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Plasma Citrulline Concentrations in Neonates With or Without Gastrointestinal Disease During Periods of Parenteral and Enteral Nutrition.
Herrera, OR, Talati, AJ, Helms, RA
JPEN. Journal of parenteral and enteral nutrition. 2019;(8):977-985
Abstract
INTRODUCTION Citrulline is synthesized primarily in enterocytes. Retrospective work revealed higher plasma concentrations in patients without gastrointestinal (GI) disease than in those with GI disease, regardless of bowel resection, leading us to speculate whether it could be used as a marker of gut function prospectively. Our purpose was to analyze plasma citrulline in these patients, comparing a period of exclusive parenteral nutrition (PN) vs both PN and enteral nutrition (PN/EN). METHODS Premature neonates were included in this study. Plasma samples were collected during 2 periods, PN and PN/EN. They were classified into groups: patients without GI disease (Group 1), patients with GI disease without resection (Group 2), and patients with GI disease and resection (Group 3). Plasma was analyzed by high-performance liquid chromatography and tandem mass spectrometry (LC-MS/MS). Data were described as median with ranges. RESULTS Fifty patients were recruited for this study, from which 164 samples were obtained and analyzed by LC-MS. Median plasma citrulline concentrations were 12.3 (5.6-39.4) µmol/L, 14.9 (6.8-39.8) µmol/L, and 10.8 (2.0-23.6) µmol/L for Groups 1, 2, and 3, respectively. After Bonferroni correction, only Group 3 had a significantly different median from the others. No differences were observed within periods of nutrition (PN vs PN/EN). Postconceptual age (PCA), among others, was assessed to determine differences for which the former demonstrated significance. CONCLUSION Premature neonates with bowel resection had lower plasma citrulline concentrations, confirming its role as gut mass marker, though without differences during transitional feeding. PCA may affect expression of this protein.
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Controlled Trial of Two Incremental Milk-Feeding Rates in Preterm Infants.
Dorling, J, Abbott, J, Berrington, J, Bosiak, B, Bowler, U, Boyle, E, Embleton, N, Hewer, O, Johnson, S, Juszczak, E, et al
The New England journal of medicine. 2019;(15):1434-1443
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Abstract
BACKGROUND Observational data have shown that slow advancement of enteral feeding volumes in preterm infants is associated with a reduced risk of necrotizing enterocolitis but an increased risk of late-onset sepsis. However, data from randomized trials are limited. METHODS We randomly assigned very preterm or very-low-birth-weight infants to daily milk increments of 30 ml per kilogram of body weight (faster increment) or 18 ml per kilogram (slower increment) until reaching full feeding volumes. The primary outcome was survival without moderate or severe neurodevelopmental disability at 24 months. Secondary outcomes included components of the primary outcome, confirmed or suspected late-onset sepsis, necrotizing enterocolitis, and cerebral palsy. RESULTS Among 2804 infants who underwent randomization, the primary outcome could be assessed in 1224 (87.4%) assigned to the faster increment and 1246 (88.7%) assigned to the slower increment. Survival without moderate or severe neurodevelopmental disability at 24 months occurred in 802 of 1224 infants (65.5%) assigned to the faster increment and 848 of 1246 (68.1%) assigned to the slower increment (adjusted risk ratio, 0.96; 95% confidence interval [CI], 0.92 to 1.01; P = 0.16). Late-onset sepsis occurred in 414 of 1389 infants (29.8%) in the faster-increment group and 434 of 1397 (31.1%) in the slower-increment group (adjusted risk ratio, 0.96; 95% CI, 0.86 to 1.07). Necrotizing enterocolitis occurred in 70 of 1394 infants (5.0%) in the faster-increment group and 78 of 1399 (5.6%) in the slower-increment group (adjusted risk ratio, 0.88; 95% CI, 0.68 to 1.16). CONCLUSIONS There was no significant difference in survival without moderate or severe neurodevelopmental disability at 24 months in very preterm or very-low-birth-weight infants with a strategy of advancing milk feeding volumes in daily increments of 30 ml per kilogram as compared with 18 ml per kilogram. (Funded by the Health Technology Assessment Programme of the National Institute for Health Research; SIFT Current Controlled Trials number, ISRCTN76463425.).
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High-Dose Human Milk Feedings Decrease Oxidative Stress in Premature Infant.
