Table 1.

Glutamine-supplemented parenteral nutrition in premature neonates.

Reference	Subjects	Design	Gln	Control	Outcomes	Results
Lacey et al. 1996 [99]	44 VLBW premature neonates age <4 d receiving PN for <3 d; birth wt: 530–1250 g; GA <32 wk	Randomized double blind	Isonitrogenous isocaloric PN supplemented with Gln (15–25% of AA mix) for 14 ± 6 d (n = 22)	Standard PN for 16 ± 10 d (n = 22)	Time to full EN, d on PN, d on ventilator, LOS, other clinical outcomes and safety monitored throughout hospitalisation	No differences for entire cohort; birth wt <800 g subgroup had fewer d on PN, fewer d to full feeds, fewer d on ventilator, higher lymphocyte count, no difference in NICU LOS, safe
Des Robert et al. 2002 [105]	13 LBW age <3 d receiving exclusive PN; birth wt: 820–1650 g; GA: 28–30 wk	Randomized double blind	Gln-supplemented 0.5 g/kg/d exclusive PN started on d3 of life for 24 h, AA intake at 1.5 g/kg/d by d3 (n = 6)	Isonitrogenous Gln-free AA (Primène) supplemented exclusive PN started on d3 of life for 24 h, AA intake at 1.5 g/kg/d by d3 (n = 7)	Whole body protein metabolism/Leu kinetics (IV infusions of NaH13CO3 and L-[1–13C]Leu) on d4 of life during continuous PN (fed state)	Decreased rates of Leu release from protein breakdown and Leu oxidation, decreased rates of nonoxidative Leu disposal (an index of whole-body protein synthesis), safe
Thompson et al. 2003 [100]	35 ELBW ill premature neonates age <1 d; birth wt: <1000 g	Randomized double blind	Standard isonitrogenous isocaloric PN supplemented with 16% of AA as Gln started on d1 of life, AA intake started at 1.0 g/kg/d to ≤3.0 g/kg/d (n = 17)	Standard PN started on d1 of life, AA intake started at 1.0 g/kg/d to ≤3.0 g/kg/d (n = 18)	(1) Feeding tolerance; (2) growth, age at discharge, infection, number of episodes of culture-positive sepsis or NEC, metabolic tolerance and safety monitored until expected date of delivery, discharge or death (whichever came first)	(1) Fewer d to reach full EN; (2) no differences in gastric residuals, d to regain birth wt, wt gain, infection, total white cell count, episodes of low white cell count, number of episodes of culture-positive sepsis or NEC, age at discharge or death, well tolerated and safe
Poindexter et al. 2004* [102]	1433 ELBW (≤72 h after birth); birth wt: 401–1000 g; GA: 26 ± 2 wk	Multicentre-randomized double blind	Isonitrogenous study AA solution with 20% of AA as Gln in PN until 120 d of age, death, or discharge (whichever came first), AA intake ≤3–3.5 g/kg/d (n = 721)	Standard AA solution without Gln (TrophAmine) in PN until 120 d of age, death or discharge (whichever came first), AA intake ≤3–3.5 g/kg/d (n = 712)	(1) Death or late onset sepsis; (2) number of episodes of late onset sepsis, NEC, d on ventilator, LOS in hospital, tolerance of enteral feeds, feeding intolerance, growth, d of PN, safety	(1) No differences in death or late onset sepsis (culture after 72 h of age), (2) no differences in number of episodes of late onset sepsis, NEC, d on ventilator, LOS in hospital, d to first/full enteral feeds, incidence/number of episodes of feeding intolerance, d to reach 1500 g or wt at 36 wk postmenstrual age, increased d of PN, well tolerated and safe
