What is the role of diuretics in the prevention and management of bronchopulmonary dysplasia?

Background: Neonatal bronchopulmonary dysplasia (BPD) is a chronic neonatal respiratory disease that is precipitated by prolonged oxygenation and mechanical ventilation (MV), leading to respiratory distress (RD). Aim of Study: The aim of the study is to assess the role of Vitamin D as adjuvant treatment in the prevention and management of BPD in neonates. Patients and Methods: Prospective randomized controlled trial with identification number TCTR20210622001 on 100 premature neonates who had RD and were put on MV. The examined neonates were classified into 2 groups: Group 1, which received Vitamin D (Vit D), and Group 2, which had placebo. Urinary β2-microglobulin (B2M) in addition to plasma Krebs von den Lungen-6 (KL-6) levels were measured on the 1st and the 14th day of hospitalization. Results: There was a decrease in urinary B2M and plasma KL-6 levels in Group 1, if compared with Group 2 neonates (P < 0.05). There was a decrease in hospitalization in Group 1 neonates (P < 0.05). Group 1 neonates showed a decrease of the developed BPD cases (P < 0.05). Conclusion: Vit D supplementation may help in the prevention of BPD in neonates, but further studies with larger number of neonates should be done. Recommendation: Routine Vit D supplementation in a dose of 800 IU to preterm who are susceptible to develop BPD.

1. Yvonne E. Vaucher, MD, MPH* 1. *Clinical Professor of Pediatrics, Division of Neonatology, University of California, San Diego, Calif. After completing this article, readers should be able to: 1. Describe the most common cause of chronic lung disease during infancy. 2. Explain the importance of a history of bronchopulmonary dysplasia throughout childhood. 3. Identify infants at high risk for developing bronchopulmonary dysplasia. 4. List the adverse effects associated with postnatal corticosteroids. Despite clinical advances in antepartum, intrapartum, and neonatal care, bronchopulmonary dysplasia (BPD) continues to challenge infants who have been in neonatal intensive care units and their caretakers. BPD is the most common cause of chronic respiratory disease during infancy and remains a major cause of long-term medical, pulmonary, and neurodevelopmental morbidity, increasing the cost of health care and the utilization of medical and educational resources throughout childhood. BPD is a clinical diagnosis, defined by oxygen dependence for a specific period of time after birth and accompanied by characteristic radiographic findings that correspond to anatomic abnormalities. Thus far, a precise physiologic definition of BPD is lacking. As the clinical presentation has evolved over the past 30 years, so has the definition. As originally described by Northway in the 1960s, the diagnosis of classic BPD was based on progressive radiographic changes in preterm infants who were treated for severe respiratory distress syndrome (RDS) immediately after birth and had prolonged ventilator and oxygen dependence. This form of BPD occurred in larger, relatively mature preterm infants, who required treatment with high-pressure mechanical ventilation and high concentrations of oxygen. Although the acute respiratory disease initially improved in these infants, oxygen requirements increased 7 to 10 days after birth and persisted for at least 28 days. The definition of BPD subsequently was modified by Bancalari to include preterm infants who had less severe RDS that initially required short-term mechanical ventilation, but who also developed persistent respiratory symptoms and an oxygen requirement for at least 28 days after birth …

69 - Bronchopulmonary Dysplasia in the Neonate

In the current era, the survival of extremely low-birth-weight infants has increased considerably because of new advances in technology; however, these infants often develop chronic dysfunction of the lung, which is called bronchopulmonary dysplasia (BPD). BPD remains an important cause of neonatal mortality and morbidity despite newer and gentler modes of ventilation. BPD results from the exposure of immature lungs to various antenatal and postnatal factors that lead to an impairment in lung development and aberrant growth of lung parenchyma and vasculature. However, we still struggle with a uniform definition for BPD that can help predict various short- and long-term pulmonary outcomes. With new research, our understanding of the pathobiology of this disease has evolved, and many new mechanisms of lung injury and repair are now known. By utilizing the novel ‘omic’ approaches in BPD, we have now identified various factors in the disease process that may act as novel therapeutic targets in the future. New investigational agents being explored for the management and prevention of BPD include mesenchymal stem cell therapy and insulin-like growth factor 1. Despite this, many questions remain unanswered and require further research to improve the outcomes of premature infants with BPD.

