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 Table of Contents  
REVIEW ARTICLE
Year : 2019  |  Volume : 3  |  Issue : 3  |  Page : 42-52

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


1 Queens Medical Centre, Nottingham Children's Hospital, Nottingham University Hospitals NHS Trust, Nottingham, England
2 Department of Paediatrics, Kwong Wah Hospital, Yau Ma Tei, Hong Kong

Date of Submission09-Apr-2020
Date of Decision25-May-2020
Date of Acceptance01-Jun-2020
Date of Web Publication18-Aug-2020

Correspondence Address:
Jayesh Mahendra Bhatt
Queens Medical Centre, Nottingham Children's Hospital, Nottingham University Hospitals NHS Trust, Derby Road, Nottingham NG7 2UH
England
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/prcm.prcm_2_20

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  Abstract 


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.

Keywords: Bronchopulmonary dysplasia, home oxygen, prematurity


How to cite this article:
Poulter C, Devaney R, Kwok CK, Bhatt JM. A practical, evidence-based approach to postneonatal management of children with bronchopulmonary dysplasia. Pediatr Respirol Crit Care Med 2019;3:42-52

How to cite this URL:
Poulter C, Devaney R, Kwok CK, Bhatt JM. A practical, evidence-based approach to postneonatal management of children with bronchopulmonary dysplasia. Pediatr Respirol Crit Care Med [serial online] 2019 [cited 2020 Sep 19];3:42-52. Available from: http://www.prccm.org/text.asp?2019/3/3/42/292387




  Introduction Top


Bronchopulmonary dysplasia (BPD) is the most commonly seen chronic lung disease in preterm infants. Despite advances in neonatal medicine, rates of BPD have not changed over the past few decades. While the characteristics of patients with BPD have changed with improved neonatal care, the consensus in the definition of BPD has not been reached. We will review the definition of BPD and management of established BPD in the postneonatal period; strategies for prevention of BPD and management of long-term complications are outside the scope of this article.


  History and Definition of Bronchopulmonary Dysplasia Top


BPD was first reported in 1967 by Northway et al. who described persistent radiological and clinical lung problems in 32 neonates born with severe hyaline membrane disease who had received warm humidified 80%–100% oxygen through mechanical ventilation.[1],[2] Since then, efforts have been made to prevent the injury caused by oxygen therapy and barotrauma from mechanical ventilation. The wide use of antenatal steroids[3],[4] and surfactant therapy has improved the survival of the more premature babies but not rates of BPD. Furthermore, the incidence of BPD was shown to be higher in babies with lower birth weight and gestational age.[5],[6] The characteristics of babies with BPD have changed over time, so has the definition of BPD.

The need of continued use of oxygen therapy for 28 days was initially used as the diagnostic criterion for BPD.[7] In 1988, Shennan et al. suggested using oxygen dependency at 36 weeks postmenstrual age (PMA) to define BPD because it was a better predictor of pulmonary morbidity.[8] However, gestational age and severity of the BPD had not been addressed; hence, in June 2000, a National Institute of Child Health and Human Development (NICHD) workshop established another set of diagnostic criteria.[9] It was later shown that both the adverse pulmonary outcomes and neurodevelopmental impairment corresponded to the severity of BPD defined.[7] With the use of new modes of noninvasive ventilation such as high flow, NICHD proposed further refinements to the definition of BPD in the 2016 workshop.[10]

In the most recent publication by NICHD in 2019, using 18 definitions of BPD with different severity to test their predictability of death or serious respiratory morbidity at 18–26 months corrected age, it was noted that the mode of respiratory support was the best predictor of both, irrespective of the supplemental oxygen use.[11] This will simplify the classification, as the duration of previous use of oxygen and current level of oxygen use will not add a further benefit in predicting mortality and morbidity. Furthermore, oxygen reduction testing was not used in this study, which further enhanced the ease of use.


  Pathophysiology over Time Top


With the advent of surfactant use three decades ago, the pathology of the BPD has changed.[12],[13],[14] There are five stages of lung growth and development: Embryonic (3–7 weeks), pseudo glandular (7–17 weeks), canalicular (17–27 weeks), saccular (27–36 weeks) and alveolar (37 weeks to 7–10 years). Recent evidence suggests that alveolar growth may continue into late teenage years not only in children born at term but also in those who were born preterm and had developed BPD.[15],[16],[17] The formation of conducting systems is mostly completed in the first two stages. Most preterm babies are delivered during the late canalicular and saccular stages, which means the alveolar formation, saccular formation, vascularization, and surfactant production would be affected.

