Neonatal Respiratory Distress Syndrome

Respiratory distress syndrome (RDS), also known as hyaline membrane disease, is caused by the lack of adequate pulmonary surfactant production in an immature lung. The syndrome is most commonly seen in preterm infants. The incidence is inversely related to gestational age, with the highest risk in neonates born at less than 28 weeks. Prenatal assessment of lung maturity and steroid administration can improve outcome if an early delivery cannot be prevented. Diagnosis is clinical. Affected newborns show signs of respiratory distress at birth, or soon thereafter, with nasal flaring, grunting respirations, and retractions. Treatment includes antenatal steroids, exogenous surfactant, and respiratory support. Neonatal RDS is associated with high morbidity and mortality in preterm infants.

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Overview

Definition

Neonatal respiratory distress syndrome (RDS) is a condition caused by a lack of pulmonary surfactant, most commonly seen in preterm infants born at < 28 weeks of gestation.

Epidemiology

  • Risk of RDS:
    • Inversely related to gestational age at delivery
    • Highest incidence in babies born < 28 weeks of gestation
  • Higher incidence in white male infants
  • Significant cause of mortality and morbidity in premature infants

Etiology

  • Prematurity:
    • Lack of mature type II alveolar cells → insufficient surfactant production
    • Different lipid and protein composition of surfactant in an immature lung → less active surfactant
  • Surfactant inactivation due to:
    • Meconium or blood in alveoli (more common in term infants)
    • Oxidative and mechanical stress such as from mechanical ventilation
  • Maternal diabetes: 
    • Maternal hyperglycemia → fetal hyperinsulinemia
    • ↑ Insulin antagonizes the action of cortisol, delaying lung surfactant production
  • C-section without labor: 
    • In the absence of labor, cortisol production (as well as other hormonal factors) is decreased.
    • Altered fluid clearance from the fetal lung compared with vaginal delivery
  • Conditions that cause fetal acidosis (may ↓ surfactant synthesis and/or activity):
    • Perinatal asphyxia (hypoxic injury to type II alveolar cells)
    • Sepsis
    • Intrapartum hypovolemia
    • Intrapartum hypotension

Pathophysiology

Normal fetal lung development

  • Stages of fetal lung development:
    • Embryonic stage (4th–7th week): The fetal lung develops from the fetal foregut and early branching begins.
    • Pseudoglandular stage (5th–16th week): branching from main bronchi to terminal bronchioles
    • Canalicular stage (16th–25th week):
      • Formation of respiratory bronchioles and alveoli
      • Differentiation to type II alveolar cells begins.
      • Surfactant production by 20 weeks, as indicated by + lamellar bodies in the type II alveolar cell cytoplasm
    • Saccular stage (24th week to term): expansion of alveoli and maturation of surfactant composition:
      • Surfactant appears in amniotic fluid between 28 and 32 weeks.
      • Mature surfactant ratios are usually present after 35 weeks.
  • Fetal lungs:
    •  Not functional for gas exchange, and are filled with fluid
    • The placenta serves as the fetus’s respiratory organ.
  • Mechanics of requiring surfactant:
    • With lung development, the alveoli are lined by fluid/liquid → surface tension produced by liquid particles
    • On expiration of air, surface particles contract due to surface tension, and this leads to alveolar collapse.
    • By LaPlace’s law (pressure = surface tension/radius):
      • With ↑ surface tension, higher pressure is needed
      • Additionally, ↑ pressure is required to keep small alveoli (small radius) from collapsing
  • Surfactant:
    • Reduces surface tension within the alveoli
    • In effect:
      • Prevents alveolar collapse at the end of the expiration
      • ↓ Risk of atelectasis and ventilatory-perfusion (V/Q) mismatch in the alveoli
    • Produced in fetal development to prepare for air-breathing at birth

