Established Bronchopulmonary Dysplasia Research Articles

Managing established bronchopulmonary dysplasia without using routine blood gas measurements

ObjectiveRoutine blood gas measurements are common in infants with severe bronchopulmonary dysplasia (sBPD) and are a noxious stimulus. We developed a guideline-driven approach to evaluate the care of infants with sBPD without routine blood gas sampling in the chronic phase of NICU care (after diagnosis at 36 weeks PMA).Study designWe examined blood gas utilization and outcomes in our sBPD inpatient care unit using data collected between 2014 and 2020.Results485 sBPD infants met inclusion criteria, and 303 (62%) never had a blood gas obtained after 36 weeks PMA. In infants who had blood gas measurements, the median number of total blood gases per patient was only 4 (IQR 1–10). We did not identify adverse effects on hospital outcomes in patients without routine blood gas measurements.ConclusionsWe found that patients with established BPD could be managed without routine blood gas analyses after 36 weeks PMA.

Furin Regulates the Alveolarization of Neonatal Lungs in a Mouse Model of Hyperoxic Lung Injury.

Despite advances in treatment options, such as corticosteroid administration and less invasive respiratory support, bronchopulmonary dysplasia (BPD) remains an important prognostic factor in preterm infants. We previously reported that furin regulates changes in lung smooth muscle cell phenotypes, suggesting that it plays a critical role in BPD pathogenesis. Therefore, in this study, we aimed to evaluate whether it regulates the alveolarization of immature lungs through activating alveolarization-driving proteins. We first examined furin expression levels, and its functions, using an established hyperoxia-induced BPD mouse model. Thereafter, we treated mice pups, as well as primary myofibroblast cell cultures, with furin inhibitors. Finally, we administered the hyperoxia-exposed mice pups with recombinant furin. Immunofluorescence revealed the co-expression of furin with alpha-smooth muscle actin. Hyperoxia exposure for 10 d decreased alveolar formation, as well as the expression of furin and its target, IGF-1R. Hexa-D-arginine administration also significantly inhibited alveolar formation. Another furin inhibitor, decanoyl-RVKR-chloromethylketone, accumulated pro-IGF-1R, and decreased IGF-1R phosphorylation in myofibroblast primary cultures. Finally, recombinant furin treatment significantly improved alveolarization in hyperoxia-exposed mice pups. Furin regulates alveolarization in immature lungs. Therefore, this study provides novel insights regarding the involvement of furin in BPD pathogenesis, and highlights a potential treatment target for ameliorating the impact of BPD.

Risk Factors for Neurodevelopmental Impairment at 2- and 5-Years Corrected Age in Preterm Infants with Established Bronchopulmonary Dysplasia

Introduction: The objective of this study was to identify risk factors for neurodevelopmental impairment (NDI) at 2- and 5-years corrected age (CA) in a cohort of preterm infants with established bronchopulmonary dysplasia (BPD). Methods: This single-center retrospective cohort study included infants born between 2009 and 2016 at a gestational age (GA) <30 weeks with moderate or severe BPD at 36 weeks’ postmenstrual age. Perinatal characteristics, (social) demographics, and comorbidities were collected from the electronic patient records. Odds ratios for NDI were calculated with univariate and multivariate logistic regression analyses adjusting for potential confounders. Results: Of the 602 eligible infants, 123 infants were diagnosed with BPD. NDI was present in 30.3% and 56.1% at 2- and 5-years CA, respectively. The only independent risk factors associated with NDI in the multivariate analyses were birthweight (adjusted odds ratio [aOR] 0.74, 95% CI 0.57–0.95; aOR 0.70, 95% CI 0.54–0.91, respectively), small for GA (SGA) (aOR 3.25, 95% CI 1.09–9.61; aOR 5.44, 95% CI 1.62–18.2, respectively) at both time points, and male gender at 5-years CA (OR 2.49, 95% CI 1.11–5.57). Conclusion: Birthweight and SGA are independent risk factors for NDI at 2- and 5-years CA and male gender at 5-years CA in preterm infants with BPD. In contrast, well-known other risk factors for NDI in the general population of preterm infants, such as GA, maternal education, and neonatal comorbidities were not independently associated with NDI.

Outpatient management of established bronchopulmonary dysplasia: An update

As the incidence of infants with bronchopulmonary dyspasia (BPD) has continued to rise, so has their rate of survival. Their medical management is often complex and requires the use of numerous therapies such as steroids, bronchodilators, diuretics and modalities to deliver supplemental oxygen and positive pressure. It also requires multi-disciplinary care to ensure adequate growth and to optimize neurodevelopmental outcomes. This review aims to discuss the most widely used therapies in the treatment of patients with established BPD. The focus will be on ongoing outpatient (post-neonatal intensive care) management of children with BPD. Since many of the mentioned therapies lack solid evidence to support their use, more high quality research, such as randomized controlled trials, is needed to assess their effectiveness using defined outcomes.

