Thomas N. Hansen and Samuel Hawgood
Neonatal respiratory distress syndrome is the most common cause of respiratory failure in the first days after birth, occurring in 1% to 2% of newborn infants. Until about 25 years ago, approximately 50% of infants with this condition died.1 Over the last three decades, improved methods of treatment have markedly reduced mortality, and the majority now survive.
Hyaline membrane disease (HMD) occurs mainly in prematurely born infants and is more common in whites than in blacks. It develops when an infant attempts to ventilate an immature lung with small respiratory units that inflate with difficulty and do not remain gas-filled between respiratory efforts. This behavior is due to rudimentary alveolarization of the lung and an inadequate amount of pulmonary surface-active material or surfactant. When surfactant is absent, the surface tension at the interface between alveolar gas and the alveolar wall is high, and the lung tends to become progressively atelectatic. This causes increasingly labored breathing and cyanosis as the volume of the lung decreases and the infant hypoventilates.
It appears to take only 1 to 2 days following birth for an immature lung to mature as it responds to the surge of glucocorticoids and β-adrenergic compounds released by the stress of delivery. Glucocorticoids increase surfactant synthesis, and β-adrenergic stimulation promotes its secretion. Also, in 1 to 2 days, structural changes occur in the lung. Thin-walled respiratory units develop, and the number of capillaries increases. With these changes, the signs and symptoms of respiratory distress subside. However, during this brief interval, lung damage may occur from the combined effects of pulmonary edema, ischemia, pulmonary air leaks, oxygen toxicity, and injury from barotrauma if high pressures are used to mechanically assist ventilation. As a consequence, HMD can result in chronic lung disease that may persist for weeks or months.
At postmortem examination, the lungs from infants with neonatal respiratory distress are firm and airless. Atelectasis is striking on gross inspection; when the lungs are fixed in inflation, only the airways and a few alveolar ducts are air filled (Fig. 54-1). Diffuse atelectasis and dilated terminal bronchioles and alveolar ducts lined with a homogenous hyaline-staining material characterize the microscopic picture (Fig. 54-2). The hyaline membranes are plasma clots containing fibrin, other plasma constituents, and cellular debris. The small pulmonary arterioles appear constricted. There is congestion of pulmonary capillaries and veins and an increase in pulmonary water with dilation of the lymphatics.
Interstitial air leaks are common, and collections of air are often seen around small airways and vessels (eFig. 54.1 ). In some cases, the alveoli and hyaline membranes contain red cells. Electron microscopic examination shows degeneration of epithelial and endothelial cells and rupture of the basement membranes. If death occurs after 3 or 4 days of respiratory distress, the hyaline membranes are fragmented and numerous macrophages appear in the intra-alveolar spaces. The pulmonary interstitium is widened and filled with round cells and fibroblasts. After the first week, there is a proliferation of alveolar epithelial type II cells and capillaries. In severe cases, chronic changes occur, including metaplasia of the bronchiolar epithelium and interstitial fibrosis. These changes are discussed more completely in Chapter 59.
When inflated with air, the lungs accept only 10% to 20% of the gas accommodated by normal lungs. If after full expansion the distending pressure is lowered, the amount of gas retained at each pressure is a smaller proportion of the maximum gas volume than in the lung from an infant without neonatal respiratory distress. This indicates that retractive forces are high in the air-filled lung with HMD. When distended with liquid, there is less difference in the pressure-volume relationships between the normal lung and the lung with HMD. This behavior was explained when Avery and Mead2 showed that post-mortem extracts of lungs of infants with the disease did not have a low surface tension when studied with a modified Wilhelmy balance. The surface tension–surface area characteristics of extracts of lung with and without neonatal respiratory distress are shown in Figure 54-3. The immature lung with an inadequate amount of surfactant in the alveoli tends to become atelectatic, producing increasing respiratory failure.
