Serum selenium levels of the very low birth weight premature newborn infants with bronchopulmonary dysplasia

BackgroundThe selenium (Se) is an essential trace element that has a critical role in synthesis and activity of a number of selenoproteins with protective properties against free radical damage. This study was conducted to detect the serum Se concentration in very low birth weight (VLBW) preterm infants and its association with bronchopulmonary dysplasia (BPD).Materials and methodsCord blood Se concentration was determined in 54 neonates with gestation age 30 week or less. Another sample was obtained from these infants at day 28 of birth and serum Se levels were measured by atomic absorption spectrophotometer. All neonates were followed for oxygen dependency at 28 day after birth and 36 week postmenstrual age.ResultsThe mean cord blood Se concentration in studied neonates was 64.78 ± 20.73 μg L^?1. Serum Se concentration was 60.33 ± 26.62 μg L^?1 at age 28-day. No significant correlation was observed for serum Se concentration at birth and at one month after birth (r = ?0.04, p = 0.72). BPD was diagnosed in 25 neonates (46%). The mean serum Se concentration at one month was 57.16 ± 29.68 μg L^?1 in patients with BPD (25 cases) and 63.27 ± 23.6 μg L^?1 in 29 patients without BPD (p = 0.40).ConclusionIn our study, serum Se concentration at 28 day of birth was lower than cord blood levels in preterm neonates, but we have not found significant difference among patients who had BPD or not with respect to serum Se concentrations at this age.     

Altered lung development in bronchopulmonary dysplasia

Bronchopulmonary dysplasia (BPD) is the main respiratory sequela of extreme prematurity. Its pathophysiology is complex, involving interactions between host and environment, likely to be significantly influenced by genetic factors. Thus, the clinical presentation and histological lesions have evolved over time, along with the reduction in neonatal injuries, and the care of more immature children. Impaired alveolar growth, however, is a lesion consistently observed in BPD, such that it is a key feature in BPD, and is even the dominant characteristic of the so‐called “new” forms of BPD. This review describes the key molecular pathways that are believed to be involved in the genesis of BPD. Much of our understanding is based on animal models, but this is increasingly being enriched by genetic approaches, and long‐term respiratory functional studies. Birth Defects Research (Part A) 100:158–167, 2014. © 2014 Wiley Periodicals, Inc.     

Nutrition of preterm infants in relation to bronchopulmonary dysplasia

Background

The pathogenesis of bronchopulmonary dysplasia (BPD) is multifactorial. In addition to prenatal inflammation, postnatal malnutrition also affects lung development.

Methods

A retrospective study was performed to analyse during the first two weeks of life the total, enteral and parenteral nutrition of premature infants (<31 weeks, birth weight ≤1500 g) born between 08/04 and 12/06.

Results

Ninety-five premature infants were analysed: 26 with BPD (27 ± 1 weeks) and 69 without BPD (28 ± 1 weeks). There was no statistical significant difference in the total intake of fluids, calories, glucose or protein and weight gain per day in both groups. The risk of developing BPD was slightly increased in infants with cumulative caloric intake below the minimal requirement of 1230 kcal/kg and a cumulative protein intake below 43.5 g/kg. Furthermore, the risk of developing BPD was significantly higher when infants had a cumulative fluid intake above the recommended 1840 ml/kg. In infants who developed BPD, the enteral nutrition was significantly lower than in non-BPD infants [456 ml/kg (IQR 744, 235) vs. 685 (IQR 987, 511)]. Infants who did not develop BPD reached 50% of total enteral feeding significantly faster [9.6 days vs. 11.5].

Conclusions

Preterm infants developing BPD received less enteral feeding, even though it was well compensated by the parenteral nutrient supply. Data suggest that a critical minimal amount of enteral feeding is required to prevent development of BPD; however, a large prospective clinical study is needed to prove this assumption.

     

Airway administration of corticosteroids for prevention of bronchopulmonary dysplasia in premature infants: a meta-analysis with trial sequential analysis

Background

Uncertainly prevails with regard to the use of inhalation or instillation steroids to prevent bronchopulmonary dysplasia in preterm infants. The meta-analysis with sequential analysis was designed to evaluate the efficacy and safety of airway administration (inhalation or instillation) of corticosteroids for preventing bronchopulmonary dysplasia (BPD) in premature infants.

Methods

We searched MEDLINE, EMBASE, CINAHL, and Cochrane CENTRAL from their inceptions to February 2017. All published randomized controlled trials (RCTs) evaluating the effect of airway administration of corticosteroids (AACs) vs placebo or systemic corticosteroid in prematurity were included. All meta-analyses were performed using Review Manager 5.3.