Bronchopulmonary Dysplasia and Carbon Dioxide Retention.

To determine the pre-discharge carbon dioxide (CO2 ) levels of preterm neonates with bronchopulmonary dysplasia (BPD) requiring ongoing nasal cannulae oxygen therapy and who were ready for discharge home. We studied a retrospective cohort of infants born <30 weeks gestational age (GA) at ≥36 weeks corrected GA who had established BPD requiring ongoing nasal cannulae oxygen therapy and were ready for discharge home. Neonates were born and admitted between May 2014 and Dec 2018. Demographic data at the time of birth and at the time of the last blood gas sampled was collected. 105 neonates with median GA 26.1 weeks and birth weight 775 g. Median (IQR) CO2 level was 54 (49-58) mmHg. 99 (94%) neonates had CO2 levels exceeding the normal range and 91 (87%) neonates had a CO2 between 45-65 mmHg. Ninety-four per cent of neonates <30 weeks GA at ≥36 weeks corrected GA requiring ongoing nasal cannulae oxygen therapy for established BPD, who were ready for discharge home, have CO2 levels outside of normocapnia (35-45 mmHg), with 87% having CO2 levels between 45-65 mmHg.

Safety and Efficacy of Mesenchymal Stem Cells for the Treatment of Evolving and Established Bronchopulmonary Dysplasia: A Systematic Literature Review.

Bronchopulmonary dysplasia (BPD) is a frequent sequela of modern medicine when infants are born prematurely. Currently, there is no single treatment or combination of treatments to prevent or fully treat BPD. Mesenchymal stem cells (MSCs) have promising properties that could aid in the reversal of lung injury, as seen in patients with BPD. This study reviews the available evidence regarding the safety and efficacy of the use of MSCs for the treatment of evolving and established BPD. This systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We found eight studies that fulfilled the inclusion and exclusion criteria. While all studies proved the safety and efficacy of MSCs administered intravenously and intratracheally, the only available randomized controlled trial (RCT) failed to demonstrate the benefit of MSC administration in the early treatment of BPD. The remaining studies varied between phase I clinical trials and case reports, but all seemed to show some evidence that MSCs may be of benefit in the late treatment of established BPD. Considering some of the studies have less evidence, early treatment to prevent lung fibrosis may be more successful, particularly in the younger gestational ages where lung development is more immature, and research should focus on this.

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

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

Steroid use for established bronchopulmonary dysplasia: study protocol for a systematic review and meta-analysis

IntroductionPostnatal steroids during the first few weeks of life have been demonstrated to be effective in decreasing the incidence of bronchopulmonary dysplasia (BPD), a serious chronic respiratory condition affecting preterm...

Corticosteroids in the prevention and treatment of infants with bronchopulmonary dysplasia: Part II. Inhaled corticosteroids alone or in combination with surfactants

This paper is the second in a two-part State-of-the-Art series that reviews the latest relevant clinical trials investigating the short-term and long-term effects of corticosteroids in the prevention and treatment of bronchopulmonary dysplasia (BPD). Inhaled postnatal corticosteroids demonstrate low systemic bioavailability and rapid systemic clearance with high pulmonary deposition and were expected to reduce the incidence of BPD with reduced adverse effects, however, increased rate of mortality in the neonatal period and at the 18-24 months follow-up was observed. In a milestone study, intratracheal instillation of corticosteroids combined with surfactant decreased the incidence of BPD without increasing the mortality or the long-term neurodevelopmental adverse outcomes. However, subsequent trials using different types of surfactants, different surfactant to budesonide ratio, different time of the drug administration for infants with different severity of respiratory distress syndrome could not reproduce all the beneficial effects. Future perspectives for the identification of premature infants at high risk of BPD and the prevention or treatment of established BPD are discussed.

