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Importance: Meta-analyses suggest that corticosteroids may be associated with increased survival without cerebral palsy in infants at high risk of bronchopulmonary dysplasia (BPD) but are associated with adverse neurologic outcomes in low-risk infants. Whether this association exists in contemporary practice is uncertain because most randomized clinical trials administered corticosteroids earlier and at higher doses than currently recommended., Objective: To evaluate whether the pretreatment risk of death or grade 2 or 3 BPD at 36 weeks' postmenstrual age modified the association between postnatal corticosteroid therapy and death or disability at 2 years' corrected age in extremely preterm infants., Design, Setting, and Participants: This cohort study analyzed data on 482 matched pairs of infants from 45 participating US hospitals in the National Institute of Child Health and Human Development Neonatal Research Network Generic Database (GDB). Infants were included in the cohort if they were born at less than 27 weeks' gestation between April 1, 2011, and March 31, 2017; survived the first 7 postnatal days; and had 2-year death or developmental follow-up data collected between January 2013 and December 2019. Corticosteroid-treated infants were propensity score matched with untreated controls. Data were analyzed from September 1, 2019, to November 30, 2022., Exposure: Systemic corticosteroid therapy to prevent BPD that was initiated between day 8 and day 42 after birth., Main Outcomes and Measures: The primary outcome was death or moderate to severe neurodevelopmental impairment at 2 years' corrected age. The secondary outcome was death or moderate to severe cerebral palsy at 2 years' corrected age., Results: A total of 482 matched pairs of infants (mean [SD] gestational age, 24.1 [1.1] weeks]; 270 males [56.0%]) were included from 656 corticosteroid-treated infants and 2796 potential controls. Most treated infants (363 [75.3%]) received dexamethasone. The risk of death or disability associated with corticosteroid therapy was inversely associated with the estimated pretreatment probability of death or grade 2 or 3 BPD. The risk difference for death or neurodevelopmental impairment associated with corticosteroids decreased by 2.7% (95% CI, 1.9%-3.5%) for each 10% increase in the pretreatment risk of death or grade 2 or 3 BPD. This risk transitioned from estimated net harm to benefit when the pretreatment risk of death or grade 2 or 3 BPD exceeded 53% (95% CI, 44%-61%). For death or cerebral palsy, the risk difference decreased by 3.6% (95% CI, 2.9%-4.4%) for each 10% increase in the risk of death or grade 2 or 3 BPD and transitioned from estimated net harm to benefit at a pretreatment risk of 40% (95% CI, 33%-46%)., Conclusions and Relevance: Results of this study suggested that corticosteroids were associated with a reduced risk of death or disability in infants at moderate to high pretreatment risk of death or grade 2 or 3 BPD but with possible harm in infants at lower risk.

Objectives: Inhaled nitric oxide (iNO) is an effective pulmonary vasodilator. However, the efficacy of iNO in former premature infants with established bronchopulmonary dysplasia (BPD) has not been studied. This study aimed to determine the efficacy of iNO in reducing pulmonary artery pressure in infants with severe BPD as measured by echocardiography., Study Design: Prospective, observational study enrolling infants born at less than 32 weeks gestation and in whom (1) iNO therapy was initiated after admission to our institution, or (2) at the outside institution less than 48 h before transfer and received an echocardiogram prior to iNO initiation, and (3) had severe BPD. Data were collected at three time-points: (1) before iNO; (2) 12-48 h after initiation of iNO; and (3) 48-168 h after initiation of iNO. The primary outcome was the effect of iNO on pulmonary artery pressure measured by echocardiography in patients with severe BPD between 48 and 168 h after initiating iNO therapy., Results: Of 37 enrolled, 81% had echocardiographic evidence of pulmonary arterial hypertension (PAH) before iNO and 56% after 48 h of iNO (p = 0.04). FiO2 requirements were significantly different between time-points (1) and (3) (p = 0.05). There were no significant differences between Tricuspid Annular Plane Systolic Excursion (TAPSE) Z-Scores, time to peak velocity: right ventricular ejection time (TPV:RVET), and ventilator changes., Conclusions: Although we found a statistically significant reduction of PAH between time-point (1) and (3), future trials are needed to further guide clinical care., (© 2023 S. Karger AG, Basel.)

