Jornal de Pediatria - Vol. 78, Supl.2, 2002 S215
0021-7557/02/78-Supl.2/S215
Jornal de Pediatria
Copyright © 2002 by Sociedade Brasileira de Pediatria
REVIEW ARTICLE
Exogenous surfactant therapy –
What is established and what still needs to be determined
Celso Moura Rebello,1 Renata S. M. Proença,2 Eduardo J. Troster,3 Alan H. Jobe4
Abstract
Objective: to review well-known aspects of exogenous surfactant therapy, and to discuss controversial
points regarding the current state of research.
Sources: review of the literature, using Medline and Cochrane Database Library, in association with
the authors’ experience in relation to exogenous surfactant replacement therapy.
Summary of the findings: the main aspects of surfactant characteristics: composition, pool, metabolism,
inactivation and immediate effects after its administration are well established. However, there are some
doubts related to the use of exogenous surfactants that need to be cleared up: choice of surfactant type, most
appropriate length of treatment, adequate dose and number of doses, best administration route and
complications associated with its use. Currently, the research about exogenous surfactant therapy focuses
on two aspects: the use of surfactant in other pathologies besides the respiratory distress syndrome of the
newborn, and the development of new surfactants through the addition of proteins or analogous proteins,
with the aim of improving its action and reducing its inactivation.
Conclusions: the use of exogenous surfactant has become a routine in neonatal intensive care units,
but both clinical and experimental research is still necessary.
J Pediatr (Rio J) 2002;78(Supl. 2):S215-S226: surfactant, newborn, respiratory distress syndrome.
Introduction
The history of exogenous surfactant therapy dates back
to 1929, when German physiologist Neergaard wrote the
article entitled “New notions about an essential principle of
respiratory mechanics: the retractive force of the lungs,
dependent on alveolar surface tension”.1 He showed that a
lung inflated with air had a greater transpulmonary pressure
than a lung inflated with the same volume of water, inferring
that atelectasis of the newborn could be caused by remarkable
retractile forces of the surface tension of the lungs.
In the 1940s, Gruenwald investigated autopsied lungs in
newborns and described hypoventilation, which caused the
lungs to resemble a solid organ that could be inflated with
fluid but would lose its normal architecture when inflated
with air.2
In the late 1950s, Avery and Mead stated that pulmonary
surfactant deficiency observed in preterm newborns caused
repetitive collapse and reexpansion of alveoli, and was
therefore crucial to the pathogenesis of the hyaline
membrane.3
1. Ph.D. in Pediatrics, School of Medicine, Universidade de São Paulo.
2. Assistant physician, Hospital das Clínicas, School of Medicine,
Universidade de São Paulo.
3. Coordinator, Pediatric ICU, Hospital Israelita Albert Einstein; coordinator,
Pediatric ICU, Instituto da Criança, HC FMUSP; Doctor of Medicine,
Department of Pediatrics, FMUSP.
4. Professor of Pediatrics. Cincinnati Children’s Hospital Medical Center.
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S216 Jornal de Pediatria - Vol. 78, Supl.2, 2002
Fugiwara, in 1980, went a step further. In a non-controlled
study, surfactant was given intratracheally to preterm
newborns with respiratory distress syndrome (RDS), with
evident improvement of oxygenation; thus showing the
efficacy of the new technique.4
In 1980s, several researchers investigated surfactants of
different origins (human, porcine, bovine, synthetic) against
placebos, culminating in the availability of surfactants for
clinical use on a regular basis in the late 1980s and in the
early 1990s.
In the last 12 years, several studies have been carried out
with the aim of determining the best therapeutic scheme,
taking into consideration the moment of treatment
(prophylactic x therapeutic), the type of surfactant (synthetic
x natural), and the dose of surfactant, among other aspects.
These studies have been recently reviewed by Roger Soll in
a series of meta-analyses.5-7
In recent years, research about surfactant therapy has
focused on three major aspects: the first one is concerned
with the use of surfactant in pathologies other than RDS,
including meconium aspiration syndrome (MAS),
pneumonia, acute respiratory distress syndrome (ARDS),
congenital diaphragmatic hernia, among others; the second
aspect deals with the investigation of the effects of alveolar
recruitment with increase in the peak inspiratory pressure
during surfactant administration; and the last one is concerned
with the development of new surfactants by the addition of
synthetic or analogous proteins, with the aim of improving
their action and reducing their inactivation by plasma
proteins.
The present article aims at reviewing exogenous
surfactant therapy and discussing the current state of
research, in which no consensus on the use of exogenous
surfactant has been reached yet.
Surfactant characteristics
Surfactant composition and pool
The chemical composition of pulmonary surfactant is
known to be quite similar among several mammalian
species,8 with no differences that justify the use of a specific
animal species for the extraction of pulmonary surfactant,
for therapeutic purpose.
Surfactants usually consist of lipids and proteins.
