From bench to bedside: in vitro and in vivo evaluation of a neonate-focused nebulized surfactant delivery strategy.

BACKGROUND: Non-invasive delivery of nebulized surfactant has been a neonatology long-pursued goal. Nevertheless, the clinical efficacy of nebulized surfactant remains inconclusive, in part, due to the great technical challenges of depositing nebulized drugs in the lungs of preterm infants. The aim of this study was to investigate the feasibility of delivering nebulized surfactant (poractant alfa) in vitro and in vivo with an adapted, neonate-tailored aerosol delivery strategy. METHODS: Particle size distribution of undiluted poractant alfa aerosols generated by a customized eFlow-Neos nebulizer system was determined by laser diffraction. The theoretical nebulized surfactant lung dose was estimated in vitro in a clinical setting replica including a neonatal continuous positive airway pressure (CPAP) circuit, a cast of the upper airways of a preterm neonate, and a breath simulator programmed with the tidal breathing pattern of an infant with mild respiratory distress syndrome (RDS). A dose-response study with nebulized surfactant covering the 100-600 mg/kg nominal dose-range was conducted in RDS-modelling, lung-lavaged spontaneously-breathing rabbits managed with nasal CPAP. The effects of nebulized poractant alfa on arterial gas exchange and lung mechanics were assessed. Exogenous alveolar disaturated-phosphatidylcholine (DSPC) in the lungs was measured as a proxy of surfactant deposition efficacy. RESULTS: Laser diffraction studies demonstrated suitable aerosol characteristics for inhalation (mass median diameter, MMD = 3 µm). The mean surfactant lung dose determined in vitro was 13.7% ± 4.0 of the 200 mg/kg nominal dose. Nebulized surfactant delivered to spontaneously-breathing rabbits during nasal CPAP significantly improved arterial oxygenation compared to animals receiving CPAP only. Particularly, the groups of animals treated with 200 mg/kg and 400 mg/kg of nebulized poractant alfa achieved an equivalent pulmonary response in terms of oxygenation and lung mechanics as the group of animals treated with instilled surfactant (200 mg/kg). CONCLUSIONS: The customized eFlow-Neos vibrating-membrane nebulizer system efficiently generated respirable aerosols of undiluted poractant alfa. Nebulized surfactant delivered at doses of 200 mg/kg and 400 mg/kg elicited a pulmonary response equivalent to that observed after treatment with an intratracheal surfactant bolus of 200 mg/kg. This bench-characterized nebulized surfactant delivery strategy is now under evaluation in Phase II clinical trial (EUDRACT No.:2016-004547-36).

Comparison of "IN-REC-SUR-E" and LISA in preterm neonates with respiratory distress syndrome: a randomized controlled trial (IN-REC-LISA trial).

BACKGROUND: Surfactant is a well-established therapy for preterm neonates affected by respiratory distress syndrome (RDS). The goals of different methods of surfactant administration are to reduce the duration of mechanical ventilation and the severity of bronchopulmonary dysplasia (BPD); however, the optimal administration method remains unknown. This study compares the effectiveness of the INtubate-RECruit-SURfactant-Extubate (IN-REC-SUR-E) technique with the less-invasive surfactant administration (LISA) technique, in increasing BPD-free survival of preterm infants. This is an international unblinded multicenter randomized controlled study in which preterm infants will be randomized into two groups to receive IN-REC-SUR-E or LISA surfactant administration. METHODS: In this study, 382 infants born at 24+0-27+6 weeks' gestation, not intubated in the delivery room and failing nasal continuous positive airway pressure (nCPAP) or nasal intermittent positive pressure ventilation (NIPPV) during the first 24 h of life, will be randomized 1:1 to receive IN-REC-SUR-E or LISA surfactant administration. The primary outcome is a composite outcome of death or BPD at 36 weeks' postmenstrual age. The secondary outcomes are BPD at 36 weeks' postmenstrual age; death; pulse oximetry/fraction of inspired oxygen; severe intraventricular hemorrhage; pneumothorax; duration of respiratory support and oxygen therapy; pulmonary hemorrhage; patent ductus arteriosus undergoing treatment; percentage of infants receiving more doses of surfactant; periventricular leukomalacia, severe retinopathy of prematurity, necrotizing enterocolitis, sepsis; total in-hospital stay; systemic postnatal steroids; neurodevelopmental outcomes; and respiratory function testing at 24 months of age. Randomization will be centrally provided using both stratification and permuted blocks with random block sizes and block order. Stratification factors will include center and gestational age (24+0 to 25+6 weeks or 26+0 to 27+6 weeks). Analyses will be conducted in both intention-to-treat and per-protocol populations, utilizing a log-binomial regression model that corrects for stratification factors to estimate the adjusted relative risk (RR). DISCUSSION: This trial is designed to provide robust data on the best method of surfactant administration in spontaneously breathing preterm infants born at 24+0-27+6 weeks' gestation affected by RDS and failing nCPAP or NIPPV during the first 24 h of life, comparing IN-REC-SUR-E to LISA technique, in increasing BPD-free survival at 36 weeks' postmenstrual age of life. TRIAL REGISTRATION: ClinicalTrials.gov NCT05711966. Registered on February 3, 2023.

