Membrana Hialina

Treat Respir Med 2005; 4 (6): 423-437
1176-3450/05/0006-0423/$34.95/0
REVIEW ARTICLE
2005 Adis Data Information BV. All rights reserved.
Pathophysiology of Neonatal Respiratory

Distress Syndrome
Implications for Early Treatment Strategies
Sean B. Ainsworth
Directorate of Women and Childrens Health, Forth Park Hospital, Kirkcaldy, Scotland, UK
Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423
1. Lung Volumes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424
2. Physiology of Gas Exchange in the Normal Newborn Lungs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425
2.1 Pulmonary Artery Pressure Changes after Birth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425
2.2 Ventilation Perfusion Mismatching . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425
2.3 Vaso-Active Mediators Influencing Peripheral Vascular Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425
2.4 Distribution of Ventilation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426
2.5 Diffusion and Pulmonary Gas Exchange . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426
3. Pathogenesis of Respiratory Distress Syndrome (RDS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426
4. Pulmonary Function in RDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427
5. Endogenous Surfactant in the Developing Lung . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429
6. Acute Physiological Effects of Surfactant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430
7. Pulmonary Function in Neonates Post Surfactant Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431
8. Effects of Surfactant on the Cardiovascular System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431
9. Translating Physiology and Pathophysiology into Clinical Practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432
9.1 Resuscitation Practices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432
9.2 Ventilation Strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433
9.3 The Dose of Surfactant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433
9.4 Re-Treatment with Surfactant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434
9.5 Inhaled Nitric Oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434
10. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434
Abstract
Neonatal respiratory distress syndrome (RDS) remains one of the major causes of neonatal mortality and
morbidity despite advances in perinatal care. The initial management of infants with RDS has almost become
too routine with little thought about the pathophysiological processes that lead to the disease and how the
clinician can use the existing therapeutic interventions to optimize care. The transition from fetus to infant
involves many complex adaptations at birth; the most important is the function of the lungs as a gas exchange
organ. Preterm surfactant-deficient infants are less well equipped to deal with this transition.
Optimum gas exchange is achieved through matching of ventilation and perfusion. In RDS, ventilation may
be affected by homogeneity of the airways with atelectasis and over distension, as hyaline membranes block
small airways. In turn this contributes to the inflammation that becomes bronchopulmonary dysplasia. Exogenous surfactant given early, particularly with positive end-expiratory pressure and, where necessary, gentle
ventilation, would seem to be the optimum way to prevent atelectasis. How this can be achieved in neonates after
surfactant therapy is explored through a review of the normal physiology of the newborn lung and how this is
affected by RDS. The therapeutic interventions of resuscitation, exogenous surfactant, ventilation and inhaled
nitric oxide are discussed in relation to their effects and what are currently the optimum ways to use these.
424
Ainsworth
It is hoped that with a better understanding of the normal physiology in the newborn lung, and the effects of
both disease and interventions on that physiology, the practising clinician will have a greater appreciation of
management of preterm infants with, or at risk of, RDS.
Respiratory distress syndrome (RDS) is the most common

reason for neonatal intensive care. Despite advances in perinatal
care RDS continues to be associated with significant mortality and
morbidity.[1,2] On its introduction in the late 1980s and early
1990s, exogenous surfactant was widely thought to be the panacea
for all the problems associated with this disease. However, despite
a reduction in mortality with the use of exogenous surfactant, it
became apparent that increased survival rates in very preterm
infants left both infants and institutions with a significant burden
of chronic lung disease.[3] The mechanisms leading to lung damage begin early, in some cases, antenatally. Postnatally, resuscitation maneuvers, oxygen and ventilation all interact to increase the
risk of lung damage.
This article reviews the physiology and pathophysiology of the
immediate postnatal changes in the lungs, how they differ in
infants with and without RDS, and also how they are affected by
treatment strategies, especially exogenous surfactant. It is hoped
that with a better understanding of the pathophysiology of RDS,
the reader will understand more fully the role of early surfactant
therapy and gentle mechanical ventilation to optimize the chances
of survival without lung damage.
Lungs of infants with RDS are said to be stiffer and that by
reducing the surface tension, surfactant improves compliance and
improves outcomes. This is an over-simplification of many
pathophysiological processes that follow preterm delivery; actual
processes are extremely complicated and subject to a number of
variables, not least of which is exogenous surfactant therapy and
Static pressurevolume curve of the
respiratory system
respiratory support. Research into surfactant and gas exchange

requires a multidisciplinary approach. Data from these disciplines
must be correlated and analyzed to understand the processes. This
is neither a review of surfactant composition and function, nor of
the wider issues of exogenous surfactant, instead the reader is
directed to other articles.[4,5] However, where relevant, data from
published studies of existing surfactants will be used to illustrate
physiological principles being discussed.
1. Lung Volumes
Ventilation, whether natural or artificial, is a cyclical process of
inspiration and expiration. The minute ventilation (MV) is that
volume of air which is expired in a period of 1 minute. The volume
of air expired in a single breath is the tidal volume (VT) which in
turn reflects the amount of air in the dead space (where no gas
exchange occurs) and the respiratory zone. MV and VT are related
such that; MV = VT respiratory frequency.
Spontaneous respirations occur at mid-range of the total lung
capacity, with a further two-thirds of total capacity available as
reserve in extreme circumstances. Reserve lung volumes are maximal volumes of gas above or below the tidal volume (figure 1).
Inspiratory reserve volume is the maximum volume of gas which
can be inspired from the peak of tidal volume. Expiratory reserve
volume (ERV) is the maximum volume that can be expired after
normal tidal expiration. The volume of gas that remains in the
lungs at the end of maximum expiration is the residual volume
Inspiratory
reserve
volume
Inspiratory
capacity
Tidal
volume
Inspiratory
capacity
Total
lung
capacity
Expiratory
reserve
volume
40
20
20
Pressure (cm H2O)
Functional
residual
capacity
40
Residual
volume
Fig. 1. Schematic representation of lung volumes and capacities as described in the review. In the disease-free normal lung, tidal volume changes occur
along the linear central portion of the static pressure-volume curve.
Treat Respir Med 2005; 4 (6)
Neonatal Respiratory Distress Syndrome
(RV). Functional residual capacity (FRC) is the volume of gas in

the lung when the lung is at rest (i.e. the volume of gas in the lung
after a normal tidal expiration), thus FRC = ERV + RV. A normal
FRC is important in determining optimum lung mechanics and
alveolar gas exchange. Understanding derivation of volumes in
ventilation helps to explain oxygenation and ventilation.
2. Physiology of Gas Exchange in the Normal
Newborn Lungs
Respiration is gas exchange, specifically the exchange of carbon dioxide for oxygen. At the cellular level, gas exchange occurs
by diffusion according to the partial pressure gradient of the gas.
Unfortunately, in humans diffusion alone cannot fulfill the minimal cellular metabolic requirements. Therefore, gas exchange is
enhanced by gas convection mechanisms with the back and forth
convection of air through the same system of conducting pipes and
a pulmonary gas exchange area located at the terminal end of the
conducting airways. Tidal respiration implies that oxygen partial
pressure (pO2) and carbon dioxide partial pressure (pCO2) will be,
respectively, lower and higher than in the environment.[6]
Adequate lung ventilation and good perfusion are not enough to
ensure that blood passing through the lung is well oxygenated, and
that CO2 is removed. For this gas exchange to take place there
must be a matching of ventilation and perfusion. This requires
adequate ventilation of the distal air spaces and a functional
circulation in close proximity to those air spaces. This latter aspect
is often forgotten when considering ventilation and oxygenation
but is an integral part to the whole process of gas exchange in the
body. Ventilation and perfusion of the lung are well adjusted to
each other under normal conditions. The ventilated respiratory gas
volume per unit of time (minute volume) is only slightly larger
than the blood volume traversing the lung over the same period of
time (cardiac output). Thus, an appropriate balance between ventilation and perfusion is a prerequisite for effective respiratory gas
exchange in the lungs.[6]
Newly born infants are susceptible to hypoxemia. Firstly, levels
of arterial oxygen in the fetus and newborn infants are lower than
in adults[7] thus, they have a smaller intravascular oxygen reserve.
Secondly, their FRC approaches airway closing volume where
atelectasis can develop easily. Thirdly metabolic demand for oxygen in newborns rapidly depletes any intra-vascular and alveolar
oxygen. Susceptibility to hypoxemia is accentuated in preterm
infants because of apnea due to an immature respiratory drive, and
lung segment collapse at the end of expiration, due to compliant
chest walls.
Good gas exchange is vital in preventing hypoxemia. Integral
to this is matching alveolar ventilation and pulmonary perfusion
such that alveolar oxygen and pulmonary capillary blood are in
close proximity. There must be sustained effective respiration (or
ventilation) to replenish oxygen within the airways and free diffu 2005 Adis Data Information BV. All rights reserved.
425
sion of oxygen and carbon dioxide across the alveolar-capillary

barrier. An adequate alveolar gas volume (i.e. FRC) must be
established shortly after birth and then be sustained. In newborns
without lung disease, the FRC is ~30 mL/kg,[8] corresponding with
the volume of fetal lung fluid.[9] FRC is established as the fluidfilled lung empties and then fills with resident gas. This acts as an
intrapulmonary oxygen reservoir, smoothing out the periodic
changes in alveolar ventilation occurring during respiration. Having aerated the lungs it is important that ventilation-perfusion
matching is then maintained; a number of factors come into play in
the regulation of this.
2.1 Pulmonary Artery Pressure Changes after Birth
After birth, pulmonary arterial pressure rapidly falls to ~50% of

