Retrospective case-control study of necrotizing enterocolitis and packed red blood cell transfusions in very low birth weight infants.

OBJECTIVE: The study objective was to explore the relationship between necrotizing enterocolitis (NEC) and packed red blood cell (pRBC) transfusion in very low birth weight (VLBW) neonates (<1500 g). STUDY DESIGN: A six-year retrospective chart review of VLBW infants with NEC (Bell's Stage > II) and a pRBC transfusion within 48 hours of diagnosis. Prenatal data, postnatal course, transfusion history, and NEC outcomes were reviewed. The transfusion associated necrotizing enterocolitis (TANEC) cases were matched with controls (1:2) who were transfused but did not develop NEC as to proximity of birth date, gestational age, and receipt of transfusion. RESULTS: Of 1139 VLBW admissions, there were 73 cases of NEC and 30 cases of TANEC (annual NEC rate 6.4%). TANEC cases were matched with 60 controls who were transfused but never developed NEC. Neonatal profiles were similar between all 3 groups, except for a higher proportion of infants <10th percentile in the non-TANEC group. Days of antibiotics and frequency of patient ductus arteriosus (PDA) ligation were lower in controls compared to NEC cases. Lower feeding rate at diagnosis of NEC/match were more common in control infants compared to TANEC infants. However, feeding abstinence rates were similar between the two groups. The number of transfusions prior to diagnosis/match was similar in all groups. There was no significant difference in pre-transfusion hematocrit values between the groups. CONCLUSION: TANEC was common among NEC cases. PDA ligation was similar among TANEC and non-TANEC but lower in controls. Similar pre-transfusion hematocrits were found among TANEC and controls. Feeding abstinence rates were also similar between TANEC and controls.

Just add water: Accuracy of analysis of diluted human milk samples using mid-infrared spectroscopy.

OBJECTIVE: To determine the maximum dilution of human milk (HM) that yields reliable results for protein, fat and lactose when analyzed by mid-infrared spectroscopy. STUDY DESIGN: De-identified samples of frozen HM were obtained. Milk was thawed and warmed (40°C) prior to analysis. Undiluted (native) HM was analyzed by mid-infrared spectroscopy for macronutrient composition: total protein (P), fat (F), carbohydrate (C); Energy (E) was calculated from the macronutrient results. Subsequent analyses were done with 1 : 2, 1 : 3, 1 : 5 and 1 : 10 dilutions of each sample with distilled water. Additional samples were sent to a certified lab for external validation. RESULTS: Quantitatively, F and P showed statistically significant but clinically non-critical differences in 1 : 2 and 1 : 3 dilutions. Differences at higher dilutions were statistically significant and deviated from native values enough to render those dilutions unreliable. External validation studies also showed statistically significant but clinically unimportant differences at 1 : 2 and 1 : 3 dilutions. CONCLUSIONS: The Calais Human Milk Analyzer can be used with HM samples diluted 1 : 2 and 1 : 3 and return results within 5% of values from undiluted HM. At a 1 : 5 or 1 : 10 dilution, however, results vary as much as 10%, especially with P and F. At the 1 : 2 and 1 : 3 dilutions these differences appear to be insignificant in the context of nutritional management. However, the accuracy and reliability of the 1 : 5 and 1 : 10 dilutions are questionable.

Improving fortification with weekly analysis of human milk for VLBW infants.

OBJECTIVE: To track individual mother's macronutrient variability in preterm human milk (HM) over 6 weeks of lactation. STUDY DESIGN: This was a prospective, observational study of mother's own milk from women who delivered a very low birth weight infant (<1500 g). A single, random maternal breast milk sample was collected and analyzed weekly for 6 consecutive weeks. Analysis was by mid-infrared spectroscopy. RESULTS: Twenty women consented to provide at least one milk sample. Fat, protein and energy content varied widely among mothers and by week of lactation. Energy content ranged from 9.5 to 30.4 kcal oz-1 across the study period. Twenty-five percent of all samples had an energy content <17 kcal oz-1. Protein content ranged from 1.1 to 2.8 g dl-1 in the first week. Sixty-three percent of all samples had a protein content <1.5 g dl-1. Fat and energy showed trends of increasing concentrations, whereas protein showed the expected decline over time. Lactose showed little variability by woman or by week of lactation. CONCLUSION: HM fat and protein content varied widely by individual woman over time. Week-to-week variability in fat and protein can impact growth. The ability to analyze HM is helpful to improve fortification of HM.

