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Rationale: Preterm birth and hyperoxic exposure increase the risk for bronchopulmonary dysplasia (BPD), a chronic lung disease characterized by impaired vascular and alveolar growth. Endothelial progenitor cells, such as self-renewing highly proliferative endothelial colony-forming cells (ECFCs), may participate in vascular repair. The effect of hyperoxia on ECFC growth is unknown.Objectives: We hypothesize that umbilical cord blood (CB) from premature infants contains more ECFCs with greater growth potential than term CB. However, preterm ECFCs may be more susceptible to hyperoxia.Methods: ECFC colonies were quantified by established methods and characterized by immunohistochemistry and flow cytometry. Growth kinetics were assessed in room air and hyperoxia (FI(O(2)) = 0.4).Measurements and Main Results: Preterm CB (28-35 wk gestation) yielded significantly more ECFC colonies than term CB. Importantly, we found that CD45(-)/CD34(+)/CD133(+)/VEGFR-2(+) cell number did not correlate with ECFC colony count. Preterm ECFCs demonstrated increased growth compared with term ECFCs. Hyperoxia impaired growth of preterm but not term ECFCs. Treatment with superoxide dismutase and catalase enhanced preterm ECFC growth during hyperoxia.Conclusions: Preterm ECFCs appear in increased numbers and proliferate more rapidly but have an increased susceptibility to hyperoxia compared with term ECFCs. Antioxidants protect preterm ECFCs from hyperoxia. [ABSTRACT FROM AUTHOR]

Bronchopulmonary dysplasia and emphysema are significant global health problems at the extreme stages of life. Both are characterized by arrested alveolar development or loss of alveoli, respectively. Both lack effective treatment strategies. Knowledge about the genetic control of branching morphogenesis in mammals derives from investigations of the respiratory system in Drosophila, but mechanisms that regulate alveolar development remain poorly understood. Even less is known about regulation of the growth and development of the pulmonary vasculature. Understanding how alveoli and the underlying capillary network develop, and how these mechanisms are disrupted in disease states, are critical for developing effective therapies for lung diseases characterized by impaired alveolar structure. Recent observations have challenged old notions that the development of the blood vessels in the lung passively follows that of the airways. Rather, increasing evidence suggests that lung blood vessels actively promote alveolar growth during development and contribute to the maintenance of alveolar structures throughout postnatal life. Our working hypothesis is that disruption of angiogenesis impairs alveolarization, and that preservation of vascular growth and endothelial survival promotes growth and sustains the architecture of the distal airspace. Furthermore, the explosion of interest in stem cell biology suggests potential roles for endothelial progenitor cells in the pathogenesis or treatment of lung vascular disease. In this Pulmonary Perspective, we review recent data on the importance of the lung circulation, specifically examining the relationship between dysmorphic vascular growth and impaired alveolarization, and speculate on how these new insights may lead to novel therapeutic strategies for bronchopulmonary dysplasia. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension contributes significantly to morbidity and mortality in bronchopulmonary dysplasia (BPD), but little is known about the relative contribution of arterial tone, structural remodeling, and vessel density to pulmonary hypertension, especially in older patients. To determine the role of high pulmonary vascular tone in pulmonary hypertension, we studied the acute effects of oxygen tension, inhaled nitric oxide (iNO), and calcium channel blockers (CCB) in 10 patients with BPD who underwent cardiac catheterization for evaluation of pulmonary hypertension. During normoxic conditions, mean pulmonary arterial pressure (PAP) and pulmonary to systemic vascular resistance ratio (PVR/SVR) were 34 +/- 3 mm Hg and 0.42 +/- 0.07, respectively. In response to hypoxia, PAP and PVR/SVR increased by 50 +/- 8% and 82 +/- 14%, respectively (p < 0.01). Hyperoxia decreased PVR/SVR by 28 +/- 9% (p = 0.05). The addition of iNO treatment (20-40 ppm) to hyperoxia decreased PAP and PVR/SVR by 29 +/- 5% (p < 0.01) and 45 +/- 6% (p < 0.05) from baseline values, respectively, achieving near normal values. CCB did not alter PAP or PVR/SVR from baseline values. We conclude that hyperoxia plus iNO causes marked pulmonary vasodilatation in older patients with BPD, suggesting that heightened pulmonary vascular tone contributes to pulmonary vascular disease in BPD. [ABSTRACT FROM AUTHOR]

The Development and Pathology working group was charged with reviewing the present knowledge, gaps in understanding, and areas for further studies in a broad range of themes. These themes in pulmonary vascular biology and pathobiology involved: 1) pulmonary vascular development; 2) pulmonary vascular disease accompanying fetal development and perinatal life; 3) properties of pulmonary vascular endothelial cells; 4) role of bone marrow cells in pulmonary vascular disease; 5) insights into pulmonary thromboembolic disease; 6) role of pathology in the assessment of pulmonary vascular disease; and 7) considerations of tissue banking for research in pulmonary hypertension. These important goals provide a blueprint for future research that may significantly impact our present and future understanding of pulmonary hypertension. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is often difficult to diagnose and challenging to treat. Untreated, it is characterized by a progressive increase in pulmonary vascular resistance leading to right ventricular failure and death. The past decade has seen remarkable improvements in therapy, driven largely by the conduct of randomized controlled trials. Still, the selection of most appropriate therapy is complex, and requires familiarity with the disease process, evidence from treatment trials, complicated drug delivery systems, dosing regimens, side effects, and complications. This chapter will provide evidence-based treatment recommendations for physicians involved in the care of these complex patients. Due to the complexity of the diagnostic evaluation required, and the treatment options available, it is strongly recommended that consideration be given to referral of patients with PAH to a specialized center. [ABSTRACT FROM AUTHOR]