FIGURE 54-1. A. Longitudinal section of the left lung of a 1560-g infant, born at 30 weeks’ gestation, who died at 2.5 days of age from neonatal respiratory distress syndrome. The lung was expanded with air to a pressure of 40 cm H2O, then deflated to 10 cm H2O and fixed with the bronchus clamped. The airways are distended, and a few of the respiratory bronchioles are overinflated. Most of the alveolar ducts and alveoli are airless. B. Cross-section of the left upper lobe of a 1220-g infant, born at 29 weeks’ gestation without lung disease, who died at 1 week of age with a sudden, massive intraventricular hemorrhage. Inflation and fixation were identical to those used for the lung in A. Almost all of the alveolar ducts are filled with air, and the airways are not overdistended.
Some infants with HMD fail to expand their lungs at birth even with vigorous inspiratory efforts and have respiratory distress from delivery. Others initially inflate their lungs but develop progressive atelectasis and increasingly labored breathing in the first few hours of life. The characteristic clinical features of infants with neonatal respiratory distress are an expiratory grunt, tachypnea, intercostal and sternal retractions, and cyanosis.3 Grunting respiration is caused by a prolonged expiratory effort against a partially closed glottis. It is usually preceded by a strong inspiratory effort during which the intrathoracic pressure drops well below atmospheric pressure. During the prolonged expiration, intrathoracic pressure is maintained above atmospheric pressure. Infants do not grunt with every breath, and those with severe disease grunt most frequently. By maintaining a positive intrapulmonary pressure during most of the respiratory cycle, grunting probably helps prevent atelectasis. When not grunting, infants with HMD have small tidal volumes and a rapid respiratory rate. Apneic periods and irregularities of respiratory rhythm are common as the work of breathing increases and the infants become fatigued.
The large negative intrathoracic pressures generated as the infant attempts to inflate its lungs cause soft tissues of the chest cage to retract. These retractions are particularly notable in very small preterm infants with compliant chest walls. With severe respiratory distress, the lower sternum may be pulled in almost to the vertebral column by the forceful contraction of the diaphragm. Because the chest wall is so compliant and infants breathe primarily with the diaphragm, they often have paradoxical breathing movements. With labored inspirations, the chest wall is sucked in while the descent of the diaphragm increases lung volume in a cephalocaudad direction, encroaching on the abdominal cavity. Thus, as the chest caves in, its circumference becomes smaller while the abdominal circumference increases. This is accompanied by flaring of the alae nasal during inspiration. Breath sounds are diminished in intensity and have a harsh, tubular quality. Occasionally, there are fine rales, particularly in those infants born by cesarean section who may have excessive lung liquid. Cyanosis is an early sign and, as the disease progresses, may be present even when an infant breathes 100% oxygen.
As the lungs become more difficult to ventilate, the work of breathing increases, the infant tires, and arterial carbon dioxide tension rises. At the same time, the hypoxemia and diminished peripheral blood flow cause metabolic acidosis as lactic acid accumulates. With the development of acidosis, potassium leaves the cells and its concentration in serum rises, in some instances to very high levels.
Urine output is usually diminished early in the course of the disease, and the infants may become progressively edematous. Some in fants, especially very-low-birth-weight infants, have systemic hypotension, peripheral pallor, slow capillary filling, and hypothermia.
FIGURE 54-2. Left portion of the lung shown in Figure 54-1A (×100). Some of the alveolar ducts are inflated, but there are no true alveoli. The cells of the interstitial tissue appear to be crowded, but no inflammatory cells are present. The homogenous staining material lining the walls of the alveolar ducts are plasma clots (ie, hyaline membranes). Right lung shown in Figure 54-1B (×100). The interstitial tissue is thin. Although there are no true alveoli in this section, the total internal surface area is large, particularly compared with the lung in the left panel.
FIGURE 54-3. Surface tension–surface area diagrams of extracts of lung from an infant with neonatal respiratory distress (A) and a lung from an infant with normal lungs (B). These were obtained from a modified Wilhelmy surface-tension balance in which surface tension is continuously recorded as the surface area of the lung extract is reduced and increased. When the surface area is reduced to 20% (ie, equivalent to a lung changing from total lung capacity to residual volume), the surface tension of the extract from the lung with neonatal respiratory distress (B) is 20 mN/m, a high tension that if present at the surface of the alveolus would favor atelectasis. The surface tension at 20% surface area for the extract of normal lung is 3 mN/m (A).
