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Am J Clin Nutr 2003;77:737–43. Printed in USA. © 2003 American Society for Clinical Nutrition 737

Effect of parenteral glutamine supplementation on plasma aminoacid concentrations in extremely low-birth-weight infants1–3

Brenda B Poindexter, Richard A Ehrenkranz, Barbara J Stoll, Matthew A Koch, Linda L Wright, William Oh, Lu-Ann Papile,

Charles R Bauer, Waldemar A Carlo, Edward F Donovan, Avroy A Fanaroff, Sheldon B Korones, Abbot R Laptook,

Seetha Shankaran, David K Stevenson, Jon E Tyson, and James A Lemons for the National Institute of Child Health

and Human Development Neonatal Research Network

ABSTRACT

Background: Glutamine is one of the most abundant amino acids

in both plasma and human milk and may be conditionally essen-

tial in premature infants. However, glutamine is not provided by

standard intravenous amino acid solutions.Objective: We assessed the effect of parenteral glutamine sup-

plementation on plasma amino acid concentrations in extremely

low-birth-weight infants receiving parenteral nutrition (PN).

Design: A total of 141 infants with birth weights of 401–1000 g

were randomly assigned to receive a standard intravenous amino

acid solution that did not contain glutamine or an isonitrogenous

amino acid solution with 20% of the total amino acids as gluta-

mine. Blood samples were obtained just before initiation of study

PN and again after the infants had received study PN (mean

intake: 2.3 ± 1.0 g amino acids· kgϪ1 · dϪ1) for Ϸ10 d.

Results: Infants randomly assigned to receive glutamine had mean

plasma glutamine concentrations that increased significantly and

were Ϸ30% higher than those in the control group in response to

PN (425±

182 and 332±

148 mol/L for the glutamine and con-trol groups, respectively). There was no significant difference

between the 2 groups in the relative change in plasma glutamate

concentration between the baseline and PN samples. In both

groups, there were significant decreases in plasma phenylalanine

and tyrosine between the baseline and PN samples; the decrease

in tyrosine was greater in the group that received glutamine.

Conclusions: In extremely low-birth-weight infants, parenteral

glutamine supplementation can increase plasma glutamine con-

centrations without apparent biochemical risk. Currently available

amino acid solutions are likely to be suboptimal in their supply of

phenylalanine, tyrosine, or both for these infants. Am J Clin

Nutr 2003;77:737–43.

KEY WORDS Glutamine, phenylalanine, tyrosine, extremelylow-birth-weight, premature infants, low-birth-weight infants,

parenteral nutrition, neonatology, neonatal care

INTRODUCTION

Glutamine is one of the most abundant amino acids in both

plasma and human milk (1–3), yet it is not a component of stan-

dard intravenous amino acid solutions because of its instability in

solution. The importance of glutamine, particularly during peri-

ods of stress, injury, and illness, is increasingly being recognized.

1 From Indiana University, Indianapolis (BBP and JAL); Yale University,

New Haven, CT (RAE); Emory University, Atlanta (BJS); the Research Trian-

gle Institute, Research Triangle Park, NC (MAK); the National Institute of

Child Health and Human Development, Bethesda, MD (LLW); the Women and

Infant’s Hospital, Providence, RI (WO); the University of New Mexico, Albu-

querque (L-AP); the University of Miami (CRB); the University of Alabama,

Birmingham (WAC); the University of Cincinnati (EFD); Case Western Reserve

University, Cleveland (AAF); the University of Tennessee, Memphis (SBK);

the University of Texas Southwestern Medical Center, Dallas (ARL); Wayne

State University, Detroit (SS); Stanford University, Stanford, CA (DKS); and

the University of Texas at Houston (JET).

2 Supported by cooperative agreements with the National Institute of ChildHealth and Human Development (U10 HD27856,U10 HD27871,U10 HD27851,

U01 HD36790, U10 HD27904, U10 HD27881, U10 HD21397, U10 HD34216,

U10 HD27853, U10 HD21364, U10 HD21415, U10 HD40689, U10 HD21385,

U10 HD27880, U10 HD21373, and HD 19089), by the General Clinical

Research Centers (MO1 RR 00750, MO1 RR 06022, MO1 RR 00997, MO1

RR 08084, and MO1 RR 00070), and by the Riley Memorial Association.3 Address reprint requests to BB Poindexter, Riley Hospital for Children,

699 West Drive RR 208, Indianapolis, IN 46202–5210. E-mail: bpoindex@

iupui.edu.

