6.3 Bronchopulmonary Dysplasia (BPD) & Apnea of Prematurity

Bronchopulmonary Dysplasia (BPD) & Apnea of Prematurity

Bronchopulmonary Dysplasia (BPD)

Bronchopulmonary Dysplasia (BPD), also known as chronic lung disease of infancy, is a major complication of prematurity. It is characterized by impaired lung development and injury.

Diagnostic Criteria

The definition of BPD is based on the requirement for supplemental oxygen.

• Primary Requirement: The infant must require supplemental oxygen for at least 28 days.
• Severity Assessment Window: The severity of BPD is assessed at 36 weeks post-menstrual age (PMA) for infants born at less than 32 weeks, or at 56 days of life / discharge (whichever comes first) for infants born at 32 weeks or later.

The severity of BPD is classified as follows:

• Mild BPD: The infant breathes room air (21% oxygen) at 36 weeks PMA or discharge.
• Moderate BPD: The infant requires less than 30% supplemental oxygen at 36 weeks PMA or discharge.
• Severe BPD: The infant requires 30% or greater supplemental oxygen and/or positive pressure support (mechanical ventilation, CPAP, or high-flow nasal cannula with flow > 2 L/min) at 36 weeks PMA or discharge.

Pathophysiology: "Old" vs. "New" BPD

The clinical and pathological description of BPD has shifted significantly:

• "Old" BPD (Northway BPD): Occurred in relatively mature preterm infants who were exposed to aggressive mechanical ventilation, high peak inspiratory pressures (barotrauma), large tidal volumes (volutrauma), and high oxygen concentrations (oxygen toxicity). Pathologically, it was characterized by severe airway inflammation, squamous metaplasia, smooth muscle hypertrophy, and extensive, heterogeneous alveolar fibrosis.
• "New" BPD: Occurs in the surfactant era among extremely low birth weight (ELBW) infants (born < 28 weeks). It represents an arrest of lung development (alveolarization and vascular growth) in an immature lung. Pathologically, it is characterized by fewer and larger alveoli (loss of surface area for gas exchange) and a simplified, dysplastic pulmonary microvasculature. Fibrosis is minimal or absent.

Clinical Management

1. Gentle Ventilation: Use Volume-Targeted Ventilation (VTV) to control tidal volumes (typically 4 to 6 mL/kg) and minimize volutrauma. Permissive hypercapnia (tolerating PaCO2 of 50 to 65 mmHg and pH down to 7.25) is standard to avoid aggressive mechanical breaths.
2. Fluid and Nutritional Management:
   • Fluid Restriction: Infants with BPD are prone to pulmonary edema due to increased capillary permeability and pulmonary hypertension. Fluids are typically restricted to 120 to 140 mL/kg/day.
   • High-Calorie Nutrition: Because volume is restricted, feeds must be concentrated (from 24 to 30 kcal/oz) to provide a high caloric intake (110 to 130 kcal/kg/day). Adequate nutrition is critical, as somatic growth is essential for the alveolarization of new lung tissue.
3. Pharmacotherapy:
   • Diuretics: Used to reduce pulmonary fluid accumulation and improve lung compliance.
     • Loop Diuretics (Furosemide): Potent but associated with calcium wasting. Long-term use can cause osteopenia of prematurity, fractures, and nephrocalcinosis.
     • Thiazides (Chlorothiazide) and Potassium-Sparing Diuretics (Spironolactone): Used for long-term therapy. These are calcium-sparing and carry a lower risk of metabolic bone disease.
   • Postnatal Corticosteroids: Systemic steroids (dexamethasone) are potent anti-inflammatory agents used to facilitate extubation in ventilator-dependent infants.
     • Risk: Systemic dexamethasone is associated with neurodevelopmental impairment (cerebral palsy), hypertrophic cardiomyopathy, hypertension, and hyperglycemia. The DART trial protocol uses a low-dose, short course of dexamethasone to minimize these risks. Hydrocortisone is sometimes used as a gentler alternative.
   • Bronchodilators: Inhaled beta-2 agonists (albuterol) are used for acute bronchospastic episodes. They should not be used routinely, as they can cause tachyphylaxis and airway instability.
   • Pulmonary Vasodilators: Inhaled nitric oxide or oral sildenafil may be used if the infant develops secondary pulmonary hypertension.