Approximately 80 to 90% of their mass consists of lipids,
including neutral lipids and phospholipids.
About 70 to 80% of phospholipids consist of
phosphatidylcholine, usually in saturated form (45% of
the surfactant mass). Phosphatidylglycerol represents 5
to 10% (in mass), whereas phosphatidylinositol,
phosphatidylethanolamine and phosphatidylserine
account for less than 10% of total lipids. Cholesterol and
Exogenous surfactant therapy... - Rebello CM et alii
cholesterol esters represent less than 5% of the surfactant
mass, and their role is not perfectly known yet, although
they change the flow and organization of lipid membranes.
The key function of phospholipids is acting as a molecule
that reduces surface tension in the air/fluid ratio inside the
alveolus. This unique characteristic allows preventing the
repetitive collapse and reexpansion of alveoli at the end of
expiration, when the forces that cause alveolar collapse are
maximized and inversely proportional to the average alveolar
radius. However, phosphatidylcholine alone is not able to
explain the main surfactant characteristics: stability during
compression, quick adsorption from subphase to the alveolar
surface and the capacity to reorganize the monolayer when
dispersed into an aqueous medium. In fact, at 37º C
phosphatidylcholine takes the gel form, changing to the
“liquid” and dispersed form at 41º C.9 Therefore, it depends
on other surfactant components to form a stable layer on the
alveolar surface when at physiological temperature.
Proteins, which include SP-A, SP-B, SP-C and SP-D,
represent approximately 10% of the surfactant mass.
SP-A is a water-soluble protein, and the most abundant
in the surfactant, accounting for 5% of its mass. It consists
of a group of 26-KD monomers strongly linked together by
covalent bonds, resulting in a 650-KD molecule. Among
the functions of SP-A are pulmonary immune defense, since
it is able to bind to carbohydrates and to interact with lung
immune cells. The absence of SP-A hinders the elimination
of both bacteria and viruses from the lungs, favoring the
systemic dissemination of infections.10 The major roles of
SP-A include protection of surfactant against the inhibition
of its functions by proteins found in the alveolar edema.11
SP-A seems to influence the surfactant metabolism only
in in vitro studies, since in transgenic animals with deficiency
of this protein no influence exists on the metabolism or
function of surfactant.
SP-B is a small 18-KD hydrophobic protein, which is
essential to the pulmonary surfactant function; its congenital
absence is incompatible with life.12,13
Among the functions of SP-B are formation and
organization of tubular myelin inside the alveolus,14 in
addition to facilitating the adsorption of phosphatidylcholine
at physiological temperature.
SP-C is also a hydrophobic peptide that forms as rigid
helical structure of 4.2 KD. Although its functions are
similar to those of SP-B, allowing the adsorption of
phosphatidylcholine at physiological temperature, its
congenital deficiency does not result in death from
respiratory insufficiency, although it might evolve into
familial interstitial pulmonary disease.15
We may say that, of all its components, lipids, SP-B and
SP-C are chiefly involved in the biophysical and functional
properties of pulmonary surfactant.
Exogenous surfactant therapy... - Rebello CM et alii
SP-D is a water-soluble glycoprotein formed by 43-KD
monomer aggregates, resulting in 560-KD multimers. Just
like SP-A, it is not present in surfactant preparations of
animal origin obtained through lipid extraction and does not
reduce surface tension, seemingly having an important role
in protecting the lungs from infection by binding to a variety
of carbohydrate and glycolipid complexes, interacting with
the surface of bacteria and other microorganisms.16
The amount of surfactant found in the lungs correlates
logarithmically with the alveolar surface in several animal
species.17 In human beings, a report based on five
subsegmental washings in volunteering adults allowed an
estimate of alveolar pool of 3mg of surfactant/kg.18 This
estimate was confirmed in a study involving 24 dead subjects,
aged between 13 months and 80 years, in which the estimated
alveolar pool of surfactant was a 4mg/kg and that for total
lung was approximately 56mg/kg.19
The amount of pulmonary surfactant decreases with
age, but not remarkably. Interestingly enough, preterm
newborns with RDS have an amount of surfactant between
1 and 5 mg/kg,20 similar to that observed in adults and
approximately tenfold as high as that observed in full-term
newborns, which is way below the dose used in the treatment
of RDS in newborn infants, showing that the structure of a
newborn’s lung and maybe the presence of proteins in the
alveolar lumen determine the necessity for a greater pool at
birth, as found in the lung of full-term newborns, in order to
guarantee proper function.
Surfactant metabolism
The surfactant is produced in pneumocyte II.
Phospholipids and proteins SP-B and SP-C are synthesized
in the rough endoplasmic reticulum, from where they are
initially stored in Golgi complex and, later, in the lamellar
bodies (Figure 1). Periodically, the latter are expelled from
pneumocyte II when the surfactant is released to the alveolar
lumen, thus organizing the tubular myelin.
