Multi-omic profiles of hepatic metabolism in TPN-fed preterm pigs administered new generation lipid emulsions.

We aimed to characterize the lipidomic, metabolomic, and transcriptomic profiles in preterm piglets administered enteral (ENT) formula or three parenteral lipid emulsions [parenteral nutrition (PN)], Intralipid (IL), Omegaven (OV), or SMOFlipid (SL), for 14 days. Piglets in all parenteral lipid groups showed differential organ growth versus ENT piglets; whole body growth rate was lowest in IL piglets, yet there were no differences in either energy expenditure or (13)C-palmitate oxidation. Plasma homeostatic model assessment of insulin resistance demonstrated insulin resistance in IL, but not OV or SL, compared with ENT. The fatty acid and acyl-CoA content of the liver, muscle, brain, and plasma fatty acids reflected the composition of the dietary lipids administered. Free carnitine and acylcarnitine (ACT) levels were markedly reduced in the PN groups compared with ENT piglets. Genes associated with oxidative stress and inflammation were increased, whereas those associated with alternative pathways of fatty acid oxidation were decreased in all PN groups. Our results show that new generation lipid emulsions directly enrich tissue fatty acids, especially in the brain, and lead to improved growth and insulin sensitivity compared with a soybean lipid emulsion. In all total PN groups, carnitine levels are limiting to the formation of ACTs and gene expression reflects the stress of excess lipid on liver function.

New generation lipid emulsions prevent PNALD in chronic parenterally fed preterm pigs.

Total parenteral nutrition (TPN) is associated with the development of parenteral nutrition-associated liver disease (PNALD) in infants. Fish oil-based lipid emulsions can reverse PNALD, yet it is unknown if they can prevent PNALD. We studied preterm pigs administered TPN for 14 days with either 100% soybean oil (IL), 100% fish oil (OV), or a mixture of soybean oil, medium chain triglycerides (MCTs), olive oil, and fish oil (SL); a group was fed formula enterally (ENT). In TPN-fed pigs, serum direct bilirubin, gamma glutamyl transferase (GGT), and plasma bile acids increased after the 14 day treatment but were highest in IL pigs. All TPN pigs had suppressed hepatic expression of farnesoid X receptor (FXR), cholesterol 7-hydroxylase (CYP7A1), and plasma 7α-hydroxy-4-cholesten-3-one (C4) concentrations, yet hepatic CYP7A1 protein abundance was increased only in the IL versus ENT group. Organic solute transporter alpha (OSTα) gene expression was the highest in the IL group and paralleled plasma bile acid levels. In cultured hepatocytes, bile acid-induced bile salt export pump (BSEP) expression was inhibited by phytosterol treatment. We show that TPN-fed pigs given soybean oil developed cholestasis and steatosis that was prevented with both OV and SL emulsions. Due to the presence of phytosterols in the SL emulsion, the differences in cholestasis and liver injury among lipid emulsion groups in vivo were weakly correlated with plasma and hepatic phytosterol content.

Resuscitation of preterm infants with different inspired oxygen fractions.

OBJECTIVE: To test the hypothesis that an initial fraction of inspired oxygen (FiO2) of 30% during resuscitation of preterm infants results in less oxidative stress and is associated with improved clinical outcomes compared with an FiO2 of 65%. STUDY DESIGN: Preterm infants of gestational age <32 weeks (n = 193) were randomized to start resuscitation with either 30% oxygen (low-oxygen group) or 65% oxygen (high-oxygen group), after which the FiO2 was adjusted based on oxygen saturation values. The primary outcome was bronchopulmonary dysplasia (BPD) assessed at 36 weeks postmenstrual age. Secondary outcomes included major neonatal illnesses and markers of oxidative stress. RESULTS: The median gestational age of included infants was 28(6)/7 weeks (IQR, 26(5)/7-30(3)/7 weeks). The incidence of BPD was not significantly different between the low-oxygen and high-oxygen groups (24% vs. 17%; P = .15). The FiO2 in both groups was adjusted to a mean of 40% by 7 minutes in the low-oxygen group and by 11 minutes in the high-oxygen group. No differences in markers of oxidative stress were noted between groups. CONCLUSION: Initial supplementation of preterm infants with 30% oxygen during the fetal-to-neonatal transition is as safe as 65% oxygen, with no differences in oxidative stress markers or BPD.

