Bronchopulmonary dysplasia: Myths of pharmacologic management

Bronchopulmonary dysplasia (BPD) is the leading cause of long-term respiratory morbidity in newborns who require respiratory support at birth. BPD is a multifactorial disorder, and infants are frequently subjected to treatment with multiple pharmacologic agents of dubious efficacy and questionable safety, including diuretics, bronchodilators, corticosteroids, anti-reflux medications, and pulmonary vasodilators. These agents, with narrow therapeutic indices, are widely used despite the lack of an evidence base, and some may do more harm than good. It is incumbent on the clinician to establish a risk:benefit ratio and to avoid drugs that have little efficacy and a high rate of toxicity.     

Bronchopulmonary dysplasia

Bronchopulmonary dysplasia (BPD) is the most common sequelae of preterm birth. It has proven a difficult condition to define as improving early management of the premature infant has led to a changing clinical picture over time. However, despite the advances in neonatal care, rates of BPD are at best unchanged and may even have risen. As BPD has significant long-term consequences, particularly from respiratory, cardiovascular and neurodevelopmentary perspectives, effective early management is key to improving long term outcomes. In this review the various definitions of BPD, and their limitations, are discussed alongside the evidence behind effective management of preterm infants, including the long-term management needed after discharge from hospital.     

Progress in discovery and evaluation of treatments to prevent bronchopulmonary dysplasia

BACKGROUND: Recent improvements in the survival of extremely preterm infants have been accompanied by evolution in the pathogenesis and histopathology of bronchopulmonary dysplasia (BPD). Although oxygen and barotrauma-induced injury remain important contributing factors, pulmonary developmental arrest appears to play an equally important causal role in prolonged respiratory illness, especially among the most immature surviving preterm newborns. To date, clinical trials have failed to demonstrate a substantial benefit of a single treatment or preventive strategy for BPD. OBJECTIVES: To evaluate the current evidence in favor of treatments that might prevent BPD. METHODS: Review of clinical studies of preventive treatment strategies for BPD. RESULTS: High frequency oscillatory ventilation, permissive hypercapnea, and inhaled nitric oxide might offer benefit to infants at risk of BPD. These and other potential preventive therapies for BPD, such as superoxide dismutase, inositol, and alpha(1)-proteinase inhibitor, deserve further study. CONCLUSIONS: Although some current treatments offer promise, no preventive therapy for BPD has proven safe and effective, except for intramuscular vitamin A. Additional studies of respiratory technologies, management strategies, and protective molecules are needed.     

Management of bronchopulmonary dysplasia

Bronchopulmonary dysplasia (BPD) is a common and important complication of prematurity and is associated with significant mortality, morbidity and healthcare resource utilization. Despite advances in both perinatal and neonatal care the incidence of the condition continues to rise. The management of BPD and its related problems remains a major challenge to neonatologists and paediatricians. There is unlikely to be a single intervention which will dramatically alter the management of BPD and thus multiple interventions have been proposed to prevent and treat the disease. Many of these interventions are still not evidence based and some of those that are have been shown to have unacceptable long-term effects. It is useful to conceptualize BPD in three stages, namely (i) prevention, (ii) treatment of evolving BPD and (iii) treatment of established BPD. In this review current and potential future management approaches to BPD and the relevant evidence for these are discussed within the framework of these three stages.     

Adjunctive therapies in chronic lung disease: examining the evidence

Chronic lung disease (CLD) or bronchopulmonary dysplasia (BPD) is one of the most common long-term complications in very premature infants. The incidence of CLD has been increasing over the past two decades in parallel with an improvement in the survival of this population. We have witnessed a revolution in the therapies that are used, either to manage these infants' respiratory distress syndrome (RDS) with an aim to prevent CLD or to manage the established condition. Several devices and strategies have been developed to provide respiratory support with minimal risk of lung injuries. Multiple adjunctive agents have also been used either to reduce the risk of CLD or to mitigate its course. There is considerable evidence supporting the use of exogenous surfactant, but unfortunately many other therapies currently used for CLD, either preventative or as a treatment, are based on very little or no evidence. The gold standard to assess a given therapy is the randomised controlled trial (RCT), designed to look at clinically meaningful outcomes and long-term safety. In this context, we discuss the support - or lack thereof - for the adjunctive therapies used in relation to CLD. Many of the therapies have been examined as systematic reviews by the Cochrane Neonatal Review Group. These reviews are noted in the references and can be easily accessed at the following website sponsored by the National Institute of Child Health and Human Development: www.nichd.nih.gov/cochrane/default.cfm.     

