1604 SECTION XXVI — Pathophysiology of Neonatal Diseases
158
Pathophysiology of Respiratory
Distress Syndrome
Alan H. Jobe
Respiratory distress syndrome (RDS) in preterm infants is the
disease most identified with the development of neonatal inten-
sive care. Before the late 1960s, the only therapy for preterm
infants who developed progressive respiratory failure shortly
after birth was supplemental oxygen and most of the infants
died. At autopsy the lungs were atelectatic and had epithelial
injury with hyaline membranes, resulting in the name hyaline
membrane disease (HMD). Avery and Mead1 reported in 1959
that saline extracts of lungs of infants with HMD had high
minimum surface tensions in contrast to lungs of infants without
HMD. The HMD lungs also inflated poorly and collapsed to low
volumes at low transpulmonary pressures.2 Saline lavages of the
air spaces recovered small amounts of surfactant lipids that had
poor function in vitro.3 Although mechanical ventilation was
used in the 1960s, the mortality rate was high. The first success-
ful therapy was continuous positive airway pressure (CPAP) first
described by Gregory and colleagues in 1971.4 Concurrently,
antenatal tests to predict the risk of what was now called RDS
were developed using amniotic fluid.5 Liggins and Howie6
(1972) reported that the risk of having RDS could be decreased
with antenatal corticosteroid treatments. These innovations,
together with the development of infant ventilators, a better
understanding of their use and the physiology of the preterm
lung, and improved intensive care for preterm infants (tempera-
ture control, nutrition, infection control) resulted in a striking
decline in deaths from RDS in the United States from 1970 to
1990 (Figure 158-1).7 The care of infants with RDS was simpli-
fied and mortality further decreased after 1990 with surfactant
therapy8 (reviewed in Chapter 86) and with the widespread use
of antenatal corticosteroids.9 The strikingly improved outcomes
for infants with RDS are the great success story in neonatology.
By 2015, an infant in the US should not die of RDS unless the
disease is complicated by severe prematurity or other lung
pathologies.
EPIDEMIOLOGY OF RESPIRATORY
DISTRESS SYNDROME
RDS is closely associated with preterm birth, with the incidence
increasing as gestational age decreases. The standard diagnosis
for RDS requires progressive respiratory failure beginning at or
 Chapter 158 — Pathophysiology of Respiratory Distress Syndrome 1605

shortly after birth. The respiratory failure is characterized by
respiratory distress as clinically identified by tachypnea, grunt-
ing, nasal flaring, and chest wall retractions and an increasing
oxygen requirement. The chest film shows poor inflation with
a uniform hazy and granular appearance with air bronchograms.
The odds ratio for RDS at 34 weeks’ gestational age is 40 relative
to term infants (Figure 158-2, A).10 The risk is much higher and
approaches 100% at gestations below 34 weeks (Figure 158-2,
B).11 The prediction of RDS with the lecithin/sphingomyelin
(L/S) ratio also is shown for normal pregnancies in the figure
relative to gestational age.12 The human lung is not consistently
mature enough to avoid RDS until a gestational age of about 35
weeks, but in clinical practice the incidence of RDS at 35 weeks
is still about 20%. This discrepancy is explained by the human
lung’s remarkable capacity to induce lung maturation from
3.0 Endotracheal tube CPAP
Mechanical ventilation with PEEP
2.5
Deaths per 1000 live births
abnormalities associated with preterm birth or in response to
antenatal corticosteroid treatments.
This epidemiology and the diagnosis of RDS can be con-
founded by a number of factors frequently encountered in neo-
natal practice. Low-birth-weight infants at high risk of RDS often
are intubated in the delivery room and treated with surfactant,
which prevents a diagnosis of surfactant-deficiency RDS. The
management strategy of initiating CPAP therapy in the delivery
room to assist newborn transition can mitigate the early respira-
tory distress and the need for oxygen.13,14 Further, for epidemio-
logic purposes, the NICHD Neonatal Research Network (NRN)
has simplified the clinical diagnosis of RDS. For the interval 1997
to 2002, the NRN diagnosis of RDS required oxygen use for the
interval of 6 to 24 hours after birth with some respiratory support
to 24 hours and a chest film consistent with RDS.15 In that era,
the incidence of RDS was 63% for infants weighing 500 to
1000 g. In contrast for the years 2003 to 2007, the diagnosis of
RDS was given to 95% of 22 to 28 weeks’ gestational age infants
based only on the need for oxygen for more than the first 6 hours
of life.16 In contrast, 69% of 309 patients with birth weights of
0.5 to 1 kg were successfully managed with CPAP and without

Nasal CPAP surfactant in South Africa.17 The delivery room management of

2.0
1.5
1.0
Oxygen
0.5
Frequent use of maternal
corticosteroids
0
1964 1969 1974 1979 1984 1989 1994 1999 2004 2009 2014
Figure 158-1 Deaths from respiratory distress syndrome (RDS)
in the United States from 1968 to 2010. The curve shows deaths
from RDS in preterm infants per 1000 live births. The curve for the
striking decrease in death is annotated for innovations that improved
outcomes for infants with RDS. The infants who died in the 1960s
and 1970s were larger and more mature than the few infants who
now die of RDS. CPAP, Continuous positive airway pressure; PEEP,
positive end-expiratory pressure. (Republished with permission from
Lee K, et al: Trend in mortality from respiratory distress syndrome in
the United States, 1970-1995. J Pediatr 434–440, 1999.)
the very preterm infant with CPAP likely can decrease the fre-
quency of the diagnosis of RDS. In contrast, intubation and
ventilation in the delivery room are likely to result in a diagnosis
of RDS even if the infant has relatively clear lungs and no oxygen
requirement. Further, the smallest and most immature infants
may need CPAP to maintain functional residual capacity (FRC)
and to decrease apnea.18 These infants may be given a diagnosis
Surfactant treatment
of RDS even if surfactant is adequate.
RDS is a diagnosis of exclusion, particularly in the very
preterm infant (Box 158-1). Very preterm infants are born
because the pregnancy is not normal. A frequent cause of very
preterm birth is preeclampsia, which can result in fetal growth
restriction and abnormal lung parenchymal and microvascular
development in animal models and in infants.19 The associated
respiratory abnormalities may coexist or mimic RDS. Severe pul-
monary hypoplasia is a distinct diagnosis resulting from space-
occupying masses in the chest, which inhibit fetal breathing, or
a lack of amniotic fluid (Potter syndrome, prolonged rupture of
membranes). However, milder variants of pulmonary hypoplasia
are probably frequent and difficult to distinguish from RDS. The
majority of preterm infants born at <30 weeks’ gestational age
will have been exposed to histologic chorioamnionitis,20 and the

