Introduction
As we have discussed in a few of our previous podcasts, respiratory distress syndrome (RDS) is very common in premature infants. The incidence of RDS and subsequent bronchopulmonary dysplasia (BPD), is inversely related to birthweight and gestational age. Meaning, the younger the gestation of an infant, the more likely they will develop respiratory distress syndrome. For a more thorough review of respiratory distress syndrome, I recommend that you go back and listen to our podcast episode 8: Take a Deep Breath – Diving Into Respiratory Distress Syndrome in Newborns.
Bronchopulmonary dysplasia is a chronic neonatal lung disease often resulting in severe sequelae for preterm infants. BPD is one of the most common conditions in preterm infants and it continues to be an ongoing source of both short-term and long-term morbidity in premature infants. Despite advances in neonatal care and management, BPD continues to affect over half of extremely premature infants. Not only does BPD affect infants while they are in the NICU, it also predisposes them to adverse neurodevelopmental outcomes and places them at risk for problematic cardio respiratory health in the future.
For our 36th podcast episode, we review the pathophysiology of BPD and why it is so common among preterm infants. We discuss preventive measures and medical management of infants with BPD and touch on some of the up and coming innovative therapies that are being looked into for prevention and the treatment as well. The episode will be beneficial for both NICU clinicians and parents who want a basic review or understanding of BPD in infants.
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Episode 36
Bronchopulmonary Dysplasia
The incidence of BPD in infants
Bronchopulmonary dysplasia or BPD is a complex, multifactorial form of chronic lung disease. Advances in the respiratory management of extremely premature infants have led to improvements in survival, but unfortunately, it has not led to a reduction in BPD. According to Gomella et al. (2020), BPD affects approximately 30% of infants with birthweights <1000 grams and Gibbs et al. (2019) states that the incidence in extremely preterm infants, or those born less than 28 weeks’ gestation, is 40% and up to 80% of infants born before 24 weeks’ gestation.
Prenatal and Postnatal Factors that Influence BPD
Part of the complexity of BPD is that it is influenced by both prenatal and postnatal factors. The prenatal factors that contribute to the development of BPD include maternal smoking, pregnancy-induced hypertension and/or preeclampsia, hypoxia or a decreased amount of oxygen in the tissues, male gender, congenital anomalies that may lead to pulmonary hypoplasia, or genetic factors.
Postnatally, the factors that influence BPD include lung immaturity, poor nutrition, the need for mechanical ventilation, oxygen injury, and an infection or sepsis. Preterm birth which often coincides with all of the aforementioned postnatal factors is the common denominator when it comes to developing BPD.
Definition of BPD
BPD was first described in 1967 by Northway and Rosan, but its definition and the stages to describe it have been recently modified. The “new BPD” is characterized by arrested lung development resulting from interference with alveolarization, vascularization, and the development of excess tone and airway reactivity, primarily in preterm infants with birth weights less than 1250 grams.
Currently, the most accepted diagnostic criteria categorizes the disease severity according to the mode of respiratory support administered to the infant at 36 weeks’ postmenstrual, or corrected gestational age despite the use of supplemental oxygen. Further clinical criteria then categorizes the severity of BPD into the subcategories of mild, moderate, and severe.
Pathophysiology of BPD
As I previously stated, BPD is a disorder that primarily affects premature infants due to their increased likelihood of respiratory distress syndrome. BPD is characterized by respiratory distress and impaired gas exchange. Oxygen toxicity, barotrauma, and volutrauma contribute the most to the development of BPD. The manner in which it develops is from chronic, constant recurring lung injury coupled with ongoing repair and healing of the injury. The injury from mechanical ventilation coupled with the predisposing prenatal factors leads to an exaggerated inflammatory response causing lung damage.
But it is a vicious cycle because it is the chronic lung injury and the intrinsic repair of the lungs that actually prolong the need for the exact factors that contribute to the development of it. Meaning, infants with BPD need additional mechanical ventilation and oxygen therapy due to the lung injury and repair of BPD which in turn causes more damage.
Clinical Course of BPD
The clinical course of BPD involves persistent respiratory distress that is often described as the chronic phase of RDS. Infants with BPD present with ongoing or worsening respiratory status. Infants may present with increased work of breathing, they require additional oxygen, have apnea and bradycardia episodes, or possibly a combination of all the signs. They are often tachypneic or are breathing fast, they may wheeze, and/or have fine rales throughout the lungs and at the bases, and display symptoms of respiratory distress including retractions and nasal flaring.