Shortly after the introduction of assisted ventilation in the newborn, bronchopulmonary dysplasia (BPD) was first described. Northway and coworkers described a group of preterm infants who developed chronic respiratory failure and characteristic radiographic changes after prolonged mechanical ventilation. The prevention and management of BPD in infants at risk is challenging due to the complex pathogenesis of multiple contributing factors that include prematurity, supplemental oxygen exposure, mechanical ventilation, patent ductus arterious, inflammation, genetic predisposition and postnatal infection. Treatment of existing BPD requires a coordinated approach including optimal nutrition, careful fluid management, evidence-based drug therapy, and gentle respiratory techniques aimed at minimizing lung injury. The best respiratory support strategy remains unclear and requires further investigation but includes avoidance of ventilator-induced lung injury (barotraumas and volutrauma), hyperoxemia, and hypocapnea. Among the available interventions antenatal steroids, caffeine, and surfactant have the best risk-benefit profile. Systemic postnatal corticosteroids should be used only in ventilated infants unable to be weaned from the ventilator. Quality improvement techniques may have a role towards improvement of hospital systems geared toward reduction of BPD.

Despite improvements in neonatal care, bronchopulmonary dysplasia (BPD) continues to occur in approximately one third of newborns who have birth weights of <1000 g and contributes to significant morbidity in this population. Gaps in knowledge about the prevention and treatment of BPD remain, resulting in unintended short- and long-term sequelae. In addition to chronic lung disease, preterm newborns with BPD are more likely to develop language delay, cerebral palsy, and cognitive impairments compared with preterm newborns without BPD. The pulmonary group identified 3 critical needs to enhance the design of clinical trials in neonates with BPD: (1) identify the stages of BPD; (2) define BPD more clearly; and (3) identify subtypes of BPD patients. The group determined that trials are needed for 3 areas of BPD: (1) prevention of BPD; (2) treatment of evolving BPD; and (3) treatment of established BPD. The severity of BPD is defined as mild, moderate, and severe, and subgroups among those with BPD are described. Here we identify gaps in basic science and pharmacologic knowledge that hamper investigators' ability to conduct effective BPD clinical trials and provide a list of drugs to be studied in BPD trials. Priorities for drug-class evaluation by stage of BPD are given. The pulmonary group proposes a BPD clinical-trials framework that varies according to the different stages of BPD and describes characteristics of the overall design for BPD clinical trials. Finally, we discuss trial-design issues that are common to all neonatal studies.

Objective: To assess the longitudinal metabolic patterns during the evolution of bronchopulmonary dysplasia (BPD) development. Methods: A case-control dataset of preterm infants (<32-week gestation) was obtained from a multicenter database, including 355 BPD cases and 395 controls. A total of 72 amino acid (AA) and acylcarnitine (AC) variables, along with infants’ calorie intake and growth outcomes, were measured on day of life 1, 7, 28, and 42. Logistic regression, clustering methods, and random forest statistical modeling were utilized to identify metabolic variables significantly associated with BPD development and to investigate their longitudinal patterns that are associated with BPD development. Results: A panel of 27 metabolic variables were observed to be longitudinally associated with BPD development. The involved metabolites increased from 1 predominant different AC by day 7 to 19 associated AA and AC compounds by day 28 and 16 metabolic features by day 42. Citrulline, alanine, glutamate, tyrosine, propionylcarnitine, free carnitine, acetylcarnitine, hydroxybutyrylcarnitine, and most median-chain ACs (C5:C10) were the most associated metabolites down-regulated in BPD babies over the early days of life, whereas phenylalanine, methionine, and hydroxypalmitoylcarnitine were observed to be up-regulated in BPD babies. Most calorie intake and growth outcomes revealed similar longitudinal patterns between BPD cases and controls over the first 6 weeks of life, after gestational adjustment. When combining with birth weight, the derived metabolic-based discriminative model observed some differences between those with and without BPD development, with c-statistics of 0.869 and 0.841 at day 7 and 28 of life on the test data. Conclusions: The metabolic panel we describe identified some metabolic differences in the blood associated with BPD pathogenesis. Further work is needed to determine whether these compounds could facilitate the monitoring and/or investigation of early-life metabolic status in the lung and other tissues for the prevention and management of BPD.