in utero levels that previously equalled or exceeded systemic
levels. Changes are modulated by prostacyclin[10] and endogenous
nitric oxide (NO),[11] and other vasoactive substances selectively
acting on pulmonary microvasculature.[12] Stimuli that affect pulmonary arterial pressure may have different responses at different
ages. Newborn lambs have a vigorous hypoxic pulmonary vasoconstrictive response unlike adult sheep,[13] and even 6 weeks after
birth there are differences in responses of the pulmonary vasculature to prostaglandin D2; vasodilatation in the newborn lamb, but
vasoconstriction after 6 weeks of age.[14]
2.2 Ventilation Perfusion Mismatching
Hypoxic pulmonary vasoconstriction prevents localized ventilation-perfusion mismatching by reducing blood flow to parts of
the lungs that are hypoventilated or not ventilated at all. As the
level of oxygen in the distal airways decrease, resistance of small
muscular arteries increases leading to shunting of blood into
ventilated areas. There is, however, only a limited capacity to
cope, and with progressively larger areas of atelectasis and collapse there is eventual ventilation-perfusion mismatching.[15] This
is particularly relevant in the case of a diseased neonatal lung
where atelectasis can affect several lung regions simultaneously
and the situation may be further complicated by localized infection
where inflammatory mediators inhibit vasoconstriction.
2.3 Vaso-Active Mediators Influencing Peripheral
Vascular Resistance
Catecholamines alter ventilation-perfusion matching by altering pulmonary arterial pressure. In neonatal lambs, dopamine can
further increase the pulmonary arterial pressure and vascular resistance already brought about by hypoxia, thus causing further
deterioration of intrapulmonary shunting and ventilation-perfusion
mismatching.[16] NO on the other hand can be beneficial; by
inducing both bronchodilatation and pulmonary vasodilatation it
can have profound effects on gas exchange.[17] Compared with
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Ainsworth
term infants, preterm infants have lower levels of endogenous NO.

In term infants, endogenous NO production in the airways peaks
during the first few hours of life, whereas in preterm infants this
feature is almost absent.[18] Preterm infants who are well, seem to
adapt to lack of peak NO levels in the first few hours of life, and
their endogenous NO levels rise over the first 24 hours.[18] Whilst
studies of exogenous NO have generally shown benefit in term
infants with severe lung disease, results in preterm infants have
been less clear cut with positive results in some studies,[19] and
little or no effect in others.[20] Possible explanations for these
differences include severity of illness and extreme immaturity of
infants in some of the studies.[21]
2.4 Distribution of Ventilation
Although there are many studies of the postnatal changes in

lung mechanics, few describe the distribution of ventilation within
the lungs. In part, this is because of difficulties in performing
analyses in sick infants due to the need for multiple breath analyses. Many infants have difficulty in clearing lung fluid because of
immature sodium[22] and water channel expression.[23] These channels should open after birth to carry water out of the airways.[24]
This is gestation-dependent and less efficient earlier in gestation.[25] There is some evidence that the water channel known as
aquaporin 4 (AQP4) is up-regulated in preterm infants exposed to
maternal corticosteroids.[23] Increased content of lung liquid
reduces pulmonary compliance and impairs ventilation. Significant heterogeneity can occur within lungs of preterm infants,
reflecting significant variations in the distribution of water and
ventilation.[26] In lungs affected by hyaline membrane disease,
proteinaceous exudates occlude airways, either fully or partially,
resulting in alveolar hypoventilation. In turn this can affect gaseous exchange (figure 2).
2.5 Diffusion and Pulmonary Gas Exchange
Once gases reach the alveolar-capillary interface there must be

a rapid diffusion between terminal airways and blood. Movement
of gases across the alveolar-capillary membrane is a passive
process. This was thought to be a rate-limiting step, but has never
been shown to be abnormal in any neonatal condition when taking
into account the size of the alveolar-capillary interface. No significant differences were seen for carbon monoxide diffusion capacity
(commonly used in measurements) in preterm infants with and
without RDS,[27] which were lower than those observed in healthy
term infants in a separate study.[28]
3. Pathogenesis of Respiratory Distress
Syndrome (RDS)
Hyaline membrane disease is the name given to the histopathological appearance of established RDS (figure 3). The membrane
is a coagulum of sloughed cellular debris and proteinaceous exudate typically seen at the junction of the respiratory bronchioles
and alveolar ducts. Distal to this, terminal air sacs (which in the
preterm human infant are not truly alveoli as these only develop
late in gestation or beyond) appear intact apart from a generalized
reduction in volume and later secondary inflammatory infiltration.
Based on this histological appearance it would seem the limitation
to gas exchange in RDS arises at the gateway to the gasexchange unit rather than within the unit itself.[29]
Animal studies reveal multiple disturbances in the adaptation to
extra-uterine life of preterm newborns, including delayed clearance of fetal lung fluid,[30] increased permeability of the epithelial
and endothelial barriers,[31] delayed lymphatic clearance[32] and an
increased pulmonary blood volume.[33] All can lead to obstruction
of small airways. In premature lambs there is a bi-directional flux
of proteins between the airways and the circulation consistent with
the destruction of the epithelium in the terminal airways.[34] This
leaves only the basement membrane as a barrier between the air
spaces and the interstitial tissues. Surfactant deficiency and local
ischemia both contribute to the epithelial injury.
In surfactant deficiency additional pressure is required to overcome the higher surface tension at the air-tissue interface in
terminal airways. Respiratory bronchioles and alveolar ducts are
poorly supported structures in the immature lung and, under
conditions such as these, are susceptible to disruption through
shear forces, especially when the alveoli are over-distended. Uncontrolled increases in pressure, such as that exerted during positive pressure resuscitation, can lead to high tidal volumes and
over-distension, disrupting the epithelium.[35] Histological comparisons between surfactant-deficient rabbits ventilated with either
conventional mandatory ventilation or high frequency oscillation
ventilation, show that the amount of damage is related to the
magnitude of changes in airway pressure (or rather VT) rather than
average pressure per se.[36]
In one of the first studies of an exogenous surfactant,[37] investigators suggested that their findings do not agree well with the
suggestion that the syndrome results from the primary lack of
pulmonary surface-active materials and suggested that pulmonary ischemia was central to the pathogenesis of RDS. Although
time has proved them wrong with respect to surfactant, their
statement about pulmonary ischemia did carry some truth the
pathological lesion of hyaline membrane disease may represent
localized ischemic necrosis of the epithelia of terminal airways.
Consistent with this are studies linking acute perinatal asphyxia to
the incidence and severity of RDS,[38] and a poorer response to
surfactant in asphyxiated infants.[39] Microscopically, vasoconstriction in arterioles, adjacent to respiratory bronchioles undergoing epithelial slough, support the idea that ischemia may be
involved in the pathophysiology of RDS.[40]
427
Pulmonary arteriole
(pO2 = 5.3 kPa, pCO2 = 6 kPa)
Acinus with partial

obstruction of distal
airway secondary to
hyaline membrane
Normal patent acinus with

normal V/Q matching
Pulmonary arteriole
to pulmonary venous
connection bypassing alveoli
(no V/Q matching therefore
pO2 = 5.3 kPa, pCO2 = 6 kPa)
Pulmonary venous connection
draining alveolar region
with normal V/Q matching
(pO2 = 17.6 kPa, pCO2 = 3.7 kPa)
Pulmonary venous connection

draining alveolar region
with low V/Q matching
(pO2 = 6.9 kPa, pCO2 = 5.9 kPa)
Fig. 2. The effects of ventilation-perfusion (V/Q) matching on blood gas tensions within the lung. This schematic diagram of airway and vascular units
shows the effects of varying degrees of ventilation on V/Q matching and resulting blood gas exchange within these units (reproduced from Truog,[6] with
permission). pO2 = partial pressure of oxygen; pCO2 = partial pressure of carbon dioxide.
Whichever mechanism predominates, the end result is disruption of the respiratory epithelium and an influx of proteins into the
airways. Apart from a purely mechanical action of blocking the
airway, this can also cause a secondary surfactant dysfunction
through inactivation: surfactant may be simply denatured by the
proteins, some of which are proteases; there may be immunological phenomena (surfactant/anti-surfactant complexes have been
found in both surfactant-treated and non-treated infants with
RDS[41]); there may also be biochemical phenomena secondary to
the inflammatory infiltrate; and surfactant itself may become
sequestered in the fibrin rich hyaline membranes. Thus, existing
low levels of endogenous surfactant in preterm infants may be
further compromised.
4. Pulmonary Function in RDS

