Pharmacology Review: Why Surfactant Works for Respiratory Distress
Syndrome
Alan H. Jobe
NeoReviews 2006;7;e95-e106
DOI: 10.1542/neo.7-2-e95
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pharmacology review
Why Surfactant Works for
Respiratory Distress Syndrome
Alan H. Jobe, MD, PhD*
Objectives
Author Disclosure
Dr Jobe has disclosed that he
received surfactant from Ross
Laboratories for studies of lung
function in preterm sheep.
After completing this article, readers should be able to:
1. Explain the sources of immediate and delayed treatment responses to
surfactant.
2. List the factors that affect surfactant distribution in the preterm lung.
3. List the mechanisms that can inhibit surfactant function.
4. Explain why antenatal corticosteroids and surfactant improve lung function
and outcomes of preterm infants.
Introduction
Surfactant treatments have been the
standard of care for infants who have
respiratory distress syndrome (RDS)
ever since the United States Food
and Drug Administration approved
its use in 1990. The development of
surfactant is one of the great success
stories in neonatal care because the
therapy specifically treats the surfactant deficiency and changes the
pathophysiology and outcome of
RDS. Many clinicians now use surfactant without appreciating the research that was essential to learning
how to use it and to understanding
why it works so well for most infants.
That research history is the basis for
interpreting new approaches to the
care of infants who have RDS, such as
the early use of continuous positive
airway pressure (CPAP). Surfactant
works because of complicated biophysical and metabolic effects within
the preterm lung. These effects are
modified by clinical variables such as
antenatal steroids, lung injury, and
gestational age.
What is RDS?
The standard diagram of the pathophysiology of RDS developed in the
1980s still holds today (Fig. 1). In*Professor of Pediatrics, Cincinnati Children’s
Hospital, University of Cincinnati, Cincinnati, Ohio.
fants who have RDS have surfactant
lipid pools of less than 10 mg/kg
compared with the surfactant lipid
pool sizes in term infants of perhaps
100 mg/kg. Further, lung structure
is immature at less than 32 weeks’
gestation. The fetal human lung is in
the saccular stage of development
during the period of viability from
23 weeks’ gestation to the initiation
of secondary septation (alveolarization), which begins at about
32 weeks’ gestation. The structure of
the preterm lung affected by RDS
limits lung function. Although the
saccular lung can exchange gas (mice
and rats are born with saccular lungs
similar in structure to a 28 weeks’
gestation human lung), the diffusion
distance for gas and surface area for
gas exchange relative to body weight
or metabolic rate are not normal. Finally, the preterm infant who has
RDS breathes at a high rate to
achieve adequate gas exchange, and
the resulting blood gas may have a
saturation of 90% and a PaO2 of
30 mm Hg on supplemental oxygen.
This oxygenation is not equivalent to
a “normal” blood gas (PO2 of
100 mm Hg on room air) achieved
with a normal respiratory rate. The
low lung gas volume of the preterm
(20 to 40 mL/kg body weight) relative to the term infant (50 mL/kg)
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pharmacology review
Figure 1. Pathophysiology of respiratory distress syndrome (RDS) circa 1985. RDS has
been understood as respiratory failure resulting from the interaction between
surfactant deficiency and a structurally immature lung that is easily injured, resulting
in pulmonary edema and surfactant inactivation.
or the adult (80 mL/kg) makes the
preterm lung susceptible to overdistention and injury with mechanical
ventilation.
The diagram in Figure 1 suggests
that lung injury resulting in pulmonary edema occurs inevitably in RDS.
Injury and edema develop if the lung
is allowed to breathe from an inadequate functional residual capacity or
is injured by overstretch. However,
the lungs of infants who have RDS
are, in most cases, not injured at
birth; severe injury and edema result
from care practices. A preterm lung
that contains low amounts of surfactant may not have RDS unless that
lung is injured.
surfactant that contains a lower percent of dissaturated phosphatidylcholine species, less phosphatidylglycerol, and less of all the surfactant
proteins than surfactant from a mature lung. Minimal surface tensions
are higher for surfactant from preterm than term infants. The surfactant from the preterm infant is intrinsically “immature” in composition
and biophysical function.