Surfactant

  • Major constituents of surfactant:
    • Phospholipids (85%):
      • Dipalmitoylphosphatidyl choline (DPPC), also referred to as “lecithin” (main component)
      • Phosphatidylglycerol (↑ in pregnancy by 35 weeks and can be used as a marker of lung maturity)
      • Phosphatidylcholine, unsaturated
    • Apoproteins (10%): 
      • SP-A
      • SP-B
      • SP-C
      • SP-D
    • Cholesterol (neutral lipid)
  • Surfactant synthesis: 
    • Phospholipid synthesized in the endoplasmic reticulum → alterations done through the Golgi apparatus → stored in lamellar bodies of type II alveolar cells
    • In the lamellar bodies, phospholipid and surfactant proteins form surfactant lipoprotein complexes.
    • These complexes are secreted into the alveoli, and the surface film created opposes alveolar collapse.
  • Surfactant recycling: 
    • Surfactant moves within the alveoli (leading to ↓ surface tension)
    • Goes back to type II alveolar cells by endocytosis → to multivesicular bodies → lamellar bodies

Respiration at birth and RDS

  • Normal transition:
    • During fetal life:
      • ↑ Pulmonary vascular resistance (PVR) from fluid distention
      • Lower systemic vascular resistance (SVR)
    • With first breaths:
      • ↑ SVR and ↓ PVR with onset of ventilation
      • Clearance of airway fluid and closure of right-to-left shunts
  • In surfactant deficiency (premature lungs), there is ↑ surface tension, requiring ↑ pressure for alveolar expansion, resulting in:
    • Lung instability at end-expiration
    • Low lung volume and ↓ compliance 
    • Collapse of portions of the lungs (atelectasis) → V/Q mismatch
  • This mismatch leads to hypoxia, hypercapnia, and acidosis:
    • May result in pulmonary arterial vasoconstriction with increased right-to-left shunting through the foramen ovale and ductus arteriosus
    • ↓ Pulmonary blood flow → ischemia and injury of alveoli and triggering of inflammatory response 
    • Inflammation → effusion/edema in alveolar spaces → ↑ pulmonary vascular resistance or PVR (which, in normal cases, should be low)
  • Low urine output in premature infants contribute to fluid retention.

Clinical Presentation

Signs and symptoms

  • RDS:
    • Starts within minutes or hours after birth
    • Becomes progressively worse over the first 48–72 hours of life
  • The affected infants are typically premature and show signs of respiratory distress:
    • Tachypnea
    • Nasal flaring
    • Expiratory grunting, which results from expiration against a partially closed glottis
    • Cyanosis (from right-to-left shunting)
  • By auscultation:
    • Breath sounds may be normal or diminished, with a harsh tubular quality.
    • Bilateral fine basal crackles

Course of RDS

  • Uncomplicated RDS typically progresses for 48–72 hours and can be followed by:
    • ↑ Endogenous production of surfactant
    • Resolution of the respiratory distress by 1 week of age
    • Infant may have diuresis in this process.
  • Severe RDS or those inadequately treated may develop:
    • Hypotension
    • Cyanosis
    • Grunting decrease or disappear
    • Mixed respiratory-metabolic acidosis
    • Apnea and irregular respirations, which indicate fatigability
  • Complications of neonatal RDS:
    • Respiratory failure
    • Alveolar air leaks (interstitial emphysema, pneumothorax)
    • Pulmonary hemorrhage
    • Intraventricular hemorrhage
  • Treatment with exogenous surfactant improves the course of the disease and leads to a faster resolution of symptoms.

Diagnosis

  • Diagnosis is mainly clinical:
    • Prematurity
    • Clinical exam
  • Chest X-ray:
    • Diffuse reticulogranular pattern (ground-glass appearance)
    • Air bronchograms: 
      • Outline of air-filled large airways against opaque lungs
      • Often more prominent at first in the left lower lobe because of superimposition of the cardiac shadow
  • Arterial blood gas (ABG):
    • Hypoxemia that improves with oxygen supplementation
    • Hypercapnia as disease progresses
    • Metabolic acidosis or mixed respiratory-metabolic acidosis
Chest X-ray respiratory distress syndrome infant

Chest radiograph 1 day after birth of a boy who, after 29 weeks and 3 days of gestational age, developed respiratory distress:
The radiograph shows signs of respiratory distress syndrome (RDS) in the form of generalized fine granular opacities that create air bronchograms. The thorax is bell-shaped due to decreased lung volume.