Chen, Y, Fantuzzi, G, Schoeny, M, Meier, P, Patel, AL
JPEN. Journal of parenteral and enteral nutrition. 2019;(1):126-132
Abstract
BACKGROUND Premature infants are susceptible to oxidative stress, increasing the risk for serious morbidities. High-dose human milk (HM) feedings decrease morbidity risks and may reduce oxidative stress in this population. The purpose of this study was to compare oxidative stress using serial urinary F2 -isoprostane concentrations in predominantly HM and preterm formula (PF)-fed premature infants over the first 21 days of life (DOL), while controlling for perinatal oxidative stress exposures including bovine-based human milk fortifier (HMF) or PF introduction to predominantly HM-fed infants. METHODS This was a quasi-experimental design that categorized 22 premature infants into mutually exclusive comparison groups based on exposure to HM and PF. Serial urine samples (before and after first feeding, and DOL 7, 14, and 21) were used to determine urine F2 -isoprostane concentrations measured by enzyme-linked immunosorbent assays. We analyzed data using Mann-Whitney U test, Wilcoxon rank test, and multilevel models. RESULTS Comparing the predominantly HM-fed and predominantly PF-fed groups over time, median F2 -isoprostane concentrations decreased significantly in the predominantly HM group (P = .003) and increased significantly in the predominantly PF group (P = .01). Perinatal oxidant exposures and the introduction of HMF did not affect results. CONCLUSIONS Our results demonstrate that predominantly HM feedings were associated with decreased oxidative stress, whereas PF feedings increased oxidative stress in premature infants, even after controlling for perinatal oxidant exposures of HMF or PF introduction.
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Maternal milk feedings reduce sepsis, necrotizing enterocolitis and improve outcomes of premature infants.
Cortez, J, Makker, K, Kraemer, DF, Neu, J, Sharma, R, Hudak, ML
Journal of perinatology : official journal of the California Perinatal Association. 2018;(1):71-74
Abstract
OBJECTIVE Human milk (donor milk (DM) and/or maternal milk (MM)) feedings protect against late onset sepsis (LOS), necrotizing enterocolitis (NEC) and death. However, DM lacks many anti-infective components of MM. Therefore, we studied exclusive MM feedings to evaluate the full effect of human milk on infectious and other outcomes in premature infants. STUDY DESIGN All infants born before 33 weeks postmenstrual age (PMA) who received exclusive (>95%) MM or exclusive preterm formula (PF) were included in this prospective investigation. RESULTS Sixty-three infants (53%) received MM and 55 infants (47%) received PF. Both groups had similar baseline characteristics. Infants in the MM group achieved full enteral nutrition sooner (14±8 vs 19±15 days, P<0.03) and required a shorter duration of central venous lines (14±10 vs 22±21, P<0.005). Fewer infants in the MM group developed LOS (9 vs 19, P<0.05) and pneumonia (8 vs 16, P<0.05) than PF infants. Only one MM and five PF infants developed NEC (Bell stage ⩾II). Logistic regression analysis using PMA and prolonged rupture of membranes as covariates demonstrated an increased rate of NEC (odds ratio=8.85, CI=1.01 to 25.17, P=0.048) in PF infants. Periventricular leukomalacia (PVL) was more common in PF (4 vs 0, P=0.04) than in MM infants. CONCLUSION Feedings of MM advanced more rapidly and were associated with fewer infections than PF. A possible protective effect of MM against PVL, not previously described, may be related to its immune and anti-inflammatory components.
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The Speed of Increasing milk Feeds: a randomised controlled trial.