Although idiopathic pulmonary arterial hypertension is perceived as a progressive disease with a uniformly poor outcome, the natural history of disease is heterogeneous, with some patients dying within months of diagnosis and others living for decades. The course of the disease has also been altered by advances in medical therapies. The outcome of patients with other types of pulmonary arterial hypertension (PAH) has been less well characterized. Assessment of prognosis of such patients is important, as it influences both medical therapy and referral for transplantation. This chapter will provide evidence based recommendations to assess the prognosis of patients with PAH. [ABSTRACT FROM AUTHOR]

The objective of this article is to review the available data on the relationship between sleep-disordered breathing (SDB) and pulmonary arterial hypertension (PAH), with a focus on the prevalence of SDB in patients with idiopathic PAH (IPAH); the prevalence of PAH in patients with SDB; and the effects of SDB treatment on PAH. The evidence to date suggests that PAH may occur in the setting of SDB, although the prevalence is low. However, pulmonary hypertension (PH) in SDB is most strongly associated with other risk factors, such as left-sided heart disease, parenchymal lung disease, nocturnal desaturation, and obesity. The limited data available also suggest that SDB is uncommon in patients with IPAH. Treatment of SDB with continuous positive airway pressure may lower pulmonary artery pressures when the degree of PH is mild. [ABSTRACT FROM AUTHOR]

In addition to persistent airways disease, survivors of premature birth with chronic lung disease are at risk of cardiovascular sequelae, including pulmonary hypertension, systemic hypertension, left ventricular hypertrophy, and exercise intolerance. The major treatment of pulmonary hypertension is supplemental oxygen, but drugs such as calcium channel blockers may also be required. The use of inhaled nitric oxide for its long term management is being investigated [ABSTRACT FROM AUTHOR]

In 26 patients, we evaluated a novel pulsed nasal delivery system for nitric oxide (NO) that, in the short term, was as effective as continuous delivery for decreasing pulmonary artery pressure and pulmonary vascular resistance. In 2 patients, NO delivered in the home using this pulsing system was well tolerated for up to 2 years. The long-term safety, efficacy, and acceptability of NO delivered in the home remains to be studied. [ABSTRACT FROM AUTHOR]

Background: Inhaled nitric oxide improves oxygenation and lessens the need for extracorporeal-membrane oxygenation in full-term neonates with hypoxaemic respiratory failure and persistent pulmonary hypertension, but potential adverse effects are intracranial haemorrhage and chronic lung disease. We investigated whether low-dose inhaled nitric oxide would improve survival in premature neonates with unresponsive severe hypoxaemic respiratory failure, and would not increase the frequency or severity of intracranial haemorrhage or chronic lung disease.Methods: We did a double-blind, randomised controlled trial in 12 perinatal centres that provide tertiary care. 80 premature neonates (gestational age < or = 34 weeks) with severe hypoxaemic respiratory failure were randomly assigned inhaled nitric oxide (n=48) or no nitric oxide (n=32, controls). Our primary outcome was survival to discharge. Analysis was by intention to treat. We studied also the rate and severity of intracranial haemorrhage, pulmonary haemorrhage, duration of ventilation, and chronic lung disease at 36 weeks' postconceptional age.Findings: The two groups did not differ for baseline characteristics or severity of disease. Inhaled nitric oxide improved oxygenation after 60 min (p=0.03). Survival at discharge was 52% in the inhaled-nitric-oxide group and 47% in controls (p=0.65). Causes of death were mainly related to extreme prematurity and were similar in the two groups. The two groups did not differ for adverse events or outcomes (intracranial haemorrhage grade 2-4, 28% inhaled nitric oxide and 33% control; pulmonary haemorrhage 13% and 9%; chronic lung disease 60% and 80%).Interpretation: Low-dose inhaled nitric oxide improved oxygenation but did not improve survival in severely hypoxaemic premature neonates. Low-dose nitric oxide in the most critically ill premature neonates does not increase the risk of intracranial haemorrhage, and may decrease risk of chronic lung injury. [ABSTRACT FROM AUTHOR]

