A randomized, controlled trial of parenteral glutamine in ill, very low birth-weight neonates. The effects of glutamine-supplemented parenteral nutrition in premature infants. Parenteral glutamine supplementation does not reduce the risk of mortality or late-onset sepsis in extremely low birth weight infants. Long-term enteral glutamine supplementation in very low birth weight infants: effects on growth parameters. Enteral glutamine supplementation for very low birth weight infants decreases morbidity. Glutamine supplementation of parenteral nutrition does not improve intestinal permeability, nitrogen balance, or outcome in newborns and infants undergoing digestive-tract surgery: results from a double-blind, randomized, controlled trial. Enteral glutamine supplementation and morbidity in low birth weight infants. A randomised controlled trial of glutamine-enriched neonatal parenteral nutrition in Malaysia. Glutamine-enriched enteral nutrition in very-low-birth-weight infants and effects on feeding tolerance and infectious morbidity: a randomized controlled trial. The impact of oral glutamine supplementation on the intestinal permeability and incidence of necrotizing enterocolitis/septicemia in premature neonates. Protective effect of parenteral glutamine supplementation on hepatic function in very low birth weight infants.
The role of "novel substrates" in neonatal nutrition has generated much interest in recent years. Glutamine has been recognized as a "conditionally essential" amino acid in critically ill adults, particularly for gut and immune function; however, its potential role in the neonate remains unclear. The authors examined the safety and benefits of parenteral glutamine in ill, preterm neonates.
                Randomized controlled trial.
                Thirty-five ill preterm neonates of <1000 g birth-weight were randomized to receive either glutamine-supplemented parenteral nutrition (PN) (n = 17) or standard PN (n = 18).
                There were no significant differences in birth-weight, gestational age, male-to-female ratio, or Clinical Risk Index for Babies (CRIB) score between the two groups. During PN there were no significant differences between the groups in white cell count, differential white cell count, blood urea nitrogen, plasma ammonia, lactate, pyruvate, plasma glutamine, or glutamate. The median time to achieving full enteral nutrition (FEN) was shorter in the study group (13 days vs. 21 days, P < 0.05). The number of episodes of culture-positive sepsis or age at discharge did not differ between groups.
                Parenteral glutamine appears to be well tolerated and safe in the ill, preterm neonate. It may reduce the time to achieving FEN. Glutamine (GLN) is the primary fuel for rapidly dividing cells, yet it is not a constituent of parenteral nutritional formulas administered to newborns. The aims of this prospective, randomized, double-blind trial were (1) to confirm the safety of glutamine supplementation for premature infants and (2) to examine the effects of glutamine-supplemented parenteral nutrition on length of stay, days on total parenteral nutrition (TPN), days on the ventilator, and other clinical outcomes.
                Premature infants received either standard or glutamine-supplemented TPN and were monitored throughout length of stay for various health and biochemical indices. The group was examined as a whole (n = 44; birth weight range: 530 to 1250 g) and in two weight subgroups, < 800 and > or = 800 g.
                Serum ammonia, blood urea nitrogen, and glutamate tended to be higher in the GLN groups, but the levels were well within normal limits. In the < 800-g cohort (n = 24), glutamine-supplemented infants required fewer days on TPN (13 vs 21 days, p = .02), had a shorter length of time to full feeds (8 vs 14 days, p = .03), and needed less time on the ventilator (38 vs 47 days, p = .04). There was a tendency toward a shorter length of stay in the NICU (73 vs 90 days, NS). These findings were not observed in the infants > or = 800 g (n = 20).
                Glutamine appears to be safe for use in premature infants and seems to be conditionally essential in premature infants with extremely low birth weights. Larger multicenter trials are needed to confirm these observations and further evaluate the efficacy of GLN in these high-risk premature infants. Glutamine is one of the most abundant amino acids in both plasma and human milk, yet it is not included in standard intravenous amino acid solutions. Previous studies have suggested that parenteral nutrition (PN) supplemented with glutamine may reduce sepsis and mortality in critically ill adults. Whether glutamine supplementation would provide a similar benefit to extremely low birth weight (ELBW) infants is not known.