Abbott, J, Berrington, J, Bowler, U, Boyle, E, Dorling, J, Embleton, N, Juszczak, E, Leaf, A, Linsell, L, Johnson, S, et al
BMC pediatrics. 2017;(1):39
Abstract
BACKGROUND In the UK, 1-2% of infants are born very preterm (<32 weeks of gestation) or have very low birth weight (<1500 g). Very preterm infants are initially unable to be fed nutritional volumes of milk and therefore require intravenous nutrition. Milk feeding strategies influence several long and short term health outcomes including growth, survival, infection (associated with intravenous nutrition) and necrotising enterocolitis (NEC); with both infection and NEC being key predictive factors of long term disability. Currently there is no consistent strategy for feeding preterm infants across the UK. The SIFT trial will test two speeds of increasing milk feeds with the primary aim of determining effects on survival without moderate or severe neurodevelopmental disability at 24 months of age, corrected for prematurity. The trial will also examine many secondary outcomes including infection, NEC, time taken to reach full feeds and growth. METHODS/DESIGN Two thousand eight hundred very preterm or very low birth weight infants will be recruited from approximately 30 hospitals across the UK to a randomised controlled trial. Infants with severe congenital anomaly or no realistic chance of survival will be excluded. Infants will be randomly allocated to either a faster (30 ml/kg/day) or slower (18 ml/kg/day) rate of increase in milk feeds. Data will be collected during the neonatal hospital stay on weight, infection rates, episodes of NEC, length of stay and time to reach full milk feeds. Long term health outcomes comprising vision, hearing, motor and cognitive impairment will be assessed at 24 months of age (corrected for prematurity) using a parent report questionnaire. DISCUSSION Extensive searches have found no active or proposed studies investigating the rate of increasing milk feeds. The results of this trial will have importance for optimising incremental milk feeding for very preterm and/or very low birth weight infants. No additional resources will be required to implement an optimal feeding strategy, and therefore if successful, the trial results could rapidly be adopted across the NHS at low cost. TRIAL REGISTRATION ISRCTN Registry; ISRCTN76463425 on 5 March, 2013.
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Neonatal Caffeine Treatment and Respiratory Function at 11 Years in Children under 1,251 g at Birth.
Doyle, LW, Ranganathan, S, Cheong, JLY
American journal of respiratory and critical care medicine. 2017;(10):1318-1324
Abstract
RATIONALE Caffeine in the newborn period shortens the duration of assisted ventilation and reduces the incidence of bronchopulmonary dysplasia, but its effects on respiratory function in later childhood are unknown. OBJECTIVES To determine if children born with birth weight less than 1,251 g who were treated with neonatal caffeine had improved respiratory function at 11 years of age compared with children treated with placebo. METHODS Children enrolled in the CAP (Caffeine for Apnea of Prematurity) randomized controlled trial and assessed at the Royal Women's Hospital in Melbourne at 11 years of age had expiratory flow rates measured according to the standards of the American Thoracic Society. Values were converted to z-scores predicted for age, height, ethnicity, and sex. Parents completed questionnaires related to their child's respiratory health. MEASUREMENTS AND MAIN RESULTS A total of 142 children had expiratory flows measured. Expiratory flows were better in the caffeine group, by approximately 0.5 SD for most variables (e.g., FEV1; mean z-score, -1.00 vs. -1.53; mean difference, 0.54; 95% confidence interval, 0.14-0.94; P = 0.008). Fewer children in the caffeine group had values for FVC below the fifth centile (11% vs. 28%; odds ratio, 0.31; 95% confidence interval, 0.12-0.77; P = 0.012). When adjusted for bronchopulmonary dysplasia, the difference in flow rates between groups diminished. CONCLUSIONS Caffeine treatment in the newborn period improves expiratory flow rates in midchildhood, which seems to be achieved by improving respiratory health in the newborn period. Follow-up lung function testing in adulthood is vital for these individuals. Future placebo-controlled randomized trials of neonatal caffeine are unlikely. Clinical trial registered with www.clinicaltrials.gov (NCT00182312).
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Long-term neurodevelopment outcome of caffeine versus aminophylline therapy for apnea of prematurity.
Khurana, S, Shivakumar, M, Sujith Kumar Reddy, GV, Jayashree, P, Ramesh Bhat, Y, Lewis, LES
Journal of neonatal-perinatal medicine. 2017;(4):355-362
Abstract
OBJECTIVE Methylxanthines are the most commonly prescribed drug in neonatal setups. However, Clinicians show indecision in choosing the right agent for Apnea of Prematurity in most of the developing countries. Present study aimed to compare rate of mortality and survival with normal neurodevelopment outcome at 18 to 24 months of corrected age, between Caffeine- and Aminophylline-treated infants for apnea of prematurity. METHODS 240 infants were randomly allocated to caffeine and aminophylline for apnea of prematurity during February 2012 to January 2015. Long-term neurodevelopmental assessment was done only from children who had attained corrected age of 18 to 24 months during April 2014 to February 2016. Cognitive, language and motor deficits were assessed by Bayley Scale of infant and toddler development (BSID - III). Postnatal characteristics such as hearing and visual impairments during NICU stay were noted and same were followed up. RESULTS Infants allocated to caffeine group showed 83% less risk of getting cognitive impairment (RR 0.16; CI 95% range 0.02 to 1.36), 50% less risk of developing motor deficits (RR 0.50; CI 95% range 0.12 to 1.95) and 24% less risk of developing language problems (RR 0.76; CI 95% range 0.36 to 1.58). However in all the neurodevelopment domains the difference between groups was not statistically significant. Risk of mortality in caffeine group was 9% less over aminophylline group which was statistically non-significant (RR - 0.92; CI 95% range - 0.45 to 1.84; p = 0.81). Physical growth parameters were found to be similar in both the groups. Risk of developing visual abnormality and hearing impairments was also statistically non-significant between the groups. CONCLUSION Caffeine and aminophylline showed similar effects in reducing the rate of mortality and improving the survival without neurodevelopment delays; though the clinical significance of caffeine over aminophylline cannot be undermined.