Surfactant is made by the synthe-
sis of lipids and proteins by the type
II cells that are part of the epithelium
of the saccule (Fig. 3). The surfactant
components are packaged in lamellar
bodies for constitutive secretion or
secretion in response to stimulators
such as beta agonists, purinergic agonists, or lung stretch. The secreted
lamellar bodies contribute to the free
surfactant pool in the fluid hypophase that lines the alveoli and distal
airways, resulting in low surface tensions in the distal lung. Surfactant
normally is taken up by macrophages
for catabolism or recycled back into
type II cells for either reprocessing
into surfactant for secretion again or
catabolism. Surfactant metabolism is
critical to the persistence of treatment responses. Thus, surfactant is a
multicomponent lipid and protein
aggregate that has striking biophysical properties at an air-water interface
and a complex metabolism.
What Are Treatment
Responses to Surfactant?
The treatment responses to surfactant empirically can be divided into
What is Surfactant?
Surfactant from adult animals and
humans is a macroaggregate of
highly organized lipids and surfactant specific proteins. The lipid and
protein contents of surfactant are
preserved across species (Fig. 2). The
major components that confer the
unique ability of surfactant to lower
the surface tension on an air-water
interface to very low values are the
saturated phosphatidylcholine species, surfactant protein B, and surfactant protein C. The preterm infant
who has RDS has low amounts of
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Figure 2. Composition of surfactant from the mature lung. Surfactant from the
preterm lung contains as percent composition less saturated phosphatidylcholine, less
of the surfactant proteins (SPs), and more phosphatidylinositol.
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pharmacology review
Figure 3. Basic pathways for surfactant metabolism. Surfactant is synthesized in type
II cells, stored in lamellar bodies, and secreted into the alveoli where it forms a surface
film. It is cleared from the airspaces by macrophages for catabolism or is taken back
into type II cells where it is reprocessed and resecreted, a recycling pathway.
three stages: an acute response that
occurs within minutes, effects that
occur over hours, and effects that last
days or perhaps weeks. The acute
treatment response results from the
biophysical properties of surfactant
and depends on rapid distribution of
surfactant to the distal lung. The surfactants used clinically are very surface active and when instilled into the
lung, rapidly adsorb and spread.
However, the magnitude of the distribution problem generally is not
appreciated. There are about 20 generations (branch points) from the
trachea to the respiratory bronchioles and saccules. Therefore, there
are about 250,000 binary branch
points and 500,000 distal airways
leading to saccules in the preterm
lung. If the distribution is not proportionate to the number of saccules
distal to each branch point, surfactant
distribution will not be uniform, that
is, the same amount of surfactant in
each of the perhaps 10 million saccules in the preterm lung prior to
32 weeks’ gestation. A nonuniformity at a proximal branch point is
amplified at subsequent branch
points.
When saline or surfactant is instilled into a lung, distribution results
from the principles outlined in Table
1. The distribution of saline is very
nonuniform. Empirically, surfactant
distribution is uniform enough in
practice because the lung fields can
clear rapidly and oxygenation can im-
prove quickly, indicating nominal atelectasis and intrapulmonary shunt.
However, treatment techniques do
matter (Fig. 4). Surfactant distributes to preterm sheep lung more uniformly when administered at birth
because it mixes with fetal lung fluid,
which increases the volume, negates
gravity, and is rapid (Table 1). In
contrast, after a period of mechanical
ventilation, the distribution is less
uniform when using four positions
for instillation and a volume of
4 mL/kg. The infusion of surfactant
into the lungs over 15 minutes to
minimize any acute physiologic
changes during treatment results in a
very poor distribution because of
gravity and the slow rate of administration.
Surfactant delivered to one lobe
or one lung will not redistribute between lobes or lungs. A second dose
of surfactant tends to distribute similarly to the first dose because the
surfactant preferentially flows to the
open or good lung. Aerosolized surfactant distributes proportionately
with ventilation, which means it
treats the open lung and not the atelectatic or edema-filled lung. Although large volumes of surfactant
improve distribution, there must be a
compromise between instillation volume and the infant’s tolerance of that
volume. More volume requires more
Variables That Contribute to Surfactant
Distribution in the Lungs
Table 1.
