Respiratory Distress Syndrome:

Predisposing Factors, 53
Pathophysiology, and Diagnosis

Mikko Hallman, Timo Saarela, and Luc J. I. Zimmermann

Contents
53.1 Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 824
53.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 824
53.3 Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 825
53.3.1 Genetic Factors Influencing Susceptibility to RDS . . . . . . . . . . . . . . . . . . . . . . . . . . . 826
53.4 Symptoms and Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 827
53.4.1 Respiratory Course and Lung Function in RDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 827
53.4.2 Course of RDS in Preterm Infants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 828
53.4.3 Extremely Preterm Infants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 828
53.4.4 Late-Preterm and Early-Term Infants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 829
53.5 Diagnostics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 829
53.5.1 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 829
53.6 Predisposing Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 831
53.6.1 Surfactant System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 831
53.6.2 Secretion of Fetal Lung Liquid and Induction of Liquid Absorption . . . . . . . . . 833
53.6.3 Structural Lung Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 835

M. Hallman (*)
Department of Children and Adolescents, Oulu University
Hospital, and PEDEGO Research Unit, Medical Research
Center Oulu, University of Oulu, Oulu, Finland
e-mail: mikko.hallman@oulu.fi
T. Saarela
Department of Children and Adolescents, Oulu University
Hospital, Oulu, Finland
e-mail: Timo.Saarela@ppshp.fi
L. J. I. Zimmermann
Department of Pediatrics and Neonatology, School for
Oncology and Developmental Biology (GROW),
Maastricht University Medical Center, Maastricht,
The Netherlands
e-mail: luc.zimmermann@mumc.nl

# Springer International Publishing AG, part of Springer Nature 2018 823

G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-29489-6_289
824 M. Hallman et al.

53.7 Mechanisms of Lung Injury in RDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 835

53.7.1 Primary and Secondary Surfactant Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 835
53.7.2 Biotrauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 836
53.7.3 Volutrauma and Barotrauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 837
53.7.4 Delay in Clearance of Lung Liquid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 837
53.7.5 High-Permeability Lung Edema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 838
53.7.6 Pulmonary Hemorrhage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 838
53.7.7 Abnormalities in Lung Perfusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 838
53.7.8 Patent Ductus Arteriosus (PDA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 839
53.8 Prevention of RDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 839
53.8.1 Prevention of Premature Birth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 839
53.8.2 Pharmacological Acceleration of Fetal Lung
Maturity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 839
53.8.3 Diagnosis of Lung Maturity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 840
53.8.4 Prevention of Low-Risk Elective Births Before Term . . . . . . . . . . . . . . . . . . . . . . . . 840
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 841

Abstract 53.1 Salient Points

Due to increased survival and new treatment
strategies, new phenotypes of respiratory dis- • RDS is the most common serious disease
tress syndrome (RDS) have emerged. RDS in affecting the newborn.
near-term to term infants is characterized by • Advances in neonatal care have led to a
seemingly effortless breathing and tendency to decrease in mortality rates.
pulmonary hypertension that can be avoided • Half of the infants with RDS are born between
by expectant management. Common prevent- 29 and 34 weeks of gestation; symptoms of
able cause is elective delivery before full respiratory distress appear soon after birth and
40 weeks of pregnancy. Sometimes these surfactant administration limits the progression
infants possess rare alleles retarding lung of the disease.
development. Extremely preterm infants are • In extremely preterm infants, RDS tends to have
often affected by intrauterine inflammation, a prolonged course and develops into BPD
accelerating surfactant maturity. Despite new through many intertwined mechanisms.
noninvasive treatment practices, initially mild • Antenatal steroid administration to the
RDS tends to become prolonged and develops pregnant women, by inducing structural
to BPD. This is due to deficient antioxidant, lung maturity and stimulating functional
anti-inflammatory, and antimicrobial capacity; maturity, are the cornerstone of prevention
predisposition to airway injury, alveolar of RDS.
flooding, and surfactant inactivation by multi-
ple mechanisms are discussed. Genetic factors
predisposing very preterm infants to RDS are
intertwined with acquired risks: lack of labor, 53.2 Introduction
non-presenting twin, and adverse metabolic
environment (e.g., hyperinsulinemia). Antena- Respiratory distress syndrome of newborn
tal steroid, inducing structural maturity and infants (RDS), called infantile RDS or IRDS,
stimulating functional maturity, is the corner- previously idiopathic RDS or hyaline mem-
stone of prevention of RDS and the develop- brane disease (HMD), is the most common seri-
mental diseases prior to week 34. Currently ous disease affecting the newborn. Since the
steroid supplementation in RDS is not description of hyaline membranes by Hochheim
recommended. in 1903, the pathogenesis and etiology were
53 Respiratory Distress Syndrome: Predisposing Factors, Pathophysiology, and Diagnosis
studied (Obladen 1992). During past 50 years,
the advances in neonatal intensive have led to
striking improvement in prognosis in advanced
perinatal centers, changing the phenotype of
RDS and allowing the decrease in RDS mortal-
ity from nearly 50% to close to 5%. In addition,
infants born extremely preterm (<28 weeks)
previously died at birth. Today nearly all sur-
vive long enough to develop RDS.
In 1926, Van Neergard described the hystere-
sis of the lung. The significance of this finding
was not appreciated until surface activity was
described by Clements and Pattle in the 1950s
(Obladen 1992). As a consequence, Avery and
Mead (1959) discovered that the airways of
infants dying of HMD had high surface tension
(Avery and Mead 1959). This finding was further
tested several years later when dipalmitoyl phos-
phatidylcholine was nebulized to the airways in
RDS with disappointing results (Chu et al. 1967).
It took the death of President Kennedy’s son Pat-
rick on HMD in 1963 to activate the research on
RDS. After defining the surfactant system and
lung structures in more detail, followed by thera-
peutic trials using natural surfactant, an increase
in the survival and an acute, dramatic decrease in
the severity of RDS became evident (Robertson
and Taeusch 1995). Antenatal glucocorticoid ther-
apy (AGC) in threatened preterm birth was shown
by Liggins and Howie in 1971 to decrease the risk
of RDS (Liggins and Howie 1972). The accep-
tance of AGC in common clinical use was delayed
until around the introduction of surfactant therapy
in the early 1990s.
Surfactant therapy, AGC, effective ventilator
treatment practices, and several supplementary
treatment strategies have improved the survival
and decreased the risk of RDS. Organ injuries
associated with RDS and the phenotype of RDS
have become remarkably less distinct (“the new
RDS”). However, the risk of bronchopulmonary
dysplasia (BPD) continues to be prevalent
among infants born extremely preterm (ELGA,
<28 weeks). Genetic and constitutional factors,
most notably the length of gestation as a proxy
of the degree of lung development, influence
clinical management and outcome.
825
53.3 Risk Factors
RDS is characterized by typical features of respi-
ratory insufficiency shortly after birth. The pri-
mary cause in most cases is lung immaturity that
results in deficient gas exchange and acute
lung injury. The clinical features depend on a
number of interactive constitutional, genetic,
and acquired factors and particularly on thera-
peutic practices. The risk factors have decreased
as a result of improved antenatal anticipation of
preterm birth, pharmacologic acceleration of
fetal lung maturity, and of early treatment prac-
tices at birth.
The reported incidence of RDS among term-
born infants is one in 2000 (Marttila et al. 2004).