Neonatal ventilation strategies and long-term respiratory outcomes

Long-term respiratory morbidity is common, particularly in those born very prematurely and who have developed bronchopulmonary dysplasia (BPD), but it does occur in those without BPD and in infants born at term. A variety of neonatal strategies have been developed, all with short-term advantages, but meta-analyses of randomized controlled trials (RCTs) have demonstrated that only volume-targeted ventilation and prophylactic high-frequency oscillatory ventilation (HFOV) may reduce BPD. Few RCTs have incorporated long-term follow-up, but one has demonstrated that prophylactic HFOV improves respiratory and functional outcomes at school age, despite not reducing BPD. Results from other neonatal interventions have demonstrated that any impact on BPD may not translate into changes in long-term outcomes. All future neonatal ventilation RCTs should have long-term outcomes rather than BPD as their primary outcome if they are to impact on clinical practice.     

Strategies for preventing bronchopulmonary dysplasia

PURPOSE OF REVIEW: Neonatologists and pulmonary biologists have long sought preventive treatments for bronchopulmonary dysplasia (BPD). The purpose of this review is to highlight recent reports of a number of potential treatments intended to prevent BPD and to discuss the controversies surrounding preventive strategies. RECENT FINDINGS: The evolution of BPD from a disorder of pulmonary injury affecting moderately preterm infants, to one characterized by a developmental pulmonary arrest among survivors of extreme prematurity has important implications for BPD prevention. Recent recognition that the pathogenesis of BPD might have prenatal origins raises new challenges and opportunities for studies of BPD prevention; however, most current preventive strategies for BPD focus on respiratory management. Neither past nor current clinical trials have shown a conclusive benefit of a single preventive treatment strategy. Promising but still largely unproven preventive respiratory treatments include: high frequency oscillatory ventilation, permissive hypercapnea, and inhaled nitric oxide. Observational and recent laboratory data support the need for randomized clinical trials of continuous positive airway pressure versus mechanical ventilation. Additionally, clinical trials are needed to address the deficit in our knowledge of the potential benefits and risks of postnatal low dose corticosteroid treatment. Further study of superoxide dismutase, inositol, and alpha-1 proteinase inhibitor also are warranted on the basis of recent clinical trials or meta-analyses. SUMMARY: Only Vitamin A has proven a safe and effective preventive treatment for BPD. Additional studies of respiratory technologies, management strategies, and protective molecules are needed. Directed cytokine and genetic therapies are on the horizon.     

Mesenchymal stem cells for the prevention of bronchopulmonary dysplasia

Bronchopulmonary dysplasia (BPD) is a chronic lung disease in preterm infants who have been treated with supplemental oxygen and mechanical ventilation. Despite major advances in perinatal and neonatal medicine, limited progress has been made in reducing BPD rates. The use of mesenchymal stem cells (MSC) is a promising and innovative therapy for several diseases because they are easy to extract and they have low immunogenicity, anti‐inflammatory properties, and regenerative ability. According to several pre‐clinical studies that have used BPD animal models, one mechanism of action for MSC in BPD is mainly due to the paracrine effects of MSC‐derived humoral factors, such as interleukin (IL)‐6, IL‐8, vascular endothelial growth factor, collagen, and elastin, rather than the multilineage and regenerative capacities of MSC. Cell‐free preparations derived from MSC, including conditioned media and exosomes, remain a pre‐clinical technology despite their great clinical potential. A first‐in‐human clinical trial of MSC treatment for BPD was performed as a phase I dose‐escalation trial using umbilical cord blood‐derived MSC. That trial demonstrated the short‐ and long‐term safety and feasibility of MSC, given that significantly reduced inflammatory marker expression was observed in tracheal aspirates. As of recently, several clinical trials of MSC use for BPD are ongoing or are planned in some countries to investigate the efficacy of MSC in the prevention or treatment of BPD in premature infants. Many clinicians are currently awaiting the results from these trials so that MSC can be used clinically for human BPD.     