Any discussion of the effects of RDS on pulmonary function
must take into account gestational age, postnatal age, disease
severity, the type and amount of respiratory support and whether
effective spontaneous respiration can (or does) occur.[42] The
effects of RDS on lung mechanics of a term 3kg infant, with and
without RDS is summarized in (figure 4). The following is a
discussion of the measurements of pulmonary function that are
pertinent to RDS.
Studies show that FRC is decreased in surfactant deficient
lungs.[8,43] This occurs as a result of displacement of the intrapulmonary gas volume by vascular congestion, interstitial edema
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Ainsworth
Collapsed alveoli with

inflammatory cellular infiltrate
Hyaline membrane
Fig. 3. The characteristic histological appearance in respiratory distress

syndrome is that of widespread collapse of distal air spaces and regularly
dispersed dilated terminal bronchioles. The bronchioles are denuded and
lined by anuclear eosinophilic hyaline membranes composed of both necrotic epithelial cells, and fibrin and other proteins leaking out of the capillaries (hematoxylin-eosin stain).
and proteinaceous exudation. Improvements in FRC mirror the

improvements in oxygenation that can be seen with distending
airways pressure,[44] surfactant therapy[45] or the spontaneous resolution that occurs in some infants on the second or third postnatal
day when a diuresis can be seen to coincide with clearance of

excess lung fluid.[46]
The decrease in lung compliance that is one of the hallmarks of
RDS is the result of several factors: firstly, there is a decrease in
the number of ventilated terminal airspaces, secondly those airspaces that are ventilated are relatively over-distended and thus
carry an increased recoil pressure, and thirdly, dynamic (but not
static) compliance is decreased due to changes in the viscoelastic
properties of the lung and inhomogeneity of ventilation.[47] Lung
resistance (the sum of lung airways resistance and lung tissue
resistance) is 3- to 6-fold greater in newborn infants with RDS
compared with newborn infants without RDS and is largely due to
the decrease in the cross-sectional area of patent airways leading to
distal lung units.[48] Alveolar instability also affects compliance;
when pressure across an unstable alveolus reaches a critical opening pressure, this alveolus opens suddenly, during expiration the
same alveolus will also close abruptly when a critical closing
pressure is reached. Because the terminal airways are not uniform
in size, there is, in the surfactant deficient lung, a range of critical
opening and closing pressures. This leads to smaller airways
collapsing and a tendency for air to enter already open airways and
distend them further (figure 5).
Normal 3kg infant
3kg Infant with respiratory distress
IRV
64mL
IC
80mL
VC
120mL
V
16mL
ERV
40mL
FRC
80mL
RV
40mL
RV
40mL
36
0.3
5
4.4
29
40
1440
Physiological
dead space
VC
55mL
IRV
26mL
IC
40mL
V
14mL
ERV
FRC 15mL
RV 40mL RV
25mL
25mL
Respiratory rate/minute
Dead space/tidal volume ratio
Intraesophageal pressure difference (cm H2O)
Compliance (mL/cm H2O)
Resistance (cm H2O/L/sec)
Total work/breath (gm cm)
Total work/minute (gm cm)
Physiological
dead space
70
0.6
18
1.0
23
111
7770
Fig. 4. The effects of respiratory distress syndrome on lung function in a 3kg infant (reproduced from Avery et al.,[42] with permission). ERV = expiratory
reserve volume; FRC = functional residual capacity; IC = inspiratory capacity; IRV = inspiratory reserve volume; RV = residual volume; V = (tidal) volume;
VC = vital capacity.
a
80
Lung unit A
70
Volume A = 43mL
Radius = R
50
40
30
20
Volume B = 4mL
Radius = r
10
5. Endogenous Surfactant in the Developing Lung

Effective lung function requires not only adequate surfactant,
but also a sufficiently developed system for gaseous exchange, the
development of chest wall rigidity and diaphragmatic musculature
and a mature respiratory drive. Terminal airways must be structurally developed enough to permit gas exchange before surfactant
can be effective. The degree of lung maturation at any gestation
can be variable and is under the influence of external factors such
as maternal, placental and fetal problems, and medical treatments
such as antenatal corticosteroids. Animal and clinical studies
provide strong support that endogenous corticosteroids modulate
the development of a number of fetal tissues. In the human,
amniotic fluid corticosteroids increase several-fold during the
third trimester in parallel with surfactant maturation.[51] In fetal
lungs glucocortocoids induce, through gene activation, a number
of proteins including all of the surfactant associated proteins and
key lipogenic enzymes.
The composition and quantities of surfactant change with fetal
maturity and this is reflected in the declining incidence of RDS
towards term.[52-54] Surfactant is synthesized and stored in pulmonary type II cells after about 22 weeks gestation. Both the amount
of surfactant and type II pneumocytes that produce it increase with
gestation; preterm infants with RDS have surfactant pool sizes of
210 mg/kg,[55] at term the total surfactant pool is ~100 mg/kg,[56]
in later life the pool decreases to ~60 mg/kg in tissue and 4 mg/kg
in airspaces.[57] In general, the greater the quantity of endogenous
surfactant the better the compliance of the lung. However, even
small amounts of endogenous surfactant can have a dramatic
effect on compliance. Good improvements in compliance can be
seen with endogenous surfactant levels of 1020 mg/kg,[58] whereas it may take 100 mg/kg of exogenous surfactant to produce
similar improvements.[59]
The overall surfactant pool consists of various components.
There is an alveolar pool of immediately available surfactant
which includes that at the air-surface interface and includes those
lamellar bodies that are enclosed within the aqueous hypophase
(figure 6). These lamellar bodies are readily incorporated into the
surface layer during the respiratory cycle when surface tension is
variable.[60] It has been proposed that there is another pool of
Lung unit B
60
Volume (mL/kg)
Impaired excretion of carbon dioxide is not always a prominent

feature of RDS. Prior to the use of mechanical ventilation, surviving infants could be seen to have only normal or slightly elevated
arterial carbon dioxide despite requiring significant amounts of
oxygen.[49] Spontaneously breathing infants with RDS have tidal
volumes of 46 mL/kg, the same as newborn infants with normal
lungs.[50] However, the dead space in lungs of infants with RDS
makes up a larger proportion of the tidal volume (6080% vs
3040%);[42] to compensate for this, spontaneously breathing infants with RDS breathe faster.
429
0
0
10
15
20
Pressure = P
25
30
35
Pressure (cm H2O)
b
Lung unit A
Lung unit B
R
r
Fig. 5. The effects of different opening pressures in the absence of

surfactant. The graph shows two hypothetical idealized lung units. At pressure, lung unit B is just beginning to open (a). In the absence of surfactant,
lung unit A has a radius of R, whereas lung unit B has a radius of r at a
pressure of P. If we apply the law of LaPlace to calculate surface tension
(P = 2/r, where is the surface tension) then the pressure in lung unit B
would have to be higher to maintain the smaller radius (b). In alveoli that
are connected, a pressure gradient will therefore exist and gas will travel
from the higher pressure region in unit B to the lower pressure region in
unit A (b). This would lead to lung unit A increasing in size, and possible
over distension, and collapse of lung unit B.
surfactant stored in, but not yet released from, lamellar bodies that
are fused with the plasma membrane of type II cells.[61] The
contents of these lamellar bodies are released as type II pneumocytes are strained during inspiration. Finally there is a slow
replenishment pool of non-fused intracellular lamellar bodies and
de novo synthesis of surfactant.
In infants with RDS who do not receive exogenous surfactant
therapy, surfactant pool sizes increase during recovery over
45 days to become comparable with that in infants without RDS,
or those who received exogenous surfactant.[62] In preterm lambs,
small increases can be seen soon after birth and continue readily.[63] This is mostly due to de novo synthesis. In rabbits it takes
~40 hours from phospholipid synthesis within the endoplasmic
reticulum to secretion into the alveoli.[59] Low surfactant pool sizes
430
Ainsworth
Air-fluid interface
Alveolar
macrophage
Aqueous
hypophase
Type I
pneumocyte
Air space
Lipid vesicles reused
by type II pneumocyte
Lipid
vesicles
Tubular
myelin
Nucleus
Golgi
complex
Type II
pneumocyte
Lamellar
bodies
Fig. 6. The surfactant cycle. Type II pneumocytes produce surfactant in the

Golgi complex. It is stored prior to release in lamellar bodies and secreted
into the aqueous hypophase. The surfactant is transformed into tubular
myelin from which both multi-layer and monolayers are formed, before
eventually forming the single monolayer. After the surfactant is used a
proportion is taken up again as lipid vesicles by the type II cells and
reused, other surfactant is lost through uptake by alveolar macrophages.
and the slow increase in these pools after birth explains why, not
only, it is initially necessary to treat RDS with exogenous
surfactant but also why it is usually unnecessary to continue to
replace surfactant after the first 12 days.
Lung inflations increase surfactant in the airways.[64] This may
account for some of the physiological role of the sigh breath in
normal respirations. In term neonates ventilated with short periods
of high tidal volumes, improvements can be seen in pulmonary
mechanics.[65] This was initially ascribed to greater recruitment of
atelectatic lung; however, it now appears that this is due to
extrusion of lamellar bodies from type II pneumocytes. In a
newborn rat model, a transient improvement in compliance was
associated with increased surfactant,[66] but whether the same is
true of the preterm (and therefore) surfactant deficient lung is
unclear. Limited data suggest that in the surfactant deficient lung,
over-distension causes additional problems.[35]
Surfactant metabolism is complicated by the multi-component
nature of surfactant itself and the presence of active recycling or
salvage pathways. Lipid components of surfactant are secreted

