Neonatal respiratory distress syndrome (NRDS) can be broadly or narrowly defined. The former refers to any respiratory distress symptoms regardless of the cause, while the latter specifically denotes respiratory distress syndrome (RDS) caused by a deficiency of pulmonary surfactant. This article primarily discusses the latter type of NRDS. It mainly occurs in premature infants, clinically presenting with progressive dyspnea as the primary symptom, and pathologically characterized by the presence of eosinophilic hyaline membranes and atelectasis, hence also known as hyaline membrane disease.

bubble_chart Etiology

The inducing factors of NRDS

1. Premature labor: In fetuses at 22–24 weeks of gestation, type II pneumocytes can already produce pulmonary surfactant (PS), but the amount is small and rarely transferred to the alveolar surface. As gestational age increases, PS synthesis gradually rises. Therefore, the more premature the infant, the lower the amount of PS in the lungs and the higher the incidence of RDS. Between 24–30 weeks of gestation, the effect of various hormones on promoting lung maturation is greatest, making this the optimal stage for prenatal prevention. After 32–34 weeks, the influence of hormones on lung maturation becomes less significant, and beyond 35 weeks, PS rapidly moves to the alveolar surface. After birth, the lungs of premature infants continue to develop, and the PS produced within 72–96 hours after birth is generally sufficient to sustain normal respiration. Thus, as long as PS supplementation is provided during the deficiency phase, premature infants can overcome the critical period, improving survival rates.
2. Infants of diabetic mothers: Pregnant women with diabetes have high blood sugar levels, which also elevates fetal blood sugar. In response, fetal insulin secretion must increase to meet the demands of glucose metabolism and convert glucose into glycogen. This condition leads to fetal macrosomia (obesity), but the lungs may not necessarily mature. Additionally, insulin antagonizes the effects of adrenal corticosteroids, impairing lung development.
3. Intrauterine distress and birth asphyxia: Intrauterine distress often occurs in fetuses with placental insufficiency. Chronic hypoxia affects fetal lung development, resulting in lower PS secretion. Birth asphyxia is frequently caused by difficult delivery and is one of the contributing factors to neonatal RDS.

bubble_chart Pathogenesis

Neonatal respiratory distress syndrome is caused by a deficiency of pulmonary surfactant (PS). Due to the surface tension at the interface between alveoli and air, the absence of surfactant leads to alveolar collapse, gradually resulting in atelectasis, which progressively expands. Blood flowing through the atelectatic areas returns to the heart without gas exchange, creating an intrapulmonary shunt. Consequently, the blood PaO₂ decreases, oxygenation is reduced, and the body's metabolism proceeds under hypoxic conditions, leading to acidosis. During acidosis, pulmonary vasospasm occurs, increasing pulmonary vascular resistance and elevating right heart pressure. In some cases, this may even cause the reopening of the stirred pulse duct, resulting in a right-to-left shunt. In severe cases, up to 80% of cardiac output becomes shunted blood, leading to pronounced cyanosis in the infant. As pulmonary blood flow decreases, inadequate lung perfusion occurs, and hypoxia increases vascular permeability, causing plasma components, including proteins, to leak out. The deposition of fibrin in the exudate forms a hyaline membrane in the lungs.

bubble_chart Pathological Changes

The lungs appear normal in size, with a deep red color due to severe congestion, and the texture is tough like liver, sinking in water. The cut surface shows deep red lung tissue. Under the microscope with Sappan Wood eosin staining, extensive reabsorption atelectasis is observed, with alveolar septa closely apposed. Only a few dilated alveoli are seen in the lungs, their walls lined with a layer of eosinophilic, homogeneous, and structureless material—the hyaline membrane. Occasionally, parts of the hyaline membrane are seen floating freely within the alveoli. The alveolar ducts and bronchioles are dilated, with hyaline membranes also attached to their walls. The lung tissue exhibits edema, and sometimes the process of edema fluid condensing into hyaline membranes can be observed. Large mononuclear and multinucleated cells are seen exuding. In cases surviving more than 32 hours, pneumonia often complicates the condition, and the hyaline membrane has either been absorbed or appears as loose granular fragments.