Growth and fatty acid profiles of VLBW infants receiving a multicomponent lipid emulsion from birth.

OBJECTIVES: Very-low-birth-weight (VLBW) infants are dependent on parenteral nutrition after birth. A parenteral lipid emulsion with a multicomponent composition may improve growth and neurodevelopment and may prevent liver injury, which is often observed in association with long-term parenteral nutrition with pure soybean oil. Our aim was to evaluate the safety and efficacy of a multicomponent lipid emulsion containing 30% soybean oil, 30% medium-chain triacylglycerol, 25% olive oil, and 15% fish oil compared with a conventional pure soybean oil emulsion in VLBW infants. METHODS: We conducted a double-blind randomized controlled trial in VLBW infants randomized to parenteral nutrition with the multicomponent (study group) or pure soybean oil emulsion (control group) from birth at a dose of 2 to 3 g · kg(-1) · day(-1) until the infants were receiving full enteral nutrition. We assessed efficacy by growth rates and measuring plasma fatty acid profiles (representative subset). Safety was evaluated by assessing hematologic and biochemical parameters, potentially harmful phytosterol concentrations (same subset), and clinical neonatal outcome parameters. RESULTS: Ninety-six infants were included (subsets n = 21). The multicomponent emulsion was associated with higher weight and head circumference z scores during admission. Plasma eicosapentaenoic acid and docosahexaenoic acid concentrations were higher in the study group. The hematological, biochemical, and neonatal outcomes were not different between groups, whereas the plasma concentrations of phytosterols were higher in the control group. CONCLUSIONS: The multicomponent lipid emulsion was well tolerated and associated with improved growth and higher plasma fatty acid profiles in VLBW infants in comparison with the pure soybean oil emulsion.

Assessment of Nutritional Status in the Diagnostic Evaluation of the Child with Growth Failure.

Current clinical guidelines provide information about the diagnostic workup of children with growth failure. This mini-review focuses on the nutritional assessment, which has received relatively little attention in such guidelines. The past medical history, in particular a low birth size and early feeding problems, can provide information that can increase the likelihood of nutritional deficits or several genetic causes. The current medical history should include a dietary history and can thereby reveal a poorly planned or severely restricted diet, which can be associated with nutritional deficiencies. Children on a vegan diet should receive various nutritional supplements, but insufficient compliance has been reported in one-third of cases. While proper use of nutritional supplements in children consuming a vegan diet appears to be associated with normal growth and development, insufficient intake of supplements may impede growth and bone formation. Physical examination and analysis of height and weight over time can help differentiating between endocrine causes, gastrointestinal disorders, psychosocial problems, or underlying genetic conditions that prevent adequate nutritional intake. Laboratory screening should be part of the workup in every child with short stature, and further laboratory tests can be indicated if warranted by the dietary history, especially in children on a poorly planned vegan diet.

Safety and efficacy of early parenteral lipid and high-dose amino acid administration to very low birth weight infants.

