Definition And Classification

• Bronchopulmonary dysplasia (BPD) or chronic lung disease of prematurity describes deviations in lung development of extreme preterm babies.
• It results in the newborn requiring respiratory support for long durations.
• The most important basis for maldevelopment is that the extremely immature lung must support gas exchange before it is functionally ready.
• The Physiologic definition of BPD relies on an oxygen challenge test performed at 36 weeks postmenstrual age (PMA).
• Persistent oxygen saturation less than 90% in room air is the cut-off below which supplemental oxygen should be considered.

Revised NICHD Definition (2018)

• BPD affects preterm infants born at less than 32 weeks of gestational age with persistent parenchymal lung disease.
• It requires radiographic confirmation of parenchymal lung disease.
• At 36 weeks PMA, the infant requires specific respiratory support for three or more consecutive days to maintain arterial oxygen saturation in the 90% to 95% range.

Jensen's Classification Of BPD

• The severity of BPD at 36 weeks PMA is classified based on the mode of respiratory support administered.

Note: Table adapted from Jensen's criteria. PPV: Positive pressure ventilation; nCPAP: Nasal continuous positive airway pressure; NIPPV: Noninvasive positive pressure ventilation.

Incidence And Epidemiology

• BPD mostly affects extreme preterm babies born at less than 28 weeks of gestation or weighing less than 1,000 grams at birth.
• The global incidence of BPD is reported to be between 10% and 89% in extremely preterm infants.
• The incidence is inversely proportional to gestational age.
• Improved survival of extremely immature infants has led to an increased absolute number of infants with BPD.

Etiology And Risk Factors

• BPD has a multi-factorial etiology.
• Extreme prematurity and low birth weight are the strongest risk factors.
• The lung is highly susceptible to injury before alveolar septation begins.

Antenatal Factors

• Intrauterine growth restriction (IUGR) and placental dysfunction contribute to the risk.
• Intrauterine or perinatal infections, such as chorioamnionitis, may modify the disease course.
• Specific organisms like Ureaplasma urealyticum and Chlamydia trachomatis are associated with BPD.
• Maternal smoking increases the risk in preterm babies.
• Genetic predisposition and polymorphisms play a role.

Postnatal Factors

• Invasive ventilation causes ventilator-induced lung injury (VILI), including volutrauma and barotrauma.
• Oxytrauma results from hyperoxia and oxidant stress.
• Preterm lungs have an insufficient production of antioxidant enzymes (superoxide dismutase, catalase) and a deficiency of free radical scavengers.
• Inadvertent fluid overload in the first postnatal week increases the risk.
• A hemodynamically significant patent ductus arteriosus (PDA) contributes to pulmonary edema.
• Alterations of the lung microbiome (lung dysbiosis) and nosocomial infections increase the risk.
• Inadequate nutrition and lack of human milk feeding are major contributors.

Pathogenesis: Old Versus New BPD

Old BPD

• Historically described by Northway in 1967 in infants with a mean gestational age of 33 weeks and birth weight of 2,000 grams.
• It resulted from severe, aggressive mechanical ventilation.
• Pathology is characterized by extreme morphological changes.
• Features include prominent small airway injury, necrotizing bronchiolitis, interstitial fibrosis, and emphysema.
• Alternating areas of collapse and hyperinflation are typical.

New BPD

• Occurs in the post-surfactant era, mostly affecting extreme preterm infants.
• Arises from incomplete lung development coupled with postnatal insults.
• The hallmark finding is decreased alveolarization.
• Lungs exhibit fewer and larger alveoli, leading to diminished surface area for gas exchange.
• Early disruption of lung vascular growth occurs due to impaired angiogenesis.
• Emphysematous changes and simplified terminal airspaces are characteristic.
• Inflammation alters molecular pathways required for lung development.

Clinical And Radiological Features

Clinical Presentations

• Infants often have fast, shallow breathing, retractions, and paradoxical breathing.
• Auscultation may reveal rales, coarse rhonchi, or wheezing.
• The neonate may experience transient or recurrent spells of oxygen desaturation despite respiratory support.
• A murmur from a PDA or tricuspid regurgitation (due to pulmonary hypertension) may be present.

Radiographic And Imaging Findings

• Chest X-ray of new BPD shows diffuse haziness reflecting a loss of lung volume or increased lung fluid.
• Old BPD radiographs showed distinct stages progressing to hyperinflated lungs with cystic areas and dense fibrotic strands.
• Lung ultrasound reveals a thickened, coarse pleural line with subpleural consolidations and B-lines.
• High lung ultrasound scores at 1 to 2 weeks of life can predict BPD with good accuracy.

Pulmonary Function Testing

• Infant pulmonary function testing shows mild-to-moderate airflow obstruction.
• Hallmarks include increased respiratory system resistance and decreased dynamic compliance.
• Air trapping, increased functional residual capacity, and increased residual volume are noted.

Preventive Strategies

Antenatal And Delivery Room Interventions

• Strategies to prevent very preterm birth fundamentally reduce the incidence of BPD.
• Antenatal corticosteroids improve survival and reduce respiratory distress syndrome.
• Delivery room continuous positive airway pressure (CPAP) establishes functional residual capacity and reduces BPD risk.
• Gentle ventilation with a T-piece resuscitator helps decrease lung injury if positive pressure ventilation is unavoidable.
• Avoid hyperoxia in the delivery room by using an oxygen blender.