X-Ray findings vary and correlate with the stage of the disease from a reticulogranular pattern and air bronchograms in Stage I up to an irregular formation with large cysts that alternate with areas of increased density in Stage IV. Infants with BPD may also have chest X-rays that show decreased lung volumes, hyperinflation, areas of atelectasis or a collapse of one or both of the lungs, pulmonary or lung edema, and a condition called pulmonary interstitial emphysema.
BPD and Pulmonary Hypertension
Infants with BPD may also develop cardiovascular changes including right ventricular hypertrophy or enlargement and septal wall thickening with elevated pulmonary pressures. Pulmonary hypertension (PH) associated with BPD (BPD-PH) is characterized by alveolar diffusion impairment and abnormal vascular remodeling which lead to increased pulmonary vascular resistance and right heart failure. About 25% of infants with moderate to severe BPD develop BPD-PH which is associated with high morbidity and mortality.
On exam, the infant’s liver may also be enlarged secondary to right-sided heart failure or it may be displaced downward into the abdomen secondary to lung hyperinflation.
Common labs that will be done to monitor infants with BPD include capillary or arterial blood gasses, electrolytes, CBCs, and BNPs.
The incidence of BPD does vary between NICUs due to different management methods with respiratory distress. The use of CPAP, non-invasive ventilation, and gentle ventilation have lowered the incidence of BPD, but practices and ventilation management do vary between institutions.
Barotrauma and Volutrauma
As you likely know, some infants with respiratory distress syndrome have to be treated with invasive ventilation for several weeks or even months due to their immature lungs. Although institutions attempt to use the least amount of peak inspiratory pressure, or PIP on the ventilator, infants with noncompliant lungs may require higher pressures for survival contributing to the lung damage. Barotrauma is caused by pressure from mechanical ventilation and may damage the airway and disrupt the alveoli or air sacs. Volutrauma, or overly stretched lungs is caused by overdistention of the lungs due to the delivery of gas which may also cause lung injury.
Non-invasive Ventilation
To minimize the risk of barotrauma and volutrauma, NICU clinicians first and foremost try to use non-invasive management strategies to manage respiratory distress syndrome. Non-invasive ventilation like CPAP or non-invasive positive pressure ventilation provide the administration of pressures but without the use of an invasive endotracheal tube. We discussed non-invasive ventilation at length on our podcast, episode 11: Non-Invasive Ventilation in the NICU – A Review of NIPPV, CPAP, HFNC, and LFNC too.
Early Extubation
While avoiding endotracheal intubation and mechanical ventilation is associated with less BPD, oftentimes, invasive mechanical ventilation is necessary and required. As I previously mentioned, the goal is to use the least amount of pressure as possible and to keep the tidal volume around 4-6 ml/kg. But, for any infant that does require invasive ventilation through an endotracheal tube, the subsequent goal is to extubate them as early as possible. Duration of invasive mechanical ventilation is one of the major risk factors associated with BPD. Therefore, early extubation or removal of the breathing tube lowers the rate of BPD. One particular study found that when extubation was delayed past the first week of life, not only did the risk of BPD increase, but it is also associated with adverse pulmonary outcomes.
Surfactant
The administration of Curosurf or Surfactant also assists with the management of minimizing BPD. Once Curosurf is administered to the lungs, it helps to reduce the surface tension, improve lung compliance, and allows the clinician to use lower pressures to ventilate resulting in less damage. Once Surfactant is administered, it also facilitates early extubation.
High Frequency Ventilation
Some institutions may use gentle ventilation with either the High Frequency Jet Ventilator or the High Frequency Oscillating Ventilator as a management method to reduce the amount of barotrauma and volutrauma. High frequency ventilation uses tiny gas volumes delivered at rapid rates. But, the study results are varied and do not show a strong correlation with the use of high frequency ventilation and a decreased incidence of BPD.
Oxygen Toxicity
Prolonged exposure to oxygen, which can lead to oxygen toxicity is also a contributing factor for BPD. Through oxidative metabolism, free radicals are formed which are toxic to living cells and tissues. Typically antioxidants protect cells against free radicals, but preterm infants are deficient in antioxidants. The deficiency of antioxidants makes preterm infants more susceptible to lung damage from free radicals and oxidative stress once exposed to excess oxygen in the tissues, even for brief periods of time. Unfortunately, infants born prematurely, especially less than 30 weeks’ gestation, typically need supplemental oxygen to maintain appropriate oxygen saturations. But, ideal target saturations for premature infants remain debatable despite years of research.
Delivery Room Management
Delivery room management for term and preterm infants is currently guided based on the Neonatal Resuscitation Program. It guides the providers with target oxygen saturations to aim for in the first 10 minutes of life so only the necessary amount of supplemental oxygen is used to prevent any unnecessary toxicity.
