Approaches to Interdisciplinary Care for Infants with Severe Bronchopulmonary Dysplasia: A Survey of the Bronchopulmonary Dysplasia Collaborative.

OBJECTIVE: Bronchopulmonary dysplasia (BPD) remains the most common late morbidity for extremely premature infants. Care of infants with BPD requires a longitudinal approach from the neonatal intensive care unit to ambulatory care though interdisciplinary programs. Current approaches for the development of optimal programs vary among centers. STUDY DESIGN: We conducted a survey of 18 academic centers that are members of the BPD Collaborative, a consortium of institutions with an established interdisciplinary BPD program. We aimed to characterize the approach, composition, and current practices of the interdisciplinary teams in inpatient and outpatient domains. RESULTS: Variations exist among centers, including composition of the interdisciplinary team, whether the team is the primary or consult service, timing of the first team assessment of the patient, frequency and nature of rounds during the hospitalization, and the timing of ambulatory visits postdischarge. CONCLUSION: Further studies to assess long-term outcomes are needed to optimize interdisciplinary care of infants with severe BPD. KEY POINTS: · Care of infants with BPD requires a longitudinal approach from the NICU to ambulatory care.. · Benefits of interdisciplinary care for children have been observed in other chronic conditions.. · Current approaches for the development of optimal interdisciplinary BPD programs vary among centers..

Prostanoids and their analogues for the treatment of pulmonary hypertension in neonates.

BACKGROUND: Persistent pulmonary hypertension of the newborn (PPHN) is a disease entity that describes a physiology in which there is persistence of increased pulmonary arterial pressure. PPHN is characterised by failure to adapt to a functional postnatal circulation with a fall in pulmonary vascular resistance. PPHN is responsible for impairment in oxygenation and significant neonatal mortality and morbidity. Prostanoids and their analogues may be useful therapeutic interventions due to their pulmonary vasodilatory and immunomodulatory effects. OBJECTIVES: Primary objective• To determine the efficacy and safety of prostanoids and their analogues (iloprost, treprostinil, and beraprost) in decreasing mortality and the need for extracorporeal membrane oxygenation (ECMO) among neonates with PHSecondary objective• To determine the efficacy and safety of prostanoids and their analogues (iloprost, treprostinil, and beraprost) in decreasing neonatal morbidity (necrotizing enterocolitis (NEC), chronic lung disease (CLD), retinopathy of prematurity (ROP), intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), length of hospital stay, and duration of mechanical ventilation) and improving neurodevelopmental outcomes among neonates with PHComparisons• Prostanoids and their analogues at any dosage or duration used to treat PPHN versus 'standard treatment without these agents', placebo, or inhaled nitric oxide (iNO) therapy• Prostanoids and their analogues at any dosage or duration used to treat refractory PPHN as an 'add-on' therapy to iNO versus iNO alone SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 9), MEDLINE via PubMed (1966 to 16 September 2018), Embase (1980 to 16 September 2018), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 16 September 2018). We also searched clinical trials databases, conference proceedings of the Pediatric Academic Societies (1990 to 16 September 2018), and the reference lists of retrieved articles for randomized controlled trials and quasi-randomized trials. We contacted authors who have published in this field as discerned from the reference lists of identified clinical trials and review authors' personal files. SELECTION CRITERIA: Randomized and quasi-randomized controlled trials evaluating prostanoids or their analogues (at any dose, route of administration, or duration) used in neonates at any gestational age less than 28 days' postnatal age for confirmed or suspected PPHN. DATA COLLECTION AND ANALYSIS: We used the standard methods of Cochrane Neonatal to conduct a systematic review and to assess the methodological quality of included studies (neonatal.cochrane.org/en/index.html). Three review authors independently assessed the titles and abstracts of studies identified by the search strategy and obtained full-text versions for assessment if necessary. We designed forms for trial inclusion or exclusion and for data extraction. We planned to use the GRADE approach to assess the quality of evidence. MAIN RESULTS: We did not identify any eligible neonatal trials evaluating prostanoids or their analogues as sole agents in the treatment of PPHN. AUTHORS' CONCLUSIONS: Implications for practiceCurrently, no evidence shows the use of prostanoids or their analogues as pulmonary vasodilators and sole therapeutic agents for the treatment of PPHN in neonates (age 28 days or less).Implications for researchThe safety and efficacy of different preparations and doses and routes of administration of prostacyclins and their analogues in neonates must be established. Well-designed, adequately powered, randomized, multi-center trials are needed to address the efficacy and safety of prostanoids and their analogues in the treatment of PPHN. These trials should evaluate long-term neurodevelopmental and pulmonary outcomes, in addition to short-term outcomes.

