Background

Pulmonary interstitial emphysema (PIE) is a collection of gases outside of the n

ormal air passages and inside the connective tissue of the peribronchovascular s
heaths, interlobular septa, and visceral pleura. This collection develops as a r
esult of alveolar and terminal bronchiolar rupture. Pulmonary interstitial emphy
sema is more frequent in premature infants who require mechanical ventilation fo
r severe lung disease.
Pulmonary interstitial emphysema (PIE) is a radiographic and pathologic diagnosi
s (see image below and Workup). The principal therapies are lateral decubitus po
sitioning, selective intubation and occlusion of the contralateral bronchus, and
high-frequency ventilation. Intensive respiratory management is required to red
uce mortality and morbidity in these patients.
This radiograph, obtained from a premature infant at 26 weeks' gestation, shows
characteristic radiographic changes of pulmonary interstitial emphysema (PIE) o
f the right lung.
Pathophysiology
Pulmonary interstitial emphysema is initiated when air ruptures from the alveola
r airspace and small airways into the perivascular tissue of the lung. The proce
ss often occurs in conjunction with respiratory distress syndrome (RDS). Other p
redisposing etiologic factors include meconium aspiration syndrome (MAS), amniot
ic fluid aspiration, and infection.
Positive pressure ventilation (PPV) and reduced lung compliance are significant
predisposing factors. However, in extremely premature infants, pulmonary interst
itial emphysema can occur at low mean airway pressure and probably reflects the
underdeveloped lung s increased sensitivity to stretch. Pulmonary interstitial emp
hysema has been rarely reported in the absence of mechanical ventilation or cont
inuous 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 incr
eased amount of pulmonary connective tissue in the immature lung. The entrapment
of air in the interstitium may initiate a vicious cycle in which compression at
electasis of the adjacent lung then necessitates a further increase in ventilato
ry pressure with still more escape of air into the interstitial tissues.
Plenat et al described two topographic varieties of air leak: intrapulmonary pne
umatosis and intrapleural pneumatosis.[3] . In the intrapulmonary type, which is
more common in premature infants, the air remains trapped inside the lung and f
requently appears on the surface of the lung, bulging under the pleura in the ar
ea of interlobular septa. This phenomenon develops with high frequency on the co
stal surface and the anterior and inferior edges but can involve all of the pulm
onary areas.
In the intrapleural variety, which is more common in more mature infants with co
mpliant lungs, the abnormal air pockets are confined to the visceral pleura, oft
en affecting the mediastinal pleura. The air of pulmonary interstitial emphysema
can be located inside the pulmonary lymphatic network.[4]
The extent of pulmonary interstitial emphysema can vary. It can present as an is
olated interstitial bubble, several slits, lesions involving the entire portion
of one lung, or diffuse involvement of both lungs. Pulmonary interstitial emphys
ema 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 morbid
ity. Pulmonary interstitial emphysema can completely regress or decompress into
adjacent spaces, causing pneumomediastinum, pneumothorax, pneumopericardium, pne
umoperitoneum, or subcutaneous emphysema.[5]
Etiology

Risk factors for pulmonary interstitial emphysema include the following:

Prematurity
Respiratory distress syndrome (RDS)
Meconium aspiration syndrome (MAS)
Amniotic fluid aspiration
Infection: Neonatal sepsis, pneumonia, [6] or both
Low Apgar score or need for positive pressure ventilation (PPV) during resuscita
tion at birth
Use of high peak airway pressures on mechanical ventilation
Incorrect positioning of the endotracheal tube in one bronchus
Epidemiology
United States statistics
The prevalence of pulmonary interstitial emphysema widely varies with the popula
tion studied. In a study by Gaylord et al, pulmonary interstitial emphysema deve
loped in 3% of infants admitted to the neonatal intensive care unit (NICU).[7]
In a retrospective case-controlled study, 11 (24%) of 45 extremely low birth wei
ght infants developed pulmonary interstitial emphysema.[8] This study was done i
n the present era of tocolysis, antenatal steroids, and postnatal surfactant adm
inistration; however, all infants included in the study were treated with conven
tional ventilator in the assist-control mode before the onset of pulmonary inter
stitial emphysema.
The reported incidence of pulmonary interstitial emphysema in published clinical
trials can be useful. In a randomized trial of surfactant replacement therapy a
t birth, in premature infants born at 25-29 weeks' gestation, Kendig et al repor
ted pulmonary interstitial emphysema in 8 (26%) of 31 control neonates and in 5
(15%) of 34 surfactant-treated neonates.[9]
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 neona
tes, and 15 (25%) of 60 control neonates with pulmonary interstitial emphysema.[
10]
Kattwinkel et al compared prophylactic surfactant administration versus the earl
y treatment of RDS with calf lung surfactant in neonates born at 29-32 weeks' ge
station; 3 of 627 neonates in the prophylaxis group and 3 of 621 neonates in the
early treatment group developed pulmonary interstitial emphysema.[11] This info
rmation suggests a higher incidence of pulmonary interstitial emphysema in more
immature infants as well as those with late surfactant therapy.
International statistics
Studies reflecting international frequency demonstrated that 2-3% of all infants
in NICUs develop pulmonary interstitial emphysema.[12, 13] When limiting the po
pulation studied to premature infants, this frequency increases to 20-30%, with
the highest frequencies occurring in infants weighing fewer than 1000 g.[14]
In another study of low birth weight infants, the incidence of pulmonary interst
itial 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.
[15] Minimal information is available about the prevalence of pulmonary intersti
tial emphysema in the postsurfactant era.
In a prospective multicenter trial comparing early high-frequency oscillatory ve
ntilation (HFOV) and conventional ventilation in preterm infants of fewer than 3
0 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 inter
stitial emphysema.[12]
Sex- and age-related demographics
In a study by Plenat et al, pulmonary interstitial emphysema developed equally i
n both sexes (21 males, 18 females). Although these data also included cases wit
h intrapleural pneumatosis, no relationship between sex and type of interstitial
pneumatosis is noted.[3]
Pulmonary interstitial emphysema is more common in infants of lower gestational
age. Pulmonary interstitial emphysema usually occurs within the first weeks of l
ife. Development of pulmonary interstitial emphysema within the first 24-48 hour

s after birth is often associated with extreme prematurity, very low birth weigh
t, perinatal asphyxia, and/or neonatal sepsis and frequently indicates a grave p
rognosis.
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 emphys
ema developed pneumothorax, compared with 41 of 169 infants without pulmonary in
terstitial emphysema.[16] In addition, 21 of 41 babies with pulmonary interstiti
al emphysema developed intraventricular hemorrhage (IVH), compared with 39 of 16
9 among infants without pulmonary interstitial emphysema.
Pulmonary interstitial emphysema may not resolve for 2-3 weeks; therefore, it ca
n increase the length of time of mechanical ventilation and the incidence of bro
nchopulmonary 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).[8]
Long-term follow-up data are scarce. Gaylord et al demonstrated a high (54%) inc
idence 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.[7]
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] Mo
risot et al reported an 80% mortality rate with pulmonary interstitial emphysema
in infants with birth weight of fewer than 1600 g and severe RDS.[17]
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]
History
Pulmonary interstitial emphysema (PIE) is a radiographic and pathologic diagnosi
s. In most cases, the discovery of pulmonary interstitial emphysema may be prece
ded by a decline in the baby's clinical condition. Hypotension and difficulty in
oxygenation and ventilation can suggest the development of pulmonary interstiti
al emphysema.
Alternatively, the baby can present with the signs of one of the complications o
f pulmonary interstitial emphysema, such as pneumothorax. Sometimes, pulmonary i
nterstitial emphysema becomes apparent following reexpansion of a collapsed lung
after drainage of a pneumothorax.
Physical Examination
No specific signs of pulmonary interstitial emphysema are reported. Overinflatio
n of the chest wall and crepitations on auscultation on the affected side may be
present.
Complications
Potential complications of pulmonary interstitial emphysema include the followin
g:
Respiratory insufficiency
Other air leaks (eg, pneumomediastinum, pneumothorax, pneumopericardium, pneumop
eritoneum, subcutaneous emphysema [rare])
Massive air embolism
Chronic lung disease of prematurity
Intraventricular hemorrhage
Periventricular leukomalacia
Death
Differential Diagnoses
Diagnostic Considerations
The roentgenologic appearance of pulmonary interstitial emphysema (PIE) can be c

onfused with the following[18] :

