Bronchopulmonary Dysplasia

Etiology

Bronchopulmonary dysplasia is a multifactorial pathology that is influenced by a variety of prenatal and postnatal factors affecting the mother and infant. The various prenatal risk factors that influence the development of BPD include[3]:

1. Lack of antenatal steroids
2. Maternal smoking
3. Pregnancy-induced hypertension/preeclampsia
4. Hypoxia
5. Maternal infection, including chorioamnionitis
6. Genetic susceptibility
7. Congenital anomalies causing pulmonary hypoplasia

Similarly, various postnatal factors predispose premature infants to develop BPD including:

1. Lung immaturity
2. Poor nutrition
3. Need for mechanical ventilation
4. Oxygen injury
5. Infection/sepsis

Epidemiology

The incidence of BPD varies significantly between different centers because of variation in perinatal practices, differences in management styles and lack of consistent definition of BPD. The highest observed rate of BPD is in infants born at a lower gestational age (GA) and lower birth weight.[4]  The data from the neonatal research network reports the incidence of BPD in very low birth weight infants (birth weight less than 1500 grams) to be 40 to 68% depending on the definition of BPD used. This incidence was found to be inversely proportional to the GA of the infant[5] The other demographic risk factors associated with BPD include male sex, low birth weight, white race, impaired growth for GA and family history of asthma.[4]

Pathophysiology

Injury from mechanical ventilation and reactive oxygen species to premature lungs in the presence of antenatal factors predisposing the lungs to BPD form the basis of pathogenesis of BPD in preterm neonates. This myriad of events leads to an exaggerated inflammatory response with an increase in proinflammatory cytokines like interleukin(IL)-6, IL 8, tumor necrosis factor alpha etc along with growth factors (transforming growth factor ) and angiogenic factors (vascular endothelial growth factor, angiopoietin 2) which ultimately results in aberrant tissue repair and arrest in lung development. Dysregulated vascular and arrested alveolar development form the basis of the pathology seen in “new BPD.”[6]

Histopathology

Bronchopulmonary dysplasia occurs when lung development arrests in the late canalicular to saccular stages of lung development. The pathology in BPD characteristically demonstrates decreased septation and alveolar hypoplasia resulting in simplified large alveoli and reduced area available for gaseous exchange. There is also dysregulated vasculature with smooth muscle hyperplasia in pulmonary vessels and abnormal alveolar capillaries. Additionally, there is also the presence of increased interstitial fibroproliferation and alveolar septation.[7]

History and Physical

The clinical phenotype of infants with BPD is very variable. Depending on the severity of their disease they may or may not need respiratory support. Some may be tachypneic and depending on the degree of pulmonary edema may have signs of respiratory distress like retractions, rales and increased work of breathing.

Evaluation

Evaluation of BPD involves assessment of blood gas, chest x-ray and evaluating the nutritional status of the patient. An arterial blood gas may reveal hypoxia, hypercarbia or acidosis. These patients remain on continuous pulse oximetry to help target adequate oxygen saturation. Many centers also utilize transcutaneous carbon dioxide monitoring to evaluate the ventilation of the infant.

Chest radiographs may show decreased lung volumes, hyperinflation, areas of atelectasis, pulmonary edema, and pulmonary interstitial emphysema. High-resolution CT may demonstrate abnormalities not readily seen with routine chest radiography. Infants with moderate or severe BPD must be screened for pulmonary hypertension(PH) at 36 PMA using an echocardiogram. Some centers chose to screen all patients with BPD since the morbidity and mortality associated with the diagnosis of PH in BPD are quite high.

The diagnosis of BPD is made clinically based on the GA, postmenstrual age (PMA), oxygen exposure and oxygen requirement at 36 weeks PMA. In 2001, the National Institute of Child Health and Human Development (NICHD) workshop proposed the current definition where infants born at less than or equal to 32 weeks GA with 28 days of oxygen exposure get diagnosed with mild, moderate or severe BPD at 36 weeks PMA based on their respiratory support at that time.[8] Table 1 illustrates the definition used for diagnosing and classifying the severity of the disease.

