Neonatal respiratory distress syndrome

• Neonatal respiratory distress syndrome (RDS) is the disease of immature lungs: type II pneumocytes (the cells that make surfactant) are not ready, so surfactant is deficient and alveoli collapse.
• It is therefore mainly a disease of preterm infants, and its frequency rises steeply as gestation falls (about 5% in late preterm infants, 30% in infants of 28 to less than 32 weeks, and 60% in those below 28 weeks).^{[2] [1]}
• The baby works harder to breathe (tachypnoea, grunting, nasal flaring, chest retractions, cyanosis) and the chest radiograph shows low lung volumes with diffuse hazy "ground-glass" opacities.^[2]
• Management is lung-protective from the delivery room: CPAP, starting at about 6 cmH2O, together with targeted surfactant replacement; mechanical ventilation only when needed, with volume-targeted modes.^[1]
• Antenatal corticosteroids before 34 weeks reduce RDS and other preterm complications, and are the most important prevention.^[1]

By the end of this page you should be able to:

1. Explain why surfactant deficiency leads to alveolar collapse, hypoxaemia and the signs of respiratory distress.
2. Name the risk factors for neonatal RDS and quote how its incidence changes with gestational age and birth weight.
3. Describe the presentation of neonatal RDS and the characteristic chest radiograph findings.
4. Distinguish RDS from transient tachypnoea of the newborn, meconium aspiration and congenital pneumonia using presentation and imaging.
5. State the indications, routes and doses of surfactant, how CPAP is started, and the principles of gentle mechanical ventilation.
6. List the major complications of neonatal RDS and the mechanisms behind them.
7. State how antenatal corticosteroids are used for prevention and the lecithin-to-sphingomyelin (L/S) ratio threshold that indicates fetal lung maturity.

It is a disease of pulmonary immaturity. Type II pneumocytes (the specialised alveolar cells that synthesise and secrete surfactant) are not mature enough to produce adequate surfactant, particularly before about 35 weeks gestation.^[2] Surfactant is a lipoprotein complex: roughly 90% lipid and 10% protein by weight; of the lipid fraction, phosphatidylcholine (mainly its saturated form, dipalmitoylphosphatidylcholine (DPPC, also called lecithin)) accounts for about 70%, with phosphatidylglycerol, phosphatidylinositol, other phospholipids and a small neutral-lipid fraction making up the rest.^[6] It forms the thin lipid film that lowers alveolar surface tension. Without it, alveoli collapse on expiration.

RDS is most common in the preterm infant and is rare in a term infant. It becomes an increasing problem when active care is offered at the margins of viability: surfactant use and mechanical ventilation are almost universal in infants of 24 to 26 weeks gestation in modern networks.^[1]

RDS is the commonest severe respiratory disease of preterm infants. In a recent educational case series of 60,000 babies below 1,500 g admitted to NICUs, about 75% of those of 24 to 26 weeks gestation survived, although bronchopulmonary dysplasia (BPD) remained high at about 60%; nearly 90% of these infants received surfactant and nearly 90% were mechanically ventilated, falling to 65% and 55% at 27 to 29 weeks and to 32% and 25% at 30 to 32 weeks.^[1]

Reported incidence varies by population and definition, because any infant who receives surfactant may be coded as having RDS. In one study quoted by the pathology case, incidence was approximately 5% in late preterm neonates (34 to less than 37 weeks), 30% in early preterm neonates (28 to less than 32 weeks), and 60% in extremely preterm neonates (less than 28 weeks).^[2] Risk rises with decreasing birth weight too: relative risk estimates compared with infants above 2,500 g are 1.4 for 2,000 to 2,500 g, 4.5 for 1,500 to 2,000 g, 8.8 for very low birth weight (below 1,500 g) and 39.3 for extremely low birth weight (below 1,000 g).^[2] Male infants are at higher risk than females.^[2]

The fundamental cause is surfactant deficiency from pulmonary immaturity, so any condition that precipitates preterm birth or interferes with surfactant production or release increases risk. Risk factors supported by current sources include:^[2]