Old bronchopulmonary dysplasia

The old BPD was characterized by alternating areas of atelectasis and hyperinflation and extensive fibroproliferation, which were featured in the pre-surfactant era as a result of lung injury caused by barotrauma and volutrauma from mechanical ventilation in premature babies with older gestational age. Advances in technology and knowledge have allowed better and lung-protective strategies such as lower peak inspiratory pressure, volume ventilation with lower tidal volume, and lower oxygen concentration. However, even brief exposure to supraphysiologic oxygen can result in morphological and functional damage in the immature lung.[18] It has been demonstrated in animal models that supraphysiologic oxygen results in impaired alveolar development and pulmonary vascular remodeling.[19]

New bronchopulmonary dysplasia

In contrast, the characteristics of the postsurfactant new BPD mainly include largely simplified alveoli and capillary hypoplasia, which is due to an arrest in lung development at the canalicular stage (24–26 weeks).


  Pathogenesis and Risk Factors Top


Inflammation

A pulmonary inflammatory response secondary to either prenatal events such as chorioamnionitis or postnatal events such as mechanical ventilation, sepsis, and oxygen therapy is suggested to explain the pathogenesis of new BPD.[20],[21],[22]

Infection

While the causal relationship between chorioamnionitis and BPD has remained controversial,[23] a recent 25-year cohort study concluded that sepsis increased the risks of developing moderate or severe BPD.[24]

Mechanical ventilation

Lung injury associated with mechanical ventilation includes barotrauma and volutrauma. Aggressive ventilation strategies using large tidal volumes to achieve a normal carbon dioxide result in hypocarbia, which is associated with higher risks of BPD.[25] The trend now is to adopt a more conservative approach using smaller tidal volumes and a volume-targeted approach.[26]

Oxygen toxicity

The lung injury induced by high concentrations of oxygen is thought to be mediated through overproduction of cytotoxic reactive oxygen metabolites, including superoxide free radicals which pose a burden that exceeds the handling ability of the preterm infants' immature antioxidant enzyme system.[27],[28],[29]

Nutrition and fetal growth restriction

Being small for gestational age (SGA) is associated with the severity of BPD[21],[30] with the abnormal development of vasculature being proposed to contribute to the development of BPD in SGA preterm babies.[31]

Impaired angiogenesis

Pulmonary vascular changes are seen in BPD infants.[32] It is proposed that disruption of angiogenesis is associated with impaired alveolarization causing the development of new BPD.[33],[34]

Genetics

Although studies have shown some support for a genetic basis for the development and severity of BPD, data are limited.[35]


  Management of Bronchopulmonary Dysplasia Top


The European Respiratory Society (ERS) recently published a guideline on the long term management of children with BPD.[36] There have also been previous statements and guidelines produced by the British Thoracic Society (BTS)[37] and American Thoracic Society (ATS) on the management of children with BPD.[38] The following subsections will look at some of the current recommendations and evidence behind them.

Oxygen

All babies with BPD will, by definition need oxygen for a period of time, with a subgroup needing home oxygen for sometimes several months or years. The importance of targeting appropriate oxygen levels to help facilitate growth and development and reduce the risk of pulmonary hypertension is known.[37],[38]

There is a lack of consensus on target saturation levels and what different indices should be used on oximetry both for initiating oxygen as well as when weaning babies off oxygen.[39],[40],[41] The BTS guideline on home oxygen in children states that saturation levels <90% in infants with BPD are associated with an increased risk of apparent life-threatening events and impaired sleep quality while saturations ≥93% are not. This guideline also discussed how saturations <92% are associated with suboptimal growth[37] and therefore recommends that oxygen therapy should be given to maintain saturations ≥93%. The recent ATS guideline recommends targeting a mean of a least 93% and percentage of total study time with saturations <90% of <5%.[42] Some of the recommendations in these guidelines are based on studies done with oxygen saturation monitors with long averaging times. There is emerging data using modern pulse oximeters with motion artifact extraction technology and shorter averaging times, which suggests that the targets should be different to those suggested in the past.[43],[44] The recent ERS guideline on BPD management suggests a target saturation range of 90%–95%, but it states that further studies in this area and evidence looking at the impact on both pulmonary and other outcomes (e.g., growth and neurological outcomes) is urgently needed[36] [Table 1].
Table 1: A summary of guidance on target saturations for oximetry