Elective delivery without labor before 40th week
of pregnancy is expected to increase the risk of
RDS. The incidence increases by each week of
decreasing the length of gestation. At
34–36 weeks, it has ranged from 5% to 10%, at
30–33 weeks from 10% to 35%, and at
28–29 weeks from 30% to 50%, and in ELGA
infants, the risk exceeds 50%. In the USA, the
reported incidence is often higher. More recently
the gestational age of the RDS population has
decreased. This has taken place because of the
successful prevention of RDS in the preterm
population and increased early survival of new-
born infants with very low gestation. Figure 1
shows schematically the risk and mortality of
RDS and application of therapies during the
past 45 years.
Increased risk of RDS is associated with elec-
tive deliveries without labor in late-preterm
(34–36 weeks) and early-term (37–38 weeks) preg-
nancies (Gerten et al. 2005; Ramachandrappa and
Jain 2008), lack of AGC before 34 weeks of preg-
nancy (Roberts and Dalziel 2006), and Caucasian
(vs. African) ethnicity. Surfactant supplementation
at preterm birth and continuous distending pressure
ventilation from birth may abolish typical symp-
toms (Morley et al. 2008; Sandri et al. 2010). Males
have a higher risk than females, the difference
corresponding to a mean of 1 week of gestation
(Table 1). The length of gestation interacts with
other risk factors. Multiple birth increases the risk
826
Fig. 1 Demographics of RDS during development of
perinatal-neonatal treatment practices. Trends in mortality
and in birth weights during 1970–2014. The figures are
from Finland with prematurity rate ranging from 5.2% to
6.0% and the incidence of RDS in the range of 0.4–0.6%
during the past 25 years. WHO definition of live birth was
introduced in 1989. Serious associated morbidity includes
of RDS in ELGA births and is a protective factor at
30 weeks or later (Marttila et al. 2004). The pre-
senting twin has a lower risk of RDS (but higher
risk of infection) than the non-presenting one.
Chorioamnionitis decreases the risk of RDS in
ELGA births (Watterberg et al. 1996; Kaukola
et al. 2009). Maternal diabetes and fetal hydrops
increase the risk of RDS. There is no consensus,
whether preeclampsia or intrauterine growth
restriction (IUGR) influences the risk. However,
chronic retroplacental bleeding (circumvallate pla-
centa) is associated with acceleration of lung
maturity.
M. Hallman et al.
bronchopulmonary dysplasia, patent ductus arteriosus,
necrotizing enterocolitis, intraventricular hemorrhage gr
2–4. S surfactant trials, SS the incidence synthetic surfac-
tant treatment of infants <32 week’s gestation, AS animal
surfactant (The figures are obtained from hospital records
and from the Finnish Perinatal Register (Finnish National
Institute for Health and Welfare; Dr. Mika Gissler))
53.3.1 Genetic Factors Influencing
Susceptibility to RDS
According to available twin studies comparing the
concordance of RDS between monozygotic and
dizygotic same sex preterm twins, a direct genetic
contribution to the susceptibility to RDS has been
small (~20%). Instead, detectable effects of indi-
vidual genes are due to gene-gene or gene-
environment interactions. They undermine the esti-
mates of the genetic effects on the basis of twin
studies. For instance, the presenting twin has
a lower risk of RDS compared to the
53 Respiratory Distress Syndrome: Predisposing Factors, Pathophysiology, and Diagnosis 827

Table 1 Pregnancy-related states and complications asso- insults. Genes with identified roles in lung func-
ciated with altered risk of RDS as compared to gestation tion have mutations or common allelic variants
controls
that influence surfactant function in stress or
Accelerated maturation Control or delayed have no detectable effect. Studies thus far show
or control maturation
that some genes expressed in type 2 cells influ-
Vaginal birth Elective birth with labor
ence the individual risk of RDS, including poly-
Elective birth with labor Elective low risk birth w/o
labor: late preterm or early morphism of SP-A, SP-B, SP-C, and ABCA3
term (37–38 weeks) (Hallman and Haataja 2007). According to
Female fetus Male fetus genetic studies, mediators influencing the risk
Closeness to cervix in Remote to cervix in twin of spontaneous premature birth and the risk of
twin pregnancy pregnancy (non-presenting) RDS are partly intertwined: SP-A and SP-D
(presenting)
influence cytokine responses mediating surfac-
First born twin pair Second born twin pair
>28 weeks, no infection >28 weeks tant synthesis and preterm labor process
Singleton <28 weeks Twin <28 weeks (Karjalainen et al. 2012).
Twin 30–36 weeks Singleton 30–36 weeks The genetic studies on the susceptibility to
Control <28 weeks Preeclampsia <28 weeks RDS have thus far been focused on major alleles
Chorioamnionitis Control 24–29 weeks of the likely candidate genes (i.e., surfactant pro-
24–29 weeksa teins). For more objective data on candidate genes
Gestation control Poor control of maternal and alleles, very large, non-biased, population-
diabetes, fetal hydrops,
based studies, their replicates, and meta-analyses
severe isoimmunization
a are required. Genome-wide association analyses
Mostly histologic chorioamnionitis. Clinical chorioam-
nionitis, when associated with fetal infection, is associated (GWAS) and whole-genome studies involving
with respiratory distress mimicking RDS siblings are appropriate. Eventually research
may help redefine the disease and its treatment.
non-presenting one, and the magnitude of this dif-
ference is influenced by gene-environment interac-
tion (Marttila et al. 2003; Hallman and Haataja 53.4 Symptoms and Clinical
2007). RDS in late-preterm and early-term infants Findings
has likely a different genetic background compared
to RDS infants with shorter gestation at birth. The 53.4.1 Respiratory Course and Lung
rare alleles with significant adverse effect to respi- Function in RDS
ratory function are more likely in RDS cases with
near-term or term gestation. Natural course of RDS is characterized by early
Mutations that may disrupt surfactant func- rapid progression of respiratory distress leading to
tion include SP-B, ABCA3, and SP-C genes. respiratory failure and often death in the absence
They cause fatal or severe chronic lung disease of treatment within 1–48 h. The stabilization
that initially resembles RDS (Wert et al. 2009). phase of respiratory distress is followed by the
Mutations involving transcription factors recovery phase, starting within 1–6 days after
TTF-1, C/EBPα, FOXA2, a glucocorticoid birth and continuing longer than progressive
receptor NR3C1, and some other genes gener- phase. The unifying features in RDS are the tran-
ally delay differentiation of specific functions, sient deficiency of surfactant in epithelial lining
including the surfactant system, causing serious and the early lung injury. Cyanosis is evaluated by
respiratory distress and often other symptoms oxygen saturation monitoring and right-to-left cir-
(Whitsett et al. 2010). Several other proteins, culatory shunt by measuring the arterial blood
including SP-A and SP-D, have important, gases and calculating the alveolar-arterial O2 ten-
partly redundant functions that influence the sion difference. Soon after birth, the breath sounds
susceptibility to infections and inflammatory are often diminished; later stridor may be evident.
828
Early RDS is characterized by low functional
residual capacity, low compliance, and high
venous admixture, indicating diffuse atelectasis.
The early lung injury often involves peripheral
airways causing obstructive small airway disease
in full-blown RDS. The short inspiratory time
constant early in the course of RDS increases as
a sign of airway obstruction (Baldwin et al. 2006).