50 100 8
% RDS L/S ratio
RDS
40 80
6
30 60
L/S ratio
% RDS

Transient tachypnea 4
20 40
2
10 20

0 0 0
32 34 36 38 40 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40
Term
A Gestational age (weeks) B Gestational age (weeks)
Figure 158-2 A, Odds ratios for respiratory morbidities diagnosed as respiratory distress syndrome (RDS) or transient tachypnea for 180,000
births from 2002 to 2008 relative to birth at 40 weeks’ gestational age. B, Curve for percent infants with RDS versus gestational age in com-
parison to curve for lecithin/sphingomyelin (L/S ratio) values for normal pregnancies. The box highlights the L/S ratio measured on amniotic
fluid that reliably predicts RDS if delivery were to occur. (A, Data from Consortium on safe labor, respiratory morbidity in late preterm births.
JAMA 304:419, 2011. B, Data from Chang E, Menard K, Vermillion S, et al: The association between hyaline membrane disease and pre-
eclampsia. Am J Obstet Gynecol 191:1414, 2004 and Gluck L, Kulovich M, Borer R, Keidel W: The interpretation and significance of the
lecithin-sphingomyelin ratio in amniotic fluid. Am J Obstet Gynecol 120:142, 1974.)
1606 SECTION XXVI — Pathophysiology of Neonatal Diseases
Box 158-1 Fetal and Newborn Conditions
That May Confound to a Diagnosis of
Respiratory Distress Syndrome
1. Fetal growth restriction/preeclampsia
2. Chorioamnionitis/fetal lung inflammation
3. Neonatal pneumonia
4. Pulmonary hypoplasia
5. Transient tachypnea of the newborn
inflammation in amniotic fluid results in inflammation in the fetal
lungs even if frank pneumonia or positive cultures are not identi-
fied.21 Tracheal aspirates of these infants contain inflammatory
cells and increased levels of cytokines. The organisms are often
low-grade pathogens such as Ureaplasma that do not grow using
standard microbiologic techniques (see Chapter 79).
Proinflammatory mediators such as lipopolysaccharide,
interleukin-1, or live organisms cause an inhibition of alveolar
development and microvascular injury in the preterm fetal lung.22
Similarly, antenatal corticosteroids inhibit saccular and alveolar
development in multiple animal models.23 In fetal sheep some
inflammatory stimuli and antenatal corticosteroids increase sur-
factant and thus mature the fetal lungs.24 However, the adverse
effects of inflammation and interference with lung structural
development may contribute to the variable presentations and
progression of RDS. Some infants will have frank pneumonia at
birth from pathogens such as Group B streptococcus and Esch-
erichia coli with clinical presentations that mimic severe RDS.
The incidence of the diagnosis of transient tachypnea of the
newborn increases as gestational age decreases (see Figure
158-2, A). Transient tachypnea is respiratory distress resulting
from delayed clearance of fetal lung fluid from the airways and
lung parenchyma. This abnormality is diagnosed primarily in
moderately preterm infants or term infants delivered by cesarean
section before labor.25 However, the sodium transporters that
help keep the air space free of excess fluid following delivery
are developmentally regulated, and low function in the preterm
lung likely contributes to RDS.26 Gastric aspirates from infants
with a diagnosis of transient tachypnea also have decreased
lamellar body counts and surfactant function.27 Therefore, RDS
likely includes the pathophysiology of delayed fluid clearance
and may be indistinguishable from severe transient tachypnea.
RDS is in part a diagnosis of exclusion because the clinician
relies only on clinical and radiologic findings. Any cause of respi-
ratory compromise will result in tachypnea, retractions, and
flaring in the term and preterm infant. The hazy lungs by radio-
logic assessment can reflect surfactant deficiency, pneumonia,
hypoplasia, or excess fluid, or simply the lungs at expiration in
the early hours of life. Although not widely used, a more specific
diagnosis can result from analyses of gastric fluid aspirated soon
after birth by counting lamellar bodies or measuring the stability
of bubbles.28,29 For infants thought to have RDS, perhaps the best
diagnostic test is the clinical response to surfactant treatment
characterized primarily by an acute increase in oxygenation.
Infants can have RDS and other lung abnormalities at the same
time. For example, fetuses exposed to chorioamnionitis and
funisitis—an indicator of a fetal inflammatory response—will
have decreased clinical response to surfactant treatment.30
LUNG STRUCTURE OF THE PRETERM LUNG
WITH RESPIRATORY DISTRESS SYNDROME
Lung structure is the substrate on which RDS develops and sur-
factant functions. The preterm lung changes structure as it
6
Adult number of alveoil (%)
100
Alveoil per week (%)
80 5
4
60
3
40
2
20
1
0
0
32 wk 2 4 6 8 10 12 14 16 18
Term
Months after term
A
5
Surface area (m2)
4
3
2
1
0
18 20 22 24 26 28 30 32 34 36 38 40 42 44 46
B Gestational age (weeks)
Figure 158-3 Lung structural maturation. A, Alveolar number and
weekly rate of accumulation of alveoli are expressed as percentage
of the adult number of alveoli. The curves assume that the term infant
has 30% of the adult number of alveoli. B, The large increase in lung
surface area does not occur until after the saccular lung begins to
alveolarize. (A, Modified from Hislop AA, Wigglesworth JS, Desai R:
Alveolar development in the human fetus and infant. Early Hum Dev
13:1, 1986. B, Modified from Langston C, Kida D, Reed M, et al:
Human lung growth in late gestation and in the neonate. Am Rev
Respir Dis 129:607, 1984.)
matures, and the structural maturation affects the responses of
the lung to surfactant and the lung complications that may occur
after preterm birth. The lung of the term infant contains approxi-
mately 30% of the 500 million alveoli that are present in the adult
lung (Figure 158-3).31-33 The fetal lung at the margin of viability
at 24 weeks’ gestation has just matured beyond the canalicular
stage to the early saccular stage of lung development.34 The sac-
cular lung has undifferentiated distal air saccules with a poorly
developed capillary microvasculature. The potential surface area
for gas exchange of the developing human lung does not increase
much before 30 weeks’ gestation, and alveolar septation of the
distal saccules does not begin until after 34 weeks. The rate of
septation to form alveoli then is high until term. After birth, the
rate of alveolar septation decreases through early infancy, but
alveolar development and remodeling probably continue at a
slow rate throughout life.35 The early lung maturation that com-
monly occurs in preterm infants with maternal glucocorticoid
treatment or with exposure to chorioamnionitis will accelerate
mesenchymal involution and increase surfactant but may delay
alveolar septation.36,37
LUNG INJURY WITH MECHANICAL VENTILATION
A major factor determining how the preterm lung will respond
to treatment and injury is the structural maturation of the lung
at delivery.38 The preterm lung with RDS has lung gas pressure-
volume characteristics quite differ from the term or adult lung.
As illustrated in Figure 158-4, all lung volume variables are less
for the preterm infant with RDS than in the adult lung. FRC is
lower, total lung capacity (TLC) is lower, and the pressures
 Chapter 158 — Pathophysiology of Respiratory Distress Syndrome 1607

ADULT LUNG PRETERM LUNG

Injury—close to TLC Injury—close to TLC

80 30

Volume (mL/kg)
50 mL/kg 50 mL/kg

30 15

Injury—below FRC Injury—below FRC

Pressure 20 Pressure 30

Figure 158-4 Pressure-volume relationships for the lung with premature respiratory distress syndrome (RDS) and the adult lung. The
preterm lung requires higher pressures to inflate to achieve a lower total lung capacity (TLC) than the adult lung. The premature lung also has
a lower functional residual capacity (FRC) than the adult lung. The lung is likely to be injured if ventilation volumes are below FRC or encroach
on TLC as indicated by the injury boxes.