Noninvasive Respiratory Severity Indices Predict Adverse Outcomes in Bronchopulmonary Dysplasia

To test the hypothesis that elevated respiratory severity indices will identify patients with severe bronchopulmonary dysplasia (BPD) at the greatest risk for adverse in-hospital outcomes. This was a retrospective cohort study. A modified respiratory severity score (mean airway pressure×fraction of inspired oxygen) and a modified pulmonary score (respiratory support score×fraction of inspired oxygen+sum of medication scores) were calculated in a consecutive cohort of patients ≥36weeks of postmenstrual age with severe BPD admitted to a referral center between 2010 and 2018. The association between each score and the primary composite outcome of death/prolonged length of stay (>75th percentile for cohort) was assessed using area under the receiver operator characteristic curve (AUROC) analysis and logistic regression. Death and the composite outcome death/tracheostomy were analyzed as secondary outcomes. In 303 patients, elevated scores were significantly associated with increased adjusted odds of death/prolonged length of stay: aOR 1.5 (95% CI 1.3-1.7) for the modified respiratory severity score and aOR 11.5 (95% CI 5.5-24.1) for the modified pulmonary score. The modified pulmonary score had slightly better discrimination of death/prolonged length of stay when compared with the modified respiratory severity score, AUROC 0.90 (95% CI 0.85-0.94) vs 0.88 (95% CI 0.84-0.93), P=.03. AUROCs for death and death/tracheostomy did not differ significantly when comparing the modified respiratory severity score with the modified pulmonary score. In our referral center, the modified respiratory severity score or the modified pulmonary score identified patients with established severe BPD at the greatest risk for death/prolonged length of stay, death, and death/tracheostomy.

Glucocorticoids in a Neonatal Hyperoxic Lung Injury Model: Pulmonary and Neurotoxic effects.

We aimed to compare the effect of dexamethasone (Dex), hydrocortisone (Hc), and methylprednisolone (Mpz) at equivalent doses on somatic growth, lung healing, and neurotoxicity in a hyperoxic rat model. We hypothesized that Mpz and Hc would be superior to Dex with less neurotoxicity by exerting similar therapeutic efficacy on the injured lung. Neonatal rats were randomized to control, bronchopulmonary dysplasia (BPD), Dex, Hc, and Mpz groups. All drugs were administered daily following day 15 over 7 days. Histopathological and immunohistochemical analyses of the lung and brain were performed on day 22. All types had much the same impact on lung repair. Oxidative markers in the lung were similar in the steroid groups. While nuclear factor erythroid 2-related factor and heat-shock protein 70 dropped following steroid treatment, no difference was noted in other biochemical markers in the brain between the study groups. Apoptotic activity and neuron loss in the parietal cortex and hippocampus were noted utmost in Dex, but alike in other BPD groups. Mpz does not appear to be superior to Dex or Hc in terms of pulmonary outcomes and oxidative damage in the brain, but safer than Dex regarding apoptotic neuron loss. This is the first study that compared the pulmonary efficacy and neurotoxic effects of Dex, Hc, and Mpz simultaneously in an established BPD model. This study adds to the literature on the importance of possible antioxidant and protective effects of glucocorticoid therapy in an oxidative stress-exposed brain. Mpz ended up with no more additional neuron loss or apoptosis risk by having interchangeable effects with others for the treatment of established BPD. Mpz and Hc seem safe as a rescue therapy in terms of adverse outcomes for established BPD in which lung and brain tissue is already impaired.

Established severe BPD: is there a way out? Change of ventilatory paradigms.

Improved survival of extremely preterm newborn infants has increased the number of infants at risk for developing bronchopulmonary dysplasia (BPD). Despite efforts to prevent BPD, many of these infants still develop severe BPD (sBPD) and require long-term invasive mechanical ventilation. The focus of research and clinical management has been on the prevention of BPD, which has had only modest success. On the other hand, research on the management of the established sBPD patient has received minimal attention even though this condition poses large economic and health problems with extensive morbidities and late mortality. Patients with sBPD, however, have been shown to respond to treatments focused not only on ventilatory strategies but also on multidisciplinary approaches where neurodevelopmental support, growth promoting strategies, and aggressive treatment of pulmonary hypertension improve their long-term outcomes. In this review we will try to present a physiology-based ventilatory strategy for established sBPD, emphasizing a possible paradigm shift from acute efforts to wean infants at all costs to a more chronic approach of stabilizing the infant. This chronic approach, herein referred to as chronic phase ventilation, aims at allowing active patient engagement, reducing air trapping, and improving ventilation-perfusion matching, while providing sufficient support to optimize late outcomes. IMPACT: Based on pathophysiological aspects of evolving and established severe BPD in premature infants, this review presents some lung mechanical properties of the most severe phenotype and proposes a chronic phase ventilatory strategy that aims at reducing air trapping, improving ventilation-perfusion matching and optimizing late outcomes.

Non-invasive Ventilation for Children With Chronic Lung Disease.