• Low gestational age and low birth weight (the strongest factors).
• Male sex.
• Caesarean section without preceding labour: the fetus misses the physiological rise in corticosteroids that labour and intrauterine stress produce, which normally stimulates surfactant production.^[2]
• Maternal diabetes mellitus: fetal hyperinsulinaemia antagonises corticosteroid action and suppresses surfactant synthesis.^[2]
• Second-born twin may be at higher risk, particularly after vaginal delivery; the mechanism appears to be a smaller benefit from the stress of labour rather than birth asphyxia.^[2]
• Fetal growth restriction can both impair lung maturation and, through stress, accelerate it, so its net effect is nuanced; clinicians should not assume growth restriction protects.^[3]
• Antenatal optimisation: lack of antenatal care increases risk of death and severe morbidity, and measures such as progesterone for a short cervix, cerclage in selected singleton pregnancies, prevention of unnecessary caesarean section and in-utero transfer to a perinatal centre all help.^[1]

Protective influences include endogenous glucocorticoids from labour and intrauterine stress, thyroid hormone (which accelerates lung maturation, although maternal thyroid hormone does not cross the placenta), and antenatal corticosteroid treatment before 34 weeks.^[2]

Everything follows from rising alveolar surface tension. Type II pneumocytes are immature, so surfactant output is low. Surface tension increases, and alveoli collapse on expiration (atelectasis).^[2] The infant cannot maintain functional residual capacity; the chest wall of a preterm infant is highly compliant and offers little resistance to collapse, so end-expiratory lung volume approaches residual volume.^[2] Each breath then has to reopen collapsed units, so the infant tires, tidal volume falls and dead space rises.^[2]

Collapsed alveoli continue to be perfused but not ventilated, producing hypoxaemia, respiratory acidosis and hypercapnia. Pulmonary arterial vasoconstriction follows, increasing right-to-left shunt through the foramen ovale and the ductus arteriosus; the deoxygenated blood reaching the systemic circulation produces cyanosis.^[2] Vasoconstriction also reduces pulmonary perfusion, worsening ischaemic injury to the alveolar epithelium and capillary endothelium; when plasma proteins such as fibrinogen and albumin leak into the airspaces they bind and inactivate whatever surfactant remains, creating a vicious cycle.^[2]

High concentrations of surfactant are present in fetal lung homogenates by 20 weeks gestation, but surfactant only reaches the lung surface between 28 and 32 weeks and mature levels only after 35 weeks.^[2] This is why gestational age is the dominant variable.

At autopsy the lungs are dark red, solid, airless and firm, resembling the liver because of atelectasis and congestion; they may sink in water.^[2] Microscopically there is focal atelectasis and haemorrhage, with dilated terminal and respiratory bronchioles lined by eosinophilic, smooth hyaline membranes composed of necrotic debris and plasma protein exudate. The hyaline membrane appears within the first 12 to 24 hours after symptoms begin and is reabsorbed within three to four days.^[2]

The infant is usually preterm. There may have been maternal risk factors such as preterm labour, diabetes, absence of antenatal corticosteroids or delivery by caesarean section without labour. Symptoms usually appear within minutes of birth, with a respiratory rate that can reach 80 breaths per minute or more and a visible struggle to breathe.^[2]

The cardinal signs reflect increased work of breathing: expiratory grunting (the infant's own attempt to generate positive end-expiratory pressure), nasal flaring, forceful intercostal and subcostal retractions, tachypnoea and cyanosis.^[2] Lung auscultation may reveal diminished breath sounds with a harsh tubular quality and scattered crackles.^[2] Weak peripheral pulses and low temperature commonly accompany severe disease.^[2]

Differentiating RDS from its mimics in the delivery room is urgent, because the causes of neonatal respiratory distress are pulmonary, cardiovascular, metabolic and systemic. The differential is therefore wide and includes transient tachypnoea of the newborn, bacterial pneumonia, air leak, cyanotic congenital heart disease, congenital and interstitial lung disease, hypoglycaemia, polycythaemia associated with maternal diabetes, and severe anaemia.^[2]

Figure 1Chest radiograph in transient tachypnea of the newborn

Enlarge

Long description

Frontal chest and upper abdomen radiograph of a newborn with a feeding tube. Both lungs are mildly hyperinflated with straightened ribs and wide intercostal spaces, streaky infiltrates radiating from the hila, and a thin line of fluid in the horizontal fissure on the right.