Intrapulmonary drug administration in neonatal and paediatric critical care: a comprehensive review.

Administration of drugs directly into the respiratory tree first was proposed a long time ago. Surfactant is the paradigmatic example of such therapies. Many other drugs have been used in the same way and further compounds are under investigation for this aim. In the last two decades, despite the wide number of drugs available for direct lung administration in critical care patients, few controlled data exist regarding their use in neonates and infants. This review will focus on drugs clinically available in a critical care setting for neonates and infants, including bronchodilators, pulmonary vasodilators, anti-inflammatory agents, mucolytics, resuscitative anti-infective agents, surfactants and other drugs. We provide an evidence-based comprehensive review of drugs available for intratracheal administration in paediatric and neonatal critical care and we examine possible advantages and risks for each proposed indication.

EIA and GC/MS analysis of 8-isoprostane in EBC of children with problematic asthma.

Asthmatic airways are characterised by enhanced oxidative stress, which can be studied by measuring biomarkers, such as 8-isoprostane. The aims of the present study were: 1) to measure the concentrations of 8-isoprostane in exhaled breath condensate (EBC) and urine of children with problematic and well-controlled asthma; 2) to compare the concentrations of 8-isoprostane measured by gas chromatographic/negative ion chemical ionisation mass spectrometry (GC/NICI-MS) and by an enzymatic immunoassay (EIA). We recruited 20 asthmatic allergic children, 13 with well-controlled asthma and seven with problematic asthma. They underwent exhaled nitric oxide measurements and spirometry, and both EBC and urine samples were collected. 8-isoprostane was measured in EBC by GC/NICI-MS and EIA. 8-isoprostane concentrations in EBC were significantly higher in children with problematic asthma than in children with well-controlled asthma (p = 0.01). An acceptable reproducibility emerged between GC/NICI-MS and EIA (coefficient of reproducibility 11.5 pg x mL(-1)). 8-isoprostane levels measured in urine did not correlate with those measured in EBC. We showed that 8-isoprostane in EBC was significantly increased in children with problematic asthma, suggesting a role for oxidative stress in this asthma phenotype. In addition we found an acceptable reproducibility of EIA compared to GC/NICI-MS, even if the latter method had higher accuracy.

Fibrinogen kinetics and protein turnover in obese non-diabetic males: effects of insulin.

BACKGROUND: Although hyperfibrinogenemia and insulin resistance are common in obesity and diabetes mellitus, the impact of obesity per se on fibrinogen turnover and the insulin effects on fibrinogen and protein kinetics is unknown. METHODS: We measured fibrinogen and albumin fractional (FSR) and absolute (ASR) synthesis rates, as well as protein turnover, in non-diabetic, obese and in control male subjects both before and following an euglycemic, euaminoacidemic, hyperinsulinemic clamp, using L-[(2)H(3)]-Leucine isotope infusion. RESULTS: In the obese, basal fibrinogen concentrations was approximately 25% greater (p < 0.035), and fibrinogen pool approximately 45% greater (p < 0.005), than in controls. Both FSR and ASR of fibrinogen were similar to control values. With hyperinsulinemia, although fibrinogen FSR and ASR were not significantly modified with respect to baseline in either group, fibrinogen ASR resulted to be approximately 50% greater in the obese than in controls (p < 0.015). Hyperinsulinemia equally stimulated albumin synthesis and suppressed leucine appearance from endogenous proteolysis in both groups. Amino acid clearance was also similar. In the obese, the insulin-mediated glucose disposal was approximately 50% lower (p < 0.03) than in controls, and it was inversely correlated with fibrinogen ASR during the clamp in both groups (r = - 0.58). CONCLUSIONS: In obese, non-diabetic males, post absorptive fibrinogen production is normal. Whole-body amino acid disposal, basal and insulin-responsive protein degradation, and albumin synthesis are also normal. However, the greater fibrinogen ASR in the obese with hyperinsulinemia, and the inverse relationship between insulin sensitivity and clamp fibrinogen production, suggest a role for hyperinsulinemia and/or insulin resistance on fibrinogen production in obesity.