Paediatric pulmonary arterial hypertension (PAH) shares common features with adult disease, but is associated with several additional disorders and challenges that require unique approaches. This article discusses recent advances, ongoing challenges and distinct approaches for caring for infants and children with PAH, as presented by the paediatric task force of the 7th World Symposium on Pulmonary Hypertension. We provide updates on diagnosing, classifying, risk-stratifying and treating paediatric pulmonary hypertension (PH) and identify critical knowledge gaps. An updated risk stratification tool and treatment algorithm is provided, now also including strategies for patients with associated cardiopulmonary conditions. Treatment of paediatric PH continues to be hindered by the lack of randomised controlled clinical trials. The challenging management of children failing targeted PAH therapy is discussed, including balloon atrial septostomy, lung transplantation and pulmonary-to-systemic shunt (Potts). A novel strategy using a multimodal approach for the management of PAH associated with congenital heart diseases with borderline pulmonary vascular resistance is included. Advances in diagnosing neonatal PH, especially signs and interpretation of PH by echocardiography, are highlighted. A team approach to the rapidly changing physiology of neonatal PH is emphasised. Challenges in drug approval are discussed, particularly the challenges of designing accurate paediatric clinical trials with age-appropriate end-points and adequate enrolment., Competing Interests: Conflict of interest: D. Ivy reports grants from the National Institutes of Health, GSK and Janssen, consultancy fees to the University of Colorado and support for attending meetings from Bayer, Merck and Janssen, and a leadership role with the Association of Pediatric Pulmonary Hypertension. E.B. Rosenzweig reports grants from National Institutes of Health, Bayer, Janssen, Insmed and SonVie, and is Director, PPHNet and Board Member, Team Phenomenal Hope. S.H. Abman reports consultancy fees from Chiasi and Oak Hills Bio, and leadership roles with BPD Collaborative and Pediatric Pulmonary Hypertension Network. M. Beghetti reports consultancy fees from Actelion/Janssen, MSD, Merck, Gossamer, GSK and Orpha, payment or honoraria for lectures, presentations, manuscript writing or educational events and support for attending meetings from Actelion/Janssen and MSD, and participation on a data safety monitoring board or advisory board with GSK, Actelion/Janssen, Gossamer, Altavant and MSD. D. Bonnet reports consultancy fees from Janssen, MSD and Novartis, and participation on a data safety monitoring board or advisory board with Lupin. J.M. Douwes has no potential conflicts of interest to disclose. A. Manes reports grants from Janssen/Actelion and Merck, payment or honoraria for lectures, presentations, manuscript writing or educational events from Janssen/Actelion, support for attending meetings from Dompè, and participation on a data safety monitoring board or advisory board with AOP Health Italy. R.M.F. Berger reports grants from Johnson & Johnson, consultancy fees from Johnson & Johnson, GSK and Ferrer, payment for educational events from Johnson & Johnson, Ferrer, AOP, MSD, Heart Medical, Occlutech Salveo, Bayer and Gossamerbio, participation on a data safety monitoring board or advisory board with MSD, and leadership roles with TOPP-registry, PPHNet and the ESC/ERS 2022 guidelines for diagnosis and treatment of pulmonary hypertension task force., (Copyright ©The authors 2024.)

Background: Bronchopulmonary dysplasia (BPD), the chronic lung disease associated with prematurity, is characterized by poor alveolar and vascular growth, interstitial fibrosis, and pulmonary hypertension (PH). Although multifactorial in origin, the pathophysiology of BPD is partly attributed to hyperoxia-induced postnatal injury, resulting in lung fibrosis. Recent work has shown that anti-fibrotic agents, including Nintedanib (NTD), can preserve lung function in adults with idiopathic pulmonary fibrosis. However, NTD is a non-specific tyrosine kinase receptor inhibitor that can potentially have adverse effects on the developing lung, and whether NTD treatment can prevent or worsen risk for BPD and PH is unknown., Hypothesis: We hypothesize that NTD treatment will preserve lung growth and function and prevent PH in an experimental model of hyperoxia-induced BPD in rats., Methods: Newborn rats were exposed to either hyperoxia (90%) or room air (RA) conditions and received daily treatment of NTD or saline (control) by intraperitoneal (IP) injections (1 mg/kg) for 14 days, beginning on postnatal day 1. At day 14, lung mechanics were measured prior to harvesting lung and cardiac tissue. Lung mechanics, including total respiratory resistance and compliance, were measured using a flexiVent system. Lung tissue was evaluated for radial alveolar counts (RAC), mean linear intercept (MLI), pulmonary vessel density (PVD), and pulmonary vessel wall thickness (PVWT). Right ventricular hypertrophy (RVH) was quantified with cardiac weights using Fulton's index (ratio of right ventricle to the left ventricle plus septum)., Results: When compared with RA controls, hyperoxia exposure reduced RAC by 64% (p < 0.01) and PVD by 65% (p < 0.01) and increased MLI by 108% (p < 0.01) and RVH by 118% (p < 0.01). Hyperoxia increased total respiratory resistance by 94% and reduced lung compliance by 75% (p < 0.01 for each). NTD administration restored RAC, MLI, RVH, PVWT and total respiratory resistance to control values and improved PVD and total lung compliance in the hyperoxia-exposed rats. NTD treatment of control animals did not have adverse effects on lung structure or function at 1 mg/kg. When administered at higher doses of 50 mg/kg, NTD significantly reduced alveolar growth in RA controls, suggesting dose-related effects on normal lung structure., Conclusions: We found that NTD treatment preserved lung alveolar and vascular growth, improved lung function, and reduced RVH in experimental BPD in infant rats without apparent adverse effects in control animals. We speculate that although potentially harmful at high doses, NTD may provide a novel therapeutic strategy for prevention of BPD and PH., Impact: Anti-fibrotic therapies may be a novel therapeutic strategy for the treatment or prevention of BPD. High-dose anti-fibrotics may have adverse effects on developing lungs, while low-dose anti-fibrotics may treat or prevent BPD. There is very little preclinical and clinical data on the use of anti-fibrotics in the developing lung. Dose timing and duration of anti-fibrotic therapies may be critical for the treatment of neonatal lung disease. Currently, strategies for the prevention and treatment of BPD are lacking, especially in the context of lung fibrosis, so this research has major clinical applicability., (© 2024. The Author(s).)