The kinetics of synthesis and secretion into the alveolus
is quite slow, and takes from 30 to 48 hours in newborn
animals;21 in general, this time is greater in newborns if
compared to adults.
After being secreted into the alveolus, the surfactant
goes through a complex cycle (Figure 1). Initially, the fat
molecules organize themselves (with the help from proteins)
so as to form the monolayer that lines the alveolar surface
- the tubular myelin. With successive movements of
contraction and stretching that occur at each respiratory
cycle, part of the tubular myelin disorganizes itself and
loosens itself from the main film in the form of small
vesicles, which are reabsorbed into pneumocyte II. In the
cell, a small part is catabolized, while the largest part of the
reabsorbed surfactant is mixed with the lamellar bodies,
where it is reorganized in a recycling process. Therefore, in
Jornal de Pediatria - Vol. 78, Supl.2, 2002 S217
preterm newborns, about 50% of the alveolar pool consists
of surfactant, with great capacity to reduce surface tension,
and another 50% is formed by inactive vesicles to be
recycled. This relation is more unfavorable in situations of
lung injury.22
This recycling process minimizes the necessity for
surfactant synthesis, whereas it maintains an adequate
alveolar pool and, at the same time, activates the surfactant
components reabsorbed into pneumocyte II, by the addition
of new elements (especially proteins) and by the structural
reorganization of lipids and proteins. The latter process is
particularly important to the treatment with exogenous
surfactant, to which SP-A and SP-D (absent in commercial
preparations) are added by means of recycling.
The exogenous surfactant used for the treatment of RDS
is quickly incorporated to the lung tissue, and only 40% is
retrieved in the alveolar space immediately after
administration.23
The treatment with exogenous surfactant does not
interfere with the metabolic pathways of the endogenous
surfactant; consequently, its production is not inhibited by
feedback.
Water-soluble proteins SP-A and SP-D are synthesized
and released independently of phospholipids and fat-soluble
proteins SP-B and SP-C.
Surfactant inactivation
The surfactant’s function of reduction of alveolar surface
tension may be inhibited by plasma proteins, which invade
the alveolar space in acute lung injuries. This inactivation
is a reversible phenomenon and basically occurs due to
interference in the formation of the surfactant monolayer,
caused by the presence of proteins, through a competition
mechanism at the air-fluid interface.
The inactivation phenomenon depends on several factors,
including the amount of surfactant and proteins that compete
for the air-fluid interface;24 the type of protein found in the
alveolar lumen (fibrin monomers are located between the
proteins with higher capacity of surfactant inactivation);25
and the amount of specific surfactant proteins (SP-A, SP-B
and SP-C), which reduce inactivation.26 This phenomenon
is mitigated with the prenatal use of corticosteroids,
presumably by a better recycling mechanism, resulting in
larger concentrations of specific proteins in the end
product.27
Immediate effects of surfactant treatment
The first response to surfactant treatment is a rapid and
intense increase in oxygenation, which occurs some minutes
after administration, allowing a fast reduction in the
concentrations of inspired oxygen.
Exogenous surfactant therapy... - Rebello CM et alii
S218 Jornal de Pediatria - Vol. 78, Supl.2, 2002
Modified by Ikegami M, et al. Seminars in Perinatol 1993; 17:4.
Figure 1 - Intracellular metabolim of the surfactant
Lung compliance improves more slowly, allowing a
gradual reduction in the maximum peak inspiratory pressure
in order to maintain an appropriate tidal volume.
This effect can be better understood by observing the
reduction in opening pressure (pressure through which the
lung is filled above the volume of the dead space) at the
inspiratory stage of the pressure-volume curve of
animalstreated with surfactant in comparison with control
animals.28
The greater alveolar recruitment results in increase of
maximum pulmonary volume and higher stability of
expiration, when alveoli remain open, resulting in larger
residual functional capacity. The sum of these effects
explains the dramatic improvement in oxygenation observed
after surfactant treatment.
Microscopically, surfactant treatment leads to greater
uniformity in alveolar expansion, reducing areas of
atelectasis/hyperdistension, with a more important effect
on the reduction of lung injury obtained with surfactant
treatment.29
The effects on pulmonary blood flow are controversial,
with the report of an increase 30 or unaltered flow31 in the
pulmonary artery.
Available surfactants and administrationtechniques
Types of surfactants
There are two basic choices for exogenous surfactant
therapy: “natural” surfactants obtained from animals by
lipid extraction by means of pulmonary washings or
homogenate, which preserves the composition of SP-B and
SP-C, with or without the addition of phospholipids to the
end product; and synthetic surfactants, produced in
laboratory. The major available surfactants are described in
Table 1.
Although both types of surfactants change the course of
RDS, the responses, especially in the short run, are different.