Enteral nutrient supply for preterm infants: commentary from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition.

The number of surviving children born prematurely has increased substantially during the last 2 decades. The major goal of enteral nutrient supply to these infants is to achieve growth similar to foetal growth coupled with satisfactory functional development. The accumulation of knowledge since the previous guideline on nutrition of preterm infants from the Committee on Nutrition of the European Society of Paediatric Gastroenterology and Nutrition in 1987 has made a new guideline necessary. Thus, an ad hoc expert panel was convened by the Committee on Nutrition of the European Society of Paediatric Gastroenterology, Hepatology, and Nutrition in 2007 to make appropriate recommendations. The present guideline, of which the major recommendations are summarised here (for the full report, see http://links.lww.com/A1480), is consistent with, but not identical to, recent guidelines from the Life Sciences Research Office of the American Society for Nutritional Sciences published in 2002 and recommendations from the handbook Nutrition of the Preterm Infant. Scientific Basis and Practical Guidelines, 2nd ed, edited by Tsang et al, and published in 2005. The preferred food for premature infants is fortified human milk from the infant's own mother, or, alternatively, formula designed for premature infants. This guideline aims to provide proposed advisable ranges for nutrient intakes for stable-growing preterm infants up to a weight of approximately 1800 g, because most data are available for these infants. These recommendations are based on a considered review of available scientific reports on the subject, and on expert consensus for which the available scientific data are considered inadequate.

Meckel's diverticulum perforation in a newborn positive to Sars-Cov-2.

The health emergency linked to the Sars-Cov-2 infection represented an absolutely new problem for all health professionals. In particular, the information regarding the spread of the virus in the pediatric field and its manifestations are still incomplete. In this paper we present a case of neonatal infection which, as far as we know, represents one of the few published cases and which occurred in a patient who came to our attention for acute abdomen from intestinal perforation. The perforation was caused by Meckel's diverticulum, an event considered infrequent in the first year of life and almost exceptional in the neonatal period. This case required particular management, putting pediatric surgeons in front of new and difficult to solve problems. New onset clinical events, such as this one described, represent an opportunity for sharing useful data for the creation of universal protocols for the management of patients with problems that are becoming common and of which little is known.

Factors affecting early-life intestinal microbiota development.

OBJECTIVES: This paper reviews the published evidence on early-life intestinal microbiota development, as well as the different factors influencing its development before, at, and after birth. A literature search was done using PubMed, Cochrane and EMBASE databases. A growing body of evidence indicates that the intrauterine environment is not sterile as once presumed, but that maternal-fetal transmission of microbiota occurs during pregnancy. The consecutive order of bacteria with which the gastrointestinal tract is colonized will influence the outcome of community assembly and the ecological success of individual colonizers. The genetic background of the infant may also strongly influence microbial colonization of the gastrointestinal tract. The composition and development of infant gut microbiota can be influenced by many prenatal factors, such as maternal diet, obesity, smoking status, and use of antibiotic agents during pregnancy. Mode of delivery is generally accepted as a major factor determining the initial colonization. Breast milk stimulates the most balanced microbiome development for the infant, mainly because of its high content of unique oligosaccharides. Feeding is another important factor to determine intestinal colonization. Compared with breastfed infants, formula-fed infants have an increased richness of species. Initial clinical studies show that infant formulas supplemented with specific human milk oligosaccharides (HMOs) -2´-fucosyllactose alone or in combination with lacto-n-neotetraose are structurally identical to those in breast milk. HMOs increase the proportion of infants with a high bifidobacterial-dominated gut microbiota typical of that observed in breastfed infants, lead to plasma immune marker profiles similar to those of breast-fed infants and to lower morbidity and antibiotics use. Further clinical studies with the same, others or more HMOs are needed to confirm these clinical effects. A growing number of studies have reported on how the composition and development of the microbiota during early life will affect risk factors related to health up to and during adulthood. If exclusive breastfeeding is not possible, the composition of infant formula should be adapted to stimulate the development of a bifidobacterial-dominated gut microbiota typical of that observed in breastfed infants. The main components in breast milk that stimulate the growth of specific bifidobacteria are HMOs.