Click here to view


The use of a structured program for monitoring and weaning oxygen has the benefits of a shorter duration of home oxygen therapy; unsupervised weaning is more likely associated with pulmonary hypertension.[46]

A protocol for monitoring and weaning home oxygen used in our center has recently been published,[46] which describes how by using a clear protocol, the duration of home oxygen therapy significantly reduced from 15 to 5 months with no difference in hospital readmission rates. This protocol recommends overnight oximetry studies (of at least 6–8 h duration) in all babies requiring ≥0.1 L/min of oxygen at 36 weeks postconceptual age. The oxygen flow rate is deemed optimal if the following targets are met on the overnight oximetry:

  • average arterial oxygen saturation measured by pulse oximetry (SpO2) of ≥93% (≥95% if there is evidence of pulmonary hypertension);
  • SpO2>90% for >95% of artifact-free total study time.


Repeat studies are conducted within 48 h of discharge in the same flow rate as at discharge and then at intervals of 3–5 weeks (generally weaning by 0.1 L/min). The same targets, as described above, are used to wean the oxygen flow rate until the flow rate is weaned to 0.1 L/min. At this point, trials in the air under supervision of the community nursing team for short periods in the day with target saturations ≥93% are used, before a study overnight in the air when the baby is tolerating day time off oxygen. A study 3 months after coming out of oxygen is also performed[46] [Figure 1].
Figure 1: The pathway for weaning oxygen for babies with bronchopulmonary dysplasia in our service.

Click here to view


Parents need to be aware of the effects of air travel on the need for oxygen. The BTS home oxygen in children guideline provides guidance on which children should undergo a hypoxic challenge test or pre-flight assessment.[37]

Tobacco smoke exposure

Studies have shown that a significant proportion of children with BPD are exposed to smoke in the home environment and have linked this to a tendency to need home oxygen therapy for longer and a trend toward increased use of inhaled corticosteroids.[47] There has also been work showing children with BPD exposed to smoke (measured by hair nicotine levels) have increased hospitalization episodes.[48] Avoidance of smoke exposure is recommended for children with BPD, as stated in the recent ERS guideline on BPD management in children[36] and the BTS guideline on home oxygen in children.[37] The ATS Information on BPD for parents also advises avoidance of tobacco smoke and air pollution[49] and links to information on smoking cessation support.

There is some research to suggest that professionals may not always broach this important topic with families, however.[50] This is clearly an important area to address. There is some work on how best to approach families to gain the most accurate information about this by correlating parental reports using questions about smoke exposure with objective parameters such as hair nicotine levels.[51] Smoking outside rather than inside the house was reported in 93% of caregivers who smoked in families with BPD,[52] suggesting that families appreciate the importance of these children avoiding smoke exposure. However, in this study, 18.9% of families of children with BPD still reported a smoker in the home, suggesting this is an ongoing challenge.[52]

Nutrition

Growth monitoring is a key component of follow-up of babies with BPD, and they will frequently have contact with a pediatric dietician to offer advice on this area. They may require supplements with breast milk or specific higher-calorie formulas.

ATS information for parents discusses the importance of good nutrition for optimal growth and the particular importance of this to optimize lung growth in the first two to three years of life. The higher calorie requirements[49] needed to help preterm babies grow, and the importance of good nutrition for a healthy immune system are other considerations.[38] The ERS BPD management guideline discusses that problems with nutrition can be a potential reason why children with BPD may require hospital admission again after discharge.[36]

It has been recognized that growth appears to be linked to when babies with BPD are ready to discontinue long-term home oxygen therapy. Studies have found that pre-weaning flow rates of ≤20 ml/kg/min were associated with successful weaning of home oxygen.[53] In our model, we have implemented flow rate per weight-based weaning and the pathway described in [Figure 1] was further modified as shown in [Figure 2] after we showed that successful weaning from home oxygen in a large cohort of babies with BPD is associated with pre-weaning flow rates of ≤20 ml/kg/min.[53] Current unpublished data confirm that three times as many babies can be successfully weaned off using the new pathway [Figure 2].
Figure 2: The modified oxygen weaning pathway for babies with bronchopulmonary dysplasia in our service.

