#55: BPD, Ya You Know Me: Bronchopulmonary Dysplasia with Dr. Jonathan Levin

July 13, 2022 | By Sam Masur

Summary

Join the Cribsiders and our double-board certified guest, Dr. Jonathan Levin, as we discuss Bronchopulmonary Dysplasia (BPD). We learn about everything from epidemiology and pathophysiology to diagnosis and treatment of this common respiratory illness. If you’ve ever been lost in the NICU wondering whether your patient has “chronic lung disease,” “evolving BPD,” or “BPD,” wonder no-more!

Credits

• Producer & Writer: Tess Curran MD, MPH & Shannon Snellgrove, MD
• Executive Producer: Max Cruz MD
• Showrunner: Sam Masur MD
• Infographic: Tess Curran MD, MPH
• Cover Art: Chris Chiu MD
• Hosts: Justin Berk MD, Chris Chiu MD, Tess Curran MD, MPH 
• Editor:Justin Berk MD; Clair Morgan of nodderly.com
• Guest(s): Jonathan Levin MD

BPD Pearls

1. BPD is common, it is the second most common condition presenting to a pulmonary specialist apart from asthma. 
2. The most well known and accepted risk factor for BPD is gestational age: the lower the gestation, the higher the risk of developing BPD. 80% of kids <28 weeks will develop BPD.
3. Diagnosis of BPD is based on treatment. Essentially, any infant who requires oxygen at 36 weeks postmenstrual age will be diagnosed with BPD. 
4. Gentle non-invasive ventilation techniques are imperative for helping decrease risks for BPD. 
5. Fluid balance! Maximize nutrition while minimizing pulmonary edema. 
6. Most studies find that 50% of kids with post-prematurity respiratory disease, which includes BPD, will respond to albuterol when they wheeze with a viral illness. 
7.  Infants with BPD should be screened by speech pathologists and nutritional specialists for swallowing/feeding dysfunction and growth dysfunction early.

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BPD Show Notes

Epidemiology of BPD

Dr. Levin points out that approximately 10-11% of infants are born preterm (<37 weeks). Although most neonatal outcomes are improving, bronchopulmonary dysplasia (BPD) outcomes themselves are not improving. Approximately 10,000 children per year are born in the United States with BPD, making it the second most common condition presenting to a pulmonary specialist from the NICU apart from asthma (Martin, Hamilton & Osterman et al 2021). 

The Evolving Pathophysiology of BPD

Bronchopulmonary dysplasia was first characterized by Dr. Bill Northway in 1967. At that time, the average premature infant was 34 weeks of age and approximately 2.3 kg. These premies were commonly exposed to mechanical ventilation and high amounts of oxygen that caused significant airway injury, squamous metaplasia, hypertrophy of the smooth muscles in the airways, and patchy, heterogenous fibrosis.  The syndrome that followed as a result of this airways injury (including hypoxia, wheezing, and poor airway compliance) became known as “BPD.” 

Today, the BPD described by Northwell and Colleagues is better known as the  “Old BPD.” This is because premature infants today are born much earlier and much smaller, with many more infants <28 weeks and <1 kg surviving delivery. This means that the issue they face is not just aggressive ventilation and exposure to inflammation, but simply underdeveloped lungs. As Dr. Levin impressively recites from his medical school days, the lungs have to undergo multiple stages of development in utero, including: embryonic, pseudoglandular, canalicular, saccular, and alveolar stages of development. Infants born between 22 and 34 weeks are usually not past the canalicular (when respiratory bronchioles form and alveolar ducts form) or saccular (when terminal sacs and pneumocytes form) stages of development. Their lungs consist of large, simple alveoli with a very primitive vascular bed. They thus struggle to oxygenate because of a very limited alveolar-gas interface.  This new pathology behind today’s BPD is referred to as “New BPD” (Kim, Bateman, Goldshtrom, et al, 2021).