Strategies for Prevention and Treatment of Broncopulmonary Dysplasia Bronchopulmonary Dysplasia (BPD) continues to be a highly frequent sequela of low birth weight infants.This, despite the many recent advances in perinatal medicine that include antenatal steroids, exogenoussurfactant, new strategies for mechanical respiratory support, parenteral nutrition improvements and amore judicious use of supplemental oxygen. The purpose of this review is to analyze and describe therecent advances in the prevention and management of BPD. New preventive therapies have been developed,and vitamin A and caffeine administration have been shown to diminish the incidence of this disorder.Postnatal corticosteroids can also be useful, but due to their negative long-term neurological effects, thesemedications are not currently recommended. Corticosteroid administration in established BPD can decreasethe need for mechanical ventilation and improve lung function. Other preventive interventions such asantioxidant administration and nitric oxide inhalation are currently being investigated. The persistence ofthe ductus arteriosus is associated with increased risk of BPD, therefore early pharmacologic closure canplay a role in preventing this disorder. New modalities of mechanical ventilation, such as synchronized andhigh frequency ventilation, have not been shown to decrease the incidence of this disease. While adiscussion regarding the best type of ventilation to be used still remains, the consensus is that that thelowest inspiratory pressure and lowest oxygen concentration necessary should be utilized to maintainadequate gas exchange. Optimal level of arterial oxygen saturation in premature infants is still controversial,but the current recommended range is between 88% and 95%.

Bronchopulmonary dysplasia (BPD) is a common morbidity affecting preterm infants and is associated with substantial long-term disabilities. There has been no change in the incidence of BPD over the past 20 years, despite improvements in survival and other outcomes. The preterm lung is vulnerable to injuries occurring as a result of invasive ventilation, hyperoxia, and infections that contribute to the development of BPD. Clinicians caring for infants in the neonatal intensive care unit use multiple therapies for the prevention and management of BPD. Non-invasive ventilation strategies and surfactant administration via thin catheters are treatment approaches that aim to avoid volutrauma and barotrauma to the preterm developing lung. Identifying high-risk infants to receive postnatal corticosteroids and undergo patent ductus arteriosus closure may help to individualize care and promote improved lung outcomes. In infants with established BPD, outpatient management is complex and requires coordination from several specialists and therapists. However, most current therapies used to prevent and manage BPD lack solid evidence to support their effectiveness. Further research is needed with appropriately defined outcomes to develop effective therapies and impact the incidence of BPD.

Management of bronchopulmonary dysplasia in Japan: A 10-year nationwide survey

Breastfeeding is one of the strategies that has been shown to be effective in preventing severe forms of bronchopulmonary dysplasia (BPD). When mother's own milk (MOM) is not available, pasteurized donor milk (DM) is the best alternative. However, the evidence is inconclusive on the difference in the incidence of bronchopulmonary dysplasia (BPD) between patients fed MOM and those fed with DM. As standard DM is usually mature pooled milk donated by mothers who have delivered their babies at term, the potential benefits of preterm milk may be lost. An observational, retrospective, single-center study was conducted in the neonatology department of a high-complexity hospital. The study included newborns <32 weeks of gestational age born between January 2020 and December 2022. When supplemental milk was needed, non-pooled preterm pasteurized donor milk (PDM) matched for gestational age and moment of lactation was used in this study, classifying preterm infants in two groups: mainly MOM (>50% of the milk) or mainly PDM (>50% of the milk). Two groups were established: those who received >50% MOM and those who received >50% PDM. They were also classified according to the diagnosis of DBP: one group included no BPD or grade 1 BPD (noBPD/1), while the other included grade 2 or 3 BPD (BPD 2-3). The objectives of this study were, firstly, to evaluate the incidence of BPD 2-3 among patients who predominantly received PDM versus MOM. Secondly, to analyze differences in the type of human milk received and its nutritional components, as well as to study the growth in patients with or without BPD. One hundred ninety-nine patients were included in the study. A comparison of noBPD/1 versus BPD 2-3 groups between those receiving mainly MOM versus PDM showed no significant differences (19% vs. 20%, p 0.95). PDM colostrum in BPD 2-3 compared to noBPD/1 was higher in protein content (2.24 g/100 mL (SD 0.37) vs. 2.02 g/100 mL (SD 0.29) p < 0.01), although the statistical significance decreased after adjustment for gestational age and birth weight z-score (OR 3.53 (0.86-14.51)). No differences were found in the macronutrients in the mature milk of patients feeding more than 50% PDM in both study groups. Growth of BPD 2-3 showed a greater decrease in the difference in z-scores for height at birth and at discharge compared to noBPD/1 (-1.64 vs. -0.43, p 0.03). The use of mainly MOM or PDM demonstrates a similar incidence of noBPD/1 or BPD 2-3. Non-pooled and matched by gestational age and time of lactation preterm donor milk can probably be an alternative when mother's own milk is not available, with a similar protective effect in the prevention of severe BPD.