Results

Twenty five RCTs retrieved (n?=?3249) were eligible for further analysis. Meta-analysis and trial sequential analysis corrected the 95% confidence intervals estimated a lower risk of the primary outcome of BPD (relative risk 0.71, adjusted 95% confidence interval 0.57–0.87) and death or BPD (relative risk 0.81, adjusted 95% confidence interval 0.71–0.97) in AACs group than placebo and it is equivalent for preventing BPD than systemic corticosteroids. Moreover, AACs fail to increasing risk of death compared with placebo (relative risk 0.90, adjusted 95% confidence interval 0.40–2.03) or systemic corticosteroids (relative risk 0.81, 95% confidence interval 0.62–1.06).

Conclusions

Our findings suggests that AACs (especially instillation of budesonide using surfactant as a vehicle) are an effective and safe option for preventing BPD in preterm infants. Furthermore, the appropriate dose and duration, inhalation or instillation with surfactant as a vehicle and the long-term safety of airway administration of corticosteroids needs to be assessed in large trials.

     

Correlation of urinary inflammatory and oxidative stress markers in very low birth weight infants with subsequent development of bronchopulmonary dysplasia

Abstract

Currently, bronchopulmonary dysplasia (BPD) occurs almost exclusively in pre-term infants. In addition to prematurity, other factors like oxygen toxicity and inflammation can contribute to the pathogenesis. This study aimed to compare urinary inflammatory and oxidative stress markers between the no/mild BPD group and moderate/severe BPD group and between BPD cases with significant early lung disease like respiratory distress syndrome (RDS) (‘classic’ BPD) and with minimal early lung disease (‘atypical’ BPD). A total of 60 patients who were a gestational age < 30 weeks or a birth weight < 1250 g were included. Urine samples were obtained on the 1^st, 3^rd and 7^th day of life and measured the levels of leukotriene E₄ (LTE₄) and 8-hydroxydeoxyguanosine (8-OHdG). The 8-OHdG values on the 3^rd day showed significant correlation to duration of mechanical ventilation. The 8-OHdG levels on the 7^th day were the independent risk factor for developing moderate/severe BPD. In ‘classic’ BPD, the 8-OHdG values on the 3^rd day were higher than those of ‘atypical’ BPD. In ‘atypical’ BPD, the LTE₄ values on the 7^th day were higher than the values in ‘classic’ BPD. These results suggest that oxidative DNA damage could be the crucial mechanism in the pathogenesis of current BPD and the ongoing inflammatory process could be an important mechanism in ‘atypical’ BPD.     

Correlation of urinary inflammatory and oxidative stress markers in very low birth weight infants with subsequent development of bronchopulmonary dysplasia

Currently, bronchopulmonary dysplasia (BPD) occurs almost exclusively in pre-term infants. In addition to prematurity, other factors like oxygen toxicity and inflammation can contribute to the pathogenesis. This study aimed to compare urinary inflammatory and oxidative stress markers between the no/mild BPD group and moderate/severe BPD group and between BPD cases with significant early lung disease like respiratory distress syndrome (RDS) ('classic' BPD) and with minimal early lung disease ('atypical' BPD). A total of 60 patients who were a gestational age < 30 weeks or a birth weight < 1250 g were included. Urine samples were obtained on the 1(st), 3(rd) and 7(th) day of life and measured the levels of leukotriene E(4) (LTE(4)) and 8-hydroxydeoxyguanosine (8-OHdG). The 8-OHdG values on the 3(rd) day showed significant correlation to duration of mechanical ventilation. The 8-OHdG levels on the 7(th) day were the independent risk factor for developing moderate/severe BPD. In 'classic' BPD, the 8-OHdG values on the 3(rd) day were higher than those of 'atypical' BPD. In 'atypical' BPD, the LTE(4) values on the 7(th) day were higher than the values in 'classic' BPD. These results suggest that oxidative DNA damage could be the crucial mechanism in the pathogenesis of current BPD and the ongoing inflammatory process could be an important mechanism in 'atypical' BPD.     

Mechanisms of bronchopulmonary dysplasia

Bronchopulmonary dysplasia (BPD) is a chronic lung disease affecting premature infants with long term effect on lung function into adulthood. Multiple factors are involved in the development of BPD. This review will summarize the different mechanisms leading to this disease and highlight recent bench and clinical research targeted at understanding the role of the mesenchyme (both its cellular and extracellular components) in the pathogenesis of BPD.     