Diagnosing BPD

Dr. Levin emphasizes a unique point about BPD, which is that the diagnosis (and severity)  is made based on the treatment. Essentially, any infant who requires oxygen at 36 weeks postmenstrual age will be diagnosed with BPD. The severity of the disease is further defined by the treatment an infant is receiving at 36 weeks. Because diagnosis is made based on treatment, the exact definition has changed over time and varies between organizations/research networks. Some of the most frequently referenced diagnostic criteria include:

• Vermont Oxford Network, 1998 Definition: Any supplemental oxygen requirement at 36 week PMA, or if an infant was transferred to another institution on supplemental oxygen, prior to 36 weeks PMA
• NICH NIH Consensus definition, 2001: Infants born <32 weeks gestation treated with supplemental oxygen for at least 28 consecutive days, with severity assessment made at 36 weeks PMA or discharge home (whichever comes first). Severity type ranges from mild BPD (required oxygen for 28 days, breathing in room air at 36 weeks PMA) to moderate (need for <30% oxygen at 36 weeks PMA) to severe, type I (need for > 305 oxygen or CPAP at 36 weeks PMA) and severe, type 2 (need for mechanical ventilation at 36 weeks PMA). 
• Revised Definition by Jensen & Colleagues:  Infants born < 32 weeks, with severity assessment made according to the mode of respiratory support administered at 36 weeks postmenstrual age, regardless of the prior duration or current level of oxygen therapy. Categories include: no BPD, no support; grade 1 BPD, nasal cannula <2 L/min; grade 2 BPD, nasal cannula .2 L/min or noninvasive positive airway pressure; and grade 3 BPD, invasive mechanical ventilation (Jensen et al 2019)

Risk Factors 

Not all risk factors have been completely identified as of yet. We do know that the number one risk factor for BPD is gestational age: the lower the gestational age, the higher the risk of developing BPD. 80% of kids <28 weeks will develop BPD. 

• Prenatal risk factors: SGA infants, mothers with preeclampsia or nicotine use during pregnancy, mothers with infections during pregnancy including chorioamnionitis. 
• Postnatal risk factors: any infections (necrotizing enterocolitis, sepsis, prolonged mechanical ventilation (>7 days of life), those who require oxygen, patent ductus arteriosus (secondary to overcirculation), some studies have identified a large pool of genes that are associated with BPD, but there is not one clear gene yet. (Geetha et al 2021)

Ventilator Strategies in BPD

The trend in neonatology has been to move away from invasive ventilation and towards various modes of noninvasive positive pressure ventilation. This is to minimize volutrauma, barotrauma, and oxygen toxicity as much as possible. When a ventilator is required, neonatologists take a gentle approach to ventilation which typically means allowing permissive hypercapnia and titrating oxygen to lower 90s. Advanced ventilation types such as high flow jet ventilation and oscillation is used in some centers to minimize volutrauma and barotrauma, but this hasn’t borne out in larger studies. A little later in this podcast, Dr. Levin mentions that multiple studies have shown that volutrauma leads to higher rates of BPD than barotrauma, so neonatologists and pulmonologists will often set a fixed volume when titrating a ventilator (Klingenberg et al 2017).

What Doesn’t Work

• Surfactant: Surfactant does decrease rates of respiratory distress syndrome, however, it has not helped to decrease rates of BPD. This is because BPD is an arrest of development, not surfactant deficiency. 
• Nitric oxide: Commonly used in persistent pulmonary hypertension of the newborn. Routine use for BPD has not been shown to be effective. 
• Vitamin A: Interestingly, was found to be effective (NNT 12) in reducing BPD in a small trial. However, in practice, vitamin A administration is logistically very challenging. When a shortage of vitamin A limited administration in multiple NICUs, BPD rates did not change. Thus, it is no longer widely used. 