In mild to moderate disease, respirations become increasingly difficult for about 48 hours, and after 72 hours of age, there is rapid improvement. Recovery is usually heralded by diuresis. Clinical improvement is accompanied by a rapid fall in pulmonary vascular resistance and a rise in systemic arterial pressure. In some infants, particularly the least mature with birth weights less than 1500 g, this may permit development of a large shunt from the aorta through a patent ductus arteriosus to the pulmonary artery. In these infants, recovery may be interrupted by the development of pulmonary edema. The symptomatic ductus arteriosus will usually require treatment with the prostaglandin inhibitor indomethacin or operative ligation (see Chapter 55).
Except during grunting, respiratory rate is rapid and tidal volumes are small. Minute ventilation is usually increased, but dead space ventilation is also increased so alveolar ventilation is low. Lung volume is low4 and tends to decrease further during the first 48 hours after birth in infants who are not being treated with positive end-respiratory pressure. As expected, lung compliance is low.5 Interestingly, airway resistance is increased. This increase occurs because noncartilaginous airways are dependent on surfactant for stability, because small airways are compressed by collections of interstitial fluid, and finally, because small airways are damaged by the large transpulmonary pressures needed to inflate the lung. The reduction in lung compliance and increase in airway resistance result in a marked increase in the work of breathing.
Evidence from nitrogen washout curves and expiratory flow volume curves suggests that infants with HMD have a marked maldistribution of ventilation. Surfactant deficiency is not uniform, and regions of the lung with adequate surfactant coexist with areas of surfactant deficiency. Compliance and resistance are normal in surfactant sufficient areas, while compliance is reduced and resistance is increased in areas of surfactant deficiency. During inspiration, most of the gas flow into the lung is distributed to the relatively normal lung units, with very little going to the abnormal lung units. In the poorly ventilated lung units, the oxygen supply from the atmosphere does not keep up with oxygen removal by the blood, so the alveolar partial pressure of oxygen (PO2) is markedly reduced. In response to the reduced alveolar PO2, blood vessels supplying the poorly ventilated lung units constrict and divert blood away from this part of the lung. Some of this blood is diverted to the more normal part of the lung, but most is diverted through right-to-left shunts. While these shunts can occur across the foramen ovale and ductus arteriosus early in the disease, for the most part, they occur in the lung through blood vessels that have developed prior to alveoli and through blood vessels supplying atelectatic alveoli. Therefore, the cause of much of the hypoxemia in infants with HMD is right-to-left shunt. However, the magnitude of the right-to-left shunt is determined by the size of the poorly ventilated compartment of the lung and by the oxygen tension in the alveoli in that compartment. In other words, the size of the right-to-left shunt is not fixed but is highly variable. If the alveolar oxygen tension in the poorly ventilated lung units can be increased by administering supplemental oxygen or by mechanical ventilation, much of the vasoconstriction can be relieved. With relief of vasoconstriction, the magnitude of the right-to-left shunt will decrease and arterial PO2 will increase.
The more normal parts of the lung in infants with HMD receive almost all of the ventilation, but because much of the right ventricular output is diverted through the shunt, these units receive a much smaller fraction of the total right ventricular output. These lung units are ventilated out of proportion to their perfusion and constitute a large physiological dead space.
