What is the definition, incidence, risk factors, pathophysiology, clinical features, diagnosis, prevention, treatment, and prognosis of Respiratory Distress Syndrome (RDS) in newborns?

Respiratory Distress Syndrome (RDS) in Newborns

Definition

Respiratory distress syndrome is a respiratory disorder of preterm newborns caused by surfactant deficiency, leading to alveolar collapse, impaired gas exchange, and characteristic clinical and radiographic findings. 1 RDS most commonly occurs in infants with birth weights less than 1,500 g, and especially in those with birth weights less than 1,000 g. 1

Incidence

• RDS predominantly affects premature infants, with the highest incidence in those born at less than 30 weeks gestation and weighing less than 1,000 g. 1
• The condition can occur in full-term neonates but with different clinical characteristics and typically secondary to other triggering insults such as severe perinatal infections, birth asphyxia, or meconium aspiration. 2
• The incidence inversely correlates with gestational age—the more premature the infant, the higher the risk of developing RDS. 1

Risk Factors

Major Risk Factors:

• Prematurity (gestational age <37 weeks) is the single most important risk factor, particularly birth weight <1,500 g. 1
• Male sex (94 of 125 full-term cases were male in one series). 2
• Elective cesarean section without labor, which prevents the normal physiological squeeze that helps clear fetal lung fluid. 2
• Maternal diabetes, which delays fetal lung maturation. 2

Additional Risk Factors:

• Perinatal asphyxia and severe birth asphyxia. 2
• Multiple gestation pregnancies. 1
• Absence of antenatal corticosteroid administration. 3
• Patent ductus arteriosus (PDA), particularly in extremely low birth weight infants. 1
• Perinatal infections including cytomegalovirus and Ureaplasma urealyticum (relative risk 1.91 in infants <1,250 g). 1
• Antenatal chorioamnionitis leading to fetal inflammatory response. 1

Pathophysiology

The fundamental defect in RDS is surfactant deficiency in immature lungs, leading to increased surface tension, alveolar collapse, and progressive atelectasis. 4

Cascade of Events:

• Surfactant deficiency causes increased alveolar surface tension, preventing alveoli from remaining open during expiration. 4
• Progressive atelectasis leads to ventilation-perfusion mismatch and impaired gas exchange. 4
• Hyaline membranes form in small airways, blocking ventilation and contributing to inflammation. 4
• High alveolar capillary permeability allows serum proteins to leak into airways, further inhibiting surfactant function. 1

Inflammatory Response:

• An early inflammatory response begins on day 1 of life, with proinflammatory cytokines (IL-1, IL-6, soluble ICAM) peaking toward the end of the second week. 1
• IL-1 antigen concentration and activity increase 16- and 61-fold during the first week. 1
• Cysteinyl leukotrienes are 10- to 20-fold higher in infants who develop chronic lung disease. 1
• Activated neutrophils mediate biochemical alterations in surfactant protein A and cause detrimental biophysical changes. 1

Contributing Factors:

• Mechanical ventilation, barotrauma, and oxygen toxicity compound the initial injury and contribute to chronic lung disease development. 1
• The "new" BPD represents a disorder of intrauterine inflammation and premature extrauterine lung development characterized by alveolar simplification. 1

Clinical Features

Timing and Presentation:

• Symptoms typically appear within the first few hours of life, with mean onset time of 3.11 ± 3.59 hours after birth in full-term infants. 2
• Cardinal signs include tachypnea (respiratory rate >60 breaths/minute), grunting, intercostal and subcostal retractions, nasal flaring, and cyanosis. 5

Specific Clinical Findings:

• Grunting represents an attempt to maintain positive end-expiratory pressure by partially closing the glottis during expiration. 5
• Progressive worsening of respiratory distress over the first 48-72 hours if untreated. 4
• Oxygen desaturation despite supplemental oxygen. 5
• In full-term neonates, RDS presents with more severe complications including persistent pulmonary hypertension of the newborn (PPHN) in 20% of cases. 2

Associated Complications:

• Multiple organ system failure (MOSF) occurs in 39% of full-term infants with RDS. 2
• Acute renal failure (14%), severe hyperkalemia (20%), and severe myocardial injury (7%). 2
• Pneumothorax and air leak syndromes. 3
• Patent ductus arteriosus, particularly in extremely low birth weight infants. 1