What Works

• Caffeine. In the same methylxanthine class as theophylline, but less toxic. The CAP trial found that rates of BPD are improved with caffeine; possibly because it stimulates infants to breathe on their own (Schmidt et al 2006). 
• Noninvasive ventilation as primary means for ventilation has been shown in meta-analyses to reduce rates of BPD (as discussed above).
• Good nutrition. Smaller, observational studies have found that mother’s own milk has helped to decrease rates of BPD.
• Diuretics: in specific situations may be helpful. Chronic exposure to diuretics has never been shown to reduce rates of BPD. They may be helpful in temporary situations for kids who have volume overload such as those with an atrial septal defect or patent ductus arteriosus. 
• Prenatal steroids are helpful for developing lungs and decreasing need for ventilation (McGoldrick 2020).
• Postnatal steroids: Prophylactic, high-dose dexamethasone for premature infants used to be a mainstay of treatment for preterm infants to reduce rates of BPD. However, the AAP now recommends against this high-dose prophylaxis because of poor neurodevelopmental outcomes. The risk of developing BPD should be assessed at 2 weeks of age. If the risk of BPD is high enough to justify using low-dose dexamethasone, neonatologists will likely give a short course of low-dose dexamethasone. See: DART trial (Doyle, 2006) which studied the impact of a 10 day taper of low-dose dexamethasone which seemed to be effective at getting kids off of ventilators and reducing oxygen requirements. 
• Fluid management: many centers will try and balance fluid intake to minimize pulmonary edema. Dr. Levin often tries to strike a balance between providing enough fluid to allow for appropriate nutrition and lung maturation and avoiding fluid overload. 

BPD and Superimposed Viral Illness 

So, now that we know a little bit about how to treat kids with garden-variety BPD, how do we treat them when they get something like the common cold? Dr. Levin says that the most important thing is to start with good counseling of families so they recognize signs of illness. He tells families to practice counting their child’s breathing while they are asleep (when not sick) so that parents can have a baseline of their child’s normal breathing. He also counsels families about watching for respiratory symptoms around feeding. 

• The risk of complications from a viral illness like bronchiolitis is much higher in infants who are premature or who have underlying respiratory illness. As Dr. Levin points out, even just a premature infant (without BPD) born <34 weeks has a 3-4x higher risk of admission than a healthy child. If a child was born premature and has BPD, they have approximately 10-15x the risk of admission compared to a healthy full-term infant. 
• The American Thoracic Society (See: Guidelines for the respiratory management of the preterm infant with post-prematurity respiratory disease, Cristea, Ren & Amin et al 2021) recommends trialing albuterol in infants with wheeze or other symptoms. Most studies (albeit, there are no randomized controlled trials as of yet) found that 50% of kids with post-prematurity respiratory disease, which includes BPD, will respond to albuterol. This is a much higher percentage than the number of healthy kids with a respiratory illness who trial albuterol and respond. Thus, for kids who respond to beta-2 agonists (albuterol), they should have a sick plan that includes albuterol as needed. Kids with chronic cough and recurrent wheeze should trial inhaled steroids. Dr. Levin’s expert practice is to trial a short course of systemic steroids such as prednisolone in a child with BPD. Antibiotics have less of a routine use unless the patient has concurrent GI dysfunction, in which case you should be concerned about aspiration pneumonia. 
• Why do steroids and albuterol work for children with BPD? Like in asthma, there is a degree of small airway narrowing and muscular hypertrophy that can occur in BPD. Note the amount of hyperresponsiveness or hypertrophy (which would respond to albuterol) vs. small airways with fixed obstruction (which would not) varies between patients with BPD given the heterogeneity of phenotypes that present in BPD. 

Palivizumab

• Palivizumab is a great monoclonal antibody against respiratory syncytial virus (NOT a vaccination) used to prevent respiratory illness in preterm infants. It has been shown to reduce risk of ICU and general hospitalization. It has not been shown to reduce long-term chronic respiratory morbidity. Patients who qualify for palivizumab in the first winter of their life include: infants born  <29 weeks and infants born <32 weeks with chronic lung disease. Patients who qualify in the second winter of their life include kids who require ventilatory support within 6 months of the second season of RSV and patients receiving chronic therapy such as inhaled corticosteroids. 

COVID-19 & BPD

There is still very limited data regarding treatment and epidemiology of patients with BPD who develop COVID. Dr. Levin’s experience has been that it has varying impacts on patients with BPD, from some requiring hospitalization to others not even having to increase their baseline oxygen needs. His counseling for patients with BPD is similar to counseling that he provides parents for prevention of any respiratory illness, which is to create a “shell” of viral protection around the patient. Caregivers should vaccinate themselves against COVID-19 and influenza, avoid having sick people visit infants, and request masking when possible. 