                We performed a multicenter, randomized, double-masked, clinical trial to assess the safety and efficacy of early PN supplemented with glutamine in decreasing the risk of death or late-onset sepsis in ELBW infants. Infants 401 to 1000 g were randomized within 72 hours of birth to receive either TrophAmine (control) or an isonitrogenous study amino acid solution with 20% glutamine whenever they received PN up to 120 days of age, death, or discharge from the hospital. The primary outcome was death or late-onset sepsis.
                Of the 721 infants who were assigned to glutamine supplementation, 370 (51%) died or developed late-onset sepsis, as compared with 343 of the 712 infants (48%) assigned to control (relative risk: 1.07; 95% confidence interval: 0.97-1.17). Glutamine had no effect on tolerance of enteral feeds, necrotizing enterocolitis, or growth. No significant adverse events were observed with glutamine supplementation.
                Parenteral glutamine supplementation as studied did not decrease mortality or the incidence of late-onset sepsis in ELBW infants. Consequently, although no harm was demonstrated, routine use of parenteral glutamine supplementation cannot be recommended in this population. Enteral and parenteral glutamine supplementation in preterm infants has been shown to have some beneficial effects on neonatal morbidity and mortality, although the results are controversial. In this study, we aimed to determine if long-term glutamine-supplemented enteral nutrition affects growth parameters in very-low-birth-weight (VLBW) preterm infants. Preterm infants with a birth weight of < or = 1500 g were assigned to receive enteral glutamine supplementation (300 mg/kg/day) or placebo between 8-120 days (4 months) of life. At the end of each month, growth parameters [weight, length, head circumference, left upper mid-arm circumference (MAC) and left mid-thigh circumference (MTC)] were determined and enteral glutamine dose was adjusted according to the current weight. In VLBW infants (n = 69), the glutamine-supplemented group (n = 36) had significantly higher mean weight, length, head circumference, MAC and MTC than the control group (n=33) at the end of the fourth month. These findings suggest that long-term enteral glutamine supplementation may lead to significant improvements in growth in all body measures in VLBW infants, possibly in a time-dependent pattern. Glutamine, described as a "conditionally essential" amino acid for critically ill patients, has not been routinely added to parenteral amino acid formulations for critically ill neonates and is provided in only small quantities by the enteral route when enteral intake is low. We conducted a blinded, randomized study of enteral glutamine supplementation in 68 very low birth weight neonates randomly assigned to receive glutamine-supplemented premature formula versus premature formula alone between days 3 and 30 of life. Primary end points consisted of hospital-acquired sepsis, tolerance to subsequent enteral feedings (days with no oral intake), and duration of hospital stay. Hospital acquired sepsis was 30% (control group) and 11% (glutamine group). Logistic regression with birth weight as a covariate showed that: (1) feeding group was significant (p = 0.048) in determining the probability of developing proven sepsis over the course of hospitalization and (2) the estimated odds of developing sepsis were 3.8 times higher for infants in the control group than for those treated with glutamine. Glutamine-supplemented infants had better tolerance to enteral feedings as measured by percent of days on which feedings needed to be withheld (mean percentage of 8.8 vs 23.8, p = 0.007). Analysis of T cells demonstrated a blunting of the rise in HLA-DR+ and CD16 subsets in glutamine-supplemented infants. There were no differences in growth; in serum ammonia, urea, liver transaminase, or prealbumin concentrations; or in mean hospital stay. This study provides evidence for decreased morbidity in very-low-birth-weight neonates who receive enteral glutamine supplementation. To assess the effect of isocaloric isonitrogenous parenteral glutamine supplementation on intestinal permeability and nitrogen loss in newborns and infants after major digestive-tract surgery.
                Glutamine supplementation in critically ill and surgical adults may normalize intestinal permeability, attenuate nitrogen loss, improve survival, and lower the incidence of nosocomial infections. Previous studies in critically ill children were limited to very-low-birthweight infants and had equivocal results.