Correlation between cardiorespiratory events and gastro-esophageal reflux in preterm and term infants: Analysis of predisposing factors.

BACKGROUND: The association between cardiorespiratory events (CRE) and gastro-esophageal reflux (GER) among neonates is still controversial. AIMS: To test such an association in preterm and term infants. STUDY DESIGN: Prospective observational study. SUBJECTS: Forty-seven infants with suspected GER and recurrent CRE admitted at a neonatal intensive care unit, who underwent simultaneous and synchronized 24-hour recording of heart rate (HR), peripheral oxygen saturation (SpO2) and pH-impedance monitoring (MII-pH). HR/SpO2 data were filtered to avoid artefactual episodes of hypoxia and hypoperfusion. OUTCOME MEASURES: The main outcome measure was the symptom association probability (SAP), with a 2-minute time window. Infants with positive (>95%) and negative (≤95%) SAP index tests were compared by univariate and multivariate statistics. RESULTS: Median gestational age at birth was 294/7 weeks, median age at study 36 days. We recorded 3341 GER events and 4936 CRE (4710 desaturations, 226 bradycardias); 609/4936 (12%) CRE were temporally associated with GER episodes: 338 preceded and 271 followed GER events. The SAP index was significant in 5/47 (11%) patients. The SAP index including only CRE following GER events was significant in 3/47 (6%). There was no significant difference in the number of acid, weakly acid, non-acid, pH-only events preceding or following CRE between infants with SAP-positive and SAP-negative tests. Infants with positive SAP-index tests compared to those with SAP-negative tests had lower weight gain in the three days preceding the test and tended to have lower birth weight. CONCLUSIONS: GER and CRE were associated in <11% of patients. The evaluation of ponderal growth might be helpful in predicting such an association.

Surgical management of Necrotizing Enterocolitis in an Incredibly Low Birth Weight infant and review of the Literature.

Survival of preterm infants have dramatically improved over the last decades. Nonetheless, infants born preterm remain vulnerable to many complications, including necrotizing enterocolitis (NEC). The severity of the disease and the mortality rate are directly correlated with decreasing gestational age and birth weight. Despite surgical treatment mortality rate remains very high in extremely premature infants, especially in newborns at the lowest limit of viability. Survival of infants of birth weight (BW) below 750 g has been increasingly reported in recent years, however the overall mortality in extremely low "BW" infants (ELBW) requiring surgery for NEC has not decreased over the past years. We describe our experience with a male preterm infant who survived after an ileostomy procedure for Bell stage II NEC, with improving neuromotor skills at 2 years follow up. Although standard indication to surgery is Bell stage III, in our case the choice of minimal laparotomy, exploration of the bowel and ileostomy at Bell stage II was safe and effective. Our experience suggest that surgery has not a negative impact on survival and ileostomy could prevent further damage of the bowel in NEC. We hypothesize that indication to surgery at an earlier stage may prevent further progression of the disease without a significantly negative impact on survival. Further studies are needed to confirm the appropriateness of this approach in ELBW infants.

Caffeine for preterm infants: current indications and uncertainties.

Caffeine is one of the most commonly used therapies in Neonatology, with different indications such as the treatment of apnea and the prevention of extubation failure and bronchopulmonary dysplasia. However, there are still uncertainties regarding effects on central nervous system development, time of discontinuation and dosing of the drug.

Size at birth by gestational age and hospital mortality in very preterm infants: results of the area-based ACTION project.

