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. This collection develops as a result of alveolar and terminal bronchiolar rupture. Pulmonary interstitial emphysema is more frequent in premature infants who require mechanical ventilation for severe lung disease.
Pulmonary interstitial emphysema (PIE) is a radiographic and pathologic diagnosis (see image below and Workup). The principal therapies are lateral decubitus positioning, selective intubation and occlusion of the contralateral bronchus, and high-frequency ventilation. Intensive respiratory management is required to reduce mortality and morbidity in these patients.
Go to Emphysema and Emergent Management of Chronic Obstructive Pulmonary Disease (COPD) for complete information on these topics.
Pulmonary interstitial emphysema is initiated when air ruptures from the alveolar airspace and small airways into the perivascular tissue of the lung. The process often occurs in conjunction with respiratory distress syndrome (RDS). 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, pulmonary interstitial emphysema can occur at low mean airway pressure and probably reflects the underdeveloped lung’s increased sensitivity to stretch. Pulmonary interstitial emphysema has been rarely reported in the absence of mechanical ventilation or continuous positive airway pressure. [1, 2]
Infants with RDS have an initial increase in interstitial and perivascular fluid that rapidly declines 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 pulmonary interstitial emphysema.
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 initiate a vicious cycle in which compression atelectasis of the adjacent lung 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 pulmonary interstitial emphysema can be located inside the pulmonary lymphatic network. 
The extent of pulmonary interstitial emphysema 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. Pulmonary interstitial emphysema does not preferentially localize in any one of the 5 pulmonary lobes.
Pulmonary interstitial emphysema compresses adjacent functional lung tissue and vascular structures and hinders both ventilation and pulmonary blood flow, thus impeding oxygenation, ventilation, and blood pressure. This further compromises the already critically ill infant and significant increases mortality and morbidity. Pulmonary interstitial emphysema can completely regress or decompress into adjacent spaces, causing pneumomediastinum, pneumothorax, pneumopericardium, pneumoperitoneum, or subcutaneous emphysema. 
Risk factors for pulmonary interstitial emphysema include the following:
Respiratory distress syndrome (RDS)
Meconium aspiration syndrome (MAS)
Amniotic fluid aspiration
Infection: Neonatal sepsis, pneumonia,  or both
Low Apgar score or need for positive pressure ventilation (PPV) during resuscitation at birth
Use of high peak airway pressures on mechanical ventilation
Incorrect positioning of the endotracheal tube in one bronchus
United States statistics
The prevalence of pulmonary interstitial emphysema widely varies with the population studied. In a study by Gaylord et al, pulmonary interstitial emphysema developed in 3% of infants admitted to the neonatal intensive care unit (NICU). 
In a retrospective case-controlled study, 11 (24%) of 45 extremely low birth weight infants developed pulmonary interstitial emphysema.  This study was done in the present era of tocolysis, antenatal steroids, and postnatal surfactant administration; however, all infants included in the study were treated with conventional ventilator in the assist-control mode before the onset of pulmonary interstitial emphysema.
The reported incidence of pulmonary interstitial emphysema in published clinical trials can be useful. In a randomized trial of surfactant replacement therapy at birth, in premature infants born at 25-29 weeks' gestation, Kendig et al reported pulmonary interstitial emphysema in 8 (26%) of 31 control neonates and in 5 (15%) of 34 surfactant-treated neonates. 
Another randomized controlled trial of prophylaxis versus treatment with bovine surfactant in neonates born at less than 30 weeks' gestation included 2 (3%) of 62 early surfactant-treated neonates, 5 (8%) of 60 late surfactant-treated neonates, and 15 (25%) of 60 control neonates with pulmonary interstitial emphysema. 
Kattwinkel et al compared prophylactic surfactant administration versus the early treatment of RDS with calf lung surfactant in neonates born at 29-32 weeks' gestation; 3 of 627 neonates in the prophylaxis group and 3 of 621 neonates in the early treatment group developed pulmonary interstitial emphysema.  This information suggests a higher incidence of pulmonary interstitial emphysema in more immature infants as well as those with late surfactant therapy.
Studies reflecting international frequency demonstrated that 2-3% of all infants in NICUs develop pulmonary interstitial emphysema. [12, 13] 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 pulmonary interstitial emphysema 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 pulmonary interstitial emphysema in the postsurfactant era.
In a 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 (11%) of 139 infants in the high-frequency group and 15 (11%) of 134 infants in the conventional group developed pulmonary interstitial emphysema. 
Sex- and age-related demographics
In a study by Plenat et al, pulmonary interstitial emphysema 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 is noted. 
Pulmonary interstitial emphysema is more common in infants of lower gestational age. Pulmonary interstitial emphysema usually occurs within the first weeks of life. Development of pulmonary interstitial emphysema within the first 24-48 hours after birth is often associated with extreme prematurity, very low birth weight, perinatal asphyxia, and/or neonatal sepsis and frequently indicates a grave prognosis.
Pulmonary interstitial emphysema can predispose an infant to other air leaks. In a study by Greenough et al, 31 of 41 infants with pulmonary interstitial emphysema developed pneumothorax, compared with 41 of 169 infants without pulmonary interstitial emphysema.  In addition, 21 of 41 babies with pulmonary interstitial emphysema developed intraventricular hemorrhage (IVH), compared with 39 of 169 among infants without pulmonary interstitial emphysema.
Pulmonary interstitial emphysema 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.
In a more recent study in the postsurfactant era, 4 of 11 infants with pulmonary interstitial emphysema developed severe IVH (grade 2 or higher) compared with 4 of 34 infants without pulmonary interstitial emphysema. Additionally, pulmonary interstitial emphysema remained significantly associated with death (odds ratio, 14.4; 95% confidence interval [CI], 1-208; P = .05). 
Long-term follow-up data are scarce. Gaylord et al demonstrated a high (54%) incidence of chronic lung disease in survivors of pulmonary interstitial emphysema compared with their nursery's overall incidence of 32%. In addition, 19% of the infants developed chronic lobar emphysema; 50% received surgical lobectomies. 
The mortality rate associated with pulmonary interstitial emphysema is reported to be as high as 53-67%. [7, 14] Lower mortality rates of 24% and 38% reported in other studies could result from differences in population selection. [13, 16] Morisot et al reported an 80% mortality rate with pulmonary interstitial emphysema in infants with birth weight of fewer than 1600 g and severe RDS. 
The early appearance of pulmonary interstitial emphysema (< 48 h after birth) is associated with increased mortality. However, this may reflect the severity of the underlying parenchymal disease. [17, 13]
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