Bronchopulmonary Dysplasia - Chronic complication in preterm babies.

Bronchopulmonary Dysplasia - A chronic lung disease seen in infants born preterm.

1. CHRONIC LUNG DISEASE.

2. i . B asic pathophysiology? ii. Who gets it/basic epidemiology? iii. P resenting symptoms? iv. Management ? v. Complications? vi. Prognosis? Objectives

3. Bronchopulmonary dysplasia (BPD) is a chronic lung disease that now occurs primarily in preterm newborns that weigh <1000 g, are born at 24 to 26 weeks of gestation, and receive respiratory support with mechanical ventilation and/or prolonged oxygenation. Prenatal intrauterine infections may predispose the fetal lung to subsequent oxidant and volutrauma injuries.1 Advances in critical care management and technology followed by more widespread use of exogenous surfactant and prenatal steroids have resulted in the present pattern of injury: an extremely immature lung due to interruption of normal gestational growth and development, and altered by subsequent reparative processes of impaired alveolization , dysmorphic vasculogenesis , and usually minimal alveolar wall fibroproliferation. So the pathogenesis of “new” BPD involves extreme lung immaturity, treatment-induced oxygen and volutrauma injury, and prenatal and/or postnatal inflammatory responses.

4. Before 1960 – ELGA babies were not surviving due to RDS; 1960s introduction of Mechanical vent – improved survival Northway & clleagues in 1967 first described old BPD due to aggressive ventilation settings and high FiO2 (prems 30 weeks/>1500 g) Now with prenatal steroid use, surfactant therapy, mx of PDA, new vent strategy and improved nutrition  more ELGA and BW are surviving with Identification of a new form of BPD. Background

5. 2 BPD was initially described in a series of premature infants with birth weights of 900 g to 2466 g who had severe Respiratory Distress Syndrome (RDS) and who were supported with supplemental oxygen and mechanical ventilation. 3 Chest radiographs demonstrated hyper expansion and bullae

6. As new treatment options became available, including surfactant replacement, expanded options for ventilator support, use of continuous positive airway pressure (CPAP) to decrease time on mechanical ventilation, oxygen saturation monitors to minimize oxygen exposure, and improved nutrition, the characteristics of BPD changed. The “new” BPD appears to be a result of arrested development, characterized by decreased number of alveoli and abnormal vascular organization.5 The main risk factors predisposing patients to BPD include prematurity, oxygen therapy, mechanical ventilation, infection, and patent ductus arteriosus (PDA) (Fig. 1).6 The pathophysiology of these factors relative to their contribution to BPD will be reviewed.

7. Definitions Northway’s original definition Bancalari et al in 1979 – supplemental O2 req at 28 days Chronic changes on Xray Tachypnea with crackles or retractions 1988 – O2 req at 36 wks PMA 2000 NIH consensus conference modified the criteria further -

8. Definitions

9. Definition BPD is defined as  oxygen dependency in neonates beyond 28 days of age  and classified according to disease severity at 36 weeks post-menstrual age. This limit was chosen as it is predictive of chronic lung disease later in life. Most classification methods rate disease severity based on the need for  supplemental oxygen  at 36 weeks, but in a 2019 article,  Jensen et al.  defined disease severity based on  respiratory support  needed at 36 weeks:

10. Age of gestation is the most significant risk factor for BPD, with disease severity increasing as gestational age decreases. Risk is inversely related to both Bw and GA at birth. Mostly ELGA and BW < 1000 g. Seventy-seven percent of infants born at <1000 g and 32 weeks postmenstrual age (PMA) develop BPD. Other risk factors include extreme low birth weight (<1,000 grams), male gender, intrauterine growth restriction and prolonged ventilator-induced injury. Genetic factors may also play a role, while perinatal infections and maternal smoking increase the likelihood of developing BPD. Basic Epidemiology/Risk Factors

11. Anatomy/physiology In extremely preterm babies, the alveoli have yet to form. Because of a complex interplay of factors including surfactant deficiency, mechanical ventilation, and increased oxygen levels, a pro-inflammatory cascade is triggered. This impairs further lung development. As a consequence, the alveoli are underdeveloped and the capillary network dysmorphic, making gas exchange more difficult.

12. Anatomy/physiology

13. B asic pathophysiology?

14. Presenting symptoms

15. Prevention Antenatal steroids NIV Early surfactant Adequate Tx of intrauterine and postnatal infections MV strategy and FiO2 Fluid restriction? PDA Tx Nutritional support Vit A Corticosteroids? Caffeine – red BPD risk by 50% iNO .