OBJECTIVE: To assess the efficacy and safety of early parenteral lipid and high-dose amino acid (AA) administration from birth onwards in very low birth weight (VLBW, birth weight <1500 g) infants. STUDY DESIGN: VLBW infants (n = 144; birth weight 862 ± 218 g; gestational age 27.4 ± 2.2 weeks) were randomized to receive 2.4 g of AA kg(-1) · d(-1) (control group), or 2.4 g AA kg(-1) · d(-1) plus 2-3 g lipids kg(-1) · d(-1) (AA + lipid group), or 3.6 g AA kg(-1) · d(-1) plus 2-3 g lipids kg(-1) · d(-1) (high AA + lipid group) from birth onwards. The primary outcome was nitrogen balance. The secondary outcomes were biochemical variables, urea rate of appearance, growth rates, and clinical outcome. RESULTS: The nitrogen balance on day 2 was significantly greater in both intervention groups compared with the control group. Greater amounts of AA administration did not further improve nitrogen balance compared with standard AA dose plus lipids and was associated with high plasma urea concentrations and high rates of urea appearance. No differences in other biochemical variables, growth, or clinical outcomes were observed. CONCLUSIONS: In VLBW infants, the administration of parenteral AA combined with lipids from birth onwards improved conditions for anabolism and growth, as shown by improved nitrogen balance. Greater levels of AA administration did not further improve the nitrogen balance but led to increased AA oxidation. Early lipid initiation and high-dose AA were well tolerated.

The present challenges of parenteral nutrition in preterm infants and children.

The goal of pediatricians involved in the nutritional management of preterm infants is to mimic intrauterine growth and to obtain a functional outcome comparable to that for infants born at term. Appropriate administration of nutrients in the first few days to weeks of life will reduce the growth restriction that is frequently observed. Existing guidelines advise providing preterm infants with both amino acids and lipids from birth onward. Despite this knowledge, many hospital units do not comply with these guidelines. Further improvement of the quality of the composition of parenteral solutions for both neonates as well as older children should be the subject of further research.

Unusual cause of congenital hypothyroidism in a term infant.

Both insufficient and excessive maternal iodine consumption can result in congenital hypothyroidism. In East Asian cultures, seaweed is traditionally consumed in high quantities by peripartum women as it is thought to improve lactation. We present a case of transient congenital hypothyroidism due to maternal seaweed consumption at a daily basis during pregnancy and lactation in a Dutch family without Asian background. This case highlights that even in families of non-Asian background, high maternal intake of iodine-rich seaweed occurs and can result in transient or permanent hyperthyrotropinemia in the neonate with risk of impaired neurodevelopmental outcome if untreated.

Nutritional support for extremely low-birth weight infants: abandoning catabolism in the neonatal intensive care unit.

PURPOSE OF REVIEW: Obviously, the ultimate goal in neonatology is to achieve a functional outcome in premature infants that is comparable to healthy term-born infants. As nutrition is one of the key factors for normal cell growth, providing the right amount and quality of nutrients could prove pivotal for normal development. However, many premature infants are catabolic during the first week of life, which has directly been linked to growth failure, disease, and suboptimal long-term outcome. This review describes the progress in research on parenteral nutrition for premature infants with a focus on amino acids and the influence of nutrition on later outcome. RECENT FINDINGS: Although randomized clinical trials on early nutrition for premature infants remain relatively sparse, evidence is accumulating on its beneficial effects both on the short-term and long-term. However, some research also warns for adverse effects. SUMMARY: Despite the fact that substantially improved nutritional therapies for preterm neonates have been implemented, still, some reluctance exists when it comes to providing high amounts of nutrition to the most immature infants. Pros and cons are outlined, as well as deficits in knowledge, when it comes to providing the optimal nutrient strategy in the first postnatal phase.

Fatal Aspergillus rhinosinusitis during induction chemotherapy in a child with acute lymphoblastic leukemia.

Invasive fungal infections are a major problem in patients treated for hematologic malignancies. We report a 3-year-old girl who suffered from febrile neutropenia during induction therapy for acute lymphoblastic leukemia. Initial chest computed tomography revealed no evidence of intrapulmonary fungal lesions, however, plasma galactomannan ratio was positive. Aspergillus flavus was cultured from nasal swab and endoscopic biopsy confirmed Aspergillus rhinosinusitis. After an initially good response to voriconazole and extensive debridement, she developed late intracranial hemorrhage and infarction with fatal outcome. This case stresses the importance of early suspicion and aggressive treatment of Aspergillus rhinosinusitis in patients with febrile neutropenia.