Property
Effect
Surface Activity
Gravity
Essential for rapid adsorption and spreading
Surfactant distributed with fluid by gravity in large
airways
The higher the volume, the better the distribution
Rapid administration results in a better distribution
Pressure and positive end-expiratory pressure clear
airways of fluid
Higher volumes of fetal lung fluid or edema fluid
may result in a better distribution
Volume
Rate of Administration
Ventilator Settings
Fluid Volume in Lung
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Figure 4. Surfactant distributions resulting from different treatment techniques. The
distribution of surfactant was measured in the lungs of preterm lambs after treatment
with radioactive surfactant and ventilation. Frozen lungs were cut into about 120
pieces and the amount of surfactant/weight of each piece measured. A mean
surfactant amount per piece was calculated and given a value of 1.0. A perfect
distribution would be 100% of pieces having a value of 1.0. Pieces with distribution
intervals less than 1 have less surfactant. A. A relatively uniform distribution of
surfactant when the surfactant was mixed with fetal lung fluid at birth and before
mechanical ventilation. B. Surfactant distribution for treatment after birth and ventilation.
The surfactant was given by the four-position maneuver commonly used clinically. The
distribution was less uniform, with about 15% of lung pieces receiving a large amount of
surfactant. C. Surfactant distribution following a 15-minute infusion of surfactant in
ventilated lambs. The surfactant was poorly distributed, with 34% of lung pieces receiving
less than 15% of the mean amount of surfactant and 25% of the lung pieces receiving
large amounts of surfactant. Figure adapted from Jobe, et al. Surfactant and pulmonary
blood flow distributions following treatment of premature lambs with natural surfactant.
J Clin Invest. 1984;73:848 – 856 and Ueda, et al. Distribution of surfactant and ventilation
in surfactant-treated preterm lambs. J Appl Physiol. 1994;76:45–55.
e98 NeoReviews Vol.7 No.2 February 2006
pressure and positive end-expiratory
pressure (PEEP) to distribute the
surfactant quickly and minimize
acute airway obstruction. Although
surfactant distribution in practice is
not ideal, it is good enough because
of the biophysical properties of the
surfactant and the small amount that
is needed regionally in the lung for a
treatment response. There are no
practical methods of improving distribution other than positioning the
infant to minimize gravity, administering surfactant quickly in a reasonable volume, and providing enough
ventilatory support to clear the airways quickly of fluid.
The effects of rapid distribution
(within seconds to minutes) to the
preterm lung are best illustrated by
the change in the pressure-volume
curve with surfactant treatment (Fig.
5). Surfactant-treated fetal lungs begin to inflate at a lower pressure
(opening pressure), inflate to a much
larger volume, and retain gas on deflation. This effect of surfactant to
open the lungs results in a rapid increase in oxygenation that can occur
almost instantaneously. The oxygenation response is the first clinical response to surfactant instillation.
Subsequent responses to surfactant treatment result from improving
lung mechanics, which may be more
gradual and depend, in part, on the
choice of ventilator styles. Empirically, infants can become hyperinflated after surfactant treatment, with
no improvement in compliance and
with an increase in PCO2. In contrast,
compliance may improve rapidly and
continue to improve over hours. As
an example of the importance of the
interaction between surfactant and
ventilation, a synthetic surfactant
containing recombinant surfactant
protein-C was not effective unless
animals were ventilated with PEEP
(Fig. 6).
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Figure 5. Representative pressure-volume curves for a surfactant-deficient preterm
lung and a surfactant-treated lung. Surfactant facilitates inflation of the lung from a
lower pressure, permits the lung to open to a higher volume, and prevents the lung
from collapsing when pressure is decreased (deflation stability). Data adapted from
Rider, et al. Treatment responses to surfactants containing natural surfactant proteins
in preterm rabbits. Am Rev Respir Dis. 1993;147:669 – 676.
Why Do Infants Continue to
Improve After Surfactant
Treatments?
The persistence of the surfactant
treatment response is explained primarily by surfactant metabolism in
the preterm lung. The similar metabolism of the surfactant lipids and proteins can be characterized metabolically by the curves illustrated in Fig.