Air-bronchogram in respiratory distress syndrome (RDS)
Aspiration pneumonia
Pulmonary edema
Distended airways in patients on a ventilator
Other differential diagnosis of persistent pulmonary interstitial emphysema incl
udes the following:
Congenital cystic adenomatoid malformation
Lymphangiectasia
Bronchogenic cysts
Congenital lobar emphysema
Cystic lymphangioma
Sequel of prior infection
Diaphragmatic hernia
Approach Considerations
Pulmonary interstitial emphysema (PIE) is a radiographic and pathologic diagnosi
s.
In addition, blood gases should be obtained in these patients, to ensure adequat
e gas exchange.
Radiography
The classic radiologic appearance of pulmonary interstitial emphysema often prov
ides a clear diagnosis. Pulmonary interstitial emphysema is best visualized in t
he anteroposterior supine projection. Pulmonary interstitial emphysema has two b
asic radiographic appearances, linear and cystlike radiolucencies, although both
types often appear together.
Linear radiolucencies are coarse and nonbranching, measure from 3-8 mm, and vary
in width but rarely exceed 2 mm. Cystlike radiolucencies are small, ranging fro
m 1-4 mm in diameter. Although generally round, they may also appear oval or sli
ghtly lobulated.
The disorganized haphazard distribution of pulmonary interstitial emphysema in l
ocalized areas is unlike the anatomically organized pattern of the air-bronchogr
am. The air-bronchogram is a classic radiographic sign of respiratory distress s
yndrome (RDS), which should not be confused with pulmonary interstitial emphysem
a.
In RDS, long, smooth, branching, linear radiolucencies decrease in caliber from
the hilum and frequently disappear at the lung periphery. Pulmonary interstitial
emphysema should be suspected when coarse radiolucencies appear in the lung per
iphery or when the lucencies do not branch in a pattern consistent with the norm
al bronchial tree.
In some patients receiving mechanical ventilation, distended airways and alveoli
have a somewhat similar radiographic appearance to that of pulmonary interstiti
al emphysema. Over time, it either progresses to a classic radiographic picture
of pulmonary interstitial emphysema or resolves very rapidly as ventilator setti
ngs are decreased.
Pulmonary interstitial emphysema can rarely be misinterpreted as normally aerate
d lung surrounded by exudate as in an aspiration syndrome or pulmonary edema.[18
]
This radiograph, obtained from a 1-day-old premature infant at 24 weeks' gestat
ion, shows bilateral pulmonary interstitial emphysema (PIE). Linear radiolucenci
es extending up to the lung periphery are visible.
This radiograph, obtained from a premature infant at 26 weeks' gestation, shows
characteristic radiographic changes of pulmonary interstitial emphysema (PIE) o
f the right lung.
This radiograph shows pneumothorax and pulmonary interstitial emphysema (PIE) o
n the right side. Interstitial air prevents collapse of the underlying lung by a
tension pneumothorax. In such cases, extreme caution is required during drainag
e of a pneumothorax to avoid perforation of the underlying lung.
CT scan of the chest can be a helpful diagnostic tool if doubt about the diagnos
is remains, particularly in persistent cases and if surgical interventions are b
eing considered. A round or linear soft-tissue component seen in the wall of or

within the air-containing spaces is a key to making the correct diagnosis.[19]

Go to Imaging in Pulmonary Interstitial Emphysema for complete information on th
is topic.
Histologic Findings
The histology of pulmonary interstitial emphysema is well described by Plenat et
al.[3] The histology demonstrates interstitial slits preferentially located in
perivenous topography.
Sometimes, the peribronchial arterial or arteriolar sheaths are involved. Air di
ssects through a plane just next to the arterial or arteriolar face, opposite th
e bronchus, which is pushed into adjoining parenchyma. The bronchoarterial solid
arity most often is respected.
Seldom, air can dissect arterioles and bronchioles and isolate them from the adj
acent lobules. On the periphery of interstitial slits, the small vessels are com
pressed but never ruptured, whereas the collagen fibers are constantly broken an
d squeezed together.