Modest abnormalities in lung function may persist
even weeks and will be evident at term after
the recovery from uncomplicated RDS, and par-
ticularly when it is complicated with BPD
(Hjalmarson et al. 2014). Surfactant therapy in
RDS increases acutely functional residual capac-
ity, decreases venous admixture, more gradually
increases the compliance, and has little effect on
airway resistance.
The post-hospitalization course of children
with RDS without development of BPD reveals
increased incidence of wheezing during infections
and therefore higher hospitalization rates during
first 2 years of life, suggesting residual lung injury
or excessive immune response during infection
(Koivisto et al. 2005; Jones 2009 Kotecha et al.
2013). Very premature birth (<32 weeks, VLGA),
followed by treatment of RDS with modern
methods and no BPD, is associated with a barely
detectable impact on FEV1 and diffusion capacity
in school children compared to term-born controls
(Ronkainen et al. 2015).
53.4.2 Course of RDS in Preterm
Infants
Half of the infants with RDS are born between
29 and 34 weeks of gestation. First symptoms are
observed very soon after birth. Tachypnea, nasal
flaring, subcostal and intercostal retractions, cya-
nosis, and expiratory grunt are characteristic,
although not very specific, findings since transient
tachypnea is initially nearly indistinguishable. In
RDS, the symptoms continue longer than 24 h,
unless specific therapies are applied.
The progression of respiratory distress is
decreased or prevented by continuous distending
pressures and by surfactant therapy. As a result
of rather mild symptoms, the diagnosis remains
M. Hallman et al.
suggestive, unless pre-treatment surfactant diag-
nostics are available or the patient has distinct
favorable response to exogenous surfactant.
The surfactant-induced remission is sometimes
followed by relapse requiring retreatment.
The response to exogenous surfactant is less pre-
dictable and generally less striking if surfactant
is given later (>6 h after birth). Some develop
signs of patent ductus arteriosus (PDA). Apnea,
infection, and pneumothorax are rare complications.
53.4.3 Extremely Preterm Infants
Infants born before 28 weeks of gestation have
simplified saccular airways, no true alveoli, and
wide interstitial spaces. The highly compliant
chest cage generates striking retractions despite
moderate negative pleural pressures. The low sur-
factant pool is susceptible to abundant inhibitors.
Without treatment, the infants often die before
development of RDS. Providing continuous
distending pressures and if necessary to gentle
ventilation limits the emerging lung injury. Sur-
factant treatment in delivery room or within few
hours after birth typically induces a sustained
remission characterized by acute lowering of sup-
plemental O2 requirements and less acute lower-
ing of airway pressure requirements. Relapse of
respiratory failure often takes place, indicating
retreatment. The course of RDS is characterized
by a high incidence of cardiopulmonary compli-
cations, particularly PDA. Air leak syndrome
(pneumothorax, interstitial emphysema), pulmo-
nary hypertension, and pulmonary hemorrhage
are less common. RDS particularly in this group
is associated with complicating diseases: BPD,
intraventricular hemorrhage (IVH), necrotizing
enterocolitis (NEC), and retinopathy of prematu-
rity (ROP). The incidence of complicating dis-
eases varies from NICU to another.
Despite AGC, noninvasive ventilation, early
surfactant, and other adjunct treatments, such as
late cord clamping, caffeine, and inhaled nitric
oxide or selective postnatal glucocorticoid, a
significant risk of BPD and other adverse effects
remain (Schmidt et al. 2008; Bassler et al.
2015).
53 Respiratory Distress Syndrome: Predisposing Factors, Pathophysiology, and Diagnosis
53.4.4 Late-Preterm and Early-Term
Infants
Late-preterm (35–36 gw) and early-term infants
with RDS are mostly born electively without
active labor. Other risk factors include acute
asphyxia and poorly controlled maternal diabetes;
genetic predisposition is a likely underlying cause
(Ramachandrappa and Jain 2009). In RDS, the
breathing is rapid but apparently effortless as the
stable chest cage does not often reveal retractions
and chest X-ray finding may be inconclusive.
Ignoring early treatment of respiratory distress
and hypoxemia escalates the later respiratory
course. Persistence of pulmonary hypertension
(PPHN) or pneumothorax are occasional compli-
cations. Studies reveal surfactant insufficiency
despite atypical presentation.
The developmental stage explains the pheno-
type. The small size of newly developed true alveoli
predisposes to therapy-resistant atelectasis. The sta-
ble chest cage and strong respiratory drive generates
high transpulmonary pressures during inspiration,
expanding alveolar ducts, improving the clearance
of edema fluid. The pulmonary vasculature has a
prominent smooth muscular layer that extends dis-
tally; hypoxemia-induced contractility predisposes
to pulmonary hypertension.
The clinical recovery often takes place within a
rather short period. Continuing severe respiratory
symptoms much beyond early neonatal period raises
the possibility of a rare lung disease, particularly
hereditary interstitial lung disease due to multiple
specific causes (▶ Chap. 59, “Rare Lung Diseases
of Newborns”).
53.5 Diagnostics
The diagnosis is based on a combination of
characteristic symptoms, clinical findings, and
the chest X-ray. Typical chest X-ray features
reveal a diffuse reticulogranularity with super-
imposed air bronchograms (Fig. 2), indicating
atelectasis and edema of respiratory units, distal
to respiratory bronchioles. The prominent air
bronchogram representing aerated bronchi and
larger bronchioles become distinct when they
829
are superimposed on a background of atelectatic
lung parenchyma. The severity of RDS on the
basis of the chest X-ray has been graded (Avery
et al. 1981). The grade is likely modified several
hours after exogenous surfactant. Pulmonary
whiteout (grade 4) is generally a sign of a severe
disease; it is also observed in mild disease very
soon after birth (<1 h). Pulmonary edema and
prominent heart shadow is a typical X-ray find-
ing in RDS complicated by PDA. In near-term
RDS population, reticulogranularity tends to be
less distinct and the lung fields may reveal
ground glass appearance. In some cases lung
fields appear hyper-expanded; this entity is
called type 2 RDS.
Lung ultrasound (LUS) diagnostics has been
recently reported as a tool for prediction of respi-
ratory failure (Sundell et al. 1971). LUS examined
within 1 h after the admission on 59 infants
with respiratory distress accurately predicted
RDS (n = 23) with sensitivity and specificity of
95.6% and 94.4%, respectively (Vergine et al.
2014). This method is still investigational.
Analysis of surfactant component or surface
activity of specimens performed on gastric or
airway aspirates at birth differentiates RDS with
specificity of and sensitivity of 50–75% and
80–97%, respectively (Verder et al. 2003;
Hallman et al. 1986). The false-positive prediction
can be due to blood contamination or to surfactant
retention due to airway liquid adsorption. A sim-
ple, rapid, and accurate bedside method would be
useful, if available.
53.5.1 Differential Diagnosis
Transient tachypnea (wet lung) becomes clearly
distinguishable from RDS within several hours
after birth. Bacterial pneumonia, mostly due to
Group B Streptococcus, often coincides with
RDS. In pulmonary infection, pleural exudate,
focal infiltrates, and sepsis are common. Amniotic
aspiration pneumonia, particularly meconium aspi-
ration, is easily distinguished by the appearance of
viscous, often green aspirate, typically in post-term
or term infant. Congenital chylothorax is distin-
guished by typical milky appearance of lipid-rich
830
Fig. 2 Typical radiographic and pathological findings of RDS. Typical chest X-rays representing RDS of infant during
surfactant (a) and pre-surfactant era (b). Autopsy findings from normal (c) and HMD (d) lungs
pleural exudate after enteral feeding. Rare cases of
small preterm infants with minimal respiratory dis-
tress develop cystic interstitial emphysema soon
after birth (Wilson-Mikity syndrome) (Hoepker
et al. 2008), a form of obstructive inflammatory
lung disease that resembles “new BPD” with min-
imal respiratory distress at birth.