Respiratory Support Strategies

• Non-invasive positive pressure ventilation (NIPPV) and CPAP are preferred over invasive ventilation.
• If mechanical ventilation is needed, volume-targeted ventilation reduces the composite outcome of BPD or death.
• Target oxygen saturation should be strictly maintained between 91% and 95% until 36 weeks PMA.
• Permissive hypoxemia (targets 85-89%) increases mortality and is not recommended.
• Avoid hypocarbia, but permissive hypercapnia has not been conclusively proven to decrease BPD rates.
• High-frequency oscillatory ventilation (HFOV) may be used, and earlier initiation might be more beneficial than later rescue.

Surfactant Administration

• Early selective surfactant therapy in extremely preterm infants is an evidence-based strategy to reduce BPD risk.
• Administration of surfactant via a thin catheter (LISA or MIST technique) reduces the need for intubation and lowers BPD incidence.
• Poractant-alfa (200 mg/kg) is associated with better respiratory outcomes compared to bovine surfactants.

Pharmacological Prevention

Nutritional And Fluid Strategies

• Human milk feeding is a biologically plausible strategy to prevent BPD.
• It improves the microbiome and provides essential growth factors.
• Early aggressive parenteral nutrition with an early transition to enteral feeding is recommended.
• Careful fluid management to prevent inadvertent fluid overload in the first week of life is protective.

Management Of Established And Evolving BPD

Respiratory Management

• The goal is to provide adequate gas exchange while minimizing further lung injury.
• Non-invasive respiratory support (CPAP or heated humidified high-flow nasal cannula) is preferred.
• Allow a compensated respiratory acidosis and target PaCO2 levels up to 60-70 mm Hg, provided pH is greater than 7.25.
• For severe BPD requiring invasive ventilation, larger tidal volumes (8 to 12 mL/kg) are beneficial due to increased dead space.
• Slower respiratory rates with longer inspiratory times (e.g., 0.5 seconds) allow adequate time for filling and emptying slow compartments.
• Higher positive end-expiratory pressure (PEEP) of at least 6 to 8 cm H2O is often required to overcome airway resistance.

Nutritional Management

• Metabolic rate and energy expenditure are significantly elevated.
• Infants require 15% to 25% extra calories, totaling up to 140 to 150 kcal/kg/day.
• Breast milk must be fortified with a human milk fortifier to optimize protein and calorie intake.
• Fat supplementation (medium-chain triglyceride oil) is preferable to adding carbohydrates, as it produces less carbon dioxide.

Pharmacological Treatment Of Established BPD

• Diuretics: Routine chronic use of furosemide is not recommended. A short course may treat acute pulmonary edema. Thiazide diuretics may be used for long-term administration, often in combination with spironolactone to minimize calcium loss. Diuretics improve lung compliance and minute ventilation.
• Bronchodilators: Routine use is not recommended. They may be used in older ventilator-dependent infants if acute obstructive episodes or bronchospasm occur. Metered-dose inhalers with a spacer are preferred over nebulization.
• Late Systemic Corticosteroids: Dexamethasone (DART protocol) significantly facilitates earlier extubation in infants remaining ventilator-dependent after the first week of life. The clinical team must discuss potential neurodevelopmental harm with parents before use.
• PDA Management: Medical or surgical closure of a hemodynamically significant PDA may be considered if it causes prolonged ventilator dependence, though routine prophylactic closure does not reduce BPD.

Monitoring

• Pulse oximetry monitoring must continue until the baby no longer requires supplemental oxygen.
• Target oxygen saturations are 91% to 95%; avoid hyperoxemia.
• Serial growth monitoring (weight, length, and head circumference) on preterm growth charts is essential.

Co-Morbidities

Pulmonary Hypertension (PH)

• PH affects 16% to 25% of infants with BPD and significantly increases mortality.
• Chronic hypoxemia leads to hypoxic vasoconstriction and eventual right ventricular hypertrophy.
• An echocardiogram screening must be performed at 36 weeks PMA if supplemental oxygen is still required.
• Management includes strict maintenance of SpO2 between 92% and 95%.
• Sildenafil may be considered for established pulmonary arterial hypertension.

Airway And Respiratory Complications

• Upper airway obstruction is common due to prolonged intubation.
• Lesions include laryngotracheobronchomalacia, subglottic stenosis, and granulomas.
• Flexible bronchoscopy may be needed to evaluate persistent stridor or extubation failures.

Other Systemic Complications

• Metabolic Bone Disease (MBD): Results in poor respiratory mechanics and a flail chest, exacerbating respiratory failure.
• Infection: Increased susceptibility to nosocomial infections and viral respiratory tract illnesses (RSV, cytomegalovirus).
• Nephrocalcinosis: Linked to chronic diuretic and steroid use; most are asymptomatic but require renal ultrasound monitoring.
• Gastroesophageal Reflux (GERD): Contributes to pulmonary decompensation and feeding intolerance.

Discharge Planning And Outpatient Therapy

• Oxygen weaning is guided by periodic assessment; portable home oxygen therapy may be considered if the infant is apnea-free and has minimal respiratory distress.
• Transition from orogastric feeding to oral feeding may be delayed.
• Parents must be trained in basic life support and recognition of emergencies.
• A multidisciplinary follow-up involving a pediatric cardiologist, ophthalmologist, and audiology services is necessary.
• Standard immunizations, along with pneumococcal, influenza, and palivizumab (for RSV prophylaxis), are highly recommended.
• Parents must be strictly counseled to avoid exposing the infant to passive smoke.

Outcomes And Prognosis

• Mortality in severe BPD is estimated at 10% to 20% during the first year of life.
• Tachypnea, wheezing, and reactive airway disease persist for months to years.
• The rehospitalization rate in the first two years is twice that of matched controls.
• BPD is an independent predictor of adverse neurologic outcomes, including motor and cognitive impairments.
• Growth failure is common, with weight being the most affected parameter.
• Although clinical recovery can occur, pulmonary function abnormalities persist into adolescence and adulthood.