# Prematurity and Respiratory Distress Syndrome

## Overview

Respiratory distress syndrome (RDS) is the most common cause of respiratory failure in preterm infants, resulting from surfactant deficiency and structural lung immaturity. Its incidence is inversely proportional to gestational age, affecting approximately 80% of infants born at 26-28 weeks and about 50% of those born at 30-32 weeks. RDS remains a significant contributor to neonatal morbidity and mortality worldwide, though outcomes have dramatically improved with advances in surfactant therapy, non-invasive ventilation, and antenatal corticosteroids.

## Pathophysiology of Surfactant Deficiency

Surfactant is produced by type II alveolar pneumocytes and is composed primarily of phosphatidylcholine (dipalmitoylphosphatidylcholine, or DPPC) and surfactant proteins (SP-A, SP-B, SP-C, SP-D). Its primary function is to reduce alveolar surface tension, preventing alveolar collapse at end-expiration. When surfactant is insufficient, the consequences cascade: alveoli collapse (atelectasis), ventilation-perfusion mismatch develops, lung compliance decreases, the work of breathing increases dramatically, and progressive hypoxemia with hypercarbia ensues. Compounding this problem, the preterm lung is structurally immature with fewer and larger alveoli and thicker gas-exchange barriers. Epithelial injury from mechanical ventilation and protein leak into the alveolar space further inactivate what little surfactant is present, creating a vicious cycle of inflammation and progressive respiratory failure.

## Antenatal Corticosteroid Therapy

Antenatal corticosteroids are the single most important intervention to prevent and reduce the severity of RDS. The standard regimen is either betamethasone (12 mg intramuscularly for 2 doses, 24 hours apart) or dexamethasone (6 mg intramuscularly for 4 doses, 12 hours apart). These are indicated for pregnancies at risk of preterm delivery between 24 0/7 and 33 6/7 weeks gestation. Benefits can be demonstrated as early as a few hours after the first dose, with maximum benefit occurring 48 hours to 7 days after course completion. Antenatal steroids reduce the incidence of RDS, intraventricular hemorrhage, necrotizing enterocolitis, and neonatal death. A rescue course may be considered if more than 14 days have elapsed since the initial course and the pregnancy remains at less than 34 weeks. For late preterm pregnancies (34-36 6/7 weeks), a single course reduces respiratory morbidity but increases the risk of neonatal hypoglycemia.

## Clinical Presentation

RDS typically presents within the first 6 hours of life, often within minutes of birth. Clinical signs include tachypnea (greater than 60 breaths per minute), nasal flaring, expiratory grunting (which represents the infant's attempt to maintain positive end-expiratory pressure), intercostal, subcostal, and suprasternal retractions, and cyanosis in room air. Without treatment, the disease progressively worsens over 48-72 hours. The characteristic chest radiograph shows bilateral diffuse reticulogranular ("ground glass") opacities with air bronchograms and low lung volumes.

## Surfactant Replacement Therapy

### Types

| Surfactant Preparation | Source | Initial Dose | Notes |
|----------------------|--------|-------------|-------|
| Poractant alfa (Curosurf) | Porcine | 200 mg/kg (superior to 100 mg/kg) | Higher phospholipid concentration |
| Beractant (Survanta) | Bovine | 100 mg/kg | Widely used |
| Calfactant (Infasurf) | Bovine | 105 mg/kg | Contains SP-B |

Natural (animal-derived) surfactant preparations include poractant alfa (Curosurf), beractant (Survanta), and calfactant (Infasurf). Poractant alfa has a higher phospholipid concentration, and an initial dose of 200 mg/kg has been shown superior to 100 mg/kg in clinical trials.

### Administration Techniques

The INSURE technique (INtubate, SURfactant, Extubate to CPAP) has been widely used and reduces the duration of mechanical ventilation compared to sustained intubation. More recently, Less Invasive Surfactant Administration (LISA) has emerged as a potentially superior approach. LISA involves inserting a thin catheter into the trachea during spontaneous breathing on CPAP, avoiding intubation and mechanical ventilation entirely. Growing evidence supports LISA as superior to INSURE in reducing bronchopulmonary dysplasia and death, though it requires a skilled operator and adequate spontaneous respiratory drive in the infant.

### Indications

Early rescue surfactant is indicated when FiO2 exceeds 0.30-0.40 on CPAP for preterm infants with clinical and radiographic evidence of RDS. Prophylactic surfactant is no longer routinely recommended when early CPAP is available. Repeat dosing may be given every 6-12 hours if ongoing high FiO2 requirements persist, up to a maximum of 3 total doses.