The use of inhaled glucocorticosteroids and recovery from adrenal suppression after systemic steroid use in a VLBW premature infant with BPD: case report and literature discussion

Despite development of many prevention and treatment modalities for bronchopulmonary dysplasia (BPD), a form of chronic respiratory insufficiency in premature infants recovering from respiratory distress syndrome, BPD remains a treatment challenge and a significant cause of long-term morbidity. A ventilator-dependent very low birth weight infant in our newborn special care unit was receiving multiple courses of systemic dexamethasone for severe respiratory failure. The infant demonstrated adrenal suppression manifested by a baseline cortisol concentration below reported levels in infants of similar birth weight and postnatal age. We hypothesized that he had developed adrenal insufficiency as a result of the prolonged systemic steroid administration used to treat his respiratory problems. We further hypothesized that inhaled beclomethasone therapy would aid in the infant's recovery phase during relative adrenal insufficiency--and so substituted inhaled for systemic steroids. Inhaled corticosteroid treatment improved the clinical respiratory course and postnatal growth of this premature infant with BPD without inhibiting his recovery from adrenal insufficiency.     

Long term outcomes in chronic lung disease requiring tracheostomy and chronic mechanical ventilation

Bronchopulmonary dysplasia (BPD) is the most common serious complication associated with preterm birth. Infants with severe BPD often require prolonged and intensive pulmonary care. Among those with the most severe lung disease, this care may include tracheostomy and long-term invasive mechanical ventilation. Although there is a plethora of data on long term respiratory and developmental outcomes of BPD survivors, relevant information on BPD survivors requiring chronic respiratory failure are limited. When compared to those born at term gestation, infants with BPD requiring chronic ventilation are at increased risk of hospitalizations and develop more frequent lower respiratory infections. In childhood and young adulthood, spirometry often shows an obstructive flow pattern. From a neurodevelopmental standpoint, the short-term outcomes appear optimistic, with improvement in growth and increased participation in development-promoting activities. Nonetheless, children born prematurely are vulnerable for long term cognitive, educational and behavioral impairments. BPD is an additional risk factor which exacerbates these deficits, thus contributing to lifelong neurodevelopmental impairments of prematurity.     

The use of non-steroidal anti-inflammatory drugs for patent ductus arteriosus closure in preterm infants

Over the last four decades, non-steroidal anti-inflammatory drugs have been widely used to induce closure of the patent ductus arteriosus (PDA) in preterm infants. Evidence to support this practice is lacking, despite performance of >50 randomized trials. The credibility of those trials may have been compromised by high rates of open treatment in controls, era of study prior to advent of modern practices, or inclusion of insufficient numbers of very immature infants. Meta-analyses show little impact of those factors on main conclusions. Essentially all trials reporting important long-term outcomes (other than mortality) initiated treatment within five days after birth, so no evidence regarding later treatment is available. Accruing clinical experience suggests that long-term outcomes are not compromised, and may be improved, with non-interventional management strategies. Future studies to identify preterm infants at greatest risk of potential harm from a persistent PDA, particularly after the second postnatal week, are urgently needed.     

Ureaplasma and bronchopulmonary dysplasia

Advances in neonatal intensive care have greatly improved survival rates for children born in a very early stage of lung development (i.e. less than 26 weeks of gestation). In these premature babies, even low levels of oxygen and methods of minimally invasive ventilation may disrupt the growth of the distal airways, a condition described as “new” bronchopulmonary dysplasia (BPD).Ureaplasma infection can occur in utero or in the perinatal period in premature infants, in some of which the infection with these organisms triggers an important lung pro-inflammatory and pro-fibrotic response, and may increase the risk of developing BPD. The inflammation may be worsened by exposure to oxygen and mechanical ventilation. At present, clinical studies have not clarified the role of Ureaplasma in the pathogenesis of BPD and there is insufficient evidence to determine whether antibiotic treatment of Ureaplasma has influence on the development of BPD and its comorbidities.Future research in the context of well-designed and controlled clinical trials of adequate statistical power should focus on how to determine whether the treatment of Ureaplasma decreases lung inflammation, reduces rates of BPD, and improves long-term neurodevelopment.     