Lung endothelium resides at the interface between the circulation and the underlying tissue, where it senses biochemical and mechanical properties of both the blood as it flows through the vascular circuit and the vessel wall. The endothelium performs the bidirectional signaling between the blood and tissue compartments that is necessary to maintain homeostasis while physically separating both, facilitating a tightly regulated exchange of water, solutes, cells, and signals. Disruption in endothelial function contributes to vascular disease, which can manifest in discrete vascular locations along the artery-to-capillary-to-vein axis. Although our understanding of mechanisms that contribute to endothelial cell injury and repair in acute and chronic vascular disease have advanced, pathophysiological mechanisms that underlie site-specific vascular disease remain incompletely understood. In an effort to improve the translatability of mechanistic studies of the endothelium, the American Thoracic Society convened a workshop to optimize rigor, reproducibility, and translation of discovery to advance our understanding of endothelial cell function in health and disease.

It is increasingly recognised that diverse genetic respiratory disorders present as severe pulmonary hypertension (PH) in the neonate and young infant, but many controversies and uncertainties persist regarding optimal strategies for diagnosis and management to maximise long-term outcomes. To better define the nature of PH in the setting of developmental lung disease (DEVLD), in addition to the common diagnoses of bronchopulmonary dysplasia and congenital diaphragmatic hernia, we established a multidisciplinary group of expert clinicians from stakeholder paediatric specialties to highlight current challenges and recommendations for clinical approaches, as well as counselling and support of families. In this review, we characterise clinical features of infants with DEVLD/DEVLD-PH and identify decision-making challenges including genetic evaluations, the role of lung biopsies, the use of imaging modalities and treatment approaches. The importance of working with team members from multiple disciplines, enhancing communication and providing sufficient counselling services for families is emphasised to create an interdisciplinary consensus., Competing Interests: Conflict of interest: E.D. Austin reports grants from the NIH and a leadership role with TBX4Life. C. Galambos reports leadership roles with PPHNet and TBX4Life. D. Yung reports grants from Merck, Janssen and the NIH. S.O. Vargas reports grants from the Chan Zuckerberg Initiative, consultancy fees from Vertex Pharmaceuticals, lecture fees from the American Academy of Allergy, Asthma & Immunology, participation on a data safety monitoring board or advisory board with Millipore Sigma, and a leadership role with the Society for Pediatric Pathology. E.O. Jackson reports support for attending meetings from Seattle Children's Hospital. E.C. Whalen reports consultancy fees from the Pulmonary Hypertension Association Care Center and a leadership role with PPHNet. N.M. Villafranco reports support for attending meetings from the Children's Hospital of Philadelphia. S.H. Abman reports grants from the NHLBI (U01 HL12118), consultancy fees from Chiesi, and participation on a data safety monitoring board or advisory board with Bayer Pharmaceuticals and the NHLBI. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024.)