A retrospective analysis of the effect of human milk on prevention of necrotizing enterocolitis and postnatal growth.

OBJECTIVE: The objective of this study is to determine whether the use of donor human milk (DHM) in very low birth weight (VLBW, ⩽1500 g) neonates in a large neonatal intensive care unit (NICU) affected the rate of necrotizing enterocolitis (NEC) or impacted growth. STUDY DESIGN: This was a retrospective chart review of 550 VLBW neonates following the introduction of DHM as the preferred diet if maternal breast milk (MBM) was not available. Demographics, growth parameters, incidence of NEC or death and days of DHM or MBM were extracted from charts. RESULT: Compared with infants who received human milk (HM) on fewer than 50% of hospital days, neonates who received HM on ⩾50% of hospital days had equivalent growth outcomes but lower rates of NEC (NEC 3.4 vs 13.5%, P<0.001) and mortality (1.0 vs 4.2%, P=0.017). Growth and NEC rates were inversely correlated with the duration of exposure to HM. CONCLUSION: HM should always be the diet of choice in preterm infants. DHM is a safe alternative, if MBM is not available. Although the use of HM is associated with lower rates of NEC, growth rates were significantly lower in infants with significant HM intake. The decline in growth rates following the introduction of DHM should draw attention to optimize fortification of all HM feedings.

Comparison of lactoferrin activity in fresh and stored human milk.

OBJECTIVE: Lactoferrin (Lf), the dominant protein in human milk (HM), has been shown to have anti-inflammatory and anti-microbial activity in the neonatal gut. Previous studies indicate that freezing significantly decreases the concentration of Lf in HM. The objective of our study was to compare the activity of Lf in fresh and frozen HM over time. STUDY DESIGN: HM samples were examined fresh and after storage at -20 °C for 3 and 6 months. Lf concentration was determined by enzyme-linked immunoassay, and the activity was measured by examination of nitric oxide (NO) production and tumor necrosis factor-α secretion from rat macrophages exposed to HM samples. RESULT: After 3 and 6 months at -20 °C, the average decrease in Lf concentrations was 55% and 65%, respectively. The bioactivity of Lf also decreased significantly over 6 months. CONCLUSION: Freezing HM for 3 or more months significantly decreases Lf levels and activity. Periodically providing fresh HM may benefit vulnerable preterm neonates.

Current trends and future challenges in neonatal parenteral nutrition.

A number of adaptations in total parenteral nutrition (TPN) protocols and practices for preterm neonates have been realized in the past several years, resulting in better survival and developmental outcomes. The early provision of appropriate concentrations of amino acids and energy are now recommended in evidence-based guidelines. Standardized TPN formulations are now available for many patients and may be associated with cost savings and improved adherence to guidelines. Several advantages of these preparations, including promotion of safer administration, consistent adherence to guidelines, and overall best practices, have been well documented. However, careful monitoring is still required to optimize nutrition for individual patients and to support overall safety as TPN practices continue to change. Additional research is needed to develop new lipid formulations that are tailored for safe use by very low birth weight (VLBW) and extremely low birth weight (ELBW) infants. This review presents recent research and improvements to guidelines, as well as future product needs for VLBW and ELBW neonates.

Stability of lactoferrin in stored human milk.

OBJECTIVE: Lactoferrin from human milk (HM) provides antimicrobial and anti-inflammatory action in the neonatal intestine. HM-fed, critically ill neonates often receive previously frozen milk. Freezing is known to have deleterious effects on proteins. The aim of this study was to determine the effect of low temperature storage of HM on the concentration of lactoferrin. STUDY DESIGN: HM samples were collected and stored for different periods of time and at different temperatures per Centers for Disease Control and Prevention recommendations. Lactoferrin concentrations following freezing were compared with that in fresh HM. RESULT: Lactoferrin concentrations in refrigerated HM samples were stable for 5 days. After 3 months at -18 to -20 C, the average decrease was 37%. Following storage for 6 months at -20 °C, lactoferrin decreased to 46%. CONCLUSION: Five-day refrigeration of HM does not appreciably decrease lactoferrin levels. Freezing HM for 3 months or more significantly lowers lactoferrin levels. There may be a role for occasionally providing fresh HM to critically ill neonates.

