High Risk For Bronchopulmonary Dysplasia Research Articles

Therapeutic Extracellular Vesicles from Mesenchymal Stromal Cells: Can they help us restore lung development and evade BPD?

There is currently no single effective therapy for either the prevention or treatment of bronchopulmonary dysplasia (BPD), whose incidence is on the rise. Therefore, the need for new tools to treat and reduce risks of further complications associated with extreme preterm birth is urgent. Therapies based on transplantation of mesenchymal stromal cells (MSCs) have shown effectiveness in preclinical models, and promise in recent Phase 1 clinical trials of preterm infants at high risk for BPD. Our studies over the past decade have established that the main therapeutic vector of MSCs is present in their secretome, and is comprised by Extracellular Vesicles (EV), including exosomes. These vectors are small (less than 150nm), lipid bilayer‐enclosed structures secreted by almost all cells. Their varied origin, biogenesis and molecular composition implicate them in diverse and pivotal physiological roles, the most intriguing of which is an effective method of cell‐to‐cell communication dubbed the ‘New Endocrinology’. Consequently, MSC exosomes/small EVs (termed MEx) represent promising novel reagents for therapeutic applications. Work from our group has shown that MEx can restore lung function in rodent experimental models of BPD. MEx treatment suppresses lung inflammation and lung emphysema and restores normal lung development when administered either prenatally to a high risk pregnancy (i.e., preeclampsia or chorioamnionitis), or postnatally, to neonatal mice exposed to hyperoxia‐induced lung injury. Importantly, MEx modulate both innate and adaptive immunity through their effect on lung monocyte/macrophage phenotypes and thymic T cell development as well as promoting bone marrow ‐ derived myeloid cells to adopt a non‐classical signature. Our observations support the hypothesis that reprogrammed monocytes, of bone marrow origin, mediate the protective effects of MEx therapy on the lung and other organs. MEx thus provide a novel platform for therapeutic intervention in the perinatal period to treat tissue injury associated with inflammatory insults and to restore lung development to a physiologic path.Support or Funding InformationSupported in part by NIH grants R01HL146128; United Therapeutics Research Grant; and Charles H. Hood Foundation Major Grants Initiative

Association of patent ductus arteriosus size with clinical features and short-term outcomes in preterm infants less than 34 weeks

Background: Preterm patent ductus arteriosus (PDA) is a challenging situation faced by the neonatologists every day. The devastating consequences of a hemodynamically significant PDA (hsPDA) compared to the harms of medical therapy, make treatment decisions challenging. The diagnosis of an hsPDA is not uniform and multiple classifications are available to assess its severity. Aim: The present study was aimed to analyze whether the size of PDA, based on echocardiography, had any association with clinical features and neonatal outcomes. Materials and Methods: This retrospective study was done in a Level 3 newborn intensive care unit (NICU) from January 2016 to December 2017. Preterm (?34 weeks) infants with hsPDA formed the study group. Data were collected from the NICU database. hsPDA was classified based on the size into small, moderate, and large and analysis was done. Data for each infant until discharge were collected in pre-designed pro forma from medical records. Results: A total of 1064 preterm infants were admitted during the study period and 94 had hsPDA. The mean gestational ages were 31.8±4.2, 29.6±3.3, and 31.9±4.2 weeks for mild, moderate, and severe PDA, respectively. Among the clinical parameters, it was found that shock, metabolic acidosis (p<0.01), and thrombocytopenia were significantly associated with larger PDA size (p=0.02). Infants with a larger PDA size had a higher risk of bronchopulmonary dysplasia (BPD) and ventilation days (p=0.03). Logistic regression was done to analyze independent factors associated with shock, BPD, and PDA severity. Conclusion: Large PDA is associated with an increased risk of higher ventilation days and BPD.

Timing of postnatal steroids for bronchopulmonary dysplasia: association with pulmonary and neurodevelopmental outcomes.

Objective:To determine the associations between age at first postnatal corticosteroids (PNS) exposure and risk for severe bronchopulmonary dysplasia (BPD) and neurodevelopmental impairment (NDI).Study Design:Cohort study of 951 infants born <27 weeks gestational age at NICHD Neonatal Research Network sites who received PNS between 8 days of life (DOL) and 36 weeks’ postmenstrual age was used to produce adjusted odds ratios (aOR).Results:Compared to infants in the reference group (22–28 DOL-lowest rate), aOR for severe BPD was similar for children given PNS between DOL 8–49 but higher among infants treated at DOL 50–63 (aOR 1.77, 95% CI 1.03–3.06), and at DOL ≥64 (aOR 3.06, 95% CI 1.44–6.48). The aOR for NDI did not vary significantly by age of PNS exposure.Conclusion:For infants at high risk of BPD, initial PNS should be considered prior to 50 DOL for the lowest associated odds of severe BPD.