16. TREATMENT Supplemental O2 - mainstay Diuretics – reduce lung edema Bronchodilators airway sm msl hypertrophy – B-agonists, anticholinergics, methylxantines , minophylline and caffeine. Steroids inhaled vs systemic Antiviral Immunization palivizumab or RSV-IVIG prophylaxis PHTN iNO , sildenafil

17. Prevention and treatment Antenatal corticosteroids do not prevent BPD, but prevent short-term mortality and morbidity secondary to respiratory distress syndrome. Peripartum antibiotics do not decrease BPD rates, but avoiding fetal compromise in cases of prolonged premature rupture of membranes or chorioamnionitis, is pivotal in preventing further lung inflammation. There are several studies that look at Neonatal Life Support (NLS) strategies to prevent BPD. Avoiding intubation is the best strategy to date reducing ventilation-associated damage to the lungs. However, if intubation is indicated, maintaining an adequate PEEP of 4-8 cm H2O and avoiding volume-induced trauma by limiting tidal volumes to 4-7 ml/kg is key. Whether volume-targeted ventilation strategies are better than pressure-targeted ones is still under debate. A 2016 Cochrane review suggested that high-frequency oscillation ventilation (HFOV) may be better at preventing moderate/severe BPD than Synchronized Intermittent Mandatory Ventilation (SIMV). However, BPD rates among extreme premature neonates remain high in most studies, no matter the ventilation strategy. It is important to note that permissive hypoxia does not prevent BPD. There is no agreement on what ventilation strategy to follow once BPD is established. Management

18. Early surfactant therapy decreases the incidence of BPD by preventing intubation. Surfactant may be delivered through Less-Invasive Surfactant Administration (LISA) using a McGill forceps, or by Minimally Invasive Surfactant Therapy (MIST) using a firm catheter. Whether all extreme premature neonates, irrespective of their need for ventilatory support, should receive early surfactant therapy is still under debate. Studies looking at regular caffeine are promising as it appears to reduce ventilation time. Given that Vitamin A is required for lung development and is low in premature neonates intramuscular vitamin A may reduce BPD rates Giving neonates corticosteroids, such as dexamethasone or hydrocortisone, to prevent BPD is controversial. In clinical practice, corticosteroids are often used to wean ventilatory support, but it is not yet clear whether this leads to long-term improvement in respiratory development. Hydrocortisone is preferable because of the neurological sequelae of dexamethasone. An interesting trial by Watterberg , published in the New England Journal of Medicine earlier this year, showed no benefit of hydrocortisone over placebo when considering the primary outcome of survival without moderate or severe BPD at 36 weeks. There were also no differences in neurodevelopmental impairment at two years (corrected). There are clinical studies underway to combine late surfactant administration in combination with corticosteroids. Management

19. Bronchopulmonary dysplasia has long-term effects on respiratory, nutritional, and neurological development. Neonates with BPD may develop pulmonary vascular disease with features of pulmonary hypertension that may persist after 36 weeks of gestational age and well into later childhood. A small subset of BPD patients may need a tracheostomy to support prolonged mechanical ventilation. Children with BPD may also experience respiratory problems later on in childhood. They are at higher risk of developing severe respiratory viral infections (around 50% require hospitalisation in early childhood) and asthma, and may have lower exercise tolerance than other children their age. Children with moderate or severe disease should be seen in specialised follow-up clinics, with lung function testing to ensure treatment is commenced promptly. There is a higher risk of developing early-onset COPD if they start smoking later in life. Some infants are discharged home with supplemental oxygen and may require tube feeding for a prolonged period of time. After weaning off oxygen, nutritional problems may persist due to poor feeding coordination and swallowing dysfunction. Oral aversion problems are commonly seen and speech therapy may be needed. Children with BPD are at higher risk of adverse neurodevelopmental outcomes. It is unclear whether this is due to a direct effect of the pulmonary disease or whether BPD and poor neurodevelopmental outcomes are shared sequelae of specific risks, such as mechanical ventilation in prematurity and very low birth weight. Children may require concurrent management with a specialised physiotherapist and paediatric neurologist. Complications