Received February 5, 2002.

Accepted for publication July 3, 2002.

Studies in critically ill adults provide compelling evidence that,

in addition to reducing episodes of sepsis, parenteral glutamine

supplementation significantly reduces mortality (4).

Extremely premature neonates are at high risk for developing

late-onset sepsis (5). The National Institute of Child Health andHuman Development Neonatal Research Network is currently

conducting a multicenter, randomized, double-masked controlled

clinical trial to assess the efficacy and safety of parenteral gluta-

mine supplementation with early parenteral nutrition (PN) in

reducing the incidence of mortality or late-onset sepsis in

extremely low-birth-weight (ELBW) infants.

The primary purpose of the current study, which is a subset of

the main trial, was to determine the effect of parenteral glutamine

supplementation on plasma amino acid concentrations as a means

of assessing the safety of parenteral glutamine supplementation

in ELBW infants. We hypothesized that substituting 20% of the

total amino acid intake as glutamine would result in a significant

increase in plasma glutamine concentrations and would not result

in significant aberrations in the remaining amino acid profile orsignificantly increase plasma ammonia concentrations.



738 POINDEXTER ET AL

Although PN is widely used in the neonatal intensive care unit,

there is a paucity of data on plasma amino acid concentrations in

ELBW infants, the population that most frequently receives pro-

longed PN. Consequently, a second aim of the current study was

to collect data on amino acid concentrations in ELBW infants

receiving PN. To address these issues, plasma amino acid and

ammonia concentrations were measured both before and during

provision of PN.

SUBJECTS AND METHODS

Study subjects and design

A priori, we determined that plasma amino acid and ammonia

concentrations would be obtained from the first 10 infants ran-

domly assigned at each of the 14 participating National Institute

of Child Health and Human Development Neonatal Research

Network centers. Inclusion criteria were a birth weight between

401 and 1000 g and enrollment at or before 72 h of age. We

excluded infants with major congenital anomalies or congenital

nonbacterial infection, those thought to have terminal illness (as

indicated by a pH below 6.80 or by the presence of hypoxia with

bradycardia for >2 h), and those for whom a decision had beenmade that full support would not be provided. The Institutional

Review Board at each center approved the study, and written

informed consent was obtained from the parents of each infant.

The infants were strati fied according to center and bi rth

weight (401–750 or 751–1000 g) and were assigned to the con-

trol or glutamine group by a hospital pharmacist using a ran-

domization list provided by the data coordinating center

(Research Triangle Institute).

Infants in the control group received TrophAmine (B Braun,

Irvine, CA) as their intravenous amino acid solution. Infants in

the glutamine group received an isonitrogenous study amino acid

solution with 20% glutamine; this solution consisted of

TrophAmine and nonpyrogenic L-glutamine powder (Ajinomoto,

Raleigh, NC). A Food and Drug Administration–approved drugmanufacturer compounded the study amino acid solution under

controlled, clean-room conditions (Central Admixture Pharmacy

Services Inc, Irvine, CA). Before beginning the study, both Cen-

tral Admixture Pharmacy Services and the laboratory at Indiana

University School of Medicine documented the sterility and sta-

bility of the glutamine-enriched amino acid solution to 17 wk. The

hospital pharmacist labeled all bags of PN with the total amount,

in g · kgϪ1 · dϪ1, of study amino acids (as ordered by the attending

physician). The glutamine-enriched solution was visually indis-

t inguishable from standard PN. A standard dose of cysteine

hydrochloride (40 mg/g amino acid; 120 mg· kgϪ1 · dϪ1 maxi-

mum) was added to the final compounded bag of PN in both

groups (6, 7).