BACKGROUND: Size at birth is an important predictor of neonatal outcomes, but there are inconsistencies on the definitions and optimal cut-offs. AIMS: The aim of this study is to compute birth size percentiles for Italian very preterm singleton infants and assess relationship with hospital mortality. STUDY DESIGN: Prospective area-based cohort study. SUBJECTS: All singleton Italian infants with gestational age 22-31 weeks admitted to neonatal care in 6 Italian regions (Friuli Venezia-Giulia, Lombardia, Marche, Tuscany, Lazio and Calabria) (n. 1605). OUTCOME MEASURE: Hospital mortality. METHODS: Anthropometric reference charts were derived, separately for males and females, using the lambda (λ) mu (µ) and sigma (σ) method (LMS). Logistic regression analysis was used to estimate mortality rates by gestational age and birth weight centile class, adjusting for sex, congenital anomalies and region. RESULTS: At any gestational age, mortality decreased as birth weight centile increased, with lowest values observed between the 50th and the 89th centiles interval. Using the 75th-89th centile class as reference, adjusted mortality odds ratios were 7.94 (95% CI 4.18-15.08) below 10th centile; 3.04 (95% CI 1.63-5.65) between the 10th and 24th; 1.96 (95% CI 1.07-3.62) between the 25th and the 49th; 1.25 (95% CI 0.68-2.30) between the 50(h) and the 74th; and 2.07 (95% CI 1.01-4.25) at the 90th and above. CONCLUSIONS: Compared to the reference, we found significantly increasing adjusted risk of death up to the 49th centile, challenging the usual 10th centile criterion as risk indicator. Continuous measures such as the birthweight z-score may be more appropriate to explore the relationship between growth retardation and adverse perinatal outcomes.

Medium-chain triacylglycerols in formulas for preterm infants: effect on plasma lipids, circulating concentrations of medium-chain fatty acids, and essential fatty acids.

Limited information is available on the metabolic fate of medium-chain triacylglycerols (triglycerides) after intestinal absorption and on their influence on essential fatty acid metabolism. We studied in preterm infants the effect of two infant formulas, one with a high (HMCT) and one with a low (LMCT) medium-chain triacylglycerol content, on plasma fatty acids. The HMCT formula contained 46 mol% 8:0 + 10:0 and the LMCT formula (4.8 mol% 8:0 + 10:0) had approximately twice the amount of long-chain saturated and monounsaturated fatty acids as the HMCT. Both formulas had similar contents of linoleic and linolenic acids. Plasma lipids and fatty acids were determined at birth and on day 24 of life in 20 infants fed the LMCT (n = 12) or HMCT (n = 8) formula. Significant amounts of medium-chain fatty acids were found in the systemic circulation of the infants fed the HMCT formula, mainly in plasma fatty acids and triacylglycerols. Despite striking dietary differences, palmitic and stearic acids were not different between groups, indicating de novo synthesis of long-chain fatty acids with the HMCT formula. Plasma phospholipid docosahexaenoic acid was significantly lower in the HMCT group than in the LMCT infants (1.38 +/- 0.07 compared with 1.73 +/- 0.07 mol%, P = 0.002). Our data indicate that a high MCT intake in preterm infants increases lipogenesis, and dietary nonessential fatty acids interfere with the metabolism of docosahexaenoic acid.

Intestinal absorption of long-chain polyunsaturated fatty acids in preterm infants fed breast milk or formula.

The importance of long-chain polyunsaturated fatty acids (LCPs) in the development of preterm infants is now well accepted but the source of dietary LCPs to be added to infant formulas remains controversial. We measured dietary intakes, fecal output, and percentages of intestinal absorption of n-6 and n-3 LCPs in healthy preterm infants fed exclusively preterm breast milk (PBM; n = 20), formula without LCPs added (NLCPs; n = 19), formula with LCPs derived from phospholipids (PL-LCPs; n = 19), or formula with LCPs from triacylglycerols (TG-LCPs; n = 19). Intestinal absorption of arachidonic acid was not different in the four groups but docosahexaenoic acid was better absorbed from PL-LCPs than from PBM (88.3 +/- 1.8% compared with 78.4 +/- 4.0%, P < 0.05) Total absorption of n-6 LCPs was not different between groups but total n-3 LCPs were better absorbed from PL-LCPs than from PBM or TG-LCPs (88.7 +/- 1.9%, 79.2 +/- 4.4%, and 80.4 +/- 2.2%, respectively). In conclusion, docosahexaenoic acid and arachidonic acid were absorbed as efficiently from TG-LCPs formula as from breast milk fat. Absorption of docosahexaenoic acid and n-3 LCPs was greater from PL-LCPs formula than from PBM or TG-LCPs formula.