Most affected infants are premature babies. At birth, their crying may be normal, but respiratory distress develops within 6 to 12 hours, gradually worsening and accompanied by moaning. Breathing becomes irregular, with intermittent apnea. The complexion turns pale or bluish-gray due to hypoxia, and cyanosis becomes pronounced after right-to-left shunting, unrelieved by oxygen therapy. Severe hypoxia leads to decreased muscle tone in the limbs. Signs include nasal flaring, initial chest bulging followed by depression as atelectasis worsens, most notably in the axillary region. Soft tissue retractions occur during inspiration, most prominent at the subcostal and lower sternal areas. Breath sounds are diminished, and fine moist rales may be heard on inspiration. This condition is self-limiting; infants surviving beyond three days show improved lung maturity and a better prognosis. However, many develop pneumonia, exacerbating the condition until infection is controlled. Most deaths occur within three days, with the highest mortality on the second day of life.

A milder form also exists, likely due to less severe surfactant deficiency, with later onset (up to 24–48 hours), milder respiratory distress, absence of moaning, minimal cyanosis, and resolution within three to four days.

bubble_chart Auxiliary Examination

1. Blood generation and transformation examination: Due to poor ventilation, PaO2 is low and PaCO2 is elevated. Due to metabolic acidosis, blood pH decreases. These three tests can be monitored percutaneously, which is very convenient but does not represent the actual condition in the blood. Periodic sampling of stirred pulse blood is required for direct testing. In metabolic acidosis, the base excess (BE) decreases, and the carbon dioxide combining power declines. During the disease process, blood is prone to low Na⁺, K⁺, and high Cl^-, so blood electrolytes need to be measured.
2. X-ray findings: In the early stage of hyaline membrane disease, there is a generalized decrease in radiolucency in both lung fields, with uniformly distributed fine granular and reticular shadows. The fine granules represent small alveolar atelectasis, and the reticular shadows represent congested small blood vessels. The bronchi show air bronchograms but are easily obscured by the shadows of the heart and thymus. Segmental and peripheral bronchi are clearly visible. If atelectasis extends to the entire lung, the lung fields appear ground-glass, making the air-filled bronchi more distinct, resembling the branches of a leafless tree. The entire thorax is well-expanded, and the diaphragm is in a normal position.
3. Laboratory tests: These include prenatal intrauterine amniotic fluid and postnatal tracheal aspirate analyses. The testing methods and result interpretations are the same for both. There are multiple testing methods, all with relatively high sensitivity and specificity.
   1. Generation and transformation method: Thin-layer chromatography (TLC) is commonly used. In the late third trimester, the amounts of PC and S are approximately equal. By 34 weeks of gestation, PC increases rapidly while S remains relatively stable or slightly decreases, leading to an elevated L/S ratio. Shortly thereafter (around 35 weeks of gestation), PG begins to appear and rises rapidly once present. Therefore, 34–36 weeks of gestation is the optimal period for testing.
      1. L/S ratio: An L/S ratio ≥2 indicates "lung maturity," 1.5–2 is a transitional or suspicious value, and <1.5 indicates "lung immaturity." If the amniotic fluid is not severely contaminated by meconium or is from vaginal discharge, it has little effect on the test results. In diabetic pregnancies, the L/S ratio is often higher; even if it exceeds 2, the infant may still develop RDS. Therefore, for diabetic pregnancies, relying solely on one test is insufficient, and results should be cross-referenced with other tests (e.g., PG) for greater reliability.
      2. PG: PG can be detected by thin-layer chromatography when it reaches 3% of PS. The presence of PG indicates "lung maturity." It has high sensitivity but lower specificity (about 75%).
      3. DPPC value: A measured value >500 mg/dL indicates lung maturity. However, about 10% of subjects with DPPC levels of 500–1000 mg/dL still develop NRDS.
   2. Foam test: This is a biophysical testing method. The principle is that PS aids in foam formation and stability, while pure alcohol inhibits foam formation. Method: Take 0.5–1.0 mL of amniotic fluid or bronchial secretions, add an equal volume of 95% alcohol, shake vigorously for 15 seconds, and let stand for 15 minutes. Observe foam formation around the tube's liquid surface. No foam is (-), ≤1/3 of the tube circumference with small bubbles is (+), >1/3 to the entire tube circumference with a layer of small bubbles is (++), and foam layers in the upper part of the tube is (+++). (-) indicates low PS and can be diagnosed as deficiency, (+) or (++) is suspicious, and (+++) indicates abundant PS. This is the single-tube foam test; a four-tube foam test can also be performed.