Figure 2Chest radiograph in meconium aspiration

Enlarge

Long description

Frontal chest and upper abdomen radiograph of a newborn. Both lungs show patchy, coarse, irregular opacities mixed with areas of overinflation, with flattened diaphragms.

TTN and meconium aspiration occur much more often in term infants.^[2]

• Pulse oximetry and blood gas. Continuous SpO2 monitoring; an arterial or capillary blood gas identifies hypoxaemia and respiratory acidosis.
• Chest radiograph. In RDS the radiograph shows low lung volumes with diffuse hazy opacities (ground-glass shadowing), representing subsegmental atelectasis from alveolar collapse. Air bronchograms may be present. These changes are late signs; early non-invasive support can prevent them.^[1][2]
• Complete blood count and blood culture. Ordered to evaluate pneumonia and early-onset sepsis; a blood culture is the gold standard for sepsis. Marked neutropenia in the first 30 to 90 minutes may also point to RDS, because inflammatory cells move from blood into the airway.^[2]
• Lung ultrasound. Increasingly used to diagnose RDS and to decide on surfactant need; a strong evidence base is emerging.^[1]

Figure 3Chest radiograph in neonatal respiratory distress syndrome

Enlarge

Long description

Frontal chest radiograph of a preterm infant with an endotracheal or feeding tube in place. Both lungs show a uniform fine granular, ground-glass haze with low lung volumes, the typical pattern of surfactant deficiency.

The hazy opacities are not "fluid" in the usual sense: they are collapsed alveoli and airspaces filled with protein-rich exudate, so the lung is airless and heavy. This contrasts with TTN, where lung volumes are normal and the problem is interstitial fluid, and with meconium aspiration, where lung volumes are large because of air trapping.^[2]

Obstetricians sometimes assess fetal lung maturity before a planned preterm delivery. The classic test is the lecithin-to-sphingomyelin (L/S) ratio in amniotic fluid. Lecithin (DPPC) is the principal surfactant phospholipid; its concentration rises as the lung matures, while sphingomyelin predominates until about 26 weeks. When the quantity of lecithin is twice that of sphingomyelin, giving an L/S ratio of 2:1, the lung is considered mature and the risk of RDS is low.^[2] Lamellar body counts are an alternative: maturity is suggested above 50,000 per microlitre, immaturity below 15,000 per microlitre, and an intermediate range between is indeterminate.^[2] These tests have been partly displaced by stricter guidance on late preterm and early term delivery, and their frequency of use has fallen markedly.^[2]

There is no single laboratory cut-off for diagnosing RDS after birth; diagnosis rests on the preterm infant, the characteristic signs and the compatible radiograph, with surfactant need judged from the combination of work of breathing, oxygen requirement and imaging.^[1] Very premature infants (22 to 23 weeks) are a special group who almost always require planned intubation and surfactant in the first minutes after birth.^[1]

• Team and transport. Mothers at high risk of delivery below 28 to 30 weeks should be transferred to a perinatal centre with experience in RDS.^[1]
• Thermal care. Room temperature at least 23 degrees Celsius, plastic bags or occlusive wrapping under radiant warmers and humidified gas for infants below 32 weeks.^[1]
• Cord clamping. Defer clamping for at least 60 seconds if the clinical condition allows; longer deferrals (more than 2 minutes) are associated with the lowest mortality, and physiological stabilisation with the cord intact is preferred where equipment permits.^[1]
• Respiratory support. Support spontaneously breathing preterm infants with CPAP from birth; it is the respiratory support least likely to cause lung injury.^[1] A starting CPAP level of 6 cmH2O is suggested, titrating up or down.^[1] Expert consensus is CPAP pressure at least 6 cmH2O and peak inspiratory pressure 25 cmH2O if ventilation breaths are needed.^[1]
• Oxygen titration. Use a blender. For infants below 29 weeks start with FiO2 0.6, for 29 to 31 weeks start with at least 0.30, and for 32 weeks and above start with 0.21 (air). Aim for SpO2 of 80% or more within 5 minutes in infants below 32 weeks.^[1]
• Intubation. Reserve intubation for infants not responding to positive pressure via mask or nasal prongs; use videolaryngoscopy and colourimetric capnography where available.^[1]

