Neonatal respiratory distress syndrome

Summary

Neonatal respiratory distress syndrome (NRDS), or surfactant deficiency disorder, is a lung disorder in infants that is caused by a deficiency of pulmonary surfactant. It is most common in preterm infants, with the incidence and severity decreasing with gestational age. Surfactant deficiency causes the alveoli to collapse, resulting in impaired blood gas exchange. Symptoms manifest shortly after birth and include tachypnea, tachycardia, increased breathing effort, and/or cyanosis. Suspected diagnosis is based on clinical features and confirmed by evaluating the extent of atelectasis via an x-ray of the chest. Blood gases show respiratory and metabolic acidosis in addition to hypoxia. Treatment primarily involves emergency resuscitative measures, including nasal continuous positive airway pressure (CPAP) and the stabilization of blood sugar levels and electrolytes. Intratracheal surfactant should be administered if infants require an increased FiO₂ to maintain a sufficient oxygen saturation despite receiving noninvasive positive pressure ventilation. Intratracheal surfactant should be administered if ventilation alone is unsuccessful. Most cases resolve within 3–5 days of treatment. However, complications such as hypoxemia, tension pneumothorax, bronchopulmonary dysplasia, or sepsis may still occur. In rare cases, NRDS may lead to neonatal death. NRDS can be prevented by administering antenatal glucocorticoids to the mother if premature delivery is expected.

Etiology

Neonatal respiratory distress syndrome is caused by impaired synthesis and secretion of surfactant. Risk factors include:

Premature birth
Maternal diabetes mellitus: leads to ↑ fetal insulin, which inhibits surfactant synthesis
Hereditary [1]
Cesarean delivery: results in lower levels of fetal glucocorticoids than vaginal delivery, in which higher levels are released as a response to stress from uterine contractions
Hydrops fetalis
Multifetal pregnancies
Male sex

Epidemiology

Incidence
[2]
- 1% of all newborns
- 10% of all preterm babies
The risk of developing NRDS depends on
gestational age.
[2]
- < 28 weeks of gestation: > 50%
- > 37 weeks of gestation: < 5%

Epidemiological data refers to the US, unless otherwise specified.

Pathophysiology

Surfactant [3]

Pulmonary surfactant is a mixture of phospholipids and proteins produced by lamellar bodies of type II alveolar cells. These phospholipids reduce alveolar surface tension, preventing the alveoli from collapsing.
Surfactant deficiency is most likely to occur in
preterm infants, because:

Surfactant production begins at approximately 20 weeks gestation.

Distribution throughout the lungs begins at 28-32 weeks' gestation and does not reach sufficient concentration until 35 weeks gestation.

Surfactant deficiency

Little or no reduction of alveolar surface tension → increased alveolar collapse → atelectasis → decreased lung compliance and functional residual capacity → hypoxemia and hypercapnia
Hypoxemia and hypercapnia → vasoconstriction of the pulmonary vessels (hypoxic vasoconstriction) and respiratory acidosis → intrapulmonary right-to-left shunt → increased permeability due to alveolar epithelial damage → fibrinous exudation within the alveoli → development of hyaline membranes in the lungs (hyaline membrane disease)

Alveolar collapse in surfactant deficiency Hyaline membranes in ARDS

Clinical features

Maternal history of premature birth
Onset of symptoms: usually immediately after birth but can occur up to 72 hours postpartum
Signs of increased respiratory effort
- Tachypnea
- Nasal flaring and moderate to severe subcostal/intercostal and jugular retractions
Characteristic expiratory grunting
Decreased breath sounds on auscultation
Cyanosis due to pulmonary hypoxic vasoconstriction

Reference:[4]

Diagnosis

Physical examination: see “Clinical features” above
Maternal history: previous preterm birth
X-ray chest

Interstitial pulmonary edema with perihilar streaking

Diffuse, fine, reticulogranular (ground-glass) densities with low lung volumes and air bronchograms

Atelectasis
Blood gas analysis
- Hypoxia with respiratory acidosis; may lead to increased lactate levels
- Evaluate for partial respiratory failure or global respiratory failure
Amniocentesis for prenatal testing of NRDS:
screening for markers of fetal lung immaturity

Lecithin-sphingomyelin ratio < 1.5 (≥ 2 is considered mature)

The amount of sphingomyelin in the amniotic fluid remains relatively consistent during pregnancy.

The amount of lecithin, which is the major component of surfactant, starts increasing after week 26 of gestation.

The lower the lecithin-sphingomyelin ratio, the more likely it is that the lungs are immature.

Foam stability index < 0.48

A semi-quantitative test used to assess fetal lung maturity

Amniotic fluid is mixed with ethanol until foam formation ceases to occur

The index refers to the highest quantity of ethanol that can be added to amniotic fluid still permitting the formation of foam.