7. Based on measurements in adult,
newborn, and preterm animals and
more recently, in preterm infants, we
know that the synthesis of surfactant
lipids and proteins from precursors
by type II cells is rapid. However,
surfactant processing to storage in
lamellar bodies and then secretion to
the airspaces occurs over many
hours. The time from synthesis to
peak labeling of airway samples is
about 3 days in preterm infants who
have RDS (Fig. 8). This time appears
to be prolonged beyond the 1 to
2 days measured in preterm lambs
because the stable isotopes are given
to infants over 24 hours and the “alveolar pool” is sampled by tracheal
suction and not lavage of the distal
lung. The general conclusion is that
the infant who has RDS requires days
to increase the surfactant pool from
endogenous synthesis and secretion.
Catabolism/clearance/loss of surfactant can be measured from the
lung and airspaces in animals and
from the airspaces using tracheal
samples in infants who have RDS.
The consistent result from measurements in multiple models and infants
who have RDS is that both the endogenous and exogenous surfactant
components have long half-life values in the airspaces of about 3 days
for infants who have RDS. The lipids
also remain in the lung compartment
(airspaces, type II cells, lung tissue)
for many days. Although synthesis
and secretion are slow, catabolism/
clearance is also very slow. A treatment dose of 100 mg/kg surfactant
exceeds the endogenous alveolar
pool in healthy adults by about 20fold. Therefore, the large surfactant
dose results in a large increase in the
total surfactant pool in the preterm
lung that persists for days. Simultaneously, the preterm infant is synthesizing new surfactant.
Part of the magic of surfactant
treatment results from how the surfactant used for treatment interacts
with the type II cells. Surfactant
components are recycled from the
airspaces back to type II cells where
the lipids are, in part, diverted into
lamellar bodies for resecretion. The
process can be measured directly in
animals because lungs can be radiolabeled and surfactant component recoveries measured in lung and subcellular fractions. The recycling has
been modeled using stable isotopes
in infants who have RDS. In general,
recycling is more efficient in the preterm than the adult lung, and recycling rates as high as 80% to 90% have
been measured in the newborn. The
very long biologic half-life values for
Figure 6. Surfactant treatment responses depend on ventilation styles.
Preterm rabbits treated with either natural surfactant recovered from adult
sheep (natural) or a synthetic surfactant
containing recombinant SP-C (r-SPC)
were compared with untreated controls.
Only the natural surfactant improved
compliance when the rabbits were ventilated without PEEP. In contrast, both
surfactants increased compliance when
the rabbits were ventilated with 3 cm
H2O PEEP. Modified from Davis, et al.
Lung function in premature lambs and
rabbits treated with a recombinant SP-C
surfactant. Am J Respir Crit Care Med.
1998;157:553–559.
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pharmacology review
Figure 7. Curves for the synthesis, secretion, and clearance of surfactant. These illustrative
curves are from experiments with preterm lambs using radiolabeled precursors of saturated
phosphatidylcholine (Sat PC). The curves illustrate the slow turnover of surfactant in the
lung and the curve for its appearance and clearance from the airspaces.
Figure 8. Measurements of surfactant metabolism in humans who have respiratory
distress syndrome. A. The incorporation of 13C-glucose infused intravascularly for the
first 24 hours after birth into the phosphatidylcholine recovered in aspirates from the
airways. Data redrawn from Bunt et al. The effect in preterm infants of prenatal
corticosteroids on endogenous surfactant synthesis as measured with stable isotopes.
Am J Respir Crit Care Med. 2000;162:844-849. B. Recovery of C13 dipalmitoylphosphatidylcholine-labeled surfactant from airways of ventilated preterm infants in
airway samples. The specific activity (atom % excess C13) decreased exponentially. C.
A second dose of C13-labeled surfactant at about 2 days of age had a similar decrease
in specific activity. Redrawn from Torresin, et al. Exogenous surfactant kinetics in
infant respiratory distress syndrome: a novel method with stable isotopes. Am J Respir
Crit Care Med. 2000;161:1584 –1589.
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airspace surfactant are explained by
continued reuptake and resecretion.
The treatment dose of surfactant
functions as substrate for recycling in
the uninjured preterm lung, partially
explaining why surfactant treatment
effects can persist for days. Surfactant
treatment quickly increases the metabolic pool for endogenous metabolism.
