Early amino acid administration, in addition to the establishment of an adequate energy intake, has been recommended in preterm neonates to avoid protein catabolism (1). However, protein administration in the first days after delivery in preterm neonates is often limited because of concerns about lack of tolerance in these vulnerable infants, especially if born small for gestational age. Indeed, increased BUN, hyperammonemia, and metabolic acidosis have been reported in infants receiving early amino acid solutions (2,3). Nevertheless, no correlation between protein intake and BUN concentration during the first 72 hours of life in preterm newborns receiving parenteral nutrition has been found (4). BUN has been proposed as a marker for the evaluation of the optimal quantity of protein intake in stable enterally fed preterm infants (5).
The aim of the present study was to investigate the relation between protein intakes and BUN during the entire duration of parenteral and enteral nutrition in a cohort of preterm infants.
PATIENTS AND METHODS
One hundred seventy-eight preterm infants among all of the consecutive newborns admitted to the same institution from January 2007 to October 2008 were considered eligible. The inclusion criterion was birth weight <1500 g. Exclusion criteria were presence of congenital diseases, chromosomal abnormalities, sepsis, metabolic, renal or congenital cardiac diseases, infant's death during the study, and infant's transfer to other hospital.
A prospective, longitudinal, observational study was conducted. Basic subject characteristics (birth weight, gestational age, sex, appropriate for gestational age, or small for gestational age [SGA]) were recorded. Gestational age was based on the last menstrual period and the first trimester ultrasonogram. Infants were classified as appropriate for gestational age or SGA based on birth weight being ≥ or <10th percentile for gestational age, respectively, according to the Fenton chart (6).
Nutrition was started soon after birth and consisted of parenteral nutrition and a minimal enteral feeding (MEF: maximal cumulative intake of 20 mL · kg−1 · day−1) with expressed breast milk or preterm formula. Intravenous amino acids (6.5% amino acid solutions, TrophAmine B Braun Medical Inc, Cherry Hill, NJ) were started at the dose of 1.5 g · kg−1 · day−1 within 24 hours from birth. The amino acid dose was then increased by 0.5 g · kg−1 · day−1 up to a maximum dose of 3.5 g · kg−1 · day−1 on day 5. Throughout the following days of parenteral nutrition 3.5 g · kg−1 · day−1 was infused continuously for 24 hours.
The infants also received intravenous glucose (at intakes to prevent serum glucose concentrations <80 mg/dL), lipids (Intralipid 20% Fresenius Kabi, Bad Homburg, Germany), minerals, trace elements, and water-soluble and lipid-soluble vitamins. Energy intakes (glucose plus lipids) increased from 40 kcal · kg−1 · day−1 on day 1 up to a maximum of 80 kcal · kg−1 · day−1 by day 5 or subsequently.
Enteral feeding was either fortified breast milk (2.2 g/100 mL and 82 kcal/100 mL) or preterm formula (2.4 g/100 mL and 80 kcal /100 mL) when breast milk was unavailable or insufficient. The fortifier used was supplemented with vitamin D and calcium.
Protein intakes (expressed as g · kg−1 · day−1) were collected from the medical records and calculated from the 24-hour period preceding the time the BUN specimens were collected. Blood samples for BUN were drawn by venipuncture on days 2, 5, and 15 of parenteral nutrition, on the day when infants consumed 160 mL/kg of milk (full enteral feeding), and at 36 weeks of postmenstrual age of the infants. Written informed consent was obtained from the infants' parents, and the study design was approved by the departmental ethics committee.
Descriptive data are expressed as mean (standard deviation [SD]) or number of observations (percentage). The effects of gestational age and protein intakes on BUN concentrations during parenteral nutrition were ascertained by multiple regression analysis. The relation between BUN and protein intakes during enteral feeding was evaluated by a simple correlation analysis.
Statistical significance was conducted at α = 0.05 level. All of the statistical analyses were performed using SPSS (version 12, SPSS Inc, Chicago, IL).