## Respiratory Support Modalities

### Non-Invasive

Continuous Positive Airway Pressure (CPAP) is the first-line respiratory support for preterm infants with RDS, typically started at 5-8 cm H2O. The COIN trial and SUPPORT trial demonstrated that early CPAP is as effective as routine intubation for many preterm infants. Nasal Intermittent Positive Pressure Ventilation (NIPPV) may be superior to CPAP for preventing extubation failure and can be delivered in synchronized or non-synchronized modes. High-flow nasal cannula (HFNC) serves as an alternative to CPAP post-extubation in larger preterm infants (greater than 28 weeks), offering easier application and less nasal trauma, though it may be inferior to CPAP for initial RDS treatment.

### Invasive Mechanical Ventilation

Mechanical ventilation is indicated when non-invasive support fails, manifested by persistent apnea, FiO2 greater than 0.40, or significant respiratory acidosis. Volume-targeted ventilation is preferred over pressure-limited modes because it reduces bronchopulmonary dysplasia and death. Target tidal volumes are 4-6 mL/kg. Permissive hypercapnia (accepting PaCO2 of 45-55 mmHg) minimizes volutrauma and barotrauma. Hyperoxia must be avoided, with target SpO2 of 90-95% in preterm infants. High-frequency oscillatory ventilation (HFOV) serves as a rescue modality when conventional ventilation fails.

## Complications

The major complications of RDS and its management include air leak syndromes (pneumothorax and pulmonary interstitial emphysema), bronchopulmonary dysplasia (chronic lung disease of prematurity), retinopathy of prematurity (related to oxygen exposure), intraventricular hemorrhage, and patent ductus arteriosus.

## Monitoring and Supportive Care

Continuous SpO2 monitoring with alarm limits set at 90-95% guides oxygen therapy. Arterial or capillary blood gases direct ventilator management decisions. Caffeine citrate (loading dose 20 mg/kg, maintenance 5-10 mg/kg/day) is a cornerstone of care: the CAP trial demonstrated that it reduces apnea, facilitates extubation, and reduces bronchopulmonary dysplasia. Fluid management aims to avoid overhydration, which contributes to both PDA and BPD. Nutritional support includes early trophic feeds with human milk and parenteral nutrition to meet caloric requirements during the acute phase.

<image>A side-by-side comparison of normal alveoli with adequate surfactant lining versus surfactant-deficient alveoli in RDS, showing collapsed atelectatic alveoli with hyaline membrane formation, protein-rich fluid exudation, and thickened gas exchange barrier. Medical histology illustration style with labeled structures.</image>

<image>A chest radiograph illustration showing the classic findings of RDS in a preterm neonate: bilateral diffuse reticulogranular (ground glass) opacities, air bronchograms, and low lung volumes, with anatomical labels and comparison to a normal neonatal chest X-ray on the adjacent panel.</image>

<image>A step-by-step procedural illustration of the LISA (Less Invasive Surfactant Administration) technique, showing a preterm infant on CPAP with a thin flexible catheter being placed through the vocal cords under direct laryngoscopy while the infant breathes spontaneously, with surfactant being slowly instilled. Labeled medical illustration.</image>

## Clinical Pearls

Antenatal steroids are the single most important intervention to prevent and reduce severity of RDS, and no preterm delivery should occur without attempting to administer them when time permits. Early CPAP is as effective as prophylactic surfactant for many preterm infants and avoids the risks associated with intubation. Caffeine should be started early in all preterm infants at risk for apnea and BPD, as its benefits extend well beyond simple apnea treatment. The LISA technique is emerging as the preferred method for surfactant delivery when expertise is available, combining the benefits of surfactant therapy with the advantages of avoiding mechanical ventilation. Both hyperoxia (SpO2 greater than 95%) and hypoxia (SpO2 less than 90%) must be avoided in preterm infants, as each carries distinct risks. RDS typically worsens over 48-72 hours before improvement as endogenous surfactant recycling begins; this natural course should be anticipated. Poractant alfa at 200 mg/kg has been shown superior to lower-dose alternatives as initial therapy.

## References
- Sweet DG, et al. European consensus guidelines on the management of RDS - 2022 update. *Neonatology*. 2023;120(1):3-23.
- SUPPORT Study Group. Early CPAP vs. surfactant in extremely preterm infants. *N Engl J Med*. 2010;362(21):1970-1979.
- Schmidt B, et al. Caffeine for Apnea of Prematurity (CAP) Trial. *N Engl J Med*. 2006;354(20):2112-2121.
- Aldana-Aguirre JC, et al. Less invasive surfactant administration versus intubation for surfactant delivery in preterm infants with RDS: a systematic review and meta-analysis. *Arch Dis Child Fetal Neonatal Ed*. 2017;102(1):F17-F23.
- AAP Committee on Fetus and Newborn. Respiratory support in preterm infants at birth. *Pediatrics*. 2014;133(1):171-174.