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Amino Acids, Glutamine, and Protein Metabolism in Very Low Birth Weight Infants

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Amino Acids, Glutamine, and Protein Metabolism in Very Low Birth Weight Infants 0031-3998/05/5806-1259 PEDIATRIC RESEARCH Vol. 58, No. 6, 2005 Copyright © 2005 International Pediatric Research Foundation, Inc. Printed in U.S.A. Amino Acids, Glutamine, and Protein Metabolism in Very Low Birth Weight Infants PRABHU S. PARIMI, MARK M. KADROFSKE, LOURDES L. GRUCA, RICHARD W. HANSON, AND SATISH C. KALHAN Department of Pediatrics, Schwartz Center for Metabolism and Nutrition, Case Western Reserve University School of Medicine, MetroHealth Medical Center, Cleveland, Ohio, 44109 ABSTRACT Glutamine has been proposed to be conditionally essential for 5 h (AA1.5) resulted in decrease in rate of appearance (Ra) of premature infants, and the currently used parenteral nutrient phenylalanine and urea, but had no effect on glutamine Ra. mixtures do not contain glutamine. De novo glutamine synthesis Infusion of amino acids at 3.0 g/kg/d for 20 h resulted in increase (DGln) is linked to inflow of carbon into and out of the tricar- in DGln, leucine transamination, and urea synthesis, but had no boxylic acid (TCA) cycle. We hypothesized that a higher supply effect on Ra phenylalanine (AA-Ext). These data show an acute of parenteral amino acids by increasing the influx of amino acid increase in parenteral amino acid–suppressed proteolysis, how- carbon into the TCA cycle will enhance the rate of DGln. Very ever, such an effect was not seen when amino acids were infused low birth weight infants were randomized to receive parenteral for 20 h and resulted in an increase in glutamine synthesis. amino acids either 1.5 g/kg/d for 20 h followed by 3.0 g/kg/d for (Pediatr Res 58: 1259–1264, 2005) 5 h (AA1.5) or 3.0 g/kg/d for 20 h followed by 1.5 g/kg/d for 5 h (AA3.0). A third group of babies received amino acids 1.5 g/kg/d Abbreviations for 20 h followed by 3.0 g/kg/d for 20 h (AA-Ext). Glutamine BGln, glutamine derived from proteolysis and protein/nitrogen kinetics were examined using [5-15N]glu- DGln, de novo glutamine synthesis 2 13 15 15 tamine, [ H5]phenylalanine, [1- C, N]leucine, and [ N2]urea TCA, tricarboxylic acid tracers. An acute increase in parenteral amino acid infusion for VLBW, very low birth weight Glutamine participates in a number of key metabolic pro- a higher amount of parenteral amino acids to these VLBW cesses (1) and is also proposed to play an important role in infants enhances the rate of DGln has not been examined. enhancing immune function (2–4). A decrease in plasma glu- Glutamine is synthesized by transamination of ␣-ketogluta- tamine concentration in response to stress (acute illness, burns, rate to glutamate and conversion of glutamate to glutamine. trauma, etc.) suggests that the rate of DGln is unable to keep The latter reaction is catalyzed by glutamine synthase. The pace with the rate of utilization/requirement. This has led sources of carbon skeleton for the synthesis of glutamine, i.e. several investigators to suggest that glutamine is a condition- glutamate and ␣-ketoglutarate, are derived from the amino ally essential amino acid. Studies in adults show that parenteral acids entering the TCA cycle (anaplerosis). An increase influx nutrition supplemented with glutamine decreased both the of these amino acids would be anticipated to result in an morbidity and mortality (5,6). increase in DGln (cataplerosis) (10). Studies in human adults Because the concentration of plasma glutamine is lower in show that supplementation of parenteral nutrition with ana- VLBW infants, and the currently used parenteral nutrient logues of ␣-ketoglutarate enhances the intracellular pool of solutions do not contain glutamine, VLBW premature infants glutamine in the muscle (11,12). We have previously shown were identified as another group of subjects who could poten- that the rate of appearance of glutamine in newborn infants is tially benefit from supplementation of enteral and parenteral positively correlated with whole body rate of protein break- nutrition with glutamine (7–9). However, whether provision of down (13), suggesting that an increased availability of amino acids augments DGln. We hypothesized that supply of a higher Received February 15, 2005; accepted May 10, 2005. amount of parenteral amino acids to clinically stable VLBW Correspondence: Prabhu S. Parimi, M.D., Schwartz Center for Metabolism and Nutri- infants will increase the anaplerotic flux of carbon into the tion, G 735, MetroHealth Medical Center, 2500 MetroHealth Dr., Cleveland, OH 44109; TCA