Lung development alterations in newborn mice after recovery from exposure to sublethal hyperoxia.

Exposure of newborn mice to hyperoxia arrests lung development, with resultant pathological characteristics similar to bronchopulmonary dysplasia in infants born prematurely. We tested the hypothesis that aberrations in lung development caused by 14 days of sublethal hyperoxia would be reversed during 14 days of recovery to room air (RA) when the concentration of oxygen exposure was weaned gradually. Newborn FVB mice were exposed to 85% oxygen or RA for 14 days. Weaning from hyperoxia was by either transfer directly into RA or a decrease in the concentration of oxygen by 10% per days. At 28 days, pups were euthanized, and the lungs were inflation fixed and assessed. At postnatal day 28, lungs of mice weaned abruptly from hyperoxia had fewer (6 ± 0.6 versus 10 ± 0.7; P < 0.001) alveoli per high-powered field and larger alveoli (4050 ± 207 versus 2305 ± 182 µm(2)) than animals weaned gradually; both hyperoxia-exposed groups were different from lungs obtained from air-breathing controls (20 ± 0.5 alveoli per high-powered field; P < 0.001). The results are consistent with the absence of catch-up alveolarization in this model and indicate that the long-term consequences of early exposures to hyperoxia merit closer examination. The effects of abrupt weaning to RA observed further suggest that weaning should be considered in experimental models of newborn exposure to hyperoxia.

Aryl hydrocarbon receptor is necessary to protect fetal human pulmonary microvascular endothelial cells against hyperoxic injury: Mechanistic roles of antioxidant enzymes and RelB.

Hyperoxia contributes to the development of bronchopulmonary dysplasia (BPD) in premature infants. Activation of the aryl hydrocarbon receptor (AhR) protects adult and newborn mice against hyperoxic lung injury by mediating increases in the expression of phase I (cytochrome P450 (CYP) 1A) and phase II (NADP(H) quinone oxidoreductase (NQO1)) antioxidant enzymes (AOE). AhR positively regulates the expression of RelB, a component of the nuclear factor-kappaB (NF-κB) protein that contributes to anti-inflammatory processes in adult animals. Whether AhR regulates the expression of AOE and RelB, and protects fetal primary human lung cells against hyperoxic injury is unknown. Therefore, we tested the hypothesis that AhR-deficient fetal human pulmonary microvascular endothelial cells (HPMEC) will have decreased RelB activation and AOE, which will in turn predispose them to increased oxidative stress, inflammation, and cell death compared to AhR-sufficient HPMEC upon exposure to hyperoxia. AhR-deficient HPMEC showed increased hyperoxia-induced reactive oxygen species (ROS) generation, cleavage of poly(ADP-ribose) polymerase (PARP), and cell death compared to AhR-sufficient HPMEC. Additionally, AhR-deficient cell culture supernatants displayed increased macrophage inflammatory protein 1α and 1ß, indicating a heightened inflammatory state. Interestingly, loss of AhR was associated with a significantly attenuated CYP1A1, NQO1, superoxide dismutase 1(SOD1), and nuclear RelB protein expression. These findings support the hypothesis that decreased RelB activation and AOE in AhR-deficient cells is associated with increased hyperoxic injury compared to AhR-sufficient cells.

Giant omphaloceles: surgical management and perinatal outcomes.