Early angiogenic proteins associated with high risk for bronchopulmonary dysplasia and pulmonary hypertension in preterm infants.

Early pulmonary vascular disease in preterm infants is associated with the subsequent development of bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH); however, mechanisms that contribute to or identify infants with increased susceptibility for BPD and/or PH are incompletely understood. Therefore, we tested if changes in circulating angiogenic peptides during the first week of life are associated with the later development of BPD and/or PH. We further sought to determine alternate peptides and related signaling pathways with the risk for BPD or PH. We prospectively enrolled infants with gestational age <34 wk and collected blood samples during their first week of life. BPD and PH were assessed at 36 wk postmenstrual age. Samples were assayed for each of the 1,121 peptides included in the SOMAscan scan technology, with subsequent pathway analysis. Of 102 infants in the study, 82 had BPD, and 13 had PH. Multiple angiogenic proteins (PF-4, VEGF121, ANG-1, bone morphogenetic protein 10 [BMP10], hepatocyte growth factor (HGF), ANG-2) were associated with the subsequent diagnosis of BPD; and FGF-19, PF-4, connective tissue activating peptide (CTAP)-III, and PDGF-AA levels were associated with BPD severity. Early increases in BMP10 was strongly associated with the late risk for BPD and PH. We found that early alterations of circulating angiogenic peptides and others were associated with the subsequent development of BPD. We further identified peptides that were associated with BPD severity and BPD-associated PH, including BMP10. We speculate that proteomic biomarkers during the first week of life may identify infants at risk for BPD and/or PH to enhance care and research.

Neonatal ibuprofen exposure and bronchopulmonary dysplasia in extremely premature infants

ObjectiveTo evaluate the association of ibuprofen exposure with the risk of bronchopulmonary dysplasia (BPD) in extremely premature infants.Study designThis was a retrospective study of all extremely premature infants admitted to a tertiary unit from 2016 to 2018.ResultsA total of 203 extremely premature infants were included in this study. The rate of BPD was significantly higher in infants with early exposure to ibuprofen (42.5%) compared to infants with no exposure (21.6%, P = 0.001). After adjusting for covariates, the risk of BPD was associated independently with ibuprofen exposure (odds ratios (OR) 2.296, 95% confidence interval (CI): 1.166–4.522, p = 0.016). Further analysis showed a trend towards higher risk of BPD in infants with successful patent ductus arteriosus (PDA) closure after ibuprofen treatment (32.3%) compared to non-treated infants (20.2%, p = 0.162).ConclusionOur findings suggest that ibuprofen exposure may contribute to the occurrence of BPD in extremely preterm infants.

Randomized Trial of 42-Day Compared with 9-Day Courses of Dexamethasone for the Treatment of Evolving Bronchopulmonary Dysplasia in Extremely Preterm Infants

To compare pulmonary and neurodevelopmental outcomes in extremely preterm infants with evolving bronchopulmonary dysplasia treated with either a 42-day course of dexamethasone or 9-day course(s) of dexamethasone. This was a prospective, randomized study in 59 infants ≤27weeks of gestation born between October 2006 and December 2010, who at day 10-21 of life had ventilatory support with mean airway pressure ≥8cmH2O and FiO2 ≥60%. Infants received dexamethasone 0.5mg/k/day×3days followed by a slow taper (42-day group, n=30) or dexamethasone 0.5mg/k/day followed by a rapid taper (9-day group, n=29). Infants in the 9-day group received additional 9-day courses if they again required entry support. The primary outcome was intact survival (normal neurologic examination, IQ >70, and functioning in school without supplemental educational support) at 7years of age. The 42-day and 9-day groups were similar for mean gestational age (25weeks) and all baseline characteristics. Nineteen of 29 infants (66%) in the 9-day group received only 1 course of dexamethasone; therefore, the total steroid dose for the 42-day group (7.56mg/kg) was significantly greater than that for the 9-day group (4.04mg/kg), P<.001. Infants in the 42-day group had shorter duration of ventilation (25 vs 37days), P<.005, received fewer transfusions (2 vs 3.5), P<.01, and reached full enteral feeds earlier (40 vs 46days), P<.05. Intact survival at school age was significantly increased in the 42-day group (75%) compared with the 9-day group (34%), P<.005. A 42-day tapering course of dexamethasone in extremely preterm infants at high risk for bronchopulmonary dysplasia decreased hospital morbidities and increased rate of survival without handicap compared with a treatment protocol that attempted to minimize steroid exposure.

