Bronchopulmonary dysplasia (BPD) Historical and Scientific Update

Editor’s note: This text-based course is an edited transcript of the webinar, Bronchopulmonary dysplasia (BPD) Historical and Scientific Update, presented by Katlyn Burr, MSM-HCA, RRT, RRT-NPS, AE-C.

It is recommended to download the course handout to supplement this text format.

Learning Outcomes

After this course, participants will be able to:

• Define BPD
• Discuss the historical background and advancement of the definition and disease
• Review best practices to drive the best patient outcomes in BPD patients

The Birth of BPD

The origins of Bronchopulmonary Dysplasia (BPD) can be traced back to the era of President Kennedy. The story begins with the challenges that President Kennedy and his wife, First Lady Jackie Kennedy, faced in starting a family. Before his presidency, the couple endured heartache. Their first pregnancy ended in a miscarriage, and their second, tragically, resulted in the stillbirth of a daughter, Arabella. Despite these losses, they were eventually blessed with two healthy children, Caroline and John. However, one year into Kennedy’s presidency, Jackie became pregnant again. This time, she gave birth prematurely to a son, Patrick, at 34 weeks. Unfortunately, Patrick only survived for 39 hours, succumbing to respiratory distress syndrome and hyaline membrane disease.

That same year, a Canadian doctor made significant strides in neonatology by pioneering the controversial use of a ventilator. His groundbreaking work saved a similarly ill 34-week-old baby, marking a pivotal moment in the history of neonatal care and the development of treatments for conditions like BPD. Unfortunately, American doctors at the time were unable to replicate the success seen elsewhere. When Patrick was born at Otis Air Force Base, it became immediately clear that he was showing signs of respiratory distress and would require urgent intervention. At that time, the available treatments for babies with respiratory distress and hyaline membrane disease were limited. The medical team focused on stabilizing his blood gases, adjusting his blood chemistry as best they could, and administering hyperbaric oxygen. Despite their efforts, these measures were not enough to save Patrick.

When President Kennedy learned about the Canadian doctor who successfully used a ventilator to save a very sick 34-week-old baby, he felt a deep sense of embarrassment. Patrick's death had already sharpened the national focus on neonatal lung disease, a condition responsible for about 20% of all neonatal deaths in the late 1960s and early 1970s. In response, President Kennedy signed into law a significant grant authorizing $265 million over five years for newborn research. This initiative was sponsored by the National Institute of Child Health and Human Development, an organization that Kennedy had established with his sister, Eunice Shriver,  a year earlier.

While $265 million was a significant sum at the time, in today’s terms, it equates to about $2.1 billion—a truly remarkable investment in advancing neonatal research, particularly in lung development, to help newborns survive. Sadly, President Kennedy was assassinated three months after Patrick’s birth and death, and he never witnessed the breakthroughs in research and treatments that have since saved countless lives.

Patrick's birth and death did indeed intensify the focus on neonatal lung disease, but other critical developments were also underway. One of the most significant was the discovery of surfactants, which played a pivotal role in the evolution of BPD. In 1957, John Clements became the first researcher to identify a mucoprotein, later known as surfactant, which was crucial for maintaining alveolar stability in animal models.

Avery and Mead, two pioneering researchers, observed that the surface tension of lung extracts from premature infants with hyaline membrane disease was significantly higher than that of similarly sized infants who were dying of non-respiratory causes. This critical finding led them to hypothesize that the increased surface tension and subsequent lung collapse were due to the absence of surfactant in infants weighing less than 1,100 grams. The term Bronchopulmonary Dysplasia (BPD) was later coined to describe this emerging pattern of lung disease in premature infants who were surviving longer, thanks to advances in ventilator care. Today, BPD is recognized as the most common cause of chronic lung disease in infancy. The clinical, radiological, and pathological features of BPD were first detailed over three decades ago.

Before the 1960s and the introduction of the controversial mechanical ventilator, premature infants who developed respiratory distress syndrome often faced two outcomes: they either passed away within their first week of life, as Patrick did, or they survived without significant pulmonary complications. However, with advancements in medical technology and the use of mechanical ventilation, infants who once would have perished are now being supported and given a chance to live. While mechanical ventilation greatly improved the survival rates of these infants, it also led to a new form of lung injury.

Old BPD

In 1967, William Northway first described this new chronic lung disease, known as Bronchopulmonary Dysplasia (BPD). He observed it in a group of premature infants with respiratory distress syndrome who had undergone prolonged ventilation with high oxygen concentrations and high peak inspiratory pressures.

The infants studied had a mean gestational age of 34 weeks and an average weight of 2.4 kilograms. All of them required oxygen 28 days after birth and showed progressive changes on chest radiographs, which were graded according to severity. Pathologic examination of their lung tissues revealed necrotizing bronchiolitis, vascular changes indicative of pulmonary hypertension, infiltration of inflammatory cells, and alternating areas of atelectasis and pulmonary fibrosis. The term "bronchopulmonary dysplasia" was coined to emphasize that both the airways and the lung parenchyma were affected. These abnormalities were attributed to injuries caused by mechanical ventilation and prolonged oxygen exposure. Since Northway’s initial definition in 1967, advancements in medical technology have led to an evolving understanding and redefinition of BPD.

In 1979, Bancalari and colleagues introduced the first revision to Northway's original definition of BPD. Their updated criteria included the need for oxygen at 28 days, chronic changes on a chest X-ray, and the presence of tachypnea with crackles or retractions, though they removed the grading system for chest X-rays. As time passed, it became evident that fewer babies required as much oxygen at 28 days post-birth, prompting another update in 1988. This revision shifted the focus to assessing supplemental oxygen needs at 36 weeks postmenstrual age. However, as medical technology continued to advance, the 1988 definition became less predictive and less useful. With the increased survival rates of extremely low birth weight infants and the broader spectrum of disease severity, new treatment options for respiratory distress have further refined our understanding and management of BPD.

New BPD

The failure to account for gestational age at birth and disease severity led to concerns that the existing definition of BPD was inadequate. In 2000, a review of the definition of BPD and chronic lung disease of infancy in preterm infants was conducted at a workshop hosted by the National Institute of Child Health and Human Development and the National Heart, Lung, and Blood Institute. The consensus from this workshop addressed two key groups of infants: those born at less than 32 weeks estimated gestational age. For infants requiring oxygen at 28 days, they were reassessed at 36 weeks postmenstrual age. Based on this reassessment, infants breathing room air at 36 weeks were classified as having mild BPD, those requiring less than 30% FiO2 were classified as having moderate BPD, and those needing more than 30% FiO2 or positive pressure ventilation were classified as having severe BPD.

Old versus New BPD

It is not until about 32 weeks of gestation that alveoli begin to form, which is a key reason why the definitions of BPD have evolved. The "old" BPD primarily affected older preterm infants who suffered from structural injuries to their lungs. In contrast, "new" BPD involves caring for infants who may not have significant structural damage but instead experience developmental arrest or delays in lung tissue maturation due to their extremely early birth. Despite the evolution of the BPD definition over time, a consensus remains: chronic lung disease develops in preterm infants exposed to oxygen and positive pressure ventilation. BPD cannot occur in term infants; it is a condition exclusive to those born preterm and who require oxygen and positive pressure ventilation.