bubble_chart Treatment Measures

1. Nursing: Intensive care should be provided as for premature labor infants. Place the infant in an incubator with moderate temperature or on a radiant infrared warming bed, and monitor body temperature, respiration, heart rate, transcutaneous TcO₂, and TcCO₂ using a monitoring device. Mean airway pressure should also be monitored. The environmental temperature should maintain abdominal skin temperature at 36.5°C or rectal temperature (core or deep body temperature) at 37°C to minimize oxygen consumption. Relative humidity should be around 50%. Frequently clear mucus from the pharynx to keep the airways open. Pay attention to fluid intake and nutrition; intravenous hyperalimentation can be administered until the infant is able to suckle and swallow, at which point breastfeeding can be initiated.
2. Oxygen Supply and Mechanical Ventilation: To improve hypoxia and reduce anaerobic metabolism, sufficient oxygen must be provided. For mild cases, a stuffy nose, mask, or continuous positive airway pressure (CPAP) can be used. If FiO2 reaches 0.8 and PaO2 remains below 6.65 kPa (50 mmHg), endotracheal intubation and mechanical ventilation are required. The peak inspiratory pressure should not exceed 2.9 kPa (30 cmH₂O), and the mean airway pressure should be <0.98 kPa (<10 cmH₂O). The respiratory rate should be 25–30 breaths per minute, with an inspiratory time (I):expiratory time (E) ratio of 1:1–2. Initially, FiO2 should be high and then gradually reduced to 0.4. When weaning off the ventilator, use intermittent mandatory ventilation (IMV) as a transition, with one assisted breath every 10 breaths. Alternatively, high-frequency ventilation can be employed, using smaller tidal volumes and higher ventilation rates. Due to the short inspiratory time, peak inspiratory pressure and mean airway pressure are both low, as is intrathoracic pressure, which facilitates venous return. A commonly used method is high-frequency jet ventilation (HFJV), where a nasal tube is inserted about 1.5–2 cm into the newborn’s nasal cavity, with a driving oxygen pressure (working pressure) of 0.125 kg/cm² and a jet frequency of 150–300 breaths per minute. Depending on the condition, this can be continued for 1–3 hours, alternating with conventional stuffy nose oxygen therapy until PaO2 can be maintained above 7.98 kPa (60 mmHg) but not exceeding 11.97–13.3 kPa (90–100 mmHg), at which point the stuffy nose method can be used instead.
3. Pulmonary Surfactant Replacement Therapy: PS has become a routine treatment for NRDS. For natural PS (including porcine and bovine PS), the first dose is 120–200 mg/kg, while the second and third doses can be reduced to 100–120 mg/kg, with intervals of approximately 8–12 hours between each dose. Each calculated dose is prepared in 3–5 mg/kg of normal saline. The endotracheal tube is temporarily disconnected from the ventilator, and the PS is directly instilled into the lungs through the endotracheal tube. During instillation, the infant's position is rotated from supine to right lateral and then to left lateral to ensure more uniform distribution of the medication into each lung lobe. If the endotracheal tube has a small side channel, the PS can be instilled through this channel to minimize fluctuations in oxygen saturation. Respiratory distress symptoms typically improve within 1–2 hours after administration. For synthetic Exosurf, the dose is 5 ml/kg, containing 67 mg/kg of DPPC, with a delayed onset of efficacy, and symptom improvement usually occurs after 12–18 hours. Whether natural or synthetic, the earlier PS is administered, the better the therapeutic effect. Natural PS does not increase the incidence of allergic diseases later in life.
   A small number of infants respond poorly to PS therapy due to various reasons: (1) extremely low birth weight infants have lungs that are not only functionally immature but also structurally underdeveloped, often accompanied by pulmonary hypoplasia; (2) grade III asphyxiated infants show very poor responses; (3) pulmonary edema (e.g., due to a large left-to-right shunt in PDA) leads to high protein levels in the exudate, which antagonizes PS; (4) concurrent conditions such as severe pneumonia. Therefore, the underlying cause should be identified and additional treatments implemented.
4. Stage of convalescence stirred pulse Treatment for patent ductus arteriosus: Indomethacin can be used, administered in three doses at 12-hour intervals. The first dose is 0.2 mg/kg, while the second and third doses are adjusted based on postnatal age: <2 days, 0.1 mg/kg per dose; 2–7 days, 0.2 mg/kg; >8 days, 0.25 mg/kg. The medication can be administered intravenously, with direct infusion into the stirred pulse duct via cardiac catheterization for better efficacy. Oral administration is also possible but less effective. Side effects of indomethacin include reduced renal function, decreased urine output, lowered blood sodium, and elevated blood potassium, which are reversible upon discontinuation. If the drug fails to close the stirred pulse duct, surgical ligation may be performed.
5. Antibiotic therapy: Due to the difficulty in distinguishing hyaline membrane disease from group B β-hemolytic streptococcal infection, penicillin treatment is often recommended concurrently. The dose is 200,000–250,000 μ/kg·d, divided into 3–4 intravenous or intramuscular administrations.
6. Fluid therapy.