Poindexter et al. 2003* [103]	141 ELBW (≤72 h after birth); birth wt: 401–1000 g; GA: 26 ± 2 wk	Multicentre-randomized double blind	Isonitrogenous study AA solution with 20% of AA as Gln in PN for ~10 d, AA intake ≤3–3.5 g/kg/d (n = 72)	Standard AA solution without Gln (TrophAmine) in PN for ~10 d, AA intake ≤3–3.5 g/kg/d (n = 69)	Safety as assessed by plasma concentrations of AA and ammonia after infants had received study PN (2.3 ± 1.0 g/kg/d AA) for ~10 d	Increased plasma Gln (Gln group only) with no apparent biochemical risk, increased plasma essential AA (both groups) whereas Phe and Tyr decreased with greater decrease in Tyr (Gln group), no change in plasma ammonia
Kalhan et al. 2005 [80]	20 LBW clinically stable (24–48 h after birth); birth wt: 694–1590 g; GA ≤32 wk	Randomized double blind	Isonitrogenous AA mixture supplemented with Gln 0.6 g/kg/d in PN for 3–5 d, AA intake ~3.0 g/kg/d (n = 10)	AA mixture without Gln in PN for 3–5 d, AA intake ~3.0 g/kg/d (n = 10)	Whole body protein and Gln kinetics (IV infusions of [2H5]Phe, L-[1–13C,15N]Leu, [15N2]urea, L-[5–15N]Gln) on d6 or d7 of life while receiving AA mixture continuously after 3–5 d	Lower endogenous rates of appearance of Phe and Leu N (indices of proteolysis), lower Gln de novo synthesis, no differences in rate of appearance of Leu C, urea turnover or plasma AA concentrations
Li et al. 2007 [101]	53 LBW premature infants (48–72 h after birth); birth wt: <2000 g; GA <37 wk	Prospective intervention	Isonitrogenous AA solution with 20% of AA content as Alanyl-Gln dipeptide in PN until >2 wk, AA intake started at 0.5–1.0 g/kg/d to ≤3.0 g/kg/d (n = 28)	Routine PN until >2 wk, AA intake started at 0.5–1.0 g/kg/d to ≤3.0 g/kg/d (n = 25)	Growth, biochemical indices, feeding tolerance, and infective episodes throughout hospitalization	Fewer d to regain birth wt, no differences in wt or head circumferences, fewer d on PN, fewer episodes of hospital-acquired infection, shorter LOS in hospital, safe
Wang et al. 2010 [104]	30 VLBW; median age (interquartile range) (d): 2.5(1.0-2.0) (Gln) and 2.2(1.0-2.0) (control); birth wt: <1500 g; PN for ≥7 d; mean GA (wk) ± SD: 31.3 ± 1.5 (Gln) and 30.5 ± 1.8 (control)	Multicentre-randomized double blind	6% pediatric AA compound injection, average AA dosage 1.7 g/kg/d with Gln 0.3 g/kg/d, PN decreased when EN increased and PN withheld when >70% of recommended intake from EN (n = 13)	6% pediatric AA compound injection, average AA dosage 2.0 g/kg/d, PN decreased when EN increased and PN withheld when >70% of recommended intake from EN (n = 15)	(1) Mortality and changes in hepatic function (bile acid, ALT, AST, total bilirubin, direct bilirubin, prealbumin, albumin), (2) time to full EN (d), episodes of gastric residual, total duration of PN (d), wt gain (g/d), head circumference (cm), LOS, d on ventilator	(1) Decreased AST and direct bilirubin, no differences in bile acid, ALT, total bilirubin, prealbumin, or albumin, (2) no differences in time to full EN, episodes of gastric residual, total duration of PN, wt gain, head circumference, LOS or d on ventilator

VLBW: very low birth weight; PN: parenteral nutrition; wt: weight; GA: gestational age; AA: amino acid; EN: enteral nutrition; LOS: length of stay; NICU: neonatal intensive care unit; LBW: low birth weight; IV: intravenous; ELBW: extremely low birth weight; NEC: necrotizing enterocolitis; AST: aspartate aminotransferase; ALT: alanine aminotransferase.

*Originating from the same cohort.