needed to achieve lung opening and TLC are higher for the
premature lung. These pressure-volume characteristics resulting
from the immature air space structures explain why the preterm
lung is easily injured with mechanical ventilation.
The lungs of infants who have died from RDS have alveolar
atelectasis, alveolar and interstitial edema, and hyaline mem-
branes, primarily in distorted small airways. Hyaline membranes
are a coagulum of cell debris, surfactant, and serum proteins that
result from epithelial injury and large amounts of soluble and
insoluble proteins in the air spaces. The earliest anatomic lesion
identified in the lungs of infants who died of RDS shortly after
birth is epithelial disruption in the small airways.39 In preterm
surfactant-deficient rabbits, bronchiolar epithelial injury devel-
ops within minutes of delivery and ventilation. This injury can
be prevented with surfactant treatment (Figure 158-5).40 The
epithelial damage occurs because the small airways of the imma-
ture lung are compliant and distort during ventilation. Lung fluid
clearance is not complete and small airways are fluid filled at A B
end-expiration.26 Ventilation requires high peak pressures in the
noncompliant lung to achieve relatively normal tidal volumes Figure 158-5 Bronchiolar-epithelial injury in respiratory distress
and carbon dioxide removal. syndrome. A, Lungs from preterm ventilated rabbits had fluid-filled
The preterm lung has both endothelial and epithelial abnor- airways with epithelial tears in the absence of surfactant treatment.
malities that cause proteinaceous pulmonary edema after deliv- B, With surfactant treatments, the bronchiolar epithelium remained
ery and ventilation.41 In preterm lambs ventilated for the first 3 intact, and fluid was cleared from the airways and alveoli. (From
hours of life, 11.5% per hour of the labeled albumin mixed with Lachmann B, Berggren P, Curstedt T, et al: Combined effects of
the fetal lung fluid at birth left the lung, and 1.7% per hour of surfactant substitution and prolongation of inspiration phase in artifi-
the labeled albumin given intravascularly at birth was recovered cially ventilated premature newborn rabbits. Pediatr Res 16:921,
from the air spaces, demonstrating the bidirectional movement 1982.)
of albumin across an injured alveolar epithelium.42 The protein
in the alveolar washes increased more than four-fold, indicating
that the net protein movement was from the intravascular com-
partment to the air spaces. The rate of protein accumulation in monkeys with RDS.44 The flash-frozen lungs, evaluated by light
the air spaces was striking in preterm ventilated rabbits. Approx- and scanning electron microscopy, of animals with RDS had
imately 2% to 3% of the intravascularly injected and labeled overexpanded distal airways and underexpanded and fluid-filled
albumin was recovered from the air spaces within 20 minutes alveolar spaces (Figure 158-6).45 By scanning electron micros-
of birth. The leakage was not homogeneous.43 Leakage involved copy, the alveoli of animals with RDS were filled with protein-
an increasing number of saccules with time and appeared to aceous liquid, and the interstitium was swollen by edema fluid
occur directly into the alveoli rather than at the bronchiolar (Figure 158-7).45 The lungs of monkeys with RDS exhibit alveolar
level. and interstitial edema because of the slow clearance of fetal lung
Lung gas volumes of infants with RDS can be low because the fluid after birth and the entrance of proteinaceous edema into
lung has not yet developed sufficiently to hold much gas or the air spaces.
because distal air spaces are uninflated (see Figure 158-4). Five clinical variables are important determinants of the
Another cause of the volume loss in the lungs of infants with amount of edema formation: gestational age, tidal volume, posi-
RDS is alveolar edema. After 3 hours of ventilation, the TLC was tive end-expiratory pressure (PEEP), antenatal corticosteroid
48 mL/kg in preterm monkeys without RDS and 19 mL/kg for treatment, and surfactant treatment. In preterm animal models,
1608 SECTION XXVI — Pathophysiology of Neonatal Diseases
A B
Figure 158-6 Fluid-filled alveoli with respiratory distress syn-
drome (RDS). A, Light micrograph of flash-frozen lung tissue from a
preterm monkey without RDS. The alveoli and alveolar ducts (indi-
cated by A) are air-filled. B, In contrast, lung tissue from a monkey
with RDS has some air-filled alveoli, and other alveoli are completely
or partially filled with proteinaceous material. The arrows indicate
partially filled alveoli. (From Jackson JC, Truog WE, Standaert TA,
et al: Effect of high-frequency ventilation on the development of
alveolar edema in premature monkeys at risk for hyaline membrane
disease. Am Rev Respir Dis 143:865, 1991.)
protein leaks from the vascular space to the alveolar space and
from the alveolar space to the vascular space increase as gesta-
tion decreases (Figure 158-8).46 The pressure needed to achieve
an adequate tidal volume and gas exchange decreases as gesta-
tional age increases. Therefore a possible explanation of the
increased leak is the barotrauma caused by the ventilatory
requirements needed to support the more immature lung. In the
mature lung, pulmonary edema occurs after lung overdistention
using high tidal volumes (volutrauma). High pressures or volumes
are not required to injure the immature surfactant-deficient lung
because nonuniform inflation causes focal overdistention.
Without surfactant treatment, pulmonary edema occurs with
relatively low tidal volume ventilation.47 The end-expiratory
volume of the preterm lung also is an important injury variable.48
Ventilation of preterm lambs with the same tidal volume results
in different amounts of protein recovery from the airways
depending on the PEEP used to support end-expiratory lung
volume.49 Antenatal treatment with antenatal corticosteroids also
can greatly decrease injury and edema.50,51
These observations describe outcomes of preterm animals
ventilated from birth for several hours. The preterm lung may
be most easily injured with the initiation of ventilation at birth
because the air spaces are fluid filled and the clinician wants to
establish gas exchange quickly. Tidal volumes increased to
15 mL/kg severely injure the airways of preterm lambs, and
subsequent ventilation amplifies and propagates that injury to
the lung parenchyma (Figure 158-9).52,53 The injury can be
decreased with lower tidal volumes, the use of PEEP to maintain
FRC, and surfactant treatment.54 These experiments in animal
models provide the context for understanding why the gentle
initiation of ventilation in the delivery room when supported
by CPAP can decrease the number of infants diagnosed with
RDS.14
An integrated perspective on the major variables that deter-
mine the pathophysiology of RDS is shown in Figure 158-10.
Lung development as modified by gestational age and exposures
such as antenatal corticosteroids, inflammation, and growth
A
B
Figure 158-7 Scanning electron micrographs from a preterm
monkey without respiratory distress syndrome (RDS; A) and a preterm
monkey at the same gestational age with RDS (B). The lung from the
RDS animal has dilated alveolar ducts and interstitial and alveolar
edema. (From Jackson JC, Truog WE, Standaert TA, et al: Effect of
high-frequency ventilation on the development of alveolar edema in
premature monkeys at risk for hyaline membrane disease. Am Rev
Respir Dis 143:865, 1991.)
restriction determine the lung structure and the amount of sur-
factant that the preterm infant has at birth. The preterm lung
structure can be injured to alter tissue function, primarily by
epithelial disruption causing pulmonary edema. An inadequate
surfactant pool can be corrected with surfactant treatment. The
integration of these variables primarily determines the severity
of RDS.
OVERVIEW OF SURFACTANT METABOLISM
IN RESPIRATORY DISTRESS SYNDROME
Surfactant metabolism in the adult lung is the basis for the discus-
sion of surfactant metabolism in the preterm lung with RDS
(Figure 158-11).55 Extensive descriptions of the surfactant lipids
and proteins, the biophysics of surfactant function, and regula-
tion of synthesis and secretion are found in Chapters 81 through
87. Surfactant lipids are synthesized from glucose and lipid
precursors by type II cells in the alveoli. The lipids are processed
via the Golgi to multivesicular bodies that aggregate the lipids
with the surfactant protein (SP)-B and SP-C. The surfactant
is stored in membrane-enclosed lipid and protein structures
called lamellar bodies in the type II cells. Lamellar bodies are
secreted by exocytosis either constitutively or when type II cells
are stimulated by secretagogues such as β-agonists and purines
 Chapter 158 — Pathophysiology of Respiratory Distress Syndrome 1609

INTRAVASCULAR 131I-ALBUMIN vesicles that contain the phospholipids but essentially no SPs.
The SPs are cleared separately by macrophages and type II cells.
Approximately half of the surfactant components are catabolized
9
by alveolar macrophages and the other half are catabolized by
type II cells in the adult mouse lung.58 However, the type II cells
6
also take up phospholipids, SP-B, SP-C, and SP-A and recycle
them via multivesicular bodies back to lamellar bodies for rese-
3 cretion. At steady state, the alveolar surfactant pool is very meta-
bolically active and is replaced every 5 hours.59 The airway
Recovery in lungs (%)

0 clearance rates and efficiencies of recycling for SP-A, -B, and -C

120 130 140 150 are similar to the lipids.60
A
CHARACTERISTICS OF SURFACTANT
INTRATRACHEAL 125I-ALBUMIN
100
IN THE PRETERM
COMPOSITION
The surfactant recovered from the air spaces of preterm animals
80 with RDS has less saturated phosphatidylcholine relative to total
phospholipids.61 The lower amount of saturated phosphatidyl-
cholines results in a surfactant with decreased surface activity.
The surfactant of a mature animal or man contains approxi-
60 mately 8% phosphatidylglycerol and little phosphatidylinositol.
120 130 140 150 In contrast, surfactant from the preterm contains much more
B phosphatidylinositol than phosphatidylglycerol.62 These two
acidic phospholipids are interchangeable in terms of surfactant
function, but the lack of phosphatidylglycerol in surfactant indi-
PROTEIN IN ALVEOLAR LAVAGE cates lung immaturity or injury to the type II cells. The changes
in the L/S ratio in amniotic fluid with advancing gestation result
150 primarily from the mixing of fetal lung fluid with amniotic fluid.
The L/S ratio increases after approximately 34 weeks of gesta-
mg/kg