A single course of antenatal corticosteroids given to mothers with threatened preterm delivery before 34 weeks improves survival and reduces the risk of RDS, necrotising enterocolitis and intraventricular haemorrhage, even in modern neonatal care and in low-resource settings.^[1] It should be offered in all pregnancies with threatened preterm birth before 34 completed weeks where active care is anticipated.^[1] In infants born at 23 to 25 weeks, observational studies support benefit, but trial data are limited.^[1] For 34 to 37 weeks the benefit is confined to short-term respiratory morbidity with increased risk of neonatal hypoglycaemia, so routine use in spontaneous preterm labour at this gestation is controversial and generally not advisable; planned caesarean section without labour between 34 and 37 weeks may be an exception.^[1]

Timing matters: ideally start at least 24 hours before birth, and the maximal benefit is seen when delivery occurs between 24 hours and 7 to 10 days after starting.^[1] Benefits diminish beyond 7 to 10 days.^[1] A single repeat course may be given before 32 weeks if the first course was at least 1 to 2 weeks earlier.^[1] Magnesium sulphate should also be given to women with imminent delivery before 32 weeks, because it reduces cerebral palsy by about 30% at 2 years of age.^[1]

The drugs are standard glucocorticoids given parenterally. Common regimens described in current literature include betamethasone as 1 to 3 doses of 12 mg intramuscularly about 24 hours apart, or dexamethasone as four 5 mg intramuscular doses about 12 hours apart; guidelines vary on exact dose and steroid.^[3] No repeat courses should be used routinely, because multiple courses reduce birth weight and head circumference without improving mortality.^[1]

Surfactant is the definitive treatment for established RDS: it improves survival, reduces oxygen exposure and minimises ventilator requirements and pneumothorax.^[1] In the earliest weeks of active care (22 to 23 weeks) nearly all infants require planned intubation and surfactant from the first minutes.^[1] Selected extremely preterm infants of less than 28 weeks who are stable on CPAP can receive an early (selective prophylactic) dose by thin catheter if they show chest retractions, to reduce the need for mechanical ventilation.^[1]

When to treat (rescue). Treat worsening RDS, usually when FiO2 is 0.30 or more on CPAP pressure of 6 cmH2O or more, or when lung ultrasound suggests surfactant need.^[1][4] For infants of more than 28 weeks with signs of RDS, suggested FiO2 thresholds of 0.30 apply; very immature infants may be treated at lower thresholds.^[1]

Which surfactant and how much. Three animal-derived surfactants are commonly used: beractant 100 mg/kg (4 mL/kg), bovactant 50 mg/kg (1.2 mL/kg), and poractant alfa 100 to 200 mg/kg (1.25 to 2.5 mL/kg).^[1] Using poractant alfa, re-dosing can be minimised with a larger initial dose of 200 mg/kg.^[1][5] LISA doses in trials are commonly 100 or 200 mg per kg.^[5]

How to give it. The preferred route in spontaneously breathing preterm infants is thin catheter (LISA/minimally invasive surfactant therapy), which reduces mechanical ventilation, death or BPD and intraventricular haemorrhage when compared with intubate-surfactant-extubate, when the same treatment threshold is used.^[1] Supraglottic airway devices can be used for larger infants.^[1] Intubated infants should receive surfactant promptly. Surfactant can be given before radiological confirmation of tube position.^[1] A second, and occasionally a third, dose is given when there is ongoing evidence of RDS.^[1] Surfactant has a useful role in congenital pneumonia and after pulmonary haemorrhage, and may help in severe pneumonia and meconium aspiration syndrome, but has no role in evolving BPD and is not recommended in congenital diaphragmatic hernia.^[1] Budesonide added to surfactant does not improve outcomes and has no place.^[1]