Low surfactant-albumin ratio
Histological findings
[5]
- Hyaline membranes lining the alveoli
  
  Composed of fibrin, cellular debris, and red blood cells
  
  Eosinophilic appearance, amorphous material lining the alveolar surface
- Engorged and congested capillary vessels in the interstitium

Respiratory distress syndrome (1/3) Neonatal respiratory distress syndrome Hyaline membranes in ARDS

References:[2][6][7]

**Neonatal respiratory distress syndrome**
X-ray chest (frontal view) of a premature infant
The lungs are opacified and have a granular appearance. Air bronchograms (green overlay) extend to the lung periphery. An endotracheal tube (red outlines) is well-positioned above the carina.
In neonatal respiratory distress syndrome (RDS), surfactant deficiency results in alveolar collapse and noncompliant lungs. Air bronchograms are visible when aerated bronchi and bronchioles are surrounded by acinar atelectasis.

Source: © IMPP

**Respiratory distress syndrome (2/3)**
X-ray chest (AP view)
A right tension pneumothorax has developed. It is accompanied by depression of part of the right hemidiaphragm (indicated by red line and arrow) and leftward shift of the mediastinum (indicated by blue line and arrow). The right lung (green overlay) is partially collapsed. A chest tube has been placed in the lower hemithorax, and endotracheal and nasogastric tubes are present. There is a left central line.

© AMBOSS

**Respiratory distress syndrome (3/3)**
X-ray chest (AP view)
The right tension pneumothorax surrounding the lung has increased in size despite chest tube placement, and lung collapse (green overlay) has worsened. There is increased leftward shift of the mediastinum (indicated by blue line and arrow) and depression of part of the right hemidiaphragm (indicated by red line and arrow). An endotracheal tube, nasogastric tube, and right central line are shown.

© AMBOSS

Differential diagnoses

Pulmonary hypoplasia
- Underdevelopment of the lungs characterized by a decreased number of alveoli and small airways and reduced lung volumes in one or both lobes
- Results in impaired gas exchange and severe respiratory distress that may require intubation
- Associated with congenital diaphragmatic hernia (usually left-sided), oligohydramnios, and Potter sequence
Congenital diaphragmatic hernia
Pneumothorax
Neonatal pneumonia

Overview of NRDS and its differential diagnoses
Characteristics	Neonatal respiratory distress syndrome	Apnea of prematurity (AOP)	Transient tachypnea of the newborn (wet lung disease) [8]	Persistent pulmonary hypertension of the newborn (PPHN) [9][10]	Meconium aspiration syndrome [11][12][13]
Term	Preterm		Most commonly full-term and near-term infants	Most commonly term and preterm infants; can also occur in postterm infants	Most commonly postterm
Etiology	Deficiency of pulmonary surfactant	Immature respiratory control	Delayed resorption and clearance of fetal lung fluid	Elevated pulmonary vascular resistance → right-to-left shunting through the foramen ovale and patent ductus arteriosus (bypassing the lungs) → pre- and postductal oxygenation gradient (e.g., preductal O₂ saturation is often higher than postductal). Associated with abnormal prenatal development of or perinatal maladaptation of pulmonary vasculature	Intrauterine passage of meconium and aspiration leading to airway obstruction
Risk factors	Preterm delivery Male sex Maternal diabetes	Preterm delivery Extremely low birth weight	Cesarean delivery, especially before the onset of labor Delivery before 39 weeks' gestation Maternal asthma Maternal diabetes Small-for-gestational-age infant Male sex [14] Macrosomia	Perinatal asphyxia Prolonged premature rupture of the membranes Infection Neonatal pneumonia Meconium aspiration syndrome	Postterm delivery Nonreassuring fetal heart rate tracing Perinatal asphyxia Placental insufficiency Oligohydramnios Cesarean delivery Maternal hypertension and diabetes Maternal infection/chorioamnionitis
Onset of symptoms	Within the first minutes/hours after birth	Within 2–3 days after birth	Immediately after birth and within the next 2 hours	Within 24 hours after birth	Immediately after birth
Clinical features	Tachypnea Increased breathing effort Cyanosis Hypoxia Decreased breathing sounds	Episodes of breathing pauses (usually > 20 seconds) that are frequently accompanied by hypoxemia and/or bradycardia	Tachypnea Increased breathing effort Diffuse crackles, diminished, or normal breathing sounds on auscultation	Low APGAR scores Cyanosis and signs of respiratory distress Heart examination: prominent precordial impulse and a narrowly split and accentuated S₂	Green amniotic fluid Low APGAR score Tachypnea Increased breathing effort Hypoxia Lung rales and rhonchi
Imaging	Diffuse, fine, reticulogranular (ground-glass) densities Low lung volumes and air bronchograms	Usually not necessary, since AOP is a clinical diagnosis of exclusion. Imaging may be used to rule out other causes of apnea (e.g., sepsis, intracranial hemorrhage).	Fluid in the lung fissures and increased lung volumes	Pulmonary hypertension on echocardiography	Increased lung volumes Asymmetric, patchy opacities Pleural effusion
Treatment	Supportive care Nasal CPAP Endotracheal administration of artificial surfactant	Supportive care (e.g., supplemental oxygen, neutral thermal environment, maintaining a physiological neck position, avoidance of excessive nasal suctioning) Nasal CPAP Methylxanthine therapy (e.g., caffeine, theophylline)	Supportive care (e.g., supplemental oxygen, neutral thermal environment, adequate nutrition)	Supportive care Continuous pulse oximetry screening [15] Severe cases: inhaled nitric oxide Last resort: ECMO	Supportive care (e.g., supplemental oxygen administration ) Continuous pulse oximetry Severe cases: standard steps of neonatal resuscitation, inhaled nitric oxide, administration of surfactant
Complications	Bronchopulmonary dysplasia Pneumothorax PDA	Resolves without complications in the majority of cases at approx. 43 to 44 weeks of postmenstrual age	Resolves without complications in the majority of cases	Severe PPHN Developmental delay Motor deficit Hearing deficit	Persistent pulmonary hypertension of the newborn (PPHN) Pneumothorax Pneumomediastinum