100 tion in normal pregnancies, indicating progressive lung matura-

50 Term
0 nancy, the phosphatidylinositol content of amniotic fluid
120 130 140 150
C Gestational age (days)
Figure 158-8 Effect of gestational age on the movement of
labeled albumin and protein in and out of the air spaces of
preterm lambs. Peak ventilatory pressures were held constant at the
three gestational ages for 3 hours of ventilation. The more preterm
lambs were treated with surfactant to achieve similar ventilatory pres-
sures. A, 131I-albumin was given into the vascular space, and the net
recovery in alveolar washes and in the total lung (sum of parenchyma
plus alveolar wash) decreased as gestational age increased toward
term. B, 125I-albumin was given into the airways at birth and the
amount that was lost from the lungs decreased as gestation increased.
C, The total amount of protein in alveolar washes decreased as gesta-
tion increased. (Data from Jobe A, Jacobs H, Ikegami M, et al: Lung
protein leaks in ventilated lambs: effects of gestational age. J Appl
Physiol 58:1246, 1985.)
or by mechanical stretch. The other SPs, SP-A and SP-D, are
primarily secreted by type II cells independently of the lamellar
bodies.
Surfactant has an extracellular life cycle once secreted to the
thin fluid hypophase lining the alveoli and small airways of the
healthy lung. The SP-A associates in the hypophase with the
lipids plus SP-B and SP-C to form tubular myelin and other loose
lipid arrays that are macroaggregated lipoprotein forms.56 These
large lipoprotein aggregates are the forms of surfactant that
adsorb to the air-water interface. The surfactant film is multilay-
ered and continuously replenished from surfactant in the hypo-
phase.57 Lipids are cleared from the air spaces as small liposomal
tion (see Figure 158-2).12,13 The L/S ratio measures primarily
saturated phosphatidylcholine relative to sphingomyelin, a lipid
not specific to the fetal lung surfactant. In the normal preg-
increases after 28 weeks’ gestation and peaks at 35 weeks, and
phosphatidylglycerol does not begin to increase until after 34
weeks’ gestation.62 Infants with early lung maturation caused
by fetal stress or fetal exposure to inflammation can increase
the amounts of saturated phosphatidylcholine, decrease phos-
phatidylinositol, and increase phosphatidylglycerol in amniotic
fluid to have a surfactant composition comparable to a mature
lung. Infants recovering from RDS have increasing amounts of
phosphatidylglycerol in the surfactant. In contrast, RDS that
progresses to bronchopulmonary dysplasia (BPD) results in sur-
factant with a delayed appearance of phosphatidylglycerol, pre-
sumably because of injury to type II cells.63
The surfactant-specific protein content of surfactant from the
preterm lung is low relative to the amount of lipid. Type II cells
with lamellar bodies appear in the human lung after approxi-
mately 22 weeks, but very little SP-A or -B mRNA is expressed
until later in gestation. The timing of gene expression and
protein secretion in the normal human preterm fetus can be
inferred from the increases in the proteins in amniotic fluid.64
SP-A increases after 32 weeks’ gestation, and SP-B increases after
34 weeks. SP-B protein must be extensively processed before it
enters lamellar bodies. With induced lung maturation in fetal
sheep, both the mRNA and the protein processing of SP-B
increase in parallel.65 SP-D mRNA in the lung is also low until
late gestation, and amniotic fluid levels of SP-D do not change
much with advancing gestation.66 SP-A and SP-D in amniotic fluid
may also come from nonpulmonary sources because these innate
host defense proteins are made in locations other than the lung.
In contrast to other SPs, SP-C mRNA is highly expressed at the
tips of branching airways during early lung development.67 SP-C
mRNA also is expressed in the developing type II cells before
SP-C is found in the fetal airways. Expression of all the SPs is
1610 SECTION XXVI — Pathophysiology of Neonatal Diseases

1 kg preterm—intubated at delivery and volume ventilated with

PEEP = 5, VT = 5 mL/kg
Birth 10 breaths 2 min 10 min

VT 0 mL +5 mL to 5 mL to 20% of 5 mL to 100% of
airways parenchyma = 25 mL/kg parenchyma = 5 mL/kg
Outcome Airless Overdistend Focal overdistention Noninjurious ventilation
lung airway
A

B Control PEEP = 5 with N2 6 mL/kg with N2

Figure 158-9 A, Hypothetical effects of initiating mechanical ventilation at birth for a 1-kg preterm using volume-targeted ventilation of 5 mL/
kg and a positive end-expiratory pressure (PEEP) of 5 cm H2O. The volume will overdistend the airways with the initial breaths. The volume
then may cause focal overdistention if the lung is only partially recruited at 2 minutes. By 10 minutes the lung is uniformly distended, but airway
and focal overdistention may have injured the lung during recruitment. B, Expression of mRNA for Egr-1 occurs primarily in the wall of the
bronchioles. Fetal sheep were exteriorized from the uterus and ventilated with nitrogen at a tidal volume of 6 mL/kg for 15 minutes. Egr-1
mRNA expression was increased in the bronchiole by the tidal volume, but not by a positive end expiratory pressure of 5 cm H2O. (A, Modified
from Kramer BW, Jobe AH: The clever fetus: responding to inflammation to minimize lung injury. Biol Neonate 202–207, 2005. B, Modified
from Hillman N, Moss T, Nitsos I, Jobe A. Moderate tidal volumes and oxygen exposure during initiation of ventilation in preterm fetal sheep.
Pediatr Res 72:593, 2012.)

Surfactant treatment Recycling

Surfactant pool Surfactant function

Surfactant inactivation
Lung development
• Gestational age Leaky epithelial
Pulmonary Severity
• Corticosteroids and endothelial
edema of RDS
• Inflammation barriers
• Growth restriction

Lung structure Tissue function

Delivery room management

mechanical ventilation oxygen
Figure 158-10 Flow diagram of major variables that contribute to the severity of respiratory distress syndrome (RDS).
 Chapter 158 — Pathophysiology of Respiratory Distress Syndrome
SP-B
SP-C
SP-A
Type II cell
Figure 158-11 Major metabolic pathways of surfactant. Surfactant components are synthesized and packaged into lamellar bodies in type
II cells. The lamellar bodies are secreted to the hypophase and surfactant is adsorbed to the air fluid interface. Surfactant components are
cleared from the air spaces primarily by type II cells and macrophages. SP, Surfactant-associated protein.
increased by fetal exposure to antenatal corticosteroids and to
intraamniotic inflammation.24
SURFACTANT POOL SIZE
During normal gestation, the lungs store progressively larger
amounts of surfactant in the maturing type II cells. The appear-
ance of surfactant in fetal air spaces lags behind the accumula-
tion of surfactant in fetal lung tissue. After approximately 34
weeks’ gestation, surfactant is secreted by the normal fetus, and
large amounts of surfactant can be isolated from amniotic fluid
at term. The term infant has a large excess of surfactant that
facilitates rapid pulmonary adaptation to air breathing. The
amount of surfactant in the lung saccules in infants younger than
32 weeks and in the developing alveoli and small airways after
32 weeks depends on the physiologic events experienced by the
fetus or newborn. With labor and the stress of delivery, some of
the lamellar bodies are secreted into the fetal lung fluid, and
surfactant concentration increases as fetal lung fluid volume
decreases.68 More surfactant is secreted after the initiation of
ventilation in response to stretch, increased catecholamines, and
purinoceptor agonists. In the preterm sheep, the fetal surfactant
stores in the type II cells are secreted within approximately 30
minutes of ventilation after birth.69
The only direct measurements of surfactant pool sizes of
infants were made by alveolar lavage of lungs of infants who died
of RDS soon after birth in the era before mechanical ventilation.70
The lavages contained approximately 5 mg/kg surfactant. Mea-
surements by bronchoalveolar lavage in preterm rabbits and
lambs with severe RDS yield values less than 3 mg/kg. Preterm
1611
SP-D
Macrophage
SP-A
SP-B, SP-C
Lipid
lambs can be supported with CPAP if their surfactant pool size
is greater than about 4 mg/kg (see Figure 158-12).71 Smaller pool
sizes result in severe respiratory failure. The differences in phos-
pholipid composition between exogenous surfactant used for
treatment and the endogenous surfactant were used to estimate
the pool size in infants with RDS. By measuring the change in
phosphatidylglycerol composition, Hallman and colleagues72
estimated a surfactant pool size of approximately 9 mg/kg for
infants with RDS. Similar measurements by Griese and col-
leagues73 yielded a surfactant pool size estimate of 20 mg/kg.
Measurements using stable isotope-labeled dipalmitoylphospha-
tidylcholine yielded a value of 5.6 mg/kg.74 These techniques
assume that there is good mixing of the treatment surfactant
with the endogenous pool, that there is no loss of the treatment
surfactant from the alveolar pool, and that airway aspirates rep-
resent what is in the distal lung. These assumptions are not
strictly valid, and the techniques used clinically will overestimate
the endogenous pool size by at least two-fold.75
The endogenous pool size of surfactant is the major deter­
minant of lung compliance in preterm animals (see Figure
158-12).76,77 Very preterm infants with severe RDS probably have
surfactant pools of less than 5 mg/kg. Although not measured in
humans, term newborn animals have surfactant pools of approxi-
mately 100 mg/kg. In contrast, the surfactant pool size in the
adult human is only approximately 4 mg/kg.78 Therefore preterm
infants have perhaps 5% of the amount of surfactant in the term
newborn lung, but they have amounts comparable to the healthy
adult human. This inconsistency will be addressed relative to
surfactant function later in this chapter.
1612 SECTION XXVI — Pathophysiology of Neonatal Diseases

