Trophic feedings for parenterally fed infants.

BACKGROUND: Because of concern that feedings may increase the risk of necrotizing enterocolitis, some high-risk infants have received prolonged periods of parenteral nutrition without enteral feedings. Providing trophic feedings (small volume feedings given at the same rate for at least 5 days) during this period of parenteral nutrition was developed as a strategy to enhance feeding tolerance and decrease time to reach full feedings. Whether trophic feedings result in better outcomes than initially withholding feedings or providing progressively increasing feedings can be established only in proper clinical trials. OBJECTIVES: 1. For high-risk neonates receiving parenteral feedings, to assess the effect of trophic feeding compared to no enteral nutrient intake on measures of feeding tolerance and neonatal outcome.2. For high-risk neonates receiving parenteral feedings to assess the effect of trophic feedings compared to a specific initial feeding regimen involving a greater enteral nutrient intake on measures of feeding tolerance and neonatal outcome. SEARCH STRATEGY: Searches were performed of MEDLINE (1966 - June 2004), CINAHL (1982 - June 2004), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2004), abstracts and conference proceedings, references from relevant publications in the English language, and studies identified by personal communication. SELECTION CRITERIA: Only randomized or quasi-randomized clinical trials were considered. Trials were included if they enrolled high-risk infants randomly assigned to receive trophic feedings (defined as dilute or full strength feedings providing < = 25 kcal/kg/d for > = 5d) compared to either 1) no enteral nutrient intake (no feedings or water only) or 2) a specific feeding regimen involving a greater enteral intake of formula or human milk than with trophic feedings. DATA COLLECTION AND ANALYSIS: The two reviewers reached consensus for inclusion of trials. Data regarding clinical outcomes were extracted and evaluated by the two reviewers independently of each other. Authors were contacted as needed and feasible to clarify or provide missing data. The specific data that were needed were requested in writing. MAIN RESULTS: 1. Trophic feedings vs. no feedings (10 trials): Among infants given trophic feedings, there was an overall reduction in days to full feeding (weighted mean difference [WMD] = -2.6 [95% confidence limits = -4.1, -1.0]), total days that feedings were held (WMD = -3.1 [-4.6, -1.6]), and total hospital stay (WMD = -11.4 [-17.2, -5.7] compared to infants given no enteral nutrient intake. Tests for heterogeneity were significant in analyses of days to full enteral feedings, days to regain birth weight, days of phototherapy, and hospital stay. There was no significant difference in necrotizing enterocolitis, although the findings do not exclude an important effect (relative risk = 1.16 [0.75, 1.79]; risk difference = 0.02 [-0.03, 0.06].2. Trophic feedings vs. advancing feedings (one trial): Infants given trophic feedings required more days to reach full enteral feeding (13.4 [8.2, 18.6]) and tended to have a longer hospital stay (11.0 [-1.4, 23.4]) than did infants given advancing feedings. With only eight total cases of necrotizing enterocolitis, trophic feedings were associated with a marginally significant reduction in necrotizing enterocolitis (relative risk =0.14 [0.02, 1.07]; risk difference = -0.09 [-0.16, -0.01]. AUTHORS' CONCLUSIONS: In both comparisons, the group with the greater enteral intake (trophic feedings in the first comparison and advancing feedings in the second comparison) required significantly less time to reach full feedings and had a significant or near significant reduction in hospital stay. In both comparisons, the group with the greater intake also had a higher incidence of necrotizing enterocolitis although the difference was not statistically significant. The concern is greatest for the advancing feeding regimen. Even when trophic feedings were compared to no feedings, the relative risk for necrotizing enterocolitis was 1.16 (0.75 - 1.79), a finding consistent with a 16% increase in necrotizing enterocolitis and a number needed to harm of 50. A true increase of this magnitude might outweigh any short- or long-term benefits of trophic feedings. Moreover, the 95% confidence interval does not exclude the possibility that trophic feedings increase necrotizing enterocolitis by as much as 79% with a number needed to harm of 17. Whether no feedings, trophic feedings, or advancing feedings should initially be used is difficult to discern for a variety of reasons--the inherent difficulty of assessing enteral feedings in high-risk infants, the limited sample size and methodologic limitations of most studies to date, unexplained heterogeneity with respect to a number of outcomes, the potential for bias to affect the findings in unblinded studies, and the large number of infants who must be studied to assess the effect on necrotizing enterocolitis. One or more large, well designed, multi-center trials are needed to compare these approaches to early feeding with respect to important clinical outcomes. A conclusive evaluation would assess effects on not only the survival rate without necrotizing enterocolitis prior to discharge from the neonatal unit but also on the survival rate without severe gastrointestinal or neurodevelopmental disability at >= 18 months age.