together with surfactant proteins as lamellar bodies to the aqueous
hypophase. After film formation, these components are recycled
by type II cells to be reprocessed into lamellar bodies or to be
catabolized. Surfactant is also catabolized by macrophages. The
recycling efficiency exceeds 90% in preterm and term animals and
is more efficient than in adult animals.[67,68]
6. Acute Physiological Effects of Surfactant
Although surfactant has a variety of functions including host
defense,[4,5] in the short period after birth it is the reduction of
surface tension that is important in the stability of small airways
and alveoli. Surface tension arises from attractive forces between
molecules, and without it liquids would spontaneously form a
vapor. Water has a surface tension of 70 mN/m (70 dynes/cm) at
body temperature; this can be altered by a second substance (e.g.
surfactant). In surfactant, phospholipids with hydrophilic (waterattracting) polar-head groups and hydrophobic (water-repelling)
fatty acyl groups reduce surface tension. Phosphatidylcholine, the
main surfactant phospholipid, can form a monolayer across an airwater interface that reduces surface tension to ~25 mN/m. When
the monolayer is compressed closer packing of molecules leads to
a further fall in surface tension. If phosphatidylcholine is unsaturated then the minimum surface tension that can be reached is
20 mN/m, however, endogenous surfactant contains saturated and
unsaturated phosphatidylcholine, other phospholipids and
surfactant associated proteins; these reduce surface tension to
almost zero.[69]
The effect of surfactants on preterm lungs can be demonstrated
by pressure-volume relationships using static or quasi-static inflation and deflation. From these it is possible to quantify the compliance of the lungs. The effects of surfactant deficiency is shown by
the pressure-volume curve followed by the control animals (rabbits) in figure 7 where there is little lung expansion until a pressure
of 25 cmH2O is reached.[70] The surfactant deficient lungs also
collapse to zero volume when the pressure is decreased. In contrast, rabbits treated with whole sheep surfactant have a lower
opening pressure (~15cm H2O) and there is retention of volume
when the pressure returns to zero. Thus, there is lung recruitment
during inspiration and greater retention of the recruitment during
expiration after exogenous surfactant the latter is a good indication of why surfactant can increase FRC.[71] Surfactants that contain surfactant-associated proteins show better pressure-volume
curves than those that do not (figure 7).[70] This is reflected in the
better outcomes after treatment with animal-derived surfactants[72]
or synthetic surfactants that contain protein mimics[73] than
surfactants that comprise only phospholipids.
Pressure-volume curves also demonstrate that the response to
surfactant is progressively less with delayed treatment.[74] Delaying treatment with surfactant resulted in a greater influx of proteins
431
with surfactant inactivation and poorer lung function. Whilst inactivation can be overcome by using more surfactant, the presence of
surfactant seems to protect against the influx of the proteins in the
first place.[75] In addition, it is apparent that pulmonary compliance
improves only relatively slowly after surfactant treatment compared with improvements in FRC.[45] In clinical practice this is
reflected by rapidly improving oxygenation but somewhat slower
improvements in ventilation (CO2 excretion).
7. Pulmonary Function in Neonates Post
Surfactant Therapy
Few studies have looked at FRC and pulmonary compliance
after surfactant therapy in neonates;[71,76-83] those that do, fail to
show early improvement in compliance but demonstrate an improvement in FRC within minutes of treatment. Compliance does
improve, albeit more slowly than FRC,[82] and only in studies that
look at compliance beyond the first few hours (figure 8).[83] These
changes in FRC and compliance are reflected in the speed with
which oxygen and ventilator settings need to be changed after
treatment with surfactant; in contrast to delivery of oxygen which
needs to be reduced rapidly, particularly after animal-derived
surfactants, changes in ventilator settings are made more slowly.
Changes in oxygenation have long been known to occur more
quickly after treatment with animal-derived compared with protein-free synthetic surfactants, but effects on compliance are less
clear. When infants were treated with poractant alfa (Curosurf 1)
Natural sheep
SP-B
SP-ABC
SP-C
LH-20
SP-A
Controls
90
80
Volume (mL/kg)
70
60
50
40
30
20
10
0
0
10
15
20
25
30
35
Pressure (cm H2O)
Fig. 7. Pressure-volume curves from preterm rabbits after 30 minutes of

ventilation with 3cm H2O positive end expiratory pressure. Animals were
treated with various surfactant preparations to show the differing effects of
the surfactant-associated proteins and their effects on lung recruitment.
The clear advantage of surfactants that contain surfactant protein (SP)-B
(and to a lesser extent SP-C) can be seen by the larger volume and the
higher deflation lung volumes compared with surfactants that are devoid of
these surfactant-associated proteins (reproduced from Rider et al.,[70] with
permission). LH-20 is a protein-free phospholipid mixture.
or colfosceril (Exosurf), treatment with the former led to improved static respiratory compliance after 3 and 12 hours, whereas
compliance was essentially unchanged after treatment with the
latter.[84] A similar difference in static respiratory compliance was
also seen in favor of the animal-derived surfactant beractant
(Survanta) compared with colfosceril.[85]
There may be some differences between various animal-derived surfactants, but studies that compare these are few. Fewer
still compare pulmonary function. Studies comparing poractant
alfa and beractant in neonate respiratory distress syndrome show
earlier improvements in oxygenation (and by inference FRC) with
poractant alfa.[86,87] Comparisons of respiratory compliance after
treatment with poractant alfa and beractant are not available, but in
infants treated with either poractant alfa or SFRI 1 (Alveofact),
compliance improved 3 hours after poractant alfa but no improvement in pulmonary compliance was seen until 24 hours after
treatment with SFRI 1.[83] Thus, there may be differences between
the various animal-derived surfactants but these are likely to be
small and would require large, randomized, controlled trials to
demonstrate clear clinical superiority of one surfactant over the
other.
8. Effects of Surfactant on the
Cardiovascular System
Surfactant instillation is often associated with hemodynamic
changes, although studies have shown contradictory results. Cerebral blood flow has been shown both to increase[88,89] and decrease;[90] such changes may lead to both intraventricular hemorrhage and periventricular leucomalacia. Likewise, studies of pulmonary arterial pressure and blood flow have also shown
contradictory effects. Those who observed a fall in pulmonary
arterial pressure claim that a primary action of surfactant was to
increase total pulmonary blood flow;[91,92] but others reported no
change in pulmonary arterial pressure.[93] Research has suggested
that pulmonary blood flow does typically increase after exogenous
surfactant administration,[94] although the mechanism for this remains unclear.
At birth systemic and pulmonary circulations are connected via
a large arterial duct and when surfactant is given in the minutes to
hours after birth any changes in one compartment must affect the
other. The balance of flow depends on vascular resistance on each
side of the duct. For example, pulmonary vasodilation increases
left-to-right ductal steal, requiring an increased left ventricular
output to maintain aortic flow beyond the duct. Major influences
on vascular tone are arterial oxygen and carbon dioxide. Factors
which cause pulmonary vasodilation (low partial pressure of arterial carbon dioxide [PaCO2] and high partial pressure of arterial
oxygen [PaO2])[95] simultaneously cause systemic and cerebral
The use of trade names is for product identification purposes only and does not imply endorsement.
432
Ainsworth
20
18
0.9
FRC (mL/kg)
0.8
14
0.7
12
0.6
10
0.5
FiO2
Compliance and FRC
16
0.4
FiO2
0.3
0.2
Static compliance
(mL/kPa x kg)
2
0
0.1
0
Pre-surfactant
1 hour
3 hours
6 hours
24 hours
Post-surfactant
Fig. 8. Changes in functional residual capacity (FRC), oxygen requirement and static compliance of neonates with severe respiratory distress disorder after
treatment with poractant alfa or Alveofact (SF-RI 1). The graph shows marked changes in FRC within 1 hour of surfactant treatment and the related
improved oxygenation. Compliance, however, improved slowly and was significantly different from pre-treatment values at 3 hours post-therapy in
poractant alfa-treated infants and at 24 hours in Alveofact-treated infants.[83] FiO2 = fraction of inspired oxygen.
vaso-constriction.[96-98] Thus, if swings in systemic, and particularly cerebral blood flow, are to be prevented large fluctuations in
PaCO2 and high PaO2 must also be avoided and the clinician must
pay close attention to both ventilation and oxygenation following
surfactant administration.
Surfactant obviously acts within the lungs, but debate continues
as to whether it acts as a primary pulmonary vasodilator. Unfortunately studies of pulmonary arterial pressure and flow[91-93,99] have
largely failed to report either PaO2 or PaCO2 values before and
after treatment. Therefore, results are difficult to interpret; for
surfactant to act as a pulmonary vasodilator, the effects must be
independent of those resulting from improved gas exchange. Two
groups found a significant fall in pulmonary arterial pressure,
coinciding with a fall in oxygen requirements after surfactant.[91,92,96] However, a third group reported no significant
change.[93] Compared to historical data from infants with RDS
who did not receive surfactant,[100] pulmonary to systemic arterial
pressure ratio fell more rapidly after surfactant replacement, but
we cannot say for certain whether the early changes were related to
ventilation practices, blood gas status, or surfactant itself. These
uncertainties may also be compounded by the type or dose of
surfactant used, as these directly affect the speed of onset of action
of the surfactant.
9. Translating Physiology and Pathophysiology into
Clinical Practice
This section looks at practices in the management of preterm
infants with RDS and puts them into context of pathophysiology of
RDS previously discussed and their impact on the effectiveness of

surfactant therapy.
9.1 Resuscitation Practices
There are several aspects of resuscitation that can impact upon

surfactant therapy, both directly (i.e. when should we give
surfactant) and indirectly (i.e. the impact of resuscitation on the
lungs). Most resuscitation guidelines have been drawn up with the
term infant in mind and events that take place during resuscitation
can have profound effects on the preterm infants morbidity.
In contrast to neonatal units, almost all newborn resuscitation is
unmonitored other than by the clinical acumen of the persons
involved. Experience is no substitute for monitoring; even experienced anesthesiologists (i.e. the so-called educated hand) cannot
reliably detect changes in pulmonary compliance.[101] Being able
to control ventilation is important as one of the major causes of
lung damage is over-inflation. Uncontrolled inflations have been
shown to cause widespread lung damage at histological level and,
in turn, reduce the effectiveness of surfactant.[34] Traditionally,
over-inflation has been called barotrauma, implying that pressure is the main culprit; however, because of a stronger association
between lung injury and lung volumes, a more appropriate term is
volutrauma.[102] The relative effects of volume and pressure on
lung injury was eloquently demonstrated by Hernandez and colleagues[103] who ventilated rabbits at high pressures. Those rabbits
whose chest expansions were limited by external body casts had
less lung damage than those whose volumes were uncontrolled,
even though pressures used were the same in both groups.
Just as over-distension can be deleterious, allowing lungs to