Beyond the delivery room and into the NICU, further studies are needed to make definitive conclusions, but most literature recommends maintaining oxygen saturations between 88% – 92% with the high alarm limit set at 96%.
Patent Ductus Arteriosus (PDA)
Infants with a patent ductus arteriosus or PDA are also more prone to develop BPD as well. To adequately support infants with a PDA, infants often require increased amounts of oxygen and higher pressures on the ventilator due to the pulmonary complications from the PDA which may result in both oxygen toxicity and barotrauma. Additionally, the increased pulmonary blood flow from the PDA may also cause pulmonary damage. With that being said, not all PDAs make infants more prone to developing BPD, but the larger, persistent ones do and should be treated accordingly.
The importance of nutrition
We all know how important adequate nutrition is for our preterm infants, but did you know that it also affects their risk for developing BPD. But, in addition to that, infants who were either diagnosed with Intrauterine Growth Restriction or IUGR in utero or as Small for Gestational Age (SGA) after delivery are twice as likely to develop BPD. Growth restriction compromises lung development and function, so it is essential to provide adequate nutrition, especially in the first week of life. Provision of adequate nutrition, especially with the use of breastmilk can potentially decrease the infant’s risk of developing BPD. Studies have shown that preterm infants who exclusively receive human breastmilk, have a significantly lower incidence of BPD when compared to preterm infants who receive either preterm formula or maternal breastmilk with bovine fortifier.
Fluid Management and BPD
Providers in the NICU must also be very cautious with their fluid management. BPD is common in preterm infants who have developed symptoms of fluid overload during their first few days of life. Monitoring and managing fluid balance in extremely low birthweight and very low birthweight infants can be tricky as we must consider large amounts of insensible water loss, their intake, output, and weight changes.
Infection Prevention
Prevention of infection is also incredibly important in minimizing the risk for BPD as infection has been identified as an antecedent for BPD. Nosocomial, or hospital-acquired infections contribute to the development of BPD. The connection is likely related to persistent inflammatory mediators. Unfortunately, although it has been considered to preventatively treat preterm infants with antibiotics, studies have now shown that VLBW infants who receive >48 hours of antibiotics during the 1st week of life are at twice the risk of developing BPD. And sadly, each additional day they receive antibiotics also increases their risk. So ultimately, the best recommendation for infection prevention is implementation of strict hand hygiene policies and central-line bundles to help reduce the risk of BPD from infections and antibiotic administration.
Postnatal Corticosteroids
Postnatal corticosteroids or steroids given to the infant have demonstrated improvements in early extubation for infants who are at risk for BPD. Overall, corticosteroids reduce inflammation and reduce the need for further mechanical ventilation. Unfortunately, postnatal steroids are not without concern as studies have shown adverse neurodevelopmental outcomes as well as several additional adverse side effects. The benefits must outweigh the risks and the parents should be presented with the benefits and risks to help guide their decision-making.
Inhaled Corticosteroids
Inhaled corticosteroids can also be used as both a preventive measure and as part of the treatment for BPD. They improve lung function, gas exchange, airway resistance, and lung compliance.
Additionally, there are some other measures that institutions commonly use in NICUs to prevent and treat BPD including administration of Caffeine, Vitamin A, diuretics, antenatal steroids given to the mother, inhaled nitric oxide, and erythropoietin or Epo.
Tracheostomy
Some infants, despite all of the preventive measures and evidence-based management methods used, are unable to either be extubated or still require elevated pressures through non-invasive ventilation. If an infant is unable to be weaned off of mechanical ventilation, as they approach or surpass term equivalent, the providers review the risks and benefits of a tracheostomy and begin to discuss the options for the plan of care with the parents.
The decision to place a trach with the ultimate goal to send the family home with a medically complex, technology-dependent child should not be taken lightly. However, studies have shown that tracheostomies have been associated with decreased respiratory support and improvements in short-term growth and neurodevelopmental outcomes. Contemporary portable ventilators are more sophisticated and have been shown to reduce hospital costs, improve quality of life, and enhance development. But again, the decision should be carefully thought through as shifting care from a NICU or PICU to a home setting can be challenging for the family and is not without risk.
BPD is a chronic illness that persists beyond discharge from the hospital and into adulthood. Preterm infants that develop BPD tend to have persistent pulmonary dysfunction and exercise intolerance beyond the neonatal years. These kiddos may frequently develop reactive airway disease, asthma, RSV bronchiolitis, and early onset emphysema. BPD can also affect their growth and neurodevelopmental outcomes. They may experience delays in fine and gross motor skills as well as language development.
