Lung Development

The lining of the alveolus consists of 90% type I cells and 10% type II cells. After 20 weeks of gestation, the type II cells contain vacuolated, osmophilic, lamellar inclusion bodies, which are packages of surface-active material (Fig. 61-1). This lipoprotein surfactant is 90% lipid and is composed predominantly of saturated phosphatidylcholine (lecithin), but also contains phosphatidylglycerol, other phospholipids, and neutral lipids. The surfactant proteins SP-A, SP-B, SP-C, and SP-D are packaged into the lamellar body and contribute to surface-active properties and recycling of surfactant. Surfactant prevents atelectasis by reducing surface tension at low lung volumes when it is concentrated at end expiration as the alveolar radius decreases; surfactant contributes to lung recoil by increasing surface tension at larger lung volumes when it is diluted during inspiration as the alveolar radius increases. Without surfactant, surface tension forces are not reduced, and atelectasis develops during end expiration as the alveolus collapses.

FIGURE 61-1 Proposed pathway of synthesis, transport, secretion, and reuptake of surfactant in the type II alveolar cell. Phospholipids are synthesized in the smooth endoplasmic reticulum (ER). The glucose/glycerol precursor may be derived from lung glycogen or circulating glucose. Phospholipids and surfactant proteins are packaged in the Golgi apparatus (GZ), emerge as small lamellar bodies (SLB), coalesce to mature lamellar bodies (MLB), migrate to the apical membrane, and are released by exocytosis into the liquid hypophase below the air-liquid interface. The tightly coiled lamellar body unravels to form the lattice (tubular) myelin figure (LMF), the immediate precursor to the phospholipid monolayer at the alveolar surface. Reuptake by endocytosis forms multivesicular bodies (MVB) that recycle surfactant. The enzymes, receptors, transporters, and surfactant proteins are controlled by regulatory processes at the transcriptional level in the nucleus (N). Corticosteroid and thyroid hormones are regulatory ligands that may accelerate surfactant synthesis.

(From Hansen T, Corbet A: Lung development and function. In Taeusch HW, Ballard R, Avery ME, editors: Diseases of the Newborn, 6th ed, Philadelphia, 1991, Saunders, p 465.)

The timing of surfactant production in quantities sufficient to prevent atelectasis depends on an increase in fetal cortisol levels that begins between 32 and 34 weeks of gestation. By 34 to 36 weeks, sufficient surface-active material is produced by the type II cells in the lung, is secreted into the alveolar lumen, and is excreted into the amniotic fluid. The concentration of lecithin in amniotic fluid indicates fetal pulmonary maturity. Because the amount of lecithin is difficult to quantify, the ratio of lecithin (which increases with maturity) to sphingomyelin (which remains constant during gestation) (L/S ratio) is determined. An L/S ratio of 2:1 usually indicates pulmonary maturity. The presence of minor phospholipids, such as phosphatidylglycerol, also is indicative of fetal lung maturity and may be useful in situations in which the L/S ratio is borderline or possibly affected by maternal diabetes, which reduces lung maturity. The absence of phosphatidylglycerol suggests that surfactant might not be mature.

Clinical Manifestations

A deficiency of pulmonary surfactant results in atelectasis, decreased functional residual capacity, arterial hypoxemia, and respiratory distress. Surfactant synthesis may be reduced as a result of hypovolemia, hypothermia, acidosis, hypoxemia, and rare genetic disorders of surfactant synthesis. These factors also produce pulmonary artery vasospasm, which may contribute to RDS in larger premature infants who have developed sufficient pulmonary arteriole smooth muscle to produce vasoconstriction. Surfactant deficiency–induced atelectasis causes alveoli to be perfused but not ventilated, which results in a pulmonary shunt and hypoxemia. As atelectasis increases, the lungs become increasingly difficult to expand, and lung compliance decreases. Because the chest wall of the premature infant is very compliant, the infant attempts to overcome decreased lung compliance with increasing inspiratory pressures, resulting in retractions of the chest wall. The sequence of decreased lung compliance and chest wall retractions leads to poor air exchange, an increased physiologic dead space, alveolar hypoventilation, and hypercapnia. A cycle of hypoxia, hypercapnia, and acidosis acts on type II cells to reduce surfactant synthesis and, in some infants, on the pulmonary arterioles to produce pulmonary hypertension.

Infants at greatest risk for RDS are premature and have an immature L/S ratio. The incidence of RDS increases with decreasing gestational age. RDS develops in 30% to 60% of infants between 28 and 32 weeks of gestation. Other risk factors include delivery of a previous preterm infant with RDS, maternal diabetes, hypothermia, fetal distress, asphyxia, male sex, white race, being the second born of twins, and delivery by cesarean section without labor.