Individualizing fortification of human milk using real time human milk analysis.

OBJECTIVE: To use real-time human milk macronutrient analysis to calculate final composition following fortification. STUDY DESIGN: Preterm HM (PHM) and pooled donor human milks (DHM) were analyzed by mid-infrared spectroscopy for protein, fat and lactose. Energy content was calculated from macronutrient results. Three lactation stages were constructed. DHM was compared to PHM. Four milk sample profiles were selected to demonstrate individualized fortification results. RESULTS: Lactose was similar in PHM and DHM. Protein in PHM showed the expected decline as lactation progressed. DHM protein was significantly lower vs. PHM. Fat was highly variable and lowest in DHM. Using standard fortification protocols, not all fortified milks met targets for protein and energy. Individualized fortification resulted in milks closer to target recommendations. CONCLUSIONS: Real-time analysis of HM provides assessment of the macronutrient content of the milk and can guide fortification. Individualized protocols, based on actual milk macronutrient profiles, may need to be considered to avoid unexpected nutrient content.

Nutritional strategies and growth in extremely low birth weight infants with bronchopulmonary dysplasia over the past 10 years.

OBJECTIVE: Changes in nutritional strategies over the past decade have been shown to improve postnatal growth in extremely low birth weight (ELBW) infants. We showed 10 years ago that the majority of these ELBW infants with bronchopulmonary dysplasia (BPD) suffer postnatal growth failure. We theorized that recent changes in nutritional support strategies would positively affect growth outcomes in ELBW infants with BPD. STUDY DESIGN: A retrospective study of 88 ELBW infants with BPD. Nutritional data, postnatal growth and BPD severity were compared across three cohorts: (1) weight gain ≤14 g kg(-1) per day, (2) 14.1 to 16 g kg(-1) per day and (3) ≥16 g kg(-1) per day from return to birth weight through discharge. We also compared these to a historical cohort. RESULT: In all, 73% of current subjects grew at or above fetal rates. There was less extrauterine growth restriction (EUGR) by weight and head circumference for those ELBW infants with BPD receiving higher amounts of protein. Aggressive early TPN and receipt of caloric-dense milk seemed to be the 'new' nutritional strategies improving growth for current ELBW infants with BPD compared with those 10 years ago. CONCLUSION: Despite a diagnosis of BPD, improved nutritional strategies have enhanced postnatal growth in infants at high risk for EUGR.

Milk as a vehicle for oral medications: hidden osmoles.

OBJECTIVE: Once critically ill, preterm infants have transitioned to enteral or oral feedings, it is common to mix oral medications with milk feedings. The osmolality of oral and intravenous drugs were tested in the 1980s and many were found to exceed the American Academy of Pediatrics (AAP) recommended limit (400 mOsm kg(-1) H(2)O). Many new milks and medications have entered the neonatal intensive care unit (NICU) since then. The objective of this study was to measure the osmolality of common milk-medication combinations administered in the NICU. STUDY DESIGN: Common milk-medication mixtures were analyzed for osmolality by freezing point depression. RESULT: Only Elecare (30 kcal per oz) exceeded AAP recommendations for osmolality in its unadulterated state. The addition of multivitamins alone resulted in an osmolality that exceeded 400 mOsm kg(-1) H(2)O. The cumulative addition of other medications resulted in some osmolalities >1000 mOsm kg(-1) H(2)O. CONCLUSION: The coadministration of medications with milk products should be evaluated as a potential contributor to gastrointestinal intolerance of feedings in preterm infants.

Early amino acids and the metabolic response of ELBW infants (< or = 1000 g) in three time periods.

OBJECTIVE: To evaluate early amino-acid (AA) administration in extremely low birth weight (ELBW) infants over three time periods, beginning with the initiation of this strategy. STUDY DESIGN: This was a retrospective study of ELBW infants between 2000 and 2007. Nutritional intake and laboratory results were monitored during the first 5 days of life. Growth rates and complications were followed until discharge. RESULT: Infants were similar in birth weight (BW), gestational age (GA) and severity of illness. The age at initiation of AA decreased significantly over time. Age at weight nadir, return to BW and percent postnatal weight loss decreased in epoch 3. There were modest increases in blood urea nitrogen (BUN), but no significant metabolic disturbances were observed. Cholestasis was more prevalent in epoch 2. CONCLUSION: AA administration within the first hours of life appears to be safe and beneficial for ELBW infants. Absent signs of renal dysfunction, a modest rise in BUN is consistent with the neonate's utilization of AAs for energy.