BUN concentrations were assessed in 92 preterm infants. Eighty-six infants were excluded from the study because of death during the hospital stay (n = 40), transfer to another hospital (n = 11), congenital/chromosomal abnormalities (n = 3), sepsis (n = 24), renal diseases (n = 7), and congenital cardiac diseases (n = 1).
Mean (SD) birth weight and mean (SD) gestational age of the infants included in the study were 1125 (224) g and 29.7 (1.8) weeks, respectively. Forty-five percent (n = 42) of the infants were boys, 31% (n = 29) were SGA, and 30% (n = 28) were extremely low birth weight (birth weight <1000 g).
BUN concentrations and mean protein and energy intakes during parenteral and enteral nutrition are shown in Table 1. Mean duration of parenteral nutrition was 16 days (2).
Using linear regression analysis, gestational age showed a significant negative correlation with BUN concentrations during parenteral nutrition, whereas protein intakes at 2, 5, and 15 days did not correlate with BUN (Table 2).
A moderately significant positive correlation between BUN and protein intake was found when the infants consumed 160 mL/kg of milk and at 36 weeks postmenstrual age (r = 0.5, P = 0.001 and r = 0.49, P = 0.012, respectively) (Fig. 1). Full enteral feeding was achieved in 30.2 (13.7) days.
To our knowledge, this is the first study that evaluates BUN concentrations longitudinally in a group of premature newborns during both parenteral and enteral nutrition. In the present study, BUN concentrations were not significantly associated with protein intake throughout the entire duration of parenteral nutrition. Furthermore, gestational age was inversely correlated with BUN during parenteral nutrition, suggesting that the more immature the preterm infant, the higher the rate of amino acid oxidation.
These findings are in agreement with Ridout et al (4), who failed to find any correlation between protein intake and BUN concentration for the first 72 hours of life in preterm newborns nourished parenterally.
Indeed, because it takes time to establish adequate energy intakes in the first days of life (7), the higher BUN concentrations found in the more immature newborns may thus reflect the amino acid oxidation by preterm infants for energy production. The establishment of an adequate and balanced energy/protein intake, which is gradually achieved during the first days of life, allows the use of amino acids for protein synthesis for normal growth (8). Furthermore, the preterm baby in the first days of life shows a metabolism similar to that in case of the fetus.
Indeed, the fetus converts >25% of this fetal amino acid uptake from protein accretion to use as metabolic fuel and consequently exhibits a high fetal urea production rate (9). Together with this high rate of amino acid oxidation, the fetal protein turnover has been demonstrated to be high, further supporting the concept that amino acids are used by the fetus both for growth and for energy production (8).
In the early postnatal period, high BUN could be related not only to amino acid oxidation and the infant's immaturity but also to additional combined factors other than amino acid intolerance, such as renal function and hydration status. In contrast, BUN concentrations were found to be moderately and positively associated with protein intakes during enteral feeding. This finding suggests that BUN may represent a measure of protein intake in clinically stable preterm infants during enteral nutrition. Our results are consistent with those of Cooke et al (10), who reported a linear increase in BUN values with protein intake during enteral nutrition. Arslanoglu et al (5) demonstrated the usefulness of BUN as a metabolic parameter, reflecting the changes in protein intake of preterm infants fed human milk intakes through an adjustable fortification.
Based on the present results, limiting protein administration in the first days after delivery in preterm neonates without congenital/chromosomal abnormalities, sepsis, or metabolic, renal, or congenital cardiac disease, solely on the basis of high BUN concentrations, may not be reasonable. Indeed, there is evidence that early amino acid administration is well tolerated, limits the large protein deficit that occurs in most preterm babies, and decreases the rate of postnatal growth retardation (11,12).
In contrast, when preterm infants achieve clinical stable conditions and are enterally nourished, BUN may represent a useful index in monitoring the adequacy of protein intake, and may thus contribute to meeting the individual nutritional needs of these vulnerable infants.
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