Advances in medical care and supportive care options have contributed to the survival of children with complex disorders, including children with chronic lung disease. By delivering a positive pressure or a volume during the patient's inspiration, NIV is able to reverse nocturnal alveolar hypoventilation in patients who experience hypoventilation during sleep, such as patients with chronic lung disease. Bronchopulmonary dysplasia (BPD) is a common complication of prematurity, and despite significant advances in neonatal care over recent decades its incidence has not diminished. Most affected infants have mild disease and require a short period of oxygen supplementation or respiratory support. However, severely affected infants can become dependent on positive pressure support for a prolonged period. In case of established severe BPD, respiratory support with non-invasive or invasive positive pressure ventilation is required. Patients with cystic fibrosis (CF) and advanced lung disease develop hypoxaemia and hypercapnia during sleep and hypoventilation during sleep usually predates daytime hypercapnia. Hypoxaemia and hypercapnia indicates poor prognosis and prompts referral for lung transplantation. The prevention of respiratory failure during sleep in CF may prolong survival. Long-term oxygen therapy has not been shown to improve survival in people with CF. A Cochrane review on the use NIV in CF concluded that NIV in combination with oxygen therapy improves gas exchange during sleep to a greater extent than oxygen therapy alone in people with moderate to severe CF lung disease. Uncontrolled, non-randomized studies suggest survival benefit with NIV in addition to being an effective bridge to transplantation. Complications of NIV relate mainly to prolonged use of a face or nasal mask which can lead to skin trauma, and neurodevelopmental delay by acting as a physical barrier to social interaction. Another associated risk is pulmonary aspiration caused by vomiting whilst wearing a face mask. Adherence to NIV is one of the major barriers to treatment in children. This article will review the current evidence for indications, adverse effects and long term follow up including adherence to NIV in children with chronic lung disease.

European Respiratory Society guideline on long-term management of children with bronchopulmonary dysplasia.

This document provides recommendations for monitoring and treatment of children in whom bronchopulmonary dysplasia (BPD) has been established and who have been discharged from the hospital, or who were >36 weeks of postmenstrual age. The guideline was based on predefined Population, Intervention, Comparison and Outcomes (PICO) questions relevant for clinical care, a systematic review of the literature and assessment of the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. After considering the balance of desirable (benefits) and undesirable (burden, adverse effects) consequences of the intervention, the certainty of the evidence, and values, the task force made conditional recommendations for monitoring and treatment of BPD based on very low to low quality of evidence. We suggest monitoring with lung imaging using ionising radiation in a subgroup only, for example severe BPD or recurrent hospitalisations, and monitoring with lung function in all children. We suggest to give individual advice to parents regarding daycare attendance. With regards to treatment, we suggest the use of bronchodilators in a subgroup only, for example asthma-like symptoms, or reversibility in lung function; no treatment with inhaled or systemic corticosteroids; natural weaning of diuretics by the relative decrease in dose with increasing weight gain if diuretics are started in the neonatal period; and treatment with supplemental oxygen with a saturation target range of 90-95%. A multidisciplinary approach for children with established severe BPD after the neonatal period into adulthood is preferable. These recommendations should be considered until new and urgently needed evidence becomes available.

Bronchopulmonary Dysplasia: a Multidisciplinary Approach to Management

We aim to present the challenges in defining bronchopulmonary dysplasia (BPD) and summarize optimized management of established BPD in a multidisciplinary fashion. In the last few years, several meta-analyses assessing the treatment of BPD have been updated to assist in guiding clinical management. In addition, a new severity grading system was proposed at the National Institute of Child Health and Human Development (NICHD) BPD workshop with more objective criteria including commonly used modes of non-invasive respiratory support. Although survival of infants born prematurely has improved over the last several decades, the incidence of BPD has remained unchanged. Defining BPD and stratifying its severity continue to be challenging for clinicians. Successful BPD management requires a multidisciplinary approach to optimize ventilator strategies, provide adequate nutrition, utilize pharmacotherapeutics in an evidence-based fashion, and screen for comorbidities.

A practical, evidence-based approach to postneonatal management of children with bronchopulmonary dysplasia

Despite increasing survival for babies born preterm, the incidence of bronchopulmonary dysplasia (BPD) remains similar and continues to be the most common chronic lung disease in the preterm population. Advances in neonatal management, including the use of antenatal steroids, exogenous surfactants and changes in ventilation, have resulted in a change in the pathophysiology of BPD to a condition characterized by an arrest in alveolar development and vascular remodeling. There are numerous diagnostic definitions used for this heterogeneous condition with those using the extent of respiratory support required at 36 weeks postmenstrual age shown to be the most effective in predicting long-term pulmonary outcomes. In this article, we will discuss definitions, etiology, and pathophysiology of BPD. Management of infants with established BPD requires a multi-disciplinary team, including neonatologists and respiratory pediatricians with support for families being crucial to long term care. In this article, we will review current guidelines on oxygen saturation targets for established BPD and discuss how the use of a structured weaning pathway, as used at our center, has been shown to reduce the total duration of home oxygen. Other cornerstones of management, including optimizing growth and nutrition, reducing second-hand smoke exposure, and infection prevention, are discussed. For infants with the most severe BPD, we will review the evidence base for pharmacological therapies and indications for long-term ventilatory support. With a number of emerging therapies such as mesenchymal stem cells at the stage of phase one clinical trials, we will discuss future directions in BPD management.