bubble_chart Prevention

1. Prenatal Prevention

refers to the administration of adreno-cortical hormone (ACH) to pregnant women at high risk of premature labor during the late stage of pregnancy (third trimester) to prevent or alleviate the symptoms of respiratory distress syndrome (RDS) in premature infants after birth. In 1969, Liggins first discovered that intravenous infusion of dexamethasone could promote lung maturation in premature lambs. Similar results were observed in other animal species, and this method was gradually applied to pregnant women to enhance lung maturation in premature infants. The most commonly used hormones are betamethasone and dexamethasone, as they more easily cross the placental barrier compared to other ACHs. The role of ACH is to stimulate type II pneumocytes in the fetal lung to produce phospholipids and small-molecular-weight proteins, reduce capillary permeability in the lungs, and decrease pulmonary edema, thereby lowering the incidence of RDS. Even if RDS occurs, the symptoms are milder, and the mortality rate is reduced. During treatment, the oxygen concentration does not need to be excessively high, which can help prevent complications such as bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP). By alleviating hypoxia, it theoretically should also reduce the incidence of neonatal necrotizing enterocolitis and hypoxic-ischemic intracranial hemorrhage.

The preventive dose of ACH for pregnant women: betamethasone or dexamethasone, 24 mg each, divided into two intramuscular injections 24 hours apart. In China, the commonly used dose is 5–10 mg, administered intramuscularly or intravenously once daily for three days. Prevention should be initiated 7 days to 24 hours before childbirth to allow sufficient time for the medication to take effect. ACH prevention does not increase the risk of infection for the mother or fetus, nor does it raise the infection rate in cases of premature rupture of membranes. Intrauterine growth restriction is not a contraindication. The effectiveness of ACH in preventing RDS in extremely low birth weight infants remains inconsistent; it is generally believed not to reduce the incidence of RDS, but it may decrease the occurrence of germinal matrix hemorrhage in surviving infants. ACH is less effective for infants of diabetic mothers, those with Rh hemolytic disease, and multiple births.

Although ACH prevention has proven efficacy, RDS still occurs in 10% of premature infants born to treated mothers. Therefore, combining other hormones to enhance efficacy has been considered. Thyroid hormone promotes lung maturation but cannot be used clinically due to its difficulty in crossing the placental barrier. Later, it was discovered that thyrotropin-releasing hormone (TRH) from animal brain tissue has a structure and function similar to thyroid hormone and can cross the placenta, making it a viable preventive agent. The dose is 0.4 mg per administration, every 8 hours for a total of four doses. Some pregnant women may experience side effects such as nausea, vomiting, and hypertension, in which case the dose can be halved. Combining TRH further reduces the incidence and mortality of RDS.

2. Postnatal Prevention

refers to the administration of pulmonary surfactant to infants within half an hour after birth to prevent the occurrence of RDS or alleviate its symptoms. This is commonly used for infants whose mothers did not receive prenatal prevention. The earlier the prevention, the better the effect. It is best to administer the surfactant through an endotracheal tube before the infant begins breathing or before initiating positive-pressure ventilation. This ensures even distribution of the surfactant in the lungs. The preventive effect is reflected in the reduced incidence and mortality rate of RDS, as well as milder symptoms in affected infants. Since surfactant can promptly improve oxygenation, some infants may not require mechanical ventilation, and the supplied oxygen concentration and mean airway pressure can be lower. As a result, the incidence of air fistula disease and oxygen toxicity significantly decreases, and the occurrence of hypoxic-ischemic intracranial hemorrhage is also reduced. Chronic lung diseases (CLD), defined as conditions requiring oxygen supplementation within 28 days after birth, become even rarer. Although prevention has many advantages, not all premature infants or asphyxiated infants will develop RDS. Administering prevention to infants who do not develop the condition increases costs and unnecessary endotracheal intubation. Moreover, asphyxiated and premature infants often require more urgent resuscitation, and surfactant prevention may temporarily interrupt the continuous resuscitation process. Therefore, in the delivery room, for premature infants with a gestational age of <28 weeks or a birth weight of <1000g whose mothers did not receive ACH prevention, surfactant prophylaxis may be administered under the care of experienced and skilled resuscitation personnel. For other infants, surfactant is administered immediately upon the onset of RDS via mechanical ventilation and endotracheal intubation, following treatment protocols.

