Glutamine supplementation to prevent morbidity and mortality in preterm infants.

BACKGROUND: Glutamine endogenous biosynthesis may be insufficient for tissue needs in states of metabolic stress. Trials in adults have suggested that glutamine supplementation improves clinical outcomes in critically ill adults. It has been suggested that glutamine supplementation may benefit preterm infants, particularly very low birth weight infants. OBJECTIVES: To determine the effects of glutamine supplementation on mortality and morbidity in preterm infants. SEARCH STRATEGY: The standard search strategy of the Cochrane Neonatal Review Group was used. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2007), MEDLINE (1966 - July 2007), EMBASE (1980 - July 2007), conference proceedings, and previous reviews. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials that compared glutamine supplementation versus no glutamine supplementation in preterm infants at any time from birth to discharge from hospital. DATA COLLECTION AND ANALYSIS: The standard methods of the Cochrane Neonatal Review Group were used, with separate evaluation of trial quality and data extraction by two authors. Data were synthesised using a fixed effects model and reported using typical relative risk, typical risk difference and weighted mean difference. MAIN RESULTS: 2365 preterm infants have participated in seven randomised controlled trials. All of the participating infants were of very low birth weight. Three trials assessed enteral glutamine supplementation and four trials assessed parenteral glutamine supplementation. The trials were generally of good methodological quality with adequate allocation concealment, blinding of caregivers and assessors to the intervention, and complete or near-complete follow-up of recruited infants. Glutamine supplementation does not have a statistically significant effect on mortality: typical relative risk 0.98 (95% confidence interval 0.80 to 1.20); typical risk difference 0.00 (95% confidence interval -0.03 to 0.02). The only trial that assessed long-term outcomes did not find any statistically significant differences in various assessments of neurodevelopment at 18 months corrected age. Glutamine supplementation does not have a statistically significant effect on other neonatal morbidities including invasive infection, necrotising enterocolitis, time to achieve full enteral nutrition, or duration of hospital stay. AUTHORS' CONCLUSIONS: The available data from good quality randomised controlled trials indicate that glutamine supplementation does not confer benefits for preterm infants. The narrow confidence intervals for the effect size estimates suggest that a further trial of this intervention is not a research priority.

Glutamine supplementation to prevent morbidity and mortality in preterm infants.

BACKGROUND: Glutamine endogenous biosynthesis may be insufficient for tissue needs in states of metabolic stress. Trials in adults have suggested that glutamine supplementation improves clinical outcomes in critically ill adults. It has been suggested that glutamine supplementation may benefit preterm infants, particularly very low birth weight infants. OBJECTIVES: To determine the effects of glutamine supplementation on mortality and morbidity in preterm infants. SEARCH STRATEGY: We used the standard search strategy of the Cochrane Neonatal Review Group. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2004), MEDLINE (1966 - August 2004), EMBASE (1980 - August 2004), conference proceedings, and previous reviews. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials that compared glutamine supplementation versus no glutamine supplementation in preterm babies at any time from birth to discharge from hospital. DATA COLLECTION AND ANALYSIS: We extracted the data using the standard methods of the Cochrane Neonatal Review Group, with separate evaluation of trial quality and data extraction by two reviewers, and synthesis of data using relative risk, risk difference and weighted mean difference. MAIN RESULTS: More than 2300 infants have participated in six randomised controlled trials. All of the participating infants were of very low birth weight. Three trials assessed enteral glutamine supplementation, and three trials assessed parenteral glutamine supplementation. These trials were generally of good methodological quality with adequate allocation concealment, blinding of care-givers and assessors to the intervention, and complete or near-complete follow-up of recruited infants. We found that glutamine supplementation does not have a statistically significant effect on mortality: typical relative risk 0.98 (95% confidence interval 0.80 to 1.21); typical risk difference 0.00 (95% confidence interval -0.03 to 0.03). One of the trials assessed longer term neurodevelopmental outcomes (Poindexter 2004). The investigators reported that they did not find any statistically significant differences in various assessments of neurodevelopment (including Bayley scales) on follow up at 18 months corrected age. We found that glutamine supplementation does not have a statistically significant effect on the incidence of systemic infection (typical relative risk 1.02 (95% confidence interval 0.92 to 1.13); typical risk difference 0.01 (95% confidence interval -0.03 to 0.05)), necrotising enterocolitis (typical relative risk 1.02 (95% confidence interval 0.79 to 1.33); typical risk difference 0.00 (95% confidence interval -0.02 to 0.03)), days to full enteral nutrition (weighted mean difference -1.1 days (95% confidence interval -3.4 to 1.2)), or duration of hospital stay (weighted mean difference 0.65 days (95% confidence interval -2.9 to 4.2)). AUTHORS' CONCLUSIONS: The available data from good quality randomised controlled trials suggest that glutamine supplementation does not confer clinically significant benefits for preterm infants. The narrow confidence intervals for the effect size estimates suggest that a further trial of this intervention is not a research priority.