• Caffeine. Standard regimen 20 mg/kg loading then 5 to 10 mg/kg daily maintenance facilitates weaning from ventilation, reduces BPD and improves neurodevelopmental outcomes; it also reduces apnoea.^[4] Caffeine reduces the rate of BPD and improves neurodevelopmental outcomes, and may be considered earlier in high-risk infants on non-invasive support.^[2][4]
• Oxygen and saturation targeting. Target SpO2 between 90 and 94% with alarm limits 89% and 95%. Targeting lower saturations reduces severe retinopathy of prematurity but increases mortality and necrotising enterocolitis.^[4] About 20% of infants with BPD develop pulmonary hypertension, and higher targets may reduce that.^[4]
• Non-invasive ventilation. Start non-invasive respiratory support from birth where intubation is not required. Mask or nasal CPAP, nasal intermittent positive pressure ventilation (synchronised or unsynchronised), nasal high-frequency oscillation and high-flow nasal cannula are all used; each centre should master a selection.^[1] Weaning from CPAP should be gradual.^[1]
• Mechanical ventilation (when needed). Minimise time on the ventilator. Prefer volume-targeted ventilation, starting at about 5 mL/kg tidal volume, with a maximal peak inspiratory pressure around 25 to 30 cmH2O and a backup rate around 30, titrating to blood gases and comfort.^[1] Use sufficient positive end-expiratory pressure to keep the lung open and avoid repeated opening and closing of atelectatic units. High-frequency oscillation is an alternative lung-protective mode.^[1] Extubation is attempted when mean airway pressure falls to around 7 to 8 cmH2O on conventional ventilation (or a continuous distending pressure of 8 to 9 cmH2O on high-frequency oscillation).^[1] Extubate straight to non-invasive support.^[4]
• Postnatal corticosteroids. Dexamethasone can facilitate weaning from ventilation and reduce BPD, but given within the first 7 days its harms outweigh its benefits. Beyond 7 days, in infants stuck on the ventilator with a high risk of BPD (roughly 60% or more), a low-dose course to facilitate extubation may be justified.^[1]

Complications of neonatal RDS are grouped by mechanism.^[2]

Complications related to anoxia and acidosis include intraventricular haemorrhage (IVH), persistent patent ductus arteriosus (PDA) and necrotising enterocolitis (NEC).^[2]

Complications related to prolonged high concentrations of oxygen and barotrauma include retrolental fibroplasia (retinopathy of prematurity, ROP) and BPD.^[2]

• Intraventricular haemorrhage. Fragile germinal matrix vessels in very preterm infants bleed under the stress of hypoxia and acidosis; the same instability that causes RDS contributes. Magnesium sulphate antenatally reduces cerebral palsy, and antenatal corticosteroids reduce IVH risk.^[1][2]
• Patent ductus arteriosus. A left-to-right shunt through a persistently open ductus (common in preterm infants) can worsen lung compliance and ventilation; it is both an early complication and a management target.^[2]
• Necrotising enterocolitis. Ischaemic gut injury in the preterm infant; co-amoxiclav should be avoided in preterm premature rupture of membranes because of its association with increased NEC risk.^[1]
• Retinopathy of prematurity. ROP develops in two phases: first hyperoxia suppresses vascular endothelial growth factor (VEGF) and causes endothelial apoptosis; then, on return to relatively hypoxic air, VEGF rebounds and drives retinal neovascularisation. Surfactant, gentler ventilation and antenatal corticosteroids have reduced its incidence.^[2]
• Bronchopulmonary dysplasia. The strongest predictors are prematurity and low birth weight: about 80% of infants born at 22 to 24 weeks develop BPD, falling to about 20% at 28 weeks or above. Two forms are recognised. "Old" BPD is ventilator- and oxygen-induced injury with inflammation and fibrosis. "New" BPD reflects arrested alveolar septation and vascular development in earlier (and now surviving) preterm infants. About 20% of infants with BPD develop pulmonary hypertension.^[2][4]

Other early complications include pneumothorax, apnoea, anaemia, hypoglycaemia, hypernatraemia and renal failure; later ones include gastro-oesophageal reflux, feeding intolerance, growth failure, apnoea, sudden death and neurodevelopmental deficits.^[2]

Prognosis depends on gestation, birth weight, and how gently the lungs are handled. In modern networks about three-quarters of infants of 24 to 26 weeks survive, but BPD remains high at about 60% at this gestation.^[1] Many infants with mild disease recover spontaneously over 48 to 72 hours as endogenous surfactant production rises; surfactant given early, before full-blown injury with atelectasis and surfactant inactivators, is most effective.^[1]