PS prevention and PS treatment are not easily separated. Many newborns who have just been resuscitated exhibit irregular breathing or distress and require continued PS treatment. The preventive and therapeutic doses are similar. For natural PS (whether porcine or bovine lung PS), the dose is 100–150 mg/kg. For synthetic Exosurf, the instilled dose is 5 ml/kg (containing 67 mg/kg of DPPC). Refer to the treatment of respiratory distress syndrome and the overview of pulmonary surfactant and its clinical applications in Chapter 3, Section 3.

III. Combined Prevention

This refers to the combined prevention approach of administering ACH to the pregnant woman before delivery and PS to the newborn after birth. It is used in the following cases: (1) when prenatal prevention is initiated relatively late, and childbirth occurs before the mother has completed 24 hours of treatment; (2) when the newborn has severe intrauterine distress, as the resulting RDS is often severe—in such cases, combined prevention is advisable. Animal experiments have demonstrated that combined prevention is more effective than single prevention.

bubble_chart Complications

The complications of hyaline membrane disease mostly occur during oxygen therapy or in the stage of convalescence after treatment.

1. Pulmonary fistula disease: Due to injury of the alveolar wall, gas leaks into the pulmonary interstitium, or due to excessively high peak inspiratory pressure or mean airway pressure (MAP) during mechanical ventilation, interstitial lung qi swelling occurs, and gas travels along blood vessels to the mediastinum, causing mediastinal emphysema. Interstitial emphysema can also lead to pneumothorax, making breathing even more difficult during pulmonary fistula disease.
2. Oxygen toxicity: When the inhaled oxygen concentration (FiO₂) is too high or the duration of oxygen supply is too long, oxygen toxicity may occur, most commonly manifesting as bronchopulmonary dysplasia (BPD) and retrolental fibroplasia. The former is a pulmonary lesion that makes it difficult to wean off the ventilator, while the latter presents as retrolental retinal membrane hyperplasia or retinal membrane detachment, leading to vision impairment or even blindness.
3. Patent ductus arteriosus (PDA) in the stage of convalescence: After mechanical ventilation and oxygen therapy, approximately 30% of cases in the stage of convalescence exhibit unclosed PDA. The tissue of the PDA in premature infants is immature and cannot close spontaneously. However, in the early stages of hyaline membrane disease, increased pulmonary vascular resistance not only prevents left-to-right shunting but may sometimes antagonistically cause right-to-left shunting. By the stage of convalescence, when pulmonary vascular resistance decreases, left-to-right shunting may occur, leading to pulmonary edema due to increased pulmonary blood flow, intermittent apnea, and congestive heart failure, which can even be life-threatening. A systolic murmur can be heard at the left sternal border of the precordium, loudest at the 2nd to 3rd intercostal spaces. If pulmonary vascular resistance drops significantly, a continuous murmur may even be present. Chest X-rays show an enlarged cardiac shadow and pulmonary congestion, while B-mode echocardiography can directly detect the unclosed PDA.

bubble_chart Differentiation

1. Group B β-hemolytic streptococcal infection: Intrauterine or intrapartum infection with Group B hemolytic streptococcus leading to pneumonia or sepsis closely resembles hyaline membrane disease and is difficult to differentiate. If the mother has a history of premature rupture of membranes or infection during the late stage (third stage) of pregnancy, the possibility of Group B β-hemolytic streptococcal infection in the infant should be considered. Blood cultures should be promptly obtained for differentiation. Before a definitive diagnosis is made, the condition should be treated as an infectious disease with penicillin.
2. Wet lung: Wet lung is more common in full-term infants, with mild symptoms and a short course, making it difficult to distinguish from mild hyaline membrane disease. However, the X-ray findings of wet lung differ and can aid in differentiation.
3. Intracranial hemorrhage: Intracranial hemorrhage caused by hypoxia is more common in premature infants, presenting as respiratory depression and irregular breathing accompanied by apnea. On the other hand, hypoxia due to NRDS can also lead to intracranial hemorrhage. Intracranial ultrasound can diagnose intracranial hemorrhage.
4. Phrenic nerve injury: Phrenic nerve injury (or abnormal diaphragmatic movement) and diaphragmatic hernia can both cause respiratory distress, but cardiac and pulmonary signs as well as X-ray findings can help differentiate them.