Labeling DNA with stable isotopes: economical and practical considerations.

Labeling DNA with stable isotopes to measure cell proliferation can be a technique as effective as 3H-thymidine labeling without the limitations imposed by using radioisotopes. Here, we investigated the relative efficiency of four nonradioactive precursors to DNA: [1-13C]-glycine, [1,2-13C2]-glycine, [U-13C]-glucose, and [U-13C, 15N]-thymidine. The efficiency of incorporation for each of these labeled precursors in HEP G2 cells in culture has been studied. When considering the actual costs of in vivo experiments in which large doses of labeled material are needed, economical constraints may play an important role in defining a practical method. Therefore, the economics of this process were also considered. Using the enrichment per dollar for whichever nucleoside had the highest incorporation in a given experiment, glycine is about five times more economical as a label than thymidine and eight times more economical than glucose in these cells.

Vitamin A supplementation for extremely-low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network.

BACKGROUND: Vitamin A supplementation may reduce the risk of chronic lung disease and sepsis in extremely-low-birth-weight infants. The results of our pilot study suggested that a dose of 5000 IU administered intramuscularly three times per week for four weeks was more effective than the lower doses given in past trials. METHODS: We performed a multicenter, blinded, randomized trial to assess the effectiveness and safety of this regimen as compared with sham treatment in 807 infants in need of respiratory support 24 hours after birth. The mean birth weight was 770 g in the vitamin A group and 769 g in the control group, and the respective gestational ages were 26.8 and 26.7 weeks. RESULTS: By 36 weeks' postmenstrual age, 59 of the 405 infants (15 percent) in the vitamin A group and 55 of the 402 infants (14 percent) in the control group had died. The primary outcome - death or chronic lung disease at 36 weeks' postmenstrual age - occurred in significantly fewer infants in the vitamin A group than in the control group (55 percent vs. 62 percent; relative risk, 0.89; 95 percent confidence interval, 0.80 to 0.99). Overall, 1 additional infant survived without chronic lung disease for every 14 to 15 infants who received vitamin A supplements. The proportions of infants in the vitamin A group and the control group who had signs of potential vitamin A toxicity were similar. The proportion of infants with serum retinol values below 20 microg per deciliter (0.70 micromol per liter) was lower in the vitamin A group than in the control group (25 percent vs. 54 percent, P<0.001). CONCLUSIONS: Intramuscular administration of 5000 IU of vitamin A three times per week for four weeks reduced biochemical evidence of vitamin A deficiency and slightly decreased the risk of chronic lung disease in extremely-low-birth-weight infants.

Vitamin A to prevent bronchopulmonary dysplasia in very-low-birth-weight infants: has the dose been too low? The NICHD Neonatal Research Network.