Although the study protocol gave specific guidelines for the useof PN, including early initiation and rapid advancement of amino

acid administration to 3.0–3.5 g · kgϪ1 · dϪ1, the neonatologist car-

ing for the infant determined the final prescription for total PN

and made all decisions related to the introduction and advance-

ment of enteral feedings.

Blood sample collection

Blood samples were obtained from each infant at 2 specific

time points: just before initiation of study PN (baseline sam-

ple) and again after the infant had received study PN for Ϸ10 d

(PN sample). A minimum of 0.5 mL whole blood was collected

in a heparin-containing microtainer and was immediately cen-

trifuged at room temperature for ≥ 5 min. The plasma was sepa-

rated and then frozen at Ϫ70 ЊC for later analysis.

Plasma amino acid analysis

All samples were shipped frozen on dry ice to a central amino

acid laboratory at Indiana University. Amino acid concentrations

were determined by using standard ion-exchange chromatographymethodology with post-column Ninhydrin detection and an auto-

mated amino acid analyzer (model 6300; Beckman Instruments,

Fullerton, CA).

Plasma ammonia analysis

For plasma ammonia analysis, arterial samples were preferen-

tially obtained and were transported on ice to the local hospital

laboratory at each of the participating centers. The laboratory

technique for ammonia analysis was not standardized between the

centers. The study coordinators recorded the values obtained on

the data collection forms.

Statistical analyses

The statistical analyses were performed with SAS, release 8.2(SAS Institute Inc, Cary, NC). To analyze the differences in base-

line characteristics, we used the Wilcoxon rank-sum test for the

continuous variables (eg, birth weight) and the Pearson chi-square

test for the categorical variables (eg, sex).

The 2 groups were compared according to the intention to

treat; subjects were included in the analysis in their original

groups regardless of the amount of PN received before or at the

time of the PN sample. A logarithmic transformation of the data

was applied to minimize the effect of skewness of the amino acid

data before statistical analysis. The Wilcoxon signed-ranks test

was then used for the wi thin-group comparisons of relative

change from baseline sample to PN sample. To assess the primary

hypothesis regarding the effect of treatment on the relative change

from baseline sample to PN sample, a general linear model mul-tiple regression analysis was performed separately for each of the

amino acids. The variables included in the regression were cen-

ter and birth weight stratum, and the outcome was the change

score calculated on the log scale. All data are presented in the

original units.

An independent Data Safety and Monitoring Committee ana-

lyzed the data after the samples were obtained from the first 10

infants at each center and determined that no further monitoring

of amino acid or ammonia concentrations was necessary to mon-

itor safety.

RESULTS

Plasma amino acid samples were obtained from 141 infants(69 in the control group and 72 in the glutamine group). The 2

groups did not differ significantly with regard to any of the

baseline characteristics (Table 1). Parenteral amino acid intake

did not differ significantly between the groups at either of the

2 times when plasma samples were obtained (Table 2). Par-

enteral amino acid intake ranged from 0 to 3.9 g · kgϪ1 · dϪ1

(median: 2.52 g · kgϪ1 · dϪ1) in the control group and from 0 to

4.1 g· kgϪ1 · dϪ1 (median: 2.68 g · kgϪ1 · dϪ1) in the glutamine

group at the time of the PN sample. Total energy intake from PN

was not significantly different between the 2 groups (268 ± 105



GLUTAMINE FOR EXTREMELY LOW-BIRTH-WEIGHT INFANTS 739

TABLE 3

Plasma amino acid concentrations at baseline and during parenteral

nutrition (PN)1

Amino acid Control group Glutamine group

and sample (n = 69) (n = 72) P2

µmol/L µmol/L

Total essential

Baseline 713 (544–830) 582 (417–742)

PN 858 (725–991)3 687 (535–842)3 0.36Phenylalanine

Baseline 69 (53–88) 61 (52–75)

PN 61 (54–71)3 55 (47–63)3 0.89

Leucine

Baseline 77 (54–109) 59 (47–92)

PN 118 (89–142)3 100 (80–126)3 0.45

Isoleucine

Baseline 35 (21–57) 29 (18–45)