A comparison of lutein and zeaxanthin concentrations in formula and human milk samples from Northern Ireland mothers.

BACKGROUND: Two carotenoids, lutein and zeaxanthin are found in the retinal pigment epithelium of the eye where they are believed to protect it against oxidative and light damage. The amounts of these carotenoids consumed by premature infants are not known. OBJECTIVE: The objective of the investigation was to measure these carotenoids in human and formulae milks. DESIGN: In all, 28 human milk samples were obtained at various times between days 1 and 41 of lactation from 13 mothers. Six formula milks commonly used in hospitals were also analysed. SETTING: Mothers who provided the milk samples had infants in the neonatal ward at the Royal Maternity Hospital, Belfast. RESULTS: Median lutein and zeaxanthin concentrations in human milk were 4.79 (range 0.42-9.98) nmol/g fat and 0.55 (0.00-1.70) nmol/g fat, respectively. Five of the six formula milks also contained lutein and zeaxanthin with concentrations that varied over a wide range (0.7-9.7 and 0.1-1.2 nmol/g fat, respectively). CONCLUSIONS: Carotenoid concentrations usually decreased with the duration of lactation. Some formula milks that were specially formulated for premature infants contained high concentrations of the lutein and zeaxanthin and the source may be egg yolk. SPONSORSHIP: These studies were supported by the University of Ulster and the Northern Ireland Mother and Baby Appeal.

A randomized, controlled trial of parenteral glutamine in ill, very low birth-weight neonates.

OBJECTIVE: 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. DESIGN: Randomized controlled trial. METHODS: 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). RESULTS: 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. CONCLUSIONS: Parenteral glutamine appears to be well tolerated and safe in the ill, preterm neonate. It may reduce the time to achieving FEN.

Glutamine supplementation for prevention of morbidity in preterm infants.

BACKGROUND: The amino acid glutamine is the preferred respiratory fuel for rapidly proliferating cells under normal conditions. Recent research has suggested a number of roles for glutamine during critical illness. This research has been largely performed in experimental animals and in adults in a variety of disease settings. There is little information on the role of glutamine in children and infants, or whether glutamine supplementation is beneficial in preterm babies. OBJECTIVES: To determine the effects of glutamine supplementation on morbidity and weight gain in preterm babies. SEARCH STRATEGY: Searches were made using the Cochrane Controlled Trials Register, Medline and Embase electronic databases from 1980 - June 2001 (MeSH terms: glutamine, preterm, newborn, nutrition), handsearching of selected English language journals (Pediatrics, Journal of Pediatrics, Archives of Disease in Childhood and Journal of Pediatric Gastroenterology and Nutrition) from 1990 - June 2001, and cross-referencing from publications where necessary. SELECTION CRITERIA: Randomised controlled trials comparing glutamine supplementation to no glutamine supplementation in preterm babies at any time from birth to discharge from hospital. DATA COLLECTION AND ANALYSIS: Data regarding clinical outcomes including duration of parenteral nutrition, time to full enteral nutrition, rate of weight gain, rate of positive blood cultures and duration of hospital stay were extracted by both reviewers. Analysis was performed by the primary reviewer (TRJT) in accordance with the standards of the Cochrane Neonatal Review Group. MAIN RESULTS: Three trials met the selection criteria. Data on proportion of babies having one or more of positive blood cultures were available from all three studies. Meta-analysis showed no significant difference between glutamine-supplemented and non-supplemented babies; RR = 0.73 (95% CI 0.44, 1.23), RD = -8.8% (95% CI -23.2, 5.5). Data for other outcome variables were pooled from two studies. There were no significant differences between glutamine-supplemented and non-supplemented babies for days to full enteral nutrition (WMD 0.4 days, 95% CI -3.0, 3.8), rate of weight gain (WMD 0.6 g/kg/d, 95% CI -1.6, 2.8) or days of hospital stay (WMD -2.4 days, 95% CI -14.9, 10.2). REVIEWER'S CONCLUSIONS: There is no evidence from randomised trials to support the routine use of parenteral or enteral glutamine supplementation in preterm babies. A large randomised controlled trial should be performed to determine whether or not glutamine supplementation enhances gut integrity and reduces sepsis rate.

