Glutamine Randomized Studies in Early Life: The Unsolved Riddle of Experimental and Clinical Studies

Table 2

Methods and short-term results of randomized, controlled studies investigating potential beneficial effects of glutamine supplementation in mortality, morbidity, hospital-acquired infections, length of stay, or inflammation in premature infants.

(a)

Premature or ELBW infants on parenteral nutrition	𝑛	Combined with other immunonutrients or inducers	Dose	Route	Duration	Mortality	Hospital-; acquired infections	Length of stay	Organ function/Morbidity	Inflammation
Extremely low birth weight infants [76]	1433	No	Isonitrogenous study amino acid solution with 20% glutamine	Early parenteral nutrition	120 days	NS	NS	NS	Increased plasma Glutamine concentrations but also more days of PN support. No differences of late onset sepsis, NEC, day to first and full enteral feeds, feeding intolerance, or growth	—
Premature infants ≤32 weeks gestation with a birth weight from 694 to 1590 g [77]	20	No	0.6 g/kg/day	Early parenteral nutrition with amino acid intake 3.0 g/kg/day for at least 3 days	Tracer isotope studies at 6 to 7 days old	—	—	—	Supplemental glutamine was associated with a lower rate of appearance of glutamine, phenylalanine, and leucine C. No difference in leucine N and urea turnover	No significant difference in plasma cortisol and C-reactive protein levels
Ill preterm neonates of <1000 g birth-weight; [78]	35	No	16% of the total amino acids (amino acids 1–3.0 g/kg/day)	Early parenteral nutrition	For 7 days or more	—	NS	NS	No significant differences between the groups in blood urea nitrogen, plasma ammonia, plasma glutamine, or glutamate	No significant differences in white cell count, differential white cell count, lactate, pyruvate
Infants after major digestive-tract surgery [79]	41	No	0.4 g/kg/day	Early parenteral nutrition	1–4 weeks	NS	NS	NS	—	—
VLBW age < 3 d, birth wt: 820–1650 g; GA: 28–30 wk [80]	13	No	0.5 g/kg/day	Exclusive parenteral nutrition	Day 4 of life for 24 hours	—	—	—	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	—
Premature infants [81]	53	No	Isonitrogenous study amino acid solution with 20% glutamine	Early parenteral nutrition	14 days	NS	Lower	Shorter	Fewer days on PN, regained birth weight sooner	—
VLBW premature neonates age < 4 d receiving PN for <3 d; birth wt: 530–1250 g; GA < 32 wk [82]	44	No	15–25% of amino acid mix	Early parenteral nutrition	14 ± 6 days	—	—	NS	Birth wt < 800 g subgroup fewer d on PN, fewer d to full feeds, fewer d on ventilator, safe	Higher lymphocyte count
Infants with birth weights of 401–1000 g; [83]	141	No	Isonitrogenous amino acid solution with 20% of the total amino acids as glutamine	Parenteral glutamine supplementation on plasma amino acid concentrations	10 days	—	—	—	No significant difference between the 2 groups in the relative change in plasma glutamate concentration but significant decreases in plasma phenylalanine and tyrosine between the baseline and PN samples
VLBW; Infants [84]	30	No	0.3 g/kg/day	Early parenteral nutrition	For ≥7 days	NS	NS	NS	No differences in time to full EN, episodes of gastric residual, total duration of PN, weight gain; hepatic function improved	—
Surgical infants less than 3 months old who required parenteral nutrition [85]	174	No	0.6 g/kg/day or isonitrogenous isocaloric parenteral nutrition (control group)	Early parenteral nutrition	Until full enteral feeding	NS	NS	—	No difference in time to full enteral feeding or time to first enteral feeding	—

(b)

Premature or ELBW infants on enteral nutrition	𝑛	Combined with other immunonutrients or inducers	Dose	Route	Duration	Mortality	Hospital-; acquired infections	Length of stay	Organ function/Morbidity	Inflammation
VLBW age < 3 d receiving PN; birth wt: 500–1250 g; GA: 24–32 wk [86]	68	No	0.08 g/kg/d on d3 and reached 0.31 g/kg/d by d13	Glutamine-enriched enteral nutrition (PN 𝑛=35)	Day 3–30 of life	NS	Reduced hospital-acquired sepsis (positive blood culture)	NS	No differences in NEC, wt, length, head circumference, mechanical ventilation, safe	Blunted the rise in HLA-DR+ and CD16/CD56 subsets
Critically ill infants 1–24 mo tolerating EN [87]	9	No	0.3 g/kg/day	Glutamine-enriched enteral nutrition	5 days	NS	NS	NS	Well tolerated and safe	—
VLBW age < 7 d receiving PN; birth wt: 500–1250 g [87]	649	No	0.3 g/kg/day	Within the first 7 d of age, randomly assigned to enteral glutamine supplement (3% glutamine in sterile water) or placebo (sterile water) given at the same time but separate from feedings	7 days–36 weeks post menstrual age	NS	NS	NS	Less gastrointestinal dysfunction, severe neurological sequelae among survivors (grades 3 and 4 intraventricular hemorrhage and paraventricular leukomalacia) in glutamine group. No difference in NEC, retinopathy of prematurity, oxygen use at 36 weeks, or growth,	—
VLBW infants < 48 h; after birth receiving PN; birth wt: <1500 g; GA < 32 wk [88]	102	No	Increasing doses from day 3–30 of life to a maximum dose of 0.3 g/kg/day	Glutamine-enriched isonitrogenous enteral nutrition added to breast milk or preterm formula	Day 3–30 of life	NS	Lower incidence of ≥1 serious infections	NS	No difference in feeding tolerance, NEC, or growth, patent ductus arteriosus, mechanical ventilation, supplemental oxygen, retinopathy	—
VLBW < 48 h after birth receiving PN; birth wt: <1500 g; GA < 32 wk [89]	86	No	Increasing doses to ≤0.3 g/kg/day	Enteral preterm formula or breast milk supplemented with Glutamine or isonitrogenous Ala	Day 3–30 of life	NS	NS	—	No difference in prevalence of intestinal microflora (bifidobacteria, lactobacilli, Escheria coli, streptococci, clostridia) at <48 h–d30 of life, by fluorescent in situ hybridization	—
VLBW < 48 h after birth receiving PN; birth wt: <1500 g; GA < 32 wk [90]	90	No	Increasing doses to ≤0.3 g/kg/day	Enteral preterm formula or breast milk supplemented with glutamine or isonitrogenous Ala	Day 3–30 of life	NS	NS	—	No difference in decreased lactulose/mannitol ratio or urinary lactulose or increased urinary mannitol concentrations	—
VLBW infants; <48 h after birth receiving PN; birth wt: < 1500 g; GA < 32 wk; [91]	63	No	Increasing doses to ≤0.3 g/kg/day	Enteral preterm formula or breast milk supplemented with glutamine or isonitrogenous Ala	Day 3–30 of life	NS	NS	—	—	No differences in Th1 or Th2 cytokine responses at 48 h–d 14 of life following in vitro whole blood cell stimulation

ELBW: extremely low birth weight; VLBW: very low birth weight; Wt: weight; GA: gestational age; AA: amino acid; PN: parenteral nutrition; EN: enteral nutrition; LOS: length of stay; NEC: necrotizing enterocolitis; NB: nitrogen balance; IL: interleukin; NS: nonstatistical difference.