PN 66 (50–78)3 55 (43–70)3 0.87

Valine

Baseline 151 (111–176) 123 (88–158)

PN 162 (133–193)3 138 (109–166)3 0.84

Threonine

Baseline 140 (99–196) 96 (69–150)

PN 216 (160–282)3 113 (83–179)3 0.055Lysine

Baseline 140 (107–188) 118 (85–161)

PN 147 (124–185) 138 (99–174) 0.89

Tryptophan

Baseline 34 (28–41) 31 (26–40)

PN 29 (26–38) 30 (25–35) 0.68

Methionine

Baseline 28 (21–35) 24 (16–33)

PN 40 (34–53)3 37 (28–47)3 0.86

Total nonessential

Baseline 1457 (1158–1745) 1272 (815–1529)

PN 1591 (1378–1910) 1513 (1181–1945)3 0.48

Histidine

Baseline 72 (56–88) 65 (53–87)

PN 83 (69–103)3 82 (65–97)3 0.83Tyrosine

Baseline 82 (52–124) 75 (43–129)

PN 50 (32–69)3 31 (18–50)3 0.014

Cysteine

Baseline 27 (19–36) 25 (18–31)

PN 33 (25–38)3 31 (24–44)3 0.80

Proline

Baseline 141 (111–187) 112 (76–165)

PN 180 (148–217)3 160 (117–193)3 0.71

Serine

Baseline 136 (99–184) 110 (72–148)

PN 196 (150–244)3 161 (123–196)3 0.48

Arginine

Baseline 45 (31–62) 38 (23–55)

PN 73 (56–107)3 62 (45–112)3 0.95Alanine

Baseline 161 (121–224) 125 (89–214)

PN 179 (156–241) 190 (138–235)3 0.26

Glycine

Baseline 268 (195–338) 205 (172–285)

PN 288 (242–382)3 274 (211–378)3 0.24

Aspartate

Baseline 11 (7–21) 9 (7–13)

PN 22 (16–37)3 16 (13–25)3 0.62

(Continued)

and 251 ± 113 kJ· kgϪ1 · dϪ1 or 64 ± 25 and 60 ± 27 kcal· kgϪ1 · dϪ1

in the glutamine and control groups, respectively; P = 0.39) at

the time of the PN sample. Although energy intake from enteral

feedings was slightly higher in the control group than in the glu-

tamine group at the time of the PN sample (67 ± 105 and 109 ±

126 kJ · kgϪ1 · dϪ1 or 16 ± 25 and 26 ± 31 kcal · kgϪ1 · dϪ1 in the

glutamine and control groups, respectively; P = 0.04), enteralfeedings provided ≤ 30% of total energy intake in both groups.

Plasma amino acid concentrations before initiation of study PN (base-

line sample) and during PN (PN sample; average age: 11.6 ± 2.8 d)

are shown in Table 3.

Essential amino acids

In both groups, the plasma concentration of total essential

amino acids increased significantly between the baseline sample

and PN sample. The PN-sample median was 20% higher than the

baseline-sample median in the control group and was 18% higher

in the glutamine group. There was no effect of treatment group on

the relative change in concentration of total essential amino acids.

There were significant increases in the concentrations of the

essential amino acids leucine, isoleucine, valine, threonine, and

methionine in both groups between the baseline sample and PN

sample. Phenylalanine was the only essential amino acid that

decreased significantly between the baseline and PN samples, with

the median value decreasing by 11% in both groups. There was

no effect of treatment group on the relative changes in concentra-

tions of any of the 8 individual essential amino acids.

TABLE 2

Age and nutritional intake of the study infants1

Control group Glutamine group

(n = 69) (n = 72)

Age (h)

At randomization 35 ± 17 39 ± 18

At initiation of any PN 29 ± 15 34 ± 18

At initiation of study PN 44 ± 18 46 ± 19

Parenteral AA intake (g· kgϪ1 · dϪ1)

At baseline sample 0.53 ± 0.87 0.44 ± 0.66

At PN sample 2.19 ± 1.09 2.40 ± 0.91

1 x –± SD. There were no significant differences between the groups on

the basis of the Wilcoxon rank-sum test. PN, parenteral nutrition; AA,

amino acid.