Simultaneous monitoring of gastric and oesophageal pH reveals limitations of conventional oesophageal pH monitoring in milk fed infants.

BACKGROUND: Monitoring oesophageal pH conventionally detects "acid reflux" (pH less than 4). The pH of the gastric contents determines whether or not reflux can be detected. AIM: To monitor gastric and oesophageal pH simultaneously in order to determine the effect of milk feeds on gastric pH and how this would influence interpretation of the oesophageal pH record. METHODS: Milk fed infants for whom oesophageal pH monitoring was requested underwent simultaneous gastric and oesophageal pH monitoring using a dual channel pH probe. RESULTS: Twenty of 24 records were technically satisfactory. Mean reflux index was 1.0%, range 0.0-4.0%. Gastric pH was less than 4 for 24.5% (range 0.6-69.1%) of the total time. The average time the gastric pH was greater than 4 after feeds was 130 minutes (range 29-212 minutes). The corrected reflux index (limited to the time the gastric pH was less than 4) was 2.6% (range 0.0-11.0%). CONCLUSION: The pH of the gastric contents may be greater than 4 for prolonged intervals, during which oesophageal pH monitoring using current criteria cannot detect reflux nor correlate it with clinical events. A low reflux index may reflect prolonged buffering of gastric acidity rather than the absence of reflux.

Study of maternal influences on fetal iron status at term using cord blood transferrin receptors.

AIMS: To determine effects of maternal iron depletion and smoking on iron status of term babies using serum transferrin receptors (STfR) and their ratio to ferritin (TfR-F index) in cord blood. METHODS: Iron, ferritin, STfR, and haemoglobin (Hb) concentration were measured and TfR-F index calculated in 67 cord /maternal blood pairs. Twenty six mothers were iron depleted (ferritin <10 microg/l) and 28 were smokers. RESULTS: Maternal iron depletion was associated with decreased cord ferritin (113 v 171 microg/l) and Hb (156 v 168 g/l) but no change in STfR or TfR-F index. Smoking was associated with increased cord Hb (168 v 157 g/l) and TfR-F index (4.1 v 3.4), and decreased ferritin (123 v 190 microg/l). Cord TfR-F index and Hb were positively correlated (r = 0.48). CONCLUSIONS: Maternal iron depletion is associated with reduced fetal iron stores but no change in free iron availability. Smoking is associated with increased fetal iron requirements for erythropoiesis.

The clinical outcome of non-RhD antibody affected pregnancies in Northern Ireland.

We assessed the clinical outcome of pregnancies with non-Rh-D antibody in Northern Ireland using retrospective case note review. During the study period (April 1999- March 2000) 186 women with clinically significant antibodies were identified from the records of the antenatal laboratory of the Northern Ireland Blood Transfusion Service. Eighty-five women were included in the study using the criteria mentioned above. None of the fetuses required intrauterine transfusion during this period. One baby required exchange transfusion, three were given top-up transfusions and 17 had phototherapy. Nine babies with a positive direct antiglobulin test (DAT) received no treatment. The incidence of anti-Kell could be reduced by transfusing Kell negative red cells to premenopausal women. It is important that all pregnant women are tested at least twice in their pregnancy to detect the antibodies formed late in the pregnancy. It is useful to formulate a standard protocol for antenatal interventions. Non Rh-D antibodies can cause significant anaemia for up to six weeks in the neonatal period, hence early detection of maternal antibodies is important so that the neonates are followed up for an appropriate length of time.

[Treatment of very low birth weight infant: is it evidenced-based?]. / Tratamiento de los recién nacidos de muy bajo peso al nacer. Se basa en la evidencia?