BACKGROUND: The purpose of this study was to describe the current management and outcomes of infants with omphalocele. METHODS: The medical records of all patients treated for omphalocele at a large children's hospital from January, 2003-February, 2014 were reviewed. Patients were classified as having an isolated omphalocele or omphalocele with minor or major associated anomalies. Prenatal data collected included fetal magnetic resonance imaging-based observed-to-expected total fetal lung volumes. Giant omphalocele (GO) was defined as >50% of liver in the omphalocele sac. RESULTS: Of 95 patients, 59 presented prenatally and had comprehensive fetal center evaluation. Of 82 live-born infants, 21 had chromosomal and 25 had major associated anomalies. No live-born baby with an isolated defect (n = 19) died, whereas mortality was 41% and 17% for those with major and minor anomalies, respectively (P = 0.006). Infants with major anomalies had significantly longer median length of intubation (36 versus 0 versus 0 d; P = 0.04) and hospital stay (157 versus 28.5 versus 18 d; P < 0.001) compared with those with minor or no anomalies. Of 40 infants with GO, the majority (85%) were managed surgically by delayed closure with a median age at repair of 10 mo (range, 3.4-23.6 mo). Six-month survival was 80%. None of the delayed repair patients required a later operative revision, whereas 2 of 5 with early repair did. CONCLUSIONS: The presence of associated anomalies is the strongest predictor of morbidity and mortality in fetuses or neonates with omphalocele. In patients with GO, delayed closure is associated with good outcomes, but larger, prospective studies comparing delayed to early closure are needed to determine the optimal timing of repair.

Revisiting outcomes of right congenital diaphragmatic hernia.

BACKGROUND: Studies comparing outcomes of right- and left-sided congenital diaphragmatic hernia (R-CDH and L-CDH) have yielded conflicting results. We hypothesized that R-CDH is associated with higher short-term pulmonary morbidity than L-CDH. METHODS: We reviewed all CDH patients at a tertiary children's hospital over 10 y. In prenatally diagnosed CDH, the observed-to-expected total fetal lung volume and percentage liver herniation (%LH) were calculated using fetal magnetic resonance imaging-based measurements. Outcomes were compared in patients with isolated CDH. Patients were subsequently matched by %LH to compare outcomes. RESULTS: Of 189 CDH patients, 37 (20.1 %) were R-CDH and 147 (79.9%) were L-CDH. Those with R-CDH were prenatally diagnosed at a significantly lower rate (40.5% versus 73.5%; P < 0.001) and later gestational age (26.5 ± 7.7 versus 22.6 ± 5.65 wk; P = 0.062). There was no difference in observed-to-expected total fetal lung volume between those with R-CDH and L-CDH (30.2 ± 11.1% versus 33.1 ± 14.2%; P = 0.471). Fetuses with R-CDH had a higher %LH than those with L-CDH (37.5 ± 14.1% versus 18.6 ± 12.2%; P < 0.001). Patients with isolated R-CDH had a higher need for extracorporeal membrane oxygenation than L-CDH (48% versus 27%; P = 0.055). There was no difference in duration of tracheal intubation, hospital stay, need for supplemental oxygen at 30-d of life or 6-mo mortality between groups. There was no difference in mortality and pulmonary morbidity when patients were matched by %LH. CONCLUSIONS: Compared to those with L-CDH, fetuses with R-CDH are less likely to be diagnosed prenatally and have a higher need for extracorporeal membrane oxygenation. The sidedness of the hernia defect was not associated with differences in short-term pulmonary morbidity in this large, contemporary single-institution experience of neonates with CDH.

Antecedent Predictors of Feeding Outcomes in Premature Infants With Protracted Mechanical Ventilation.

OBJECTIVES: The aim of the present study was to define risk factors associated with gastrostomy in premature infants receiving protracted mechanical ventilation (≥30 days). METHODS: Retrospective data collected on 170 preterm neonates (birth weight <1500 g) who received uninterrupted mechanical ventilation for ≥30 days were analyzed with logistic regression methods to predict the association of gastrostomy with cardiorespiratory, infectious, and neurological morbidities. RESULTS: A total of 32 of 170 infants had gastrostomy tubes. Including all of the covariates in 1 model, duration of cumulative ventilation (P < 0.001) and uninterrupted ventilation (P < 0.001), and ventriculoperitoneal shunt (P = 0.02) were significant predictors, whereas sepsis, intraventrical hemorrhage grade III or IV, and patent ductus arteriosus ligation were not. Respiratory severity score (mean airway pressure × fraction of inspired oxygen) calculated at 30 days of life was also a significant predictor (P = 0.01). CONCLUSIONS: In infants with protracted mechanical ventilation, the degree of respiratory support at 1 month of age, prolonged respiratory morbidity, and neuropathology are the significant predictors for gastrostomy.