Rationale: Aerosolized albuterol is widely used, but its tolerability and efficacy in infants with severe bronchopulmonary dysplasia (sBPD) is not well established., Objectives: To compare the tolerability and efficacy of two dose levels of aerosolized albuterol to saline placebo in infants with sBPD., Methods: Single-center, multiple-crossover trial in 24 ventilated very preterm infants with sBPD. Albuterol (1.25 mg, 2.5 mg) and 3 ml of normal saline were administered every 4 h during separate 24-h treatment periods assigned in random order with a 6-h washout phase between periods. The primary outcome was the absolute change (post and pretherapy) in expiratory flow at 75% of exhalation (EF75). Secondary endpoints were changes in ventilator parameters, vital signs, and heart arrhythmia., Results: Average within subject EF75 values improved with each therapy: saline placebo ( + 0.45 L/min ± 2.5, p = .04), 1.25 mg of albuterol ( + 0.70 L/min ± 2.4, p < .001), and 2.5 mg of albuterol ( + 0.38 L/min ± 2.4, p = .06). However, 1.25 mg of albuterol (0.26 L/min; 95% CI -0.19, 0.72) and 2.5 mg (-0.10 L/min; 95% CI -0.77, 0.57) produced similar changes in EF75 when compared to saline. All secondary outcomes were similar between saline and 1.25 mg of albuterol. Peak inspiratory pressure needed to deliver goal tidal volumes (7.5% relative decrease, 95% CI 2.6, 12.3) and heart rate (6.5% increase, 95% CI 2.2, 10.8) differed significantly between albuterol 2.5 mg and saline., Conclusion: Albuterol at 1.25 mg and 2.5 mg, compared to aerosolized saline, did not affect EF75 in infants with sBPD receiving invasive ventilation. Greater improvement in peak inspiratory pressures with albuterol 2.5 mg suggests benefit, but close heart monitoring may be indicated., (© 2020 Wiley Periodicals LLC.)

Objective: Compare rates of hypoxaemia during transpyloric and gastric feedings in very preterm infants with severe bronchopulmonary dysplasia., Design: N-of-1 multiple crossover trials with individual patient and pooled data analyses., Setting: Level IV intensive care nursery., Patients: Infants receiving positive airway pressure between 36 and 55 weeks postmenstrual age were enrolled between December 2014-July 2016., Intervention: N-of-1 trial consisting of two blocks, each with a 4-day gastric and 4-day transpyloric feeding period assigned in random order., Main Outcome Measures: The primary outcome was the frequency of daily intermittent hypoxaemic events (SpO 2 ≤80% lasting 10-180 s). Secondary outcomes included the daily proportion of time with an SpO 2 ≤80% and mean daily fraction of inspired oxygen., Results: Of 15 infants, 13 completed the trial and 2 stopped early for transient worsening in respiratory status during gastric feedings. In the intention-to-treat analyses, transpyloric feedings resulted in increased rates of intermittent hypoxaemia in five infants, greater time per day in hypoxaemia in three infants and more supplemental oxygen use in three infants. One infant received more supplemental oxygen during gastric feedings. The remaining study outcomes were similar between the feeding routes in all other infants. Pooling all data, transpyloric feedings resulted in a higher frequency of intermittent hypoxaemic events (median 7.5/day (IQR 1-23.5) vs 3/day (1-11); adjusted incidence rate ratio 1.8, 95% CI 1.3 to 2.5) and a greater proportion of daily hypoxaemia time (median 0.8% (IQR 0.1-2.3) vs 0.4% (0.07-1.8); adjusted mean difference 1.6, 95% CI 1.1 to 2.5)., Conclusions: Transpyloric compared with gastric feedings modestly increased rates of hypoxaemia among study participants., Trial Registration Number: NCT02142621., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Rationale: Current diagnostic criteria for bronchopulmonary dysplasia rely heavily on the level and duration of oxygen therapy, do not reflect contemporary neonatal care, and do not adequately predict childhood morbidity. Objectives: To determine which of 18 prespecified, revised definitions of bronchopulmonary dysplasia that variably define disease severity according to the level of respiratory support and supplemental oxygen administered at 36 weeks' postmenstrual age best predicts death or serious respiratory morbidity through 18-26 months' corrected age. Methods: We assessed infants born at less than 32 weeks of gestation between 2011 and 2015 at 18 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Measurements and Main Results: Of 2,677 infants, 683 (26%) died or developed serious respiratory morbidity. The diagnostic criteria that best predicted this outcome defined bronchopulmonary dysplasia according to treatment with the following support at 36 weeks' postmenstrual age, regardless of prior or current oxygen therapy: no bronchopulmonary dysplasia, no support ( n  = 773); grade 1, nasal cannula ≤2 L/min ( n  = 1,038); grade 2, nasal cannula >2 L/min or noninvasive positive airway pressure ( n  = 617); and grade 3, invasive mechanical ventilation ( n  = 249). These criteria correctly predicted death or serious respiratory morbidity in 81% of study infants. Rates of this outcome increased stepwise from 10% among infants without bronchopulmonary dysplasia to 77% among those with grade 3 disease. A similar gradient (33-79%) was observed for death or neurodevelopmental impairment. Conclusions: The definition of bronchopulmonary dysplasia that best predicted early childhood morbidity categorized disease severity according to the mode of respiratory support administered at 36 weeks' postmenstrual age, regardless of supplemental oxygen use.

Rationale: Infants with severe bronchopulmonary dysplasia (sBPD) and airway obstruction may develop dynamic hyperinflation and intrinsic positive end-expiratory pressure (PEEP i ), which impairs patient/ventilator synchrony., Objectives: To determine if PEEP i is present in infants with sBPD during spontaneous breathing and if adjusting ventilator PEEP improves patient/ventilator synchrony and comfort., Methods: Interventional study in infants with sBPD. PEEP i measured by esophageal pressure (Pes) and pneumotachometer, during pressure-supported breaths. PEEP i defined as the difference between Pes at start of the inspiratory effort minus Pes at onset of inspiratory flow. The set PEEP was adjusted to minimize PEEP i . "Best PEEP" was the setting with minimal wasted efforts (WE), an inspiratory effort seen on the Pes waveform without a corresponding ventilator breath. FiO 2 and SpO 2 measured pre- and post-PEEP adjustment. Sedation requirements evaluated 72 hours preprocedure and postprocedure., Results: Twelve infants were assessed (gestational age, 24.9 ± 1.4 weeks; study age, 48.8 ± 1.5 weeks, postmenstrual age). Mean baseline ventilator PEEP was 16.4 cm H 2 O (14-20 cm H 2 O). Eight infants required an increase, one, a reduction, and three, no change in the set PEEP. For the eight infants requiring an increase in set PEEP, there was an 18.9% reduction in WE and a reduction in FiO 2 (0.084  ±  0.058) requirements in the subsequent 24 hours. Conditional sedation was reduced in five infants postprocedure. No adverse events occurred during testing., Conclusion: PEEP i is measurable in infants with sBPD with concurrent esophageal manometry and flow-time tracings without the need for pharmacological paralysis. In those with PEEP i , increasing ventilator PEEP to offset PEEP i improves synchrony., (© 2019 Wiley Periodicals, Inc.)