• Antenatal corticosteroids before 34 weeks (see above).^[1]
• Progesterone and cerclage for women at high risk of spontaneous preterm birth (shortened cervix), together with measures to prevent preterm birth.^[1]
• Magnesium sulphate before 32 weeks for neuroprotection.^[1]
• In-utero transfer to a perinatal centre.^[1]
• ROP screening in survivors, especially the most preterm.
• BPD follow-up by an interdisciplinary team (paediatrician, developmental paediatrician, nutritionist, and therapists).^[2]

• Extremely preterm (22 to 23 weeks). Nearly always require intubation and surfactant within minutes; guidelines derived from older populations may not directly apply.^[1]
• Infants of diabetic mothers. Higher risk because of fetal hyperinsulinaemia; manage maternal diabetes antenatally and expect increased surfactant need.^[2]
• Second-born twins. Higher risk, especially after vaginal delivery.^[2]
• Late preterm (34 to 37 weeks). Lower incidence (about 5%), but when RDS occurs it is often milder; surfactant for late preterm infants with early signs is under study and current evidence is insufficient for firm recommendations.^[1][2]

• CPAP is cheap and effective. Bubble CPAP uses simple underwater-seal gas circuits and can be run where ventilators are scarce.^[1]
• Avoid intubation and mechanical ventilation where possible: the core of lung protection is non-invasive support and early, targeted surfactant.^[1]
• Antenatal corticosteroids work in low-resource settings when indications are defined.^[1]
• Master a few modes: staff who fully understand CPAP and a single method of surfactant administration achieve more than those with unmastered equipment.^[1]
• Surfactant availability may be limited; knowing preparation-specific doses (beractant 100 mg/kg, poractant alfa 100 to 200 mg/kg) allows rational use.^[1]
• ROP surveillance must be organised before scaling up oxygen therapy.

• RDS is surfactant-deficiency disease of preterm lungs: without surfactant, alveolar surface tension rises, alveoli collapse and hypoxaemic respiratory failure follows.^[2]
• Incidence rises steeply with decreasing gestation: about 5% late preterm, 30% at 28 to less than 32 weeks and 60% below 28 weeks; risk also rises with low birth weight and male sex.^[2]
• Caesarean section without labour and maternal diabetes are important additional risk factors.^[2]
• Antenatal corticosteroids before 34 weeks reduce RDS, necrotising enterocolitis and intraventricular haemorrhage; they should be given so that delivery ideally occurs 24 hours to 7 to 10 days afterwards.^[1]
• Presenting signs are tachypnoea, grunting, nasal flaring, retractions and cyanosis; the typical chest radiograph shows low lung volumes with diffuse ground-glass opacities.^[2]
• TTN has normal lung volumes with interstitial oedema; meconium aspiration shows large volumes with cord-like opacities.^[2]
• An L/S ratio of 2:1 indicates fetal lung maturity.^[2]
• Start CPAP at 6 cmH2O from birth, titrating oxygen to SpO2 of 80% or more by 5 minutes.^[1]
• Give surfactant for worsening RDS at FiO2 0.30 or more on CPAP 6 cmH2O or more, using a thin catheter where possible; beractant 100 mg/kg, poractant alfa 100 to 200 mg/kg; repeat if needed.^[1]
• Target SpO2 between 90 and 94% in preterm infants receiving oxygen.^[4]
• Use volume-targeted mechanical ventilation when needed and minimise ventilation time; extubate to non-invasive support.^[1]
• Major complications are intraventricular haemorrhage, patent ductus arteriosus, necrotising enterocolitis, retinopathy of prematurity and bronchopulmonary dysplasia.^[2]
• ROP has a hyperoxia-suppression phase followed by relative-hypoxia-driven neovascularisation; BPD includes ventilator-induced "old" and development-arrest "new" forms.^[2]
• Caffeine (20 mg/kg loading, 5 to 10 mg/kg maintenance) eases weaning and reduces BPD.^[4]

Bronchopulmonary dysplasia; retinopathy of prematurity; patent ductus arteriosus; intraventricular haemorrhage; necrotising enterocolitis; transient tachypnoea of the newborn; meconium aspiration syndrome; congenital pneumonia; apnoea of prematurity.