Effect of dietary triacylglycerol fatty acid positional distribution on plasma lipid classes and their fatty acid composition in preterm infants.

Seven premature infants were each fed, for 1 wk in a crossover design. The beta formula contained triacylglycerols resembling the stereoisomeric structure of human milk fat (25.4% by wt 16:0, 76.1% of which is at the sn-2 position), whereas in the alpha formula 87.3% of total 16:0 (25.7% by wt was at the sn-1,3 positions. Plasma lipids and their fatty acid compositions were determined at the end of each 1 wk study period. Infants fed with the beta formula had higher percentages of palmitic acid in plasma sterol esters, triacylglycerols, and free fatty acids, and lower linoleic acid in triacylglycerols than with the alpha formula. Premature infants fed formulas with triacylglycerols 16:0 predominantly in the sn-2 rather than the sn-1,3 positions had alterations in their plasma fatty acids consistent with enhanced absorption of 16:0 from the sn-2 compared with the sn-1,3 positions.

Feeding premature newborn infants palmitic acid in amounts and stereoisomeric position similar to that of human milk: effects on fat and mineral balance.

The effect of the structure of human milk triglycerides on intestinal fat absorption remains controversial. Twelve infants were each fed, for 1 wk in a crossover design, two formulas that differed only in triglyceride configuration. The "beta" formula contained triglycerides similar to those in human milk (26% palmitic acid, esterified predominantly to the sn-2 position) whereas in the "alpha" formula, which contained triglycerides similar to those in formulas currently marketed, palmitate was mainly at the sn-1,3 positions. Fatty acid, fat, and mineral balances were measured at the end of each 1-wk period. Myristic, palmitic, and stearic acids were absorbed better from the beta formula, but total fat excretion was not reduced. During the feeding of beta formula fecal calcium excretion was lower, urinary calcium higher, and urinary phosphate lower. A formula containing triglycerides similar to those in human milk has significant effects on fatty acid intestinal absorption and improves mineral balance in comparison with a conventional formula.

Conversion of octanoic acid into long-chain saturated fatty acids in premature infants fed a formula containing medium-chain triglycerides.

A large number of very-low-birth weight infants are fed formulas containing medium-chain triglycerides (MCT) to enhance fat and calcium absorption. Studies are available on the intestinal absorption of MCT, which is nearly complete, but uncertainties exist on the metabolic fate of octanoic acid, the major component of MCT. Oxidation accounts for approximately 50% of the dietary intake, and losses as dicarboxylic acids in the urine are negligible. Since storage in adipose tissue is limited, conversion into long-chain fatty acids (LCFA) is likely to be an important route. To study the nonoxidative metabolism of MCT, six preterm infants fed a standard premature formula containing 38 weight% (wt%) MCT (54 mol% medium-chain fatty acids (MCFA), of which 35 mol% is octanoic acid) were studied at 4 weeks of age, when on full oral intake and receiving on average 130 kcal/kg/d. The study consisted of an oral primed constant-rate infusion of [13C]-octanoate and the measurement of the 13C enrichment of individual fatty acids in plasma triglycerides (TG) by a highly sensitive on-line combustion method using gas chromatography-isotope ratio mass spectrometry (GC-IRMS). We observed a significant incorporation of the dietary [13C]-octanoic acid in plasma TG (10.0% +/- 4.5% of the enrichment of the diet). A noticeable incorporation of the label was detected in myristic and palmitic acids (4.6% +/- 2.5% and 7.8% +/- 4.1% of the octanoic enrichment of the diet). The absolute amount of the fatty acids was studied with conventional GC, and the plasma TG fatty acid profile differed markedly from the diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Iron supplementation enhances response to high doses of recombinant human erythropoietin in preterm infants.