TABLE 1

Characteristics of the study infants at baseline1

Control group Glutamine group

(n = 69) (n = 72)

Birth weight (g)2 775 ± 130 783 ± 129

Gestational age (wk)2 26.3 ± 1.8 26.2 ± 2.0

SGA [n (%)] 10 (14) 13 (18)

Male [n (%)] 23 (33) 31 (43)

Antenatal glucocorticoid 60 (87) 58 (81)therapy [n (%)]

1 There were no significant differences between the groups on the basis

of the Wilcoxon rank-sum and Pearson chi-square tests. SGA, small for ges-

tational age.2 x –

± SD.




TABLE 3 (Continued)

Amino acid Control group Glutamine group

and sample (n = 69) (n = 72) P2

µmol/L µmol/L

Asparagine

Baseline 30 (20–53) 31 (17–46)

PN 16 (11–28)3 16 (12–25)3 0.99

Glutamate

Baseline 37 (25–87) 30 (20–51)PN 56 (41–92)3 53 (37–76)3 0.13

Glutamine

Baseline 316 (249–430) 291 (201–380)

PN 316 (230–383) 381 (290–537)3 0.0003

Citrulline

Baseline 12 (10–21) 12 (9–18)

PN 17 (13–27)3 18 (12–26)3 0.60

1 Median (interquartile range).2 Test of treatment effect from a general linear model including terms

for center and birth-weight stratum, as applied to pre-post differences of the

log-transformed data (log relative changes).3 Significantly different from baseline within treatment group, P < 0.05

(Wilcoxon signed-ranks test on log-transformed values).

FIGURE 1. Mean (±SD) plasma ammonia concentrations at baseline

(open bars) and during parenteral nutrition (PN; solid bars) in the control

group (n = 51) and glutamine group (n = 59). The between-group compar-

ison regarding the effect of treatment on the relative change between the

baseline sample and PN sample was significant at P = 0.023. The within-

group comparison regarding the change from the baseline sample to the PN

sample was significant in the control group at P < 0.05.Nonessential amino acids

The plasma concentration of total nonessential amino acids

increased in response to PN by 9% in the control group and by 19%

in theglutaminegroup.This increase was significant in theglutamine

group only, in which theincrease wasaccounted forby thesignificant

increase in glutamineconcentration. There was no effectof treatment

on therelativechangein theconcentration of total nonessential amino

acids. There were significant increases in the concentrations of histi-

dine,cysteine, proline, serine,arginine, glycine, aspartate, glutamate,

and citrulline in both groups. There were significant increases in the

concentrations of alanine and glutamine in theglutamine group only.

Concentrations of tyrosine and asparagine decreased significantly in

both groups. Therewas an effect of treatment on the relative changes

in the concentrations of glutamine and tyrosine between the baselinesample and PN sample.

Plasma glutamine and glutamate concentrations

In the infants randomly assigned to receive glutamine, plasma

glutamine concentrations increased significantly, by 31% on aver-

age, between the baseline sample and PN sample. Plasma gluta-

mine concentrations were unchanged in the control group between

the baseline sample and PN sample.

In bothgroups, most of the infants had an increase inplasma gluta-

mate concentrationin response to PN.Therewasnodifferencebetween

the groups in the relative change in plasma glutamate concentrations.

Plasma tyrosine concentrations

Plasma tyrosine concentrations decreased significantly in bothgroups (by 39% in the control group and by 59% in the glutamine

group) between the baseline and PN samples. There was also a

statistically significant effect of treatment; the glutamine group

had a significantly greater decrease in plasma tyrosine than did

the control group.

Plasma ammonia concentrations

We measured plasma ammonia concentrations in 110 infants

at each of the 2 time points; these results are shown in Figure 1.

In the control group, the mean plasma ammonia concentration

decreased by 6% (from 68 to 64 mol/L) between the baseline

sample and PN sample. In the glutamine group, there was no

significant change in the mean plasma ammonia concentration

between the baseline sample and PN sample. Comparison of

the 2 groups regarding the relat ive change in ammonia con-

centration between the baseline and PN samples (with adjust-

ments for center and birth weight group) showed a significant

but clinically inconsequential difference between the groups.