The differential diagnoses listed here are not exhaustive.

Treatment

Ventilation
[8]
- Nasal CPAP with a PEEP of 3–8 cm H₂O
- If respiratory insufficiency persists, start intubation with mechanical ventilation and O₂inhalation.
Endotracheal administration of artificial surfactant within 2 hours postpartum
Supportive measures: IV fluid replacement; stabilization of blood sugar levels and electrolytes

Physiologic O₂saturation in neonates is around 90%. A saturation of 100% is considered toxic for neonates!

Complications

Bronchopulmonary dysplasia (BPD) [16]

Definition: chronic lung condition secondary to prolonged mechanical ventilation and oxygen therapy for NRDS
Etiology: Pulmonary barotrauma and oxygen toxicity with subsequent inflammation of lung tissue due to ventilation of the immature lung (ventilation for more than 28 days)
Clinical features
- Seen in infants < 32 weeks
- Persistence of symptoms similar to NRDS (e.g., tachypnea, grunting, nasal flaring)
- Episodes of desaturation
Diagnostics
- X-ray chest: diffuse, fine, granular densities, areas of atelectasis interspersed with areas of hyperinflation
- Blood gas analysis: respiratory and metabolic acidosis
- Histology: atelectasis, fibrosis, emphysematous alveolar changes (decreased number and septation of alveoli)
Treatment: controlled oxygenation, diuretics, rarely glucocorticoids

Bronchopulmonary dysplasia

Further complications

Pneumothorax
Patent ductus arteriosus (the persistently low partial pressure of oxygen in the blood contributes to PDA)
Hypoxia
Cardiovascular arrest
Neonatal sepsis
Complications of O₂inhalation: retinopathy of prematurity, bronchopulmonary dysplasia, intraventricular hemorrhage

Baby oxen have RIBs: Babys receiving too much oxygen get Retinopathy of prematurity, Intraventricular hemorrhage, and Bronchopulmonary dysplasia.

We list the most important complications. The selection is not exhaustive.

**Bronchopulmonary dysplasia**
X-ray chest (AP view) of an intubated newborn with bronchopulmonary dysplasia
Ill-defined reticular markings (examples indicated by red arrowheads) and small rounded lucent areas (examples indicated by green arrowheads) are diffusely present throughout both lungs.
An endotracheal tube (green overlay), nasogastric tube (red overlay), and central venous catheter (yellow overlay) are properly positioned. Rotation of the patient to the left has resulted in an appearance of elongation of the left ribs compared to the right ribs and leftward positioning of the cardiomediastinal silhouette.

Source: “CXR - Bronchopulmonary dysplasia” by Pulmonological, Wikimedia Commons, licensed under CC BY-SA 3.0. The supplementary image with overlays of relevant areas was adapted from the image mentioned above and licensed under CC BY-SA 3.0.

Prognosis

Mortality rate: < 10% [17]
Most cases resolve within 3–5 days if treated promptly

Prevention

Prevent premature birth if possible. See tocolysis.
Antenatal corticosteroid therapy administered to the mother (stimulates infant lung maturation) [18]

Given 48 hours before delivery

2 doses of IM betamethasone 24 hours apart or 4 doses of IM dexamethasone 12 hours apart

References

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"Respiratory Distress Syndrome in Neonates (Hyaline Membrane Disease)". http://www.msdmanuals.com/professional/pediatrics/perinatal-problems/respiratory-distress-syndrome-in-neonates#v1089988. [2015-01-01]
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