The radiographic appearance of the lungs in infants with neonatal respiratory distress is characterized by a diffuse reticulogranular pattern of increased density, usually uniform in distribution (Fig. 54-4) but occasionally more marked in the bases or on one side. The densities are due to miliary atelectasis and interstitial edema. Lung volume is small, and even radiographs taken after a maximal inspiration rarely show the diaphragm to be below the eighth to ninth interspace. The bronchial tree is clearly outlined by air against the poorly aerated lung—an air bronchogram. The heart is usually normal in size, although it often appears large because of the large thymic shadow and decreased lung volume. Often, diffuse atelectasis is not seen because the radiographic appearance of the lung can be markedly altered by treatment. Infants breathing against a positive pressure or being ventilated with intermittent positive pressure with positive end-expiratory pressure may have well-aerated lungs without air bronchograms. On the other hand, some infants with very severe disease may be unable to expand their lungs and have totally opaque radiographs in which even the heart borders are obscured. Later in the course of the disease, pulmonary edema, air leaks, or pulmonary hemorrhage can also affect the radiological appearance.
HMD is caused by atelectasis that develops from 3 interrelated factors: small respiratory units, a weak chest cage, and an amount of pulmonary surfactant that is inadequate to cover the internal surface of the lung.2 In the adult, the alveolar diameter is about 200 μm, and in the term infant, 100 μm. In the prematurely born infant, the alveolar ducts or acini are about 80 μm in diameter; there are no true alveoli. The diameter of the respiratory bronchioles of the prematurely born infant is relatively smaller than that of infants born at term. Because the respiratory units are curved, they are governed by the Laplace relationship, which states that the pressure difference (P) across a curved surface, needed to maintain a given radius (r), is inversely proportional to the radius and directly related to twice the surface tension (ST):
FIGURE 54-4. Chest radiograph of an infant with hyaline membrane disease. An endotracheal tube is present. Despite the application of positive pressure, the lung volume is reduced with the diaphragm at the eighth interspace. The lung parenchyma has a diffuse reticular granular pattern, and air bronchograms are present.
P = 2 ST/r
The small respiratory units of the preterm infant therefore require a greater force to inflate, and a relatively larger transpulmonary pressure at end-expiration to prevent deflation, than in the infant born at term. Infants born prematurely may not be able to create these pressures because their chest walls are weak and compliant.
The prematurely born infant has a poorly supported chest cage, and as the diaphragm descends during inspiration, the chest wall is drawn in as intrathoracic pressure becomes negative. The inability to fix the lateral dimensions of the chest cage limits the amount of negative intrathoracic pressure that can be produced. In addition, the highly compliant chest wall of the immature infant does not resist the natural tendency of the lungs to collapse, so that at end-expiration, the volume of the lungs tends to approach the residual volume of the lungs. Incomplete initial inflation and a small lung volume at end-expiration promote atelectasis.
Surprisingly, despite these handicaps, most prematurely born infants can inflate their lungs and develop a stable surface area sufficient for the gas transfer required to meet their metabolic needs. The success of their adaptation to extrauterine life depends on the structural development of the lung at the time of birth and a mature surfactant system.
Pulmonary surfactant is a complex mixture of lipids and proteins synthesized in alveolar epithelial type II cells.6 Type II cells are one of the 2 epithelial cell types that line the alveolus. The surfactant component most responsible for lowering surface tension is the phospholipid dipalmitoylphosphatidylcholine,7 which makes up about 45% to 50% of the mass of surfactant stored and secreted by the type II cell. Other phospholipids, neutral lipids, and specific apoproteins (surfactant proteins A, B, C, and D) are needed to give surfactant the biophysical properties necessary to form a film at the alveolar air-liquid interface and regulate surfactant turnover.8 A rare congenital deficiency of surfactant protein-B gene leads to fatal respiratory distress in affected term infants.9 The similarity of the clinical, radiological, and pathological features of this autosomal recessive disorder to HMD underscores the importance of a functional surfactant in perinatal lung adaptation. Other genetic causes of respiratory distress syndrome in term infants include surfactant protein C mutations and ABCA3 mutations.10 ABCA3 is a protein found in the limiting membrane of lamellar bodies, the intracellular surfactant storage granule in type II epithelial cells.