BPD Definitions

The evolution of BPD definitions reflects our growing understanding of the condition and the advancements in neonatal care over the decades.

• 1967 (Northway): The initial definition of BPD was based on progressive clinical symptoms, radiographic findings, and histological changes. This definition highlighted the physical changes in the lungs that could be observed over time.
• 1988 (Shennan): The definition was refined to focus on the need for supplemental oxygen at 36 weeks postmenstrual age (PMA) as a key criterion, marking a shift toward recognizing the ongoing oxygen dependency as a critical aspect of BPD.
• 2004 (Walsh): A more physiological approach was introduced, defining BPD in infants ≤32 weeks gestational age (GA) at 36 weeks PMA by the requirement for invasive mechanical ventilation (IMV) or continuous positive airway pressure (CPAP). Additional criteria included a PaO₂/FiO₂ ratio ≥0.3 or failure to maintain oxygen saturation ≥90% for 30 minutes following an oxygen reduction test.
• 1979 (Tooley): This definition focused on radiographic abnormalities, identifying abnormal lung findings on a radiograph at 30 days of life as a key indicator. Critical PaO₂ was defined as less than 60 mmHg in room air, and PaCO₂ as less than 45 mmHg, with oxygen dependency at 30 days being a significant marker.
• 2001 (NIH): BPD was categorized based on FiO₂ requirements for 28 or more days. The severity was graded according to the level of oxygen support required: mild BPD was associated with breathing in room air, moderate BPD with FiO₂ less than 0.3, and severe BPD with FiO₂ ≥ 0.3 and/or the need for CPAP or IMV.
• 2018 (NIH): The definition was further refined to apply to infants ≤32 weeks GA with persistent radiographic lung disease who required respiratory support at 36 weeks PMA for three or more days to maintain arterial oxygen saturation between 90-95%. The grading system became more detailed, with specific criteria based on the type and level of respiratory support needed, including considerations for the risk of death.
• 2019 (Jensen): This definition focused on grading BPD in infants less than 32 weeks GA based on the level of respiratory support required at 36 weeks PMA or discharge. The grades ranged from mild, involving nasal cannula flow ≤2 LPM, to severe, requiring invasive mechanical ventilation.

This progression in BPD definitions shows a trend towards more precise and individualized criteria, reflecting the complexities of the condition as we better understand its varied presentations and underlying mechanisms. As neonatal care continues to evolve, the hope is that more preventive and less invasive treatments will be developed, reducing the need for intensive interventions. However, as we push the boundaries of survival for younger and more fragile infants, the necessity for advanced medical technologies, including potentially more invasive options like external wound management or liquid ventilation, may also increase. This duality underscores the ongoing challenge of balancing advancements in care with the needs of an increasingly vulnerable patient population.

BPD Evolvement

The evolution of BPD definitions continued with significant updates in 2018 and 2019. In 2018, the NIH introduced a new grading system, replacing the traditional terms of mild, moderate, and severe BPD with a more nuanced classification of grades I, II, III, and IIIa. This change aimed to provide a more precise characterization of the disease based on the level of respiratory support required by the infant.

In 2019, the grading system was further refined. The NIH removed grade IIIa and focused on grades I, II, and III, specifically for infants born at less than 32 weeks gestational age. This updated system categorizes BPD based on the level of respiratory support required at 36 weeks postmenstrual age or at discharge, whichever occurs first.

• Grade I BPD is assigned to infants who are on nasal cannula flow rates of less than or equal to two liters per minute.
• Grade II BPD applies to those with nasal cannula flow rates greater than two liters per minute, or those who require CPAP or other non-invasive respiratory support.
• Grade III BPD is used for infants who require invasive mechanical ventilation at 36 weeks postmenstrual age or at discharge.

This refined classification system allows for a more detailed understanding of the severity of BPD, which can better guide treatment decisions and provide clearer prognostic information. By categorizing BPD based on specific respiratory needs, clinicians can more accurately assess the level of care required and anticipate potential challenges as these infants continue to develop.

Review of BPD

• Chronic Lung Disease
• Developed in preterm infants who are exposed to:
  • Oxygen
  • Positive Pressure Ventilation
• Difficult to manage because conventional treatment of symptoms results in the disease
• The premature development of the lung allows for recovery if we provide appropriate intervention
   

If you recall your anatomy and physiology classes as a respiratory therapy student, you likely had a lecture on fetal lung development. During that course, you might remember learning about the stages of lung development. Around 16 weeks of gestation, the fetus enters the canalicular stage, and by approximately 23 weeks, the development progresses to the saccular stage.

All of these factors must converge for BPD to develop. The disease has always been challenging to manage because the very treatments used to address it can also cause or exacerbate the condition. Additionally, the premature development of the lungs presents its own set of challenges. However, due to the immaturity of these lungs, there is a narrow window in which appropriate interventions can aid recovery without further damaging lung tissue.

BPD occurs when lung development arrests during the late canalicular to saccular stages. The pathology of BPD is characterized by decreased septation and alveolar hypoplasia, leading to the formation of large, simplified alveoli. This abnormality significantly reduces the surface area available for gas exchange, further complicating the condition.

These infants also exhibit dysregulated vasculature, characterized by smooth muscle hyperplasia in their pulmonary vessels and abnormal alveolar capillaries. Additionally, there is increased interstitial fibroproliferation and impaired alveolar septation. The advantage of being born early is that their lung development is still ongoing. Although these infants may not have fully formed alveolar sacs at birth, their lung tissue continues to develop after they are born.

Review of BPD- Lung Development

Remarkably, babies grow approximately 3.3 alveoli per second from birth until they reach the age of one. This means that every moment spent caring for a baby at the bedside during their first year of life, they were developing around three new alveoli every second. These alveoli are the tiny air sacs in the lungs where gas exchange occurs, and their development is crucial for establishing healthy lung function.

This rapid growth does not stop after the first year; it continues at a rate of about one alveolus per second until the age of two. This incredible pace of alveolar development is vital for building the lung’s capacity to exchange oxygen and carbon dioxide efficiently, which is especially critical in premature infants. Premature infants often have underdeveloped lungs, making them more susceptible to conditions like bronchopulmonary dysplasia (BPD).

For these vulnerable infants, receiving protective ventilation strategies, such as gentle ventilation and permissive hypercapnia, can make a significant difference. By minimizing lung injury and promoting a favorable environment for lung development, these interventions help ensure that the new alveoli they rapidly form are healthy. This not only has the potential to reduce the severity of lung disease but also supports better long-term outcomes, including improved lung function and a reduced risk of respiratory complications as they grow.

Understanding the critical period of alveolar development underscores the importance of providing optimal care during the early stages of life, particularly for those born prematurely. It also highlights the potential for targeted interventions to make a lasting impact on the health and well-being of these infants.