The second bit of magic is the
effect that endogenous surfactant
metabolism has on the surfactant
used for treatment. All surfactants
used to treat infants are far from
“natural” in that the compositions
and lipoprotein aggregate forms differ from the surfactant in the hypophase of the healthy lung. However,
within hours of surfactant treatment,
the preterm lamb lung transforms
treatment surfactant into a surfactant
that is more effective when recovered
and used for a second treatment; that
is, the surfactant is improved or activated by contact with the preterm
lung (Fig. 9). The presumption is
that the lung contributes surfactant
proteins and recycles the exogenous
surfactant components for secretion
in the lung saccules at the right place
and time. Therefore, the persistence
of a surfactant response after a single
treatment results from the uninjured
lung integrating the exogenous surfactant into endogenous surfactant
metabolism, a process that continues
over many days. A single treatment
can cure the surfactant deficiency
disease component of RDS in most
infants.
Why Do Some Infants Need
More Than One Dose of
Surfactant?
Based on the alveolar pool size of
surfactant in the healthy adult (about
5 mg/kg) and the metabolic characteristics of surfactant in the preterm
lung that favor a persistent response
over days, a second dose 6 to
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Figure 9. Change in function of surfactant after treatment. Preterm lambs at 121 or
131 days’ gestation were treated at birth with 100 mg/kg surfactant and gently
ventilated for 5 hours. Surfactant was recovered by bronchoalveolar lavage, and the
recovered surfactant then was used to treat preterm rabbits, with the resultant lung
function used as a bioassay for the quality of the surfactant. The lung compliance
(mL/cm H2O/kg) of the preterm rabbits was increased by the surfactant used to treat
the lambs. Surfactant recovered from very preterm lambs at 121 days’ gestation was
similar to the surfactant used to treat the lambs. However, surfactant from the more
mature lambs had improved function. Redrawn from Ueda, et al. Developmental
changes of sheep surfactant: in vivo function and in vitro subtype conversion. J Appl
Physiol. 1994;76:2701–2706.
12 hours after the first dose should
not be needed. We recently measured the minimal amount of endogenous surfactant needed for preterm
lambs with uninjured lungs to maintain PO2 values on CPAP (Fig. 10).
Lambs that had endogenous pool
sizes greater than about 4 mg/kg
did not develop severe respiratory
failure.
The crucial variable for the need
for a second dose of surfactant is lung
injury. The preterm infant who has
RDS has a low surfactant pool size,
and if lung injury results in edema,
the proteins in the edema fluid can
inhibit surfactant function. This concept can be illustrated by the inverse
relationship between oxygenation
and minimal surface tension in preterm lambs following a surfactant
treatment (Fig. 11).
The preterm infant can injure the
lung with spontaneous breathing if
the lung is very surfactant-deficient
or if PEEP is not provided to help
stabilize the lung. Mechanical ventilation certainly can injure the lung.
Once injury has occurred, the airspaces fill with fluid, proteins, and
inflammation.
Surfactant function can deteriorate by multiple mechanisms that in
aggregate are called surfactant inhibition (Table 2). An example of how
ventilation causing lung injury can
alter the surfactant treatment response is demonstrated by the doseresponse curves for preterm rabbits
treated with surfactant at birth or
after 30 minutes of ventilation (Fig.
12). The delayed treatment after
ventilator-induced lung injury resulted in less response. Lung injury
also interferes with the normal metabolism of surfactant by type II cells.
The net effect is a loss of biophysical
Figure 10. Relationship between endogenous surfactant pool size and respiratory
failure in preterm lambs receiving 5 cm H2O continuous positive airway pressure
(CPAP). Preterm lambs of a mean gestational age of 133 days were given CPAP from
birth. Lambs with surfactant pool sizes greater than 2 mcmol saturated phosphatidylcholine (Sat PC)/kg (about 4 mg/kg surfactant) in bronchoalveolar lavages (BALF)
maintained reasonable Pco2 values at 2 hours of age. Data redrawn from Mulrooney,
et al. Surfactant and physiologic responses of preterm lambs to continuous positive
airway pressure. Am J Respir Crit Care Med. 2005;171:1– 6.