Congenital cardiac diseases associated with
respiratory distress and congestive edema, most
notably anomalous pulmonary venous return with
abnormal infra diaphragmatic pulmonary vein
return (Scimitar syndrome), require early diagno-
sis and surgery. Equally critical is the prompt diag-
nosis and early onset of prostaglandin E2 infusion
for maintenance of ductal patency and pulmonary
circulation of ductus-dependent cardiac defects.
Early respiratory distress due to diaphragmatic
M. Hallman et al.
hernia, other causes of lung hypoplasia, cystic
adenomatous malformation, esophagus atresia,
isolated fistula, lung sequestration, tumors, and
malformations require early diagnosis and specific
treatment strategies.
A slow recovery from RDS may be a constitu-
tional feature with likely genetic involvement.
Failure to recover is a feature of congenital inter-
stitial lung disease due to a mutation in genes that
are essential in postnatal lung function (Wert et al.
2009). PPHN mostly develops as a consequence
of primary lung disease, often RDS. Alveolar
capillary dysplasia with misalignment of pulmo-
nary vessels is suspected on the basis of persis-
tence of acute severe defect in gas exchange;
autopsy diagnosis increasingly has identified
genetic background (Bishop et al. 2011).
53 Respiratory Distress Syndrome: Predisposing Factors, Pathophysiology, and Diagnosis
Acute (also called acquired or adult) respiratory
distress syndrome (ARDS) may develop in severe
infection or asphyxia also in newborn infants.
These patients often have beneficial response to a
high dose of exogenous surfactant. However, sur-
factant therapy has not significantly improved the
outcome of this severe, heterogeneous syndrome
that requires proper antibiotics and comprehensive
cardiopulmonary management.
53.6 Predisposing Factors
The lung has developed relatively late in evolu-
tion (250 million years), and human evolution is
recent (5 million years). The regulation of the
expression of individual genes generates much of
the diversity in human genome. The regulation of
the birth process and the involvement of the fetus
in the transition is particularly species specific.
Preterm birth is exceptionally common in human
species. Spontaneous preterm birth particularly in
chorioamnionitis (CA) accelerates surfactant
maturity decreasing the risk of RDS. The periph-
eral lining of air spaces at 20–22 weeks of gesta-
tion contains epithelial cells that morphologically
resemble type 2 cells, and pulmonary capillaries
align with future potential airways. Later in ges-
tation, both the number of type 2 cells and the
content of lamellar bodies increase. At term, the
surfactant content of the lungs reaches maximum
and has a critical role in adaptation. Other pulmo-
nary host defense systems have distinct perinatal
developmental patterns as well.
53.6.1 Surfactant System
The major surfactant component, dipalmitoyl
phosphatidylcholine (DPPC), concentrates at the
air liquid interphase as a tightly packed lipid
film (Fig. 3). Other surfactant components provide
the extraordinary rapid surface adsorption of DPPC.
These include phosphatidylcholine (PC) containing
unsaturated fatty acids, often unsaturated phospho-
lipids containing anionic charge [phosphatidyl-
glycerol (PG), phosphatidylinositol (PI)] and
831
hydrophobic surfactant proteins (SP-B and
SP-C). The latter contain stretches of hydrophobic
amino acids interrupted by hydrophilic amino
acids with cationic charge. Natural surfactant
additionally contains SP-A and SP-D: they are
collagen-containing lectins that have roles in
innate immunity, surfactant metabolism, and for-
mation of tubular myelin.
The hydrophobic components are synthesized
in ER, followed by serial cleavage of hydrophilic
stretches of SP-B- and SP-C proproteins, and they
are transported to intracellular lamellar bodies
(LB) (Fig. 3). After secretion from LB into
the alveolar lining, hydrophobic surfactant binds
Ca++ and SP-A, transforming to aggregates that
resemble tubular myelin and have instantaneous
surface adsorption. During breathing movements,
surfactant aggregates are transformed to smaller
vesicles. Only a minor fraction of the surfactant
complex is removed by cilia, and most of it is taken
up by both alveolar macrophages (AM) and type
2 (T2) alveolar cells. Surfactant is catabolized in
these cells and additionally reutilized in T2 cells.
Lowering of Surface Tension Surfactant greatly
reduces surface tension thus preventing the col-
lapse of small airspaces. Surface tension during
expiration is assumed to be close to zero, and it
rarely rises above 20 mN/m during normal expi-
ration. Surfactant additionally serves as a lubri-
cant that reduces barotrauma.
Immune Functions and Ancillary Pro-
teins Individual surfactant components serve as
immune modulators influencing together with
AM and other systems in defense against
microbes and other insults. Several surfactant
components inhibit the signaling of the Toll-like
receptors.
The coincidence of pneumonia and RDS
reflects the immaturity of the innate immune
system. The major defense functions of surfactant
components are focused against airborne microbes,
involving in their destruction without evoking
excessive inflammatory response: most surfactant
components are involved (PG, PI, SP-C, SP-B,
SPPC, and PC). Surfactant collections, SP-A and
SP-D, inhibit Toll-like receptor (TLR) signaling,
832
Fig. 3 Surfactant metabolism in alveolar epithelial cells
and in epithelial lining fluid (ELF). Surfactant is synthesized
endoplasmic reticulum (ER) of type 2 (T2) cells. Surfactants
(DPPC, PC, PG, PI, SP-B, and SP-C) are synthesized in
endoplasmic reticulum (ER) and processed via Golgi and
multivesicular bodies (MVB) into lamellar bodies (LB).
SP-A and SP-A are processed by constitutional pathway.
After release of LB content into alveoli, surfactant binds
aggregate viruses, and stimulate phagocytosis of
bacteria. Collectins, absent in exogenous surfac-
tants, are proposed to serve important functions in
innate immunity (Wright 2005).
Regulation of Surfactant System: An Example
of Antenatal Regulation of Functional Maturity -
Glucocorticoid is the main hormone regulating
spontaneous functional differentiation of the
lung (Bird et al. 2015). The effects of glucocorti-
coid on the surfactant system are mediated by
several pathways, one being fibroblast-derived
growth factor that influences the differentiation
of type 2 alveolar epithelial cells involved in sur-
factant synthesis and secretion. Glucocorticoid
typically promotes differentiation of other func-
tions in lung and in other organs and structural
maturation of the lung. High persistent glucocor-
ticoid activity decreases the growth. Absent
M. Hallman et al.
SP-A and transforms to tubular myelin (TM) figures. In ELF,
surfactant is transformed to smaller vesicles that are taken up
by alveolar macrophages (AM) and T2 cells for either catab-
olism in lysosomes (LS) or for reprocessing into LB
(recycling). In RDS, surfactant in ELF is deficient at birth,
and it increases to near-control level within a few days after
birth. At the same time, acquired surfactant defects appear as
a result of airway and alveolar injury
glucocorticoid activity in fetus leads to lung
hypercellularity, lack of functional differentiation,
and respiratory failure at birth. Other hormones
contributing to biochemical lung maturity include
adrenergic agents, thyroid hormone, and prolac-
tin, whereas testosterone delays lung maturity.
