights ≤1250 g who were receiving exclusive parenteral nutrition over the first 72 hours of life. The Combined Institutional Review Board for human subject research for The Children's Hospital of Denver and the University of Colorado Hospital approved all studies. Exclusion criteria included sepsis and congenital or metabolic abnormalities known to affect energy or nutrient metabolism. Data from a subset of patients are published elsewhere.3
This is a retrospective review of BUN concentration data from parenterally nourished neonates over the first 72 hours of life. Each neonate received a parenteral nutrition solution with composition and delivery based on the design of their particular study. The parenteral nutrition typically consisted of a dextrose and electrolyte preparation with added amino-acids (TrophAmine, McGaw, Irvine, CA, USA, with added cysteine hydrochloride, Abbott, Abbott Park, IL, USA) and lipid (Intralipid 20%, Fresenius Kabi Clayton, L.P., Clayton, NC, USA). Minerals, trace elements, and vitamins were provided according to nursery protocol. Glucose was administered at intakes to maintain serum glucose concentrations >80 to 100 mg/dl but which avoided hyperglycemia (i.e. serum glucose concentrations greater than 150 mg/dl). No patient received insulin. Target energy intakes (glucose plus lipid) were 35 to 40 kcal kg−1 day−1 over the first 24 hours of life with daily advancement based on the study design, patient factors, and the attending neonatalogist's discretion. Amino-acid intakes were calculated from the 24-hour period prior to the time the BUN concentration was obtained.
Simple linear regression analyses were performed for BUN vs various patient and nutritional variables (Prism 4 for Macintosh, GraphPad Software, San Diego, CA, USA).
Study subject demographic characteristics are detailed in Table 1. Data from a total of 121 infants were included in this study. A total of 136 separate BUN concentration measurements were available, with 15 infants having serial measurements spaced by a minimum interval of 24 hours. The majority of infants received empiric antibiotic therapy during the first 72 hours of life, although no patient had a positive blood culture. None of the infants received postnatal corticosteroids or required insulin infusion during the study period. At the amino-acid intake (range 0 to 3.7 g kg−1 day−1; 1.8±0.9 g kg−1 day−1, mean±SEM) and nonprotein calorie intake (45±17 kcal kg−1 day−1) seen in this study, there was no correlation between BUN concentration and amino-acid intake (Figure 1). When subdividing the infants by amino-acid intake levels (<1.0, 1.0 to 1.9, 2.0 to 2.9, or >3.0), no correlation with BUN concentration was noted (Figure 2). There was a significant inverse correlation between BUN concentration and both gestational age and birthweight (Figure 3).
According to current American Academy of Pediatrics guidelines, the goal of nutritional management of preterm infants is to achieve a postnatal growth approximating that of a normally grown fetus of the same postconceptional age. While weight gain is the most obvious marker of postnatal growth, protein accretion may be a more appropriate indicator of nutritional status. A number of studies in preterm infants have demonstrated that infusion of amino-acids as early as the first day of life have resulted in a positive protein balance.4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 Many of these studies have shown an amino-acid intake of as little as 1.5 to 2.0 g kg−1 day−1, when given with ≥30 kcal kg−1 day−1 of nonprotein calories, is sufficient to avoid negative nitrogen balance in neonates with higher amino-acid and energy intakes resulting in net protein accretion.16 With the goal of replicating intrauterine protein accretion rates, amino-acid intakes are estimated to be 3.5 to 4.0 g kg−1 day−1 particularly for those infants with birthweights <1000 g.17, 18 As an elevated BUN concentration is often cited as the reason for limiting amino-acid intakes in this population, we chose to conduct the current study to evaluate the relationship between amino-acid intakes and BUN concentrations in a group of preterm neonates with birthweights <1250 g who were exclusively parenterally nourished over the first 72 hours of life. A number of prior studies have presented BUN concentration data along with concomitant parenteral amino-acid intakes. However, these studies were limited by the small number of patients. This is the first study to evaluate BUN concentrations in a large group of premature neonates receiving exclusive parenteral nutrition over the first days of life.
With the quantitative and qualitative growth of the fetus as a goal of neonatal nutrition, understanding fetal amino-acid and urea metabolism is critical. Given the ethical and technical difficulties associated with human fetal and placental studies, human data is limited, and much of the research carried out in this area has been accomplished in the fetal sheep model. Throughout gestation, the placenta has been shown to actively transport amino-acids from the maternal compartment to the fetal compartment.19 Of interest is the finding that fetal amino-acid uptake greatly exceeds fetal protein accretion requirements. Over 25% of this fetal amino-acid uptake has been shown to undergo oxidation (a process in which the substrate is used as an energy source).20 Through oxidation, amino-acids serve as a significant energy source for the growing fetus. In addition to this high rate of amino-acid oxidation, the fetus also demonstrates a similarly high rate of protein turnover. Associated with this high rate of fetal amino-acid oxidation is an equally high rate of urea production. Urea is produced in the liver as a by-product of amino-acid oxidation. When excreted, urea represents irreversible nitrogen loss. The human fetus has the ability to synthesize urea within the first month of gestation with appreciable enzymatic activity present by the third month of gestation. In fact, fetal weight-specific urea production rates have been found to exceed those of neonates and even adults.21, 22 Accompanying such high urea synthetic rates are high fetal BUN concentrations, as has been shown in the human fetus when compared to simultaneously obtained maternal blood.23 The higher BUN concentrations seen in infants of lower gestational age (Figure 3) may be a reflection of appropriate utilization of the supplied amino-acids for accretion and as an energy source. In addition to the rate of amino-acid oxidation, BUN concentration is a complex outcome of hydration status, renal function, energy quality and quantity, and the patient's degree of illness. Evaluating a BUN concentration as a single marker of protein intolerance without considering these many factors is not justified.
In a group of infants with birthweight less than 1250 g who were receiving exclusive parenteral nutrition over the first days of life, no correlation was found between amino-acid intake and serum BUN concentration. Given the data supporting the importance of early amino-acid administration in premature infants, limiting amino-acid intake based on serum BUN concentrations is not warranted. There is great need for further study to define markers of protein sufficiency, both quantitative and qualitative, and markers of protein intolerance.
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This work was supported by National Institutes of Health Grants RO3HD39842 and M01RR00069, General Clinical Research Center Program, National Centers for Research Resources.
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Ridout, E., Melara, D., Rottinghaus, S. et al. Blood Urea Nitrogen Concentration as a Marker of Amino-Acid Intolerance in Neonates with Birthweight Less than 1250 g. J Perinatol 25, 130–133 (2005). https://doi.org/10.1038/sj.jp.7211215
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