Epidemiology of bronchopulmonary dysplasia

Bronchopulmonary dysplasia (BPD) is among the most common and serious sequelae of preterm birth. BPD affects at least one‐quarter of infants born with birth weights less than 1500 g. The incidence of BPD increases with decreasing gestational age and birth weight. Additional important risk factors include intrauterine growth restriction, sepsis, and prolonged exposure to mechanical ventilation and supplemental oxygen. The diagnosis of BPD predicts multiple adverse outcomes including chronic respiratory impairment and neurodevelopmental delay. This review summarizes the diagnostic criteria, incidence, risk factors, and long‐term outcomes of BPD. Birth Defects Research (Part A) 100:145–157, 2014. © 2014 Wiley Periodicals, Inc.     

Pulmonary hypertension in bronchopulmonary dysplasia

Pulmonary hypertension is common in bronchopulmonary dysplasia and is associated with increased mortality and morbidity. This pulmonary hypertension is due to abnormal microvascular development and pulmonary vascular remodeling resulting in reduced cross‐sectional area of pulmonary vasculature. The epidemiology, etiology, clinical features, diagnosis, suggested management, and outcomes of pulmonary hypertension in the setting of bronchopulmonary dysplasia are reviewed. In summary, pulmonary hypertension is noted in a fifth of extremely low birth weight infants, primarily those with moderate or severe bronchopulmonary dysplasia, and persists to discharge in many infants. Diagnosis is generally by echocardiography, and some infants require cardiac catheterization to identify associated anatomic cardiac lesions or systemic‐pulmonary collaterals, pulmonary venous obstruction or myocardial dysfunction. Serial echocardiography and B‐type natriuretic peptide measurement may be useful for following the course of pulmonary hypertension. Currently, there is not much evidence to indicate optimal management approaches, but many clinicians maintain oxygen saturation in the range of 91 to 95%, avoiding hypoxia and hyperoxia, and often provide inhaled nitric oxide, sometimes combined with sildenafil, prostacyclin, or its analogs, and occasionally endothelin‐receptor antagonists. Birth Defects Research (Part A) 100:240–246, 2014. © 2014 Wiley Periodicals, Inc.     

Perturbation of gene expression of the chromatin remodeling pathway in premature newborns at risk for bronchopulmonary dysplasia

Background

One-third to one-half of all infants born before the 28th week of gestation develop bronchopulmonary dysplasia (BPD). Inflammatory regulators appear to be involved in the pathogenesis of BPD, possibly beginning in fetal life. To evaluate the feasibility of using expression profiling in umbilical cord tissue to discover molecular signatures for developmental staging and for determining risk of BPD, we conducted a cross-sectional study of infants born at less than 28 weeks of gestation (n = 54). Sections of umbilical cord were obtained at birth from 20 infants who later developed BPD and from 34 of their peers who did not develop BPD.

Results

Umbilical cord expression profiles at birth exhibited systematic differences in bioenergetic pathways with respect to gestational age. Infants who subsequently developed BPD had distinct signatures involving chromatin remodeling and histone acetylation pathways, which have previously been implicated in several adult onset lung diseases. These findings are consistent with prior work on inflammatory processes and bioenergetics in prematurity.

Conclusion

This study of gene expression of the newborn umbilical cord implicates the chromatin remodeling pathways in those premature infants who subsequently develop BPD. Larger sample sizes will be required to generate prognostic markers from umbilical cord profiles.     

Epithelial lining fluid free IGF-I-to-PAPP-A ratio is associated with bronchopulmonary dysplasia in preterm infants

Preterm newborns developing retinopathy of prematurity (ROP) and bronchopulmonary dysplasia (BPD) show persistently low levels of insulin-like growth factor-I (IGF-I) in sera. They also present higher free IGF-I concentrations in epithelial lining fluids (ELFs) and lung tissues. Pregnancy-associated plasma protein-A (PAPP-A) is a metalloproteinase that dissociates three binding proteins from the active form of IGF-I, namely free IGF-I. The present study analyzes the ELF concentrations of free IGF-I, PAPP-A, and their ratios in preterm newborns developing or not BPD, defined as O(2) dependence at 36 wk postmenstrual age. Bronchoalveolar lavage fluids of 41 infants (34 without and 7 with BPD) were analyzed on the 2nd and 4th day after birth. Infants developing BPD showed increased ELF free IGF-I and decreased PAPP-A concentrations on both days 2 and 4 compared with newborns without BPD. A nonsignificant trend between these 2 days was observed for free IGF-I (increasing) and PAPP-A (decreasing). On the same days, the free IGF-I-to-PAPP-A ratio was always significantly higher in patients developing BPD. These differences were more significant than those of IGF-I or PAPP-A when individually evaluated. A multivariate analysis confirmed the significance for free IGF-I on day 4, whereas the ratio was confirmed on both days 2 and 4. The same ratio was significantly correlated with some indexes of disease severity, such as hours of oxygen administration, days of hospitalization, and ROP severity scores. Finally, the ratio between ELF free IGF-I and PAPP-A appears to be a useful marker for lung injury of premature newborns.     