Two-Year Follow-up of a Randomized Controlled Nutrition Intervention Trial in Very Low-Birth-Weight Infants.

BACKGROUND: Very low-birth-weight (VLBW) infants are at risk for neurodevelopment impairment. This study assessed the effect of early aggressive parenteral nutrition (PN) on long-term outcome in VLBW infants. MATERIALS AND METHODS: Directly after birth, VLBW infants (birth weight <1500 g, n = 142) were randomized to 5 different PN regimes. Controls (n = 46) received glucose and standard-dose amino acids (AAs; 2.4 g/[kg·d]) from birth onward and pure soybean oil fat emulsion (SOY) on the second day of life. Two intervention groups received glucose, standard-dose AAs, and lipids from birth onward: SOY (n = 24) or mixed fat emulsion (MIX, n = 25). The 2 other intervention groups received glucose, high-dose AAs (3.6 g/[kg·d]), and lipids from birth onward: SOY (n = 24) or MIX (n = 23). The primary outcome of this follow-up study was the composite outcome of "death or major disability" at 2 years corrected age. Secondary outcomes were death, major disabilities, neurodevelopmental scores, and anthropometry. RESULTS: Follow-up rate was 92% (n = 134). Thirty-five (26%) infants had died or had a major disability, with no differences between intervention groups and controls. Increased odds for death were observed in the standard-dose AA-MIX group (odds ratio, 5.4; 95% confidence interval [CI], 1.1-27.0). Neurodevelopmental scores and incidence of major disabilities did not differ between groups. Growth in the high-dose AA-MIX group was enhanced compared with growth in controls at 2 years corrected age (+0.51 [0.01-1.02] weight SDS). CONCLUSION: This randomized controlled hypothesis-generating study demonstrated no beneficial effect of early high-dose AA administration and mixed fat emulsions on survival and neurodevelopmental outcome in VLBW infants, although growth was enhanced.

Lipids in the intensive care unit: Recommendations from the ESPEN Expert Group.

This article summarizes the presentations given at an ESPEN Workshop on "Lipids in the ICU" held in Tel Aviv, Israel in November 2014 and subsequent discussions and updates. Lipids are an important component of enteral and parenteral nutrition support and provide essential fatty acids, a concentrated source of calories and building blocks for cell membranes. Whilst linoleic acid-rich vegetable oil-based enteral and parenteral nutrition is still widely used, newer lipid components such as medium-chain triglycerides and olive oil are safe and well tolerated. Fish oil (FO)-enriched enteral and parenteral nutrition appears to be well tolerated and confers additional clinical benefits, particularly in surgical patients, due to its anti-inflammatory and immune-modulating effects. Whilst the evidence base is not conclusive, there appears to be a potential for FO-enriched nutrition, particularly administered peri-operatively, to reduce the rate of complications and intensive care unit (ICU) and hospital stay in surgical ICU patients. The evidence for FO-enriched nutrition in non-surgical ICU patients is less clear regarding its clinical benefits and additional, well-designed large-scale clinical trials need to be conducted in this area. The ESPEN Expert Group supports the use of olive oil and FO in nutrition support in surgical and non-surgical ICU patients but considers that further research is required to provide a more robust evidence base.

Albumin synthesis in very low birth weight infants is enhanced by early parenteral lipid and high-dose amino acid administration.