Diagnosis

Clinical Diagnosis:

• Diagnosis is based on the combination of clinical presentation (tachypnea, retractions, grunting, cyanosis), gestational age/birth weight, and characteristic imaging findings. 5

Radiographic Findings:

• Chest X-ray shows diffuse bilateral alveolar opacification with a ground-glass appearance, air bronchograms, and low lung volumes. 2, 6
• Traditional CXR grading includes four stages based on progression and severity of changes. 7

Lung Ultrasound (Emerging Modality):

• Lung ultrasound is gaining recognition with higher sensitivity and specificity than chest X-ray, reducing misdiagnosis rates. 7
• Ultrasound grading methods for RDS are the latest advancement in diagnostic accuracy. 7
• Management under lung ultrasound monitoring has achieved treatment success rates up to 100% by reducing unnecessary mechanical ventilation and surfactant use. 7

Laboratory Evaluation:

• Arterial blood gas showing hypoxemia and hypercapnia with respiratory acidosis. 5
• Blood cultures, serial complete blood counts, and C-reactive protein for sepsis evaluation. 5
• Pulse oximetry for continuous oxygen saturation monitoring. 5

Differential Diagnosis Considerations:

• Transient tachypnea of the newborn, meconium aspiration syndrome, pneumonia, sepsis, pneumothorax, persistent pulmonary hypertension, congenital heart defects, and airway malformations must be excluded. 5

Prevention

Antenatal Interventions:

• Antenatal corticosteroids are the most effective preventive intervention, working synergistically with postnatal surfactant to reduce mortality, severity of RDS, and air leaks. 3
• Administration of antenatal steroids to mothers at risk of preterm delivery significantly reduces RDS incidence and severity. 3

Delivery Room Management:

• Early initiation of CPAP at or soon after birth is recommended as first-line prevention for preterm infants at risk of RDS. 3
• CPAP helps maintain functional residual capacity and prevents alveolar collapse. 3
• Avoiding elective cesarean section before 39 weeks gestation reduces RDS risk in near-term infants. 2

Avoiding Iatrogenic Factors:

• Minimizing barotrauma and oxygen toxicity during mechanical ventilation. 1
• Judicious fluid management, though the relationship between fluid balance and chronic lung disease remains controversial. 1

Treatment

Primary Treatment Strategy:

• Surfactant replacement therapy is the cornerstone of RDS treatment, significantly reducing mortality and respiratory morbidity in preterm infants with surfactant deficiency. 3
• Animal-derived surfactants are superior to first-generation synthetic surfactants, showing lower mortality rates (RR 0.86; 95% CI 0.76–0.98) and fewer pneumothoraces (RR 0.63; 95% CI 0.53–0.75). 3

Timing of Surfactant Administration:

• Early rescue surfactant (within 1-2 hours of birth) is superior to delayed treatment (≥2 hours), significantly decreasing mortality (RR 0.84; 95% CI 0.74-0.95), air leak (RR 0.61; 95% CI 0.48-0.78), and chronic lung disease (RR 0.69; 95% CI 0.55-0.86). 3
• Surfactant should be administered selectively to infants who show worsening respiratory distress despite CPAP support. 3
• Preterm infants born at <30 weeks' gestation who need mechanical ventilation because of severe RDS should receive surfactant after initial stabilization. 3

INSURE Technique:

• The INSURE strategy (Intubation, Surfactant administration, and Extubation to CPAP) significantly reduces the need for mechanical ventilation (RR 0.67; 95% CI 0.57-0.79) and oxygen requirement at 28 days. 3, 5
• This approach allows surfactant delivery while minimizing ventilator-induced lung injury. 3

Respiratory Support:

• Continuous Positive Airway Pressure (CPAP) is recommended as initial respiratory support in preterm infants with RDS, with surfactant administered if respiratory distress worsens. 3
• Early CPAP with selective surfactant administration results in lower rates of bronchopulmonary dysplasia and death compared to prophylactic surfactant therapy (mortality RR 0.53,95% CI 0.34 to 0.83). 3
• Routine intubation with prophylactic surfactant is no longer recommended as the first-line approach due to increased risk of complications. 3

Mechanical Ventilation:

• For infants requiring mechanical ventilation, expeditious changes in ventilator settings may be necessary after surfactant administration to minimize lung injury and air leak. 3
• Gentle ventilation strategies should be employed to prevent barotrauma. 4
• In full-term infants with severe respiratory distress, a trial of positive end-expiratory pressure ≥6 cm H₂O should be considered, which can produce prompt increases in PaO₂ (median increase 84 mm Hg, range 22-196 mm Hg). 6

Surfactant Administration Details:

• Surfactant is traditionally administered through an endotracheal tube either as a bolus, in smaller aliquots, or by infusion. 3
• The optimal method of administration remains unclear, as clinical trials show no significant differences in outcomes between bolus and infusion techniques. 3
• Redosing should not be needed more frequently than every 12 hours unless surfactant is being inactivated by infection, meconium, or blood. 3

Monitoring During Treatment:

• Surfactant administration may cause transient airway obstruction, oxygen desaturation, bradycardia, and alterations in cerebral blood flow, requiring careful monitoring and adjustment of ventilator settings. 3
• Continuous pulse oximetry and blood gas monitoring are essential. 5

Adjunctive Therapies:

• Bronchodilators (terbutaline, metaproterenol, salbutamol, ipratropium bromide) can improve lung mechanics with 20-30% decreases in airway resistance. 1
• Bronchodilator responsiveness has been demonstrated in infants as young as 3 days of age and with gestational ages as low as 26 weeks. 1
• Diuretics and bronchodilators may have synergistic effects in improving lung mechanics. 1

Treatment for Secondary Surfactant Deficiency:

• Surfactant therapy may benefit late-preterm and term neonates with secondary surfactant deficiency from conditions such as meconium aspiration syndrome, pneumonia/sepsis, and pulmonary hemorrhage. 3

Special Considerations:

• Surfactant therapy is not recommended for infants with congenital diaphragmatic hernia, as it has not shown improved outcomes. 3
• Hyperventilation and tolazoline trials typically fail to improve oxygenation in full-term infants with RDS. 6

Prognosis

Short-term Outcomes:

• With modern treatment including early CPAP and selective surfactant therapy, survival rates have improved dramatically, with mortality rates of 3.2% reported in full-term infants receiving comprehensive treatment. 2
• The main cause of death is severe infection complicating multiple organ system failure. 2
• Most patients require prolonged mechanical ventilation and supplemental oxygen. 2, 6

Long-term Pulmonary Outcomes:

• Airway obstruction and airway hyperreactivity persist into childhood in survivors, with average FEV₁ about 80% of control subjects at 6-15 years of age. 1
• The pattern is obstructive, with low FEV₁/VC ratio and high residual volume to total lung capacity ratio averaging about 130% of control subjects. 1
• 40-50% of children demonstrate airway hyperreactivity to histamine, methacholine, or exercise. 1
• There may be gradual improvement of these abnormalities over time. 1
• Airway obstruction and airway hyperreactivity can persist into early adult life. 1

Chronic Lung Disease Development:

• RDS is the primary precursor to bronchopulmonary dysplasia (BPD), a chronic condition that usually evolves after premature birth and respiratory distress syndrome due to surfactant deficiency. 1
• Chronic lung disease of infancy (CLDI) most commonly occurs in infants with birth weights less than 1,500 g who are treated for RDS. 1
• The "new" BPD represents a disorder of intrauterine inflammation and premature extrauterine lung development characterized by alveolar simplification, rather than the classic postnatal inflammation and fibrosis. 1

Factors Affecting Prognosis:

• CLDI predisposes to abnormal lung function in childhood independently from premature birth alone. 1
• Infants born prematurely without RDS who do not develop CLDI also have increased prevalence of airway hyperreactivity compared with full-term control subjects, but less severe than those with CLDI. 1
• Comprehensive management strategies including early mechanical ventilation and broad-spectrum antibiotics improve prognosis in full-term infants with RDS. 2

Exercise Capacity:

• Maximal workloads and V̇O₂max are normal or slightly reduced in children with history of RDS. 1
• Limited ventilatory reserve is suggested by low V̇emax and high ratio of V̇emax to maximal voluntary ventilation. 1
• Oxyhemoglobin desaturation during exercise has been reported, possibly related to reduced gas transfer secondary to reduced alveolar surface area. 1

Multisystem Implications:

• CLDI is truly a multisystem disorder with far-reaching consequences that extend into childhood and beyond, affecting not only the respiratory system but multiple organ systems. 1