AIM: To determine what percentage of therapeutic interventions for very low birth weight infants undergoing neonatal intensive care is evidence based. METHODS: The management of 80 very low birth weight infants admitted to our neonatal unit during 1998 was retrospectively reviewed. For each clinical diagnosis e.g. respiratory distress syndrome, patent ductus arteriosus or chronic lung disease all interventions were recorder. Each intervention was then categorised according to the level of supporting evidence. Level I was supported by evidence from randomised controlled trials or meta-analysis of multiple trials. Level II included interventions backed by convincing non-experimental evidence where randomised controlled trials would be unnecessary or unethical. Level III were treatments in common use without substantial supporting evidence. These categorizations were made after extensive researching of Medline, The Cochrane Database and the Randomised Controlled Trial Register, detailed hand-searching of the literature as well as using local expertise and knowledge. RESULTS: 943 separate interventions were recorded in the charts of the 80 babies. Overall 91.3% were shown to be evidence-based of which 58.7% were level I, 32.6% were level II and only 8.7% were level III. CONCLUSIONS: 91.3% of interventions for very low birth weight infants in our neonatal intensive care unit were evidence-based and only 8.7% had no substantial supporting evidence. Care of the very low birthweight infants is largely evidence-based.

Glutamine supplementation for preventing morbidity in preterm infants.

BACKGROUND: The amino acid glutamine is the preferred respiratory fuel for rapidly proliferating cells under normal conditions. Recent research has suggested a number of roles for glutamine during critical illness. This research has been largely performed in experimental animals and in adults in a variety of disease settings. There is little information on the role of glutamine in children and infants, or whether glutamine supplementation is beneficial in preterm babies. OBJECTIVES: To determine the effects of glutamine supplementation on morbidity and weight gain in preterm babies. SEARCH STRATEGY: Searches were made using Medline and Embase electronic databases and specific handsearching in the English language. The search strategy followed the guidelines of the Neonatal Cochrane Review Group. SELECTION CRITERIA: Randomised controlled trials comparing glutamine supplementation to no glutamine supplementation in preterm babies at any time from birth to discharge from hospital. DATA COLLECTION AND ANALYSIS: Data regarding clinical outcomes including duration of parenteral nutrition, time to full enteral nutrition, rate of weight gain, rate of positive blood cultures and duration of hospital stay were extracted by both reviewers. Analysis was performed by the primary reviewer (TRJT) in accordance with the standards of the Cochrane Neonatal Review Group. MAIN RESULTS: Three trials met the selection criteria. Data on proportion of babies having one or more of positive blood cultures were available from all three studies. Meta-analysis showed no significant difference between glutamine-supplemented and non-supplemented babies; RR = 0.73 (95% CI 0.44, 1.23), RD = -8.8% (95% CI -23.2, 5.5). Data for other outcome variables were pooled from two studies. There were no significant differences between glutamine-supplemented and non-supplemented babies for days to full enteral nutrition (WMD 0.42, 95% CI -3.0, 3.8), rate of weight gain (WMD 0.6 g/kg/d, 95% CI -1.6, 2.8) or days of hospital stay (WMD -2.4, 95% CI -14.9, 10.2). REVIEWER'S CONCLUSIONS: There is no evidence to support the routine use of parenteral or enteral glutamine supplementation in preterm babies. A large randomised controlled trial should be performed to determine whether or not glutamine supplementation enhances gut integrity and reduces sepsis rate.

Retinopathy of prematurity in surfactant treated infants.

Seventy six babies of less than 1500 g birth weight who had surfactant replacement therapy for severe respiratory distress syndrome were studied to assess the presence and stage of subsequent retinopathy of prematurity (ROP). A control group of 90 babies, matched for birth weight and gestational age, who did not have surfactant therapy were also studied. Threshold ROP or greater was found in 1.7% of the surfactant group and 7.8% of the controls. For the babies of less than 1000 g birth weight 4.0% of the surfactant babies and 16.3% of the controls reached threshold disease or greater. It is concluded that surfactant therapy is not associated with an increased incidence or severity of severe ROP in this preterm population.

Raised plasma hypoxanthine levels as a prognostic sign in preterm babies with respiratory distress syndrome treated with natural surfactant.