Information value of ante- and intranatal risk factors for bronchopulmonary dysplasia in preterm newborns

Aim of the study. To identify the leading antenatal and intranatal risk factors for bronchopulmonary dysplasia based on the analysis of their prevalence and information content Materials and methods. We performed a prospective follow-up of 124 infants of gestational age of less than 32 weeks with the classical form of bronchopulmonary dysplasia (study group). The control group included 119 newborns with gestational age of less than 32 weeks without bronchopulmonary dysplasia. The parents of the compared groups were questioned, with the following assessment of the prevalence and informative value of antenatal and intranatal risk factors. Results. The leading antenatal and intranatal risk factors for the development of bronchopulmonary dysplasia are: acute respiratory viral infection in II-III trimester, threatened miscarriage, intrauterine growth retardation, Apgar score at the 1st (3 or less) and 5th minute (5 or less), body weight of less than 1400g at birth, body length less than 36 cm at birth, cesarean section, more then 6-hours waterless period. Conclusion. The combination of these intranatal and antenatal risk factors can be attributed to a group with high risk of bronchopulmonary dysplasia.

Human amnion epithelial cells for the prevention of bronchopulmonary dysplasia: a phase 1 dose escalation study

Background & Aim Background: Advances in neonatal intensive care have been associated with improved survival of preterm infants. But along with survival, the morbidity bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, is also increasing. BPD is associated with adverse respiratory outcomes into adulthood and greater risk of adverse neurodevelopment. Infants born ≤ 28 weeks’ gestation, during the canalicular phase of lung development prior to alveolar and distal capillary development, are at greatest risk of BPD. Disruption of lung maturation by the pro-inflammatory environment created by lifesaving neonatal intensive care interventions results in the BPD we see today – a disease characterised by arrested development with simplified alveoli and abnormal angiogenesis. As the role of inflammation in BPD comes into focus, cell therapy presents a promising intervention for its prevention. Human amnion epithelial cells (hAECs), stem-like cells derived from placental tissues, have multi-lineage potential, are immune privileged and, in small animal models are non-teratogenic. Preclinical work demonstrates the cells capacity to modulate the inflammatory environment to both prevent injury and aid repair of established injury in diverse models of lung disease. A first-in-human study recently demonstrated the safety of low dose hAECs in preterm infants with established BPD. However, hAECs are likely to have greater therapeutic potential when used to prevent lung injury thus, the next step in translation is to evaluate the safety of hAECs in less mature infants at high risk of developing BPD. Aim To evaluate the safety of escalating doses of intravenous hAECs in infants born ≤ 28 weeks’ gestation at high risk of BPD. Methods, Results & Conclusion Method In this phase 1 study, 24 infants born at ≤28 weeks’ gestation at high risk of BPD will each receive intravenous hAECs from Day 14 of life. The infusion dose will escalate from 2 million cells/kg to 10 million cells/kg. Further dose escalation will be achieved by repeat infusions at 5 day intervals to achieve a maximum cumulative dose of 30 million cells/kg. Safety is the primary outcome. Infants will be followed until 2 years of age corrected for prematurity. Results The first dose cohort, comprising of 4 infants, has been recruited. Infants received an intravenous infusion of 2 million hAECs/kg. Infusions have been well tolerated with no short term adverse events observed.

Enteral iron supplementation, red blood cell transfusion, and risk of bronchopulmonary dysplasia in very-low-birth-weight infants.