There was no difference between groups regarding the number

of infants with an ammonia concentration > 100 mol/L at the

t ime of the PN sample (glutamine group: n = 12/59; control

group: n = 6/51; P = 0.23).

Comparative data

Amino acid concentrations determined in 4 previously pub-

lished studies are shown in Table 4. In 3 of the studies, amino acid

concentrations were measured in plasma; the subjects were nor-

mally growing, breast-fed term infants (8), premature low-birth-

weight infants receiving unsupplemented human milk (9), and

low-birth-weight infants receiving TrophAmine (7). In the fourth

study, amino acid concentrations were measured in cord blood

from neonates at 29 wk gestation (10). The mean amino acid con-

centrations from the current study are shown in Table 4 and rep-

resent the values obtained from both treatment groups for most of

the amino acids. Data from the individual treatment groups are

shown for glutamine and tyrosine, the only 2 amino acids forwhich there was a significant treatment effect, and for threonine,

because the treatment effect was nearly significant (P = 0.055).

DISCUSSION

In the present study, we evaluated the effect of parenteral glu-

tamine supplementation on plasma amino acid and ammonia con-

centrations in ELBW infants. The amount of glutamine supple-

mentation in the current trial, 20% of the total amino acid intake,

is similar to that administered in a study by Lacey et al (11). The




TABLE 4

Amino acid concentrations of infants in the current study and of 4 comparative groups1

Preterm, Low-birth-weight

Current study, Term, breast-fed human-milk-fed Neonates at 29 wk infants receiving

ELBW infants infants (8) infants (9) gestational age (10) TrophAmine3 (7)

(n = 1412) (n = 16) (n = 14) (n = 8) (n = 28)

µmol/L

Alanine 212.2 ± 117.2 385.9 ± 122.7 265 ± 53 635 ± 238 150.5 ± 72.1

Arginine 81.4 ± 51.6 95.3 ± 24.9 69 ± 20 82 ± 55 88.6± 40.6Asparagine 23.2 ± 22.1 48.2 ± 15.2 — 45 ± 14 24.1 ± 10.0

Aspartate 25.1 ± 20.1 28.0 ± 11.0 33 ± 13 93 ± 21 16.4 ± 10.6

Citrulline 19.6 ± 10.7 14.4 ± 4.3 14 ± 3 4 ± 4 11.4 ± 5.6

Cysteine 33.0 ± 15.5 51.9 ± 8.0 34 ± 7 — 45.1 ± 16.1

Glutamate 69.0 ± 49.4 133.7 ± 51.4 44 ± 13 479 ± 124 42.2 ± 27.3

Glutamine

Control 332 ± 148 496.4 ± 166.2 499 ± 167 229 ± 125 293.3 ± 171.7

Glutamine 425 ± 182 — — — —

Glycine 324.3 ± 185.9 226.4 ± 70.3 244 ± 55 423 ± 78 283.2 ± 98.5

Histidine 88.1 ± 30.5 76.2 ± 20.0 80 ± 10 93 ± 20 80 ± 22.2

Isoleucine 63.5 ± 30.4 58.2 ± 14.9 50 ± 7 66 ± 11 57.4 ± 23.1

Leucine 114.7 ± 51.4 111.3 ± 27.3 87 ± 14 153 ± 36 101.5 ± 36.4

Lysine 158.2 ± 72.1 155.9 ± 35.5 85 ± 24 433 ± 56 157.2 ± 71.6

Methionine 40.3 ± 15.1 35.8 ± 6.7 17 ± 5 32 ± 11 38.6 ± 14.2

Phenylalanine 61.0 ± 18.9 45.8 ± 11.3 52 ± 10 139 ± 35 67.9 ± 13.9Proline 183.8 ± 105.5 200.9 ± 55.6 163 ± 32 227 ± 51 137.8 ± 57.4