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Figure 12. Dose-response curves for
Figure 11. Relationship between PO2 and surface tension after treatment of preterm
lambs with surfactant. Preterm lambs were ventilated for about 1 hour without
surfactant treatment. The treatment dose of surfactant caused a rapid increase in PO2,
but the improved oxygenation did not persist. Minimal surface tensions in airway
samples decreased when PO2 increased but again increased as PO2 decreased. The high
surface tensions were caused by protein inhibition of surfactant function. Redrawn
from Ikegami, et al. Surface activity following natural surfactant treatment in
premature lambs. Am J Physiol Lung Cell Mol Physiol. 1981;51:L306 –L312.
function and deterioration in lung
function. The infant may respond favorably to a second dose of surfactant, but few infants improve much
with subsequent doses. The use of
repetitive dosing has decreased in clinical practice, probably because more
attention is being paid to avoiding
lung injury prior to the first dose.
Surfactant
Inhibition
Table 2.
Inhibition of Surface Tension
●
●
●
Plasma proteins: albumin,
fibrinogen
Plasma lipids
Products of inflammation: fibrin
Surfactant Degradation
●
●
Oxidation
Lipases
Virtually all infants who are born preterm and have surfactant deficiency
respond to surfactant. The nonresponders either have lung injury
prior to birth (infection), lung injury
after birth and prior to treatment,
pulmonary hypoplasia, or a cardiovascular explanation for the lack of
response (low blood pressure, congenital heart disease). The clinician
should seek diagnoses other than
RDS in the preterm infant who has
respiratory failure and does not respond to surfactant.
Clinical Variables That Alter
Surfactant Treatment
Responses
Gestational Age
Changes in Surfactant Structure
●
Why Do Occasional Infants
Who Have “RDS” Not
Respond to Surfactant?
Increased conversion to inactive
forms
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As the fetus matures, lung structure
also matures. The more mature lung
responds more favorably to surfactant treatments for a number of rea-
treating preterm rabbits with surfactant
at birth or after 30 minutes of mechanical ventilation. Treatment at birth resulted in a greater improvement in lung
gas volumes at a lower surfactant dose
than did surfactant treatment after
30 minutes of ventilation. Redrawn from
Seidner, et al. Decreased surfactant
dose-response after delayed administration to preterm rabbits. Am J Respir Crit
Care Med. 1995;152:113–120.
sons. The surface area is larger, the
microvasculature is better developed,
and the lung is less susceptible to
injury. Activation of exogenous surfactant is less effective at early gestational ages, as demonstrated in Figure 9. Surfactant from the preterm
sheep also is easier to inhibit by
plasma than is surfactant from adult
sheep (Fig. 13). The more immature
the infant, the more immature the
surfactant, the less the metabolic capabilities of the type II cells, and the
more potential interference with surfactant function.
Antenatal Steroids
Antenatal corticosteroids have multiple effects on gene expression in
the fetal lung that result in decreased lung mesenchyme, increased
lung gas volume, decreased tendency
of the lung to leak proteins into the
airspaces, and in some models, increased surfactant. These induced
maturational changes in the preterm
lung often may not be sufficient to
prevent RDS. Fortunately, the
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randomizing infants to antenatal glucocorticoids and postnatal surfactant
treatments has not been done (and
will not be done because both therapies are standard of care), the clinical
information from large data sets and
the surfactant trials support improved outcomes after both antenatal glucocorticoids and postnatal surfactant relative to either therapy. An
example of the clinical outcomes of
infants randomized to surfactant
treatment and the added benefits of
antenatal corticosteroids is given in
Table 3.
Figure 13. Inhibition of minimum surface tension by plasma protein. The inhibitory
effects of plasma proteins occur at a low protein concentration for surfactant from
128 days’ gestation preterm lambs. The surfactant from 134 days’ gestation lambs is
less sensitive to inhibition, and surfactant from adult sheep is minimally inhibited.