Five-year experience with an early discharge program in well newborns.

PURPOSE: This study was conducted to determine if early postnatal discharge (< or = 48 hrs; EDC) in well newborns had an effect on the rate of hospital readmission within the first week after hospital discharge when compared to infants who remained > 48 hrs after birth (LDC). METHODS: This was a retrospective medical chart review. Infants who were born at Norton Hospital in Louisville, Kentucky, between 1/1/94 and 12/31/98, discharged as well newborns and treated at Kosair Children's Hospital, Louisville, Kentucky, within 7 days of neonatal discharge, were eligible for review. Infants were categorized by length of neonatal hospital stay, level of medical intervention (emergency department treatment or hospital admission) and final diagnosis. RESULTS: There was a significant increase in hospital readmission rates for LDC infants when compared to EDC infants. When considering jaundice alone as an admitting diagnosis, EDC infants were admitted at a rate 4 times that of LDC infants and with higher serum bilirubin concentrations. Jaundiced infants were almost uniformly breast-fed. CONCLUSIONS: Overall, early discharge of well newborns appears to be a safe and reasonable practice. However, the risk for severe jaundice is an unresolved issue which requires a discharge strategy and early follow-up to prevent serious morbidity. Early discharge should not be implemented without a mechanism for early follow-up within 48 hours of discharge.

Intravenous gamma-glutamyl-tyrosine elevates brain tyrosine but not catecholamine concentrations in normal rats.

A number of clinical situations may benefit from intravenous supplements of tyrosine (Tyr). In total parenteral nutrition (TPN), the supply of Tyr is limited by its poor solubility. In both rats and infants maintained on pediatric TPN, plasma Tyr levels are approximately 30% of normal, and in rat brains Tyr concentrations are similarly reduced. We reported previously that supplementing a TPN solution with the soluble peptide, gamma-glutamyl-Tyr [Glu(Tyr)], normalizes plasma Tyr and doubles brain Tyr in rats. To assess more fully the behavior of intravenous Glu(Tyr) in vivo, 20 mmol/L Glu(Tyr) was infused into the inferior vena cava of rats at rates increased every 2 hours over an 8-hour period (300 to 450 mumol Glu(Tyr)/kg body weight/h). The surgical procedure for catheterization is described. At the maximum rate of infusion, plasma Tyr and Glu(Tyr) concentrations reached mean plateau values of 326 and 252 mumol/L, respectively. Brain Tyr concentrations were 71 and 264 nmol/g wet weight in control rats infused with heparinized saline (SAL group) and rats infused with Glu(Tyr) (PEP group) respectively. No differences were found in concentrations of norepinephrine (NE), dopamine (DA), or homovanillic acid (HVA) in prefrontal cortex (PFC), striatum (STR), or remaining brain (RB) tissue in PEP and SAL rats. We did not detect undergraded Glu(Tyr) in the brain, and less than 0.5% of infused Glu(Tyr) appeared in the urine.

Comparison of a neonatal versus general-purpose amino acid formulation in preterm neonates.

Twenty preterm infants were randomly assigned to receive either a general-purpose intravenous amino acid solution or a neonatal formula at 1.5 gm/kg/day with 50 nonprotein energy calories for 1 week. Both groups demonstrated similar rates of weight gain and similar liver function test results, but comparison of changes from baseline amino acid values disclosed significant intergroup differences for levels of plasma glycine, taurine, valine, and methionine after 7 days of infusion. Comparison of plasma aminograms of study patients with those of normally growing, enterally fed preterm infants showed that infants who received the neonatal solution had similar amino acid profiles, with the exception of low plasma concentrations of tyrosine and elevated concentrations of threonine. The general-purpose solution, as compared with findings in historic enteral controls, produced low plasma valine, tyrosine, and taurine levels, and elevated levels of glycine and methionine. Advantages with the neonatal amino acid solution include reductions in plasma glycine and methionine levels, plus the provision of taurine. Providing tyrosine remains a problem.