Long-term Outcomes and Comorbidities

For infants with BPD on oxygen, pulmonologists first focus on weaning oxygen off during the day and then weaning it off entirely at night. Remote monitoring technology for following oxygen trends at home allows for weaning more quickly than just following oxygen trends in the clinic.  

On average, it can take about 3-4 months to wean off oxygen,, but it can take up to 12-24 months. 

• Respiratory comorbidities include tracheobronchomalacia, subglottic stenosis, asthma and higher risk of other obstructive lung disease. 
• Pulmonary hypertension: This can result in right ventricular strain and lead to high morbidity and mortality. Infants with identified pulmonary hypertension will have oxygen weaned more slowly and be followed more closely by cardiology
• Feeding difficulties, acid reflux, obvious/ silent aspiration, and higher risk of growth failure. Infants with BPD should be screened by speech and lung pathologists and nutritional specialists for swallowing/feeding dysfunction and growth dysfunction early!
• Neurodevelopmental outcomes: early intervention services are very important, particularly for preterm infants with BPD. 

Racial Disparities & BPD

Epidemiologic data shows that infants born to black mothers have lower risk of developing BPD than infants born to white mothers. This is despite the fact that infants born to black mothers are more likely to be born preterm than infants to white mothers. However, once it is established that an infant has BPD, the outcomes of infants with BPD born to black mothers are worse than the outcomes of infants with BPD born to white mother. Infants with BPD born to black mothers have higher odds of tracheostomy, higher rates of hospitalization, and longer lengths of hospital stay (Ryan, Feng & Bazacliu et al 2019). This paradox makes it hard to argue that there is a biologically plausible explanation for worse outcomes in black infants, and highlights the need for sociopolitical research and interventions to change these disparities.

Take-Home Points 

1. BPD is an arrest of lung development. The best treatment is to allow for adequate time for the lungs to grow. All treatments should be targeted towards pro-growth and pro-development strategies and avoid exposures that prevent growth including infections, aspirations, and other inflammatory states.
2. All preterm infants are at risk of adverse respiratory outcomes. Even if a patient does not have an obvious diagnosis of BPD, they are at a higher risk of adverse respiratory outcomes than a full-term child. 
3. BPD refers to a very heterogeneous pathophysiology. Some infants will be diagnosed with BPD and have simply underdeveloped lungs, whereas others will have more of an asthma/COPD phenotype with airway hypertrophy and narrowing, and others may suffer more from large airway and malacia difficulties. 

Links

Follow the International BPD collaborative (www.thebpdcollaborative.org ) for the latest trials, research, and outcomes of infants with BPD from 30+ research centers around the world.

Goal

Listeners will explain the basic pathophysiology, diagnosis, management, and current understanding of the longterm prognosis of BPD to improve both inpatient care and outpatient counseling. 

Learning objectives

After listening to this episode listeners will be able to…  

1. Recall the basic pathophysiology of bronchopulmonary dysplasia and some of the most commonly used diagnostic criteria for BPD. 
2. Discuss the epidemiology of BPD, particularly as it relates to race-based diagnosis and outcomes. 
3. Describe acute treatments that have been tried for BPD and which ones are evidence-based. 
4. Describe the rationale for avoiding invasive ventilation in infants with BPD, and the strategies used when ventilation is required. 
5. Counsel families about the risk of viral illness in infants with BPD and how to minimize risk of their infant getting respiratory illness. 
6. List common comorbidities that affect infants with BPD.

Disclosures

Dr Levin reports no relevant financial disclosures. The Cribsiders report no relevant financial disclosures. 

Citation

Curran T, Snellgrove S, Levin J, Cruz M, Masur S, Chiu C, Berk J. “#55: BPD Ya You Know Me: Bronchopulmonary Dysplasia with Dr. Jonathan Levin”. The Cribsiders Pediatric Podcast. https:/www.thecribsiders.com/ July 13, 2022.