Click here to view


Discharge

For several years statements about the care of babies with BPD have recognized the importance of optimizing the time of discharge home, both to avoid the adverse impacts of prolonged hospitalization of families and to reduce the economic impact of these long stays on the health-care system.[38] The impact of prolonged hospital stays on families in terms of psychological impact and quality of life for both the infant and family is being considered in recent guidelines on this area. In 2019, the ERS guideline focused on the longer-term management of these babies postdischarge.[36]

These statements have also provided guidance on areas that it is suggested are important to consider when assessing whether a patient is ready for discharge. These include factors such as patient medical stability, family and home environment factors as well as the available community support.[38] Families need to have achieved appropriate training and feel supported at the point of discharge. Research in this area states the importance of considering the stress placed on families of taking home infants who are still medically fragile.[54]

Examples of published criteria that signify medical stability include a lack of apneas for at least 2 weeks, infrequent episodes of desaturation, and the ability to cope in the air for short periods (in case oxygen is accidentally displaced at home for a short period). In general, this occurs when babies are in oxygen flow rates of ≤0.5 L/min. Babies should be meeting targets on a set flow rate of oxygen. They should be otherwise medically stable and well, for example, gaining weight.[37],[55]

It is important that we consider discharge criteria carefully to minimize the risk of babies with BPD needing readmission. As stated in the ERS guideline on BPD management, children with BPD may be readmitted due to a variety of reasons including increased susceptibility to respiratory viral illnesses requiring hospital care, nutritional problems, and other associated conditions secondary to preterm birth.[36]

Follow-up arrangements may differ between centers and may be provided by pediatric respiratory physicians or neonatologists. Babies with BPD may also benefit from the involvement of other specialists, for example, cardiologists for those with pulmonary hypertension.[36]

Infection prevention

As stated in the ERS guideline on BPD management, respiratory infection is a common reason for babies with BPD to require hospital readmission.[36] Guidance on ways to reduce the risk of babies with BPD acquiring infections is provided in family information provided by the ATS.[49] This provides basic information about good hand hygiene, avoiding unwell contacts, and the importance of routine childhood immunizations.

This guidance also recommends the seasonal influenza vaccine for babies with BPD over 6 months chronological age and advises parents and caregivers to have the influenza vaccine if possible if their baby is too young to receive this. In addition, these babies should be offered passive immunization against the respiratory syncytial virus (RSV). Palivizumab is a humanized monoclonal antibody that provides passive immunity against RSV.[56] It is administered as five injections at monthly intervals during the winter months to try to reduce hospitalizations and complications secondary to RSV infection in “high risk” patient groups such as those with BPD.[57] The summary of product characteristics (SPC) from the European Medicines Compendium 2015 states that Palivizumab is indicated in children under two years of age who have required treatment for BPD within the past 6 months. Palivizumab is a high-cost drug however and therefore cost-effectiveness criteria have been published to guide clinicians as to which children should be offered Palivizumab, which are more restrictive than in the SPC.[56],[58] Several strategies, including maternal immunization against RSV and the use of a long-acting monoclonal antibody against RSV, are well described in a recent review.[59]

Daycare attendance

The ERS taskforce focusing on longterm BPD management recently looked at the evidence for whether daycare attendance affected important outcomes in babies with BPD such as hospital admissions, respiratory symptoms, neurodevelopment, and home oxygen duration.[36] They found no evidence to help support an answer to this question in the literature and thus suggested individual advice is given to families on this topic.

The task force members did not recommend or discourage parents from using daycare for their children but commented that the risk of this might be influenced by factors such as the age of the child, the time of year, and the severity of BPD. The decision about whether children with BPD should go to daycare centers is one to be made by the parents considering all factors (including pragmatic factors such as availability of alternative care arrangements) and the potential social and developmental benefits of attendance. In contrast, the ATS parent information suggests parents should avoid daycare for children with BPD if possible as well as crowded places like shopping malls.[49]