250 200

Percent change in compliance

200 160

(mL/cm H2O/kg)
Respiratory failure
150 120 Endogenous pool
pCO2

100 80

Treatment with surfactant

50 40

0 0
0 4 8 12 16 20 24 28 0 10 20 30 40 50 60 70 80
A Sat PC in alveolar lavage (mg/kg) B Amount of surfactant (mg/kg)
Figure 158-12 Relationship between surfactant pool sizes and lung function. A, Preterm lambs were delivered and supported with con-
tinuous positive airway pressure (CPAP) for 2 hours. Lambs with surfactant pool sizes estimated by alveolar wash to be greater than about
4 mg/kg could maintain PCO2 values on CPAP. B, The curve for the endogenous pool was estimated by alveolar wash of ventilated preterm
rabbits that were 27 to 29 days’ gestational age. The increase in compliance includes increased surfactant and spontaneous lung structural
maturation that occurred in the 2-day interval. The curve for treatment with surfactant gives the dose-response curve for ventilated 27-day
gestation rabbits. (Data from Ikegami M, Jobe AH, Yamada T, et al: Relationship between alveolar saturated phosphatidylcholine pool sizes
and compliance of preterm rabbit lungs, the effect of maternal corticosteroid treatment. Am Rev Respir Dis 139:367, 1989 and Seidner S,
Pettenazzo A, Ikegami M, et al: Corticosteroid potentiation of surfactant dose response in preterm rabbits. J Appl Physiol 64:2366, 1988.)

sible for the biophysical properties of surfactant. Measurements

CHANGES IN SURFACTANT POOL SIZE AFTER BIRTH
The pool sizes of surfactant that can be recovered by alveolar
lavage increase slowly after birth in preterm ventilated monkeys
and sheep. In monkeys recovering from RDS, surfactant increases
from approximately 5 mg/kg toward term values by 3 to 4 days
of age (Figure 158-13).79,80 No direct measurements of surfactant
pool sizes as infants recover from RDS are available. The changes
in surfactant concentration in airway samples will, in part, reflect
pool sizes. The concentration of surfactant was similar for infants
without RDS and for infants with RDS who were treated with
surfactant.81 Infants with RDS had a progressive increase in sur-
factant concentration during approximately 4 days.
Surfactant treatments with the commonly used dose of
100 mg/kg do not result in large or sustained increases in alveo-
lar surfactant pool size. For example, in sheep only approxi-
mately 25% of the treatment dose is recovered 5 hours after
treatment.82 In preterm ventilated baboons, approximately 20%
of the treatment amount of surfactant was recovered 24 hours
later.83 Infants with RDS had a mean surfactant pool size esti-
mated with stable isotopes of 17 mg/kg, 33 hours after an initial
100 mg/kg surfactant treatment.74 The increase in alveolar sur-
factant that accompanies the resolution of RDS does not occur
in preterm ventilated baboons that are developing BPD.84 The
alveolar pool size after surfactant treatment at birth and 6 days
of ventilation was approximately 30 mg/kg, which was not
increased after a second surfactant treatment and a further 8 days
of ventilation. The alveolar content of the SP-A and SP-D also
were low in preterm baboons developing BPD.85 Nevertheless
the lung tissue content of saturated phosphatidylcholine
increased approximately four-fold, and the tissue content of SP-A
and SP-D increased, indicating a defect in surfactant processing
and secretion in the early phases of BPD.
SURFACTANT METABOLISM IN THE PRETERM
To understand how the alveolar surfactant pool is maintained in
the lung, it is helpful to divide metabolism into the anabolic
components of synthesis and secretion and the catabolic activi-
ties of uptake, degradation, and recycling. In clinical studies,
surfactant components labeled with stable isotopes were used
to evaluate surfactant metabolism in infants. Most metabolic
studies have focused on saturated phosphatidylcholine because
it is the major component of surfactant and is primarily respon-
of synthesis of surfactant phospholipids generally involve the
intravascular injection of labeled precursors. The labeled precur-
sors are taken up by type II cells and incorporated into phospha-
tidylcholine, which is transacylated to increase the amount of
saturated phosphatidylcholine. The surfactant lipids together
with SP-B and SP-C are processed and packaged via multivesicu-
lar bodies to become the storage-secretion granule, the lamellar
body (see Figure 158-11). Secretion can be measured by recover-
ing the labeled surfactant components from the air spaces,
which evaluates the overall kinetics of synthesis and secretion.
The absolute amount of a surfactant component that is synthe-
sized cannot be easily determined because the radiolabeled pre-
cursor is diluted into the plasma pool and is further diluted by
the precursor pool in the type II cell. However, the net kinetics
of synthesis and secretion provide critical information for under-
standing why surfactant deficiency requires days to resolve in
infants with RDS.
After term delivery and ventilation of lambs, an intravascular
injection of radiolabeled palmitic acid is incorporated into lung
phosphatidylcholine within minutes.86 However, radiolabeled
surfactant is not detected in the air spaces for approximately 5
hours, and the amount of radiolabeled surfactant continues to
accumulate in the air spaces for 30 to 40 hours (Figure 158-14).87
A similar curve for accumulation of de novo synthesized surfac-
tant was measured for ventilated preterm lambs with mild RDS.
Subsequent surfactant treatment of these preterm lambs caused
a large dilution of the endogenous surfactant. After a 13C-glucose
infusion, surfactant lipids labeled with 13C-glucose could not be
detected in airway samples of surfactant-treated very preterm
baboons until 24 hours of age.88 The peak accumulation of
13
C-glucose in phosphatidylcholine was at approximately 100
hours. The curve for preterm baboons has a longer delay in
detection than the curve for preterm sheep because the radiola-
bel was not given as a pulse label and time was required to get
enough label into the air space to be detected. Preterm surfactant-
treated infants with RDS given infusions of 13C-palmitic acid and
13
C-glucose have curves similar to baboons for surfactant lipids
in airway samples (see Figure 158-14).89 The conclusion is that
secretion is delayed for hours after synthesis, and surfactant
made shortly after birth is secreted gradually over a prolonged
period of time. The curves are not altered much by surfactant
treatment or by age after birth when the labeled precursor is
 Chapter 158 — Pathophysiology of Respiratory Distress Syndrome 1613

the air space by type II cells and macrophages and recycling by

3–4 day term

type II cells. Little surfactant is lost from adult lungs to the lymph

4–5 day RDS (recovery)

or vascular space unless the lung is injured, and minimal amounts

3–4 day (no RDS)

150 of surfactant are lost by suctioning the airways, unless edema
fluid is present. In the term lamb, a trace dose of surfactant given
Surfactant in airspaces (mg/kg)

125 at birth had a half-life of approximately 6 days, which is longer

than values of approximately 10 hours for adult animals.92 Almost
100 all of a trace dose of surfactant given to preterm lambs with mild
RDS was recovered in the lungs after 24 hours of ventilation,

2–3 day RDS

75 demonstrating minimal catabolism (Figure 158-15).93 However,
only 20% of the labeled surfactant was still in the air spaces, and
140 day fetal

80% was associated with lung tissue. Similar measurements in

50
1 day RDS

preterm lambs with more severe RDS that were treated with
surfactant demonstrated a 30% loss of surfactant used for treat-
25 ment by 24 hours and only 14% of the surfactant recovered by
alveolar lavage.94 This rate of loss of surfactant from the lungs
0 yielded a biological half-life of approximately 48 hours. The
A Age of monkeys percentage of a treatment dose of surfactant that was lost from
the air spaces was similar with high tidal volume ventilation or
with high-frequency oscillatory ventilation in preterm lambs.47,95
6 Surfactant-treated and ventilated preterm baboons that were
developing BPD retained only 4% of the treatment in the air
5
Concentration sat PC (mM)