Pulmonary capillary hemangiomatosis in a neonate with congenital diaphragmatic hernia.

Pulmonary capillary hemangiomatosis (PCH) is a rare cause of pulmonary hypertension (PHTN). We present a neonate with congenital diaphragmatic hernia (CDH) and concurrent PCH. Severe PHTN was unrelenting and death occurred at 4 months. Diagnosis of PCH is challenging in the setting of CDH and portends a poor prognosis.

The airway microbiome of intubated premature infants: characteristics and changes that predict the development of bronchopulmonary dysplasia.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is associated with perinatal inflammatory triggers. Methods targeting bacterial rRNA may improve detection of microbial colonization in premature infants. We hypothesize that respiratory microbiota differs between preterm infants who develop BPD and those unaffected and correlates with inflammatory mediator concentrations. METHODS: Twenty-five infants, born at ≤32 wk of gestation and intubated in the first 24 h, were enrolled. Tracheal aspirates were obtained at intubation and on days 3, 7, and 28. Bacterial DNA was extracted, and 16S rRNA genes were amplified and sequenced. Concentrations of interleukins (IL-1ß, IL-6, IL-8, IL-10, and IL-12), tumor necrosis factor-α, interferon-γ, lipopolysaccharide (LPS), and lipoteichoic acid (LTA) were measured. Chorioamnionitis was diagnosed by histology. BPD was defined as an oxygen requirement at 36 wk postmenstrual age. RESULTS: Acinetobacter was the predominant genus in the airways of all infants at birth. Ten infants developed BPD and showed reduced bacterial diversity at birth. No differences were detected in bacterial diversity, cytokines, LPS, and LTA from infants with and without exposure to chorioamnionitis. CONCLUSION: The airways of premature infants are not sterile at birth. Reduced diversity of the microbiome may be an important factor in the development of BPD and is not associated with differences in inflammatory mediators.

Comparing characteristics and outcomes in infants with prenatal and postnatal diagnosis of esophageal atresia.

BACKGROUND: Previous studies of infants with esophageal atresia (EA) suggest those diagnosed prenatally have worse outcomes because of a higher incidence of associated anomalies. The purpose of this study was to compare characteristics and outcomes of infants with EA diagnosed after fetal center evaluation to those diagnosed postnatally. METHODS: The records of all neonates treated for EA at our institution from 2002-2012 were reviewed. Infants with a prenatal diagnosis of EA were compared with those postnatally diagnosed using chi-square and Student t-test as appropriate. RESULTS: Of 91 patients treated with EA during the study period, 15 (16%) were diagnosed prenatally at our fetal center. Although those prenatally diagnosed had a higher incidence of pure EA and polyhydramnios, the gestational age and birth weight in that group were similar to those diagnosed postnatally. There were no differences in outcomes between groups with regard to the incidence of major cardiac anomalies, surgical complications, hospital length of stay, and survival. CONCLUSIONS: Treatment at a tertiary care center provides excellent outcomes for all infants with EA, despite an 80% frequency of concurrent anomalies. Prenatal diagnosis of EA and attentive obstetric management of polyhydramnios decrease the risk for prematurity and prematurity-associated morbidity.

Managing established bronchopulmonary dysplasia without using routine blood gas measurements.

OBJECTIVE: Routine blood gas measurements are common in infants with severe bronchopulmonary dysplasia (sBPD) and are a noxious stimulus. We developed a guideline-driven approach to evaluate the care of infants with sBPD without routine blood gas sampling in the chronic phase of NICU care (after diagnosis at 36 weeks PMA). STUDY DESIGN: We examined blood gas utilization and outcomes in our sBPD inpatient care unit using data collected between 2014 and 2020. RESULTS: 485 sBPD infants met inclusion criteria, and 303 (62%) never had a blood gas obtained after 36 weeks PMA. In infants who had blood gas measurements, the median number of total blood gases per patient was only 4 (IQR 1-10). We did not identify adverse effects on hospital outcomes in patients without routine blood gas measurements. CONCLUSIONS: We found that patients with established BPD could be managed without routine blood gas analyses after 36 weeks PMA.