RDS may develop immediately in the delivery room in extremely immature infants at 26 to 30 weeks of gestation. Some more mature infants (34 weeks’ gestation) may not show signs of RDS until 3 to 4 hours after birth, correlating with the initial release of stored surfactant at the onset of breathing accompanied by the ongoing inability to replace the surfactant owing to inadequate stores. Manifestations of RDS include cyanosis, tachypnea, nasal flaring, intercostal and sternal retractions, and grunting. Grunting is caused by closure of the glottis during expiration, the effect of which is to maintain lung volume (decreasing atelectasis) and gas exchange during exhalation. Atelectasis is well documented by radiographic examination of the chest, which shows a ground-glass haze in the lung surrounding air-filled bronchi (the air bronchogram) (Fig. 61-2). Severe RDS may show an airless lung field or a whiteout on a radiograph, even obliterating the distinction between the atelectatic lungs and the heart.

FIGURE 61-2 Respiratory distress syndrome. The infant is intubated, and the lungs show a dense reticulonodular pattern with air bronchograms (A). To evaluate rotation on the frontal chest, the lengths of the posterior ribs are compared from left to right (arrows). Because the infant is supine, the side of the longer ribs indicates to which side the thorax is rotated. In this case, the left ribs are longer, and this radiograph is a left posterior oblique view. Surfactant was administered, resulting in significant improvement in the density of the lung (B). The right lung is slightly better aerated than the left. Uneven distribution of clearing is common.

(From Hilton S, Edwards D: Practical Pediatric Radiology, 2nd ed, Philadelphia, 1994, Saunders.)

During the first 72 hours, infants with RDS have increasing distress and hypoxemia. In infants with severe RDS, the development of edema, apnea, and respiratory failure necessitates assisted ventilation. Thereafter, uncomplicated cases show a spontaneous improvement that often is heralded by diuresis and a marked resolution of edema. Complications include the development of a pneumothorax, a patent ductus arteriosus (PDA), and bronchopulmonary dysplasia (BPD). The differential diagnosis of RDS includes diseases associated with cyanosis and respiratory distress (see Table 58-10).

Prevention and Treatment

Strategies to prevent preterm birth include maternal cervical cerclage, bed rest, treatment of infections, and administration of tocolytic medications. Additionally, prevention of neonatal cold stress, birth asphyxia, and hypovolemia reduces the risk of RDS. If premature delivery is unavoidable, the antenatal administration of corticosteroids (e.g., betamethasone) to the mother (and thus to the fetus) stimulates fetal lung production of surfactant; this approach requires multiple doses for at least 48 hours.

After birth, RDS may be prevented or its severity reduced by intratracheal administration of exogenous surfactant immediately after birth in the delivery room or within a few hours of birth. A mammalian-derived surfactant is currently preferred. Exogenous surfactant can be administered repeatedly during the course of RDS in patients receiving endotracheal intubation, mechanical ventilation, and oxygen therapy. Additional management includes the general supportive and ventilation care presented in Table 61-3.

TABLE 61-3 Potential Causes of Neonatal Apnea

IVH, intraventricular hemorrhage; RDS, respiratory distress syndrome.

The PaO₂ level should be maintained between 60 and 70 mm Hg (oxygen saturation 90%), and the pH should be maintained greater than 7.25. An increased concentration of warm and humidified inspired oxygen administered by an oxygen hood or nasal cannula may be all that is needed for larger premature infants. If hypoxemia (PaO₂ <50 mm Hg) is present, and the needed inspired oxygen concentration is 70% to 100%, nasal continuous positive airway pressure should be added at a distending pressure of 8 to 10 cm H₂O. If respiratory failure ensues (PCO₂ >60 mm Hg, pH <7.20, and PaO₂ <50 mm Hg with 100% oxygen), assisted ventilation using a respirator is indicated. Conventional rate (25 to 60 breaths/min), high-frequency jet (150 to 600 breaths/min), and oscillator (900 to 3000 breaths/min) ventilators all have been successful in managing respiratory failure caused by severe RDS. Suggested starting settings on a conventional ventilator are fraction of inspired oxygen, 60% to 100%; peak inspiratory pressure, 20 to 25 cm H₂O; positive end-expiratory pressure, 5 cm H₂O; and respiratory rate, 30 to 50 breaths/min.