Background: To characterize a cohort of ventilator-dependent infants and children with bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH) and to describe their cardiorespiratory outcomes., Methods: Subjects with BPD on chronic home ventilation were recruited from outpatient clinics. PH was defined by its presence on ≥1 cardiac catheterization or echocardiogram on or after 36 weeks post-menstrual age. Kaplan-Meier analysis was used to compare the timing of key events., Results: Of the 154 subjects, 93 (60.4%) had PH and of those, 52 (55.9%) required PH-specific medications. The ages at tracheostomy, transition to home ventilator, and hospital discharge were older in those with PH. Most subjects were weaned off oxygen and liberated from the ventilator by 5 years of age, which did not occur later in subjects with PH. The mortality rate after initial discharge was 2.6%., Conclusions: The majority of infants with BPD-PH receiving chronic invasive ventilation at home survived after initial discharge. Subjects with BPD-PH improved over time as evidenced by weaning off oxygen and PH medications, ventilator liberation, and tracheostomy decannulation. While the presence of PH was not associated with later ventilator liberation or decannulation, the use of PH medications may be a marker of a more protracted disease trajectory., Impact Statement: There is limited data on long-term outcomes of children with bronchopulmonary dysplasia (BPD) who receive chronic invasive ventilation at home, and no data on those with the comorbidity of pulmonary hypertension (PH). Almost all subjects with BPD-PH who were on chronic invasive ventilation at home survived after their initial hospital discharge. Subjects with BPD-PH improved over time as evidenced by weaning off oxygen, PH medications, liberation from the ventilator, and tracheostomy decannulation. The presence of PH did not result in later ventilator liberation or decannulation; however, the use of outpatient PH medications was associated with later ventilation liberation and decannulation., (© 2024. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Objective: To determine the association between indoor air pollution and respiratory morbidities in children with bronchopulmonary dysplasia recruited from the multicenter Bronchopulmonary Dysplasia (BPD) Collaborative., Study Design: A cross-sectional study was performed among participants less than 3 years old in the BPD Collaborative Outpatient Registry. Indoor air pollution was defined as any reported exposure to tobacco or marijuana smoke, electronic cigarette emissions, gas stoves, and/or wood stoves. Clinical data included acute care use and chronic respiratory symptoms in the past 4 weeks., Results: A total of 1,011 subjects born at a mean gestational age of 26.4 ± 2.2 weeks were included. Most (66.6%) had severe BPD. Over 40% of subjects were exposed to at least one source of indoor air pollution. The odds of reporting an emergency department visit (OR 1.7 [1.18, 2.45], antibiotic use (OR 1.9 [1.12, 3.21]), or a systemic steroid course (OR 2.18 [1.24, 3.84]) were significantly higher in subjects reporting exposure to secondhand smoke (SHS) compared with those without SHS exposure. Subjects reporting exposure to air pollution (not including SHS) also had a significantly greater odds (OR 1.48 [1.08, 2.03]) of antibiotic use as well. Indoor air pollution exposure (including SHS) was not associated with chronic respiratory symptoms or rescue medication use., Conclusion: Exposure to indoor air pollution, especially SHS, was associated with acute respiratory morbidities, including ED visits, antibiotics for respiratory illnesses, and systemic steroid use., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To identify factors associated with the timing of ventilator liberation and tracheostomy decannulation among infants with severe bronchopulmonary dysplasia (sBPD) who required chronic outpatient invasive ventilation., Study Design: Multicenter retrospective study of 154 infants with sBPD on outpatient ventilators. Factors associated with ventilator liberation and decannulation were identified using Cox regression models and multilevel survival models., Results: Ventilation liberation and decannulation occurred at median ages of 27 and 49 months, respectively. Older age at transition to a portable ventilator and at discharge, higher positive end expiratory pressure, and multiple respiratory readmissions were associated with delayed ventilator liberation. Surgical management of gastroesophageal reflux was associated with later decannulation., Conclusions: Ventilator liberation timing was impacted by longer initial admissions and higher ventilator pressure support needs, whereas decannulation timing was associated with more aggressive reflux management. Variation in the timing of events was primarily due to individual-level factors, rather than center-level factors., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective: Initial surfactant studies demonstrated improvements in survival and need for respiratory support. However, as the use of non-invasive respiratory support has increased the use of surfactant has decreased. We examined in a contemporary cohort of BPD patients if surfactant use was associated with BPD severity., Study Design: An observational study using data from the BPD Collaborative Registry., Results: 971 infants with BPD met entry criteria, 864 (89%) had received surfactant in the first 72 h of life (SURF) and the remainder had not (no surfactant). There was an association between SURF and BPD grade, with a greater likelihood of grade 3 BPD in infants who received surfactant in the DR or who had 2 or more doses., Conclusions: We speculate that the use of surfactant in the DR and use of multiple doses reflect the impact of perinatal factors beyond immaturity alone that increase the risk for grade 3 BPD., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Bronchopulmonary dysplasia (BPD) is the heterogeneous chronic lung developmental disease of prematurity, which is often accompanied by multisystem comorbidities. Pulmonary vascular disease and pulmonary hypertension (PH) contribute significantly to the pathogenesis and pathophysiology of BPD and dramatically influence the outcomes of preterm infants with BPD. When caring for those patients, clinicians should consider the multitude of phenotypic presentations that fall under the "BPD-PH umbrella," reflecting the need for matching therapies to specific physiologies to improve short- and long-term outcomes. Individualized management based on the patient's prenatal and postnatal risk factors, clinical course, and cardiopulmonary phenotype needs to be identified and prioritized to provide optimal care for infants with BPD-PH., (Copyright © 2024 by the American Academy of Pediatrics.)

Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest.

Bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, is characterized by impaired lung development with sustained functional abnormalities due to alterations of airways and the distal lung. Although clinical studies have shown striking associations between antenatal stress and BPD, little is known about the underlying pathogenetic mechanisms. Whether dysanapsis, the concept of discordant growth of the airways and parenchyma, contributes to late respiratory disease as a result of antenatal stress is unknown. We hypothesized that antenatal endotoxin (ETX) impairs juvenile lung function as a result of altered central airway and distal lung structure, suggesting the presence of dysanapsis in this preclinical BPD model. Fetal rats were exposed to intraamniotic ETX (10 μg) or saline solution (control) 2 days before term. We performed extensive structural and functional evaluation of the proximal airways and distal lung in 2-week-old rats. Distal lung structure was quantified by stereology. Conducting airway diameters were measured using micro-computed tomography. Lung function was assessed during invasive ventilation to quantify baseline mechanics, response to methacholine challenge, and spirometry. ETX-exposed pups exhibited distal lung simplification, decreased alveolar surface area, and decreased parenchyma-airway attachments. ETX-exposed pups exhibited decreased tracheal and second- and third-generation airway diameters. ETX increased respiratory system resistance and decreased lung compliance at baseline. Only Newtonian resistance, specific to large airways, exhibited increased methacholine reactivity in ETX-exposed pups compared with controls. ETX-exposed pups had a decreased ratio of FEV in 0.1 second to FVC and a normal FEV in 0.1 second, paralleling the clinical definition of dysanapsis. Antenatal ETX causes abnormalities of the central airways and distal lung growth, suggesting that dysanapsis contributes to abnormal lung function in juvenile rats.