OBJECTIVE: Inconsistent effects of vitamin A supplementation on prevention of bronchopulmonary dysplasia have been reported. Meta-analysis of these reports resulted in a relative risk of 0.69-1.02 for death or bronchopulmonary dysplasia associated with vitamin A supplementation. Effective dosage regimens or serum retinol concentrations have not been determined in previous reports. The purpose of this pilot study was to define a vitamin A regimen that produces serum retinol concentrations of 25-55 micrograms/dl. STUDY DESIGN: In this three-phase study, 91 infants (mean birth weight 799-864 g) were enrolled. Vitamin A was administered three times/week for 4 weeks at an average daily dose of 986-2143 IU/day. Physical examinations were performed and serum retinol specimens were collected weekly to assess clinical signs of toxicity. RESULTS: The majority of serum retinol concentrations remained < 25 micrograms/dl until an intramuscular vitamin A dose of 5000 IU/dose three times/week was used. No clinical signs of toxicity were associated with the higher dosage and higher serum concentrations of vitamin A. CONCLUSION: A large clinical trial of vitamin A supplementation with 5000 IU/dose three times/week (25-114% more than the dose used in the three published clinical trials) is needed to assess whether vitamin A supplementation safely reduces the risk of bronchopulmonary dysplasia in very-low-birth-weight infants.

Vitamin E alters alveolar type II cell phospholipid synthesis in oxygen and air.

Newborn rats were injected with vitamin E or placebo daily until 6 days after birth. The effect of vitamin E pretreatment on in vitro surfactant phospholipid synthesis was examined in isolated type II cells exposed to oxygen or air form 24 h in vitro. Type II cells were also isolated from untreated 6-day-old rats and cultured for 24 h in oxygen or air with control medium or vitamin E supplemented medium. These cells were used to examine the effect of vitamin E exposure in vitro on type II cell phospholipid synthesis and ultrastructure. Phosphatidylcholine (PC) synthesis was reduced in cells cultured in oxygen as compared with air. This decrease was not prevented by in vivo pretreatment or in vitro supplementation with vitamin E. Vitamin E pretreatment increased the ratio of disaturated PC to total PC and increased phosphatidylglycerol synthesis. The volume density of lamellar bodies in type II cells was increased in cells maintained in oxygen. Vitamin E did not affect the volume density of lamellar bodies. We conclude that in vitro hyperoxia inhibits alveolar type II cell phosphatidylcholine synthesis without decreasing lamellar body volume density and that supplemental vitamin E does not prevent hyperoxia-induced decrease in phosphatidylcholine synthesis.

Clinical trial of vitamin A supplementation in infants susceptible to bronchopulmonary dysplasia.

We conducted a randomized, double-blind, controlled trial to determine whether vitamin A supplementation from early postnatal life could reduce the morbidity associated with bronchopulmonary dysplasia in very low birth weight (VLBW) neonates. Forty VLBW neonates (700 to 1300 g birth weight, 26 to 30 weeks gestational age), who were oxygen dependent and required mechanical ventilation for at least 72 hours after birth, were given by the intramuscular route either supplemental vitamin A (retinyl palmitate 2000 IU) or 0.9% saline solution on postnatal day 4 and every other day thereafter for a total of 14 injections over 28 days. The study groups were comparable in gestational maturity, clinical characteristics, initial lung disease, and vitamin A status at entry into the trial. Vitamin A administration resulted in significantly higher mean plasma concentrations of vitamin A and retinol-binding protein in treated infants compared with controls. Bronchopulmonary dysplasia was diagnosed in nine of 20 infants given vitamin A supplement and in 17 of 20 control infants (P less than 0.008). Four of 19 infants in the vitamin A group and 11 of 20 in the control group required mechanical ventilation on study day 28 (P less than 0.029). The need for supplemental oxygen, mechanical ventilation, and intensive care was reduced in infants given vitamin A supplement compared with controls. Airway infection and retinopathy of prematurity were less frequent in the vitamin A group. We conclude that vitamin A supplementation at the dosage used in this trial in VLBW neonates not only improves their vitamin A status but also appears to promote regenerative healing from lung injury, as evidenced by a decrease in the morbidity associated with bronchopulmonary dysplasia.