20. Prognosis

21. Our understanding of BPD has evolved since it was first described 50 years ago. While advances in  neonatal care  have resulted in improved survival rates of premature infants, this in turn has led to an increase in long-term BPD survivors in the community. A multidisciplinary approach is essential in supporting the complex pulmonary, nutritional, and developmental requirements of these children. It is important that future studies investigate factors influencing long-term morbidity and disease burden. Summary

22. https://dontforgetthebubbles.com/bronchopulmonary-dysplasia-bpd/ Jacqueline J. Coalson. Pathology of Bronchopulmonary Dysplasia. Seminars in Perinatology, Volume 30, Issue 4, 2006, Pages 179-184. ISSN 0146-0005. https://doi.org/10.1053/j.semperi.2006.05.004 . ( https://www.sciencedirect.com/science/article/pii/S0146000506000693 ) Eduardo Bancalari , Nelson Claure. Definitions and Diagnostic Criteria for Bronchopulmonary Dysplasia. Seminars in Perinatology, Volume 30, Issue 4, 2006, Pages 164-170, ISSN 0146-0005, https://doi.org/10.1053/j.semperi.2006.05.002 . ( https://www.sciencedirect.com/science/article/pii/S014600050600067X ) Patricia R. Chess, Carl T. D’Angio , Gloria S. Pryhuber , William M. Maniscalco. Pathogenesis of Bronchopulmonary Dysplasia. Seminars in Perinatology, Volume 30, Issue 4, 2006, Pages 171-178, ISSN 0146-0005. https://doi.org/10.1053/j.semperi.2006.05.003 . (https://www.sciencedirect.com/science/article/pii/S0146000506000681) References

23. ? Thank you.

24. Bronchopulmonary dysplasia (BPD) was originally described by Northway and collaborators in a group of preterm infants who developed chronic respiratory failure and characteristic radiographic pulmonary changes after prolonged mechanical ventilation.1 The lung damage in these infants was attributed primarily to the use of aggressive mechanical ventilation and high inspired oxygen concentrations. These infants had severe respiratory symptoms and characteristic radiographic changes and therefore did not offer much diagnostic difficulty. With the introduction of widespread use of antenatal corticosteroids, the use of postnatal surfactant, and less aggressive mechanical ventilation, this classic presentation of BPD has become relatively uncommon. At the same time, there has been a striking increase in survival rate for the extremely premature infants in whom the underlying lung immaturity plays a predominant role in the pathogenesis and the clinical presentation of BPD. This new presentation has created some inconsistencies and confusion in the definition and in the diagnostic criteria of BPD.2

25. Today, the severe forms of BPD described by Northway have been replaced by a milder form that presents in the smaller infants who frequently have only mild or no initial respiratory distress.3, 4, 5 Therefore, these infants are not exposed to very high airway pressures or oxygen concentrations, the two main factors thought to play a key role in the pathogenesis of the original form of BPD. This milder form of the disease has been described as “new BPD.” Classic Versus New BPD The severe form of BPD was mostly seen in infants who received aggressive ventilation, had a prolonged exposure to high inspired oxygen concentrations, and had characteristic changes in their chest radiographs, and hence, these factors were included in the diagnostic criteria for the original BPD. These infants had severe respiratory failure from the time of birth followed by severe lung injury due to the aggressive respiratory support, and they remained on ventilation and supplemental oxygen for long periods of time. Although this presentation is less common today, there are still some infants who have this course and end up with severe respiratory failure, pulmonary hypertension, and marked alterations in their chest radiographs. These patients offer little diagnostic controversy since they are ventilator- and oxygen-dependent for long periods of time and almost any of the proposed diagnostic criteria will apply to them.

26. The difficulty with the diagnosis occurs with the milder forms of BPD when the infants have only mild initial respiratory failure and spend shorter lengths of time on respiratory support. In these infants, the radiographic presentation can also be quite different from the classic pattern described by Northway and coworkers.1 The radiographs frequently show only haziness, reflecting diffuse loss of volume or increased lung fluid. Occasionally they also have dense areas of segmental or lobar atelectasis or pneumonic infiltrates, but they do not show the areas of severe overinflation characteristic of the classic BPD. These different clinical and radiographic manifestations reflect the different pathogenic process that underlines the new presentation of BPD.