Antioxidants: Role the in prevention and treatment of bronchopulmonary dysplasia

Bronchopulmonary dysplasia (BPD) is one of the major causes of chronic respiratory diseases among infants. Both pharmacological and nonpharmacological approaches have been proposed for its management. Since oxidative stress is known to play a pivotal role in the pathogenesis of BPD, it is reasonable to consider the potential of antioxidant strategies in the prevention and treatment of this condition. Indeed, antioxidants can prevent or inhibit substrate oxidation. Some studies have evaluated the efficacy of the exogenous administration of vitamins and micronutrients in reducing the propagation of free radicals through their scavenging capacity. Nonetheless, encouraging preclinical results did not translate into effective preventive and/or therapeutic interventions. This narrative review evaluates the current evidence about the antioxidants that are potentially useful for preventing and treating BPD and explores the most relevant issues affecting their implementation in clinical practice, as well as their associated evidence gaps and research limitations.     

Targeting inflammation to prevent bronchopulmonary dysplasia: can new insights be translated into therapies?

Bronchopulmonary dysplasia (BPD) frequently complicates preterm birth and leads to significant long-term morbidity. Unfortunately, few therapies are known to effectively prevent or treat BPD. Ongoing research has been focusing on potential therapies to limit inflammation in the preterm lung. In this review we highlight recent bench and clinical research aimed at understanding the role of inflammation in the pathogenesis of BPD. We also critically assess currently used therapies and promising developments in the field.     

Bronchopulmonary dysplasia and surfactant

Bronchopulmonary dysplasia (BPD) is the most common respiratory complication in preterm infants who survive prolonged mechanical ventilation. Exogenous surfactant administration clearly reduces the severity of respiratory distress syndrome (RDS) and consequently the need for aggressive ventilation and prolonged oxygen therapy. However, the overall incidence of BPD has not decreased but in fact may even have increased after the introduction of surfactant therapy. There are several reasons for the lack of effect on the incidence of BPD. First, surfactant therapy and antenatal steroids have markedly increased survival of the smallest infants, i.e. those at higher risk of BPD. Second, there has been a change in the pathogenesis and the presentation of BPD. While the classic BPD was mainly the consequence of barotrauma and oxygen toxicity, the new BPD seen in the surfactant era results from the interaction of many factors that lead to prolonged mechanical ventilation and colonization of the airway with pathogens that may trigger an inflammatory cascade. While the overall incidence of BPD has not been substantially modified by surfactant therapy, the more severe cases of BPD have become less common. The data regarding the effect of surfactant administration on the incidence and severity of BPD is conflicting. There is substantial evidence that the administration of exogenous surfactant, either as prophylaxis or as a treatment in infants with established RDS, can reduce neonatal mortality and the occurrence of BPD or death. The data also suggest that prophylactic or early administration is more effective than late treatment in reducing mortality and BPD or death. No clear difference has been documented between natural or synthetic surfactant treatment in terms of their effect on incidence of BPD or mortality. The lack of consistency in the results with surfactant replacement may reflect the changing pathogenesis of BPD and the multiplicity of factors involved among which surfactant deficiency is only one.     

Fetal growth restriction and neonatal-pediatric lung diseases: Vascular mechanistic links and therapeutic directions

Bronchopulmonary dysplasia (BPD) is the most common respiratory sequela of prematurity, and infants born with fetal growth restriction (FGR) are disproportionately represented in BPD statistics, as factors which affect somatic growth may also affect pulmonary growth. Effects of in-utero hypoxia underlying FGR on lung parenchymal architecture predisposing to BPD are well documented, but the pulmonary vascular constructs are not well appreciated. Disruption of angiogenesis during critical periods of lung growth impairs alveolarization, contributing to BPD pathogenesis. Pulmonary artery thickness/stiffness has been noted in FGR in the initial postnatal weeks, and also in well-grown infants with established BPD. The lack of waveform cushioning by the major arteries exposes the pulmonary resistance vessels to higher pulsatile stress, thereby accelerating microvascular disease. Reactive oxygen species, increased sympathetic activity and endothelial dysfunction are common mediators in FGR and BPD; each putative targets for prevention and/or therapeutics using interleukin (IL)-1 receptor antagonist (IL-1Ra), melatonin or inhibition of renin–angiotensin–aldosterone system. While BPD is the archetypal respiratory disease of infancy, effects of FGR on pulmonary function are long-term, extending well into childhood. This narrative links FGR in very/extremely preterm infants with BPD through the vascular affliction as a mechanistic and potentially, therapeutic pathway. Our objectives were to depict the burden of disease for FGR and BPD amongst preterm infants, portray vascular involvement in the placenta in FGR and BPD cohorts, provide high resolution vascular ultrasound information in both cohorts with a view to address therapeutic relevance, and lastly, link this information with paediatric age-group lung diseases.     