Forty years after Dancis: the very-very low birth weight infant grids.

Postnatal body weight changes were assessed in 99 infants with birth weights of less than 1200 gm. Growth was monitored during the first 50 postnatal days, and two growth curves were generated for comparison with the lowest Dancis grids. Our critically ill infants, in whom parenteral alimentation was a major source of nutrition, closely paralleled the 1000 gm Dancis grid, whereas our infants of approximately 750 gm birth weight did not lose as much weight as predicted by Dancis and gained weight at a faster rate.

Measured energy expenditure in mechanically ventilated very low birth weight infants.

Forty-nine calorimetric studies were performed on 24 very low birth weight infants with respiratory distress syndrome on mechanical ventilation during the first seven postnatal days. Mean resting energy expenditure for the entire study was 59 +/- 21 kilocalories/kg daily, with a respiratory quotient of 0.93 +/- 0.1, reflecting the predominance of carbohydrate calories. A comparison of mean energy intake with mean resting energy expenditure showed a mean caloric deficit of 31 kcal/k daily during the first 4 postnatal days, followed by 3 days where resting energy expenditure was met by equivalent caloric intake. Wide variation was noted in resting energy expenditure.

Use of the soluble peptide gamma-L-glutamyl-L-tyrosine to provide tyrosine in total parenteral nutrition in rats.

Limited solubility restricts amounts of tyrosine (Tyr) in amino acid solutions used in total parenteral nutrition (TPN). Excess phenylalanine (Phe) is included in TPN for conversion to Tyr by liver Phe hydroxylase. However, this conversion is limited, especially in infants. We have confirmed that infants receiving TPN have low Tyr concentrations and high Phe/Tyr ratios in plasma compared with published values for enterally fed neonates. Tyr is important in the synthesis of proteins and other biomolecules, including catecholamines in the brain. We tested the soluble peptide gamma-glutamyl-tyrosine (Glu(Tyr)) as a possible precursor of Tyr in TPN. Groups of five rats were given infusions of TPN containing an amino acid mixture simulating a commercial formulation (group A), TPN in which Glu(Tyr) was substituted for half the Phe in the group A solution) (group B), or saline (group C). Control animals (group C) were fed rodent chow. Blood was sampled at 0 time and daily for 4 days. Brains were collected at 96 hours, and aromatic amino acids in plasma and brains were measured by high-performance liquid chromatography. Throughout the experiment, plasma of animals in group A had significantly elevated Phe and reduced Tyr concentrations compared with control values; plasma concentrations in groups B and C were similar. In groups A and B, brain Tyr levels were 31% and 63% of control values, respectively. In group B, Glu(Tyr) was not detected in brains. These data suggest that supplementing current TPN mixtures with Glu(Tyr), which is stable in solution, can produce normal plasma Tyr concentrations and Phe/Tyr ratios and improve the supply of Tyr to the brain.

Use of intravenous lipid and hyperbilirubinemia in the first week.

Serum triglycerides, free fatty acids, unconjugated bilirubin, and albumin were evaluated in 40 neonates receiving 0.5-3.5 g/kg/day of a 50/50 soybean-safflower lipid emulsion infused during 18 h. The purpose of the study was to evaluate lipid tolerance and unconjugated hyperbilirubinemia according to our total parenteral nutrition protocol, which initiates lipid on postnatal day 4. Mean serum triglycerides and free fatty acids were within the range of prelipid infusion values at all dosages, and no statistically significant differences were noted between very-low-birth-weight neonates and those greater than 1,500 g birth weight. Mean free fatty acid:albumin molar ratio was less than 1.0 at all dosages and no individual patient values exceeded a ratio of 3.0. Mean peak serum unconjugated bilirubin of 5.8 mg/dl on postnatal day 3 was stable or fell the next 10 days of lipid-inclusive total parenteral nutrition. Initiating intravenous lipid on the 4th postnatal day at 0.5 g/kg/day and increasing at 0.5 g/kg/day increments at the end of the 1st postnatal week appears to be tolerated well. However, 5% of serum triglyceride levels exceeded 200 mg/dl. Therefore, in view of the unpredictability of a given patient's tolerance to lipid infusion, there should be monitoring for lipemia.