                Eighty newborns and infants were included in a double-blind, randomized trial comparing standard parenteral nutrition (sPN; n = 39) to glutamine-supplemented parenteral nutrition (GlnPN; glutamine target intake, 0.4 g kg day; n = 41), starting on day 2 after major digestive-tract surgery. Primary endpoints were intestinal permeability, as assessed by the urinary excretion ratio of lactulose and rhamnose (weeks 1 through 4); nitrogen balance (days 4 through 6), and urinary 3-methylhistidine excretion (day 5). Secondary endpoints were mortality, length of stay in the ICU and the hospital, number of septic episodes, and usage of antibiotics and ICU resources.
                Glutamine intake plateaued at 90% of the target on day 4. No differences were found between patients assigned sPN and patients assigned GlnPN regarding any of the endpoints. Glutamine supplementation was not associated with adverse effects.
                In newborns and infants after major digestive-tract surgery, we did not identify beneficial effects of isonitrogenous, isocaloric glutamine supplementation of parenteral nutrition. Glutamine supplementation in these patients therefore is not warranted until further research proves otherwise. To determine if glutamine-supplemented enteral nutrition decreased the incidence of nosocomial sepsis in neonates.
                In a multicenter (n = 20) clinical trial, we randomly allocated infants (n = 649) with birth weight between 500 and 1250 g, who were <7 days of age, and had no major anomalies to receive enteral glutamine supplementation (0.3 g/kg/day) or sterile water (placebo) for the first 28 days. The primary outcome variable was the number of infants who had blood culture-proven nosocomial sepsis between 7 days' and 36 weeks' postmenstrual age.
                Infants were assigned to placebo (n = 335) or to glutamine supplementation (n = 314). Neonates assigned to glutamine were similar to those assigned placebo for demographic characteristics and nutritional support during the first week. There was no difference in the occurrence of culture-proven nosocomial sepsis (33.7% vs 30.9%) or suspected sepsis (51.6% vs 47.1%) between the placebo and glutamine groups; however, neonates treated with glutamine less often had gastrointestinal dysfunction (7.5% vs 2.5%, P <.01) and severe neurologic sequelae (15.1% vs 10.4%, P =.08).
                At a dose of 0.3 g/kg/day, enteral glutamine does not appear to reduce nosocomial sepsis in premature neonates. The addition of glutamine to parenteral nutrition (PN) in neonates has not shown significant benefits as compared to adults thus far. This study aimed to determine the potential benefits of the addition of glutamine to neonatal PN in a tertiary hospital in a middle-income country.
                This was a double-blinded randomised controlled trial. Babies who were admitted to the neonatal intensive care unit (NICU) and who required PN were eligible for inclusion in the study. The subjects were randomised to receive either glutamine-added PN (intervention) or standard PN (control). The most important outcomes included time to full enteral nutrition, incidence of sepsis and necrotising enterocolitis (NEC), clinical or culture-proven sepsis.
                Out of 270 subjects, 132 were randomised to the intervention group and 138, to the control group. Baseline data were comparable in both groups. The median time taken to reach full enteral nutrition was similar for both intervention and control groups (six days in each group, p-value is 0.52). The incidences of NEC, clinical sepsis and culture-proven sepsis did not differ significantly in the intervention and control groups (5.8 vs. 7.1 percent, p-value is 0.68; 15.7 percent vs. 10.2 percent, p-value is 0.21 and 16.5 percent vs. 15.7 percent, p-value is 0.38, respectively). Other outcomes such as duration of ventilation, duration of NICU stay and a subgroup analysis for preterm and term babies also showed no statistically significant differences.
                Addition of glutamine to neonatal PN was not shown to improve outcome. Glutamine depletion has negative effects on the functional integrity of the gut and leads to immunosuppression. Very-low-birth-weight (VLBW) infants are susceptible to glutamine depletion because nutrition is limited in the first weeks of life.
                The objective was to determine the effect of glutamine-enriched enteral nutrition on feeding tolerance, infectious morbidity, and short-term outcome in VLBW infants.