In response to persistent hypercapnia, alveolar ventilation (tidal volume − dead space × rate) must be increased. Ventilation can be increased by an increase in the ventilator’s rate or an increase in the tidal volume, which is the gradient between peak inspiratory pressure and positive end-expiratory pressure. In response to hypoxia, the inspired oxygen content may be increased. Alternatively, the degree of oxygenation depends on the mean airway pressure. Mean airway pressure is directly related to peak inspiratory pressure, positive end-expiratory pressure, flow, and inspiratory-to-expiratory ratio. Increased mean airway pressure may improve oxygenation by improving lung volume, enhancing ventilation-perfusion matching. Because of the difficulty in distinguishing sepsis and pneumonia from RDS, broad-spectrum parenteral antibiotics (ampicillin and gentamicin) are administered for 48 to 72 hours, pending the recovery of an organism from a previously obtained blood culture.

Patent Ductus Arteriosus

PDA is a common complication that occurs in many low birth weight infants who have RDS. The incidence of PDA is inversely related to the maturity of the infant. In term newborns, the ductus closes within 24 to 48 hours after birth. However, in preterm newborns, the ductus frequently fails to close, requiring medical or surgical closure. The ductus arteriosus in a preterm infant is less responsive to vasoconstrictive stimuli, which when complicated with hypoxemia during RDS, may lead to a persistent PDA that creates a shunt between the pulmonary and systemic circulations.

During the acute phase of RDS, hypoxia, hypercapnia, and acidosis lead to pulmonary arterial vasoconstriction and increased pressure. The pulmonary and systemic pressures may be equal, and flow through the ductus may be small or bidirectional. When RDS improves and pulmonary vascular resistance declines, flow through the ductus arteriosus increases in a left-to-right direction. Significant systemic-to-pulmonary shunting may lead to heart failure and pulmonary edema. Excessive intravenous fluid administration may increase the incidence of symptomatic PDA. The infant’s respiratory status deteriorates because of increased lung fluid, hypercapnia, and hypoxemia. In response to poor blood gas levels, the infant is subjected to higher inspired oxygen concentrations and higher peak inspiratory ventilator pressures, both of which can damage the lung and cause chronic lung disease.

Clinical manifestations of a PDA usually become apparent on day 2 to 4 of life. Because the left-to-right shunt directs flow to a low-pressure circulation from one of high pressure, the pulse pressure widens; a previously inactive precordium shows an extremely active precordial impulse, and peripheral pulses become easily palpable and bounding. The murmur of a PDA may be continuous in systole and diastole, but usually only the systolic component is auscultated. Heart failure and pulmonary edema result in rales and hepatomegaly. A chest radiograph shows cardiomegaly and pulmonary edema; a two-dimensional echocardiogram shows patency; and Doppler studies show markedly increased left-to-right flow through the ductus.

Treatment of a PDA during RDS involves initial fluid restriction and diuretic administration. If there is no improvement after 24 to 48 hours, indomethacin or ibuprofen, prostaglandin synthetase inhibitors, is administered. Contraindications to using indomethacin include thrombocytopenia (platelets <50,000/mm³), bleeding, serum creatinine measuring more than 1.8 mg/dL, and oliguria. Because 20% to 30% of infants do not respond initially to indomethacin and because the PDA reopens in 10% to 20% of infants who do, a repeat course of indomethacin or surgical ligation is required in some patients.

Pulmonary Air Leaks

Assisted ventilation with high peak inspiratory pressures and positive end-expiratory pressures may cause overdistention of alveoli in localized areas of the lung. Rupture of the alveolar epithelial lining may produce pulmonary interstitial emphysema as gas dissects along the interstitial space and the peribronchial lymphatics. Extravasation of gas into the parenchyma reduces lung compliance and worsens respiratory failure. Gas dissection into the mediastinal space produces a pneumomediastinum, occasionally dissecting into the subcutaneous tissues around the neck, causing subcutaneous emphysema.

Alveolar rupture adjacent to the pleural space produces a pneumothorax (Fig. 61-3). If the gas is under tension, the pneumothorax shifts the mediastinum to the opposite side of the chest, producing hypotension, hypoxia, and hypercapnia. The diagnosis of a pneumothorax may be based on unequal transillumination of the chest and may be confirmed by chest radiograph. Treatment of a symptomatic pneumothorax requires insertion of a pleural chest tube connected to negative pressure or to an underwater drain. Prophylactic or therapeutic use of exogenous surfactant has reduced the incidence of pulmonary air leaks.

FIGURE 61-3 Pneumothorax. Right-sided hyperlucent pleural air is obvious. The findings of linear interstitial air and the resultant noncompliant but collapsed lung are noted.

(From Heller RM, Kirchner SG: Advanced exercises in diagnostic radiology: The Newborn, Philadelphia, WB Saunders, 1979).

Pneumothorax also is observed after vigorous resuscitation, meconium aspiration pneumonia, pulmonary hypoplasia, and diaphragmatic hernia. Spontaneous pneumothorax is seen in less than 1% of deliveries and may be associated with renal malformations.