Alveolar Multiplication

The theory of alveolar multiplication, which involves the subdivision of terminal units, the formation of primary pulmonary saccules and secondary alveolar crests, and the alveolarization of non-alveolated and partly alveolated airways, is not new. Although the precise mechanisms of alveolar development and the relative importance of these processes are still not fully understood, it is clear that alveolar growth is most rapid in the first years of life and appears to slow down as we age.

Some research suggests that alveolar growth stops by around age eight, while other evidence indicates it may continue until somatic growth ceases. For example, a 2011 study published in the American Journal of Respiratory and Critical Care Medicine examined 100 patients aged 7 to 21 years. The researchers used hyperpolarized helium, which the patients inhaled before undergoing MRI scans. The hyperpolarized gas, acting like a magnet, is aligned in one direction, as you can see in the image on the screen. By analyzing how the gas decayed in the lungs, the researchers could estimate the size of the alveoli. They found that while the size of the alveoli showed very little difference, total lung volume increased significantly, ranging from about one to four liters.

Researchers concluded that if the size of the alveoli remains largely unchanged, the increase in lung size must be due to the growth of new alveoli. This suggests that until we stop growing in height, we likely continue developing alveoli. This is particularly fascinating for those who care for pediatric patients, who are constantly growing.

BPD- CXR Findings

• Coarse, irregular, rope-like, linear densities
• Could represent atelectasis or fibrosis
• Lucent cyst-like foci
• Areas of air-trapping
• Shifting atelectasis
• May be combined with pneumonia

In children with BPD, chest X-rays typically reveal irregular rope-like densities that can resemble atelectasis or fibrosis. These images often show lucent cyst foci and multiple areas of air trapping. When comparing serial X-rays taken on different days, one might observe shifting atelectatic areas within the lungs of these patients. All of these factors, including conditions like pneumonia, can occur simultaneously in a child with BPD. 

BPD Prevalence

• 45-68% of VLBW infants diagnosed with BPD
• 80% of infants born 22-24 weeks of gestation are diagnosed with BPD, whereas only 20% of infants at 28 weeks develop BPD
• ~40% of preterm infants born prior to 29 weeks GA
• 11-50% in different countries around the world
• 10,000 births annually in the US with BPD
• 12-39% for preterm babies born before 32 weeks GA
• <1000g babies is 30-50%
• Overall, younger, smaller, less mature babies are at higher risk (Mandell et al., 2019; Clin Perinatol Zhang et al., 2022)

The prevalence of BPD varies widely depending on the definitions used, as you have seen with the different criteria that have evolved over time. The reported prevalence is influenced by factors such as whether the definition of very low birth weight versus extremely low birth weight infants is used and whether all babies are included or only a subset. In 2010, the National Institute of Child Health and Human Development Neonatal Research Network used severity-based and physiologic definitions of BPD and estimated that as many as 68% of very low birth weight infants could be diagnosed with BPD.

In the United States, approximately 10,000 babies born each year will either have or develop Bronchopulmonary Dysplasia (BPD). The risk of developing BPD is directly related to the baby's age, size, and maturity—the younger, smaller, and less mature the infant, the higher the risk of developing BPD. This risk is also closely linked to the severity of the disease.

BPD remains the most expensive morbidity in neonatal intensive care units (NICUs), with an estimated annual economic burden of $1.7 billion in the United States. Caring for these patients in NICUs costs the healthcare system $1.7 billion each year, making the reduction of BPD risk a critical clinical and economic priority in the care of very low birth weight infants.

BPD Impact

These patients face a significant challenge, with mortality rates reaching up to 40%. Additionally, about 25% of infants with moderate to severe BPD develop BPD-associated pulmonary hypertension, a condition linked to even higher rates of mortality and morbidity. The most common causes of death in these patients include recurrent respiratory tract infections, pulmonary heart disease, and pulmonary hypertension.

For those who survive, the challenges do not end there. About 50% of these patients are readmitted within the first year, often due to lower respiratory tract infections. Survivors also face a heightened risk of various complications, including gross motor delays, reactive airway disease, asthma, emphysema, RSV, bronchiolitis, growth delays, language delays, and ongoing cardiopulmonary issues.

Given these severe outcomes, it is crucial to do everything possible to reduce the risk of developing BPD or mitigate its severity in the patients we care for. Early intervention, careful management, and ongoing monitoring are essential to improve long-term outcomes and quality of life for these vulnerable infants.

Predisposing Factors

The development of BPD is influenced by several predisposing factors, especially in infants born prematurely. These infants have underdeveloped lungs and often experience stressors that not only contribute to their premature birth but also play a role in the onset of BPD. These stressors can directly impede lung development or trigger an immune response that worsens the condition.

When the immune response is activated, it leads to an increase in free radicals and inflammatory markers. This reaction causes the body to enter a defensive mode, halting normal developmental processes. The resulting inflammation, swelling, and injury further contribute to the development of BPD.

From a postnatal perspective, premature birth alone is a significant risk factor for BPD. The combination of underdeveloped lungs and the immune responses triggered by various stressors creates a challenging environment for healthy lung development, highlighting the importance of prevention and careful management in reducing the impact of BPD.

Lung immaturity at birth increases the likelihood of developing BPD. Other risk factors include poor nutrition, the need for mechanical ventilation and oxygen, and the development of infection or sepsis shortly after birth. Certain demographic groups are also at higher risk, including male infants, those with low birth weight, white infants, and those with impaired growth for gestational age. A family history of asthma further increases the likelihood of developing BPD.

In addition to underdeveloped lungs, premature babies are often affected by conditions such as chorioamnionitis, sepsis, and pneumonia. These conditions contribute to inflammation and oxidative stress, which increase microvascular permeability and lead to pulmonary edema. Treatment for these symptoms typically involves the use of oxygen, positive pressure ventilation, and sometimes nitric oxide. Unfortunately, while necessary, these interventions can lead to aberrant tissue repair and a slowed rate of alveolarization. For instance, instead of the normal rate of developing 3.3 alveoli per second, this process might slow to one or none, leading to impaired alveolar and vascular development—key factors in the progression of BPD.

The complexity of BPD underscores the need for individualized care and ongoing research to better understand and mitigate the risks associated with this condition.

Maternal Factors

From a maternal standpoint, several factors can significantly contribute to a baby's risk of developing BPD. If the mother smoked during pregnancy, had intrauterine growth restriction, or was diagnosed with preeclampsia, her baby is at an elevated risk for BPD. Additionally, preterm babies, who are often born with low birth weight and underdeveloped organs, are already at a greater risk for developing bronchopulmonary dysplasia due to their premature status. These maternal and neonatal factors combined can increase the vulnerability of these infants to BPD and related complications.

Pre-Term Delivery

The same increased risk applies to babies with lower gestational ages. Unfortunately, in our efforts to support these extremely low and very low birth weight infants, as well as those born at reduced gestational ages, we often rely on mechanical ventilation and supplemental oxygen. While these interventions are crucial for sustaining life, they can inadvertently contribute to the development of BPD, further compounding the problem. The very treatments that are necessary for survival can also increase the risk of lung injury, highlighting the delicate balance required in the care of these vulnerable infants.