  Severe Bronchopulmonary Dysplasia Top


Severe BPD (sBPD) represents around 16% of babies with BPD and is associated with the highest mortality and morbidity.[60] It is defined using the National Institute of Health criteria as the need for supplemental oxygen ≥30%, noninvasive or invasive respiratory support at 36 weeks PMA in babies born at <32 weeks gestation.[61] The BPD Collaborative recommends that sBPD be further sub-classified into those requiring nasal cannula oxygen, CPAP, or high flow nasal cannula oxygen (sBPD type 1) and those with a persisting need for mechanical ventilation (sBPD type 2).[60] Babies with sBPD constitute some of the sickest babies on the neonatal unit with longer length of stay, poorer cardiopulmonary long-term outcomes, and increased incidence of developmental problems.[60],[61],[62]

sBPD is a heterogeneous condition representing a broad spectrum of the underlying pathophysiology and clinical presentation. Physiological definitions based on pulmonary function testing and oxygen withdrawal tests have been proposed but are not routinely used.[63] The presence of pulmonary hypertension is not included in diagnostic criteria but likely contributes to the severity of the disease.[62]

Below we will discuss the current management strategies for sBPD and summarize evolving therapies.

Pharmacological management

Corticosteroids

Previously, courses of systemic steroids (largely dexamethasone) were frequently used at either early or late time points to prevent the development of BPD.[64],[65] Steroids are potent anti-inflammatory agents and have been found to both shorten the duration of mechanical ventilation and facilitate extubation.[66],[67] Although consistently effective in reducing the development of BPD at all time points used, concerns about the increased risk of cerebral palsy and neurodevelopmental problems have led to them being used more sparingly with a move toward lower doses of steroids being reserved for the most unwell, ventilator-dependent infants after the 1st week of life.[68],[69],[70]

A number of alternative steroid regimens have been trialed. The use of low dose hydrocortisone in the PREMILOC study resulted in a significant increase in survival without BPD in the treatment group; however, neurodevelopmental outcomes were not reported.[71] The NEUROSIS trial of inhaled budesonide in babies requiring respiratory support showed a reduction in the total duration of supplemental oxygen therapy but also did not assess neurodevelopmental outcomes.[72],[73] With the aim of developing a more targeted therapy, Yeh et al. trialed the use of intra-tracheal delivery of budesonide with the surfactant, showing a significant reduction in BPD in the budesonide group with no significant adverse effects at follow-up two to four years later.[74],[75]

Research into postnatal steroids has largely focused on the prevention of sBPD with little known about their efficacy in the long-term treatment of infants with established sBPD.[76] Consequently, the ERS Taskforce recommends that inhaled and systemic steroids should not be used routinely in established BPD however, if considered for use, for example, in those with severe symptoms or recurrent hospitalizations, the effects of treatment should be closely monitored for a trial period.[36]

Azithromycin

Macrolide antibiotics have anti-inflammatory effects with actions at multiple points in the inflammatory cascade and have been found to reduce hyperoxic lung injury in animal models.[77] A recent meta-analysis showed that prophylactic azithromycin is associated with a significant reduction in BPD development; however, larger clinical studies are needed before it is routinely used.[78],[79]

Azithromycin has also been studied as a therapeutic agent in babies already colonized with ureaplasma. It has increased antimicrobial activity against ureaplasma and a better safety profile than erythromycin with better drug concentrations in the lung epithelium and alveolar macrophages.[80],[81] However, studies have not shown a reduction in the development of BPD, and work is needed to determine the dose needed to achieve ureaplasma clearance.[82]

Hydroxychloroquine

Hydroxychloroquine is a quinolone and acts by inhibiting immune activation by reducing Toll-like receptor signaling and cytokine production.[83] Evidence for its use in BPD is extrapolated from use in interstitial lung disease in children where it has been observed to be effective in children with ABCA3 mutations.[84] In babies with sBPD, it has been used as part of a treatment protocol alongside methylprednisolone and azithromycin; however, further studies are needed.[85]

Diuretics

Diuretics are frequently used with the aim of reducing pulmonary edema and have been shown to result in a short-term benefit on pulmonary mechanics with improved lung compliance, reduced airway resistance, and improved oxygenation.[86] Patterns of use vary significantly across institutions, with the most frequently used being furosemide, a loop diuretic, and chlorothiazide which is often combined with spironolactone to minimize renal salt wasting.[87] There is a lack of evidence of benefit from long-term use with a recent Cochrane review showing no evidence of benefit on length of stay, need for ventilatory support, duration of home oxygen therapy[88] or long-term outcomes and a risk of adverse events including nephrocalcinosis, electrolyte disturbances, and osteopenia.[89]