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Apnea of Prematurity (AOP)

Apnea of Prematurity is a developmental disorder characterized by a lack of respiratory control due to neurological and physiological immaturity.

Definition & Classifications

Apnea is defined as the cessation of breathing for more than 20 seconds, OR any duration of respiratory pause if accompanied by bradycardia (heart rate < 100 beats/minute) or oxygen desaturation (< 85% to 90%).

It is classified into three types:

1. Central Apnea: No respiratory effort and no airflow. It is caused by an immature brainstem that fails to send signals to the respiratory muscles.
2. Obstructive Apnea: Respiratory effort is present, but there is no airflow because the upper airway (pharynx) is collapsed or obstructed.
3. Mixed Apnea: Characterized by a central pause followed by airway obstruction. This is the most common type, accounting for over 50% of cases.

Pathophysiology

AOP is primarily caused by an immature central respiratory drive in the medulla oblongata and pons.

• Blunted Carbon Dioxide Response: The respiratory center has a decreased sensitivity to hypercapnia.
• Paradoxical Response to Hypoxia: While term infants hyperventilate in response to hypoxia, preterm infants show a transient hyperventilation followed by respiratory depression and apnea.
• Poor Airway Muscle Tone: Weak pharyngeal and laryngeal muscles allow the airway to collapse during inspiration, particularly with neck flexion or hyperextension.

Pharmacological Management: Caffeine Citrate

Caffeine Citrate is the methylxanthine of choice for treating AOP.

• Dosing:
  • Loading Dose: 20 mg/kg (caffeine citrate) IV or PO.
  • Maintenance Dose: 5 to 10 mg/kg/day IV or PO, typically administered once daily starting 24 hours after the loading dose.
• Mechanism of Action: Caffeine acts as a competitive adenosine receptor antagonist. Adenosine is an inhibitory neuromodulator that depresses the central nervous system and respiration. By blocking adenosine receptors, caffeine:
  1. Stimulates the respiratory center in the medulla, increasing its sensitivity to carbon dioxide (shifting the CO2 response curve to the left).
  2. Increases diaphragmatic contractility and muscle tone.
  3. Enhances minute ventilation and respiratory rate.
  4. Improves upper airway muscle tone to reduce obstructive apnea.
• Therapeutic Monitoring: Caffeine has a very wide therapeutic index (levels between 5 and 25 mcg/mL are therapeutic). Routine serum level monitoring is not necessary unless there are signs of toxicity.
• Signs of Toxicity: Tachycardia (heart rate > 180 to 200 beats/minute), feeding intolerance (residuals, vomiting), jitteriness, tremors, insomnia, excessive diuresis.
• Comparison to Theophylline: Caffeine is preferred over theophylline/aminophylline because caffeine has a longer half-life (allowing once-daily dosing), does not require frequent blood level monitoring, and has a wider safety margin with fewer cardiovascular side effects.

Non-Pharmacological Management

• Continuous Positive Airway Pressure (CPAP): Administered at 5 to 6 cmH2O. CPAP provides splinting pressure to keep the pharyngeal airway open, reducing obstructive and mixed apneas, and maintains FRC.
• Positioning: Prone positioning improves chest wall stability and reduces apnea. Ensure the neck is kept in a neutral, "sniffing" position to prevent airway occlusion.
• Neutral Thermal Environment: Avoiding hypothermia and hyperthermia, which can trigger apnea.

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Clinical Pearls & Exam Traps

• Anatomy of Apnea vs. Reflux: While gastroesophageal reflux (GER) is common in preterm infants, clinical studies have shown no temporal relationship between reflux episodes and apnea. On the exam, do not assume treating reflux will resolve apnea. The primary treatment for AOP remains caffeine and CPAP.
• Caffeine and BPD (The CAP Trial): The Caffeine for Apnea of Prematurity (CAP) trial demonstrated that early caffeine administration not only treats apnea but also significantly reduces the incidence of BPD and improves neurodevelopmental outcomes at 18 months, likely due to facilitating earlier extubation.