Chorioamnionitis

Chorioamnionitis, an inflammation of the fetal membranes typically caused by an ascending infection, has been investigated as a potential cause of BPD. The research findings in this area have been mixed. Some studies have indicated an increased risk of BPD in the presence of maternal chorioamnionitis, while others have shown no difference or even a decreased risk.

In 2009, a significant 13-year multicenter study conducted by Lahra and colleagues examined this relationship and concluded that histologic chorioamnionitis was actually protective against BPD. This surprising finding led other researchers, such as Wright and Kirpani, to explore whether the fetal response to chorioamnionitis might play a role in the development of BPD. This area of research continues to be explored as we seek to better understand the complex factors contributing to BPD. Wright and Kirpani delved into the role of a transcription factor, nuclear kB, and its involvement in inflammation in the pathogenesis of BPD. This area is still under investigation, and much more research is needed to fully understand these mechanisms.

Ureaplasma Colonization in the Infant Lung and Bacteria Sepsis

In 2005, Schelonka and colleagues conducted a meta-analysis of 23 studies, which revealed a significant association between ureaplasma colonization and the development of BPD at 36 weeks gestational age. The meta-analysis included 23 studies that measured BPD at 28 days postnatally and eight studies that measured BPD at 36 weeks postmenstrual age. The analysis found a significant association between ureaplasma colonization and BPD at both measurement points, although the association was more pronounced in smaller studies with fewer participants.

Additionally, bacterial sepsis has consistently been linked to higher rates of BPD, further emphasizing the complex interplay between infections and the development of this condition. Understanding these connections is crucial for improving prevention and treatment strategies for BPD. In one cohort study, researchers reviewed recent literature ranging from bench studies to clinical trials and discovered that BPD rates increased from 35% to 62% following early onset sepsis. This and other studies demonstrate a strong association between sepsis and chronic lung disease, particularly highlighting the role of gram-negative bacteria in the development of bronchopulmonary dysplasia (BPD).

Patent Ductus Arteriosus (PDA)

Patent ductus arteriosus (PDA) is another condition that can contribute to hemodynamic instability, and it has been linked to an increased risk of BPD. The left-to-right shunting through a PDA can cause lung endothelial damage, which, combined with the increased need for mechanical ventilation due to pulmonary edema and lung dysfunction, may elevate the risk of BPD in patients with PDA. These findings underscore the complex interplay between various conditions and the development of BPD, making it clear that managing these risk factors is crucial in reducing the incidence and severity of the disease.

However, some studies have shown that despite reducing the size of PDA, indomethacin prophylaxis does not decrease the rates of BPD. Interestingly, PDA ligation has been associated with an increased risk of BPD rather than reducing it. This suggests that the relationship between PDA and BPD may not be direct or causal. Instead, it appears that factors such as high fluid intake in the first days after birth may predispose infants to both PDA and BPD, leading to an observed association.

Moreover, lower serum cortisol levels in very low birthweight infants have been correlated with both PDA and BPD. This correlation suggests that early adrenal insufficiency in these infants could be a contributing factor that explains the link between the two conditions.

Genetic Factors

Genetic factors are also being explored as potential predispositions for BPD. Significant research is currently underway to identify specific genes, nucleotides, alleles, and mRNA that may contribute to a genetic predisposition to BPD. This ongoing work could provide valuable insights into the underlying causes of BPD and help identify at-risk infants earlier, allowing for more targeted interventions.

Yu and colleagues, along with Parad and Torgerson in the TOLSURF study, are currently investigating various genetic factors related to BPD. These researchers are exceptionally knowledgeable, and while we do not have enough time today to delve into all their findings, it is important to note that the evidence so far is mixed. Some studies suggest that BPD can run in families—if one baby has BPD, there is a higher likelihood that a subsequent baby might also develop it. However, twin studies have not consistently shown strong heritability, indicating that more research is needed to understand which genetic factors might predispose infants to BPD.

What we do know is that premature babies are at a significantly higher risk for developing BPD due to their underdeveloped lungs. These immature lungs often lead to signs of respiratory distress, which we commonly treat with positive pressure and oxygen therapy. While these treatments are necessary, they can also contribute to the development of BPD, underscoring the complexity of managing and preventing this condition. More research is needed to clarify the genetic components and improve our strategies for treating at-risk infants.

Given this complex cycle, the critical question becomes: How can we prevent it from occurring? The literature discusses a variety of prevention strategies, each with potential roles in the treatment and management of BPD. We'll explore these strategies, examining how they are supported by current research and their practical application in clinical settings.

Prevention Strategies

Reducing PPV

When we discuss prevention strategies for BPD, one key principle is to minimize the amount of oxygen and positive pressure ventilation these babies receive. Both barotrauma and volutrauma can cause significant lung damage, and this is especially true in the fragile lungs of premature infants. Any ventilation with increased volumes or pressures can lead to immediate lung injury. For instance, even a small number of large-volume breaths delivered with a bag valve mask during resuscitation can cause harm, particularly in surfactant-deficient lungs that do not inflate uniformly.

The risk of injury is especially high during initial resuscitation attempts. During this critical period, the goal is to create functional residual capacity while carefully managing ventilator volumes to stay below the total lung capacity. Striking this balance is challenging but crucial to avoid lung damage.

Reducing oxygen %

Oxygen toxicity is another major factor in the development of BPD. Exposure to high levels of oxygen (hyperoxia) can halt lung development, generate reactive oxygen species, and trigger the inflammatory process. This cascade of events can lead to the type of lung injury that contributes to BPD. Therefore, the careful management of oxygen levels is essential in preventing the development of this condition.

In 2009, a significant study published in Pediatrics by Vento explored the impact of oxygen levels during resuscitation on infants born between 24 and 28 weeks of gestational age. This randomized controlled trial assigned babies to two different FiO₂ groups for resuscitation—one group received 30% FiO₂, while the other received 90% FiO₂. The results were striking: in the group that received 30% FiO₂, the incidence of BPD was reduced by half, from 32% to 15%.

Moreover, the study found that biomarkers of oxidative stress increased exponentially in the group exposed to 90% FiO₂, and these increases correlated strongly with the development of BPD. This research underscores the importance of minimizing oxygen exposure in these vulnerable infants. Providing less oxygen not only reduces oxidative stress but also supports the creation of new alveoli, which is crucial for healthy lung development. These findings highlight the need for careful oxygen management in the care of premature infants, particularly those at risk for or diagnosed with BPD.

When managing infants at risk for BPD, even small adjustments in oxygen delivery can make a significant difference. For instance, when administering a nebulizer treatment, it is beneficial to use 21% oxygen (room air) rather than 100%. Similarly, employing a high-flow device can be advantageous because it allows for the use of higher flow rates with lower FiO₂, with the settings for flow and FiO₂ being adjustable independently rather than being tied together. This approach helps reduce the risk of oxygen toxicity while still providing the necessary respiratory support.