Natural surfactants produce an immediate response as
to the improvement of oxygenation and of pulmonary
function, demanding a close and constant monitoring of
Exogenous surfactant therapy... - Rebello CM et alii
Jornal de Pediatria - Vol. 78, Supl.2, 2002 S219
newborns soon after treatment, in order to avoid undesirable
complications. Synthetic surfactants take some hours to
show the same effects. The explanation for this phenomenon
is probably related to the fact that synthetic surfactants have
the main role of increasing the alveolar and tissue pool,
which will be recycled inside pneumocyte II, being added
to specific proteins, which are not present in the commercial
product.
A meta-analysis has recently compared the studies
conducted with extracts of natural surfactants against
synthetic surfactants for the treatment of RDS; however,
none of them used the new synthetic surfactants (KL-4 and
rSP-C). The review of results obtained from the 11 studies
revealed that both types of surfactants proved effective in
the treatment of RDS, but with a lower risk of pneumothorax
and lower mortality associated with the treatment using
natural surfactant, as well as a tendency towards a lower risk
of evolution into bronchopulmonary dysplasia or death.
Table 1 -
Time of treatment
Classically, the prophylactic use of surfactant for the
treatment of RDS was compared with the therapeutic use.
The term “prophylactic” may create some confusion;
however, in most studies, it was used with the meaning of
treatment within a time interval preset by researchers,
usually in the resuscitation room.
The logic of prophylactic use is based on the better
distribution of surfactant, when administered before the
first breath and on reduced lung injury, resulting in less
alveolar edema and less inactivation by proteins.
The logic of therapeutic use is based exclusively on the
treatment of newborns who evolved into RDS and developed
possible unnecessary complications.
Other studies comparing prophylactic and therapeutic
use were reviewed in a meta-analysis that has been updated
recently.32 All the studies used natural surfactants.
Main surfactants available for clinical and experimental use
Brand name
Generic name
Preparation
Laboratory
Surfacten
Surfactant-TA
Bovine lung extract plus DPPC,
tripalmitoylglycerol and palmitic acid
Tokyo Tanabe
(Japan)
Survanta
Beractant
Bovine lung extract plus DPPC,
tripalmitoylglycerol and palmitic acid
Ross Products Division of
Abott Laboratories (USA)
Curosurf
Poractant
Pig lung submitted to extraction
with chloroform-methanol;
purified by liquid-gel chromatography
Chiesi Pharmaceuticals
(Italy)
Infasurf
Calf lung
surfactant extract
Extract of calf lung fluid submitted
to extraction with chloroform-methanol
Forrest Laboratories
(USA)
BLES
Bovine lipid
extract surfactant
Extract of cow lung fluid submitted to
extraction with chloroform-methanol
BLES Biochemical
(Canada)
Alveofact
SF-RI 1
Extract of cow lung fluid submitted to
extraction with chloroform-methanol
Boehringer Inglheim
(Germany)
Exosurf
Colfosceril plamitate,
hexadecanol, tyloxapol
DPPC with 9% of hexadecanol
and 6% of tyloxapol
Burroughs-Wellcome Co.
(USA and England)
Pneumactant*
Artificial Lung Expanded
Compound (ALEC)
DPPC and PG at 7:3 ratio
Brittannia Pharmaceuticals
(England)
Surfaxin
Lucinactant
Chemically synthetized peptide combined
with phospholipids and palmitic acid
Discovery Laboratories
(EUA)
Venticute
rSP-C Surfactant
Recombinant SP-C combined
with phospholipids and palmitic acid
Byk Gulden
(Germany)
DPPC = dipalmitoylphosphatidylcholine, PG = phosfatidylglycerol, SP-C = Surfactant protein C, rSP-C = recombinant surfactant protein C
S220 Jornal de Pediatria - Vol. 78, Supl.2, 2002
This meta-analysis showed a reduction in the risk of
pneumothorax, interstitial emphysema, mortality,
bronchopulmonary dysplasia or mortality associated with
the prophylactic treatment. The study suggests that for
every 100 newborns prophylactically treated, there will be
a reduction of pneumothorax in two newborns and five
deaths. On the other hand, the possible attenuating role of
the prenatal use of corticoids in the results was not clarified.
Also, early treatment (within the first two hours of life)
or late treatment (after the second hour of life) of RDS has
been studied as well. A meta-analysis including four studies
(two with synthetic surfactant and two with natural surfactant)
showed a reduction in the risk of pneumothorax, interstitial
emphysema, prenatal mortality, chronic pulmonary disease
and death at 36 weeks’ corrected gestational age. With
treatment within the first two hours of life, there is a
tendency towards the reduction in the risk of
bronchopulmonary dysplasia or death after 28 days of life.6
Exogenous surfactant therapy... - Rebello CM et alii
Most clinical studies used the dose of 100mg/kg, except
for the studies with Curosurf™ (surfactant obtained through
pig’s lung extract), in which the dose consisted of 200
mg/kg and most part of studies with human surfactant used
the dose of 60mg/kg.