AIMS: To determine whether iron supplementation would enhance erythropoiesis in preterm infants treated with high doses of human recombinant erythropoietin (r-HuEPO). METHODS: Sixty three preterm infants were randomly allocated at birth to one of three groups to receive: r-HuEPO alone, 1200 IU/kg/week (EPO); or r-HuEPO and iron, 1200 IU/kg/week of r-HuEPO plus 20 mg/kg/week of intravenous iron (EPO + iron); or to serve as controls. All three groups received blood transfusions according to uniform guidelines. RESULTS: Infants in the EPO + iron group needed fewer transfusions than controls--mean (95% CI) 1.0 (0.28-1.18) vs 2.9 (1.84-3.88) and received lower volumes of blood--mean (95% CI) 16.7 (4.9-28.6) vs 44.4 (29.0-59.7) ml/kg. The EPO group also needed lower volumes of blood than the controls--mean (95% CI) 20.1 (6.2-34.2) vs 44.4 (29.0-59.7) ml/kg, but the same number of transfusions, 1.3 (0.54-2.06) vs 2.9 (1.84-3.88). Reticulocyte and haematocrit values from postnatal weeks 5 to 8 were higher in the EPO + iron than in the EPO group, and both groups had higher values than the controls. Mean (SEM) plasma ferritin was lower in the EPO group-65 (55) micrograms/l than in the EPO + iron group 780 (182) micrograms/l, and 561 (228) micrograms/l in the control infants. CONCLUSIONS: Early administration of high doses of r-HuEPO with iron supplements significantly reduced the need for blood transfusion. Intravenous iron (20 mg/kg/week in conjunction with r-HuEPO yielded a higher reticulocyte count and haematocrit concentration after the forth week of life than r-HuEPO alone. Infants treated with r-HuEPO alone showed signs of reduced iron stores.

Metabolic and respiratory effects of theophylline in the preterm infant.

BACKGROUND: Methylxanthines are often administered to preterm infants for the treatment of apnoea. AIMS: To study the effects of theophylline on energy metabolism, physical activity, and lung mechanics in preterm infants. METHODS: Indirect calorimetry was performed for six hours before and after administration of a bolus of theophylline (5 mg/kg) in 18 preterm infants while physical activity was recorded with a video camera. Lung mechanics measurements were performed at baseline and 12 and 24 hours after theophylline treatment. RESULTS: Theophylline increased mean (SEM) energy expenditure by 15 (5) kJ/kg/day and augmented carbohydrate utilisation from 6.8 to 8.0 g/kg/day, but fat oxidation was unchanged. After theophylline treatment, preterm infants had faster respiration, lower transcutaneous CO2, and improved static respiratory compliance without increased physical activity. CONCLUSIONS: A bolus of 5 mg/kg theophylline increased energy expenditure independently of physical activity, increased carbohydrate utilisation, and improved respiratory compliance. The increased energy expenditure could be detrimental to the growth of the preterm infant.

Amino acid solutions for premature neonates during the first week of life: the role of N-acetyl-L-cysteine and N-acetyl-L-tyrosine.

Tyrosine and cyst(e)ine are amino acids that are thought to be essential for preterm neonates. These amino acids have low stability (cyst(e)ine) or low solubility (tyrosine) and are therefore usually present only in small amounts in amino acid solutions. Acetylation improves the stability and solubility of amino acids, facilitating a higher concentration in the solution. We compared three commercially available amino acid solutions, Aminovenös-N-päd 10%, Vaminolact 6.5%, and Primène 10%, administered to 20 low-birth-weight neonates on total parenteral nutrition from postnatal day 2 onward. Aminovenös-N-päd 10% contains acetylated tyrosine and acetylated cysteine; the other solutions do not contain acetylated amino acids and differ in the amount of tyrosine and cysteine added. On postnatal day 7, plasma amino acids were measured together with urinary excretion of amino acids and the total nitrogen excretion; 38% of the intake of N-acetyl-L-tyrosine and 53% of the intake of N-acetyl-L-cysteine were excreted in urine. Plasma levels of N-acetyl-L-tyrosine (331 +/- 74 mumol/L) and N-acetyl-L-cysteine (18 +/- 29 mumol/L) were higher than those of tyrosine (105 +/- 108 mumol/L) and cystine (11 +/- 9 mumol/L), respectively. Plasma tyrosine levels in the groups receiving small amounts of tyrosine remained just below the reference range. We show a linear correlation of plasma cystine with the intake of cysteine (r = .75, p = 0.01), but not with N-acetyl-L-cysteine. The estimated intake of cysteine should be 500 mumol.kg-1.d-1 in order to obtain levels comparable with those shown in normal term, breast-fed neonates. Nitrogen retention did not differ among the three groups (247 to 273 mg.kg-1.d-1).(ABSTRACT TRUNCATED AT 250 WORDS)