collapse at the end of expiration can also lead to lung damage,
especially when surfactant deficient. It requires considerably
greater pressure to open atelectatic alveoli than to inflate those
already open; these higher pressures can over-distend any airways
already open, generating shear forces and disrupting epithelium.
This can occur quickly in surfactant deficient lungs.[104] The
hypothesis that damage occurs during periods of low lung volume,
with recurrent collapse and re-expansion, is supported by the
protective effect of positive end-expiratory pressure helping to
keep alveoli open.[105]
Surfactant should be given as early as possible. Most protein
leak occurs early in RDS and tails off over the first 24 hours of
age.[106] In animal models exogenous surfactant protects against
protein leak and the earlier the surfactant is given the more
effective it is in preventing any leak.[74,107] This fits well with
outcomes in the meta-analysis of prophylactic versus rescue
surfactant where prophylaxis reduces mortality, pulmonary air
leaks and chronic lung disease.[108] It would be expected that the
surfactants that restore surfactant function the quickest are associated with better clinical outcomes; this can be seen in comparisons
between animal-derived and protein-free synthetic surfactants.[72] The greatest benefit from prophylactic surfactant seems to
be in more immature infants. Moderately mature infants (mean
gestation 32.8 weeks, birth weight ~2050g) with mild to moderate
RDS, defined as fraction of inspired oxygen (FiO2 ) 0.4, did not
benefit from routine intubation to administer surfactant compared
with expectant management with subsequent intubation and
surfactant treatment as clinically indicated.[109]
How early should the first dose of surfactant be administered?
Kendig et al.[110] using calf lung surfactant extract, randomized
651 infants to receive surfactant either before the first mechanical
breath or after stabilization. There were no differences in mortality
between groups, but more infants in the pre-ventilation arm required supplemental oxygen at 36 weeks and there were significantly more problems with surfactant administration. Does this
mean that a pre-ventilation surfactant administration strategy is
incorrect? One possibility may lie in the differences in the way
surfactant was administered. In the pre-ventilation group it was
administered as a single 3 mL/kg bolus, whereas the other group
received four aliquots of 0.75 mL/kg, 2 minutes apart. Just as lack
of surfactant increases the opening pressure of the lungs, so too
does an excess of lung fluid.[111] A larger volume of surfactant has
been shown to spread more homogeneously[112] but this was in an
animal model more akin to acute RDS where there is surfactant
dysfunction rather than RDS seen in the newborn where there is
surfactant deficiency and some fetal lung fluid. It remains unclear
from studies in human infants whether the volume of surfactant is
important.
433
9.2 Ventilation Strategies
Continuous positive airways pressure (CPAP) used in the delivery room (with and without surfactant), avoids the need for longterm intubation and ventilation, and in experienced hands appears
to be an effective method of respiratory care for even the smallest
infants.[113-115] The disadvantage is that those infants who develop
RDS have their surfactant therapy delayed with the potential
consequences that this can bring. Two studies have examined the
effect of surfactant administration to infants on CPAP and found
that it not only helps prevent the need for ventilation,[116] but also
the earlier the surfactant can be given the greater the effect.[117]
Preliminary data from the IFDAS (Infant Flow Driver And
Surfactant) study (not yet published in full) suggest CPAP with or
without surfactant is no different from surfactant and ventilation in
terms of mortality and chronic lung disease, but that CPAP can
reduce the need for surfactant therapy per se.[118] Additional data
are emerging about this mode of respiratory support[119] but more
large randomized trials are required to fully address this issue.
With the advent of microprocessor technology, volumetargeted ventilators have been developed as alternatives to traditional pressure-limited ventilators. They are capable of delivering
consistent and, importantly, appropriate tidal volumes in small
preterm infants. It is suggested that these could provide an effective, safer means of ventilating the newborn infant. Evidence from
meta-analysis of four randomized controlled trials suggests that
there may be benefits particularly with respect to lung damage
(demonstrated by reduced rates of pneumothoraces and chronic
lung disease at 36 weeks post-menstrual age).[120] However, more
suitably powered studies are required.
Infants who are ventilated with conventional ventilation have
cyclical lung volume changes that lead to alveolar disruption
allowing protein leak. High frequency oscillatory ventilation
(HFOV) uses a higher mean airway pressure but with cyclical
volumes that are smaller than physiological VTs. In comparison to
conventional ventilation, HFOV limits exudation of proteinaceous
material in animals with RDS,[121,122] and when combined with
exogenous surfactant there is a greater reduction in lung injury
than if surfactant or HFOV had been used alone (figure 9).[123]
Early use of HFOV prolongs the effectiveness of any exogenous
surfactant by reducing the protein leak.[124] Despite these benefits
of HFOV in early RDS, there is no clear evidence from systematic
reviews that longer-term outcomes are better than for conventional
ventilation.[125]
9.3 The Dose of Surfactant
Most exogenous surfactants are given at a dose of 100 mg/kg of

phospholipids which fits well with the size of the surfactant pool in
term infants without RDS. Evidence from randomized controlled
trials showed smaller doses were less effective[126-128] but that
434
Ainsworth
30
9.5 Inhaled Nitric Oxide
Protein debris (%)
25
20
15
10
5
0
CMV
CMV + surfactant
HFOV
HFOV + surfactant
Fig. 9. Comparison between high frequency oscillatory ventilation (HFOV)

with conventional mandatory ventilation (CMV) as a mode of ventilation in
a preterm baboon model of respiratory distress syndrome, demonstrating
the effect of surfactant therapy on both modes of ventilation. HFOV resulted in less radiographic injury, lower oxygenation and less alveolar proteinaceous debris, and HFOV was highly synergistic when combined with
surfactant (reproduced from Jackson et al.,[123] with permission).
higher doses confer no long-term advantage. Poractant alfa at

200 mg/kg produced a more rapid reduction in oxygen requirements than at 100 mg/kg,[127] but this did not translate to better
longer-term outcomes. All of these studies of different doses were
performed using a rescue strategy when the arterial/alveolar oxygen ratio (a/ADO2) was <0.22 or the FiO2 was 0.4); thus any
surfactant might be inactivated by proteinaceous exudates that
were already present. We do not know if the larger doses were
simply overcoming inactivation rather than being better in their
own right.
9.4 Re-Treatment with Surfactant
Just as the proteinaceous exudates affect the function of the first

surfactant dose, the second dose can also be affected. Most
surfactants are given according to the manufacturers guidelines,
which, in all cases, are based on temporal criteria such as give the
second dose 12 hours after the previous dose. Whilst it is unreasonable to expect that surfactant will remedy all the problems with
gas exchange, waiting for the 12 hours to expire before giving the
next dose whilst the infants ventilation worsens will only add to
the problem. Ongoing protein leak continues adding to the existing
lung disease and it can further act to inactivate the second
surfactant dose. Giving a second dose of surfactant (beractant) at
2 hours of age in moderately severe RDS was shown to have
greater effect on a/ADO2 at 1248 hours than if the second dose
was given as per the manufacturers instructions.[129] Likewise in
mild RDS (minimal ventilator settings and uncomplicated RDS),
omitting the second dose does not seem to affect outcome, and
could lead to substantial cost savings.[130] There is much to be said
regarding tailoring the administration regimen to the infants
disease but there is little evidence for this in the literature at this
point in time.
Inhaled NO has become a useful rescue therapy in term infants