Fujiwara, compared the dose of 120mg/kg with the dose
of 60mg/kg, and found better results (less need for ventilatory
support and reduction in the incidence of intracranial
hemorrhage and of bronchopulmonary dysplasia) with the
dose of 120mg/kg.36
A sensible therapeutic proposal is the treatment of the
cases with established diagnosis of RDS, as soon as possible,
preferably within the first two hours of life.
It is reasonable to suppose that the initial dose of
100mg/kg (which was empirically used in the initial phase)
may be held as adequate for most clinical situations, based
on the technical considerations regarding the minimum
amount of surfactant necessary to line the alveolar surface,
along with studies that compare different doses of surfactant,
and given the currently available information that the
inactivation of the alveolar surfactant (even in adequate
amounts of surfactant) is a highly dose-dependent
phenomenon. An exception would be the situation in which
inhibition of the exogenous surfactant function is expected
(late treatment, where alveolar edema is already present and
is intense, SAM, pulmonary hemorrhage, etc.). In view of
the dose-dependent effect of inactivation, the initial dose of
200mg/kg may be more appropriate.
Studies comparing prophylactic and therapeutic use
within the first two hours may help to clarify the approach
at the time of treatment.
A second approach would be to use multiple doses of
surfactant, in relation to treatment with a single dose, with
the aim of reverting inactivation.
The analysis of the results of two approaches showed the
advantages of prophylactic or therapeutic treatment up to
the second hour of life. It is therefore evident that the earlier
the treatment, the better the results.
Dose and administration technique
Given the fact that the alveolar pool of surfactant in
newborns with RDS does not differ remarkably from the
alveolar pool in adults without respiratory disorder,19
showing the crucial role of the “quality of the surfactant”
(protein contents), of the pulmonary structural immaturity
of newborns and the inactivation of protein release into the
alveolar lumen, which occurs in the premature lung
immediately after birth,33 the need to determine the adequate
dose of exogenous surfactant is clear if the situation is to be
reverted or minimized in premature lungs.
One of the first studies to address this issue was carried
out by Ikegami et al, in 1980 (34). By using premature lambs
with natural sheep surfactant (containing SP-A, SP-B, SPC and SP-D) in doses ranging from 19, 53, 64 to 173 mg/kg
and by means of an in vitro analysis by determination of the
surface tension of the surfactant, using a Wilhelmy scales,
the authors observed that the dose of 64mg/kg of surfactant
produced worse results if compared to a higher dose.
These results are in agreement with the proposal made
by Clements and King, who suggest that the theoretical
amount of surfactant necessary to cover the alveolar surface
would be 1mg (by mass) per gram of lung, which would
correspond approximately to a dose of surfactant of at least
36.4 mg (total lipids) per kilo or 40mg of surfactant/kg.35
In this sense, a meta-analysis including the results of two
studies that compared single dose with multiple doses of
natural surfactant (100mg/kg) showed that the latter approach
resulted in improved oxygenation with less need for
mechanical ventilation, a reduction in the incidence of
pneumothorax and a tendency towards reduced mortality.7
The author did not observe an increase in the incidence of
complications associated with the use of surfactant in
multiple doses.
In general, considering the metabolic cycle within
pneumocyte type II, especially if an initial lung injury is
avoided, it is not necessary to apply more than one dose of
surfactant.
Administration technique
Several administration techniques have been used,
yielding different results.
The use of nebulized surfactant was put aside after
several attempts, since even using ultrasonic nebulization,
the amount of surfactant that reaches the alveoli is quite
low; about 7.6% of the dose of surfactant reaches the
lungs.37 However, this approach allows a more homogenous
distribution than conventional instillation. The efficiency
of nebulization is directly correlated with compliance and
the rate of ventilatory efficiency after the treatment. This
inefficiency of the technique is probably related to the
Exogenous surfactant therapy... - Rebello CM et alii
particle size created by the nebulizer, loss of surfactant to
the circuit, and location of the nebulizer in the ventilator
circuit.
The use of the bolus administration technique was based
on experimental studies, where it proved efficient. Instillation
right after birth and prior to the first breath results in a
uniform distribution of the surfactant, with excellent clinical
response,38 while the administration after a short period of
ventilation results in a less uniform distribution. On the
other hand, due to the obvious interference of the treatment
at birth with resuscitation maneuvers, the treatment should
be implemented after stabilization of the newborn, preferably
at the neonatal ICU.
Newborns treated with stable thorax in the horizontal
position have a comparable distribution of surfactant in
both lungs,39 with no difference in efficacy when the
administration technique in two or four aliquots40 is
compared with positioning maneuvers of the chest.