Enteral iron supplementation and RBC transfusions are routinely administered to very-low-birth-weight (VLBW) infants, although the potential risks of these exposures have not been adequately quantified. This study evaluated the association between the cumulative dose of enteral iron supplementation, total volume of RBCs transfused, and risk of bronchopulmonary dysplasia (BPD) in VLBW infants. Retrospective, multicenter observational cohort study in Atlanta, Georgia. Cumulative supplemental enteral iron exposure and total volume of RBCs transfused were measured until the age at assessment of BPD. Multivariable generalized linear models were used to control for confounding, and the reliability of the factors was assessed in 1000 bootstrap models. A total of 598 VLBW infants were studied. In multivariable analyses, a greater cumulative dose of supplemental enteral iron exposure was associated with an increased risk of BPD (adjusted relative risk per 50-mg increase, 1.07; 95% confidence interval [CI], 1.02-1.11; p = 0.002). Similarly, a greater volume of RBCs transfused was associated with a higher risk of BPD (adjusted relative risk per 20-mL increase, 1.05; 95% CI, 1.02-1.07; p < 0.001). Both factors were reliably associated with BPD (>50%). Volume of RBCs transfused was similar to gestational age in reliability as a risk factor for BPD (present in 100% of models) and was more reliable than mechanical ventilation at 1 week of age. The cumulative dose of supplemental enteral iron exposure and total volume of RBC transfusion are both independently associated with an increased risk of BPD in VLBW infants.

Growth restriction increases the risk of bronchopulmonary dysplasia, death, and sepsis in twins of 30 weeks or less of gestation.

Multiple factors influence the risk of morbidity and mortality of premature infants with intrauterine growth restriction (IUGR). The comparison of twins with different intrauterine growth allows evaluating the effect of the restriction, excluding maternal factors and prenatal mana gement. Our objective was to assess the effect of IUGR on acute and chronic morbidity, and mortality of extreme preterm twins. Twins weighing less than 1500 grams and gesta tion equal to or less than 30 weeks, of the Neocosur Network. Separate analyses were performed on concordant twin pairs, and on mild and severe discordant twins, evaluating the effect of IUGR on morbidity and mortality. A multivariate analysis was performed in order to establish the impact of this effect. 459 twin pairs, 227 concordant twins, 110 of mild discordance, and 122 of severe discordance. Among the concordant ones, there was only a difference in oxygen uptake at 36 weeks. In those of mild discordance, the smaller twin presented a lower frequency of hyaline membrane disease and required fewer doses of surfactant, but had a higher risk of bronchopulmonary dysplasia (BPD) or death. In severe discordant twins, the smaller one presented higher mortality, sepsis, use and permanence in mechanical ventilation, despite the lower frequency of hyaline membrane disease. In multiple regression analysis, the combined risk of BPD or death was higher in the smaller twin and of severe discordance. In discordant twins, the acute respiratory pathology was more frequent in the larger one, although the risk of BPD or death was higher in the one with IUGR.

Timing of postnatal corticosteroid treatment for bronchopulmonary dysplasia and its effect on outcomes.

To determine the association of timing of steroid therapy for bronchopulmonary dysplasia (BPD) and outcomes. Retrospective cohort study of preterm infants treated with low-dose dexamethasone for BPD. Infants treated with steroids at day of life (DOL) 14-28 (moderately late group) were compared to infants treated at DOL 29-42 (delayed group). Inverse probability of treatment weighting (IPTW) adjusted propensity scores were used to correct for potential confounders. The primary outcome of interest was postmenstrual age (PMA) at discharge. Fifty-five infants (25 with moderately late treatment; 30 with delayed treatment) were identified. The mean age at treatment was 23 days in the moderately late group and 35 days in the delayed group. At time of treatment, infants treated moderately late were more likely to be on high frequency ventilation (96% vs 47%, P < 0.0001) and had higher fraction of inspired oxygen (70.7 ± 17.9% vs 56.2 ± 18.4%, P = 0.005) compared to infants treated later. Despite being the sicker group, moderately late treated infants were discharged at an earlier corrected age compared to infants with delayed treatment (PMA 42.9 ± 4.5 vs 47.5 ± 8.3 weeks, IPTW adjusted P = 0.03). Moderately late treatment was also associated with fewer days on mechanical ventilation (46.0 ± 19.0 days vs 77.4 ± 67.0 days, IPTW adjusted P = 0.02) and fewer days on supplemental oxygen (114.3 ± 40.8 days vs 149.8 ± 57.0 days, IPTW adjusted P = 0.005). Among preterm infants at high risk of BPD, delaying treatment with postnatal steroids is associated with comparatively worse short-term outcomes as compared to earlier treatment.