Bronchopulmonary dysplasia (BPD) remains a major complication of prematurity and currently lacks efficient treatments. Mesenchymal stem/stromal cells (MSCs) have been extensively explored as a potential therapy in several preclinical and clinical settings. Human and animal MSCs have been shown to prevent and treat lung injury in various preclinical models of lung diseases, including experimental BPD. To determine if MSCs, administered intravenously or endotracheally, are safe and effective in preventing or treating BPD, or both, in preterm infants. We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 10), MEDLINE via PubMed (1966 to 6 November 2016), Embase (1980 to 6 November 2016), and CINAHL (1982 to 6 November 2016). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials (RCTs) and quasi-RCTs. We considered RCTs and quasi-RCTs investigating prevention or treatment of BPD, or both, in preterm infants. Two review authors independently assessed trial quality according to prespecified criteria. We found no RCTs or quasi-RCTs addressing the use of MSCs for prevention or treatment of BPD in premature infants. Two RCTs are currently registered and ongoing. There is insufficient evidence to determine the safety and efficacy of MSCs in the treatment or prevention of BPD in premature infants. The results of the ongoing trials addressing this issue are expected in the near future.

Bronchopulmonary dysplasia (BPD) is a common cause of morbidity and mortality in preterm neonates and at present its management is unclear. Over the past three decades there has been a growing use of corticosteroids in the postnatal period; first for the treatment and then, more recently, for the prevention of BPD. The first published use of corticosteroids to treat neonatal lung disease was in 1956; however, it was only in the 1980s and 1990s that their use in neonates became commonplace. Concerns about their long-term neurodevelopmental consequences arose in the late 1990s when follow-up of randomised controlled trials indicated an increased risk of cerebral palsy after postnatal dexamethasone exposure. Dexamethasone has been the most frequently used corticosteroid in neonatal units, although others, including hydrocortisone, prednisolone and methylprednisolone, have been studied, as have inhaled corticosteroids. Systematic reviews indicate that systemic corticosteroids improve respiratory function in the short term and expedite extubation in preterm neonates. However, there is a high risk of hypertension, hyperglycaemia and gastrointestinal complications in corticosteroid-treated neonates and, if administered in the first 4 days of life, an association with long-term neurodevelopmental delay. There should be emphasis on prevention of BPD by reducing the risk factors associated with its development. There is no role for use of corticosteroids in the first 4 days of life as the high risk of long-term adverse effects outweighs any likely short-term benefits. Corticosteroid use should be limited to exceptional clinical circumstances, such as a ventilator-dependent infant after the second week of life who cannot be weaned from ventilation and whose condition is worsening. If used, they should be prescribed at the lowest effective dose for the shortest possible time. Further randomised trials of low-dose corticosteroids given after the first week of life are warranted and should assess both short- and long-term outcomes.