spaces, and approximately 80% of the surfactant was lost from

the lungs by 6 days, yielding a half-life of approximately 60
4 hours.83 These results indicate that the term and preterm lung
degrades surfactant lipids slowly and that injury can increase the
3 loss of surfactant from the lungs.
No information is available in the preterm about where deg-
2 radation of surfactant occurs. The normal preterm lung at birth
contains few macrophages and essentially no granulocytes.
RDS infants
However, inflammation and injury will rapidly recruit inflamma-
1 RDS infants + surfactant
tory cells to the lung, which may then increase the loss of
No RDS infants surfactant. A significant amount of a treatment dose of surfac-
0 tant that becomes associated with the lung tissue probably is
0 1 2 3 4 5 6 7 21–28 in type II cells. In the term newborn rabbit, more than 90% of
B Days after delivery the surfactant phospholipids are recycled back into the type II
Figure 158-13 Surfactant pool sizes with resolution of respira- cells for resecretion.96 In the only estimate available, ventilated
tory distress syndrome (RDS). A, The amount of surfactant recov- preterm lambs with mild RDS had a turnover time for surfactant
ered by alveolar lavage from mechanically ventilated preterm monkeys phosphatidylcholine of approximately 13 hours.93 These animals
with RDS is shown relative to age and stage of the disease. B, The had no measurable surfactant catabolism, indicating efficient
concentrations of saturated phosphatidylcholine (sat PC) in airway recycling.
samples from infants with RDS, infants with RDS treated with surfac- The only practical measurement of surfactant pool size and
tant, and infants without RDS are graphed relative to age from birth. biological half-life in the human is to give a trace or treatment
The concentrations of sat PC approached values for healthy preterm dose of surfactant containing a stable isotope and to follow the
infants by 4 to 7 days. (A, Data from Jackson JC, Palmer S, Truog change in concentration of the label in the surfactant sampled
WE, et al: Surfactant quantity and composition during recovery from by aspiration of the air spaces. This measurement gives an inte-
hyaline membrane disease. Pediatr Res 20:1243, 1986 and Jackson grated assessment of the mixing of the exogenous label with the
JC, Palmer S, Flandaert T: Developmental changes of surface active endogenous air space surfactant and tissue pools of surfactant.
material in newborn non-human primates. Am Rev Respir Dis A decrease in the concentration of the label in the airway sample
129:A204, 1984. B, Data from Hallman M, Merritt TA, Akino T, et al: represents dilution of the label with surfactant from the lung,
Surfactant protein-A, phosphatidylcholine, and surfactant inhibitors but it does not necessarily measure catabolism. Such measure-
in epithelial lining fluid: correlation with surface activity, severity of ments have been made in surfactant-treated preterm ventilated
respiratory distress syndrome, and outcome in small premature baboons and infants with RDS (see Figure 158-15).74,83 In baboons
infants. Am Rev Respir Dis 144:1376, 1991.) the concentration of labeled lipid (specific activity) did not
change for approximately 24 hours, indicating that little endog-
enous surfactant was present. However, independent data from
preterm lambs and baboons indicate that only approximately
given.88 Antenatal glucocorticoids may increase lipid synthesis.89 20% of the surfactant would have been in the air spaces at 24
Surfactant treatment does not inhibit de novo synthesis of lipids hours, and 25% of the surfactant would have been lost from the
or the SPs in the preterm lungs. Surfactant treatment also does lung compartment.93,94 Subsequently the specific activity
not alter the ultrastructure of type II cells or the volume fraction decreased exponentially, yielding a biological half-life of approxi-
of lamellar bodies in type II cells.90 The timing of phosphatidyl- mately 30 hours. The biological half-life values for infants with
choline secretion measured with stable isotopes was similar for RDS measured with 13C-dipalmitoylphosphatidylcholine were 34
infants with RDS ventilated with conventional or high-frequency ± 9 hours after surfactant treatment at a mean of 4.6 hours of
oscillatory ventilation.91 age, and they were similar after a second dose of surfactant given
The other half of the metabolic equation is the loss of surfac- at a mean age of 37 hours. The consistency of the indirect mea-
tant from the lung. This measurement has two components that surements in humans and animals indicates that surfactant catab-
include uptake and catabolism of surfactant components from olism is slow in the preterm with RDS. The treatment dose of
1614 SECTION XXVI — Pathophysiology of Neonatal Diseases

TERM LAMBS Figure 158-14 Time course of appearance of de novo synthe-

1.2 sized surfactant phosphatidylcholine (PC) in airway samples of
Specific activity

0.9 term lambs, preterm lambs, preterm baboons, and preterm

infants. A, Radiolabeled saturated PC in airway samples of ventilated
of PC

0.6 term lambs given 3H-palmitic acid as a bolus intravascular injection

0.3 at birth. Data are mean ± standard error of specific activities (counts/
minute/µmol PC) normalized to the maximal values for each animal.
0.0 B, Labeled saturated PC in airway samples of ventilated preterm
0 10 20 30 40 50 lambs given a single intravascular injection of 3H-palmitic acid at birth
A and not treated with surfactant until approximately 38 hours of age.
The discontinuity in the curve demonstrates the fall in the specific
activity after treatment with surfactant (dilution of surfactant pool with
PRETERM LAMBS treatment dose of surfactant). C, Labeling of PC in airway samples
1.5
of preterm surfactant-treated baboons that were ventilated for 6 days.
Specific activity

The animals received 13C-glucose by intravascular infusion for the first

1.0
24 hours of age and the 13C in the palmitate of PC is expressed as
of PC

13
C-atom percent excess. D, Labeling of PC in airway samples of
0.5
surfactant treated and mechanically ventilated infants with RDS fol-
lowing an intravascular infusion of 13C-glucose for the first 24 hours
0.0
of life. The label in the PC is expressed as atom percent excess. (A
0 10 20 30 5 10 50
and B, Data from Jobe AH, Ikegami M, Glatz T, et al: Saturated
B phosphatidylcholine secretion and the effect of natural surfactant on
premature and term lambs ventilated for 2 days. Exp Lung Res 4:259,
PRETERM BABOONS 1983. C, Data from Bunt JE, Carnielli VP, Seidner SR: Metabolism of
0.10 endogenous surfactant in premature baboons and effect of prenatal
C13 atom excess

corticosteroids. Am J Respir Crit Care Med 160:1481, 1999. D, Data

from Bunt JE, Carnielli VP, Darcos Wattimena JL, et al: The effect in
in PC (%)

0.05 premature infants of prenatal corticosteroids on endogenous surfac-

tant synthesis as measured with stable isotopes. Am J Respir Crit
Care Med 162: 844, 2000.)
0.00
0 24 48 72 96 120 144
C

PRETERM INFANTS
0.15 SURFACTANT FUNCTION IN THE ALVEOLUS
C13 atom excess
in PC (%)

0.10 SURFACTANT FORMS

0.05
0.00
0 24 48 72 96
D Hours
surfactant does not remain in the air space but becomes part of
the overall metabolic pool of surfactant. Measurements with
stable isotopes in preterm infants also indicate that surfactant
catabolism is increased and recycling efficiency is decreased
with lung injury and development of BPD.
The SPs (SP-A, SP-B, and SP-C) are cleared from the air spaces
and the lung compartment of adult animals in parallel with the
surfactant lipids.60 The proteins are recycled with an efficiency
somewhat lower than the lipids, and degradation of SP-A occurs
approximately equally in macrophages and type II cells.58 The
preterm ventilated lamb lung clears SP-A from the air spaces
more rapidly than the lipids.97 The lipophilic proteins SP-B and
SP-C are cleared from the air spaces and from the lung compart-
ment similarly to saturated phosphatidylcholine in ventilated
preterm lamb lungs.82,95 SP-B clearance is similar in lambs venti-
lated with a conventional style of ventilation or with high-
frequency oscillatory ventilation. In the only measurement in
humans, SP-B secretion paralleled and clearance was somewhat
faster than saturated phosphatidylcholine.98
Surfactant is in the alveolus in different structural forms that have
different characteristics and functions.99 After secretion, the
lamellar bodies unravel to form the elegant structure called
tubular myelin. This lipoprotein array has SP-A at the corners
120 144 of the lattice and requires at least SP-A, SP-B, and the phospho-
lipids for its unique structure. Tubular myelin and other loose
surfactant lipoprotein arrays in the hypophase generate the
surface film within the alveolus and small airways. New surfac-
tant enters the surface film and “used” surfactant leaves as small
vesicles, which then are cleared from the air spaces. The major
differences in composition between the surface-active tubular
myelin and the biophysically inactive small vesicles are that the
small forms contain little SP-A, SP-B, or SP-C.
Surfactant is secreted to yield an alveolar pool that is primarily
lamellar bodies and tubular myelin. During neonatal transition
to air breathing, the percent of surface-active forms falls as the
small vesicular forms increase (Figure 158-16).100 At steady state,
approximately 50% of the surfactant in the air spaces is in a
surface-active form, and 50% is in the inactive vesicular form.
The total surfactant pool size is not equivalent to the amount of
active surfactant. The maintenance of surfactant function
depends on the preservation of the active forms of surfactant in
the air space.
SURFACTANT INACTIVATION
Surfactant inactivation or inhibition is a complex concept
because it is the integrated result of multiple factors that can
alter the alveolar forms and biophysical properties of the surfac-
tant in the air spaces (Box 158-2).101 The net effects can be a
 Chapter 158 — Pathophysiology of Respiratory Distress Syndrome 1615