with respiratory disease. By improving the ventilation and perfusion matching it allows greater oxygenation at lower ventilation
than is otherwise achievable. Endogenously released NO plays a
key role in the lungs of the newly born infant. Although there are
several studies of inhaled NO in preterm infants, the results have
been variable in terms of outcomes.[19,20,131,132] Whereas there are
significant reductions in oxygen requirements after starting inhaled NO, these do not translate into better long-term outcomes. In
particular there is concern about the effects of NO on the developing brain and the risks of intracranial bleeding.[19] Further research
is required into the use of inhaled NO in infants at risk or with
RDS.
10. Conclusions
Despite advances in antenatal and neonatal care, chronic lung
disease remains a major problem and what we do to the infant
during the first minutes can play a role in its pathophysiology.
Using surfactant and ventilation to their best advantage could
potentially improve outcomes further, but in the absence of large
randomized trials we must use physiological data to aid understanding. The key to optimizing management would be to administer surfactant early or prophylactically, establish the FRC either
through the use of CPAP, conventional or high frequency ventilation and to ensure an adequate blood pressure to enable ventilation
and perfusion in the lungs to be matched.
Both under-inflation and over-distension of the lungs leads to
lung damage both in the short term, as worsening RDS, and in the
long term as chronic lung disease or bronchopulmonary dysplasia.
Under-inflation leads to atelectasis and can be prevented by using
surfactant usually in conjunction with some form of positive endexpiratory pressure. Over-inflation can be limited by the use of inline pulmonary graphics monitoring which is widely available and
blood gas analyses. Hypocarbia is a relatively late sign of overdistension and should be avoided.
Whilst there may be further improvements in surfactants and
respiratory support, these therapeutic options are only as good as
the hands that use them. Understanding the pathophysiology of the
disease process is the key to optimizing outcome and tailoring any
management strategies to achieve the best outcomes.
Acknowledgements
Supported by an educational grant from Chiesi Pharmaceuticals. The
author has been an invited speaker at symposia sponsored by manufacturers of
surfactants (Chiesi Pharmaceuticals and Abbott Laboratories). There are no
other conflicts of interest that are directly relevant to the contents of this
manuscript.
References
1. Wen SW, Smith G, Yang Q, et al. Epidemiology of preterm birth and neonatal
outcome. Semin Fetal Neonatal Med 2004; 9: 429-35
2. Horbar JD, Badger GJ, Carpenter JH, et al. Trends in mortality and morbidity for
very low birth weight infants, 1991-1999. Pediatrics 2002; 110: 143-51
3. Hintz SR, Poole WK, Wright LL, et al. Changes in mortality and morbidities
among infants born at less than 25 weeks during the post-surfactant era. Arch
Dis Child Fetal Neonatal Ed 2005; 90: F128-33
4. Creuwels LA, van Golde LM, Haagsman HP. The pulmonary surfactant system:
biochemical and clinical aspects. Lung 1997; 175: 1-39
5. Ainsworth SB, Milligan DW. Surfactant therapy for respiratory distress syndrome
in premature neonates: a comparative review. Am J Respir Med 2002; 1: 417-33
6. Truog WE. Pulmonary gas exchange in the developing lung. In: Polin RA, Fox
WW, editors. Fetal and neonatal physiology. 2nd ed. Philadelphia (PA): WB
Saunders, 1998: 1094-105
7. Nelson NM, Prodhom LS, Cherry RB, et al. A further extension of the in vivo
oxygen-dissociation curve for the blood of the newborn infant. J Clin Invest
1964; 43: 606-10
8. McCann EM, Goldman SL, Brady JP. Pulmonary function in the sick newborn
infant. Pediatr Res 1987; 21: 313-25
9. Bland RD. Lung liquid clearance before and after birth. Semin Perinatol 1998; 12:
124-33
10. Leffler CW, Hessler JR, Green RS. The onset of breathing at birth stimulates
pulmonary vascular prostacyclin synthesis. Pediatr Res 1984; 18: 938-42
11. Fineman JR, Heymann MA, Soifer SJ. N-nitro-L-arginine attenuates endothelium
dependent pulmonary vasodilation in lambs. Am J Physiol 1991; 260:
H1299-306
12. Dawson CA. The role of pulmonary vasomotion in physiology of the lung. Physiol
Rev 1984; 64: 544-616
13. Custer JR, Hales CA. Influence of alveolar oxygen on pulmonary vasoconstriction
in newborn lambs versus sheep. Am Rev Respir Dis 1985; 132: 326-31
14. Phillips III JB, Lyrene RK, McDevitt M, et al. Prostaglandin D2 inhibits hypoxic
pulmonary vasoconstriction in neonatal lambs. J Appl Physiol 1983; 54: 1585-9
15. Marshall BE. Importance of hypoxic pulmonary vasoconstriction with atelectasis.
Adv Shock Res 1982; 8: 1-12
16. Truog WE, Standaert TA. Effects of dopamine infusion on pulmonary gas exchange in lambs. Biol Neonate 1984; 46: 200-8
17. Gaston B, Drazen JM, Loscalzo J, et al. The biology of nitrogen oxides in the
airways. Am J Respir Crit Care Med 1994; 149: 538-51
18. Colnaghi M, Condo V, Pugni L, et al. Endogenous nitric oxide production in the
airways of preterm and term infants. Biol Neonate 2003; 83: 113-6
19. Van Meurs KP, Wright LL, Ehrenkranz RA, et al. Inhaled nitric oxide for
premature infants with severe respiratory failure. N Engl J Med 2005; 353:
13-22
20. Schreiber MD, Gin-Mestan K, Marks JD, et al. Inhaled nitric oxide in premature
infants with the respiratory distress syndrome. N Engl J Med 2003; 349:
2099-107
21. Martin RJ, Walsh MC. Inhaled nitric oxide for preterm infants: who benefits? N
Engl J Med 2005; 353: 82-4
22. OBrodovich HM. Immature Na+ channel expression is one of the pathogenetic
mechanisms leading to human neonatal respiratory distress syndrome. Proc
Assoc Am Physicians 1996; 108: 345-55
23. Zelenina M, Zelenin S, Aperia A. Water channels (aquaporins) and their role for
postnatal adaptation. Pediatr Res 2005; 57: 47R-53R
24. Strang LB. Fetal lung liquid: secretion and reabsorption. Physiol Rev 1991; 71:
991-1061
25. Walters DV, Ransden CA, Olver RE. Dibutyryl cAMP induces a gestationdependent absorption of fetal lung fluid. J Appl Physiol 1990; 68: 2054-9
26. Adams EW, Counsell SJ, Hajnal JV, et al. Magnetic resonance imaging of lung
water content and distribution in term and preterm infants. Am J Respir Crit
Care Med 2002; 166: 397-402
27. Krauss AN, Klain DB, Auld PA. Carbon monoxide diffusing capacity in newborn
infants. Pediatr Res 1976; 10: 771-6
28. Stahlman MT. Pulmonary ventilation and diffusion in the human newborn infant. J
Clin Invest 1957; 36: 1018-91
29. Maitra A. Neonatal respiratory distress syndrome (RDS). In: Kumar V, Abbas AK,
Fausto N, editors. Robbins & Cotran pathologic basis of disease. 7th ed.
Philadelphia (PA): WB Saunders, 2005: 481-3
435
30. Egan EA, Dillon WP, Zorn S. Fetal lung liquid absorption and alveolar epithelial
solute permeability in surfactant deficient, breathing fetal lambs. Pediatr Res
1984; 18: 566-70
31. Egan EA, Nelson RM, Beale EF. Lung solute permeability and lung liquid
absorption in premature fetal goats. Pediatr Res 1980; 14: 314-8
32. Jackson JC, MacKenzie AP, Chi EY, et al. Mechanisms for reduced total lung
capacity at birth and during hyaline membrane disease in premature newborn
monkeys. Am Rev Respir Dis 1990; 142: 413-9
33. Sundell HW, Harris TR, Cannon JR, et al. Lung water and vascular permeabilitysurface area in premature newborn lambs with hyaline membrane disease. Circ
Res 1987; 60: 923-32
34. Jobe A, Ikegami M, Jacobs H, et al. Permeability of premature lamb lungs to
protein and the effect of surfactant on that permeability. J Appl Physiol 1943;
55: 169-76
35. Bjorklund LJ, Ingimarsson J, Curstedt T, et al. Manual ventilation with a few large
breaths at birth compromises the therapeutic effect of subsequent surfactant
replacement in immature lambs. Pediatr Res 1997; 42: 348-55
36. Hamilton PP, Onayemi A, Smyth JA, et al. Comparison of conventional and highfrequency ventilation: oxygenation and lung pathology. J Appl Physiol 1983;
55: 131-8
37. Chu J, Clements AJ, Cotton EK, et al. Neonatal pulmonary ischaemia. Part 1:
clinical and physiological studies. Pediatrics 1967; 40: 709-66
38. Linderkamp O, Versmold HT, Fendel H, et al. Association of neonatal respiratory
distress with birth asphyxia and deficiency of red cell mass in premature infants.
Eur J Pediatr 1978; 129: 167-73
39. Skelton R, Jeffrey HE. Factors affecting the neonatal response to artificial
surfactant. J Paediatr Child Health 1996; 32: 236-41
40. Stahlman MT, Lequire VS, Young WC, et al. Pathophysiology of respiratory
distress in newborn lambs. Circulatory, biochemical, and pathological considerations. Am J Dis Child 1964; 108: 375-93
41. Strayer DS, Merritt TA, Lwebuga-Mukasa J, et al. Surfactant-anti-surfactant
immune complexes in infants with respiratory distress syndrome. Am J Pathol
1986; 122: 353-62
42. Avery ME, Fletcher BD, Williams RG. The lung and its disorders in the newborn
infant. 4th ed. Philadelphia (PA): WB Saunders, 1981
43. Krauss AN, Auld PAM. Measurement of functional residual capacity in distressed
neonates by helium rebreathing. J Pediatr 1970; 77: 228-32
44. Richardson CP, Jung AL. Effects of continuous distending pressure on pulmonary
function and blood gases in infants with respiratory distress syndrome. Pediatr
Res 1973; 12: 771-4
45. Edberg KE, Ekstrom-Jodal B, Hallman M, et al. Immediate effect on lung function
of instilled human surfactant in mechanically ventilated newborn infants with
IRDS. Acta Paediatr Scand 1990; 79: 750-5
46. Engle WD, Arant Jr BS, Wiriyathian S, et al. Diuresis and respiratory distress
syndrome: physiological mechanisms and therapeutic implications. J Pediatr
1983; 102: 912-7
47. Sullivan KJ, Mortola JP. Dynamic lung compliance in newborn and adult cats. J
Appl Physiol 1986; 60: 743-50
48. Cotton RB, Olsson T. Lung mechanics in respiratory distress syndrome. In:
Robertson B, Taeusch HW, editors. Surfactant therapy for lung disease. New
York: Marcel Dekker, 1985: 121-49
49. Gregory GA, Kitterman JA, Phibbs RH, et al. Treatment of the idiopathic respiratory distress syndrome with positive end expiratory airway pressure. N Engl J
Med 1971; 284: 1333-40
50. Hislop AA, Wigglesworth JA, Desai R. Alveolar development in the human fetus
and infant. Early Hum Dev 1986; 13: 1-11
51. Murphy BE. Conjugated glucocorticoids in amniotic fluid and fetal lung maturation. J Clin Endocrinol Metab 1978; 47: 212-5
52. Farrell PM, Avery ME. State of the art HMD. Am Rev Respir Dis 1975; 111:
657-88
53. Robertson PA, Sniderman SH, Laros Jr RK, et al. Neonatal morbidity according to
gestational age and birthweight from five tertiary care centers in the United
States, 1983 through 1986. Am J Obstet Gynecol 1992; 166: 1629-41
54. Madar J, Richmond S, Hey E. Surfactant-deficient respiratory distress after elective delivery at term. Acta Paediatr 1999; 88: 1244-8
55. Adams FH, Fujiwara T, Emmanouilides GC, et al. Lung phospholipids of human
fetuses and infants with and without hyaline membrane disease. J Pediatr 1970;
77: 833-41
56. Jackson JC, Palmer S, Truog WE, et al. Surfactant quantity and composition during
recovery from hyaline membrane disease. Pediatr Res 1986; 20: 1243-7
436
57. Rebello CM, Jobe AH, Eisele JW, et al. Alveolar and tissue surfactant pool sizes in
humans. Am J Respir Crit Care Med 1996; 154: 625-8
58. Seidner S, Pettenazzo A, Ikegami M, et al. Corticosteroid potentiation of surfactant
dose response in preterm rabbits. J Appl Physiol 1988; 64: 2366-71
59. 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 1989; 139:
367-9
60. Haller T, Dietl P, Stockner H, et al. Tracing surfactant transformation from cellular
release to insertion into an air-liquid interface. Am J Physiol Lung Cell Mol
Physiol 2004; 286: L1009-15
61. Dietl P, Frick M, Mair N, et al. Pulmonary consequences of a deep breath revisited.
Biol Neonate 2004; 85: 299-304
62. Hallman M, Merritt TA, Akino T, et al. Surfactant protein A, phosphatidylcholine,
and surfactant inhibitors in epithelial lining fluid: correlation with surface
activity, severity of respiratory distress syndrome, and outcome in small premature infants. Am Rev Respir Dis 1991; 144: 1376-84
63. Jacobs H, Jobe A, Ikegami M, et al. Accumulation of alveolar surfactant following
delivery and ventilation of premature lambs. Exp Lung Res 1985; 8: 125-40
64. Wirtz HR, Dobbs LG. Calcium mobilization and exocytosis after one mechanical
stretch of lung epithelial cells. Science 1990; 250: 1266-9
65. Ratjen F, Zinman R, Stark AR, et al. Effect of changes in lung volume on