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Probiotics and Time to Achieve Full Enteral Feeding in Human Milk-Fed and Formula-Fed Preterm Infants: Systematic Review and Meta-Analysis.
Aceti, A, Gori, D, Barone, G, Callegari, ML, Fantini, MP, Indrio, F, Maggio, L, Meneghin, F, Morelli, L, Zuccotti, G, et al
Nutrients. 2016;(8)
Abstract
Probiotics have been linked to a reduction in the incidence of necrotizing enterocolitis and late-onset sepsis in preterm infants. Recently, probiotics have also proved to reduce time to achieve full enteral feeding (FEF). However, the relationship between FEF achievement and type of feeding in infants treated with probiotics has not been explored yet. The aim of this systematic review and meta-analysis was to evaluate the effect of probiotics in reducing time to achieve FEF in preterm infants, according to type of feeding (exclusive human milk (HM) vs. formula). Randomized-controlled trials involving preterm infants receiving probiotics, and reporting on time to reach FEF were included in the systematic review. Trials reporting on outcome according to type of feeding (exclusive HM vs. formula) were included in the meta-analysis. Fixed-effect or random-effects models were used as appropriate. Results were expressed as mean difference (MD) with 95% confidence interval (CI). Twenty-five studies were included in the systematic review. In the five studies recruiting exclusively HM-fed preterm infants, those treated with probiotics reached FEF approximately 3 days before controls (MD -3.15 days (95% CI -5.25/-1.05), p = 0.003). None of the two studies reporting on exclusively formula-fed infants showed any difference between infants receiving probiotics and controls in terms of FEF achievement. The limited number of included studies did not allow testing for other subgroup differences between HM and formula-fed infants. However, if confirmed in further studies, the 3-days reduction in time to achieve FEF in exclusively HM-fed preterm infants might have significant implications for their clinical management.
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Cardiovascular risk factors in children after repeat doses of antenatal glucocorticoids: an RCT.
McKinlay, CJ, Cutfield, WS, Battin, MR, Dalziel, SR, Crowther, CA, Harding, JE, ,
Pediatrics. 2015;(2):e405-15
Abstract
BACKGROUND Treatment of women at risk for preterm birth with repeat doses of glucocorticoids reduces neonatal morbidity but could have adverse long-term effects on cardiometabolic health in offspring. We assessed whether exposure to repeat antenatal betamethasone increased risk factors for later cardiometabolic disease in children whose mothers participated in the Australasian Collaborative Trial of Repeat Doses of Corticosteroids. METHODS Women were randomized to betamethasone or placebo treatment, ≥ 7 days after an initial course of glucocorticoids, repeated each week that they remained at risk for preterm birth at <32 weeks' gestation. In this follow-up study, children were assessed at 6 to 8 years' corrected age for body composition, insulin sensitivity, ambulatory blood pressure, and renal function. RESULTS Of 320 eligible childhood survivors, 258 were studied (81%; 123 repeat betamethasone group; 135 placebo [single course] group). Children exposed to repeat antenatal betamethasone and those exposed to placebo had similar total fat mass (geometric mean ratio 0.98, 95% confidence interval [CI] 0.78 to 1.23), minimal model insulin sensitivity (geometric mean ratio 0.89, 95% CI 0.74 to 1.08), 24-hour ambulatory blood pressure (mean difference systolic 0 mm Hg, 95% CI -2 to 2; diastolic 0 mm Hg, 95% CI -1 to 1), and estimated glomerular filtration rate (mean difference 1.2 mL/min/1.73 m(2), 95% CI -3.2 to 5.6). CONCLUSIONS Exposure to repeat doses of antenatal betamethasone compared with a single course of glucocorticoids does not increase risk factors for cardiometabolic disease at early school age.