Introduction: Bronchopulmonary dysplasia (BPD) is the most common pulmonary morbidity associated with Prematurity and pre- mature infants with BPD are at an increased risk of death and severe developmental disability. Despite the devastating impact Of BPD on premature infants, there are currently no therapies labeled by the US Food and Drug Administration to prevent BPD. Neonatologists commonly use furosemide as off-label in premature infants. Aims: To evaluate the role of Furosemide in prevention of Bronchopulmonary Dysplasia in preterm infants. Materials and Methods: This hospital-based retrospective observational study was conducted in the Special Newborn Care Unit (SNCU) and Neonatal Intensive Care Unit (NICU) of Burdwan Medical College and Hospital over a period of two years, from November 2019 to November 2021. A total of 50 preterm babies with a gestational age between 28 and 32 weeks, admitted to the SNCU/NICU during the study period, were included. The study population comprised babies who met the gestational age criteria, and relevant data, particularly regarding exposure to furosemide, were collected retrospectively from hospital medical records. Results: In this retrospective study, baseline characteristics such as gestational age, birth weight, sex ratio, antenatal steroid use, and Apgar scores were comparable between the Furosemide and Non-Furosemide groups. In the Furosemide group, therapy was started at a mean age of 5.4 days, with an average duration of 4.6 days and a total dose of 3.2 mg/kg, mainly for oxygen requirement and PDA management. Neonates receiving Furosemide had a significantly lower incidence of bronchopulmonary dysplasia (20% vs 44%) and shorter oxygen support duration (12 vs 18 days). Respiratory outcomes also favored the Furosemide group, with shorter CPAP use and a trend toward reduced ventilation duration, though re-intubation rates were similar. Adverse events such as electrolyte imbalance, nephrocalcinosis, and mortality did not differ significantly. Importantly, the hospital stay was significantly shorter in the Furosemide group (26.4 vs 31.2 days). Conclusions: This study concludes that Furosemide use in preterm neonates was associated with reduced incidence of bronchopulmonary dysplasia, shorter oxygen and CPAP support, and decreased hospital stay, without a significant increase in adverse events or mortality.

Preterm-associated complications remain the main cause of neonatal death. Survivors face the challenges of short- and long-term complications. Among all complications, bronchopulmonary dysplasia (BPD) remains the first important cause of neonatal mortality and morbidity. Current treatment does not address this main preterm complication. Cord blood is regarded as a convenient source of stem cells. The paracrine bioactive factors of stem cells contribute to tissue repair and immune modulation. Our clinical studies and those of others have shown that cord blood cell infusion is both safe and possibly effective in the prevention and treatment of BPD. The therapeutic use of cord blood has emerged as a promising therapy. However, the genetic heterogeneity between control and intervention groups may reduce the comparability especially among small sample trials. The purpose of this study protocol is to investigate the effects of autologous cord blood mononuclear cell (ACBMNC) infusion on the prevention of BPD in very preterm monozygotic twins of less than 32 gestation weeks. In this prospective, randomized, placebo-controlled, double-blinded multicenter clinical trial, 60 pairs of monozygotic twin preterm neonates of less than 32 weeks admitted to the Neonatal Intensive Care Unit are randomly assigned to receive intravenous ACBMNC infusion (targeted at 5 × 107 cells/kg) or placebo (normal saline) within 24 h after birth in a 1:1 ratio. The primary outcome will be survival without BPD at 36 weeks of postmenstrual age. The secondary outcomes will include the mortality rate, BPD severity, other common preterm complication rates, respiratory support duration, length and cost of hospitalization, and long-term respiratory and neurodevelopmental outcomes during a 2-year follow-up. Furthermore, we will perform single-cell RNA sequencing for cord blood cells and blood cells 3-10 days after intervention and detect whether reactive oxygen species and inflammatory cytokines are present. This will be the first randomized, placebo-controlled, double-blinded trial to evaluate the efficacy of ACBMNC infusion to prevent BPD in monozygotic twin premature infants and investigate the underlying protective mechanisms. The results of this trial will provide valuable clinical evidence for translational application of cord blood cell therapy in very preterm infants.Trial registration: ClinicalTrials.gov, NCT05087498, registered 10/09/2021, https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S000BAD7&selectaction=Edit&uid=U0002PLA&ts=2&cx=qvyylv.