PULMONARY INTERSTITIAL EMPHYSEMA PIE

Pulmonary Interstitial Emphysema PIE
Pulmonary interstitial emphysema (PIE) is a collection of gases outside of the normal air passages and inside the connective tissue of the peribronchovascular sheaths, interlobular septa, and visceral pleura secondary to alveolar and terminal bronchiolar rupture. PIE is more frequent in premature infants who require mechanical ventilation for severe lung disease. Once PIE is diagnosed, intensive respiratory management is required to reduce mortality and morbidity.

Pathophysiology: PIE often occurs in conjunction with respiratory distress syndrome (RDS), but other predisposing etiologic factors include meconium aspiration syndrome (MAS), amniotic fluid aspiration, and infection. Positive pressure ventilation (PPV) and reduced lung compliance are significant predisposing factors. However, in extremely premature infants, PIE can occur at low mean airway pressure and probably reflects increased sensitivity of the underdeveloped lung to stretch. The process of PIE is initiated when air ruptures from the alveolar airspace and small airways into the perivascular tissue of the lung.

Infants with RDS have an initial increase in interstitial and perivascular fluid that declines rapidly over the first few days of life. This fluid may obstruct the movement of gas from ruptured alveoli or airways to the mediastinum, causing an increase of PIE. Another possible mechanism for entrapment of air in the interstitium is the increased amount of pulmonary connective tissue in the immature lung. The entrapment of air in the interstitium may result in a vicious cycle causing compression atelectasis of the adjacent lung, which then necessitates a further increase in ventilatory pressure with still more escape of air into the interstitial tissues.

Plenat et al described two topographic varieties of air leak, intrapulmonary pneumatosis and intrapleural pneumatosis. In the intrapulmonary type, which is more common in premature infants, the air remains trapped inside the lung and frequently appears on the surface of the lung, bulging under the pleura in the area of interlobular septa. This phenomenon develops with high frequency on the costal surface and the anterior and inferior edges but can involve all of the pulmonary areas. In the intrapleural variety, which is more common in more mature infants with compliant lungs, the abnormal air pockets are confined to the visceral pleura, often affecting the mediastinal pleura. The air of PIE may be located inside the pulmonary lymphatic network.

The extent of PIE can vary. It can present as an isolated interstitial bubble, several slits, lesions involving the entire portion of one lung, or diffuse involvement of both lungs. PIE does not localize preferentially in any one of the 5 pulmonary lodes.

PIE compresses adjacent functional lung tissue and vascular structures and hinders both ventilation and pulmonary blood flow, resulting in impedance of oxygenation, ventilation, and blood pressure. This further compromises the already critically ill infant with a significant increase in mortality and morbidity. PIE can regress completely or decompress into adjacent spaces causing pneumomediastinum, pneumothorax, pneumopericardium, pneumoperitoneum, or subcutaneous emphysema.

Frequency:
• In the US: The prevalence of PIE varies widely with the population studied. In a study by Gaylord et al, PIE developed in 3% of infants admitted to the neonatal intensive care unit (NICU). No specific data are available on the prevalence of PIE in the postsurfactant era; reported incidence of PIE in published clinical trials can be useful. In a randomized trial of surfactant replacement therapy at birth, in premature infants of 25-29 weeks' gestation, Kendig et al found PIE in 8 of 31 (26%) control neonates and 5 of 34 (15%) surfactant-treated neonates.

Another randomized controlled trial of prophylaxis versus treatment with bovine surfactant in neonates of less than 30 weeks' gestation included 2 of 62 (3%) early surfactant-treated, 5 of 60 (8%) late surfactant-treated, and 15 of 60 (25%) control neonates with PIE. Kattwinkel et al compared prophylactic surfactant administration versus the early treatment of RDS with calf lung surfactant in neonates of 29-32 weeks' gestation. Three of 627 neonates in the prophylaxis group and 3 of 621 neonates in the early treatment group developed PIE. This information suggests a higher incidence of PIE in more immature infants.

• Internationally: Studies reflecting international frequency demonstrated that 2-3% of all infants in NICUs develop PIE. When limiting the population studied to premature infants, this frequency increases to 20-30%, with the highest frequencies occurring in infants weighing fewer than 1000 g. In another study of low birth weight infants, the incidence of PIE was 42% in infants with birth weight of 500-799 g, 29% in those with birth weight of 800-899 g, and 20% in those with birth weight of 900-999 g. Minimal information is available about the prevalence of PIE in the postsurfactant era. In a recent prospective multicenter trial comparing early high-frequency oscillatory ventilation (HFOV) and conventional ventilation in preterm infants of fewer than 30 weeks' gestation with RDS, 15 of 139 (11%) infants in the high-frequency group and 15 of 134 (11%) infants in the conventional group developed PIE.