Plasma hypoxanthine concentration was measured in twelve preterm babies with respiratory distress syndrome (RDS) treated with 200 mg/kg of a porcine surfactant (Curosurf). Five of the babies died within one week and seven survived the neonatal period. Surviving babies had no significant changes in plasma hypoxanthine concentration throughout a one hour study period following the administration of surfactant. By contrast, in nonsurvivors the mean plasma hypoxanthine concentrations increased from 6.8 mumol/l before surfactant administration to 14.2 mumol/l 15 minutes after surfactant treatment. Survivors had a mean maximal increase in plasma hypoxanthine of 1.9 mumol/l 15-30 min factor surfactant treatment compared with 9.4 mumol/l in nonsurvivors (p < 0.05). The babies who developed intracranial hemorrhage had significantly higher maximal plasma hypoxanthine increase (mean 9.6 mumol/l) compared with babies who did not develop intracranial hemorrhage (mean 1.1 mumol/l) (p < 0.01). The combination of high PaO2 and high hypoxanthine concentration could lead to an increased production of oxygen radicals which might be harmful. We conclude that plasma hypoxanthine concentration may serve as an indicator of the prognosis in preterm babies treated with natural surfactant. Further, it seems important to reduce oxygen supplementation as soon as surfactant is given to possibly limit oxygen radical production.

Surfactant replacement therapy and the prevalence of acute retinopathy of prematurity.

To determine if surfactant replacement treatment is associated with an increase in the prevalence of retinopathy of prematurity (ROP) we studied 76 preterm babies who were treated with porcine surfactant (Curosurf) for severe respiratory distress syndrome from 1985 to 1990. Babies were first examined by indirect ophthalmoscopy at the equivalent of 32 weeks post-menstrual age and subsequently at 2-week intervals until discharge from hospital. Findings were documented according to the International Classification of ROP. Sixty-two (82%) babies survived to discharge, 7 survivors were not examined due to transfer elsewhere. Acute ROP developed in 14 (29%) of the 49 babies examined (7 stage I, 4 stage II, 2 stage III, and 1 stage IV); one baby required cryotherapy. No baby of birthweight greater than 1,500 g developed ROP. The prevalence of ROP was similar to that reported for non-surfactant-treated very-low-birthweight babies. We conclude that Curosurf treatment does not increase the risk of acute ROP in surviving very-low-birthweight babies.

Plasma manganese levels in the very low birth weight infant are high in early life.

Plasma manganese levels were determined at birth and then serially to 3 months of age in 40 very low birth weight (VLBW) infants (mean birth weight 1,027 g). Mean plasma manganese concentration was 3.6 micrograms/l at birth and 3.0 micrograms/l at 3 months of age. These levels were approximately 3-fold greater than those of a group of 9 adults analysed using the same methods (mean 1.1 micrograms/l). Manganese was also measured in parenteral nutrition fluids, breast milk and 3 preterm formulas. There was no relationship between manganese intake and plasma manganese concentration.

Congenital heart disease in Down's syndrome: two year prospective early screening study.

OBJECTIVE: To determine the effectiveness of clinical examination, chest radiography, and electrocardiography compared with echocardiography in detecting congenital heart disease early in the life of children with Down's syndrome. DESIGN: Prospective two year screening survey. SETTING: Regional paediatric cardiology service, Northern Ireland. PATIENTS: 81 newborn infants with Down's syndrome born in Northern Ireland between November 1987 and November 1989. INTERVENTIONS: Clinical examination, chest radiography, and electrocardiography soon after birth followed by cross sectional Doppler echocardiography. MAIN OUTCOME MEASURES: Diagnostic ability of clinical examination, radiography, and electrocardiography compared with echocardiographic findings. RESULTS: 34 babies had congenital heart disease detected by echocardiography (13 had atrioventricular septal defects, seven secundum atrial septal defects, six a solitary patent ductus arteriosus, five isolated ventricular septal defects, and three combinations of heart defects). Individual examination methods were insensitive (the sensitivity of clinical examination was 0.53, of radiography 0.44, and of electrocardiography 0.41) but highly specific (the specificity of clinical examination was 0.94, of radiography 0.98, and of electrocardiography 1.0), although sensitivity improved when the three techniques were combined (the sensitivity was 0.71, the specificity 0.91). CONCLUSION: Echocardiography performed early in life can detect congenital heart disease that might otherwise be missed. Early detection may help prevent complications such as pulmonary vascular disease that may adversely affect the outcome of cardiac surgery.

Effect of blood transfusion on plasma selenium, glutathione peroxidase and manganese levels in very low birth weight infants.

Very low birth weight infants often receive multiple blood transfusions. We measured the plasma levels of the trace elements selenium, manganese, and glutathione peroxidase in 20 very low birth weight infants prior to blood transfusion and then at 24, 48 and 72 h after transfusion. There was no detectable change in mean selenium or glutathione peroxidase concentrations after transfusion, but the mean (SD) plasma manganese increased from 3.8 (1.5) to 6.0 (2.3) micrograms/l at 72 h.