Functional deficiency of aryl hydrocarbon receptor augments oxygen toxicity-induced alveolar simplification in newborn mice.

Hyperoxia contributes to the development of bronchopulmonary dysplasia (BPD) in premature infants. New BPD is characterized as having alveolar simplification. We reported previously that aryl hydrocarbon receptor (AhR) deficiency increased susceptibility to hyperoxic lung injury in adult mice, and this was associated with decreased expression of cytochrome P450 1A enzymes and increased lung inflammation. Whether AhR protects newborn mice against hyperoxia-induced alveolar simplification is unknown. Thus, we tested the hypothesis that decreased activation of the pulmonary AhR augments hyperoxia-induced alveolar simplification and lung inflammation in newborn mice. Experimental groups included one-day old wild type (WT) and AhR dysfunctional (AhRd) mice exposed to 21% O2 (air) or 85% O2 (hyperoxia) for 14 days. Exposure of newborn WT mice to hyperoxia resulted in increased protein, enzyme and mRNA expression of the AhR-regulated lung cytochrome P450 1A1, NAD(P)H quinone oxidoreductase-1, and microsomal glutathione S-transferase 1 enzymes, suggesting that hyperoxia increases activation of the pulmonary AhR. On the other hand, in the AhRd mice, hyperoxia induced the AhR-regulated enzymes to a lesser extent probably due to the dysfunctional AhR in these mice. Alveolar simplification and lung inflammation was increased in mice exposed to hyperoxia compared with those exposed to air, and AhRd mice were more susceptible to hyperoxia-induced alveolar simplification and lung inflammation compared with WT mice. These findings suggest that decreased activation of the pulmonary AhR in newborn AhRd mice augments hyperoxia-induced alveolar simplification and lung inflammation in these mice.

Prenatal inflammation exacerbates hyperoxia-induced functional and structural changes in adult mice.

Maternally derived inflammatory mediators, such as IL-6 and IL-8, contribute to preterm delivery, low birth weight, and respiratory insufficiency, which are routinely treated with oxygen. Premature infants are at risk for developing adult-onset cardiac, metabolic, and pulmonary diseases. Long-term pulmonary consequences of perinatal inflammation are unclear. We tested the hypothesis that a hostile perinatal environment induces profibrotic pathways resulting in pulmonary fibrosis, including persistently altered lung structure and function. Pregnant C3H/HeN mice injected with LPS or saline on embryonic day 16. Offspring were placed in room air (RA) or 85% O(2) for 14 days and then returned to RA. Pulmonary function tests, microCTs, molecular and histological analyses were performed between embryonic day 18 and 8 wk. Alveolarization was most compromised in LPS/O(2)-exposed offspring. Collagen staining and protein levels were increased, and static compliance was decreased only in LPS/O(2)-exposed mice. Three-dimensional microCT reconstruction and quantification revealed increased tissue densities only in LPS/O(2) mice. Diffuse interstitial fibrosis was associated with decreased micro-RNA-29, increased transforming growth factor-ß expression, and phosphorylation of Smad2 during embryonic or early fetal lung development. Systemic maternal LPS administration in combination with neonatal hyperoxic exposure induces activation of profibrotic pathways, impaired alveolarization, and diminished lung function that are associated with prenatal and postnatal suppression of miR-29 expression.

The use of ECMO for persistent pulmonary hypertension of the newborn: a decade of experience.

PURPOSE: Despite improvements in the management of persistent pulmonary hypertension of the newborn (PPHN), a number of infants with inadequate gas exchange are treated with extracorporeal membrane oxygenation (ECMO). The objectives of this study were to use the Extracorporeal Life Support Organization Registry to review the outcomes of neonates with PPHN receiving ECMO, and to identify pre-ECMO variables that may be associated with increased mortality. MATERIALS AND METHODS: The study is a retrospective analysis of all patients with PPHN supported with ECMO and reported to the Extracorporeal Life Support Organization registry from 2000 to 2010. Prematurity was defined as <37 wk gestation. Univariate analysis was performed using Student's t-test or Fisher's exact test. Variables found to be statistically significant underwent multivariate analysis by logistic regression. Kaplan-Meier survival curves were generated to analyze the relationship between duration of ECMO support and patient survival. RESULTS: A total of 1569 neonates with PPHN received ECMO support during the study period, at an average age of 3.1 d of life and for a duration of 6.9 d. Survival among neonates with PPHN receiving ECMO support was 81%, and those receiving support for 7, 10, 14, and 21 d survived at rates of 88%, 78%, 55%, and 25%, respectively. By logistic regression, prematurity (P < 0.01), pre-ECMO pH ≤7.2 (P = 0.02), pre-ECMO SaO(2) ≤65% (P = 0.01), and duration of ECMO ≥7 d (P < 0.001) were independent predictors of death in this group. An average of 2.2 complications occurred per patient, with cardiovascular, mechanical, and renal complications being the most common. CONCLUSIONS: Neonates with PPHN have high survival rates with ECMO support. Prematurity, acidosis, and profound hypoxemia are independently associated with increased mortality. Furthermore, prolonged ECMO support (>7 d) is associated with a higher risk of mortality in this cohort than in patients supported for <1 wk.