Synthesis and storage of surfactant begins at about 16 weeks’ gestation, and lung homogenates have high concentrations of surfactant by 20 weeks. However, surfactant is not secreted until later, appearing in amniotic fluid between 28 and 38 weeks’ gestation. Secretion of surfactant starts at about the same time that alveolar development begins, but the times of appearance of these events vary greatly among individuals. This explains why some infants with a gestational age of less than 30 weeks do not develop neonatal respiratory distress while other infants, with a longer gestation, do.
In addition to premature birth, several factors predispose newborn infants to neonatal respiratory distress. It is twice as common in males as in females at every gestational age and more common in white infants. It frequently follows delivery by cesarean section, particularly if performed before labor has begun. Infants of diabetic mothers are 5 times more likely to develop HMD than infants of nondiabetic mothers with the same gestational age, sex, and mode of delivery. The second-born twin is more likely to be affected, and a family history of HMD increases the risk for any given premature infant.
On the other hand, complications of pregnancy, such as pregnancy-induced hypertension, chronic maternal hypertension, premature rupture of membranes, and subacute placental abruption, all decrease the incidence of HMD. Infants born to mothers addicted to narcotics are also at less risk for developing HMD.
Once surfactant begins to be secreted by the alveolar epithelial type II cells in the fetus, lung fluid moves from the fetal lung into the amniotic cavity and transports suspended surfactant from the alveoli to the amniotic fluid. The concentration of surfactant in amniotic fluid reflects the amount of surfactant available at the alveolar surfaces and thus the potential stability of the respiratory units and risk of HMD. Gluck and associates11 showed that the concentrations of the phospholipids lecithin and sphingomyelin are equal in amniotic fluid in midgestation, but after 34 weeks, there is twice as much lecithin as sphingomyelin; this change parallels the maturation of the lung. Their work led to the widespread use of the lecithin-sphingomyelin (L/S) ratio for predicting which fetuses will develop HMD when delivered.
Several other amniotic fluid tests for assessing lung maturity are now widely available, including the measurement of phosphatidylglycerol, a relatively surfactant-specific phospholipid, and the simple and rapid foam stability or shake test. Although these tests can provide very useful clinical guidance in certain situations, they are all limited by a high false-negative rate secondary to the accumulation of normal intracellular surfactant stores well before amniotic fluid levels of surfactant change.
Because neonatal respiratory distress is associated with incomplete development of the lung at the time of birth, premature delivery should be delayed, where possible, at least until the lung is mature, as judged by analysis of amniotic fluid for surfactant. When premature delivery cannot be avoided, additional efforts should be made to accelerate lung maturation. In 1972, Liggins and Howie reported that administration of beta-methasone to women in premature labor at least 2 days before delivery significantly reduced the incidence of respiratory distress in infants born at a gestation of less than 32 weeks.12This observation is consistent with experimental studies13 showing that glucocorticoids accelerate lung maturation in fetal rabbits and lambs (eFig. 54.2 ). Based on a review of the available data, a National Institutes of Health–sponsored panel of scientific advisors developed the following recommendations for the use of antenatal corticosteroids14:
1. The benefits of antenatal administration of corticosteroids to fetuses at risk of preterm delivery vastly outweigh the potential risks. These benefits include not only a reduction in the risk of respiratory distress syndrome but also a substantial reduction in mortality and intraventricular hemorrhage.
2. All fetuses between 24 and 34 weeks’ gestation at risk of preterm delivery should be considered candidates for antenatal treatment with corticosteroids.
3. The decision to use antenatal corticosteroids should not be altered by fetal race or gender or by the availability of surfactant replacement therapy.
4. Patients eligible for therapy with tocolytics should also be eligible for treatment with antenatal corticosteroids.
5. Treatment consists of 2 doses of 12 mg of betamethasone given intramuscularly 24 hour apart or 4 doses of 6 mg of dexamethasone given intramuscularly 12 hours apart. Optimal benefit begins 24 hours after initiation of therapy and lasts 7 days.
6. Because treatment with corticosteroids for less than 24 hours is still associated with significant reductions in neonatal mortality, respiratory distress syndrome, and intraventricular hemorrhage, antenatal corticosteroids should be given unless immediate delivery is anticipated.