Antenatal corticosteroids

Antenatal corticosteroids have become a standard of care for women between 24 and 34 weeks of gestation who are experiencing preterm labor. These steroids are administered to help accelerate fetal lung development. However, their effect on the incidence of BPD remains a topic of debate. While the mechanism of action for corticosteroids in promoting lung maturation is well understood and listed on the current slide, some animal studies have raised concerns. These studies suggest that corticosteroids might arrest alveolarization and microvascular development, potentially contributing to the development of BPD. Therefore, while antenatal corticosteroids are widely used, their role in BPD prevention continues to be carefully evaluated.

Postnatal corticosteroids

The use of postnatal corticosteroids in managing BPD should be carefully considered on a case-by-case basis. Early studies indicated that administering corticosteroids within the first two weeks of birth could reduce the risk of developing BPD and shorten the time to extubation. However, when corticosteroids are administered later, more than three weeks after birth, they may not reduce the risk of BPD but can still help facilitate earlier extubation.

The side effects of corticosteroids in this population are consistent with those observed in others, including hyperglycemia, hypertension, gastrointestinal bleeding, hypertrophic cardiomyopathy, and an increased risk of infection. Importantly, long-term studies have highlighted a clear association between postnatal corticosteroid use and poor neurodevelopmental outcomes, including an increased risk of cerebral palsy.

A recent study published in JAMA in 2021 suggested that early initiation of medium cumulative doses of systemic dexamethasone might be the most effective regimen for reducing mortality associated with BPD by 36 weeks postmenstrual age. This finding underscores the importance of carefully weighing the benefits and risks of corticosteroid use in premature infants to optimize outcomes.

Azithromycin

Azithromycin and other macrolides, known for their antibiotic and anti-inflammatory properties, have been investigated as potential therapies for preventing BPD in preterm infants, particularly due to their activity against ureaplasma infections. In one randomized controlled trial, a six-week course of azithromycin was administered to very low birth weight infants, but the results showed no statistically significant difference in BPD incidence compared to a placebo. However, among infants colonized with ureaplasma, azithromycin did reduce the incidence of BPD, indicating a potential benefit in this specific subgroup.

Vitamin A

Vitamin A, or retinol, plays a crucial role in the regulation of lung development and injury repair. Low levels of vitamin A have been associated with an increased risk of developing BPD. Consequently, prophylactic administration of vitamin A has been shown to significantly reduce the risk of BPD in extremely low birth weight infants. Importantly, this intervention did not result in any difference in neurodevelopmental impairment at 18- and 22-month follow-up visits for this patient population, making it a promising strategy for BPD prevention without long-term adverse effects.

Vitamin E and Selenium

Currently, there is no evidence to support the use of vitamin E or selenium for reducing or preventing the development of BPD in preterm infants. However, other prevention strategies have shown promise.

Caffeine

One such strategy is the use of caffeine, as demonstrated in the Caffeine for Apnea of Prematurity Trial. This trial compared caffeine to a placebo administered within the first 10 days after birth. Although the primary focus was on preventing apnea of prematurity, the study unexpectedly found a significant reduction in the incidence of BPD at 36 weeks postmenstrual age in the group that received caffeine compared to the placebo group. The exact mechanism by which caffeine reduces the risk of BPD is still unclear.

Pentoxifylline

Another potential intervention is pentoxifylline, a non-specific phosphodiesterase inhibitor known for its ability to decrease pulmonary inflammation. In a study comparing nebulized pentoxifylline to intravenous dexamethasone, nebulized pentoxifylline was found to reduce the risk of BPD by 27%. This suggests that pentoxifylline might offer a beneficial approach to reducing BPD risk, though further research is needed to confirm these findings and better understand the underlying mechanisms.

Cromolyn

Cromolyn, a mast cell stabilizer commonly used in the treatment of asthma, has not been effective in preventing BPD in preterm infants. Despite its benefits in other respiratory conditions, it does not appear to offer protection against BPD.

Nitric Oxide

Nitric oxide, on the other hand, has shown promise in reducing oxidative stress and supporting lung development. However, studies in humans have produced mixed results. Because of this inconsistency, the National Institutes of Health (NIH) consensus statement does not recommend the routine use of nitric oxide in the care of preterm infants. Nonetheless, the NIH acknowledges that basic research, particularly animal studies, has provided valuable insights into the potential benefits of nitric oxide for lung development and function in infants at high risk for BPD. The consensus calls for more research in this area to better understand its role and potential applications.

Surfactant

Surfactant therapy, delivered either through the INSURE (Intubation-SURfactant-Extubation) approach or the LISA (Less Invasive Surfactant Administration) technique, offers a way to administer surfactant to premature infants without the need for intubation. This approach has been effective in reducing the risk of respiratory distress syndrome (RDS) in these babies. However, despite its benefits in managing RDS, surfactant therapy has not been shown to significantly reduce the incidence of BPD by 36 weeks gestational age.

Ventilatory Strategies

In terms of ventilatory strategies, goals for managing infants with BPD have included practices like permissive hypercapnia and gentle ventilation. Although clinical trials have not demonstrated a significant reduction in BPD rates with permissive hypercapnia, some trends suggest a potential reduction in BPD without an increase in adverse events.

Studies comparing ventilation strategies, specifically high-frequency ventilation versus conventional ventilation, have shown that both methods result in nearly comparable rates of BPD in this population. This indicates that while the choice of ventilation strategy is crucial for managing premature infants, neither approach has proven to be markedly superior in reducing the incidence of BPD.

Acetylcysteine

Acetylcysteine, a mucolytic agent, has been explored for its potential to prevent BPD development. However, current evidence does not support its effectiveness in reducing the risk of BPD.

Nutrition

One of the most discussed topics in the literature concerning BPD patients is fluid management, which is crucial from the day these infants are born through all of their outpatient care. Babies at risk for BPD are often fluid-restricted because excessive fluid intake during the first 10 days after birth has been linked to an increased risk of BPD. To compensate for the reduced fluid intake, feedings are fortified to ensure these infants receive adequate calories. Infants who develop BPD may require up to 40% more kilocalories than their age-matched peers to meet their energy needs and support their growth and development.

Infants with BPD continue to have an increased caloric expenditure, approximately 35% above their typical needs. Unfortunately, 30 to 65% of these infants experience growth failure soon after their initial hospital discharge. To mitigate this risk, it is crucial to ensure that they are set up for success with the appropriate formula and caloric intake before they leave the hospital. However, even with optimal in-hospital care, strong outpatient follow-up is essential. This follow-up ensures that these babies continue to meet their elevated caloric needs and support their growth and development.

When it comes to prevention strategies for BPD, there is a wide array of options and interventions to consider. Each has its own set of benefits, limitations, and areas where further research is needed to optimize care for these vulnerable infants. The various prevention strategies we've discussed are categorized based on their proven benefits, according to the available literature. it is important to remember that no two patients with BPD are exactly alike, and their care must be tailored to their individual needs and circumstances.

Treatment of Established BPD

Each patient with BPD has a unique journey, making it crucial to tailor treatment and care to the individual needs of the child and their family. Once a child begins to show signs of BPD or is diagnosed with the condition, the focus naturally shifts from prevention to treatment. Several strategies can be employed to manage BPD effectively. Among these, inhaled steroids, diuretics, and bronchodilators are the most commonly referenced treatments in the literature. These therapies are central to managing the symptoms and complications associated with BPD, helping to improve outcomes for these vulnerable patients.