Bronchopulmonary Dysplasia (Chronic Lung Disease)

BPD is a clinical diagnosis defined by oxygen dependence at 36 weeks’ postconceptual age and accompanied by characteristic clinical and radiographic findings that correspond to anatomic abnormalities. Oxygen concentrations greater than 40% are toxic to the neonatal lung. Oxygen-mediated lung injury results from the generation of superoxides, hydrogen peroxide, and oxygen free radicals, which disrupt membrane lipids. Assisted ventilation with high peak pressures produces barotrauma, compounding the damaging effects of highly inspired oxygen levels. In most patients, BPD develops after ventilation for RDS that may have been complicated by PDA or pulmonary interstitial emphysema. Inflammation from prolonged assisted ventilation and repeated systemic and pulmonary infections may play a major role. Failure of RDS to improve after 2 weeks, the need for prolonged mechanical ventilation, and oxygen therapy required at 36 weeks’ postconception age are characteristic of patients with RDS in whom BPD develops. BPD also may develop in infants weighing less than 1000 g who require mechanical ventilation for poor respiratory drive in the absence of RDS. Fifty percent of infants of 24 to 26 weeks’ gestational age require oxygen at 36 weeks’ corrected age.

The radiographic appearance of BPD is characterized initially by lung opacification and subsequently by development of cysts accompanied by areas of overdistention and atelectasis, giving the lung a spongelike appearance. The histopathology of BPD reveals interstitial edema, atelectasis, mucosal metaplasia, interstitial fibrosis, necrotizing obliterative bronchiolitis, and overdistended alveoli.

The clinical manifestations of BPD are oxygen dependence, hypercapnia, compensatory metabolic alkalosis, pulmonary hypertension, poor growth, and development of right-sided heart failure. Increased airway resistance with reactive airway bronchoconstriction also is noted and is treated with bronchodilating agents. Severe chest retractions produce negative interstitial pressure that draws fluid into the interstitial space. Together with cor pulmonale, these chest retractions cause fluid retention, necessitating fluid restriction and the administration of diuretics.

Patients with severe BPD may need treatment with mechanical ventilation for many months. To reduce the risk of subglottic stenosis, a tracheotomy may be indicated. To reduce oxygen toxicity and barotrauma, ventilator settings are reduced to maintain blood gases with slightly lower PaO₂ (50 mm Hg) and higher PaCO₂ (50 to 75 mm Hg) levels than for infants during the acute phase of RDS. Dexamethasone therapy may reduce inflammation, improve pulmonary function, and enhance weaning of patients from assisted ventilation. However, dexamethasone may increase the risk of cerebral palsy or abnormal neuromotor developmental outcome. Older survivors of BPD have hyperinflation, reactive airways, and developmental delay. They are at risk for severe respiratory syncytial virus pneumonia and as infants should receive prophylaxis against respiratory syncytial virus.

Retinopathy of Prematurity (Retrolental Fibroplasia)

Retinopathy of prematurity (ROP) is caused by the acute and chronic effects of oxygen toxicity on the developing blood vessels of the premature infant’s retina. The completely vascularized retina of the term infant is not susceptible to ROP. ROP is a leading cause of blindness in very low birth weight infants (<1500 g). Excessive arterial oxygen tensions produce vasoconstriction of immature retinal vasculature in the first stage of this disease. Vaso-obliteration follows if the duration and extent of hyperoxia are prolonged beyond the time when vasoconstriction is reversible. Hypercarbia and hypoxia may contribute to ROP. The subsequent proliferative stages are characterized by extraretinal fibrovascular proliferation, forming a ridge between the vascular and avascular portions of the retina, and by the development of neovascular tufts. In mild cases, vasoproliferation is noted at the periphery of the retina. Severe cases may have neovascularization involving the entire retina, retinal detachment resulting from traction on vessels as they leave the optic disc, fibrous proliferation behind the lens producing leukokoria, and synechiae displacing the lens forward, leading to glaucoma. Both eyes usually are involved, but severity may be asymmetrical.

The incidence of ROP may be reduced by careful monitoring of arterial blood gas levels in all patients receiving oxygen. Although there is no absolutely safe PaO₂ level, it is wise to keep the arterial oxygen level between 50 and 70 mm Hg in premature infants. Infants who weigh less than 1500 g or who are born before 28 weeks’ gestational age (some authors say 32 weeks) should be screened when they are 4 weeks of age or more than 34 weeks’ corrected gestational age, whichever comes first. Laser therapy or (less often) cryotherapy may be used for vitreous hemorrhage or for severe, progressive vasoproliferation. Surgery is indicated for retinal detachment. Less severe stages of ROP resolve spontaneously and without visual impairment in most patients.