This definition still has many deficiencies and does not adequately predict respiratory outcomes; hence in 2016, the NICHD workshop on BPD proposed a revision of this definition. The suggested refinement suggests utilizing radiographic confirmation and accounts for the newer modes of non-invasive ventilation.[9] Although this new definition classifies BPD further, it does not address the primary limitation of utilizing the treatment modality as the primary factor defining the disease and its severity.[10]

Treatment / Management

The global aim in the management of infants with BPD is to support them while lung growth occurs, limit further injury to the lungs, optimize lung function and detect complications associated with BPD. The various measures employed in the care of these infants are-

1. Nutrition: Infants with BPD need an increased amount of energy to promote lung growth and repair. Their nutritional need maybe up to 140 to 150 Kcal/Kg/day and protein intake from 3.5 to 4 g/kg/day.[11] Breast milk is preferable to formula. Commercial milk fortifiers can be used to fortify the mother’s milk or donor breast milk to higher calories.[12] Intramuscular supplementation of vitamin A started within a few days of birth and administered three times a week for 4 weeks has been shown to decrease the risk of BPD by 7%.[13]
2. Fluid restriction: Based on the severity of their lung disease, infants are restricted to a total fluid volume of 120 to 150 ml/kg/day. Restriction of fluid intake allows for improved pulmonary function by preventing pulmonary edema and improving gas exchange. Although frequently followed, there is insufficient data to support this practice.[14]
3. Minimize ventilator-associated lung injury: Non-invasive ventilation is the preferred mode of ventilation wherever feasible. If mechanical ventilation is necessary, care should be taken to limit barotrauma and volutrauma. Early extubation has been shown to lower the rates of BPD.[15]
4. Minimize oxygen associated injury: Exposure to hyperoxia is one of the most critical factors in the pathogenesis of BPD. There is significant controversy regarding SpO target ranges. One approach attempts to target SpO of 88-94% with a lower alarm limit of 88% and a higher alarm limit of 96%.[16]
5. Pharmacological interventions:
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• Corticosteroids: Systemic corticosteroids have been used in BPD to improve lung function, reduce inflammation and reduce the need for mechanical ventilation. However, concerns about long term neurodevelopmental outcomes have led to recommendations to restrict their use to infants with severe BPD who remain ventilator dependent with high oxygen needs.[17][18] Despite many clinical trials, it is unclear as to which corticosteroid provides the most benefit and at the optimal dose. Notwithstanding the variable evidence, low dose dexamethasone and hydrocortisone continue to be used in practice in the treatment of BPD.[19] The current data does not demonstrate support for the routine use of inhaled corticosteroids to prevent BPD.[20]
• Diuretics: Thiazides and loop diuretics are the most commonly used diuretics in the setting to improve short term pulmonary mechanics of BPD. These agents are most commonly used in infants who are ventilator dependent with increasing requirement of positive end-expiratory pressure despite fluid restriction. A systemic review of available literature does not show any improvement in long term clinical outcome in infants with established or developing BPD.[21]
• Bronchodilators:- administration of beta-2 agonists can decrease airway resistance and improve compliance. However, their routine use is not recommended in BPD as it has not been shown to improve long term outcomes. Their use should be restricted to manage acute episodes of bronchoconstriction in older infants who remain ventilator dependent.[22]
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Differential Diagnosis

1. Pulmonary atelectasis
2. Pneumonia
3. Pulmonary hypertension
4. Tracheomalacia
5. Pulmonary interstitial emphysema

Prognosis

BPD is a chronic illness that persists beyond discharge from the hospital and into adulthood. Infants with BPD have a 50% chance of readmission to the hospital during their first year of life. They have an increased risk of developing reactive airway disease, asthma, emphysema, and RSV bronchiolitis. BPD also affects their growth and neurodevelopmental outcome. VLBW infants with BPD are more likely to have delays in fine and gross motor skills, and language.[23]

Infants with BPD are at high risk for cardiopulmonary sequelae like pulmonary hypertension (PH), cor pulmonale, and systemic hypertension. A recent meta-analysis reported an accumulative estimated prevalence of PH in BPD to be 20% and can be as high as 40% in severe BPD. A newer, prospective study showed that BPD-associated pulmonary hypertension (BPD-PH) affects at least 8 to 25% of extremely low birth weight (birth weight less than 1000g) infants. Retrospective studies demonstrate a 2-year morbidity rate of 26 to 47% in patients with BPD-PH.[24]

Complications

BPD is one of the most prevalent morbidities associated with prematurity and carries associations with the following complications-

1. Systemic hypertension
2. Poor neurodevelopmental outcome
3. Pulmonary Hypertension
4. Left ventricular hypertrophy and left ventricular dysfunction