Rescue therapy with betamethasone in preterm infants (day of life&gt;14) at high risk for bronchopulmonary dysplasia to assist weaning from ventilator support: a case series

Rescue therapy with betamethasone in preterm infants (day of life&gt;14) at high risk for bronchopulmonary dysplasia to assist weaning from ventilator support: a case series

N-terminal-probrain natriuretic peptide as a biomarker of moderate to severe bronchopulmonary dysplasia in preterm infants: A prospective observational study.

N-terminal-probrain natriuretic peptide (NT-proBNP) is a marker of hemodynamically significant patent ductus arteriosus (HsPDA) in preterm infants. In this study, we assessed whether NT-proBNP levels could predict the risk of moderate to severe bronchopulmonary dysplasia (BPD) and/or death. This was an observational prospective study of preterm infants with GA ≤32 weeks. Infants who died within the first 48 h or who had major congenital malformations or incomplete information were excluded. NT-proBNP was determined at 48-96 h of life and at 5-10 days of life. The predictive capacity of NT-proBNP for the combined outcome of BPD and/or death was evaluated using receiver operator characteristic (ROC) curves and multivariate regression. Of the 125 eligible patients, 110 completed the analysis. Twenty-eight developed BPD (n = 15) and/or died (n = 13). Infants who developed BPD and/or died had higher NT-proBNP levels ​​at 48-96 h (26,848 ng/L, interquartile range [IQR] 7818-60,684 vs 3008 ng/L, IQR 1425-9876) and at 5-10 days (8849 ng/L, IQR 3796-19,526 vs 1427 ng/L, IQR 907-2889). The NT-proBNP levels at 5-10 days, but not at 48-96 h, were independently associated with BPD and/or death after adjustments for HsPDA and other confounders (OR = 3.36; 95%CI: 1.52-7.4, P = 0.006). For the prediction of this result, a cutoff of 3348 ng/L had a sensitivity and specificity of 82% and 83%, respectively (area under the curve [AUC] = 0.87; 95%CI: 0.79-0.95). The NT-proBNP levels at 5-10 days of life may identify preterm infants with an HsPDA who are at high risk of BPD or death and may be useful for individualized preventive and therapeutic strategies.

Usefulness of an Online Risk Estimator for Bronchopulmonary Dysplasia in Predicting Corticosteroid Treatment in Infants Born Preterm

To assess the usefulness of a bronchopulmonary dysplasia (BPD) outcome estimator developed by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) in identifying high-risk preterm infants treated with steroids. This was a single-center retrospective study of infants born ≤30 weeks of gestational age. The NICHD BPD outcome estimator was used to retrospectively calculate BPD risk at various postnatal ages. The best combination of risk estimates for identifying steroid treatment was identified using stepwise model selection. A cut-off value with the best combination of sensitivity and specificity was identified using receiver operating characteristic analysis. A total of 165 infants born preterm (mean gestational age 26 ± 1.6 weeks, mean birth weight 837 ± 171 g) were included. Of these, 61 were treated with steroids for BPD and 104 were not. Risk estimates for BPD or death were significantly greater in infants treated with steroids compared with controls. Both combined risk for severe BPD or death and single risk of no BPD were identified as factors with the best predictive power for identifying treatment with steroids, with accurate prediction possible as early as the second week of life. A greater than 37% risk for severe BPD or death or a less than 3% risk of no BPD on day of life 14 had 84%-92% sensitivity and 77%-80% specificity for predicting steroid treatment. The NICHD BPD outcome estimator can be a useful objective tool for identifying infants at high risk for BPD who may benefit from postnatal steroids.

Race Effects of Inhaled Nitric Oxide in Preterm Infants: An Individual Participant Data Meta-Analysis

To assess whether inhaled nitric oxide (iNO) improves survival without bronchopulmonary dysplasia (BPD) for preterm African American infants. An individual participant data meta-analysis was conducted, including 3 randomized, placebo-controlled trials that enrolled infants born at <34 weeks of gestation receiving respiratory support, had at least 15% (or a minimum of 10 infants in each trial arm) of African American race, and used a starting iNO of >5 parts per million with the intention to treat for 7 days minimum. The primary outcome was a composite of death or BPD. Secondary outcomes included death before discharge, postnatal steroid use, gross pulmonary air leak, pulmonary hemorrhage, measures of respiratory support, and duration of hospital stay. Compared with other races, African American infants had a significant reduction in the composite outcome of death or BPD with iNO treatment: 49% treated vs 63% controls (relative risk, 0.77; 95% CI, 0.65-0.91; P = .003; interaction P = .016). There were no differences between racial groups for death. There was also a significant difference between races (interaction P = .023) of iNO treatment for BPD in survivors, with the greatest effect in African American infants (P = .005). There was no difference between racial groups in the use of postnatal steroids, pulmonary air leak, pulmonary hemorrhage, or other measures of respiratory support. iNO therapy should be considered for preterm African American infants at high risk for BPD. iNO to prevent BPD in African Americans may represent an example of a racially customized therapy for infants.