Outcomes of neonates requiring extracorporeal membrane oxygenation for irreversible pulmonary dysplasia: the Extracorporeal Life Support Registry experience.

OBJECTIVE: Neonates with an irreversible pulmonary dysplasia such as alveolar capillary dysplasia, surfactant protein deficiency, and pulmonary lymphangiectasis may have a deteriorating clinical course requiring cardiopulmonary support with extracorporeal membrane oxygenation. These neonates are often difficult to distinguish from those with persistent pulmonary hypertension of the newborn. The objective of this study was to identify clinical variables that distinguish infants with irreversible pulmonary dysplasia from those with persistent pulmonary hypertension of the newborn before, and while receiving, extracorporeal membrane oxygenation support. DESIGN: A retrospective analysis of the Extracorporeal Life Support Registry from 2000 to 2010 was performed. SETTING: A total of 114 extracorporeal membrane oxygenation centers providing data to the Extracorporeal Life Support Registry. PATIENTS: All neonates day of life 0-31 reported to the Extracorporeal Life Support Registry with irreversible pulmonary dysplasia and persistent pulmonary hypertension of the newborn were identified. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patient demographics, pre-extracorporeal membrane oxygenation variables, and survival were analyzed. Univariate analysis was performed using Student's t test or Fisher's exact test, and variables found to be significant underwent multivariate analysis by logistic regression. Neonates with irreversible pulmonary dysplasia were placed on extracorporeal membrane oxygenation later (day of life 5.3 vs. 3.0, p = .045) and for a longer duration (11.1 vs. 6.8 days, p < .001) than those with persistent pulmonary hypertension of the newborn. Initiation of extracorporeal membrane oxygenation at day of life ≥5 (p = .026) and a duration of extracorporeal membrane oxygenation ≥10 days (p = .003) were independent predictors of irreversible pulmonary dysplasia by multivariate analysis. No differences in demographics, blood gas values, or vascular access were observed. Survival to discharge was significantly lower for neonates with irreversible pulmonary dysplasia (3%) vs. persistent pulmonary hypertension of the newborn (81%, p < .001). CONCLUSION: Although neonates with irreversible pulmonary dysplasia and persistent pulmonary hypertension of the newborn have similar presentations, those with irreversible pulmonary dysplasia require extracorporeal membrane oxygenation support later in the perinatal period and for a longer duration. For neonates with a diagnosis of persistent pulmonary hypertension of the newborn, irreversible pulmonary dysplasia should be considered when extracorporeal membrane oxygenation is initiated on day of life ≥5 and/or the duration of extracorporeal membrane oxygenation ≥10 days.

Plasma lipid metabolites are associated with gestational age but not bronchopulmonary dysplasia.

AIM: To test the hypothesis that plasma lipid metabolite levels in premature infants are associated with the development of bronchopulmonary dysplasia (BPD). The studies also tested a secondary hypothesis that plasma lipid metabolite levels were correlated with gestational age. METHODS: Infants born <32 weeks' gestation were enrolled during the first 72 h of life. Plasma samples were obtained and lipid levels were measured by LC-MS/MS. Clinical data were collected to determine infant outcomes and BPD diagnosis. RESULTS: Following adjustment for confounders, lipid levels were not associated with BPD; however, levels of specific lipid metabolites were correlated with gestational age. CONCLUSION: Immature lipid metabolism pathways in premature infants may contribute to the pathogenesis of BPD and other diseases.