respiratory system compliance in newborn infants. J Appl Physiol 1989; 67:
1192-7
66. Martinez F, Lewis J, Copland I, et al. Mechanical ventilation effect on surfactant
content, function, and lung compliance in the newborn rat. Pediatr Res 2004;
56: 19-25
67. Jacobs H, Jobe A, Ikegami M, et al. Surfactant phosphatidylcholine source, fluxes,
and turnover times in 3-day-old, 10-day-old, and adult rabbits. J Biol Chem
1982; 257: 1805-10
68. Jacobs H, Jobe A, Ikegami M, et al. The significance of reutilization of surfactant
phosphatidylcholine. J Biol Chem 1983; 258: 4156-65
69. Veldhuizen R, Nag K, Orgeig S, et al. The role of lipids in pulmonary surfactant.
Biochim Biophys Acta 1998; 1408: 90-108
70. Rider ED, Ikegami M, Whitsett JA, et al. Treatment responses to surfactants
containing natural surfactant proteins in preterm rabbits. Am Rev Respir Dis
1993; 147: 669-76
71. Goldsmith LS, Greenspan JS, Rubenstein SD, et al. Immediate improvement in
lung volume after exogenous surfactant: alveolar recruitment versus increased
distention. J Pediatr 1991; 119: 424-8
72. Soll RF, Blanco F. Natural surfactant extract versus synthetic surfactant for
neonatal respiratory distress syndrome. Cochrane Database Sys Rev 2001; (2):
CD000144
73. Moya FR, Gadzinowski J, Bancalari E, et al. A multicenter, randomized, masked,
comparison trial of lucinactant, colfosceril palmitate, and beractant for the
prevention of respiratory distress syndrome among very preterm infants. Pediatrics 2005; 115: 1018-29
74. Seidner SR, Ikegami M, Yamada T, et al. Decreased surfactant dose-response after
delayed administration to preterm rabbits. Am J Respir Crit Care Med 1995;
152: 113-20
75. Edberg KE, Ekstrom-Jodal B, Hallman M, et al. Immediate effects on lung function
of instilled human surfactant in mechanically ventilated newborn infants with
IRDS. Acta Paediatr Scand 1990; 70: 750-5
76. Chung EH, Ko SY, Kim IY, et al. Changes in dead space/tidal volume ratio and
pulmonary mechanics after surfactant replacement therapy in respiratory distress syndrome of the newborn infants. J Korean Med Sci 2001; 16: 51-6
77. Morley CJ, Greenough A. Respiratory compliance in premature babies treated with
artificial surfactant (ALEC). Arch Dis Child 1991; 66: 467-71
78. Svenningsen NW, Bjorklund L, Vilstrup C, et al. Lung mechanics (FRC and static
pressure-volume diagram) after endotracheal surfactant instillation: preliminary
observations. Biol Neonate 1992; 61 Suppl. 1: 44-7
79. Cotton RB, Olsson T, Law AB, et al. The physiologic effects of surfactant
treatment on gas exchange in newborn premature infants with hyaline membrane disease. Pediatr Res 1993; 34: 495-501
80. Farstad T, Bratlid D. Pulmonary effects after surfactant treatment in premature
infants with severe respiratory distress syndrome. Biol Neonate 1995; 68:
246-53
81. Dimitriou G, Greenough A, Kavadia V. Changes in lung volume, compliance and
oxygenation in the first 48 hours of life in infants given surfactant. J Perinat
Med 1997; 25: 49-54
Ainsworth
82. Bjorklund LJ, Vilstrup CT, Larsson A, et al. Changes in lung volume and static
expiratory pressure-volume diagram after surfactant rescue treatment of neonates with established respiratory distress syndrome. Am J Respir Crit Care
Med 1996; 154: 918-23
83. Dinger J, Topfer A, Schaller P, et al. Functional residual capacity and compliance
of the respiratory system after surfactant treatment in premature infants with
severe respiratory distress syndrome. Eur J Pediatr 2002; 161: 485-90
84. Stenson BJ, Glover RM, Parry GJ, et al. Static respiratory compliance in the
newborn: III. Early changes after exogenous surfactant treatment. Arch Dis
Child Fetal Neonatal Ed 1994; 70: F19-24
85. Cotton RB, Olsson T, Law AB, et al. The physiologic effects of surfactant
treatment on gas exchange in newborn premature infants with hyaline membrane disease. Pediatr Res 1993; 34: 495-501
86. Speer CP, Gefeller O, Groneck P, et al. Randomised clinical trial of two treatment
regimens of natural surfactant preparations in neonatal respiratory distress
syndrome. Arch Dis Child Fetal Neonatal Ed 1995; 72: F8-13
87. Ramanathan R, Rasmussen MR, Gerstmann DR, et al. A randomized, multicenter
masked comparison trial of poractant alfa (Curosurf) versus beractant
(Survanta) in the treatment of respiratory distress syndrome in preterm infants.
Am J Perinatol 2004; 21: 109-19
88. Saliba E, Nashashibi M, Vaillant MC, et al. Installation rate effects of Exosurf on
cerebral and cardiovascular haemodynamics. Arch Dis Child 1994; 71: F174-8
89. Rabe H, Jorch G. Cerebral haemodynamics in perinatal pharmacology. Dev
Pharmacol Ther 1991; 17: 128-32
90. Cowan F, Whitelaw A, Wertheim D, et al. Cerebral blood flow velocity changes
after rapid administration of surfactant. Arch Dis Child 1992; 66: 1105-9
91. Seppanen M, Kaapa P, Kero P. Acute effects of synthetic surfactant replacement on
pulmonary blood flow in neonatal respiratory distress syndrome. Am J Perinatol 1994; 6: 382-5
92. Hamden AH, Shaw NJ. Changes in pulmonary arterial pressure in infants with
respiratory distress syndrome following treatment with Exosurf. Arch Dis Child
1995; 72: F176-9
93. Bloom M-C, Roques-Gineste M, Fries F, et al. Pulmonary haemodynamics after
surfactant replacement in severe neonatal respiratory distress syndrome. Arch
Dis Child 1995; 73: F95-8
94. Milner AD. How does surfactant work? Arch Dis Child 1993; 68: 253-4
95. Peckham GJ, Fox WW. Physiologic factors affecting pulmonary artery pressure in
infants with persistent pulmonary hypertension. J Pediatr 1978; 93: 1005-10
96. Dreyfuss D, Saumon G. Barotrauma is volutrauma, but which volume is the one
responsible? Intensive Care Med 1992; 18: 139-41
97. Leahy FAN, Cates D, MacCallum M, et al. Effect of CO2 and 100% O2 on cerebral
blood flow in preterm infants. J Appl Physiol 1980; 48: 468-74
98. Lundstrom KE, Pryds O, Greisen G. Oxygen at birth and prolonged cerebral
vasoconstriction in preterm infants. Arch Dis Child 1995; 73: F81-6
99. Kaapa P, Seppanen M, Kero P, et al. Pulmonary heamodynamics after synthetic
surfactant replacement in neonatal respiratory distress syndrome. J Pediatr
1993; 123: 115-9
100. Skinner JR, Boys RJ, Hunter S, et al. Pulmonary and systemic arterial pressure in
hyaline membrane disease. Arch Dis Child 1992; 67: 366-73
101. Spears Jr RS, Yeh A, Fisher DM, et al. The educated hand: can anesthesiologists
assess changes in neonatal pulmonary compliance manually? Anesthesiology
1991; 75: 693-6
102. Dreyfuss D, Saumon G. Barotrauma is volutrauma, but which volume is the one
responsible? Intensive Care Med 1992; 18: 139-41
103. Hernandez LA, Peevy KJ, Moise AA, et al. Chest wall restriction limits high
airway pressure-induced lung injury in young rabbits. J Appl Physiol 1989; 66:
2364-8
104. Nilsson R, Grossmann G, Robertson B. Bronchiolar epithelial lesions induced in
the premature rabbit neonate by short periods of artificial ventilation. Acta
Pathol Microbiol Scand [A] 1980; 88: 359-67
105. Nilsson R, Grossmann G, Robertson B. Artificial ventilation of premature newborn
rabbits: effects of positive end-expiratory pressure on lung mechanics and lung
morphology. Acta Paediatr Scand 1980; 69: 597-602
106. Ikegami M, Jobe AH, Tabor BL, et al. Lung albumin recovery in surfactant-treated
preterm ventilated lambs. Am Rev Respir Dis 1992; 145: 1005-8
107. Maeta H, Vidyasagar D, Raju TN, et al. Early and late surfactant treatments in
baboon model of hyaline membrane disease. Pediatrics 1988; 81: 277-83
108. Soll RF, Morley CJ. Prophylactic versus selective use of surfactant in preventing
morbidity and mortality in preterm infants. Cochrane Database Sys Rev 2001;
(2): CD000510
437
109. Escobedo MB, Gunkel JH, Kennedy KA, et al. Early surfactant for neonates with
mild to moderate respiratory distress syndrome: a multicenter, randomized trial.
J Pediatr 2004; 144: 804-8
123. Jackson JC, Truog WE, Standaert TA, et al. Reduction in lung injury after
combined surfactant and high frequency oscillatory ventilation. Am J Respir
Crit Care Med 1994; 150: 534-9
110. Kendig JW, Ryan RM, Sinkin RA, et al. Comparison of two strategies for
surfactant prophylaxis in very premature infants: a multicenter randomized
trial. Pediatrics 1998; 101: 1006-12
124. Froese AB, McCulloch PR, Sugiura M, et al. Optimizing alveolar expansion
prolongs the effectiveness of exogenous surfactant therapy in the adult rabbit.
Am Rev Respir Dis 1993; 148: 569-77
111. Faridy EE. Air opening pressure in fetal lungs. Respir Physiol 1987; 68: 293-300
112. van der Bleek J, Plotz FB, van Overbeek FM, et al. Distribution of exogenous
surfactant in rabbits with severe respiratory failure: the effect of volume.
Pediatr Res 1993; 34: 154-8
113. Lundstrm KE. Initial treatment of preterm infants-continuous positive airway
pressure or ventilation? Eur J Pediatr 1996; 155 Suppl. 2: S25-9
114. Lindner W, Vossbeck S, Hummler H, et al. Delivery room management of
extremely low birth weight infants: spontaneous breathing or intubation? Pediatrics 1999; 103: 961-7
115. Stevens TP, Blennow M, Soll RF. Early surfactant administration with brief
ventilation vs selective surfactant and continued mechanical ventilation for
preterm infants with or at risk for respiratory distress syndrome. Cochrane
Database Sys Rev 2004; (3): CD003063
116. Verder H, Robertson B, Griesen G, et al. Surfactant therapy and nasal continuous
positive airway pressure for newborns with respiratory distress syndrome. N
Engl J Med 1994; 331: 1051-5
117. Verder H, Albertsen P, Ebbesen F, et al. Nasal continuous positive airway pressure
and early surfactant therapy for respiratory distress syndrome in infants of less
than 30 weeks gestation. Pediatrics 1999; 103: e24
118. Thomson MA, on behalf of the IFDAS Study Group. Early nasal continuous
positive airways pressure (nCPAP) with prophylactic surfactant for neonates at
risk of RDS. The IFDAS multi-centre randomised trial [abstract]. Arch Dis
Child 2002; 86 Suppl. 1: A7
119. Tooley J, Dyke M. Randomized study of nasal continuous positive airway pressure
in the preterm infant with respiratory distress syndrome. Acta Paediatr 2003;
92: 1170-4
120. McCallion N, Davis PG, Morley CJ. Volume-targeted versus pressure-limited
ventilation in the neonate. Cochrane Database Sys Rev 2005; (3): CD003666
121. Coalson JJ, deLemos RA. Pathologic features of various ventilatory strategies.
Acta Anaesthesiol Scand 1989; 90: 108-16
122. Niblett DJ, Sandhar BK, Dunnill MS, et al. Comparison of the effects of high
frequency oscillation and controlled mechanical ventilation on hyaline membrane formation in a rabbit model of the neonatal respiratory distress syndrome.
Br J Anaesth 1989; 62: 628-36
125. Henderson-Smart DJ, Bhuta T, Cools F, et al. Elective high frequency oscillatory
ventilation versus conventional ventilation for acute pulmonary dysfunction in
preterm infants. Cochrane Database Sys Rev 2003; (4): CD000104
126. Konishi M, Fujiwara T, Naito T, et al. Surfactant replacement therapy in neonatal
respiratory distress syndrome: a multi-centre, randomized clinical trial: comparison of high- versus low-dose of Surfactant TA. Eur J Pediatr 1988; 147:
20-5
127. Halliday HL, Tarnow-Mordi WO, Corcoran JD, et al. Multicentre randomised trial
comparing high and low dose regimens for the treatment of respiratory distress
syndrome (the Curosurf 4 Study). Arch Dis Child 1993; 69: 276-80
128. Berry DD, Pramanik AK, Philips III JB, et al. Comparison of the effect of three
doses of a synthetic surfactant on the alveolar-arterial oxygen gradient in infants
weighing > or = 1250 grams with respiratory distress syndrome. American
Exosurf Neonatal Study Group II. J Pediatr 1994; 124: 294-301
129. Figueras-Aloy J, Quero J, Carbonell-Estrany X, et al. Early administration of the
second dose of surfactant (beractant) in the treatment of severe hyaline membrane disease. Acta Paediatr 2001; 90: 296-301
130. Kattwinkel J, Bloom BT, Delmore P, et al. High- versus low-threshold surfactant
retreatment for neonatal respiratory distress syndrome. Pediatrics 2000; 106:
282-8
131. Kinsella JP, Walsh WF, Bose CL, et al. Inhaled nitric oxide in premature neonates
with severe hypoxaemic respiratory failure: a randomised controlled trial.
Lancet 1999; 354: 1061-5
132. Field D, Elbourne D, Truesdale A, et al. Neonatal ventilation with inhaled nitric
oxide versus ventilatory support without inhaled nitric oxide for preterm infants
with severe respiratory failure: the INNOVO multicentre randomised controlled
trial. Pediatrics 2005; 115: 926-36
Correspondence and offprints: Sean B. Ainsworth, Directorate of Women