It is recommendable that the administration be made in
a single aliquot with the stable newborn in the horizontal
position, after proper positioning of the tracheal tube. The
ventilator circuit should be closed at the time of
administration in order to prevent loss of airway pressure,
which could cause pulmonary collapse. The use of adapters
with side opening or tracheal tube with injector port at the
extremity allows the administration of surfactant without
the need of opening the ventilator circuit. Larger volumes of
surfactant (usually 4 ml/kg of preparations at 25 mg/ml)
have a better distribution than that obtained with more
concentrate surfactants.
Treatment complications
A series of less important events without major
repercussions in the long run may be associated with the
bolus administration of surfactant, especially in larger
volumes. These events, which include transient cyanosis,
increase in PaCO2, tachycardia, bradycardia, and reflow of
surfactant to the ventilator circuit, among others, may be
avoided or are corrected easily with the administration of
surfactant by qualified personnel. The elevation of FiO2
10% above the necessity of the newborn at the moment of
treatment, the use of a lateral injector port or a tube with an
infusion device, combined with a relatively slow (but not
extremely slow) infusion speed with continuous control of
oxygen saturation, can avoid or minimize these events,
which perhaps should not be named “complications”
associated with the use of surfactant.
A major complication with surfactant treatment, although
rare, and more severe as it is associated with high morbidity
and mortality, is pulmonary hemorrhage.
Several authors have reported an increase in the incidence
of pulmonary hemorrhage, both after treatment with synthetic
Jornal de Pediatria - Vol. 78, Supl.2, 2002 S221
and natural surfactant, of which the latter showed a higher
incidence of hemorrhage.41 The hemorrhage occurs several
hours after treatment, and an association between its
occurrence and the increase of left-right flow through the
ductus arteriosus has been made.42
What is still unclear
The role of new surfactants
Although the composition of pulmonary surfactants is
quite complex, the major elements in charge of their function
can be summarized in four components: phosphatidylcholine
(the key element in surface tension), phosphatidylglycerol,
and fat-soluble proteins SP-B and SP-C. The latter two have
specific functions in the surfactant, and their absence causes
considerable function loss, indicating that they should be
present in the end product. Both proteins are found in
commercial surfactants obtained by lipid extraction from
mammalian lungs, although in lower amounts than that
found in the natural surfactant.
Given the crucial importance that these proteins have to
the function of the pulmonary surfactant, new products have
been developed, although they are not commercially
available, with the aim of developing surfactant proteins
synthetically without the need for animal extraction. A
concern regarding the use of natural SP-C is with its purity
level and its tendency towards aggregation at the moment of
extraction.43
A surfactant based on a recombinant form of modified
human SP-C (rSP-C) has been recently developed and
tested (Venticute™, BYK Gulden Kenstanz, Germany).
Human SP-C consists of dipalmitoyl cystine in positions 4
and 5, which in the rSP-C molecule were replaced with
phenylalanine. This change in the molecular structure did
not interfere with the final function assessed in vivo.43-45 In
a premature animal model, the function of this new surfactant
was similar to the natural sheep surfactant (which contains
SP-B and SP-C) in the dose of 100 mg/kg, assessed by
respiratory mechanical parameters (necessary ventilatory
pressure to obtain a tidal volume of 6 to 8 ml/kg, dynamic
compliance and functional residual capacity), and gas
analysis.
The new surfactant was very effective in two wellestablished models of pulmonary immaturity, namely rabbits
and premature lambs. The pulmonary function in premature
lambs after treatment with SP-C or sheep surfactant was
equivalent, except for a slight difference in oxygenation. 46
In premature rabbits the response to treatment with both
surfactants was similar, when the animals were ventilated
with positive end-expiratory pressure (PEEP) of 3 cm/
H2O.46
Also using animal models, it has been observed that
both dexamethasone and phosphodiesterase inhibitors
maximize surfactant action with rSP-C,47,48 and that their
S222 Jornal de Pediatria - Vol. 78, Supl.2, 2002
use in a hypersensitive animal model did not result in
increased risk for anaphylaxis.49
Recently, adults with ARDS have been treated with rSPC and have shown improved gas exchange, less necessity
for ventilatory support and better survival rates. 50
Phase III clinical studies, including adults with ARDS,
are being carried out.
Another synthetic surfactant recently developed is KL4 (Surfaxin™, Discovery Laboratories, Daylestown, United
States), which contains a 21-unit peptide
(KLLLLKLLLLKLLLLKLLLLK, where K = lysine and L
= leucine) that emulates the properties of SP-B, and
phospholipids
(phosphatidylcholine
and
phosphatidylglycerol). This new surfactant showed to be
efficient in improving gas exchange in experimental
models51 and in newborns with RDS treated up to four
hours after birth.52
Further randomized, phase III studies are necessary
before the regular clinical use of these new surfactants.
