Management of Respiratory Distress Syndrome: An Update
Ricardo J Rodriguez MD
Introduction
Composition and Metabolism of Surfactant
Surfactant Replacement for Respiratory Distress Syndrome
Ventilatory Management
Nitric Oxide for Premature Babies with Respiratory Distress Syndrome
Summary
Respiratory distress syndrome is the most common respiratory disorder in preterm infants. Over
the last decade, because of improvements in neonatal care and increased use of antenatal steroids
and surfactant replacement therapy, mortality from respiratory distress syndrome has dropped
substantially. However, respiratory morbidity, primarily bronchopulmonary dysplasia, remains
unacceptably high. The management of respiratory distress syndrome in preterm infants is based
on various modalities of respiratory support and the application of fundamental principles of
neonatal care. To obtain best results, a multidisciplinary approach is crucial. This review discusses
surfactant replacement therapy and some of the current strategies in ventilatory management of
preterm infants with respiratory distress syndrome. Key words: pediatric, respiratory, pulmonary,
respiratory distress syndrome, RDS, surfactant replacement therapy, preterm newborn, bronchopulmo-
nary dysplasia. [Respir Care 2003;48(3):279 –286. © 2003 Daedalus Enterprises]
Introduction
Respiratory distress syndrome (RDS) is the most com-
mon respiratory disorder of premature infants. Since the
initial description of the association of RDS with surfac-
tant deficiency more than 30 years ago, enormous strides
have been made in understanding the pathophysiology and
treatment of this disorder.
1
The introduction of antenatal
steroids for acceleration of lung maturity and the devel-
opment of exogenous surfactant can be credited with the
dramatic improvement in the outcome of patients affected
with RDS.
2– 6
Typically, RDS affects preterm infants below 35 weeks
of gestational age; however, older infants with delayed
lung maturation of different etiologies can also be afflicted.
Common risk factors associated with RDS include low
gestational age, perinatal asphyxia, and maternal diabe-
tes.
7
Hack et al have reported that 56% of infants between
501 and 1,500 g were noted to have RDS and/or respiratory
insufficiency of prematurity, including 86% between 501 and
750 g; 79% between 751 and 1,000 g; 48% between 1,001
and 1,250 g; and 27% between 1,251 and 1,500 g.
8
RDS presents at birth, or shortly thereafter, with grunt-
ing respiration, chest wall retractions, nasal flaring, and
increased work of breathing. These patients usually show
progression of symptoms and require supplemental oxy-
gen. Hypoxemia and hypercarbia, accompanied by various
degrees of respiratory and metabolic acidosis, are the typical
findings from arterial blood gas analysis. The pathogno-
monic radiology findings are bilateral, homogeneous,
ground-glass appearance of the lung fields, with hypoin-
Ricardo J Rodriguez MD is affiliated with the Department of Pediatrics,
Division of Neonatology, Case Western Reserve University, and Rain-
bow Babies and Children’s Hospital, Cleveland, Ohio.
Ricardo J Rodriguez MD presented a version of this report at the 31st
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Journal Conference, Current Trends in Neonatal and
Pediatric Respiratory Care, August 16–18, 2002, in Keystone, Colorado.
Correspondence: Ricardo J Rodriguez MD, Department of Pediatrics,
Division of Neonatology, Rainbow Babies and Children’s Hospital, 11100
Euclid Avenue, Cleveland OH 44106. E-mail: rjr8@po.cwru.edu.
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flation and superimposed air bronchogram. In more se-
verely affected babies, a complete “white-out” of the lung
fields is often observed.
The pathophysiology of this disorder has been clearly
elucidated. Briefly, the structurally immature and surfac-
tant-deficient lung has a tendency to collapse. The pres-
ence of relatively well perfused but poorly ventilated areas
of the lung results in ventilation/perfusion mismatch, with
hypoxemia and hypercarbia. In some patients, pulmonary
vasoconstriction leads to persistence of pulmonary hyper-
tension and right-to-left shunts (via the patent ductus ar-
teriosus and/or the foramen ovale), resulting in more se-
vere hypoxemia. This phenomenon, once thought to be
patrimony of the full term infant, is frequently observed in
preterm babies with RDS and has led some clinicians to
consider the use of inhaled nitric oxide in preterm infants
when hypoxemia is unresponsive to adequate support with
mechanical ventilation. Fortunately, the natural course of
the disease in many low-birthweight infants has been al-
tered by the introduction of exogenous surfactant.