Several other growth factors and cytokines also
influence the differentiation and growth of alveo-
lar tissue (Torday and Rehan 2015).
Besides regulation of normal differentiation,
inflammatory cytokine and corticosteroid signal
both the acceleration of lung maturation and
spontaneous preterm labor in chorioamnionitis
(Kallapur et al. 2014). IL-1 has been identified
as a primary agonist upregulating the surfactant
system in intrauterine inflammation (Bry et al.
1997). Lipopolysaccharide from cell wall of
Gram bacteria (LPS or endotoxin) or inflamma-
tory cytokine introduced to the amniotic fluid
53 Respiratory Distress Syndrome: Predisposing Factors, Pathophysiology, and Diagnosis
accelerates differentiation of the surfactant and
induces lung inflammation that extends systemi-
cally. Severe systemic infections and very high
cytokine levels associate with adverse fetal
consequences.
Secondary Injuries Affecting Lung and Surfactant
System Pulmonary interstitium, individual lung
cells, including T2 cells, and the surfactant system
are exposed to multiple inflammatory and bio-
chemical insults as part of the manifestation of
lung injury in RDS: disruption of ER processing
of surfactant components, inhibition, inactivation,
degradation, de-aggregation, and displacement of
surfactant complex have been documented
(Mulugeta et al. 2015; Sáenz et al. 2010). Despite
lung injury, RDS is mostly a self-healing disease, as
the activation of differentiation-promoting inflam-
matory cytokines and of the anti-inflammatory
endocrine axis promotes spontaneous maturation
and healing.
In infants developing RDS, generally very low
although variable quantities of surfactant are pre-
sent in the airways at birth. Surfactant sufficiency
is established within 2–7 days in most cases
(Hallman et al. 1994; Carnielli et al. 2009). In
infants at risk of BPD, the surfactant proteins
and surface activity in the air spaces continue to
be deficient after the first week of life. Excessive
inflammation and other toxins suppress surfactant
synthesis and function. The inactivated surfactant
is degraded and replaced by newly synthesized
surfactant. As yet unidentified step(s) in surfactant
turnover is deficient in infants developing BPD.
53.6.2 Secretion of Fetal Lung Liquid
and Induction of
Liquid Absorption
During the second trimester, the rapidly growing
fetal lung secretes Cl (150 mEq/L) from epithe-
lial lining of air spaces and airways (Olver et al.
2004). This results in osmosis-driven liquid secre-
tion of 0.2–0.5 l per 24 h of protein-poor liquid or
5–15% of total liquid intake into the amniotic
cavity. At the same time, 6–9% of the cardiac
output is perfusing lung tissue. A normal fetus
833
makes periodic breathing movements with a
small tidal volume (0.2–3 mL), resulting in trans-
fer of liquid in and out from the airways. Toward
the end of the second trimester, most of the amni-
otic fluid originates from hypotonic fetal urine,
and it is cleared by fetal swallowing, with a turn-
over time of 48 h.
The secretion of the lung liquid, tidal respira-
tory movements, and airway contractility dilate
the future peripheral airways. The tidal move-
ments of the chest wall deliver some of the amni-
otic fluid content to the airways. Experimental
ligation of the fetal airways expands the future
airways and inhibits lung maturity. Lack of fetal
breathing movements leads to poor lung growth.
Lack of amniotic fluid or compression of lungs
(diaphragmatic hernia, intrathoracic tumor, small
chest cage) causes lung hypoplasia if present from
midpregnancy (Potter syndrome from fetal anuria
in particular).
Chloride ion exits the epithelial cells of the
airways and alveoli through apical anion-selective
channels, including cystic fibrosis transmembrane
regulator protein (CFTR). The driving force of the
pump is linked to the Na+,K+-ATPase activity,
generating the electrical potential difference allo-
wing basolateral entry of Cl (Fig. 4).
Absorption of the Fetal Lung Liquid is Linked
to Surfactant Function Toward term the secre-
tion of lung liquid secretion decreases dramati-
cally. The lung liquid during active term labor
decreases by 40–50% as a result of active absorp-
tion of lung water and surfactant concentrates in
air spaces. Lung extracellular water further
decreases by another 40% during the first 6 h of
life after term birth. A bulk of it exits the lung
during the first breaths as the permeability of
epithelium in small airways and air spaces
increases acutely (Fig. 4). Both T2 and T1 epi-
thelial cells contain amiloride-sensitive ENaC
protein complex, attached in the apical plasma
membrane. Besides the luminal transporters,
basolateral Na+,K+-ATPase and voltage gated
Cl channels transport Na+ and Cl ions to
lung interstitium. Aquaporins facilitate the
movement of water across cell membranes. In
addition, a large transepithelial leak is induced
834
Fig. 4 Fetal lung liquid secretion (risk of RDS) and lung
liquid absorption during labor (protective). Both are energy
dependent driven by various transporters in the epithelial
membranes. Glucocorticoid and adrenergic agents
upregulate sodium channels (ENaC), promoting liquid
absorption, together with aquaporins [AQP5] and Na+,
at birth promoting bulk liquid from the airways
(Van Driessche et al. 2007).
Adrenaline via cyclic AMP and corticosteroid
induces the absorptive state of the fetal lung.
Corticosteroid increases the synthesis of ENaC
protein and adrenaline activates ENaC, particu-
larly the rate-limiting ENaC-α. Cortisol increases
as a result of activation of the pituitary-adrenal
axis toward the term. Adrenalin increases during
labor, and a further increase takes place shortly
after birth.
In infants developing RDS, the ion channels
responsible for clearance of the lung liquid are
not active at birth. This is likely to aggravate the
M. Hallman et al.
K+-ATPase. Constitutional liquid secretion is driven by
Na+,K+-Cl cotransporter (CLC). Cl exits the apical
membrane through cystic fibrosis transmembrane conduc-
tance regulator (CFTR) and other channels. A paracellular
leak across the epithelium is induced during first breaths
after birth
symptoms of RDS, and activation of ion
channels involved in liquid adsorption is associ-
ated with the recovery. Wet lung syndrome is
characterized by insufficient clearance of lung
liquid and apparently critical deficiency of the
active clearance mechanism (O’Brodovich 2005;
Helve et al. 2009).
Induction of the active adsorptive state of
fetal lung liquid during normal labor leads to
retention and accumulation of surfactant in
future air spaces and airways, providing the
critical surfactant pool available at birth, thus
facilitating the liquid clearance from airways
and air spaces.
53 Respiratory Distress Syndrome: Predisposing Factors, Pathophysiology, and Diagnosis
53.6.3 Structural Lung Development
During fetal development, there are changes in lung
structure, including in the microanatomy and in the
amount and composition of the extracellular matrix.
These factors influence the phenotype of RDS.
During the canalicular phase between 16th and
25th weeks of gestation, the airway branching
is complete and the lung transforms to organ, poten-
tially capable of gas exchange (chapter by Moretti).
This is accomplished by formation of cartilage,
bronchial grands, and growth of the distal ends of
the preacinar terminal bronchioles that grow and
branch to two to four respiratory bronchioles. The
potential gas exchange surface enlarges as a result of
simultaneous vascular sprouting and acinar growth.