For children with BPD who were commenced on diuretics in the neonatal period, the ERS Taskforce recommends a natural wean by a relative decrease in dose with weight gain, and if continued beyond this, careful monitoring of the effects of treatment during a trial period.[36]

Inhaled bronchodilators

Inhaled bronchodilators have a short-term effect on reducing airway resistance and improving lung compliance;[86],[90] however, there is wide variability in response and a lack of evidence to suggest benefit in this cohort.[91] The recent ERS Taskforce Recommendations suggest that consideration of inhaled bronchodilators should be reserved for a subgroup of children, namely those with asthma-like symptoms, recurrent hospital admissions due to respiratory morbidity, exercise intolerance, and reversibility in lung function.[36]

Long term ventilation

The BPD Collaborative report tracheostomy insertion rates of around 12% in infants with sBPD across tertiary centers.[60] There is a lack of evidence to suggest which babies are most likely to benefit from long term ventilation and the optimal timing for this however Luo et al. propose that it could be considered in postterm babies with sBPD who are expected to need invasive respiratory support for a prolonged period of time if weaning their respiratory support negatively impacts on growth, development or the stability of pulmonary hypertension.[92]

The decision to initiate long term ventilation via tracheostomy is the complex and detailed discussion between the clinical team and family is crucial. Long-term ventilation for patients with sBPD has been shown to facilitate growth, improve developmental outcomes, and reduce sedative medication requirements.[92]

Management of co-morbidities

Babies with sBPD may have multiple prematurity related comorbidities, which both complicate and exacerbate their lung disease. Management of these should be optimized as part of the treatment of sBPD.

Pulmonary hypertension

Pulmonary hypertension affects around 25% of those with sBPD and is associated with increased morbidity and mortality.[60],[62] It evolves due to abnormal vascular development and remodeling with increased pulmonary vascular resistance.[62] The gold standard diagnostic test is cardiac catheterization; however, echocardiogram is more widely used in practice.[93] The ATS has recently recommended screening for pulmonary hypertension using echocardiography in all babies with sBPD.[94]

Management should focus on the treatment of the underlying lung disease, avoiding periods of hypoxemia with oxygen saturation limits set between 92% and 95%.[60] While inhaled nitric oxide has been shown to cause transient improvement in pulmonary pressures, its longer-term use poses practical challenges.[86],[95] Sildenafil, a selective type 5 phosphodiesterase inhibitor, has a longer half-life and causes vasodilatation and smooth muscle growth inhibition.[86],[95],[96] Studies have shown it to be effective in reducing pulmonary artery pressures and respiratory severity score, but it can have systemic side effects, including hypotension.[96],[97] Further studies are needed to determine long term outcomes in this population.

Gastroesophageal reflux disease

Gastroesophageal reflux may exacerbate lung disease in sBPD.[60] Studies have shown increased pH events on esophageal pH impedance testing in babies with BPD compared to those without, with proposed mechanisms for this, including impaired esophageal motility and an altered autonomic nervous system response pattern.[98],[99] Pharmacological measures should only be considered when other measures have been unsuccessful as there is limited evidence supporting their use in preterm babies and risk of adverse effects.[100] Surgical interventions for gastroesophageal reflux have shown a small but significant reduction in respiratory rate and oxygen requirement postintervention; however, data regarding longer-term outcomes is lacking.[101]

Large airway disease

Over five percent of babies with BPD have comorbid tracheobronchomalacia;[60] which may present with acute life-threatening episodes due to intermittent airway collapse and ventilatory requirements out of proportion to those expected.[102] They are likely to have a longer length of stay, spend longer requiring mechanical ventilatory support and are more likely to be mechanically ventilated on discharge.[103] Babies with suspected airway problems should be considered for bronchoscopy to assess airway anatomy.[104] A recent ERS statement describes the management of tracheobronchomalacia in children in detail.[105]