7. In preterm premature rupture of membranes at less than 30 to 32 weeks’ gestation in the absence of clinical chorioamnionitis, antenatal corticosteroid use is recommended because of the high risk of intraventricular hemorrhage at these early gestational ages.
8. In complicated pregnancies where delivery prior to 34 weeks’ gestation is likely, antenatal corticosteroid use is recommended unless there is evidence that corticosteroids will have an adverse effect on the mother or delivery is imminent.
Widespread acceptance of these recommendations has greatly increased the number of preterm infants exposed to prenatal steroids and contributed to the steadily improving outcomes reported. Although no long-term negative effects have been detected in infants treated by these guidelines, valid concerns remain about potential deleterious developmental effects of repeated prenatal steroid exposures from early in gestation. For this reason, treatment with repeated courses of steroid courses requires further evaluation.
Infants born prematurely, infants of diabetic mothers, or infants subjected to marked asphyxia during delivery are at high risk of developing HMD and should be resuscitated immediately at birth. This should include expansion of the lungs with positive pressure if spontaneous respiratory efforts do not completely expand the lung, and assisted ventilation or continuous positive airway pressure (CPAP) with a mixture of oxygen and air in order to maintain the arterial PO2 between 50 and 70 mm Hg. While overcoming or, better yet, preventing atelectasis is key in the treatment of respiratory distress syndrome, increasing evidence shows that even brief overexpansion of the lung during resuscitation can be damaging. Assisted ventilation or CPAP should be continued until the infant can keep the PO2 in these ranges while breathing spontaneously. (See also Chapters 42 and 61.)
The infant should be cared for in a warm, neutral thermal environment. Fluid intake should be restricted until lung fluid is absorbed and diuresis is complete, usually on the third day of life. Usually, 60 to 80 ml/kg/d of 10% glucose or hyperalimentation solution is adequate. The amount should be increased if the sodium concentration rises. No sodium should be given, because newborn infants have a large extracellular fluid volume and hence a relative excess of sodium. After any initial asphyxia is corrected, hypokalemia and hypocalcemia may occur, so both potassium (2 mEq/kg/d) and calcium (calcium gluconate, 200 mg/kg/d) should be added to the intravascular infusion. If the arterial pressure remains low in the early course of the disease and if peripheral circulation is inadequate, as judged by poor capillary filling, the circulating volume may be increased with normal saline or colloid. Infusion of dopamine (5–10 μg/kg/min) may help maintain the circulation and avoid excessive fluid administration, especially in the very-low-birth-weight infant.
The only way to increase the arterial PO2 in infants with HMD is to increase the alveolar PO2 in poorly ventilated lung units. This can be accomplished by increasing the inspired oxygen tension or by applying positive pressure to the lung and improving ventilation in poorly ventilated lung units. Oxygen is administered by hood initially, and the inspired oxygen tension should be kept just high enough to maintain the oxygen saturation between 85% and 90%.
Because progressive atelectasis is the central characteristic of neonatal respiratory distress, distention of the lung is the most direct treatment. If the infant is reasonably vigorous, this can be achieved by providing a continuous positive pressure by nasal prongs or nasal mask.15 There is increasing evidence that continuous positive end-expiratory pressure applied at birth may minimize the need for mechanical ventilation and surfactant therapy even in extremely premature infants.16 Usually, a continuous positive pressure of up to 6 to 10 cm H2O can be tolerated by the nasal route. If nasal continuous positive end-expiratory pressure is not effective in maintaining oxygenation or if severe apnea occurs, intubation and mechanical ventilation with positive end-expiratory pressure is required. One of the most striking results of treating neonatal respiratory distress with positive end-expiratory pressure ventilation is the ability to maintain oxygen saturation between 85% and 95% while decreasing the inspired oxygen concentration. The increase in aeration of the lung with positive pressure is shown dramatically in Figure 54-5. If the infant becomes apneic or if continuous positive end-expiratory pressure alone is not sufficient to maintain oxygenation, intermittent mandatory ventilation with positive end-expiratory pressure will be needed. Strategies for intermittent mandatory ventilation that are based on keeping the inspiratory time short, tidal volumes low, and the ventilator synchronized with the patient’s own efforts result in the least risk of pulmonary air leak and chronic lung disease.17,18The saturation is maintained between 85% and 95% by increasing the inspired oxygen tension or positive end-expiratory pressure. To avoid barotraumas and volutrauma to the fragile developing lung, hypercarbia (PCO2 above 50 mm Hg) should be tolerated, especially in infants with severe HMD.