Future airways and capillaries also approach each
other, decreasing the length of gas diffusion path.
The epithelium undergoes thinning from columnar
to cuboidal form as type 2 cells differentiate.
During the saccular phase between 23 and
28–36 weeks, clusters of thin-walled saccules form
the acinus that simultaneously expands and grows
in length as the respiratory bronchioles divide into
six–seven further generations by branching. Elastic
fibers are deposited along the airways and capil-
laries. The capillaries still form a double capillary
network between individual saccules.
Toward the end of gestation and particularly
after birth, the elongated T1 alveolar cells expand
and increasingly cover the alveolar lining,
whereas surfactant-secreting T2 cells arrange
around the alveolar corners. The alveolar stage
involves microvascular maturation that starts pre-
term and continues during the first years. True
alveoli grow from the walls of terminal saccules
as spherical structures. They grow in size, and the
inter-saccular tissue containing a double capillary
network transforms into a single capillary network
in close apposition to alveoli (Burri 2006).
53.7 Mechanisms of Lung Injury
in RDS
Although the effect of surfactant therapy is often
dramatic in reducing or even abolishing the symp-
toms of respiratory distress, in some cases its effect
835
is either transient or in rare cases missing altogether.
Transient effect endogenous surfactant is a sign of
perturbed endogenous metabolism of surfactant and
surfactant inhibitors. This emphasizes the interac-
tive nature of factors influencing the alveolar stabil-
ity, pulmonary circulation, and structural integrity,
essential to the gas exchange function. These fac-
tors also include the conducting airways that are
intimately involved in lung injury, pulmonary per-
fusion, and cardiac contractility. Ductus arteriosus
increasingly remains open as the duration of preg-
nancy shortens, perturbing cardiopulmonary func-
tion and increasing lung edema. Regardless of
length of gestation and pregnancy complications,
diffuse atelectasis, lung edema, and hyaline mem-
branes are a consequence of functional immaturity
of alveolar epithelium. Infections and severe
asphyxia, extreme immaturity, and other adverse
events complicate and dominate the symptoms of
cardiorespiratory distress. Figure 5 illustrates fac-
tors involved in pathogenesis.
53.7.1 Primary and Secondary
Surfactant Deficiency
High surface tension retracts the air spaces with
very small principal radii (R1 and R2) according
to the law of Laplace: P (collapsing surface pres-
sure) = γ (surface tension constant)  {1/R1 + 1/R2}.
In true alveoli or at the tip of respiratory ducts
of immature lung, the two principal radii are very
similar (P = 2  γ/R), whereas in tubular surfaces,
the second radius is indefinite (P = γ/R). During
inspiration, surfactant components adsorb to the
lining, while during expiration, unsaturated lipids
with higher surface tension are squeezed out from
the lining, helping the surface tension to reach
near-zero level. During tidal ventilation, surface
tension increases slightly during inspiration
and returns to near-zero during expiration (i.e.,
hysteresis) preventing atelectasis and decreasing
alveolar edema. In the absence of surfactant, the
tendency to atelectasis is due to the high surface
pressures that increase during expiration. Surface
tension in vitro is measured quantitatively using
captive bubble or pulsating bubble surfactometer.
These measurements have been confirmed in
836
SURFACTANT DEFICIENCY
INFLAMMATION
Surfactant
FREE RADICALS
therapy
Management
LUNG DEVELOPMENT LEAKY CELLULAR
BARRIERS
Gestational age
Corticosteroids
Genetic risk Management
Intrauterine
inflammation Lung congestion, PDA
Gender
Twin gestation Defects in ion transport
LUNG STRUCTURE
SPECIFIC FUNCTIONS
Fig. 5 Pathogenesis of RDS. Primary surfactant defi-
ciency that is augmented by other defects in differentiation
(e.g., lack of absorptive ion transport) and acquired factors
situ by microscopy of the alveolar surface
containing droplets of specific fluorocarbons
with constant, generally low surface tension
(Schürch et al. 2001).
During the first breaths, surfactant in lung liq-
uid rapidly adsorbs and concentrates on the
emerging air liquid interface. Lowering the sur-
face tension (72 mN/m in isotonic saline) toward
0 mN/m decreases the force required for liquid
clearance from narrow tubular structures and alve-
olar saccules; additional force required is due to
viscous resistance of the small airways. Transient
negative interstitial pressures generated during
the first few forceful inspirations (as high as
50–70 cm H2O) and airway pressures during
forced expirations with semi-closed vocal cords,
i.e., “first cry” (25–50 cm H2O), are exceptionally
high and contribute to the rapid paracellular
increase in epithelial permeability and possibly
injure immature airways. Low surface tension
facilitates clearance of lung liquid and decreases
airway injury.
Secondary surfactant defects emerge after
birth. The leakage of proteinous liquid across the
epithelial lining dilutes surfactant and inactivates
surfactant (Hallman et al. 1991). Proteins, cationic
amino acids, carbohydrates, and lipids inhibit
M. Hallman et al.
POOR SURFACTANT FUNCTION
SURFACTANT
INACTIVATION
EDEMA Lung function
Chronization
REPROGRAMMING
Tissue damage, remodeling of growth air
leaks, cytokines, metaplasia, fibrosis
(e.g., asphyxia, volutrauma). Persistence of lung injury is
opposed by the lung healing, plasticity, and differentiation
(e.g., induction/increase in surfactant)
surfactant function in vitro. Fibrin monomer is
one of the most potent surfactant inhibitors
described. Other mechanisms of surfactant inacti-
vation include excess of proteolytic and phospho-
lipase activities. Finally, oxidant injury by
hydroxyl radicals and peroxynitrite and other nox-
ious factors deteriorate surfactant function and
metabolism (Sáenz et al. 2010; Hallman et al.
1994; Carnielli et al. 2009). Many of these nox-
ious agents originate from inflammatory cells as a
consequence of lung injury by barotrauma, hyper-
oxia, and endotoxins. ER stress and associated
defect in intracellular processing and dysfunction
of surfactant proteins is consistent with the
observed abnormalities in surfactant composition
and metabolism in infants developing BPD
(Mulugeta et al. 2015).
53.7.2 Biotrauma
As a consequence of ante-, intra-, and postnatal
events particularly those taking place at birth, the
innate immune system is activated. The inflamma-
tory reaction as a result of biotrauma induces both
healing and tissue destruction (e.g., phagocytosis,
oxidants, lytic proteins, oxidants, free radicals).
53 Respiratory Distress Syndrome: Predisposing Factors, Pathophysiology, and Diagnosis
The degree of biotrauma depends on management
practices, constitution, and hereditary factors. Both
antenatal (e.g., antenatal steroid and antibiotics
after preterm rupture of fetal membranes), delivery
room (e.g., early introduction of PEEP, limitation
of inspiratory pressures, noninvasive surfactant
administration), and neonatal (early extubation,
noninvasive ventilation, anti-inflammatory airway
therapies, prevention of infections) treatment
practices are primary aimed to decrease biotrauma.
An experimental study by Jobe et al. illustrates
an example of research on biotrauma (Hillman
et al. 2007).
Besides the components of the surfactant system,
other proteins, including Clara cell protein 16, SOD,
eNAC, number of other anti-inflammatory peptides
(e.g., defensins), signaling receptors, transcription
factors, hormones, and growth factors, control the
development of innate immunity.