                In a double-blind randomized controlled trial, VLBW infants (gestational age <32 wk or birth weight <1500 g) were allocated to receive enteral glutamine supplementation (0.3 g . kg(-1) . d(-1)) or isonitrogenous control supplementation (alanine) between days 3 and 30 of life. The supplementations were added to breast milk or to preterm formula. The primary endpoint for the study was time to full enteral feeding. Secondary endpoints were other variables of feeding tolerance, infectious morbidity, and short-term outcome.
                Baseline patient and nutritional characteristics were not significantly different in the glutamine-supplemented (n = 52) and the control (n = 50) groups. The median time to full enteral feeding was 13 d (range: 7-31 d) in the glutamine-supplemented group and 13 d (range: 6-35 d) in the control group (hazard ratio: 1.19; 95% CI: 0.79, 1.79; P = 0.40). In the glutamine-supplemented group, 26 of 52 infants (50%) had >/=1 serious infection compared with 38 of 50 (76%) in the control group (odds ratio: 0.32; 95% CI: 0.14, 0.74; P = 0.008). Other variables of feeding tolerance and short-term outcome were not significantly different between groups.
                Glutamine-enriched enteral nutrition did not improve feeding tolerance or short-term outcome in VLBW infants. However, infectious morbidity was significantly lowered in infants who received glutamine-enriched enteral nutrition. To examine the impact of oral glutamine (Gln) supplementation on gut integrity and on the incidence of necrotizing enterocolitis (NEC)/septicemia of premature neonates.
                Preterm neonates (n = 101, gestational age <34 weeks, birth weight <2000 g) were randomly allocated to receive from day 3 to day 30 postpartum, either oral Gln (0.3 g/kg/day, n = 51-Gln group) or placebo (caloreen-isocaloric, n = 50-control group). Intestinal permeability was determined from the urinary lactulose/mannitol recovery (L/M ratio) following their oral administration and assessed at three time points: day 2 (before first administration), day 7 and day 30 of life. The incidence of NEC and septicemia over the study period was also recorded.
                A decrease of lactulose recovery at days 7 (p = 0.001) and 30 (p < 0.001) and a decrease of L/M ratio at day 7 (p = 0.002) were observed only in the Gln group. Lactulose recovery and L/M ratio at day 7 (p = 0.022 and p = 0.004, respectively), as well as lactulose recovery (p = 0.001), mannitol recovery (p = 0.042), and L/M ratio (p = 0.001) at day 30, were decreased in the Gln group as compared to controls. NEC and septicemia were lower in the Gln group at the end of the first week (p = 0.009 and p = 0.041, respectively) and up to the end of the study (p < 0.001 and p = 0.048, respectively).
                Oral Gln administration may have beneficial effects on intestinal integrity and the overall incidence of NEC/septicemia in preterm infants. Hepatic dysfunction is one of the most frequent complications of parenteral nutrition. Very low birth weight (VLBW) infants are more sensitive to liver injury due to physiological immaturity. Our studies in animals showed that glutamine supplementation could attenuate TPN-associated liver injury. The aim of study was to investigate whether parenteral glutamine supplementation can improve hepatic tolerance in VLBW infants.
                We performed a double-blind, randomized, and controlled clinical study to investigate whether parenteral glutamine supplementation can improve hepatic tolerance in VLBW infants. Thirty VLBW infants at two children's centers were randomly assigned to either a control group or a glutamine-supplemented group. The primary endpoints were hepatic function and mortality. The secondary endpoints were the time to achieve full enteral nutrition, episodes of gastric residuals, duration of parenteral nutrition, weight and head circumference gain, length of hospitalization, and days on ventilator.
                The serum levels of aspartate aminotransferase (AST) and total bilirubin (Tbi) were decreased after PN in the glutamine-supplemented group (P < 0.05). No deaths occurred in this study. Four infants assigned to the control group and two infants in the glutamine-supplemented group were withdrawn from the study, according to intention to treat: relative risk [RR]: 1.182; 95% confidence interval [CI]: 0.937-1.490.
                Parenteral glutamine supplementation can improve hepatic tolerance in very low birth weight infant, suggesting a hepato-protective effect.
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The available trial data do not provide evidence that glutamine supplementation confers important benefits for preterm infants.