Drug treatment for bronchopulmonary dysplasia in Japan: Questionnaire survey

Bronchopulmonary dysplasia (BPD) is one of the most common complications in premature infants. Although several different drugs have been developed for BPD, there is a wide variation in the choice of drug used among facilities. The aim of this study was to carry out a survey of the current drugs used to treat BPD in Japan. Questionnaires regarding the current use of drugs for BPD were sent to tertiary neonatal units. The response rate was 80% (77/96). Most units used antenatal steroids and oral diuretics for the prevention and treatment of BPD, respectively. Only 4% used caffeine for prevention, whereas 88% used systemic corticosteroids for treatment. Few units used inhaled anticholinergics and i.v. vitamins for the prevention and treatment of BPD, respectively. It was found that the drugs used to treat BPD vary greatly among institutions. Further research is required to develop evidence‐based clinical guidelines for BPD in premature infants.     

Bronchopulmonary dysplasia and cytomegalovirus pneumonia]

Hyaline membrane disease (HMD) of premature newborn can lead to bronchopulmonary dysplasia (BPD). We report the observation of a 33 weeks premature newborn with HMD, treated with exogenous surfactant and mechanical ventilation. The patient developed respiratory distress with oxygen dependency initially related to BPD. Because of worsening of respiratory condition after 2 months, despite corticosteroid therapy, further investigation was performed. Cytomegalovirus (CMV) was found in urine and in the pharynx and CMV-pneumonia was diagnosed. Treatment with gancyclovir allowed a rapid regression of symptoms. Association between BPD and CMV-pneumonia has been previously reported but the causal relationship is controversial. In premature newborn, CMV-pneumonia can appear clinically and radiologically like a BPD. When evolution is atypical, with persistence of respiratory distress despite BPD treatment, CMV-pneumonia must be considered as a specific antiviral therapy may be discussed.     

间充质干细胞治疗支气管肺发育不良作用机制的研究进展

支气管肺发育不良（bronchopulmonary dysplasia,BPD）是一种因早产儿肺发育受阻和损伤而导致的慢性肺疾病,是造成早产儿呼吸衰竭的主要病因之一。合并BPD的早产儿其他并发症发生率和病死率显著高于一般早产儿。目前主要通过综合管理对BPD进行干预,包括合理的呼吸循环支持,恰当的肠内、外营养,咖啡因、糖皮质激素及肺表面活性物质等药物的应用和出院后的院外管理。近年来干细胞医学的不断进展为治疗BPD提供了新的思路。多项临床前试验已证实干细胞治疗在有效避免肺损伤的同时促进肺的生长和损伤修复。因此,该文对间充质干细胞治疗BPD的作用机制进行全面分析,以期为临床应用提供依据。     

Impact and aetiology of respiratory infections, asthma and airway disease in Australian Aborigines

In this review, we describe the burden of respiratory illness in Australian indigenous communities and examine evidence of aetiology. We have reviewed the results from studies of respiratory infections and asthma-like symptoms conducted in remote and non-remote indigenous communities and contrasted them with data from comparable studies in non-indigenous communities. Although bias cannot be controlled and generalizability is an issue, the data are the only information available and, as such, provide a basis for a hypothesis generating approach to better health care. The evidence suggests that many indigenous people, especially those who live in non-remote regions, have asthma-like symptoms that are largely of an infectious rather than an allergic origin. Moreover, indigenous communities continue to be exposed to low immunisation rates, to have low rates of breastfeeding and to have high rates of cigarette smoking, all of which have the potential to increase the prevalence of respiratory illnesses. It is important to identify the most effective treatments and preventive strategies for respiratory symptoms that are prevalent in indigenous children. Respiratory symptoms that are largely of a bacterial-infectious origin may not benefit from commonly prescribed asthma therapies and, without appropriate treatment, may lead to ongoing health problems.