Patent Ductus Arteriosus Treatment in Very Preterm Infants: A European Population-Based Cohort Study (EPICE) on Variation and Outcomes

Background: Spontaneous closure of patent ductus arteriosus (PDA) occurs frequently in very preterm infants and despite the lack of evidence for treatment benefits, treatment for PDA is common in neonatal medicine. Objectives: The aim of this work was to study regional variations in PDA treatment in very preterm infants (≤31 weeks of gestation), its relation to differences in perinatal characteristics, and associations with bronchopulmonary dysplasia (BPD) and survival without major neonatal morbidity. Methods: This was a population-based cohort study in 19 regions in 11 European countries conducted during 2011 and 2012. A total of 6,896 infants with data on PDA treatment were included. The differences in infant characteristics were studied across regions using a propensity score derived from perinatal risk factors for PDA treatment. The primary outcomes were a composite of BPD or death before 36 weeks postmenstrual age, or survival without major neonatal morbidity. Results: The proportion of PDA treatment varied from 10 to 39% between regions (p < 0.001), and this difference could not be explained by differences in perinatal characteristics. The regions were categorized according to a low (<15%, n = 6), medium (15-25%, n = 9), or high (>25%, n = 4) proportion of PDA treatment. Infants treated for PDA, compared to those not treated, were at higher risk of BPD or death in all regions, with an overall propensity score adjusted risk ratio of 1.33 (95% confidence interval 1.18-1.51). Survival without major neonatal morbidity was not related to PDA treatment. Conclusions: PDA treatment varies largely across Europe without associated variations in perinatal characteristics or neonatal outcomes. This finding calls for more uniform guidance for PDA diagnosis and treatment in very preterm infants.

Long-Term Neurodevelopmental Outcome after Doxapram for Apnea of Prematurity

Background: Doxapram has been advocated as a treatment for persistent apnea of prematurity (AOP). Objective: To evaluate the effect of doxapram on long-term neurodevelopmental outcome in preterm infants as its safety still needs to be established. Methods: From a retrospective cohort of preterm infants with a gestational age (GA) <30 weeks and/or a birth weight <1,250 g, born between 2000 and 2010, infants treated with doxapram (n = 142) and a nontreated control group were selected (n = 284). Patient characteristics and clinical and neurodevelopmental outcome data at 24 months' corrected age were collected. Neurodevelopmental delay (ND) was defined as having a Mental or Psychomotor Developmental Index (MDI/PDI) <-1 standard deviation (SD), cerebral palsy, or a hearing or visual impairment. Odds ratios (OR) were calculated using multiple logistic regression analyses adjusting for potential confounders. Results: Infants treated with doxapram had a lower GA compared to controls. The number of infants with a MDI or PDI <-1 SD was not different between the groups. The risk of the combined outcome death or ND was significantly lower in the doxapram group after adjusting for confounding factors (OR = 0.54, 95% CI: 0.37, 0.78). Doxapram-treated infants had a higher risk of bronchopulmonary dysplasia and patent ductus arteriosus, but a lower risk of spontaneous intestinal perforation. All other morbidities were not different between the groups. Conclusions: This study suggests that doxapram is not associated with an increased risk of ND. These findings need to be confirmed or refuted by a large, well-designed, placebo-controlled randomized trial.

Abstract 14661: Early Predictive Markers of Right Ventricular - Pulmonary Vascular Dysfunction in Preterm Infants With Bronchopulmonary Dysplasia