Inhaled Steroids

Inhaled corticosteroids have been increasingly employed in the treatment of both developing and established BPD. The growing body of evidence supports their use, particularly in terms of their positive impact on patient outcomes. This underscores the importance of continuously refining and personalizing treatment strategies to meet the specific needs of each child with BPD.

A Cochrane Systematic Review of randomized controlled trials provided significant insights into this treatment approach. The review found that early administration of inhaled steroids to very low birth weight infants effectively reduces the incidence of death or chronic lung disease at 36 weeks postmenstrual age, whether considering all randomized infants or the survivors.

However, it is crucial to identify the optimal risk-benefit ratio for these patients. This involves exploring different delivery techniques and dosing schedules to maximize both short- and long-term benefits while minimizing adverse effects. Of particular concern are the neurodevelopmental outcomes associated with the use of inhaled steroids, making it essential to carefully weigh the potential benefits against any potential risks. Further research in this area will be key to optimizing care for infants with BPD.

Diuretics

Diuretics are commonly used in patients with known BPD to reduce pulmonary alveolar and interstitial edema and improve lung function. However, the effectiveness of diuretics, particularly systemic loop diuretics like furosemide, has been subject to extensive research with mixed results.

A systematic review of clinical trials investigating the use of intravenous (IV) or enteral furosemide in infants with developing or established BPD found no consistent benefit for infants less than three weeks old. For infants older than three weeks, a single dose of 1 mg per kg of IV furosemide only provided transient improvement in lung mechanics. Based on this evidence, the literature suggests that systemic loop diuretics should not be routinely used for infants with BPD.

In contrast, a Cochrane Review focusing on thiazides and spironolactone for patients with moderate BPD found that these medications improved lung mechanics. Moreover, when administered for four weeks, they were associated with a reduction in mortality among these patients.

Aerosolized diuretics have also been studied, but they have not shown long-term benefits and are not routinely recommended. For patients with BPD who are on diuretics in an outpatient setting, the best approach is to allow for growth rather than increasing the diuretic dose. A gradual weaning of diuretics as the child grows is often the preferred strategy in managing these patients.

Bronchodilators

Studies have shown that inhaled bronchodilators, particularly beta-agonists, can provide short-term improvement in lung function for infants with BPD, especially during acute exacerbations. These medications are not necessary on a regular basis but can be beneficial during respiratory infections or when reversible bronchospasm occurs.

Growth and Nutrition

In terms of growth and nutrition, it is crucial to select the appropriate caloric intake for these infants, typically ranging from 22 to 30 calories per ounce. The balance between fat and carbohydrates is also important, as these babies need nutrients like zinc to support tissue repair, carbohydrate tolerance, and immune healing. Additional vitamin A is often recommended, and it is important to avoid lipid restriction and excessive glucose infusion in this patient population.

European Respiratory Society Guideline

The European Respiratory Society's consensus group (Duijts et al., 2020) conducted a thorough review of several key areas related to the care of BPD patients after discharge, but they concluded that the evidence supporting many interventions is generally low. For instance, they do not recommend routine lung imaging for BPD patients unless the patient has severe BPD or significant respiratory symptoms. Similarly, they advise against using lung function tests to monitor children with BPD, citing the low certainty of the evidence.

When it comes to deciding whether to send a child with BPD to daycare, the task force suggests that this decision should be based on a combination of factors, including local experience, the child's age, the season, and the family's preferences and circumstances. They support the use of inhaled bronchodilators only during acute exacerbations, as we discussed earlier. Additionally, they recommend against treating BPD children with inhaled or systemic corticosteroids and advocate for the weight growth weaning strategy for diuretics.

This comprehensive approach underscores the importance of individualized care for BPD patients. It emphasizes the need to base treatment decisions on evidence-based practices while also considering the unique needs and circumstances of each child and their family. The European Respiratory Society's consensus group also recommended that for children with BPD, supplemental oxygen should be maintained with a minimum saturation target level of 90% until further studies provide more definitive guidance.

Van Hus et al., in a study published in Acta Paediatrica in 2016, examined neurologic outcomes in NICU babies through a multicenter randomized controlled trial. This study involved 176 infants who were either born at less than 32 weeks of gestational age or weighed less than 1,500 grams at birth. The infants were divided into two groups: an intervention group and a control group. Neurological assessments were conducted at 12 and 24 months to evaluate the impact of the intervention on their cognitive and motor development.

The intervention group received seven to nine physical therapy visits in their home, while the control group received standard care. Importantly, if infants in the control group met the criteria for home physical therapy, they still received those visits as part of their standard care. The researchers were able to follow these infants for an impressive 5 1/2 years, which is a substantial duration when studying BPD patients. After this period, they had a good follow-up rate, with 69 and 67 patients remaining in the intervention and control groups, respectively.

The study found that children with BPD who received home physical therapy showed significant benefits in both cognitive and motor domains compared to those who received standard care. The differences observed between the intervention and control groups were quite pronounced, as illustrated in the slides.

This research highlights the importance of recommending outpatient support, such as physical therapy, for children with BPD. Such interventions can have a profound impact on their neurodevelopmental, learning, and cognitive outcomes in the long term, underscoring the need for a comprehensive approach to their care beyond the NICU.

Surfactant Study

The next study, conducted by Hascoet et al. and published in JAMA Pediatrics in 2016, focused on the effects of late surfactant administration in infants with prolonged respiratory distress who remained on ventilators at 36 weeks postmenstrual age and at one year postmenstrual age. This was a double-blind, randomized, controlled trial conducted across 13 centers involving 113 patients. The infants were randomized to receive either 200 mg per kg of surfactant or a syringe filled with air. To maintain blinding, the syringes were weighted the same and covered in light-protective tubing, so those administering the treatment were unaware of whether they were delivering surfactant or air. This careful design aimed to ensure the objectivity of the trial’s outcomes.

The study by Hascoet et al. showed no significant difference in outcomes at 36 weeks postmenstrual age between the two groups. However, the intervention group that received late surfactant administration was associated with reduced respiratory morbidity at one year of age, indicating a potential long-term benefit.

The next study, conducted by Yeh et al. and published in the American Journal of Respiratory and Critical Care Medicine in 2015, was a clinical trial conducted at two neonatal centers in the US and Taiwan. This trial included infants with severe respiratory distress who required mechanical ventilation and had oxygen requirements exceeding 50%. The intervention group received a combination of surfactant and budesonide, while the control group received only surfactant until the infants required 30% or less FiO2 or were extubated.

In this study, Survanta, a specific type of surfactant, was administered every eight hours for up to six doses, following the manufacturer's instructions. The results were significant: the incidence of BPD or death in the intervention group was reduced from 66% in the control group to 42%. This finding suggests that the combination of surfactant and budesonide could be effective in reducing the incidence of BPD or death in infants with severe respiratory distress. The study demonstrated a significant reduction in the incidence of BPD or death when multiple doses of surfactant and budesonide were administered to infants with severe respiratory distress. This treatment was continued until the patients were either extubated or required less than 30% FiO2. The intervention group saw a reduction in the incidence of BPD or death from 66% in the control group to 42%, highlighting the potential effectiveness of this combined therapy in improving outcomes for these high-risk infants.