The management of these infants is complex and re-
quires a multidisciplinary team approach to obtain best
outcomes. The application of the basic principles of neo-
natal care, such as thermoregulation, cardiovascular and
nutritional support, treatment of early neonatal infection,
and prevention of nosocomial infection, is crucial to achieve
the therapeutic goals. Clearly, surfactant replacement ther-
apy, continuous positive airway pressure (CPAP), and me-
chanical ventilation in its different modalities are the main-
stay for the respiratory support of these patients.
Composition and Metabolism of Surfactant
In the early 1950s, Clements, Pattle, and others de-
scribed the presence of a thin layer of material on the
alveolar surface of the lungs, which is capable of reducing
surface tension to a low level upon dynamic compres-
sion.
9,10
These were the initial descriptions of the physio-
logic properties and the role of endogenous pulmonary
surfactant in the maintenance of alveolar stability. Surfac-
tant is a complex mixture of phospholipids and proteins
and is present in the lungs of all mammalian species. Sur-
factant obtained from alveolar wash contains 80% phos-
pholipids, (phosphatidylcholine, phosphatidylglycerol,
phophatidylinositol, and phophatidylethanolamine), 10%
protein (surfactant protein [SP] SP-A, SP-B, SP-C, SP-D
and other proteins), and 10% neutral lipids, mainly cho-
lesterol. Phosphatidylcholine, represents 60% of surfactant
by weight and accounts for 80% of the phospholipids.
Furthermore, saturated phosphatidylcholine is the princi-
pal surface-active material in surfactant.
11,12
The synthesis of endogenous surfactant is carried out by
type II pneumonocytes. The synthetic pathways and en-
zymes involved in the synthesis of each phospholid have
been characterized. The process takes place in the intra-
cellular organelles of the type II cell and results in the
formation of the surfactant lipoprotein complex. Surfac-
tant is subsequently stored in lamellar bodies, which are
the intracellular storage granules.
The release of surfactant into the alveolar space, by
exocytosis, can be enhanced by several mechanisms, in-
cluding lung expansion and
 receptor stimulation. Once
in the alveolar space, lamellar bodies unravel to adopt a
lattice-like appearance referred to as tubular myelin. The
presence of SP-A and SP-B is essential for the formation
of this structure.
13
This and other loose arrays of surfactant
lipoproteins are thought to constitute the reserve pool from
which the surfactant layer that lines the alveoli and small
airways is generated and maintained.
12
Surfactant leaves
the alveolar space and reenters the type II pneumonocytes
in the form of small vesicles, which contain small amounts
of SP-A and SP-B. In the intracellular space, the surfactant
components are recycled.
12,13
Pulmonary surfactant contains 3 surfactant-specific pro-
teins: SP-A, SP-B, and SP-C. In recent years, another lung-
specific protein, SP-D, has been identified.
12
Although not
strictly associated with surfactant phospholipids in the al-
veolar space, SP-D shares certain structural, biochemical,
and functional characteristics with SP-A.
14
These proteins
are synthesized primarily by type II cells, although the
presence of messenger ribonucleic acid (mRNA) for their
synthesis has been identified in other airway cell types.
Though it has been known for several decades that sur-
factant deficiency can result in RDS in the premature in-
fant, it is only recently that the absence of surfactant pro-
teins has been implicated in the etiology of RDS and other
respiratory disorders.
15–20
The lack of surfactant proteins precludes tubular myelin
formation, a surfactant conformation with surface tension
activity, thus promoting alveolar instability and collapse.
Low levels of SP-A and SP-B are characteristically found
in tracheal secretions and lungs of newborns with RDS.
16
Furthermore, an association between the level of SP-A and
severity of RDS has been noted.
21
Interestingly, in vivo
studies with knock-out mice have shown that SP-A is not
crucial for surface-tension-lowering activity or surfactant
homeostasis. This is consistent with the fact that the avail-
able surfactants, which have well-documented efficacy, do
not contain surfactant protein A. However, SP-A-deficient
animals are more prone to infections, highlighting the im-
portance of SP-A in host defense against pathogens.
SP-B, present in the available surfactants in various
concentrations, is critical for surface-tension-lowering ac-
tivity at birth, formation of lamellar bodies, and surfactant
homeostasis. SP-B deficiency is associated with a severe
form of RDS unresponsive to surfactant replacement. These
patients generally die despite intensive care. Lung trans-
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