Redrawn from Ueda, et al. Distribution of surfactant and ventilation in surfactanttreated preterm lambs. J Appl Physiol. 1994;76:2701–2706.
corticosteroid-mediated effects augment surfactant treatment responses
by multiple mechanisms. Antenatal
corticosteroids increase lung gas volumes, as do surfactant treatments in
fetal sheep (Fig. 14). The combined
treatments result in an additive increase in lung gas volumes. This interaction of antenatal corticosteroids
and surfactant occurs at multiple levels. For example, following treatment of preterm lambs with surfactant and ventilation, the sensitivity of
the surfactant recovered from the
lambs to inhibition by plasma proteins decreases, and that sensitivity to
inhibition is decreased further by antenatal corticosteroid treatments
(Fig. 15). A final example of these
beneficial interactions is the effects of
antenatal corticosteroids on the endogenous and exogenous surfactant
dose-response curves for lung compliance (Fig. 16). Although a trial
Is the Incidence of RDS and
the Need for Surfactant
Treatment Decreasing?
There is no consensus in the neonatal
community about the optimal timing
of surfactant treatments for RDS.
Delivery room treatments are preferable to treatment of established RDS
Figure 14. Lung gas volumes following ventilation of control lambs, lambs treated
with surfactant, lambs delivered after cortisol infusions (steroids), and cortisol-infused
lambs treated with surfactant. Surfactant treatment or fetal cortisol infusions
improved lung gas volumes, and both treatments increased the lung gas volumes more
than either treatment. Data redrawn from Ikegami, et al. Corticosteroid and
thyrotropin-releasing hormone effects on preterm sheep lung function. J Appl Physiol.
1991;70:2268 –2278.
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pharmacology review
Figure 15. The effect of antenatal corticosteroids on inhibition of surfactant by
protein. The surfactant used to treat preterm lambs was inhibited by plasma proteins.
This same surfactant recovered by bronchoalveolar lavage from preterm lambs after
treatment at birth and mechanical ventilation was less sensitive to inhibition by plasma
protein. The same surfactant recovered from ventilated lambs exposed to corticosteroids as
fetuses was even less sensitive to inhibition by plasma proteins. Redrawn from Rebello, et
al. Postnatal lung responses and surfactant function after fetal or maternal corticosteroid
treatment of preterm lambs. J Appl Physiol. 1996;80:1674 –1680.
Figure 16. Dose-response curves of surfactant effects on lung compliance. The curves
under ENDOGENOUS SURFACTANT are for preterm rabbits delivered over a narrow
gestational age range. Lung compliance with mechanical ventilation was measured and
expressed relative to the surfactant pool sizes that were present in the rabbits. Rabbits
exposed prenatally to corticosteroids required less endogenous surfactant to achieve
higher compliance values during spontaneous lung maturation. The curves under
SURFACTANT TREATMENT demonstrate that preterm rabbits that received surfactant
at birth have better lung compliance at lower surfactant treatment doses if they were
exposed to antenatal corticosteroids. Data redrawn from Ikegami, 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;139:367-369 and Seidner, et al. Corticosteroid potentiation of surfactant dose
response in preterm rabbits. J Appl Physiol. 1988;64:2366 –2371.
e104 NeoReviews Vol.7 No.2 February 2006
based on a number of trials and metaanalyses. Thus, the recommendation
has been that evidence-based therapy
requires delivery room intubation
and treatment. However, it must be
recognized that in the trials used for
the meta-analyses, the infants were
treated much later than is current
practice. Furthermore, attempts to
treat before the infant breathes were
of no benefit relative to a brief 15minute delay in treatment. Neither
extreme of very early or late treatment seems to be optimal. If intubation and treatment are delayed until
the infant either demonstrates inadequate respiratory effort or has signs
of early RDS, the infant will not be
overventilated as easily during initial
stabilization, and infants who do not
have RDS will not be treated with
surfactant. A benefit of surfactant
treatments for infants who do not
have RDS has not been demonstrated.
An important question is how
many very low-birthweight (VLBW)
infants do not have RDS. The surprising answer is that in the hands of
clinicians who use nasal CPAP very
early to assist infants with respiratory
transition after birth, surfactant was
used to treat only 16% of infants. In
another clinical experience, 73% of
infants weighing less than 1,500 g
did not receive surfactant for RDS.
These numbers are strikingly lower
than the recent experiences of the
Vermont-Oxford and National Institutes of Child Health and Development Neonatal Research Networks, where almost 80% of such
infants received surfactant treatments.
Most preterm infants now have
been exposed to prenatal corticosteroids, antibiotics, and tocolytics.
Furthermore, many have been exposed to chorioamnionitis, which
also can mature the preterm lung.