BACKGROUND & AIMS: Albumin is one of the most important plasma proteins and plays a key role in many physiologic processes, such as preserving colloid osmotic pressure, scavenging radicals, and binding and transporting bilirubin, hormones, and drugs. However, albumin concentrations are often low in preterm infants during the first days of life. We hypothesized that early parenteral lipid and high-dose amino acid (AA) administration to very low birth weight (VLBW) infants from birth onwards increases hepatic albumin synthesis rates. METHODS: Inborn VLBW infants were randomized to receive from birth onwards either 2.4 g amino acids/(kg(·)d) (control group), 2.4 g amino acids/(kg(·)d) plus 2 g lipids/(kg(·)d) (AA + lipid group), or 3.6 g amino acids/(kg(·)d) plus 2 g lipids/(kg(·)d) (high AA + lipid group). On postnatal day 2, infants received a primed continuous infusion of [U-(13)C6,(15)N]leucine. Mass spectrometry was used to determine the fractional and absolute albumin synthesis rates (FSR and ASR, respectively). RESULTS: In total, 28 infants (median gestational age 27 weeks (IQR 25-28), median birth weight 810 g (IQR 679-998) were studied. The median FSR was 6.5%/d in the control group, 10.6%/d in the AA group, and 12.3%/d in the high AA + lipid group, while the median was 84 mg/(kg(·)d) in the control group, 138 mg/(kg(·)d) in the AA group, and 160 mg/(kg(·)d) in the high AA + lipid group. CONCLUSION: A group of VLBW infants given parenteral nutrition containing lipids and high-dose amino acids showed a higher rate of albumin synthesis compared to infants receiving no lipids and standard amounts of amino acids during the first two days of life.

Intravenous lipids in preterm infants: impact on laboratory and clinical outcomes and long-term consequences.

Postnatal growth failure is still one of the most commonly observed morbidities in preterm infants. Intolerance of enteral nutrition is a common problem in these infants and in neonates with surgical conditions. Therefore, adequate parenteral nutrition is crucial to support organ development, including that of the brain. Short-term studies on the early introduction of parenteral lipids have demonstrated that early lipid administration seems safe and well tolerated and prevents essential fatty acid deficiency. Further well-designed and adequately powered studies are necessary to determine the optimal dose of lipid infusion and the long-term effects on morbidity, growth, and neurodevelopment. Administration of a pure soybean oil emulsion might result in excess formation of proinflammatory eicosanoids and peroxidation, and their use reduces the availability of the long-chain polyunsaturated fatty acids necessary for central nervous system development and immune function. Alternatives to the use of pure soybean oils include emulsions with partial replacement of soybean oil with medium-chain triglycerides, olive oil, and/or fish oil. These newer lipid emulsions offer many theoretical advantages. Future large-scale randomized controlled trials in premature infants should demonstrate whether these newer lipid emulsions are truly safe and result in improved short- and long-term outcomes. It seems safe to start lipid emulsions from birth onward at a rate of 2 g lipids/kg/day (based on short-term results only). Mixed lipid emulsions, including those containing fish oil, seem to reduce nosocomial infections in preterm infants and might reduce bile acid accumulation. Liver damage may be reduced by decreasing or removing lipids from parenteral nutrition or may be reduced by using fish oil-containing lipid emulsions containing high levels of vitamin E.

Amino acids and proteins.

Amino acids and protein are key factors for growth. The neonatal period requires the highest intake in life to meet the demands. Those demands include amino acids for growth, but proteins and amino acids also function as signalling molecules and function as neurotransmitters. Often the nutritional requirements are not met, resulting in a postnatal growth restriction. However, current knowledge on adequate levels of both amino acid as well as protein intake can avoid under nutrition in the direct postnatal phase, avoid the need for subsequent catch-up growth and improve later outcome.

Adaptive regulation of amino acid metabolism on early parenteral lipid and high-dose amino acid administration in VLBW infants - a randomized, controlled trial.