Serine 191.4 ± 93.7 158.7 ± 78.4 252 ± 82 222 ± 26 171.2 ± 79.9

Threonine

Control 247.8 ± 169.5 133.5 ± 29.9 152 ± 30 263 ± 61 182 ± 69.6

Glutamine 143.2 ± 84.0 — — — —

Tryptophan 31.4 ± 9.8 59.5 ± 19.6 42 ± 11 — 31.9 ± 12.5

Tyrosine

Control 57 ± 35 78.8 ± 19.0 69 ± 22 79 ± 11 33.2 ± 20.2

Glutamine 38 ± 34 — — — —

Valine 156.7 ± 51.6 155.2 ± 31.3 104 ± 15 299 ± 125 148.7 ± 50.2

1 x –± SD. ELBW, extremely low-birth-weight.

2 Control group, n = 69; glutamine group, n = 72.3 B Braun, Irvine, CA.

latter is the only other published study in which parenteral gluta-

mine was given to premature infants and their glutamine concen-

trations increased in response to the glutamine-supplemented PN.

In the current study, at the time of the PN sample, mean plasma

glutamine concentrations were Ϸ30% higher in the infants who

received supplemental glutamine and were similar to those meas-

ured in the trial by Lacey et al (439 mol/L) (11). Although an

increase in plasma glutamine concentration suggests increased

availability of this amino acid, the clinical efficacy of this increase

remains to be determined by the primary and secondary clinical

outcomes of the main randomized clinical trial.

Currently available intravenous amino acid solutions such as

TrophAmine and Aminosyn-PF do provide glutamate. The meta-

bolic interrelationship between glutamine and glutamate necessi-tates careful monitoring of glutamate as a measure of potential

toxicity of glutamine supplementation (12). In our study, there

was no significant difference between the 2 groups in the increase

in glutamate, providing assurance that the amount of glutamine

administered did not cause a significant increase in glutamate,

which is potentially neurotoxic. Nonetheless, neurodevelopmen-

tal follow-up assessment will also play an important role in fur-

ther evaluating the safety of glutamine supplementation in this

population.

Although plasma ammonia concentrations decreased by 6% in

the control group, there was no significant change in plasma

ammonia in response to parenteral glutamine supplementation in

the glutamine group. In addition, there was no significant differ-

ence between the 2 groups in the number of infants with an ammo-

nia concentration >100 mol/L during the study PN. We found

no evidence of a clinically significant change in ammonia con-

centration related to glutamine supplementation or to this level of

PN support in the ELBW infant during the first 2 wk of age. How-

ever, note that ammonia was not measured in all of the infants. In

addition, those samples analyzed for ammonia were not analyzed

in a central laboratory, nor was the technique for analysis of

ammonia standardized.

Currently available parenteral amino acid solutions may not beoptimal for ELBW premature infants. One of the most commonly

used mixtures for premature infants in the United States,

TrophAmine, was formulated to result in plasma amino acid con-

centrations similar to those of full-term, growing, 1-mo-old breast-

fed infants (7, 8). Whether this should be the standard in extremely

premature infants is unknown.

Several amino acids are considered to be conditionally essen-

tial or indispensable in premature infants. That is, the infant’s abil-

ity to synthesize these amino acids de novo is less than adequate

to meet functional demands (13). Glutamine is one such amino




acid that is potentially indispensable in premature infants, yet is

not supplied by standard intravenous amino acid solutions.

Phenylalanine, leucine,isoleucine, valine,threonine, lysine, trypto-

phan, andmethionineareconsidered essentialaminoacids inhumans.

As expected, theconcentration of total essentialamino acids increased

inbothgroups in response toPN. Despite the fact that20% of the total

essential amino acidsupplywasreplacedbyglutamine in thetreatment

group, there was no significant difference in the magnitude of the

increase in total essential amino acids between the2 study groups.The decrease in phenylalanine concentration in both groups

was unexpected. Plasma concentrations of phenylalanine in both

study groups were comparable to those measured by Heird et al

(7) in their subgroup of infants who weighed <1250 g at study

entry and receivedϷ2 g TrophAmine/kg daily (68.9 ± 16.1 mol/L).