Maternal docosahexaenoic acid supplementation decreases lung inflammation in hyperoxia-exposed newborn mice.

DHA is a long-chain fatty acid that has potent antiinflammatory properties. Whereas maternal DHA dietary supplementation has been shown to improve cognitive development in infants fed DHA-supplemented milk, the antiinflammatory effects of maternal DHA supplementation on the developing fetus and neonate have not been extensively explored. Pregnant C3H/HeN dams were fed purified control or DHA-supplemented diets (~0.25% of total fat) at embryonic d 16 and consumed these diets throughout the study. At birth, the nursing mouse pups were placed in room air (RA; 21% O(2)) or >95% O(2) (hyperoxia) for up to 7 d. These studies tested the hypothesis that maternal DHA supplementation would decrease inflammation and improve alveolarization in the lungs of newborn mouse pups exposed to hyperoxia. Survival, inflammatory responses, and lung growth were compared among control diet/RA, DHA/RA, control/O(2), and DHA/O(2) pups. There were fewer neutrophils and macrophages in lung tissues from pups nursed by DHA-supplemented dams than in those nursed by dams fed the control diet at 7 d of hyperoxia exposure (P < 0.015). Although differences due to hyperoxia exposure were observed, maternal diet did not affect keratinocyte-derived chemokine, macrophage inflammatory protein-2, IL-1ß, or TNFα mRNA levels in pup tissues. Hyperoxia also induced NF-κB activity, but maternal diet did not affect NF-κB or PPARγ activities. In mice, DHA supplementation decreases leukocyte infiltration in the offspring exposed to hyperoxia, suggesting a potential role for DHA supplementation as a therapy to reduce inflammation in preterm infants.

Riboflavin supplementation does not attenuate hyperoxic lung injury in transgenic (spc-mt)hGR mice.

The aims of this study were to test the hypothesis that mice expressing mitochondrially targeted human glutathione reductase (GR) driven by a surfactant protein C promoter ((spc-mt)hGR) are functionally riboflavin deficient and that this deficiency exacerbates hyperoxic lung injury. The authors further hypothesized that dietary supplementation with riboflavin (FADH) will improve the bioactivity of GR, thus enhancing resistance to hyperoxic lung injury. Transgenic (mt-spc)hGR mice and their nontransgenic littermates were fed control or riboflavin-supplemented diets upon weaning. At 6 weeks of age the mice were exposed to either room air (RA) or >95% O(2) for up to 84 hours. GR activities (with and without exogenous FADH) and GR protein levels were measured in lung tissue homogenates. Glutathione (GSH) and glutathione disulfide (GSSG) concentrations were assayed to identify changes in GR activity in vivo. Lung injury was assessed by right lung to body weight ratios and bronchoalveolar lavage protein concentrations. The data showed that enhanced GR activity in the mitochondria of lung type II cells does not protect adult mice from hyperoxic lung injury. Furthermore, the addition of riboflavin to the diets of (spc-mt)hGR mice neither enhances GR activities nor offers protection from hyperoxic lung injury. The results indicated that modulation of mitochondrial GR activity in lung type II cells is not an effective therapy to minimize hyperoxic lung injury.

The challenge of accurately describing the epidemiology of bronchopulmonary dysplasia (BPD) based on the various current definitions of BPD.

Despite marked improvements in the survival of extremely low birth weight preterm infants, bronchopulmonary dysplasia (BPD) remains a prevalent morbidity. BPD has evolved pathologically and epidemiologically but the definition has failed to keep up. The majority of the definitions of BPD still use the respiratory support provided to the infants at a single timepoint. The lack of a uniform definition of BPD presently reflects the changing BPD pathogenesis and phenotype and limits defining the epidemiology. To address the epidemiology of BPD, the definition should be clarified; even the newer definitions have not been validated entirely. The definition needs to be meaningful clinically and be predictive of long-term respiratory outcomes. We believe the definition should have a composite assessment like a score (quantitative measurement) and include the different phenotypes (qualitative measurements) so that optimally they can be applied to the different phases of BPD and at different timepoints. Furthermore, the definitions need to be easy to measure and assess so that generalizability is enhanced.