Objective: To characterise the excess risk for death, grade 3-4 intraventricular haemorrhage (IVH), bronchopulmonary dysplasia (BPD) and stage 3-5 retinopathy of prematurity independently associated with birth small for gestational age (SGA) among very preterm infants, stratified by completed weeks of gestation., Methods: Retrospective cohort study using the Optum Neonatal Database. Study infants were born <32 weeks gestation without severe congenital anomalies. SGA was defined as a birth weight <10th percentile. The excess outcome risk independently associated with SGA birth among SGA babies was assessed using adjusted risk differences (aRDs)., Results: Of 6708 infants sampled from 717 US hospitals, 743 (11.1%) were SGA. SGA compared with non-SGA infants experienced higher unadjusted rates of each study outcome except grade 3-4 IVH among survivors. The excess risk independently associated with SGA birth varied by outcome and gestational age. The highest aRD for death (0.27; 95% CI 0.13 to 0.40) occurred among infants born at 24 weeks gestation and declined as gestational age increased. In contrast, the peak aRDs for BPD among survivors (0.32; 95% CI 0.20 to 0.44) and the composites of death or BPD (0.35; 95% CI 0.24 to 0.46) and death or major morbidity (0.35; 95% CI 0.24 to 0.45) occurred at 27 weeks gestation. The risk-adjusted probability of dying or developing one or more of the evaluated morbidities among SGA infants was similar to that of non-SGA infants born approximately 2-3 weeks less mature., Conclusion: The excess risk for neonatal morbidity and mortality associated with being born SGA varies by adverse outcome and gestational age., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2019. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: To characterize the independent association between antibiotic exposure in the first week of life and the risk of bronchopulmonary dysplasia (BPD) or death among very preterm infants without culture-confirmed sepsis., Methods: Retrospective cohort study using the Optum Neonatal Database. Infants without culture-confirmed sepsis born less than 1500 g and less than 32 weeks gestation between 1/2010 and 11/2016 were included. The independent association between antibiotic therapy during the first week of life and BPD or death prior to 36 weeks postmenstrual age (PMA) was assessed by multivariable logistic regression., Results: Of 4950 infants, 3946 (79.7%) received antibiotics during the first week of life. Rates of BPD or death (41.5% vs. 31.1%, p < 0.001) and the two individual outcomes were significantly higher among antibiotic treated infants. After adjusting for potential confounding variables, antibiotic use in the first week of life was not associated with increased risk of BPD or death (OR 0.96, 95% CI [0.76,1.21]) or BPD among survivors (OR 0.86, 95% CI [0.67,1.09]). Antibiotic use was associated with increased risk of death prior to 36 weeks PMA (OR 3.01, 95% CI [1.59,5.71]), however, secondary analyses suggested this association may be confounded by unmeasured illness severity., Conclusions: Antibiotic exposure in the first week of life among preterm infants without culture-confirmed sepsis was not independently associated with increased risk of BPD or death.

Competing Interests: Conflict of Interest: None.

Objective: To assess the association between prophylactic indomethacin and bronchopulmonary dysplasia (BPD) in a recent, large cohort of extremely preterm infants., Study Design: Retrospective cohort study using prospectively collected data for infants with gestational ages < 29 weeks or birth weights of 401-1000 g born between 2008 and 2012 at participating hospitals of the National Institute of Child Health and Human Development Neonatal Research Network. Infants treated with indomethacin in the first 24 hours of life were compared with those who were not. Study outcomes were BPD, defined as use of supplemental oxygen at 36 weeks postmenstrual age among survivors to that time point, death, and the composite of death or BPD. Prespecified subgroup analyses were performed., Results: Prophylactic indomethacin use varied by hospital. Treatment of a patent ductus arteriosus after the first day of life was less common among 2587 infants who received prophylactic indomethacin compared with 5244 who did not (21.0% vs 36.1%, P < .001). After adjustment for potential confounders, use of prophylactic indomethacin was not associated with higher or lower odds of BPD (OR 0.89, 95% CI 0.72-1.10), death (OR 0.80, 95% CI 0.64-1.01), or death or BPD (OR 0.87, 95% CI 0.71-1.05). The only evidence of subgroup effects associated with prophylactic indomethacin were lower odds of death among infants with birth weights above the 10th percentile and those who were not treated for a patent ductus arteriosus after the first day of life., Conclusions: Prophylactic indomethacin was not associated with either reduced or increased risk for BPD