FIGURE 54-5. Chest radiographs, aortic blood pressure, pH, and blood gases in an infant with neonatal respiratory distress during spontaneous breathing (left) and 1 minute after constant positive airway pressure was temporarily removed (right). The marked fall in arterial oxygen tension from 80 to 25 mm Hg parallels the rapid development of atelectasis shown in the radiograph.
Some centers advocate using high-frequency oscillatory ventilation for management of infants with respiratory distress syndrome. The oscillator ventilates the infants at very rapid rates (3000 breaths/min) at very low tidal volumes. Theoretically, low tidal volume ventilation might lead to less barotrauma to the lung and fewer complications. However, controlled trials of oscillatory ventilation for infants with HMD have not shown any consistent benefit over conventional ventilation.19 (See Chapter 61 for further information.)
The causes of neonatal respiratory distress can be favorably altered by instilling pulmonary surfactant at birth into the lungs of infants born at high risk of having immature lungs.20 Since the mid-1980s, a large number of carefully controlled clinical trials have been published showing that therapy with surfactant is safe, that it clearly reduces mortality from respiratory distress syndrome, that it decreases the incidence of air leaks, and that in small infants it decreases the incidence of intracranial hemorrhage.
Many different formulations of surfactant preparations are commercially available. Surfactant formulations fall into 3 major classes: (1) animal surfactants purified from animal lungs or bronchoalveolar lavage, (2) synthetic surfactants consisting primarily of phospholipids, and (3) synthetic surfactants that combine phospholipids mixtures with recombinant surfactant proteins or peptides based on surfactant protein structures. These preparations appear to be equally effective in treating and preventing HMD as measured by mortality and incidence of chronic lung disease. Accumulating evidence shows that the animal-derived surfactants containing surfactant proteins B and C have a faster onset of action and prevent more air leaks.21,22 The more recent generation of surfactants with recombinant proteins or peptides mimicking surfactant proteins are still being evaluated in clinical trials.
In addition, there are now 2 clearly defined treatment strategies for administration of surfactant: (1) prophylactic therapy, which requires that the surfactant preparation be instilled in the infant’s trachea shortly after birth, preferably in the delivery room; and (2) rescue therapy, which is designed to treat infants with established hyaline membrane disease. While both therapies are probably efficacious for larger infants, prophylactic therapy or therapy as early as possible in the course of disease appears to be superior for very-low-birth-weight infants (< 30 weeks’ gestation).23 Recent studies suggest that prophylactic nasal continuous positive end-expiratory pressure applied immediately after birth may reduce the need for surfactant treatment and mechanical ventilation without any negative effects on mortality.16
While surfactant replacement therapy has a major impact on the outcome for premature infants, the important role of glucocorticoids in preventing HMD should be remembered. The combination of antenatal corticosteroids and surfactant replacement therapy synergistically reduce mortality.24
Of infants with HMD, 80% to 90% survive, and most of the survivors have normal lungs by 1 month of age. A few develop persistent respiratory distress, however, and may require an increased inspired oxygen concentration for many weeks.25 Those with a protracted chronic course have a high incidence of respiratory illness with wheezing in the first years of life. Although most lung functions become normal, these children tend to have reduced expiratory flow rates and, in late childhood, often have exercise or methacholine-induced bronchospasm. Premature infants with neonatal respiratory distress are more likely to have developmental disabilities than prematurely born infants without neonatal respiratory distress.