Feeding problems

Optimizing nutrition is key to achieving the “pro-growth” state required for lung growth and development. Babies with sBPD have increased metabolic demands alongside growth suppression induced by chronic stress, inflammation, and steroid use[60] with an estimated 15%–25% higher energy requirement than those without BPD.[106] A caloric intake of around 140 kcal/kg/day may be needed to achieve this, and concentrated formulas or fortified breast milk are likely to be needed to avoid very high fluid volumes.[106],[107] Linear growth should be closely monitored, and nutritional intake titrated to maintain growth. Enteral feeding through naso-gastric tube or gastrostomy may be required postdischarge to supplement oral feeding.[60],[108]

Aspiration is a risk factor for persistent lung injury in sBPD and may be due to dysfunctional swallowing, reflux, and pooling of oral secretions. It may present acutely with pneumonia necessitating increased respiratory support or more insidiously with chronic coughing, wheeze, tachypnea, desaturations and poor weight gain. Assessment by an experienced speech and language therapist is advised.[60]

Atypical presentation

In babies with an atypical presentation or progression of severe lung disease, thought should be given to excluding additional or alternative diagnoses such as cystic fibrosis, primary ciliary dyskinesia, and diffuse parenchymal lung disease. Pertinent investigations to perform in this population could include an echocardiogram, sweat test, immune function testing, and bronchoscopy.[60] The yield of positive results for surfactant protein gene mutations and the alveolar-capillary dysplasia spectrum is much less when pre-term babies with respiratory distress, which does not run the normal clinical course, are tested.[84]

Emerging therapies

Developing an understanding of the specific risk factors and mechanisms that lead to the development of this severe phenotype is crucial to tailoring therapeutic approaches.[60] There is a need to develop biomarkers and other early predictors for the development of sBPD. This has proven challenging due to the heterogeneous nature of sBPD and difficulty in determining the optimal specimen type, timing of collection, and an appropriate control cohort.[62],[109] Potential biomarkers aim to target the causal pathways implicated in BPD pathogenesis including markers of inflammation e.g., serum cytokines, angiogenic growth factors e.g., vascular endothelial growth factor and platelet-derived growth factor and markers of pulmonary hypertension e.g., brain natriuretic peptide.[62],[109],[110]

A number of cell-based therapies are being investigated with the most promising results from the use of mesenchymal stem cells (MSCs), which have shown the potential to reduce inflammation via modulation of macrophages, prevent fibrosis, and promote alveolar growth in phase one trials.[111],[112] However, a recent Cochrane review concluded that there is currently insufficient evidence for the safety and efficacy of MSCs in the prevention and treatment of BPD.[113] Endothelial progenitor cells (EPCs) have been found to promote the repair of damaged blood vessels, and the finding that they become depleted in hyperoxic lung injury has led to exogenous EPC therapy being proposed.[114]

Exploration of anti-inflammatory modulators includes trials of prophylactic use of the anti-inflammatory agents interleukin-1 receptor antagonist (IL1-Ra) and Protein C (PC), which have been shown to be protective against the development of BPD in animal models with no adverse effects on brain development.[115],[116],[117],[118]

In conclusion, BPD remains one of the most common morbidities of prematurity with implications for lung health and development into childhood and adolescence.[62] Although definitions vary, the extent of respiratory support required at 36 weeks PMA appears to be the most reliable indicator of longer-term outcomes.[10],[11] BPD is now understood to be a complex disease resulting from an interaction of antenatal, perinatal, and postnatal factors affecting both alveolar and vascular development, with its incidence being inversely proportional to gestational age and birth weight.[5],[6],[61],[62]

A number of babies with BPD will require supplemental oxygen on discharge, and we have summarized guidance on the target oximetry parameters, although there remains a lack of consensus on this.[36],[37],[39],[40],[41] A structured approach to oxygen weaning is important to facilitate growth and development, and at our center has been effective in reducing the total duration of home oxygen therapy with no increase in hospital readmission rates.[46] Support and education for families facilitated by a multi-professional team are essential and should include information on nutrition, reducing second-hand smoke exposure, and prevention of infections.[36],[37],[38]

A small cohort of infants will have a more severe form of BPD and may require a longer period of mechanical ventilation and hospital stay.[60] There are a number of pharmacological therapies used, although the evidence base underlying them is lacking in some cases. Alongside managing BPD, the management of any comorbidities should be optimized, and in atypical presentations, alternative or additional diagnoses should be considered.[60] There have been promising findings from early studies into new treatments for BPD, including the use of mesenchymal stem cells and anti-inflammatory therapies.[113],[116],[118]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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