or death., Trial Registration: ClinicalTrials.gov: NCT00063063., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective  Bacterial colonization of the airway may contribute to the development of bronchopulmonary dysplasia. Whether airway colonization increases risk for later adverse respiratory outcomes is less clear. We described tracheal aspirate culture results obtained from preterm infants receiving mechanical ventilation at 36 weeks postmenstrual age (PMA) and evaluated the association between bacteria type and the risk for prolonged supplemental oxygen use. Study Design  We conducted a retrospective, single-center cohort study comparing infants (1) with and without a tracheal aspirate culture that grew a Gram-negative rod (GNR) and (2) with and without a culture that grew a Gram-positive cocci (GPC). Results  Among 121 infants, 65 (53.7%) and 51 (42.2%) had a tracheal aspirate culture that grew a potentially pathogenic GNR and GPC prior to 36 weeks PMA, respectively. GNR were associated with increased risk for death or use of supplemental oxygen at discharge (adjusted odds ratio [aOR], 6.2; 95% confidence interval [CI], 1.8-21.1), and use of supplemental oxygen at discharge among survivors (aOR, 5.5; 95% CI, 1.6-19.0). GPC did not affect the risk for any study outcomes. Conclusion  GNR but not GPC in the airways of preterm infants receiving mechanical ventilation at 36 weeks PMA is associated with increased risk for prolonged supplemental oxygen use., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Objective The objective of this study was to determine differences in the incidence of bronchopulmonary dysplasia (BPD) or death in very low-birth-weight (VLBW) infants managed successfully on continuous positive airway pressure (CPAP) versus mechanical ventilation on the first day of life (DOL). Study Design This is a retrospective analysis of the Alere neonatal database for infants born between January 2009 and December 2014, weighing ≤ 1,500 g. Baseline demographics, clinical characteristics, and outcomes were compared between the two groups. Multivariable regression analysis was performed to control the variables that differ in bivariate analysis. Results In this study, 4,629 infants (birth weight 1,034 ± 290 g, gestational age 28.1 ± 2.5 weeks) met the inclusion criteria. The successful use of early CPAP was associated with a significant reduction in BPD or death (p < 0.001), as well as days to room air, decreased oxygen use at discharge, lower risk for severe intraventricular hemorrhage, and patent ductus arteriosus requiring surgical ligation (p < 0.001 for all outcomes). Conclusion Successful use of early CPAP on the first DOL in VLBW infants is associated with a reduced risk of BPD or death., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Objective: To determine differences in the incidence of bronchopulmonary dysplasia (BPD) or death in extremely low birth weight infants managed on high flow nasal cannula (HFNC) vs continuous positive airway pressure (CPAP)., Study Design: This is a retrospective data analysis from the Alere Neonatal Database for infants born between January 2008 and July 2013, weighing ≤1000 g at birth, and received HFNC or CPAP. Baseline demographics, clinical characteristics, and neonatal outcomes were compared between the infants who received CPAP and HFNC, or HFNC ± CPAP. Multivariable regression analysis was performed to control for the variables that differ in bivariate analysis., Results: A total of 2487 infants met the inclusion criteria (941 CPAP group, 333 HFNC group, and 1546 HFNC ± CPAP group). The primary outcome of BPD or death was significantly higher in the HFNC group (56.8%) compared with the CPAP group (50.4%, P < .05). Similarly, adjusted odds of developing BPD or death was greater in the HFNC ± CPAP group compared with the CPAP group (OR 1.085, 95% CI 1.035-1.137, P = .001). The number of ventilator days, postnatal steroid use, days to room air, days to initiate or reach full oral feeds, and length of hospitalization were significantly higher in the HFNC and HFNC ± CPAP groups compared with the CPAP group., Conclusions: In this retrospective study, use of HFNC in extremely low birth weight infants is associated with a higher risk of death or BPD, increased respiratory morbidities, delayed oral feeding, and prolonged hospitalization. A large clinical trial is needed to evaluate long-term safety and efficacy of HFNC in preterm infants., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Importance: Extubation failure is common in extremely preterm infants. The current paucity of data on the adverse long-term respiratory outcomes associated with reinitiation of mechanical ventilation prevents assessment of the risks and benefits of a trial of extubation in this population., Objective: To evaluate whether exposure to multiple courses of mechanical ventilation increases the risk of adverse respiratory outcomes before and