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Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants.
Cools, F, Offringa, M, Askie, LM
The Cochrane database of systematic reviews. 2015;(3):CD000104
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Abstract
BACKGROUND Respiratory failure due to lung immaturity is a major cause of mortality in preterm infants. Although the use of intermittent positive pressure ventilation (IPPV) in neonates with respiratory failure saves lives, its use is associated with lung injury and chronic lung disease. A newer form of ventilation called high frequency oscillatory ventilation has been shown in experimental studies to result in less lung injury. OBJECTIVES The objective of this review was to determine the effect of the elective use of high frequency oscillatory ventilation (HFOV) as compared to conventional ventilation (CV) on the incidence of chronic lung disease (CLD), mortality and other complications associated with prematurity and assisted ventilation in preterm infants who were mechanically ventilated for respiratory distress syndrome (RDS). SEARCH METHODS Searches were made of the Oxford Database of Perinatal Trials, MEDLINE, EMBASE, previous reviews including cross references, abstracts, conference and symposia proceedings; and from expert informants and handsearching of journals by The Cochrane Collaboration, mainly in the English language. The search was updated in January 2009 and again in November 2014. SELECTION CRITERIA Randomised controlled trials comparing HFOV and CV in preterm or low birth weight infants with pulmonary dysfunction, mainly due to RDS, who required assisted ventilation. Randomisation and commencement of treatment needed to be as soon as possible after the start of CV and usually in the first 12 hours of life. DATA COLLECTION AND ANALYSIS The methodological quality of each trial was independently reviewed by the review authors. The standard effect measures were relative risk (RR) and risk difference (RD). From 1/RD the number needed to benefit (NNTB) to produce one outcome was calculated. For all measures of effect, 95% confidence intervals (CIs) were used. For interpretation of subgroup analyses, a P value for subgroup differences as well as the I(2) statistic for between-subgroup heterogeneity were calculated. Meta-analysis was performed using both a fixed-effect and a random-effects model. Where heterogeneity was over 50%, the random-effects model RR was also reported. MAIN RESULTS Nineteen eligible studies involving 4096 infants were included. Meta-analysis comparing HFOV with CV revealed no evidence of effect on mortality at 28 to 30 days of age or at approximately term equivalent age. These results were consistent across studies and in subgroup analyses. The risk of CLD in survivors at term equivalent gestational age was significantly reduced with the use of HFOV but this effect was inconsistent across studies, even after the meta-analysis was restricted to studies that applied a high lung volume strategy with HFOV. Subgroup analysis by HFOV strategy showed a similar effect in trials with a more strict lung volume recruitment strategy, targeting a very low fraction of inspired oxygen (FiO2), and trials with a less strict lung volume recruitment strategy and with a somewhat higher or unspecified target FiO2. Subgroup analyses by age at randomisation, routine surfactant use or not, type of high frequency ventilator (oscillator versus flow interrupter), inspiratory to expiratory (I:E) ratio of high frequency ventilator (1:1 versus 1:2) and CV strategy (lung protective or not) could not sufficiently explain the heterogeneity. Pulmonary air leaks, defined as gross air leaks or pulmonary interstitial emphysema, occurred more frequently in the HFOV group, whereas the risk of severe retinopathy of prematurity was significantly reduced.Although in some studies an increased risk of severe grade intracranial haemorrhage and periventricular leukomalacia was found, the overall meta-analysis revealed no significant differences in effect between HFOV and CV. The short-term neurological morbidity with HFOV was only found in the subgroup of two trials not using a high volume strategy with HFOV. Most trials did not find a significant difference in long-term neurodevelopmental outcome, although one recent trial showed a significant reduction in the risk of cerebral palsy and poor mental development. AUTHORS' CONCLUSIONS There is evidence that the use of elective HFOV compared with CV results in a small reduction in the risk of CLD, but the evidence is weakened by the inconsistency of this effect across trials. Probably many factors, both related to the intervention itself as well as to the individual patient, interact in complex ways. In addition, the benefit could be counteracted by an increased risk of acute air leak. Adverse effects on short-term neurological outcomes have been observed in some studies but these effects are not significant overall. Most trials reporting long-term outcome have not identified any difference.