Alveolar recruitment and exogenous surfactant
treatment
Several recent studies have suggested that alveolar
recruitment obtained through the increase in peak inspiratory
pressure (PIP) during surfactant administration improves
the results of the treatment.53-55
Considering that a preterm newborn with surfactant
deficiency has a tendency towards repetitive collapse and
reexpansion of alveoli with a reduction of functional residual
capacity, recruitment maneuvers before surfactant
instillation allow the aeration of the collapsed and
reexpanded parts of the lung, resulting in better distribution
and better results with the administered surfactant.
In rabbits with surfactant deficiency, caused by
bronchoalveolar lavage, submitted to mechanical ventilation
with PEEP = 1 cmH2O, the increase in inspiratory pressure
by 8 to 9 cmH2O two minutes before and maintained up to
four minutes after treatment, resulted in improvement of
functional residual capacity, tidal volume, dynamic
compliance and gasometric parameters.53
On the other hand, by using a higher PEEP (3 cmH2O),
recruitment maneuvers did not produce a better performance
in terms of respiratory or gasometric mechanics.
By also using an experimental model with surfactant
deficiency caused by pulmonary lavage, recruitment
maneuvers resulted in a more homogeneous distribution of
surfactant with improvement of alveolar ventilation and
oxygenation.55
On the other hand, it has been well established that the
use of higher expiratory pressure at the moment of surfactant
treatment brings, at least theoretically, a better alveolar
Exogenous surfactant therapy... - Rebello CM et alii
recruitment, improving pulmonary function and maintaining
the surfactant in its active form, when compared to the
absence or low levels of PEEP.56,57 It has also been
established that the use of elevated tidal volumes causes
greater conversion of surfactant to inactive forms 22 and
increased lung injury, which could predispose the premature
lung to bronchopulmonary dysplasia.
Finally, in the physiopathology of RDS, hypoventilated
areas might not necessarily present atelectasis, but might be
filled with fluid and proteins, which would cancel out the
effect of recruitment maneuvers.
This way, at present, it is not possible to recommend
alveolar recruitment strategies based on the increase of tidal
volume secondary to elevated peaks of inspiratory pressure,
because of the unwanted long-term effects secondary to a
possible lung injury induced by this type of strategy, which
would counteract any positive effect of surfactant distribution
with immediate improvement of oxygenation and of
respiratory mechanics.
It is also important to underscore that the moderate
pulmonary recruitment obtained through the use of PEEP
above physiological levels may improve the distribution
and the response of surfactant treatment.
Use of surfactant in other diseases than RDS
Meconium aspiration syndrome (MAS)
Meconium is an inhibitor of the pulmonary surfactant
activity. Aside from its obstructive and inflammatory
characteristics, meconium causes an increase in surface
tension that results in repeated collapse and reexpansion of
alveoli with deterioration of pulmonary function. This
inhibitory effect of meconium on surfactant function may
be reverted by increasing the concentration of surfactant.
This is the principle of surfactant treatment in meconium
aspiration syndrome.
Sun et al. have assessed pulmonary function in full-term
newborn rabbits after meconium aspiration, after treatment
with porcine surfactant in the dose of 200 mg/kg, and
observed improvement of dynamic compliance and better
pulmonary aeration in the treated group. 58 In a subsequent
study, the same author compared the effects of early or late
administration of exogenous surfactant (ES), and found
improvement of gas exchange, lung compliance, alveolar
expansion and reduced lung injury in treated animals,
regardless of the time of ES administration. The author also
observed reduced necessity for oxygenation and mean
airway pressure, less formation of hyaline membranes, less
intra-alveolar edema and less neutrophil inflow into intraalveolar spaces.
There are few controlled studies that assess the use of ES
in the treatment of MAS; in addition, the existing studies
were carried out with a small number of patients and have
conflicting results. Halliday treated 54 newborns with MAS
Exogenous surfactant therapy... - Rebello CM et alii
with porcine surfactant and observed a slight improvement
in oxygenation: 44 % of newborns did not have any
improvement, 20 % had pneumothorax and 19 % died.
Among survivors, 18% developed chronic lung disease.59
Lotze et al., in a multicenter study, assessed the use of
bovine surfactant in a population of 328 full-term newborns
with severe respiratory insufficiency, of which 21% had
MAS. No difference was observed as to mortality, days of
oxygen supplementation, length of mechanical ventilation
or length of hospital stay, when compared to treated and
untreated groups.60
Only one controlled and randomized study was
conducted to assess the use of ES in the treatment of MAS.
Twenty newborns with MAS were treated with continually
infused ES for 20 minutes. A significant improvement in
oxygenation occurred after six to 12 hours, especially after
additional surfactant doses. The author recommends further
clinical studies before the routine use of ES for the treatment
of MAS.61.