Influence of common non-synonymous Toll-like receptor 4 polymorphisms on bronchopulmonary dysplasia and prematurity in human infants

Bronchopulmonary dysplasia (BPD) is a common chronic lung disease and major risk factor for severe respiratory syncytial virus (RSV) infection among preterm infants. The Toll-like receptor 4 (TLR4) is involved in oxidative injury responses in the lungs. Two non-synonymous single nucleotide polymorphisms in the TLR4 gene have been associated with RSV infection in children. However, it is unclear to what extent this association is confounded by BPD or prematurity. In this study, we analyzed two population-based cohorts of preterm infants at risk for BPD as well as ethnicity-matched infants born at term, to test whether the TLR4 polymorphisms Asp299Gly (rs4986790) and Thr399Ile (rs4986791) are independently associated with BPD or premature birth. In a Canadian cohort (n = 269) composed of a majority of Caucasian preterm infants (BPD incidence of 38%), the TLR4-299 heterozygous genotype was significantly under-represented in infants without BPD (1.6% of infants versus 12% in infants with severe BPD) after adjusting for twins, ethnicity, gestational age, birth weight and gender (p = 0.014). This association was not replicated in a Finnish cohort (n = 434) of premature singletons or first-born siblings of Caucasian descent, although the incidence of BPD was substantially lower in this latter population (15%). We did not detect a significant association (>2-fold) between TLR4 genotypes and prematurity (p>0.05). We conclude that these TLR4 genotypes may have, at best, a modest influence on BPD severity in some populations of high-risk preterm infants. Further studies are warranted to clarify how clinical heterogeneity may impact genetic susceptibility to BPD.     

Plasma and erythrocyte selenium and glutathione peroxidase activity in preterm infants at risk for bronchopulmonary dysplasia

The purpose of this study was to examine the relationships between selenium status, as measured by plasma and erythrocyte selenium and glutathione peroxidase (GPx) activity, and other postnatal factors, including selenium intake, gestational age, and oxygen dependence in preterm infants at risk for bronchopulmonary dysplsia. Eighteen preterm infants of 30 wk gestational age or less were included. At postnatal wk 1 and 4, selenium concentrations and GPx activity were measured and oxygen dependence and daily selenium intakes were determined from the medical chart. Plasma and erythrocyte selenium concentrations decreased from wk 1 to wk 4, whereas erythrocyte GPx activity increased. Increased selenium intakes during wk 1 were associated with increased erythrocyte GPx activity at both time-points, as well as a decreased need for supplemental oxygen on d 28. Preterm infants display increasing erythrocyte GPx activity despite declines in plasma and erythrocyte selenium. GPx activity might be enhanced by very early selenium supplementation.     

Postnatal inflammation in the pathogenesis of bronchopulmonary dysplasia

Exposure to hyperoxia, invasive mechanical ventilation, and systemic/local sepsis are important antecedents of postnatal inflammation in the pathogenesis of bronchopulmonary dysplasia (BPD). This review will summarize information obtained from animal (baboon, lamb/sheep, rat and mouse) models that pertain to the specific inflammatory agents and signaling molecules that predispose a premature infant to BPD. Birth Defects Research (Part A) 100:189–201, 2014. © 2014 Wiley Periodicals, Inc.     

Nitric oxide levels and antioxidant enzyme activities in jaundices of premature infants