Introduction: Improved survival of extremely preterm infants has led to an increased recognition of bronchopulmonary dysplasia (BPD) associated with abnormal cardio-pulmonary hemodynamics. Reliable non-invasive quantitative markers for early recognition of BPD in preterm infants are lacking. The aim of this study was to evaluate quantitative echocardiographic measures of right ventricular hemodynamics (RV) as early predictive markers in infants at risk for development of BPD. Methods: A prospective study was conducted in 115 preterm infants (&lt; 29 weeks gestational age) enrolled through the Prematurity and Respiratory Outcomes Program (NCT01435187). Echocardiographic measures of RV function and pulmonary hemodynamics were evaluated at 32 and 36 weeks post-menstrual age (PMA). RV systolic function was assessed with fractional area of change (FAC), tricuspid annular plane systolic excursion (TAPSE), and global and free wall longitudinal strain. RV morphometrics were assessed with RV dimensions and areas. Pulmonary hemodynamics were assessed by pulmonary artery acceleration time (PAAT). Commonly used qualitative measures (tricuspid regurgitation velocity and septal flattening) were evaluated for comparison. BPD was classified by the NIH workshop definition. Results: RV global and free wall strain, FAC, TAPSE, and PAAT were significantly reduced, and RV morphometrics were significantly larger at 32 and 36 weeks PMA in preterm infants who developed BPD (Table 1). Qualitative measures were present in &lt; 20% of patients, and only septal flattening was significant at 32 weeks PMA in the BPD group. Conclusions: Quantitative echocardiographic measures of RV function and pulmonary hemodynamics are reliable early predictive markers of subsequent development of BPD in preterm infants. These measures are superior to commonly used qualitative measures and can be useful tools for early identification of preterm infants at high risk for BPD.

Nebulized Pentoxifylline for Reducing the Duration of Oxygen Supplementation in Extremely Preterm Neonates

To evaluate the efficacy and safety of nebulized pentoxifylline for reducing the duration of oxygen supplementation in extremely preterm neonates at high risk of bronchopulmonary dysplasia (BPD). Single-center, randomized, double-blind, placebo-controlled trial was conducted. Infants of 23(0) to 27(6) weeks' gestational age requiring mechanical ventilation or ≥30% supplemental oxygen on continuous positive airway pressure at 72-168 hours were randomized to receive 20 mg/kg (1 mL/kg) nebulized pentoxifylline or an equal volume of normal saline placebo every 6 hours for 10 consecutive days via a vibrating mesh nebulizer. The primary outcome was the duration of oxygen supplementation at 40 weeks' postmenstrual age. We used Cox proportional hazards regression modeling to analyze outcomes. All infants had adequate data for analysis of the primary outcome. Intention-to-treat analysis revealed no differences in duration of oxygen supplementation at 40 weeks' postmenstrual age between pentoxifylline (n=41) and placebo (n=40) groups (median 2262 vs 2160 hours, adjusted hazard ratio: 1.14, 95% CI 0.72-1.80, P=.63). There was no difference in mortality and further secondary outcomes. No adverse effects were noted. Nebulized pentoxifylline is safe but did not reduce the duration of oxygen supplementation in extremely preterm infants at high risk of BPD. Dose-ranging studies and large, well-designed clinical trials are required to determine whether the use of nebulized or systemic pentoxifylline as a prophylactic therapy offers small but relevant benefits for prevention of BPD. Australian New Zealand Clinical Trials Registry: ACTRN12611000145909.

Early pulmonary vascular disease in preterm infants at risk for bronchopulmonary dysplasia.

Pulmonary hypertension (PH) is associated with poor outcomes among preterm infants with bronchopulmonary dysplasia (BPD), but whether early signs of pulmonary vascular disease are associated with the subsequent development of BPD or PH at 36 weeks post-menstrual age (PMA) is unknown. To prospectively evaluate the relationship of early echocardiogram signs of pulmonary vascular disease in preterm infants to the subsequent development of BPD and late PH (at 36 wk PMA). Prospectively enrolled preterm infants with birthweights 500-1,250 g underwent echocardiogram evaluations at 7 days of age (early) and 36 weeks PMA (late). Clinical and echocardiographic data were analyzed to identify early risk factors for BPD and late PH. A total of 277 preterm infants completed echocardiogram and BPD assessments at 36 weeks PMA. The median gestational age at birth and birthweight of the infants were 27 weeks and 909 g, respectively. Early PH was identified in 42% of infants, and 14% were diagnosed with late PH. Early PH was a risk factor for increased BPD severity (relative risk, 1.12; 95% confidence interval, 1.03-1.23) and late PH (relative risk, 2.85; 95% confidence interval, 1.28-6.33). Infants with late PH had greater duration of oxygen therapy and increased mortality in the first year of life (P < 0.05). Early pulmonary vascular disease is associated with the development of BPD and with late PH in preterm infants. Echocardiograms at 7 days of age may be a useful tool to identify infants at high risk for BPD and PH.