SUPPORT Trial 2017

The SUPPORT trial, conducted in 2017, was a significant randomized controlled trial that used a multicenter approach to examine the effects of different oxygen saturation (SpO2) targets on preterm infants. The study specifically focused on infants born between 24 and 27 weeks of gestational age and included a large cohort of 1,316 infants. These infants were randomized into two groups with different SpO2 targets: 85-89% and 91-95%.

The trial aimed to determine the association of PaCO2 levels with severe intraventricular hemorrhage (IVH), BPD, and neurodevelopmental outcomes at 18 and 22 months of age. The analysis of blood gases revealed that a higher PaCO2 was an independent predictor of several adverse outcomes, including severe IVH and death, BPD and death, and neurodevelopmental impact and death.

These findings underscore the importance of closely monitoring and managing PaCO2 levels in preterm infants to minimize the risk of these severe complications. The SUPPORT trial provided critical insights into how different oxygenation strategies and PaCO2 levels can influence the long-term outcomes of very preterm infants.

Montelukast Treatment in Severe BPD

The study by Ruprecht et al., published in Respiration in 2014, explored the use of montelukast as a treatment for severe BPD in preterm infants. This unblinded prospective trial included infants between 23 and 27 weeks of gestational age, all of whom were diagnosed with severe BPD. The treatment regimen involved administering montelukast at a dose of 1 mg per kg once daily for the first week, increasing to 1.5 mg per kg in the second week and 2 mg per kg in the third week. Treatment continued until the clinical signs of BPD cleared or the infant was discharged.

The results were quite compelling. The survival rate in the treatment group was 91%, compared to 36% in the non-treatment group, demonstrating a significant survival advantage for those receiving montelukast. Additionally, the treatment group experienced a dramatic reduction in the number of days on mechanical ventilation, from an average of 103 days down to 41 days. This reduction in ventilation days by more than half further highlights the potential effectiveness of montelukast in managing severe BPD and improving outcomes in this vulnerable population.

Hydrocortisone

Renault et al. published a significant study in 2016 that investigated the effects of hydrocortisone on infants born at less than 27 weeks gestational age. The study was conducted between 2005 and 2008 across two centers, with one center administering hydrocortisone to these infants while the other did not. The results were notable: the use of hydrocortisone was associated with a reduction in the incidence of bronchopulmonary dysplasia (BPD). Moreover, at the two-year follow-up, there was no observed neurodevelopmental impairment in the infants who received hydrocortisone, suggesting that this treatment could be both effective and safe in preventing BPD without long-term neurodevelopmental risks.

The following two studies you mentioned are more recent and represent some of the cutting-edge research currently being explored. These studies are part of the ongoing efforts to expand our understanding of BPD prevention and treatment and could shape future approaches to neonatal care.

Mesenchymal Stem Cells

If you haven't heard about mesenchymal stem cells, or MSCs for short, they play a crucial role in lung development. Stem cell dysfunction can hinder the self-repair mechanisms of immature lung tissue, contributing to the development of BPD. Research has shown that the depletion or dysfunction of endogenous or progenitor stem cells can increase the risk of BPD. In animal studies, exogenous stem cells have been found to protect and repair lung injury, partly due to their ability to preserve the pools of endogenous stem cells.

Bone marrow-derived MSCs have shown considerable promise in improving BPD by preventing lung inflammation. What's particularly interesting is that the beneficial effects of MSCs are believed to be primarily hormone-related rather than due to the cells' ability to engraft into lung tissue. The discovery of MSCs in human umbilical cord tissue and cord blood marked a significant advancement, as it provided a clinically relevant and feasible source of these potent cells for the treatment of neonatal diseases, including BPD. This breakthrough opens new avenues for treating BPD and potentially improving outcomes for affected infants. This development opens up new possibilities for treating BPD by harnessing the regenerative potential of MSCs, offering hope for better outcomes in affected infants.

For example, Chang et al., in The Journal of Pediatrics, reported on a phase I trial of human cord blood-derived MSCs successfully conducted in South Korea involving nine extremely preterm neonates. The two-year outcomes from this trial did not reveal any safety concerns, which is encouraging for the continued exploration of this treatment. In the United States, another phase I clinical trial of human umbilical cord blood-derived MSCs has been completed, with a phase II trial currently underway. In this trial, the babies received three doses of MSCs, and it was found that the severity of BPD was lower in those who received the transplant.

Beyond MSCs, other sources of cells are also under investigation. An Australian group has been studying stem-like cells derived from placental membranes, specifically human amnion epithelial cells (HAECs), which have shown therapeutic promise in preclinical models of BPD. This group conducted the first-in-human clinical trial of HAECs in neonates with BPD to assess the safety of these cells. With the exception of one patient who developed respiratory distress attributed to an embolic event, the investigators reported no other adverse events related to the administration of these cells. This suggests that HAECs could be another promising avenue for treating BPD.

Additionally, there is growing interest in the potential role of insulin-like growth factor (IGF-1) in treating BPD. IGF-1, part of the insulin family, is crucial for promoting mitosis, stimulating cell proliferation, and driving DNA synthesis, which are key processes in pulmonary development during both the fetal and postnatal periods. IGF-1 is an important regulator of fetal growth, lung angiogenesis, and overall lung development, making it a potential therapeutic target for improving outcomes in infants at risk of or suffering from BPD. These emerging therapies, including MSCs, HAECs, and IGF-1, represent exciting developments in the quest to better understand and treat BPD, offering new hope for improving the lives of affected infants.

Insulin-like Growth Factor-1

IGF-1 levels increase significantly during the last two trimesters of pregnancy, with a sharp rise that you would clearly see on a graph. After birth, these levels decrease rapidly. In extremely preterm neonates, lower serum IGF-1 levels have been independently associated with an increased risk of BPD and other complications such as retinopathy of prematurity.

In neonatal rodent models, administering IGF-1 appears to reduce lung injury caused by hypoxia, even when the animals are exposed to oxygen. This suggests that IGF-1 could help mitigate some of the damage associated with oxygen therapy, which is often necessary for preterm infants. Several studies have reported that IGF-1 influences BPD development and progression by regulating biological processes related to the disease. Additionally, the exogenous administration of IGF-1 has been shown to alleviate lung inflammation, reduce cell apoptosis, and correct alveolar development disorders in children with BPD.

These findings suggest that IGF-1 could be a promising new target for treating BPD. For instance, recombinant human IGF-1, when combined with its binding protein (known as RH1 GF-1), has been shown to reduce the number of extremely preterm neonates developing severe BPD and shift the disease severity towards a milder form of BPD. This means that even if these infants are born prematurely and require oxygen and positive pressure ventilation, increasing their IGF-1 levels could potentially reduce their risk of developing BPD or at least lead to a milder form of the disease.