and Childrens Health, Forth Park Hospital, Kirkcaldy, KY2 5RA, Scotland.
E-mail: sean.ainsworth@faht.scot.nhs.uk

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Treat Respir Med 2005; 4 (6): 423-437

2005 Adis Data Information BV. All rights reserved.

Pathophysiology of Neonatal Respiratory

Respiratory distress syndrome (RDS) is the most common

respiratory support. Research into surfactant and gas exchange

Pressure (cm H2O)

Treat Respir Med 2005; 4 (6)

Neonatal Respiratory Distress Syndrome

(RV). Functional residual capacity (FRC) is the volume of gas in

sion of oxygen and carbon dioxide across the alveolar-capillary

After birth, pulmonary arterial pressure rapidly falls to ~50% of

term infants, preterm infants have lower levels of endogenous NO.

Although there are many studies of the postnatal changes in

Once gases reach the alveolar-capillary interface there must be

Neonatal Respiratory Distress Syndrome

Acinus with partial

Normal patent acinus with

Pulmonary venous connection

4. Pulmonary Function in RDS

Collapsed alveoli with

Fig. 3. The characteristic histological appearance in respiratory distress

and proteinaceous exudation. Improvements in FRC mirror the

day when a diuresis can be seen to coincide with clearance of

Normal 3kg infant

3kg Infant with respiratory distress

2005 Adis Data Information BV. All rights reserved.

Treat Respir Med 2005; 4 (6)

Neonatal Respiratory Distress Syndrome

5. Endogenous Surfactant in the Developing Lung

Impaired excretion of carbon dioxide is not always a prominent

Pressure (cm H2O)

Fig. 5. The effects of different opening pressures in the absence of

Fig. 6. The surfactant cycle. Type II pneumocytes produce surfactant in the

salvage pathways. Lipid components of surfactant are secreted

Neonatal Respiratory Distress Syndrome

Pressure (cm H2O)

Fig. 7. Pressure-volume curves from preterm rabbits after 30 minutes of

2005 Adis Data Information BV. All rights reserved.

Treat Respir Med 2005; 4 (6)

Compliance and FRC

RDS previously discussed and their impact on the effectiveness of

There are several aspects of resuscitation that can impact upon

Neonatal Respiratory Distress Syndrome

Just as over-distension can be deleterious, allowing lungs to

9.2 Ventilation Strategies

Most exogenous surfactants are given at a dose of 100 mg/kg of

9.5 Inhaled Nitric Oxide

Protein debris (%)

Fig. 9. Comparison between high frequency oscillatory ventilation (HFOV)

higher doses confer no long-term advantage. Poractant alfa at

Just as the proteinaceous exudates affect the function of the first

Inhaled NO has become a useful rescue therapy in term infants

Neonatal Respiratory Distress Syndrome

Neonatal Respiratory Distress Syndrome

2005 Adis Data Information BV. All rights reserved.

Correspondence and offprints: Sean B. Ainsworth, Directorate of Women

Treat Respir Med 2005; 4 (6)

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