Many of today’s VLBW infants
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pharmacology review
Outcomes of Preterm Infants Treated
With Surfactant in Randomized, Controlled
Trials Based on Antenatal Corticosteroid
Treatments
Table 3.
Maternal Corticosteroids
ⴙ
Surfactant
Number of Patients 57
Air Leak
1.7%
Grade III/IV IVH
7%
28-d Mortality
0
No Maternal Corticosteroids
No
Surfactant
ⴙ
Surfactant
No
Surfactant
46
13%
11%
15%
555
11%
25%
18%
566
23%
23%
25%
IVH⫽intraventricular hemorrhage
Data abstracted from Jobe, Mitchell, Gunkel, Am J Obstet Gynecol. 1993.
probably have minimal RDS, and if
lung injury is avoided, the infants
may do well with CPAP therapy
alone. The surfactant treatment
and CPAP management options
for VLBW infants need to be tested
by prospective trials, but experience
with CPAP suggests that lung injury from ventilation can contribute to the clinical syndrome of RDS
by causing surfactant inactivation
when a small endogenous surfac-
tant pool might otherwise be adequate.
Suggested Reading
Horbar JD, Carpenter JH, Buzas J, et al.
Collaborative quality improvement to
promote evidence based surfactant for
preterm infants: a cluster randomised
trial. BMJ. 2004;329:1004
Jobe AH. Pulmonary surfactant therapy.
N Engl J Med. 1993;328:861– 868
Jobe A. Techniques for administering surfactant. In: Robertson B. Surfactant
Therapy for Lung Disease. New York,
NY: Marcel Dekker, Inc; 1995:
309 –324
Jobe AH, Ikegami M. Mechanisms initiating lung injury in the preterm. Early
Hum Dev. 1998;53:81–94
Jobe AH, Ikegami M. Biology of surfactant.
Clin Perinatol 2001;28:655– 669
Soll RF. Prophylactic natural surfactant extract for preventing morbidity and mortality in preterm infants. Cochrane Database of Systematic Reviews. 1997; Issue 4.
Art. No.: CD000511
NeoReviews Quiz
10. The pathophysiology of respiratory distress syndrome (RDS) in the preterm neonate is complex and
involves many factors, including antenatal events, lung immaturity, surfactant deficiency, and postnatal
care practices. Of the following, the most critical factor in the development of RDS in the preterm
neonate is:
A.
B.
C.
D.
E.
Immature composition and biophysical function of surfactant.
Leaking epithelium/endothelium barrier from lung injury.
Low lung gas volume with susceptibility to overdistention.
Low surfactant lipid pool size.
Saccular versus alveolar stage of lung development.
11. The activity of exogenous surfactant administered through intratracheal instillation depends on how
rapidly and uniformly it is adsorbed and spread throughout the lungs. Of the following, the distribution of
surfactant in the lungs is most efficient when surfactant is administered:
A.
B.
C.
D.
E.
After a period of mechanical ventilation.
As an aerosolized preparation.
At a slow rate of infusion.
At birth in the presence of fetal lung fluid.
Using a smaller volume of the drug.
Continued
NeoReviews Vol.7 No.2 February 2006 e105
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pharmacology review
12. Surfactant metabolism has been studied extensively in adult, newborn, and preterm animals, particularly
sheep, and more recently in human infants. Of the following, the most accurate statement regarding
surfactant metabolism is that:
A. A treatment dose of 100 mg/kg of surfactant exceeds the endogenous surfactant pool in healthy
adults by about twofold.
B. Exogenous surfactant administration suppresses endogenous surfactant production and prevents
sustained surfactant action on lung function.
C. Surfactant is recycled more efficiently in the preterm than in the adult lung, amounting to a recycling
rate of 80% to 90%.
D. Surfactant processing in the alveolar type 2 epithelial cell from storage in lamellar bodies to secretion
into airspaces occurs over a few minutes.
E. The half-life of both exogenous and endogenous surfactant components in the airspaces is
approximately 24 hours.
106 NeoReviews Vol.7 No.2 February 2006
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Pharmacology Review: Why Surfactant Works for Respiratory Distress
Syndrome
Alan H. Jobe
NeoReviews 2006;7;e95-e106
DOI: 10.1542/neo.7-2-e95
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