Image: “X-ray of infant respiratory distress syndrome (IRDS)” by Mikael Häggström. License: CC0 1.0

Management

Prevention of neonatal RDS

  • As RDS is a disease of prematurity, the most effective preventive method is to avoid preterm delivery, when possible.
  • Determine fetal lung maturity (via amniotic fluid) for threatened preterm birth:
    • Phosphatidylglycerol levels
    • Lecithin/sphingomyelin levels:
      • Level > 2 (by 35 weeks) indicates low risk for RDS.
      • Time consuming
    • Lamellar body counts:
      • Measures surfactant production
      • ≥ 50,000 consistent with maturity
  • If an early delivery cannot be avoided, treatment includes: 
    • Antenatal corticosteroid therapy:
      • Enhances surfactant synthesis and release
      • Accelerates lung maturity
      • Indicated for preterm delivery
    • Exogenous surfactant replacement therapy:
      • Beneficial to preterm infants born < 30 weeks gestation
      • Provides support until endogenous production begins
      • Administration within 30–60 minutes of life provides the most benefit.
      • Administered via endotracheal or less-invasive route (i.e., aerosolized)

Respiratory management

  • Resuscitation and evaluation in the delivery room focuses on airway, breathing, and circulation (ABCs).
  • Respiratory support especially for babies under 28 weeks gestational age
  • The goal is for effective ventilation and oxygenation in the least invasive manner possible:
    • Keep PaO2 at 50–80 mm Hg:
      • To maintain tissue oxygenation
      • To avoid the risk of oxygen toxicity
    • Should maintain pH at > 7.25
  • Interventions:
    • Nasal continuous positive airway pressure (nCPAP):
      • Considered an alternative to endotracheal intubation or mechanical ventilation, if possible
      • CPAP (pressure of 5 cm H2O, and increase to 6–8 cm H2O as indicated)
    • Endotracheal intubation and assisted mechanical ventilation for respiratory failure:
      • PaO2 < 50 mm Hg despite 100% oxygen or FiO₂ requirement on CPAP ≥ 0.40
      • PCO2 > 60 mm Hg
      • pH < 7.20
    • High-frequency oscillatory ventilation (HFOV) may be considered in severe cases or to reduce ventilator-associated lung injury.
Newborn premature infant on CPAP

Respiratory distress syndrome: newborn premature infant (on continuous positive airway pressure)

Image: “Premature infant CPAP” by Brian Hall. License: Public Domain

Additional treatment

  • Thermal regulation:
    • Needed to avoid neonatal hypothermia
    • Place the infant in an isolette or radiant warmer with the core temperature maintained between 36.5°C (97.7°F) and 37°C (98.6°F).
  • Fluids and nutrition:
    • Balance fluids as the neonatal kidneys have limited concentrating abilities:
      • Daily weights
      • Close attention to input and output
      • Regular electrolyte monitoring
      • Avoid fluid overload (↑ the risk of patent ductus arteriosus/PDA)
    • Nutritional support: total parenteral nutrition
  • Cardiovascular support:
    • Closely monitor blood pressure and avoid hypotension.
    • Options for low blood pressure:
      • Normal saline (with caution), vasopressors when indicated
      • Stress doses of hydrocortisone (in persistent hypotension)