As previously reported by Heird et al (7), this concentration of

phenylalanine is higher than that measured in healthy, term

infants receiving breast milk. However, previous studies in pre-

mature infants generally have not measured the change in amino

acid concentrations in response to parenteral amino acid solu-

tions. It is possible that plasma phenylalanine concentrations

decrease with increasing postnatal age irrespective of the pheny-

lalanine supply. Alternatively, it is also possible that the com-

bined supply of phenylalanine and tyrosine in currently avail-able amino acid solutions is inadequate, resulting in declines

such as that measured in this s tudy. Both animal and human

studies of premature infants have suggested that the combined

phenylalanine and tyrosine supply may be a limiting factor in

protein accretion during the provision of PN (14–17).

Phenylalanine and tyrosine are related in that tyrosine is syn-

thesized endogenously from phenylalanine via phenylalanine

hydroxylase. Several investigators have shown that premature

infants have the capacity for phenylalanine hydroxylation (14, 18,

19). Consequently, tyrosine is not thought to be an essential amino

acid in the classic sense of the definition. Nonetheless, although

tyrosine is widely considered to be a conditionally essential amino

acid in premature infants, it is not present in appreciable amounts

in currently available amino acid solutions because of its low sol-ubility. In some currently available amino acid solutions, tyrosine

is supplied as the peptide N -acetyl tyrosine in amounts much

lower than the tyrosine content/g protein supplied by enteral for-

mulas and human milk. However, the bioavailability of N -acetyl

tyrosine has been questioned (6, 17, 20).

To address the issue of l imited tyrosine supply, one poten-

t ial solution would be to provide an amino acid solution con-

taining sufficient phenylalanine not only for protein anabolism,

but also to meet the need for tyrosine (via phenylalanine

hydroxylation). However, this strategy has not been effective

in animal models (21). In the current study, median tyrosine

concentrations while the infants were receiving PN were 39%

lower in the control group and 59% lower in the glutamine

group compared with the baseline median (P = 0.014 for treat-ment effect). In both groups, the decline in tyrosine may reflect

the limited supply and bioavailabil ity of the tyrosine source

provided by the amino acid solution. We speculate that, to the

extent that glutamine supplementation increases overall protein

anabolism, it may exacerbate specific amino acid deficiencies

such as the combined supply of phenylalanine and tyrosine; this

may explain the greater decline in tyrosine concentration in the

glutamine group.

Relatively little research has been done on plasma amino acid

concentrations in ELBW infants. Studies have reported plasma

amino acid concentrations in low-birth-weight infants receiving

unsupplemented human mi lk (9) or moderat e amounts of

TrophAmine (7). To our knowledge, the current study is the

largest published collection of data on plasma amino acid con-

centrations in ELBW infants. Although caution must be used in

interpret ing these data as normative for ELBW infants , i t i s

somewhat reassuring that the amount of PN in the current study

resul ted in plasma amino acid concent ra tions that were not

vastly different from those of the comparison groups (Table 4).Although these values reflect current clinical practice, the par-

enteral amino acid solut ion provided , and the amount of PN

administered, may not have been optimal (22, 23).

Although there is no apparent biochemical risk posed by par-

enteral glutamine supplementation in ELBW infants, the poten-

tial clinical effects of glutamine supplementation remain to be elu-

cidated. In addition, careful neurodevelopmental follow-up of

these infants is currently in progress; these results will be critical

and are necessary before a recommendation regarding supple-

mentation of PN solution with glutamine can be made.

We are indebted to William C Heird for his help in reviewing the amino ac id

and ammonia data for the Data Safety and Monitoring Committee, to Edward

A Liechty and Larry Auble for their performance of the amino acid analysis, toBill Buss for his help with the pharmacy procedures, to Lisa Wrage for her

assistance with the statistical analyses, and to the medical and nursing staff,

parents, and infants in the centers for participating in the study.

For this multicenter trial, each author contributed to protocol develop-

ment, implementation, and drafting of the manuscript as specified by the

publication policy of the National Institute of Child Health and Human

Development Neonatal Research Network. None of the authors have any

financial or personal interest in any company or organization sponsoring

the research.

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