PRETERM LAMBS—
PRETERM LAMBS SURFACTANT TREATED PRETERM BABOONS
100 100 1.5

Specific activity
Recovery (%)

Recovery (%)
75 75
1.0
50 50
0.5
25 25

0 0 0.0
0 5 10 15 20 25 0 5 10 15 20 25 0 24 48 72 96 120 144
A Hours B Hours C Hours

SURFACTANT-TREATED PRETERM PRETERM HUMANS AFTER SECOND

HUMANS WITH RDS SURFACTANT TREATMENT
1
1
Atom excess (%)

0.1

0.1
0.01

0 12 24 36 48 0 24 48 72 96 120 144
D Hours E Hours
Figure 158-15 Loss of labeled phosphatidylcholine (PC) given into the airways of preterm lambs not treated with surfactant (A); preterm
lambs treated with surfactant (B); preterm surfactant-treated baboons (C); and surfactant-treated preterm infants (D and E). All animals and
infants were mechanically ventilated and had respiratory distress syndrome. A, The preterm lambs received a trace dose of natural sheep
surfactant labeled with 3H-dipalmitoylphosphatidylcholine. Recoveries in alveolar washes, lung tissue, and total lungs (alveolar + tissue) were
measured 2 hours, 5 hours, 10 hours, and 24 hours after birth. B, Preterm lambs were treated at birth with 100 mg/kg of natural sheep
surfactant, containing radiolabeled phosphatidylcholine and the lambs were ventilated for periods up to 24 hours for measurements of the
percent recovery of the phosphatidylcholine from the surfactant used for treatment. A and B, Green line, Lung tissue; red line, alveolar wash;
purple line, total lung. C, Curve for specific activity of phosphatidylcholine in airway samples of preterm baboons treated at birth with 14C
-dipalmitoylphosphatidylcholine–labeled surfactant. The specific activities were normalized to the values for the surfactant used to treat the
baboons. D, Curve for atom percent excess in airway samples for 13C-dipalmitoylphosphatidylcholine–labeled surfactant used to treat preterm
ventilated infants with RDS. The atom percent excess in the initial surfactant dose given after delivery fell exponentially for 48 hours. E, A
second dose given at approximately 2 days of age resulted in a similar curve. (A, Data from Jobe AH, Ikegami M, Seidner SR, et al: Surfactant
phosphatidylcholine metabolism and surfactant function in preterm, ventilated lambs, Am Rev Respir Dis 139:352, 1989. B, Data from Ikegami
M, Jobe A, Yamada T, et al: Surfactant metabolism in surfactant-treated preterm ventilated lambs, J Appl Physiol 67:429, 1989. C, Data from
Seidner SR, Jobe AH, Coalson JJ, et al: Abnormal surfactant metabolism and function in preterm ventilated baboons, Am J Respir Crit Care
Med 158:1982, 1998. D and E, Data from Torresin M, Zimmermann L J, Cogo PE, et al: Exogenous surfactant kinetics in infant respiratory
distress syndrome: a novel method with stable isotopes. Am J Respir Crit Care Med 161:1584, 2000.)

decrease in the effective pool size, a degradation of the surface
tension-lowering properties of the surfactant, or both. Injury to
the alveolar epithelium and edema change the environment
where surfactant acts. The mechanisms that contribute to sur-
factant inactivation will vary with the type of lung injury. The
biophysically active surfactant pool can be depleted by an
increased rate of conversion to the inactive vesicular forms. This
conversion is accelerated by proteinaceous edema and inflam-
matory products, probably because proteases degrade SPs.102
Ventilation styles that use large tidal volumes and no PEEP can
deplete the active surfactant pool and high-frequency oscillatory
ventilation can preserve surfactant in adult animal models.103
However, in surfactant-treated preterm lambs, ventilation with
high-frequency oscillation did not have an advantage over con-
ventional ventilation.95 Meconium and bilirubin can accelerate
the conversion to inactive surfactant forms, and surfactant with
less SP will be inactivated more quickly.
Another mechanism of inactivation is the removal of the sur-
factant by sequestration into clots or hyaline membranes. Surfac-
tant is a thromboplastin and will activate clotting, and in vitro
the clot will capture most of the pulmonary surfactant.101
Although most soluble proteins can interfere with surface
adsorption and film formation, the products of clot lysis are
particularly inhibitory.104 Albumin is not as inhibitory as fibrino-
gen, although it is the protein that is in the highest concentration
in edema and inflammatory fluid. Hemoglobin and other protein
products of lung injury also are inhibitors. The phenomenon of
interference with film formation by soluble proteins is depen-
dent on both the relative and absolute concentrations of the
surfactant and the inhibiting proteins.105 If surfactant concentra-
tions are high, potent inhibitors at high concentration have little
adverse effect when tested in vitro. However, when surfactant
concentrations are low, low concentrations of inhibitors can
severely degrade surfactant function. Surfactants that contain
low amounts of SPs also are more sensitive to inactivation by
soluble proteins.
Lung function will deteriorate when inactivation interferes
with enough surfactant to alter the function of the surfactant at
the air-fluid interface. Therefore, inactivation can be a severe
problem when the surfactant pool size is small, as in RDS. Airway
samples taken at the time of intubation from infants with RDS
had high minimal surface tensions (Figure 158-17).106 Inhibition
1616 SECTION XXVI — Pathophysiology of Neonatal Diseases

100 40

Minimum surface tension (dynes/cm)

Samples from
air spaces
80 30
Recovery SPC (%)

Large aggregates
60 20

Isolated
40
10 surfactant
Small aggregates
20
0
RDS Control RDS Control
0 A
Cell debris
25

Minimum surface tension (dynes/cm)

Birth 6 12 18 24 Adult
Term Hours
fetus
20 RDS
Figure 158-16 Changes in surfactant aggregate size distribution
with time after birth. Surfactant suspensions recovered by alveolar
15
wash from term rabbit fetuses and at various ages after birth were
fractionated by centrifugation. The distribution of saturated phospha-
tidylcholine (SPC) in fractions is also indicated for alveolar washes 10
from adult rabbits. (Modified from Bruni R, Baritussio A, Quaglino D,
et al: Postnatal transformations of alveolar surfactant in the rabbit: Control
5
changes in pool size, pool morphology and isoforms of the 32-38 kDa
apolipoprotein. Biochim Biophys Acta 958:255, 1988.)
0
0.0 0.4 0.8 1.2 1.6 2.0
B Protein from air space samples (mg)
Figure 158-17 Minimum surface tensions of airway samples
from infants with respiratory distress syndrome (RDS; A) and
Box 158-2 Mechanisms of Surfactant control infants and inhibition of surfactant by proteins (B). A,
Inactivation and Substances That Samples from infants with RDS had high minimum surface tensions,
Contribute to Inactivation whereas control samples had low minimum surface tensions. After
isolation of surfactant by centrifugation, the surfactants from RDS and
Form Conversions in Air Spaces control infants had low minimum surface tensions. B, Supernatant
protein fractions from airway samples were added to a constant
• Normal process of alveolar metabolism
amount of natural sheep surfactant. Protein fractions from infants with
• Increased conversion with proteinaceous edema
RDS had higher inhibitory activity than proteins from the control
(proteases?)
infants. (From Ikegami M, Jacobs H, Jobe AH: Surfactant function in
• Ventilation, meconium, decreased surfactant protein
the respiratory distress syndrome. J Pediatr 102:443, 1983.)
content