BACKGROUND & AIMS: An anabolic state can be achieved upon intravenous amino acid administration during the immediate postnatal phase despite a low energy intake. The optimal dosing of amino acid and energy intake has yet to be established. The aim was to quantify the efficacy of early initiation of parenteral lipids and increased amounts of amino acids on metabolism and protein accretion in very low birth weight infants. METHODS: 28 very low birth weight infants were randomized to receive parenteral nutrition with glucose and either 2.4 g amino acids/(kg·d) (control group), 2.4 g amino acids/(kg·d) plus 2-3 g lipid/(kg·d) (AA + lipid group), or 3.6 g amino acids/(kg·d) plus 2-3 g lipid/(kg·d) (high AA + lipid group) from birth onward. On postnatal day 2, we performed a stable isotope study with [1-(13)C]phenylalanine, [ring-D4]tyrosine, [U-(13)C6,(15)N]leucine, and [methyl-D3]α-ketoisocaproic acid to quantify intermediate amino acid metabolism. RESULTS: The addition of lipids only had no effect on phenylalanine metabolism, whereas the addition of both lipids and additional amino acids increased the amount of phenylalanine used for protein synthesis. In addition, high amino acid intake significantly increased the rate of hydroxylation of phenylalanine to tyrosine, increasing the availability of tyrosine for protein synthesis. However, it also increased urea concentrations. Increasing energy intake from 40 to 60 kcal/(kg·d) did not increase protein efficiency as measured by phenylalanine kinetics. The leucine data were difficult to interpret due to the wide range of results and inconsistency in the data between the phenylalanine and leucine models. CONCLUSIONS: High amino acid and energy intakes from birth onwards result in a more anabolic state in very low birth weight infants, but at the expense of higher urea concentrations, which reflects a higher amino acid oxidation. Long-term outcome data should reveal whether this policy deserves routine implementation. This trial was registered at www.trialregister.nl, trial number NTR1445, name Nutritional Intervention for Preterm Infants-2.

Amino acid homeostasis in the preterm infant.

Functional outcome of preterm infants is highly related to the quality and quantity of nutrients provided during the first few weeks of life. New guidelines, as published by the ESPGHAN in 2010, have provided means to prevent undernutrition in the NICU. Especially proteins and amino acids seem to play a pivotal role, and the optimal regimen has not yet been determined. New data on the intrauterine nutrient supply suggest a high amino acid intake during the fetal period. How these results might translate into improvement of especially neurocognitive outcome needs to be investigated.

Parenteral lipid administration to very-low-birth-weight infants--early introduction of lipids and use of new lipid emulsions: a systematic review and meta-analysis.

BACKGROUND: The use of intravenous lipid emulsions in preterm infants has been limited by concerns regarding impaired lipid tolerance. As a result, the time of initiation of parenteral lipid infusion to very-low-birth-weight (VLBW) infants varies widely among different neonatal intensive care units. However, lipids provide energy for protein synthesis and supply essential fatty acids that are necessary for central nervous system development. OBJECTIVE: The objective was to summarize the effects of initiation of lipids within the first 2 d of life and the effects of different lipid compositions on growth and morbidities in VLBW infants. DESIGN: A systematic review and meta-analysis of publications identified in a search of PubMed, EMBASE, and Cochrane databases was undertaken. Randomized controlled studies were eligible if information on growth was available. RESULTS: The search yielded 14 studies. No differences were observed in growth or morbidity with early lipid initiation. We found a weak favorable association of non-purely soybean-based emulsions with the incidence of sepsis (RR: 0.75; 95% CI: 0.56, 1.00). CONCLUSIONS: The initiation of lipids within the first 2 d of life in VLBW infants appears to be safe and well tolerated; however, beneficial effects on growth could not be shown for this treatment nor for the type of lipid emulsion. Emulsions that are not purely soybean oil-based might be associated with a lower incidence of sepsis. Large-scale randomized controlled trials in preterm infants are warranted to determine whether early initiation of lipids and lipid emulsions that are not purely soybean oil-based results in improved long-term outcomes.

Initial nutritional management of the preterm infant.

Postnatal nutrition has a large impact on long-term outcome of preterm infants. Evidence is accumulating showing even a relationship between nutrient supply in the first week of life and later cognitive development in extremely low birth weight infants. Since enteral nutrition is often not tolerated following birth, parenteral nutrition is necessary. Yet, optimal parenteral intakes of both energy and amino acids are not well established. Subsequently, many preterm infants fail to grow well, with long-term consequences. Early and high dose amino acid administration has been shown to be effective and safe in very low birth weight infants, but the effect of additional lipid administration needs to be defined.