after adjustment for the cumulative duration of mechanical ventilation., Design, Setting, and Participants: We performed a retrospective cohort study of extremely low-birth-weight (ELBW; birth weight <1000 g) infants born from January 1, 2006, through December 31, 2012, who were receiving mechanical ventilation. Analysis was conducted between November 2014 and February 2015. Data were obtained from the Alere Neonatal Database., Exposures: The primary study exposures were the cumulative duration of mechanical ventilation and the number of ventilation courses., Main Outcomes and Measures: The primary outcome was bronchopulmonary dysplasia (BPD) among survivors. Secondary outcomes were death, use of supplemental oxygen at discharge, and tracheostomy., Results: We identified 3343 ELBW infants, of whom 2867 (85.8%) survived to discharge. Among the survivors, 1695 (59.1%) were diagnosed as having BPD, 856 (29.9%) received supplemental oxygen at discharge, and 31 (1.1%) underwent tracheostomy. Exposure to a greater number of mechanical ventilation courses was associated with a progressive increase in the risk of BPD and use of supplemental oxygen at discharge. Compared with a single ventilation course, the adjusted odds ratios for BPD ranged from 1.88 (95% CI, 1.54-2.31) among infants with 2 ventilation courses to 3.81 (95% CI, 2.88-5.04) among those with 4 or more courses. After adjustment for the cumulative duration of mechanical ventilation, the odds of BPD were only increased among infants exposed to 4 or more ventilation courses (adjusted odds ratio, 1.44; 95% CI, 1.04-2.01). The number of ventilation courses was not associated with increased risk of supplemental oxygen use at discharge after adjustment for the length of ventilation. A greater number of ventilation courses did not increase the risk of tracheostomy., Conclusions and Relevance: Among ELBW infants, a longer cumulative duration of mechanical ventilation largely accounts for the increased risk of chronic respiratory morbidity associated with reinitiation of mechanical ventilation. These results support attempts of extubation in ELBW infants receiving mechanical ventilation on low ventilator settings, even when success is not guaranteed.

Objective: To determine if an early commencement of caffeine is associated with improved survival without bronchopulmonary dysplasia (BPD) in preterm infants., Methods: Retrospective data analysis from the Alere Neonatal Database for infants weighing ≤1250 g, and treated with caffeine within the first 10 days of life. The neonatal outcomes were compared between the infants who received early caffeine (0-2 days) with the infants who received delayed caffeine (3-10 days)., Results: A total of 2951 infants met the inclusion criteria (early caffeine 1986, late caffeine 965). The early use of caffeine was associated with reduction in BPD (OR 0.69, 95% CI 0.58-0.82, p < 0.001) and BPD or death (OR 0.77, 95% CI 0.63-0.94, p = 0.01). Other respiratory outcomes also improved with the early commencement of caffeine. The frequency of severe intraventricular hemorrhage and patent ductus arteriosus was lower and the length of hospitalization was shorter in infants receiving early caffeine therapy. However, early use of caffeine was associated with an increase in the risk of nectrotizing enterocolits (NEC) (OR 1.41, 95% CI 1.04-1.91, p = 0.027)., Conclusion: Early commencement of caffeine was associated with improvement in survival without BPD in preterm infants. The risk of NEC with early caffeine use requires further investigation.

Objective Bacterial colonization of the airway may contribute to the development of bronchopulmonary dysplasia. Whether airway colonization increases risk for later adverse respiratory outcomes is less clear. We described tracheal aspirate culture results obtained from preterm infants receiving mechanical ventilation at 36 weeks postmenstrual age (PMA) and evaluated the association between bacteria type and the risk for prolonged supplemental oxygen use. Study Design We conducted a retrospective, single-center cohort study comparing infants (1) with and without a tracheal aspirate culture that grew a Gram-negative rod (GNR) and (2) with and without a culture that grew a Gram-positive cocci (GPC). Results Among 121 infants, 65 (53.7%) and 51 (42.2%) had a tracheal aspirate culture that grew a potentially pathogenic GNR and GPC prior to 36 weeks PMA, respectively. GNR were associated with increased risk for death or use of supplemental oxygen at discharge (adjusted odds ratio [aOR], 6.2; 95% confidence interval [CI], 1.8-21.1), and use of supplemental oxygen at discharge among survivors (aOR, 5.5; 95% CI, 1.6-19.0). GPC did not affect the risk for any study outcomes. Conclusion GNR but not GPC in the airways of preterm infants receiving mechanical ventilation at 36 weeks PMA is associated with increased risk for prolonged supplemental oxygen use. [ABSTRACT FROM AUTHOR]