53.7.3 Volutrauma and Barotrauma
Intubation and the associated bagging and
mechanical ventilation without full control of
the tidal volumes and pressures are the most
important source of volutrauma and barotrauma.
By increasing the airway pressure requirements,
high surface tension influences volutrauma,
i.e., overstretching of patent air spaces. Volu-
trauma predominates when large tidal volumes
(>6–12 mL/kg) are delivered during mechanical
ventilation shortly after birth (Hillman et al.
2007). It manifests as rupture, laceration, increase
in permeability and compliance of central air-
ways, perivascular edema, bronchiolar obstruc-
tion, and inflammatory response (biotrauma).
In RDS the minimum surface tension ranges
from 20 to 50 mN/m. Distending pressures that
maintain patency of alveoli with a radius of 50 μm
or of alveolar ducts (very preterm) with radius of
100 μm is estimated to be 8–20 cm H2O and
4–10 cm H2O, respectively. High surface tension
and high viscous resistance caused by airway
edema and particles deteriorate lung homogeneity
and predispose to volutrauma.
Volutrauma and barotrauma are decreased con-
siderably by avoiding mechanical ventilation.
837
Lack of lubricant property of surfactant contrib-
utes to barotrauma.
53.7.4 Delay in Clearance of Lung
Liquid
Prenatal events influence the lung liquid adsorption
and the amount of lung liquid at birth (Olver et al.
2004; Van Driessche et al. 2007; O’Brodovich
2005). Spontaneous labor, advanced gestation,
and vaginal birth additively decrease the liquid in
the airways at birth. In healthy human infants, the
clearance of most airway liquid to lung
interstitium takes place within seconds to minutes
after the first breaths. Both active, energy-
requiring, and passive pressure-driven mecha-
nisms are stretch activated.
In normal adaptation, the clearance of liquid
from lung interstitium takes place during the first
day as the solute directly enters the circulation or
is cleared via lymphatics. The bulk of the liquid
removed from the airways accumulates in disten-
sible perivascular spaces of large lung vessels and
airways, away from the gas exchange path.
In very premature lung, low activities of devel-
opmentally regulated sodium and water transport
weaken the absorptive state of premature fetal
lung, delaying the accumulation of the surfactant
pool before birth and the liquid clearance after
birth (Van Driessche et al. 2007; Helve et al.
2009; Bland 2001). This is a major problem in
elective late-preterm and early-term births: the
alveolar surfactant pool at birth is small as a result
of surfactant secretion into amniotic fluid and lack
of adsorption of lung liquid.
Lung immaturity adversely affects lung liquid
clearance as the compliant chest cage complicates
generation of high negative interstitial pressures,
and the activities involving ion and water transport
across the epithelium toward lung interstitium are
low. Diaphragmatic fatigue and particularly lack of
respiratory drive due to deficient respiratory center
responses contribute for alveolar edema and respi-
ratory distress.
The passive stretch-activated bulk solute trans-
fer takes place in both directions. It is thus respon-
sible for either the clearance of lung fluid or the
838
formation of alveolar edema after very preterm
birth. Edema is imminent, in case hydrostatic
pressures (interstitial pressure and the airway
distending pressure) fail to compensate for the
high surface pressures in surfactant deficient lung.
53.7.5 High-Permeability Lung Edema
The injury of capillary endothelium and airway
epithelial cells and their basement membranes is
a characteristic early feature. The injury mecha-
nisms include mechanical trauma, biotrauma, and
toxins (oxygen). An important functional conse-
quence is an increase in permeability to macro-
molecules soon after preterm birth. An increase in
permeability exceeds the capacity of pulmonary
lymphatics, resulting in interstitial edema. Small
airways, bronchioles, and air spaces are suscepti-
ble to flooding and obstruction, and alveolar
edema further decreases gas exchange.
Increased epithelial permeability leads to
protein-rich alveolar edema and accumulation of
surfactant inhibitors. Accumulation of fibrinogen
into alveolar space precedes the formation of hya-
line membranes. A residue of inactivated surfac-
tant components and other residues are
incorporated into the matrix of fibrin-rich hyaline
membranes. They interfere with gas exchange,
obstruct the air spaces, and may initiate intra-
alveolar coagulation. Hyaline membranes are
eventually cleared by phagocytosis and fibrino-
lytic activity (Idell et al. 1994).
Continuous distending pressure to the airways;
avoidance of mechanical ventilation; avoidance of
fluid overload, cardiac failure, and of infections;
and activation of anti-inflammatory mechanisms
(steroid) all contribute toward decreasing high-
permeability lung edema.
53.7.6 Pulmonary Hemorrhage
Pulmonary hemorrhage complicates RDS mostly
in extremely preterm infants. It may be seen as an
extreme form of high-permeability lung edema
that is associated with PDA, decrease in pulmo-
nary vascular resistance, and rapidly developing
M. Hallman et al.
left cardiac failure resulting in flooding of alveolar
capillaries (e.g., in hypothermia). Hemorrhage
may be precipitated by surfactant therapy as it
lowers pulmonary vascular resistance increasing
the left-to-right shunt through ductus arteriosus.
Inadequate continuous positive airway pressure
levels may further decrease pulmonary vascular
resistance, allowing hydrostatic congestion and
eventually rupture of capillaries and airway epi-
thelium (▶ Chap. 55, “Pulmonary Hemorrhage,
Transient Tachypnea, and Neonatal Pneumonia”).
53.7.7 Abnormalities in Lung
Perfusion
Acetylcholine, nitric oxide (NO), and potentially
other vasoactive agents triggered dilate pulmo-
nary arterioles during normal neonatal transition.
During the early hours in RDS, the failure of
alveolar capillary gas exchange may in part be
due to poor perfusion of alveoli, whereas mainly
in later stages of RDS, symptoms of pulmonary
vascular congestion prevail. Pulmonary perfusion
needs to be carefully considered throughout the
respiratory course.
In extremely immature lung, the marginal size
capillary bed barely provides a reservoir against
hypo-hypervolemia and excessive distending
pressures.
Besides lung hypoplasia, predisposition to
PPHN can be the result of acute biotrauma, caused
by microbes and inflammatory agents.
Prolonged rupture of fetal membranes in pre-
term infants is occasionally complicated by severe
surfactant-nonresponsive respiratory distress,
associated pulmonary hypertension, and low air-
way nitrite and inflammatory cytokine levels,
suggesting transient immune paralysis. A dra-
matic, acute favorable response to inhaled NO
has been demonstrated in several small studies.
However, the actual improvement in the outcome
has not been shown in a randomized trial (Aikio
et al. 2012).
Increase in pulmonary vascular resistance in
severe acute lung disease is well recognized
(Steinhorn 2010). This applies also to RDS.
Toward term, the muscularity of pulmonary
53 Respiratory Distress Syndrome: Predisposing Factors, Pathophysiology, and Diagnosis
arteries increases. Treatment of RDS in near-term
infants is often delayed, allowing progression of
respiratory distress and development of PPHN
that favorably responds to inhaled NO.
53.7.8 Patent Ductus Arteriosus (PDA)
Prostaglandin inhibitor-induced contraction of the
fetal ductus arteriosus is detectable in the begin-
ning in the third trimester and increases toward
term. After birth, the cascade of events leading to
permanent constriction followed by anatomical
closure of the ductus takes place in nearly all
term-born infants, whereas the degree of
prematurity progressively increases the risk of
hemodynamically significant PDA (Hamrick and
Hansmann 2010).