Differential Diagnosis

  • Meconium aspiration syndrome (MAS): mild-to-severe respiratory distress more often in term or post-term infants who are delivered with meconium-stained fluid. Aspiration of thick meconium can lead to hypoxia and acidosis with partial airway obstruction causing pneumothorax or pneumomediastinum. Chest X-rays may be normal or may show parenchymal opacification, patchy infiltrates, and/or flattening of the diaphragm. Management is ideally antenatal with prevention of delivery past 41 weeks and intrapartum fetal heart monitoring. After delivery, support is based on neonatal resuscitation guidelines.
  • Choanal atresia: most common nasal malformation. This deformity can be isolated or part of a dysmorphic syndrome with bony abnormalities of the pterygoid plate. Choanal atresia can be suspected in infants with cyclic cyanosis, which is aggravated by feeding and relieved by crying when the mouth is open. Unilateral choanal atresia (⅔ of cases) may not be diagnosed initially. Inability to pass a catheter through the nose 3–4 cm into the oropharynx is suggestive of the diagnosis. Diagnosis is confirmed by a CT scan with intranasal contrast that shows narrowing at the level of the pterygoid plate. Management consists of placing an oral airway and gavage feeding until repair of the obstruction with surgery or endoscopy.
  • Transient tachypnea of the newborn (TTN): delayed clearance of lung fluid more common in late preterm infants and term infants born via C-section without labor as well as babies born with respiratory depression. This disorder often follows an uneventful normal term vaginal delivery or Cesarean delivery with early onset of tachypnea, sometimes with retractions or expiratory grunting. A chest X-ray would show prominent pulmonary vascular markings, fluid lines in the fissures, over-aeration, flattened diaphragms, and pleural fluid. This disorder usually resolves in 2–3 days, and treatment is supportive.
  • Congenital diaphragmatic hernia (CDH): a congenital defect in the fetal diaphragm that allows herniation of abdominal contents into the thorax, leading to pulmonary hypoplasia on the affected side. The types are posterolateral Bochdalek hernia (left-sided Bochdalek in 85% of cases), anterior Morgagni hernia, paraesophageal hernia, and hiatal hernia. Mild cases can be repaired in the first days of life with good long-term prognosis. More-severe cases require high levels of support; involve long-term respiratory, neurodevelopmental, and growth issues; and can be lethal.
  • Persistent pulmonary hypertension (PPHN): the pulmonary vascular pressure remains high after birth instead of transitioning to a lower-pressure system. This condition leads to right-to-left shunting across the foramen ovale and patent ductus arteriosus, causing severe hypoxemia. This condition is more common in term and late-preterm (≥ 34 weeks) infants. Patients often exhibit distress at delivery or within 24 hours, with tachypnea, grunting, cyanosis, and nasal flaring. Definitive diagnosis is with echocardiogram (showing pulmonary hypertension). Management is supportive and includes oxygen administration, ventilatory support, and circulatory support.

References

  1. Ballast, A. (2019). Respiratory distress syndrome in neonates (Hyaline membrane disease). Merck Manuals. Retrieved March 22, 2021, from https://www.merckmanuals.com/professional/pediatrics/respiratory-problems-in-neonates/respiratory-distress-syndrome-in-neonates
  2. Garcia-Prats, J. (2021). Meconium aspiration syndrome: Prevention and management. UpToDate. Retrieved April 4, 2021, from https://www.uptodate.com/contents/meconium-aspiration-syndrome-prevention-and-management
  3. Gillen-Goldstein, J, MacKenzie, A, Funai, E. (2019). Assessment of fetal lung maturity. UpToDate. Retrieved April 11, 2021, from https://www.uptodate.com/contents/assessment-of-fetal-lung-maturity
  4. Isaacson, G. (2021). Congenital anomalies of the nose. UpToDate. Retrieved April 4, 2021, from https://www.uptodate.com/contents/congenital-anomalies-of-the-nose
  5. Martin, R. (2020). Pathophysiology, clinical manifestations, and diagnosis of respiratory distress syndrome in the newborn. UpToDate. Retrieved March 22, 2021, from https://www.uptodate.com/contents/pathophysiology-clinical-manifestations-and-diagnosis-of-respiratory-distress-syndrome-in-the-newborn
  6. Martin, R, Deakins, K. (2021). Respiratory support, oxygen delivery, and oxygen monitoring in the newborn. UpToDate. Retrieved April 12, 2021, from https://www.uptodate.com/contents/respiratory-support-oxygen-delivery-and-oxygen-monitoring-in-the-newborn
  7. Ramachandrappa, A. (2021). Elective Cesarean section: Its impact on neonatal respiratory outcome. Retrieved March 26, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2453515/
  8. Stark, A, Eichenwald, E. (2021). Persistent pulmonary hypertension of the newborn. UpToDate. Retrieved April 4, 2021, from https://www.uptodate.com/contents/persistent-pulmonary-hypertension-of-the-newborn
  9. Yadav, S, Lee, B. (2020). Neonatal respiratory distress syndrome. Retrieved March 26, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK560779

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