Mortality/Morbidity: The mortality rate associated with PIE is reported to be as high as 53-67%. Lower mortality rates of 24% and 39% reported in other studies could result from differences in population selection. Morisot et al reported an 80% mortality rate with PIE in infants with birth weight of fewer than 1600 g and severe RDS. The early appearance of PIE (<48 h after birth) is associated with increased mortality, but this may reflect the severity of the underlying parenchymal disease.

In survivors, morbidity also is high. PIE can predispose an infant to other air leaks. In a study by Greenough et al, 31 of 41 infants with PIE developed pneumothorax, compared to 41 of 169 infants without PIE. In addition, 21 of 41 babies with PIE developed intraventricular hemorrhage (IVH), compared to 39 of 169 among infants without PIE. PIE may not resolve for 2-3 weeks; therefore, it can increase the length of time of mechanical ventilation and the incidence of bronchopulmonary dysplasia. Some infants may develop chronic lobar emphysema, which may require surgical lobectomies. No specific mortality and morbidity data concerning PIE in the postsurfactant era are available.

Sex: In a study by Plenat et al, PIE developed equally in both sexes (21 males, 18 females). Although these data also included cases with intrapleural pneumatosis, no relationship between sex and type of interstitial pneumatosis exists.

Age: PIE is more frequent in infants of lower gestational age. PIE usually occurs within the first weeks of life. Development of PIE within the first 24-48 hours after birth often is associated with extreme prematurity, very low birth weight, perinatal asphyxia, and/or neonatal sepsis and frequently indicates a grave prognosis.

History: PIE is a radiographic and pathologic diagnosis. In most cases, the discovery of PIE may be preceded by a decline in the baby's clinical condition. Hypotension and difficulty in oxygenation and ventilation can suggest the development of PIE. Alternatively, the baby can present with the signs of one of the complications of PIE, such as pneumothorax. Sometimes, PIE becomes apparent following reexpansion of a collapsed lung after drainage of a pneumothorax. Physical: No specific signs of PIE exist. Overinflation of the chest wall and crepitations on auscultation on the affected side may be present.

Causes:
• Risk factors
o Prematurity
o Respiratory distress syndrome
o Meconium aspiration syndrome
o Amniotic fluid aspiration
o Infection - Neonatal sepsis, pneumonia, or both
o Low Apgar score or need for PPV during resuscitation at birth o Use of high peak airway pressures on mechanical ventilation
o Incorrect positioning of the endotracheal tube in one bronchus

Lab Studies: Blood gases should be obtained to ensure adequate gas exchange.

Imaging Studies:
• Chest radiograph
o The classic radiologic appearance of PIE often provides a clear diagnosis. PIE is best visualized in the anteroposterior supine projection. PIE has two basic radiographic appearances, linear and cystlike radiolucencies, although both types often appear together.

o Linear radiolucencies are coarse and nonbranching, measure from 3-8 mm, and vary in width but rarely exceed 2 mm.

o Small cystlike radiolucencies extend in diameter from 1-4 mm, and, though generally round, they may appear oval or slightly lobulated.

o Disorganized haphazard distribution of PIE in localized areas is unlike the anatomically organized pattern of the air-bronchogram. The air-bronchogram is a classic radiographic sign of RDS, which should not be confused with PIE. In RDS, long, smooth, branching, linear radiolucencies decrease in caliber from the hilum and frequently disappear at the lung periphery. PIE should be suspected when coarse radiolucencies appear in the lung periphery or when the lucencies do not branch in a pattern consistent with the normal bronchial tree.

o In some patients receiving mechanical ventilation, distended airways and alveoli have a somewhat similar appearance to that of PIE on radiographs. Over time, it either progresses to a classic radiographic picture of PIE or resolves very rapidly as ventilator settings are decreased.

o PIE rarely can be misinterpreted as normally aerated lung surrounded by exudate as in an aspiration syndrome or pulmonary edema.

Histologic Findings: The histology of PIE is well described by Plenat et al. Their histologic study demonstrates interstitial slits preferentially located in perivenous topography. Sometimes, the peribronchial arterial or arteriolar sheaths are involved. Air dissects through a plane just next to the arterial or arteriolar face, opposite the bronchus, which is pushed into adjoining parenchyma. The bronchoarterial solidarity most often is respected. Seldom, air can dissect arterioles and bronchioles and isolate them from the adjacent lobules. On the periphery of interstitial slits, the small vessels are compressed but never ruptured, while the collagen fibers constantly are broken and squeezed together.