Amnion Epithelial Stem Cells for Established Bronchopulmonary Dysplasia: A First‐In‐Human Safety Trial

Amnion Epithelial Stem Cells for Established Bronchopulmonary Dysplasia: A First‐In‐Human Safety Trial

Fluid restriction for treatment of preterm infants with chronic lung disease.

Fluid restriction is often recommended as part of the management of infants with early or established bronchopulmonary dysplasia (BPD). To determine whether fluid restriction as part of the therapeutic intervention for early or established BPD improves clinical outcomes. We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 1) in the Cochrane Library (searched 16 February 2016), MEDLINE via PubMed (1966 to 16 February 2016), Embase (1980 to 16 February 2016), and CINAHL (1982 to 16 February 2016). We also searched clinical trials' databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. Prospective randomised clinical trials comparing two distinct fluid administration volumes in preterm infants with early or established BPD. We used the standard methods of Cochrane Neonatal. For the included trial, we extracted data and assessed the risk of bias, and used GRADE methods to assess the quality of the evidence. The outcomes considered in this review are effects on mortality or requirement for oxygen at 36 weeks' postmenstrual age (primary outcome measure), the duration of supplemental oxygen therapy, proportion of infants discharged from hospital on oxygen, duration of assisted ventilation, duration of hospitalisation, weight gain, feeding tolerance, apnoea, necrotizing enterocolitis, renal dysfunction or nephrocalcinosis, lung mechanics, and use of diuretic therapy (secondary outcome measures). One trial was found, including 60 preterm infants at 28 days of age with persistent oxygen requirements. Infants were randomised to either 180 mL/kg/day of standard formula or 145 mL/kg/day of concentrated formula. This single study did not provide data regarding our primary outcome. No effects of the intervention were found on any of our secondary outcomes. The quality of the evidence from this study was graded low. There is no evidence to support the practice of fluid restriction in infants with early or established BPD.

Inhaled hydrofluoalkane-beclomethasone dipropionate in bronchopulmonary dysplasia. A double-blind, randomized, controlled pilot study.

The efficacy of inhaled steroids in spontaneously breathing infants with established bronchopulmonary dysplasia (BPD) is debatable. The inhaled steroid hydrofluoalkane-beclomethasone dipropionate (QVAR) is unique in its small particle size that results in higher lung deposition. Our objective was to determine if inhaled QVAR could decrease respiratory rehospitalizations of infants with established BPD. Double-blind, randomized placebo-controlled, multicenter pilot study. Preterm infants with moderate-to-severe BPD were randomized to inhaled QVAR 100 μg per dose or placebo twice daily via Aerochamber with face mask. Treatment was administered daily from recruitment at 36 weeks post menstrual age until 3 months post discharge. Analysis was carried out by intention to treat. The QVAR (n=18) and placebo (n=20) groups were comparable in birth and recruitment characteristics. Length of stay (108.5±26.3 vs 108.7±36.0 days) and infants requiring oxygen at discharge (5/17 vs 6/19) or at study end (0/17 vs 2/19) were comparable. Respiratory rehospitalizations/infant (0.1±0.5 vs 0.4±0.6), rehospitalization days (0.5±1.5 vs 4.1±10.3), and post-discharge additive inhaled (0.3±0.9 vs 6.4±21.5 days), systemic (0.7±2.8 vs 1.0±1.4 days) and combined (inhaled/systemic) steroids (1.0±2.9 vs 7.8±25.8 days) tended to be lower in the QVAR compared with the placebo group. Blood pressure, height and weight gain, and urine cortisol/creatinine ratio at study end were comparable between groups. Our study was unable to detect a significant effect of inhaled QVAR on the respiratory course of established BPD. The study was underpowered. Possible benefits of QVAR could be masked by a tendency toward higher use of additional steroids in the placebo group.

Where Are We Now with the Role of Steroids in the Management of Bronchopulmonary Dysplasia in Extremely Premature Babies?

Where Are We Now with the Role of Steroids in the Management of Bronchopulmonary Dysplasia in Extremely Premature Babies?