Pulmonary vasodilator treatment can improve hemodynamics, right ventricular function, symptoms, and survival in pediatric pulmonary hypertension (PH). However, clinical trial data are lacking due to many constraints. One major limitation is the lack of relevant trial endpoints reflective of hemodynamics or functional status in patients in whom standard exercise testing is impractical, unreliable, or not reproducible. The Kids Mod PAH trial (Mono- vs. Duo Therapy for Pediatric Pulmonary Arterial Hypertension) is an ongoing multicenter, Phase III, randomized, open-label, pragmatic trial to compare the safety and efficacy of first-line combination therapy (sildenafil and bosentan) to first-line monotherapy (sildenafil alone) in 100 pediatric patients with PH across North America. Investigators will measure participants' physical activity with a research-grade, wrist-worn actigraphy device at multiple time points as an exploratory secondary outcome. Vector magnitude counts per minute and activity intensity will be compared between the treatment arms. By directly and noninvasively measuring physical activity in the ambulatory setting, we aim to identify a novel, simple, inexpensive, and highly reproducible approach for quantitative assessment of exercise tolerance in pediatric PH. These data will increase the field's understanding of the effect of pulmonary vasodilator treatment on daily activity - a quantitative measure of functional status and wellbeing in pediatric PH and a potential primary outcome for future clinical trials in children with cardiopulmonary disorders., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Preterm infants with bronchopulmonary dysplasia (BPD) are prone to develop pulmonary hypertension (PH). Strong laboratory and clinical data suggest that antenatal factors, such as preeclampsia, chorioamnionitis, oligohydramnios, and placental dysfunction leading to fetal growth restriction, increase susceptibility for BPD-PH after premature birth. Echocardiogram metrics and serial assessments of NT-proBNP provide useful tools to diagnose and monitor clinical course during the management of BPD-PH, as well as monitoring for such complicating conditions as left ventricular diastolic dysfunction, shunt lesions, and pulmonary vein stenosis. Therapeutic strategies should include careful assessment and management of underlying airways and lung disease, cardiac performance, and systemic hemodynamics, prior to initiation of PH-targeted drug therapies., Competing Interests: Disclosure The authors report no conflicts of interest related to this chapter., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Diverse genetic developmental lung diseases can present in the neonatal period with hypoxemic respiratory failure, often associated with with pulmonary hypertension. Intractable hypoxemia and lack of sustained response to medical management should increase the suspicion of a developmental lung disorder. Genetic diagnosis and lung biopsy are helpful in establishing the diagnosis. Early diagnosis can result in optimizing management and redirecting care if needed. This article reviews normal lung development, various developmental lung disorders that can result from genetic abnormalities at each stage of lung development, their clinical presentation, management, prognosis, and differential diagnoses., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Oxygen is a specific pulmonary vasodilator. Hypoxemia causes pulmonary vasoconstriction, and normoxia leads to pulmonary vasodilation. However, hyperoxia does not enhance pulmonary vasodilation but causes oxidative stress. There are no clinical trials evaluating optimal oxygen saturation or Pao 2 in pulmonary hypertension. Data from translational studies and case series suggest that oxygen saturation of 90% to 97% or Pao 2 between 50 and 80 mm Hg is associated with the lowest pulmonary vascular resistance., Competing Interests: Disclosure The authors have no conflict of interest to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Bronchopulmonary dysplasia (BPD) is a significant contributor to morbidity and death in infants who are born premature. Male sex is an independent risk factor for the development of BPD. However, whether male sex is associated with adverse outcomes that occur after formal diagnosis of severe BPD prior to hospital discharge remains unclear., Research Question: Is male sex associated with a higher risk of adverse outcomes in infants with established severe BPD?, Study Design and Methods: A retrospective, multicenter cohort study of infants enrolled in the BPD Collaborative Registry from January 1, 2015, to June 29, 2022, was performed. Demographics, clinical characteristics, and outcomes were stratified by sex (ie, male vs female). Regression modeling was used to estimate the association of sex with the primary composite outcome of death or tracheostomy at hospital discharge., Results: We identified 1,156 infants with severe BPD, defined at 36 weeks postmenstrual age by the National Institutes of Health 2001 consensus definition. The cohort was predominantly male (59% male infants, 41% female infants). However, rates of mechanical ventilation at 36 weeks postmenstrual age (ie, type 2 severe BPD) did not differ by sex. Overall mortality rates within the cohort were low (male infants, 5.3%; female infants, 3.6%). The OR of death or tracheostomy for male-to-female infants was 1.0 (95% CI, 0.7-1.5)., Interpretation: Our results lead us to speculate that, although sex is an important variable that contributes to the development and pathogenesis of severe BPD, it does not appear to be associated with adverse outcomes in this cohort of infants with established disease. The surprising results raise important questions surrounding the temporal role of biological sex in the development of severe BPD and its progression during the neonatal ICU stay. As we explore the phenotypes and endotypes of BPD, it is imperative to consider how sex modulates the disease from birth through hospital discharge., Competing Interests: Financial/Nonfinancial Disclosures None declared., (Copyright © 2024. Published by Elsevier Inc.)