The potential of IGF-1 as a therapeutic target is indeed exciting, as it offers a new avenue for improving outcomes in preterm infants who are at high risk of BPD

Limitations

When discussing BPD research, it is important to acknowledge several limitations, particularly the ongoing controversy over meaningful endpoints. One of the biggest questions in the field is determining the appropriate duration for studying patients with BPD. Should research focus only on the period when they are in the NICU, or should it extend to when they leave the PICU, their first outpatient primary care visit, or even further? Some argue that studies should continue until these individuals reach significant life milestones, such as entering kindergarten, graduating from high school, starting their first job, or even until they have children or pass away. The challenge lies in deciding at what point the data collected provides the most meaningful and relevant insights.

Additionally, there are significant gaps in our understanding of long-term clinical outcomes for BPD patients. Specifically, there is limited information on what certain treatments or diagnoses mean for these individuals as they progress into adulthood and geriatrics. For example, how does BPD impact their long-term lung function, overall health, and quality of life? What are the potential late-onset complications? These are critical questions that remain largely unanswered due to the difficulty of conducting long-term studies and the variability in individual outcomes.

The controversy over meaningful endpoints and the scarcity of long-term data make it challenging to develop a comprehensive understanding of BPD and its implications across the lifespan. This highlights the need for continued research that not only addresses immediate outcomes but also tracks patients well into adulthood to provide a fuller picture of how BPD affects long-term health and well-being.

These are critical questions that highlight the complexities and uncertainties in BPD research, particularly regarding the long-term consequences of current treatments. For instance, if patients receive multiple doses of surfactant during infancy, we do not yet know if this could lead to stiffer lungs later in life, potentially contributing to conditions like COPD or emphysema as they age. The long-term pulmonary outcomes for BPD survivors are not well understood, especially as these individuals reach older adulthood, and this remains an area needing further study.

Another area of active discussion in the literature is the role of placental dysfunction as a primary factor in the development of BPD. The relationship between antenatal exposures—such as maternal smoking—and early postnatal events—like neonatal sepsis—has not been fully explored in terms of which has the most significant impact on BPD risk and severity.

There are still many unknowns regarding how these factors interact. For example, if a mother smokes during pregnancy and the infant later develops neonatal sepsis, does the combination of these factors exacerbate the risk of BPD, or does one dominate? Additionally, we need to understand better whether prevention strategies can mitigate these risks or if certain predisposing factors might offset the benefits of interventions aimed at reducing BPD incidence.

These gaps in our knowledge underscore the need for more comprehensive studies that examine the interplay between antenatal exposures, postnatal events, and various treatment strategies. Understanding these relationships could inform better prevention and treatment approaches, potentially leading to improved long-term outcomes for individuals with BPD.

There is still much to learn about the complex and multifactorial nature of BPD. Currently, there is limited research that connects the dots between various factors, such as antenatal exposures, postnatal events, and the development of BPD. Some researchers are now exploring the idea that BPD may actually begin during early fetal life. If this proves to be true, it could revolutionize our understanding of BPD and how we predict its occurrence. For instance, it might be possible in the future to identify babies at risk for BPD through amniotic fluid samples or choriocentesis long before they are exposed to oxygen or positive pressure ventilation. This would represent a significant shift from our current understanding and the traditional definition of BPD, which primarily focuses on postnatal factors.

The fact that we do not fully understand the pathophysiologic mechanisms leading to BPD highlights how complex this condition is. We are gradually learning more, but the pathogenesis of BPD remains highly multifactorial. It involves a wide range of pre and post-natal exposures that influence lung development in ways we do not yet fully comprehend. The interplay between these factors—ranging from genetic predispositions to environmental influences like maternal smoking or neonatal sepsis—makes it challenging to pinpoint a single cause or to develop a one-size-fits-all prevention or treatment strategy.

As research continues to evolve, gaining a deeper understanding of these mechanisms and their interactions will be crucial. It could open the door to new diagnostic tools, early interventions, and personalized treatment approaches that could significantly improve outcomes for infants at risk of or diagnosed with BPD.

The explanation captures the complexity of BPD and how various exposures and factors interact to influence its development. BPD likely involves multiple different pathophysiologies, depending on the timing and combinations of exposures. Some exposures may protect against BPD and promote lung repair, while others may injure the preterm lung and contribute to BPD pathogenesis. This dynamic interaction leads to the clinical manifestations observed, where BPD-typical lungs develop or, alternatively, where lung health is preserved. For those seeking a deeper understanding of BPD, it is essential to address any questions related to the evidence and historical context. 

Questions and Answers

Could you share your thoughts on how the decision to administer antenatal corticosteroids is made, particularly given that it is made before birth?

Certainly. The decision to administer antenatal corticosteroids can vary greatly depending on where you are—whether in different regions of the United States or around the world. The recommendations can differ based on the provider's experience and the specific circumstances of the pregnancy. From what I've seen in the literature, the key takeaway is to administer these steroids early if they are deemed beneficial. However, it is important not to continue administering them after the baby has been in the NICU for three weeks and has been on a ventilator. At that point, the evidence indicates a significant risk of poor neurodevelopmental outcomes, which suggests that it wouldn't be appropriate to continue treatment at that stage.

We discussed how nutrition is crucial for these children. After they leave the hospital or ICU, how long should we continue to monitor their nutritional status? Additionally, how significant is the impact of nutrition on their growth? It seems like these factors are interrelated—almost like a "chicken or the egg" situation. Could you elaborate on that?

Absolutely, that makes perfect sense. I think it is really important to communicate to the families of BPD patients that they are facing significant challenges. A large proportion of these babies—around 65%—are diagnosed with growth failure after they leave the hospital. While we can do a lot to support them nutritionally in the hospital, the resources available at home are often more limited. it is crucial to emphasize to parents that inadequate nutrition could lead to their child needing to be readmitted. We should provide them with resources and guidance to ensure they feel in control. Something as seemingly small as not finishing a full bottle can have a much bigger impact on a child with BPD than on a healthy newborn. If a healthy newborn only takes three ounces instead of six, it might not be a big deal. However, for a child with BPD, that difference can be significant. That is why it is so important to share information and educate families about the challenges they may face. By helping them understand what they are up against, we can better partner with them to ensure their child’s success.

Given all the research you have reviewed, do you believe we’re on the right path toward effectively bridging the gap between the evidence-based recommendations you presented and what we are currently implementing? Considering that change can often be gradual, how do you see this progress unfolding?

I agree that having multiple definitions is something we need to address by working towards a consensus definition that everyone can agree on. However, I understand that it is challenging because we cannot predict the medical advancements that will occur in five or ten years when we set the definition today. Considering the history of how these definitions have evolved and the new treatments we're implementing, it makes sense, but it also complicates determining the best treatment plans. The constant changes and shifting targets make it difficult. That said, it is wonderful to see these babies surviving and thriving—becoming functional toddlers, attending school, and eventually creating families of their own. However, it is crucial that we continue to follow up and support these patients into adulthood and even into their geriatric years. I believe we’re on the right track, but it would be beneficial to see more global collaboration and consensus.

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