Future Advances in BPD Management
BPD can be a life-altering condition and as I stated, despite great advances in neonatal medicine and an improvement in survival rates, the incidence of BPD continues to remain high. Luckily, there is continuous research being done in attempts to find better preventative measures and treatment plans for premature infants at risk for BPD.
Mesenchymal Stem Cells
Advances in stem cell biology over the past two decades have now positioned stem cells as an emerging treatment in medicine. Mesenchymal stem cells (MSCs) have specifically emerged as a potential new therapeutic agent in both the prevention and treatment for BPD.
Insulin-Like Growth Factor
Insulin-like growth factor (IGF-1) is a growth factor involved in vascular development. The levels typically increase during the third trimester of pregnancy leaving preterm infants with lower levels. IGF-1 levels are important for tissue growth, and it stimulates cell proliferation, maturation, and differentiation. Lower IGF-1 levels in preterm infants are associated with suboptimal weight gain and an increased risk of chronic lung disease, retinopathy of prematurity (ROP), and necrotizing entercolitis (NEC). Therefore, IGF-1 is being looked at as a potential therapy for BPD as well as being beneficial in prevention of ROP and NEC.
Vitamin C
Treatment with high-dose Vitamin C has also been looked at as a potential treatment for mothers who smoke during the pregnancy which as you may recall places infants at an increased risk for BPD. In a study, it showed an association between Vitamin C and improved lung function in term-born infants.
Vitamin D
Prenatal treatment with Vitamin D is also being looked at as another treatment strategy for BPD. When given prenatally and postnatally, Vitamin D resulted in an improvement in alveolarization and vascular growth.
Although some of these recent findings are still being looked into, I am hopeful that researchers can continue studies and find more definitive treatments for BPD that will help our preterm infants and their parents.
Closing
In the NICU, we continue to gain a better understanding of the pathophysiology and progression of BPD, but unfortunately, preventative and therapeutic measures continue to be a challenge for NICU providers. As you just read, many of the treatments lack strong evidence and also come with the risk of long-term adverse outcomes. So despite all of the advances in neonatology for survival of preterm infants, many infants will continue to be diagnosed with BPD. Also, as a reminder, different NICUs will use varied methods for both prevention and treatment of BPD based on their particular guidelines or protocols.
On our next episode, you will hear from a mother of a little girl who had a tracheostomy placed prior to her discharge from the NICU. Tune in to hear their personal NICU journey and life after the NICU with a medically complex child. She very vulnerably shares what they have learned along the way, what they regret, and advice for parents who are either considering a tracheostomy for their child or are home and trying to manage life with a child who has a trach. You will not want to miss it!
References
Alvarez-Fuente, M., Moreno, L., Mitchell, J., Reiss, I., Lopez, P., Elorza, D., Duijts, L., Avila-Alvarez, A., Arruza, L., Orellana, M., Baraldi, E., Zaramella, P., Rueda, S., Gimeno-Diaz de Atauri, A., Guimaraes, H., Rocha, G., Proenca, E., Thebaud, B., & Jesus del Cerro, M. (2019). Preventing Bronchopulmonary Dysplasia: New Tools for an Old Challenge. Pediatric Research, 85, 432-441.
Eichenwald, E., Hansen, A., Martin, C., & Stark, A. (2017). Cloherty and Stark’s Manual of Neonatal Care, 8th edition. Wolters Kluwer.
Gardner, S., Carter, B., Enzman-Hines, M., & Hernandez, J. (2011). Merenstein & Gardner’s Handbook of Neonatal Intensive Care. Mosby Elsevier.
Gibbs, K., Jensen, E., Alexiou, S., Munson, D., & Zhang, H. (2019). Ventilation Strategies in Severe Bronchopulmonary Dysplasia. Neoreviews, 21(4), e226-e237.
Gilfillan, M. & Bhandari, V. (2022). Moving Bronchopulmonary Dysplasia Research From the Bedside to the Bench. American Journal of Physiology, 322, L804-L821.
Gomella, T., Eyal, F., & Bany-Mohammed, F. (2020). Gomella’s Neonatology: Management, Procedures, On-Call Problems, Diseases, and Drugs, 8th Edition. McGraw-Hill.
Hennelly, M., Greenberg, R., & Alex, S. (2021). An Update on the Prevention and Management of Bronchopulmonary Dysplasia. Pediatric, Health, Medicine, and Therapeutics, 12, 405-419.
Nelin, L. & Blandari, V. (2017). How to Decrease Bronchopulmonary Dysplasia in Your Neonatal Intensive Care Unit Today and “Tomorrow.” F1000 Research, 6, 539-546.
Sahni, M. & Moses, A. (2022). Bronchopulmonary Dysplasia. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK539879/
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