Free radicals are effective in the genesis of several diseases in the neonatal period. This study aimed to show the relationship between serum bilirubin levels and plasma nitric oxide and the activity of enzymes in the erythrocyte such as superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) in premature infants. In the study, 20 premature infants with newborn jaundice were included and the control group was formed by 15 premature infants without jaundice. Venous blood samples were taken from all neonates in the study and control groups on the first day of hospitalization. Plasma nitric oxide levels and activities of SOD, GSH-Px and CAT enzymes in the erythrocytes were investigated in these samples. Plasma nitric oxide and serum bilirubin levels were found to be significantly higher in the study group (47.4 +/- 7.25 micromol l(-1), 18.41 +/- 3.28 mg dl(-1), respectively) than those in the control group (33.46 +/- 6.43 micromol l(-1), 4.35 +/- 0.60 mg dl(-1), respectively; p < 0.001). In addition, erythrocyte SOD, GSH-Px and CAT enzyme activities (724 +/- 78.61, 673 +/- 90.5, 63 +/- 12.8 U g(-1) Hb, respectively) were found to be significantly lower in the study group than those in the control group (1208 +/- 129.04, 1097.6 +/- 75.8, 99.06 +/- 12.4 U g(-1) Hb, respectively, p < 0.001). It was concluded that in the aetiology of hyperbilirubinemia, neonatal erythrocytes and nitric oxide reactions are affected differently and that erythrocyte haemolysis caused as a result of these effects may play a role in the aetiopathogenesis of unconjugated hyperbilirubinemia. Haemolysis may also be seen because of the inadequacy of the protection by erythrocytes against the cytotoxic effects of free radicals resulting from the lack of antioxidant enzymes in these cells.     

Assessment of inhibited alveolar‐capillary membrane structural development and function in bronchopulmonary dysplasia

Bronchopulmonary dysplasia (BPD) is a chronic lung disease of extreme prematurity and is defined clinically by dependence on supplemental oxygen due to impaired gas exchange. Optimal gas exchange is dependent on the development of a sufficient surface area for diffusion. In the mammalian lung, rapid acquisition of distal lung surface area is accomplished in neonatal and early adult life by means of vascularization and secondary septation of distal lung airspaces. Extreme preterm birth interrupts secondary septation and pulmonary capillary development and ultimately reduces the efficiency of the alveolar‐capillary membrane. Although pulmonary health in BPD infants rapidly improves over the first few years, persistent alveolar‐capillary membrane dysfunction continues into adolescence and adulthood. Preventative therapies have been largely ineffective, and therapies aimed at promoting normal development of the air‐blood barrier in infants with established BPD remain largely unexplored. The purpose of this review will be: (1) to summarize the histological evidence of aberrant alveolar‐capillary membrane development associated with extreme preterm birth and BPD, (2) to review the clinical evidence assessing the long‐term impact of BPD on alveolar‐capillary membrane function, and (3) to discuss the need to develop and incorporate direct measurements of functional gas exchange into clinically relevant animal models of inhibited alveolar development. Birth Defects Research (Part A) 100:168–179, 2014. © 2014 Wiley Periodicals, Inc.     

Surfactant disaturated phosphatidylcholine kinetics in infants with bronchopulmonary dysplasia measured with stable isotopes and a two-compartment model.

We previously found a shorter surfactant disaturated phosphatidylcholine palmitate (DSPC-PA) half-life in infants with bronchopulmonary dysplasia (BPD) by using a single stable isotope tracer and simple formulas based on a one-exponential fit of the final portion of the enrichment decay curve. The aim of this study was to apply noncompartmental and compartmental analysis on the entire enrichment decay curve of DSPC-PA and to compare the kinetic data with our previous results. We analyzed 10 preterm newborns with BPD (gestational age 26 +/- 0.6 wk, weight 777 +/- 199 g) and 6 controls (gestational age 26 +/- 1.4 wk, weight 787 +/- 259 g). All took part in our previous study. Endotracheal 13C-labeled dipalmitoyl phosphatidylcholine was administered, and the 13C-enrichment of surfactant DSPC-PA was measured from serial tracheal aspirates by gas chromatography-mass spectrometry. Noncompartmental and compartmental models were numerically identified from the tracer-to-tracee ratio and kinetic parameters related to the accessible (pool accessible to sampling, likely to be the lung alveolar pool) and to the nonaccessible pools (pools not accessible to samplings, likely to be the intracellular storage pool) were estimated in the two study groups. Comparison was performed by Mann-Whitney test. A two-compartment model provided the most reliable assessment of DSPC-PA kinetics. In BPD vs. controls, mean +/- SE residence time of DSPC-PA in the accessible was 17.5 +/- 2.6 vs. 32.2 +/- 6.4 h (P < 0.05), whereas it was 49.7 +/- 3.5 vs. 54.4 +/- 3.9 h (NS, not significant) in the nonaccessible pool; DSPC-PA recycling was 0.26 +/- 0.05 vs. 0.43 +/- 0.04% (NS), respectively. A two-compartment model of surfactant DSPC-PA kinetics allowed a thorough assessment of DSPC-PA kinetics, including masses, synthesis, and fluxes between pools. The most important findings of this study are that in BPD infants DSPC-PA loss from the alveolar pool was higher and recycling through the intracellular pool lower than in controls.