Removal of Surfactant From Alveolar Pool

• Clots and hyaline membranes
of surfactant function contributed to the problem because the
Inhibitors of Adsorption and Film Stabilization airway samples contained surfactant with good function that
• Proteins could be isolated by centrifugation. The soluble proteins from
• Edema fluid these airway samples inhibited natural surfactant more than did
• Plasma proteins from airway samples from infants without RDS. The
• Fibrinogen, monomers importance of surfactant inactivation can be demonstrated using
• Albumin a preterm ventilated lamb model of RDS (Figure 158-18).107 Ven-
• Laminin tilation for 30 minutes caused severe lung injury in preterm
• Hemoglobin lambs with surfactant pools of less than 1 mg/kg. Surfactant
• Lipids treatment resulted in improved oxygenation and a fall in minimal
• Lysophosphatidylcholine surface tensions of the surfactant in airway samples. However,
• Cholesterol decreased oxygenation recurred because these animals had pro-
• Red cell membranes gressive lung injury and surfactant inhibition.
These inhibitory effects explain the progressive deterioration
Other Inactivators in lung function after birth in infants with RDS. Surfactant
• Meconium function may initially be adequate but with low surfactant
• Bilirubin pool sizes (a honeymoon period). Spontaneous or mechanical
• Oxidizing agents ventilation can cause edema, inflammation, and progressive lung
• Amino acids injury. The combination of clot formation (hyaline membranes)
and increased soluble inhibitory proteins deplete the small
 Chapter 158 — Pathophysiology of Respiratory Distress Syndrome
250
PO2
mm Hg 200
150
100
50
0
30
Dynes/cm
20
Surface tension
10
0 for several hours. Surfactant was recovered by alveolar wash and
–1 0 1 2 3 4
Surfactant Hours
treatment
Figure 158-18 Surface tension and clinical response to surfac-
tant treatment. Immature lambs had severe respiratory failure
despite ventilatory support and 100% O2. With surfactant treatment
at approximately 45 minutes of age, PO2 values increased and surface
tensions of airway samples decreased. Subsequently the respiratory
function of the lambs deteriorated as minimum surface tension values
increased in the airway samples. (From Ikegami M, Jobe A, Jacobs
H, et al: A protein from airways of premature lambs that inhibits
surfactant function. J Appl Physiol 57:1134, 1984.)
functional surfactant pool, which results in progressive respira-
tory failure.
Inactivation phenomena depend on the type of surfactant
being tested. The animal-source surfactants in clinical use have
in common organic solvent extraction steps that remove nonspe-
cific contaminating proteins, SP-A and SP-D. SP-B and SP-C are
retained in the surfactant extract in variable amounts with the
phospholipids and neutral lipids. The only functional abnormal-
ity in surfactant from mice that lack SP-A is increased sensitivity
to inhibition.108 The addition of SP-A to an organic solvent-
extracted surfactant made that surfactant less sensitive to inacti-
vation by albumin and fibrinogen.109 The potent inactivation of
surfactant by fibrinogen was reversed by 0.5% SP-A. Addition of
SP-A to SP-B and SP-C–containing surfactant preserved the in vivo
function of the surfactant in the presence of plasma when the
mixture was used to treat preterm rabbits.110,111 These observa-
tions may have direct clinical relevance because Hallman and
colleagues72 reported that soluble proteins in airway samples
from infants with RDS were much more inhibitory to surfactant
samples with low SP-A to saturated-phosphatidylcholine ratios
than were surfactant samples with higher ratios.
SP-B and SP-C also influence the sensitivity of lipid mixtures
to inactivation.112 Synthetic surfactants that lack these SPs are
sensitive to inactivation by albumin or fibrinogen. Addition of
native SP-B and SP-C improved resistance to inactivation.113
Recombinant SP-C and lipids and mixtures of SP-B and SP-C and
lipids are less sensitive to protein inactivation than are lipid
mixtures alone.
QUALITY OF SURFACTANT IN THE PRETERM INFANT
The preterm infant with RDS has surfactant with properties that
are inferior to surfactant from the mature lung, which com-
pounds the problem of a small pool size of surfactant.61 Surfac-
tant from the preterm with RDS has a different composition
from surfactant from the mature or adult lung. The phosphati-
dylglycerol content is lower, the phosphatidylinositol content is
1617
1.00
Compliance (mL/cm H2O/kg)
1.75
1.50
1.25
0.00
No + Surfactant 128d 131d
surfactant
Gestational age of lamb
Figure 158-19 Surfactant function after surfactant treatment.
Preterm lambs were treated with 100 mg/kg surfactant and ventilated
used to treat preterm surfactant-deficient rabbits. The surfactant from
the more mature lambs at 131 days of gestation had enhanced func-
tion relative to the surfactant used to treat the lambs. (Modified from
Ikegami M, Ueda T, Absolom D, et al: Changes in exogenous surfac-
tant in ventilated preterm lamb lungs. Am Rev Respir Dis 148:837,
1993.)
higher, and the percent-saturated phosphatidylcholine is lower.
The alveolar pool from preterm lambs with RDS has a higher
percentage of the surfactant in inactive forms than more mature
lambs, and in vitro conversion rates from active to inactive
forms are more rapid. The surfactant from the preterm is also
more sensitive to inactivation in vitro by soluble proteins, most
likely because of a lower SP content. Furthermore, when surfac-
tants from preterm lambs or baboons were tested in preterm
surfactant-deficient rabbit lungs, they were less effective at
improving compliance than surfactant from term animals.61,83
Therefore, surfactant from the preterm is intrinsically less effec-
tive and more susceptible to inactivation than surfactant from
the mature lung.
SURFACTANT FUNCTION WITH
SURFACTANT TREATMENT
The surfactants used clinically are organic solvent extracts of
alveolar washes or lung tissue. These surfactants contain no SP-A,
the amount of SP-B and SP-C is variable, and processing and
sterilization disrupt the lipoprotein structure. The clinical surfac-
tants are more sensitive to inactivation by plasma proteins than
natural surfactant. However, surfactant can have improved func-
tion after exposure to the preterm lung. When surfactant is
recovered by alveolar wash after surfactant treatment of preterm
lambs with RDS, the surfactant has enhanced function.114 This
improved function can be demonstrated by comparing the sur-
factant used to treat the lambs with the surfactant recovered
from the lambs for treatment responses in surfactant-deficient
rabbit lungs (Figure 158-19). The very preterm lung cannot
improve the function of surfactant used for treatment; the more
mature lung can. The mechanism for the enhanced function
probably is the mixing of the surfactant used for treatment with
small amounts of endogenous surfactant lipids and proteins.
Many hours after treatment, the enhanced function of surfactant
can occur by recycling of components from the surfactant used
for treatment through the type II cells. The sensitivity of the
surfactants used clinically to inactivation also can be modulated
after exposure to the preterm lung.115 The surfactants become
less susceptible to inactivation if mixed with 5% or 10% by
weight natural surfactant. Therefore, small endogenous surfac-
tant pools can interact with the large doses of surfactant used
clinically to result in improved function of surfactant. This activa-
tion phenomenon will not occur if the lung is injured.
1618 SECTION XXVI — Pathophysiology of Neonatal Diseases
SURFACTANT AND INNATE HOST DEFENSES
The lung of the infant with RDS is not inflamed at birth unless
chorioamnionitis and infection were present before birth.
However, the initiation of ventilation and oxygen initiates inflam-
mation in the preterm lung.48 The ventilation results in nonuni-
form inflation of the surfactant-deficient lung and stretch-mediated
injury. If the tidal volume is high or the FRC is too high or too
low, further lung injury will occur. Supplemental oxygen also
may initiate an inflammatory response. Surfactant treatment
decreases the severity of this initial inflammation, in part by its
mechanical effects on the lungs to make lung inflation more
uniform at lower pressures. However surfactant also can have
effects on the inflammatory response because of its multiple
innate host defense functions.116 The preterm lung is severely
deficient in SP-A and SP-D. These proteins opsonize a variety of
organisms and promote phagocytosis and suppress inflammation
in the adult lung. Addition of recombinant SP-D to surfactant
prevented the systemic shock caused by intratracheal endotoxin
in preterm ventilated sheep.117 The commercial surfactants do
not contain SP-A or SP-D. The hydrophobic proteins SP-B and
SP-C also have antiinflammatory properties and can mitigate
oxidant-induced injury. The potential for surfactant components
to modulate the inflammation that accompanies RDS has not
been tested clinically.
SUMMARY
Modern neonatology has conquered the initial management of
RDS in infants of reasonable size and gestational age who do not
have other abnormalities that degrade lung function (see Figure
158-1). That success has resulted from the general improvements
in obstetrics and neonatal care for the preterm and the specific
therapies of CPAP, improved ventilation strategies, antenatal cor-
ticosteroids, and surfactant treatment. Therapies to improve out-
comes depend on meticulous efforts to prevent lung injury.
Progress is being made with noninvasive methods of respiratory
support from the delivery room and new strategies for the timing
and methods of surfactant treatment. The imprecision of the
diagnosis of RDS, particularly in extremely low-birth-weight
infants, confounds epidemiologic documentation of the inci-
dence of RDS and its severity. A remaining concern is that
improvements in the initial management of RDS and decreases
in mechanical ventilation have not translated into decreases in
BPD. New synthetic surfactants will become available, but they
likely will not have substantial outcome benefits over those cur-
rently available. The core problem for the very preterm infant
with RDS is not the treatment of RDS, but rather the subsequent
lung development. Fortunately, the human preterm lung seems
to have the capacity to grow and remodel to compensate for
early lung maturity and injury.35
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 Chapter 158 — Pathophysiology of Respiratory Distress Syndrome 1619.e1
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