PDA particularly in ELGA infants continues to
be a challenge and an important factor influencing
the duration of the course of RDS. A large left-to-
right shunt through PDA causes pulmonary con-
gestion at the expense of systemic perfusion. This
sometimes happens within few days after birth, as
a result of surfactant-induced remission of RDS
that decreases pulmonary vascular resistance.
Attempts to close ductus arteriosus during the
first days after birth by indomethacin or ibuprofen
or by ligation have been associated with serious
side effects, including pulmonary hypertension
and IVH. Appropriate emergency treatment of
early PDA is to promote the treatment of lung
edema, particularly by increasing inappropriately
low continuous distending airway pressure and
reducing excessive liquid intake. Adverse effects
associating with PDA include pulmonary edema/
IVH, NEC, ROP, and BPD. Antenatal glucocorti-
coid, neonatal caffeine, and inhaled budesonide
decrease the risk of PDA. The potential benefit of
paracetamol in early treatment of PDA is currently
investigated.
53.8 Prevention of RDS
Obstetric and early neonatal management of pre-
term infants influence the risk and severity
of RDS.
839
Available therapies convert RDS from lethal
to manageable or preventable disease. The cost
of treatment is high, and the disease may asso-
ciate with complications that may be life-
threatening (Gilbert 2006). In very preterm
infants, RDS is a common disease that has a
major influence in the risk of both acute and
chronic morbidity.
53.8.1 Prevention of Premature Birth
Elimination of prematurity would be most effec-
tive in prevention. There are remarkable variation
in the risk of prematurity based on the lifestyle,
working conditions, risk behavior, ethnicity,
socioeconomic status, and the healthcare system.
In vitro fertilization practices increase the risk of
premature birth.
Tocolytic agents have a limited capacity to
prolong the pregnancy in threatened preterm
labor. Despite side effects, they are shown to be
efficacious in delaying the preterm birth for a few
days required for full effect of ACG. Ca-channel
antagonists delay preterm birth without causing
serious adverse effects.
Supplementation of progesterone acetate from
midterm pregnancies has reduced the prematurity
rate only in rare cases of cervix insufficiency.
Thus far, no long-term risks have been observed,
and the follow-up continues (WHO 2015).
53.8.2 Pharmacological Acceleration
of Fetal Lung Maturity
AGC became an accepted therapy for prevention
of RDS first in the 1990s when the concerns of
serious adverse long-term effects were not mate-
rialized (Liggins and Howie 1972; Roberts and
Dalziel 2006). Glucocorticoid influences the
development of the fetal lung, gastrointestinal
tract, cardiovascular system, liver, kidney, and
central nervous system. It accelerates the differ-
entiation of the surfactant system, promotes the
absorptive state of fetal lung, enhances the closure
of ductus after birth, increases the generally low
blood pressure of preterm infants shortly after
840
birth, improves the performance of the immature
left ventricle, and has beneficial effects on the
immune and antioxidant systems.
According to meta-analysis of randomized trials
on AGC, it resulted in overall reduction of the risk
of RDS (relative risk, RR 0.66, 95% CI 0.59–0.73).
The most beneficial effect was observed when
AGC was started 1–7 days before threatened pre-
term birth prior to 34 full weeks of pregnancy.
According to cohort studies, AGC was efficacious
of improving the postnatal survival and decreasing
the risk of RDS among ELGA and preterm twin
pregnancies, respectively. AGC further decreased
the risks of RDS in preterm infants exposed to
chorioamnionitis and rupture of fetal membranes.
Although AGC decreases the risk of respiratory
distress in near-term pregnancies, most fetuses are
exposed only to potential adverse effects (e.g.,
hypoglycemia); ACG is not routinely indicated at
34 weeks or later.
AGC and exogenous surfactant supplement
each other in decreasing the risk of RDS and
IVH (Hallman et al. 2010). According to meta-
analysis, glucocorticoid decreased neonatal
mortality, IVH, and NEC and tended to decrease
early neonatal infections. The cognitive and neu-
rological problems observed in rodents following
AGC have not been replicated as there is a trend
toward improved neurological outcome. Expo-
sure to AGC is associated with mild insulin resis-
tance in young adults (Dalziel et al. 2005).
Repeating the AGC dosage in threatened pre-
term birth decreases the risk of RDS and of severe
RDS (Peltoniemi et al. 2011). Repeating the drug
weekly decreased the birth weight and head cir-
cumference dose-dependently. Although no
adverse influence on growth or on neurologic or
cognitive function has been detected, longer
follow-up studies are required. Currently a single
repeat dosage of AGC is recommended in threat-
ened very preterm birth (<32 weeks) in case the
fetus remains undelivered for more than week.
53.8.3 Diagnosis of Lung Maturity
Lung surfactant secreted into liquid-filled air
spaces is carried by the lung liquid into the
M. Hallman et al.
amniotic fluid. This amniotic surfactant pool starts
emerging with imminent functional maturity of
fetal lung. Surfactant increases in concentration
and quality in a characteristic fashion as the preg-
nancy proceeds. Surfactant indices, measured in
the amniotic fluid [lecithin/sphingomyelin (L/S)
ratio, PG, the lung profile, saturated lecithin, LB],
are used to evaluate the risk of RDS of an unborn
fetus, particularly in the era when AGC or exog-
enous surfactant were not used (Hallman 1992).
Assessment of fetal maturity in preterm and near-
term pregnancies is still indicated when there is a
need to balance the risk of continuing a risk preg-
nancy against the risk of iatrogenic RDS. The
reported specificity and sensitivity of the surfac-
tant indices in amniotic fluid have ranged from
92–100% to 30–70%, respectively. Due to surfac-
tant retention in active labor, the sensitivity of
surfactant indices in amniotic fluid or gastric aspi-
rate at birth is likely rather low.
53.8.4 Prevention of Low-Risk Elective
Births Before Term
A significant fraction of near-term (34–36 weeks)
and early-term-born infants (37–38 weeks)
develop RDS if delivered electively before the
onset of active labor (Tita et al. 2009). In infants
born at 39 weeks of pregnancy or later, RDS is very
rare (<1%) regardless of the mode of delivery,
whereas the risk of meconium aspiration syndrome
and acute asphyxia continues to increase after term.
In elective near-term births without onset of
labor, the fetus is exposed to increased risk of
transient tachypnea, spontaneous pneumothorax,
RDS, and persistence of fetal circulation. The
induction of the adsorptive state of lung liquid
allows the accumulation of surfactant in future
air spaces before birth. The labor-associated hor-
mones, cortisol, and adrenalin additionally
increase the secretion of surfactant. According to
available trials, AGC in elective near-term births
decreases the risk of transient respiratory distress.
Before ACG treatment is accepted as a therapy
in elective late-preterm and early-term births with-
out labor, it is important to know that the mostly
healthy fetuses exposed to steroid are not
53 Respiratory Distress Syndrome: Predisposing Factors, Pathophysiology, and Diagnosis
adversely affected long term. In near-term births,
AGC is indicated when the risk of respiratory
distress is considerable. These cases include
maternal diabetes with poor metabolic control,
severe Rh immunization, diaphragmatic hernia,
near-term RDS in the family, and documentation
of immaturity of fetal lung.
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