cycle, increase transamination, and accelerate the rate of e-mail: [email protected] This work was supported by National Institutes of Health grant RO1 HD042154 and DGln. We have tested the hypothesis by examining the effect General Clinical Research Center grant RR00080. of parenteral amino acids, either 1.5 g/kg/d or 3 g/kg/d for DOI: 10.1203/01.pdr.0000185130.90205.1f either5hor20h,onglutamine, phenylalanine, leucine nitro- 1259 1260 PARIMI ET AL. gen, and urea kinetics in premature infants Յ32 wk gestation Table 1. Clinical characteristics and Յ1500 g birth weight using a randomized study design. Birth Gestational Age M/F Weight at SNAP weight (g) age (wk) (d) study (g) METHODS AA 1.5 1139 Ϯ 276 29 Ϯ 25Ϯ 1 6/6 1009 Ϯ 270 12 (5–18)* (n ϭ12) Յ Յ Subjects. Preterm infants 32 wk gestation and 1500 g were recruited. AA 3.0 1189 Ϯ 324 28 Ϯ 25Ϯ 1 8/4 1093 Ϯ 308 12 (7–20) After verbal assent from their primary physician, written informed consent was (n ϭ12) obtained from the parent(s), after fully explaining the procedures. The study AA-Ext 1132 Ϯ 289 28 Ϯ 24Ϯ 1 0/5 1035 Ϯ 263 13 (9–21) protocol was approved by the Institutional Review Board. All studies were ϭ performed in the neonatal intensive care unit at MetroHealth Medical Center. (n 5) Premature infants were randomized to receive an initial parenteral nutrition AA1.5: Parenteral amino acids 1.5 g/kg/d for 20 h, 3 g/kg/d for 5 h. AA3.0: ϭ ϭ containing either 1.5 g/kg/d (AA1.5, n 12) or 3 g/kg/d (AA3.0, n 12) of Parenteral amino acids 3 g/kg/d for 20 h, 1.5 g/kg/d for 5 h. AA-Ext: Parenteral amino acids (10% TrophAmine, McGaw, Irvine, CA). After 16 h of amino acid amino acids 1.5 g/kg/d for 20 h, 3 g/kg/d for 20 h. infusion, kinetic studies were performed as described below. Thereafter, the Data shown are mean Ϯ SD. *Median (25–75%). No significant difference amino acid load was increased to 3 g/kg/d in AA1.5 group and decreased to 1.5 g/kg/d in AA3.0 group and infused for the next 5 h, while the infants continued between the groups. to receive isotopic tracer infusion. Because the second part of the study in AA1.5 and AA3.0 groups was only5hascompared with 20 h in the first part, 2 2 15 dover, MA). L-[ H5]phenylalanine (98 atom% H), [ N2]urea (98 atom % a third group (AA-Ext) was also studied where the tracer studies were 15 13 15 13 15 performed after 20 h of amino acid infusion at 1.5 g/kg/d and at 3.0 g/kg/d (Fig. N) and L-[ C, N]leucine (98% C and 98% N) were purchased from 1). Clinical characteristics of the infants and the acuity of illness at birth, Merck & Co. (Dorvall, Canada). Each batch of the tracers was tested for assessed by Scoring of Neonatal Acute Physiology (SNAP), were not different sterility and pyrogenicity as previously described (14). The administered doses 15 ␮ between the study subjects (Table 1). Tracer isotope studies were performed at of various tracers were as follows: L-[5- N]glutamine (prime, 30 mol/kg; ␮ 2 ␮ a mean age of 5 Ϯ 1 d. Infants were on either minimal ventilator support constant rate 30 mol/kg/h, L-[ H5]phenylalanine (prime, 6 mol/kg; constant ␮ 15 ␮ ␮ (defined by FiO Յ35% and mean air way pressure Յ8) (AA1.5, n ϭ 5; AA rate, 4 mol/kg/h), [ N2]urea (prime, 33 mol/kg; constant rate, 3.3 mol/ 2 13 15 ␮ ␮ 3.0, n ϭ 5, AA-Ext, n ϭ 2), or were receiving supplemental oxygen via nasal kg/h) and 1-[ C, N]leucine (prime, 7.5 mol/kg; constant rate, 7.5 mol/ ϳ canula. None of the infants were on insulin or vasopressor support or were kg/h). Blood samples ( 0.7 mL each depending upon the baby’s weight) were receiving corticosteroids. All babies were placed on antibiotics immediately obtained before beginning the tracer infusion and again at 15-min intervals after birth for presumed infection, as per the clinical practice at our institution. between 210 and 240 min. At 240 min, following the last blood sample, the None of the study infants had bacteriologically proven sepsis. Their primary parenteral amino acids solution was changed as described. Another set of blood neonatologist was responsible for all the clinical care including necessary samples were collected between 510 and 540 min. adjustments in intravenous fluids, initiation of parenteral nutrition, and enteral In the AA-Ext group, tracer infusion was begun 16 h after parenteral feeding. None of the infants were receiving enteral feeds at the time of tracer nutrition at 1.5 g/kg/d and continued for 4 h. Blood samples were obtained study. Generally, babies received 10% dextrose water during the first 24 h after between 210 and 240 min, after which the tracer infusion was discontinued, birth and were started on parenteral amino acids between 24 and 72 h of age.
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