Objective: To estimate the association of transpyloric feeding (TPF) with the composite outcome of tracheostomy or death for patients with severe bronchopulmonary dysplasia (sBPD)., Study Design: Retrospective multi-center cohort study of preterm infants <32 weeks with sBPD receiving enteral feedings. We compared infants who received TPF at 36, 44, or 50 weeks post-menstrual age to those who did not receive TPF at any of those timepoints. Odds ratios were adjusted for gestational age, small for gestational age, male sex, and invasive ventilation and FiO 2 at 36 weeks., Results: Among 1039 patients, 129 (12%) received TPF. TPF was associated with an increased odds of tracheostomy or death (aOR 3.5, 95% CI 2.0-6.1) and prolonged length of stay or death (aOR 3.1, 95% CI 1.9-5.2)., Conclusions: Use of TPF in sBPD after 36 weeks was infrequent and associated with worse in-hospital outcomes, even after adjusting for respiratory severity at 36 weeks., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Tbx4 protein, expressed in mesenchyme of the developing lung, contributes to airway branching and distal lung growth. An association between pediatric onset of pulmonary arterial hypertension (PAH) and genetic variations coding for the T-box transcription factor 4 gene ( TBX4 ) has been increasingly recognized. Tbx4-related PAH onset has a bimodal age distribution, including severe to lethal PAH in newborns and later onset PAH. We present an autopsy study of a 24-year-old male with a heterozygous TBX4 variant, who developed pulmonary arterial hypertension at age 12 years. This unique case highlights the complex pulmonary histopathology leading to lethal cardiopulmonary failure in the setting of TBX4 mutation., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Importance: Bronchopulmonary dysplasia (BPD) is often associated with pulmonary vascular disease and secondary pulmonary hypertension (PH). The pathogenesis of BPD-associated PH (BPD-PH) is complex and involves prenatal and postnatal factors that disrupt pulmonary vascular development, and patent ductus arteriosus (PDA) is a factor potentially associated with risk of BPD-PH that has been identified in very recent studies., Objective: To explore the association of PDA with BPD-PH using a bayesian model-averaged (BMA) meta-analysis of studies., Data Sources: PubMed and Embase were searched up to April 2023. Key search terms included BPD and PH., Study Selection: Studies examining infants with gestational age 32 weeks or less and reporting data on PDA and risk of BPD-PH., Data Extraction and Synthesis: This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and the Meta-Analysis of Observational Studies in Epidemiology reporting guidelines. Two independent reviewers extracted data, with a third reviewer checking for accuracy and completeness. Data pooling and effect size calculations were performed by BMA., Main Outcomes and Measures: The primary outcome was BPD-PH. BMA was used to calculate Bayes factors (BFs). The BF10 is the ratio of the probability of the data under the alternative hypothesis (H1, association of PDA with BPD-HP) over the probability of the data under the null hypothesis (H0)., Results: A total of 32 studies (8513 infants) were included. BMA showed that the evidence in favor of H1 was weak for any PDA (BF10 = 2.90; 10 studies), moderate for hemodynamically significant PDA (BF10 = 3.77; 3 studies), and extreme for surgically ligated or catheter-occluded PDA (BF10 = 294.9; 16 studies). In contrast, the evidence in favor of H0 was weak for medically treated PDA (BF10 = 0.55; 6 studies). In addition, BMA found strong evidence in favor of H1 when prolonged exposure to PDA was analyzed as a dichotomous variable (BF10 = 11.80; 6 studies) and extreme evidence (BF10 = 113.60; 3 studies) when PDA exposure time was analyzed as a continuous variable., Conclusions and Relevance: In this bayesian meta-analysis, the data suggest that prolonged exposure to PDA might be associated with increased risk of pulmonary vascular disease in extremely preterm infants. This highlights the need to monitor for PH in high-risk preterm infants with prolonged exposure to PDA and to incorporate PH risk into clinical decisions regarding PDA management.

Objective: To describe current treatment practices of preterm infants with early hypoxemic respiratory failure (HRF) and pulmonary hypertension (PH) and their association with patient outcomes., Study Design: We developed a prospective, observational, multicenter clinical registry of preterm newborns <34 weeks' gestation with HRF and PH, based on either clinical or echocardiographic evidence during the first 72 hours of life, from 28 neonatal intensive care units in the US from 2017 through 2022. The primary end point was mortality among those who did or did not receive PH-targeted treatment, and the secondary end points included comparisons of major morbidities. Variables were compared using t tests, Wilcoxon rank-sum tests, Fisher exact tests, and χ² tests., Results: We analyzed the results of 224 preterm infants enrolled in the registry. Of which, 84% (188/224) received PH-targeted treatment, most commonly inhaled nitric oxide (iNO). Early mortality in this cohort was high, as 33% (71/224) of this sample died in the first month of life, and 77% of survivors (105/137) developed bronchopulmonary dysplasia. Infants who received PH-targeted treatment had higher oxygenation indices at the time of enrollment (28.16 [IQR: 13.94, 42.5] vs 15.46 [IQR: 11.94, 26.15]; P = .0064). Patient outcomes did not differ between those who did or did not receive PH-targeted therapy., Conclusions: Early-onset HRF with PH in preterm infants is associated with a high early mortality and a high risk of developing bronchopulmonary dysplasia. iNO is commonly used to treat early-onset PH in preterm infants with HRF. In comparison with untreated infants with lower oxygenation indices, iNO treatment in severe PH may prevent poorer outcomes., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest. This study was sponsored by an investigator-initiated research grant from Mallinckrodt Pharmaceuticals (grant number IIR-USA-003947 to J.P.K.). The study was also supported by NIH/NCATS Colorado CTSA Grant Number UL1 TR002535. The manuscript's contents are the authors' sole responsibility and do not necessarily represent the sponsors' views. The sponsors had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Pulmonary hypertension (PH) is a significant health problem that contributes to high morbidity and mortality in diverse cardiac, pulmonary, and systemic diseases in children. Evidence-based advances in PH care have been challenged by a paucity of quality endpoints for assessing clinical course and the lack of robust clinical trial data to guide pharmacologic therapies in children. While the landmark adult AMBITION trial demonstrated the benefit of up-front combination PH therapy with ambrisentan and tadalafil, it remains unknown whether upfront combination therapy leads to more rapid and sustained clinical benefits in children with various categories of PH. In this article, we describe the inception of the Kids Mod PAH Trial, a multicenter Phase III trial, to address whether upfront combination therapy (sildenafil and bosentan vs. sildenafil alone) improves PH outcomes in children, recognizing that marked differences between the etiology and therapeutic response between adults and children exist. The primary endpoint of this study is WHO functional class (FC) 12 months after initiation of study drug therapy. In addition to the primary outcome, secondary endpoints are being assessed, including a composite measure of time to clinical worsening, WHO FC at 24 months, echocardiographic assessment of PH and quantitative assessment of right ventricular function, 6-min walk distance, and NT-proBNP levels. Exploratory endpoints include selected biomarkers, actigraphy, and assessments of quality of life. This study is designed to pave the way for additional clinical trials by establishing a robust infrastructure through the development of a PPHNet Clinical Trials Network., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Pulmonary Circulation published by Wiley Periodicals LLC on behalf of the Pulmonary Vascular Research Institute.)