27. The classic BPD was characterized by severe morphologic changes that included emphysema, atelectasis and fibrosis, and marked epithelial squamous metaplasia and smooth muscle hypertrophy in the airways and in the pulmonary vasculature. These changes were associated with severe respiratory failure with airway obstruction, pulmonary hypertension, and cor pulmonale. The milder form of BPD seen more frequently today is characterized mainly by increased lung fluid, a diffuse inflammatory response, and a striking decrease in alveolar septation and impaired vascular development.6, 7, 8, 9, 10, 11 These changes are more compatible with an arrest in lung development than with mechanical injury. It is not clear to what extent this arrest in lung development is secondary to the exposure of the premature lung to gas breathing versus the effects of volutrauma and oxygen toxicity. Additional factors including incomplete development, inflammatory processes due to ante or postnatal infections,12, 13, 14, 15, 16, 17 and the exposure of the immature pulmonary vasculature to increased flow through a persistent ductus arteriosus18, 19 are also implicated in the pathogenesis of BPD. Hormonal and nutritional factors are also likely to play an important role.20, 21, 22, 23

28. Definition of BPD There is a striking lack of uniformity in the diagnostic criteria for BPD among clinicians and in the literature. This explains, in part, the wide variation in the reported incidence of BPD among different centers. A major problem with the definition of BPD is that it is based primarily on the need for supplemental oxygen used as a marker of the pulmonary damage. Supplemental oxygen is an important part in the management of these infants, and in addition, it is implicated in the pathogenesis of BPD. The indications for supplemental oxygen vary from center to center because there is no clear evidence on what is the optimal arterial oxygen level for these infants. Moreover, the need for supplemental oxygen can be influenced by drugs such as steroids, diuretics, and respiratory stimulants, and by the use of other forms of respiratory support such as intermittent or continuous positive airway pressure.

29. The proposed criteria to define BPD suggested in a National Institutes of Health (NIH) sponsored workshop in 1979 included a continued oxygen dependency during the first 28 days plus compatible clinical and radiographic changes.24 Although these criteria were appropriate for the classic presentation of BPD, they are not always appropriate for the “new BPD.”

30. To address this issue, many authors and clinicians have simplified this criterion and diagnose BPD in infants who are oxygen-dependent “at” day 28. Although this simplified approach may work in most infants, it is possible that some infants who do not have significant lung disease may require supplemental oxygen only around day 28 because of acute conditions. This will result in the erroneous labeling of those infants as BPD, when in reality they do not have chronic lung damage. It is also possible that an infant may be on room air on day 28 and subsequently develop chronic lung damage and prolonged oxygen dependency. To avoid these problems, it is essential not to use oxygen dependency at a single time point to label infants as BPD or free of BPD. It is also important to include other indicators, such as persistent radiographic changes and a minimal duration of oxygen therapy, to reflect chronic pulmonary damage.

31. Supplemental Oxygen at 28 days Versus 36 w PMA In an attempt to circumvent some of the problems described before, and to focus on the more severely afflicted infants, it has been proposed to use the need for supplemental oxygen at 36 w PMA as a better criterion for BPD.25 Since this is a stricter criterion than the 28-day oxygen supplementation, it identifies a group of infants with more severe lung disease and therefore may better predict poor long-term outcome. The introduction of this criterion was also based on the assumption that smaller infants require longer periods of supplemental oxygen because of their immaturity and therefore selecting a given post conceptional age would adjust for the gestation-dependent oxygen need. However, this assumption may not be entirely correct. Although it is true that smaller infants commonly require longer periods of time on supplemental oxygen, this relationship is highly variable and, as mentioned before, many extremely premature infants evolve without requiring supplemental oxygen for significant periods of time during the first weeks. The criteria of oxygen dependency at 36 w PMA requires for an infant born at 24 weeks of gestation to be on oxygen for 12 weeks, whereas an infant born at 32 weeks of gestation would be labeled as BPD if he or she requires oxygen for only 4 weeks after birth.

32. The NIH organized a workshop in 2000 to address the inconsistencies in the diagnostic criteria of BPD and to come up with a better definition.26 As a result of this workshop, there was a proposal for a uniform criteria to diagnose BPD. The recommendation was to use oxygen need for ≥28 days and at 36 w PMA to identify different severity of BPD and also to include oxygen concentration at 36 w PMA to further define the severity of lung injury. It was also agreed that a minimum of 28 days of supplemental oxygen was necessary to make the diagnosis of BPD (Table 1). These recommendations are very important and solve many of the problems with previous criteria. It still has the limitations of using 36 w PMA that were discussed earlier.