Background: Acute kidney injury (AKI) is common in sick neonates and associated with poor pulmonary outcomes, however, the mechanisms responsible remain unknown. We present two novel neonatal rodent models of AKI to investigate the pulmonary effects of AKI., Methods: In rat pups, AKI was induced surgically via bilateral ischemia-reperfusion injury (bIRI) or pharmacologically using aristolochic acid (AA). AKI was confirmed with plasma blood urea nitrogen and creatinine measurements and kidney injury molecule-1 staining on renal immunohistochemistry. Lung morphometrics were quantified with radial alveolar count and mean linear intercept, and angiogenesis investigated by pulmonary vessel density (PVD) and vascular endothelial growth factor (VEGF) protein expression. For the surgical model, bIRI, sham, and non-surgical pups were compared. For the pharmacologic model, AA pups were compared to vehicle controls., Results: AKI occurred in bIRI and AA pups, and they demonstrated decreased alveolarization, PVD, and VEGF protein expression compared controls. Sham pups did not experience AKI, however, demonstrated decreased alveolarization, PVD, and VEGF protein expression compared to controls., Conclusion: Pharmacologic AKI and surgery in neonatal rat pups, with or without AKI, decreased alveolarization and angiogenesis, producing a bronchopulmonary dysplasia phenotype. These models provide a framework for elucidating the relationship between AKI and adverse pulmonary outcomes., Impact: There are no published neonatal rodent models investigating the pulmonary effects after neonatal acute kidney injury, despite known clinical associations. We present two novel neonatal rodent models of acute kidney injury to study the impact of acute kidney injury on the developing lung. We demonstrate the pulmonary effects of both ischemia-reperfusion injury and nephrotoxin-induced AKI on the developing lung, with decreased alveolarization and angiogenesis, mimicking the lung phenotype of bronchopulmonary dysplasia. Neonatal rodent models of acute kidney injury provide opportunities to study mechanisms of kidney-lung crosstalk and novel therapeutics in the context of acute kidney injury in a premature infant., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

We report the case of a preterm infant who died at 10 months of age with severe bronchopulmonary dysplasia (sBPD) with refractory pulmonary hypertension and respiratory failure who had striking histologic features compatible with the diagnosis of alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) but without genetic confirmation of the diagnosis. We further demonstrate dramatic reductions in lung FOXF1 and TMEM100 content in sBPD, suggesting common mechanistic links between ACDMPV and sBPD with impaired FOXF1 signaling., (© 2023 Wiley Periodicals LLC.)

Introduction: Evidence-based ventilation strategies for infants with severe bronchopulmonary dysplasia (BPD) remain unknown. Determining whether contemporary ventilation approaches cluster as specific BPD strategies may better characterize care and enhance the design of clinical trials. The objective of this study was to test the hypothesis that unsupervised, multifactorial clustering analysis of point prevalence ventilator setting data would classify a discrete number of physiology-based approaches to mechanical ventilation in a multicenter cohort of infants with severe BPD., Methods: We performed a secondary analysis of a multicenter point prevalence study of infants with severe BPD treated with invasive mechanical ventilation. We clustered the cohort by mean airway pressure (MAP), positive end expiratory pressure (PEEP), set respiratory rate, and inspiratory time (Ti) using Ward's hierarchical clustering analysis (HCA)., Results: Seventy-eight patients with severe BPD were included from 14 centers. HCA classified three discrete clusters as determined by an agglomerative coefficient of 0.97. Cluster stability was relatively strong as determined by Jaccard coefficient means of 0.79, 0.85, and 0.77 for clusters 1, 2, and 3, respectively. The median PEEP, MAP, rate, Ti, and PIP differed significantly between clusters for each comparison by Kruskall-Wallis testing (p < 0.0001)., Conclusions: In this study, unsupervised clustering analysis of ventilator setting data identified three discrete approaches to mechanical ventilation in a multicenter cohort of infants with severe BPD. Prospective trials are needed to determine whether these approaches to mechanical ventilation are associated with specific severe BPD clinical phenotypes and differentially modify respiratory outcomes., (© 2023 Wiley Periodicals LLC.)

Competing Interests: Declaration of competing interest The authors declare no conflicts of interest.