Pneumonia
Extensive pneumonia may lead to surfactant dysfunction
by an inhibitory process secondary to extensive inflammatory
process and edema that occurs along with the underlying
process, or by abnormal phospholipid and protein fractions
that have been described, associated with a variety of
pathogens, including bacteria, viruses and fungi. 62
Reports of treatment of pneumonia with surfactant in
humans are rare and controlled studies are not available. In
preterm newborns with respiratory failure secondary to
pneumonia, the surfactant proved to be safe,63 with
improvement of hypoxemia in adults.64 Similarly, newborns
infected by Streptococcus group B and treated with
exogenous surfactant showed improvement in oxygenation
one hour after treatment.65
The immunogenicity and modulator activity of
exogenous surfactants also needs to be further investigated
before their routine use in severe pneumonia is allowed.
Congenital diaphragmatic hernia
There is some evidence regarding animal66 and human67
experiments that suggest improved pulmonary function and
oxygenation with the use of exogenous surfactant in cases
of congenital diaphragmatic hernia, with better survival
rates. However, the lack of randomized, controlled studies
with a larger number of patients does not allow us to affirm
that the beneficial effects in the short run mean improvement
of mortality or morbidity rates in the long run. This is mainly
important if we take into consideration that congenital
diaphragmatic hernia is a disease that maintains high
mortality rates despite extreme interventions, such as nitric
oxide therapy and extracorporeal membrane oxygenation.
Jornal de Pediatria - Vol. 78, Supl.2, 2002 S223
Bronchiolitis
Bronchiolitis affects children younger than two years of
age and those outside the neonatal period. It is an infection
chiefly caused by the respiratory syncytial virus. The typical
histopathological finding is injury to terminal alveoli and
bronchioli, involving the alveolocapillary membrane and
pneumocytes, with obstructive lesion on the small airways.
Lesion on pneumocytes type II causes a qualitative
surfactant dysfunction68 that contributes to alveolar collapse
and increased capillary permeability, deteriorating surfactant
dysfunction by inactivation.
Surfactant treatment was proposed because of its
stabilizing action on terminal bronchioli and alveoli and
improvement of gas exchange. In a randomized study, the
use of Curosurf™ showed improved oxygenation, reduction
in the length of mechanical ventilation and reduction in the
length of stay in the ICU.69
Acute respiratory distress syndrome (ARDS)
In 1996, Anzueto et al. conducted a randomized clinical
assay with 725 adult patients with sepsis-induced ARDS to
assess the efficacy of aerosolized surfactant. 70 No
statistically significant difference was observed as to survival
rate 30 days after treatment, length of stay in the ICU, length
of mechanical ventilation or physiological outcome
(oxygenation).
The article written by Anzueto et al.70 was commented
in an editorial by Matthay.71 The possible explanations for
aerosolized surfactant failure in ARDS are:
– The amount of surfactant that reached the peripheral
alveoli was only 5% of the administered dose;
– The synthetic surfactant preparation, Exosurf, does not
contain the protein component. Protein-containing
surfactants may reduce surface tension more quickly
and are more resistant to inhibitors, such as plasma
proteins.
– Another possible reason for surfactant therapeutic failure
is that, in spite of similarities, ARDS and RDS in infants
are fundamentally different. The inflammatory injury
caused by ARDS, which often results in fibrotic
destruction of the lung, might not improve with surfactant
treatment.
– Most patients in Anzueto’s study died of sepsis and
multiple organ failure, not of respiratory insufficiency.
With surfactant therapy, we could not expect deaths of
patients with ARDS to be reduced, due to generalized
infection or dysfunction of organs.
Final considerations
Exogenous surfactant therapy is very effective and
considerably simplified the treatment of newborns with
respiratory distress syndrome. The therapy is effective
because it combines correction of quantitative primary
S224 Jornal de Pediatria - Vol. 78, Supl.2, 2002
deficiency of surfactant (the major cause of respiratory
failure) with a favorable metabolism. In uninjured lungs, a
single dose is sufficient to improve pulmonary function
until the newborn is able to synthesize an adequate amount
of endogenous surfactant. After the establishment of lung
injury, surfactant function deteriorates and the ability of the
premature lung to produce surfactant decreases. Although
surfactant treatment does not seem to reduce the incidence
of bronchopulmonary dysplasia, this finding results in greater
survival of newborns, who would surely die without this
treatment and who are at a greater risk for bronchopulmonary
dysplasia. The interactions between surfactant functions
and ventilator variables are important areas where general
pulmonary response may be improved. The use of adequate
PEEP, low tidal volume, and the avoidance of hyperventilation improve surfactant function and minimize lung
injury. Although surfactants obtained from animal lungs
are comparable in terms of efficacy, they are costly and
nonstandardized. For the future, we should work towards
the development of less expensive and more uniformly
consistent surfactants.
References
1. Von Neergaard K. Neue auffassungen uber einen Grundbergriff
der Atemmechanik. Die retraktion-skraft der lunge, abhangig
von der Oberflachenspannung in den Alveolen. Z Gesamte Exp
Med 1929;66:373.
2. Gruenwald P. Surface tension as a factor in the resistance of
neonatal lungs to aeration. Am J Obstet Gynecol 1947;53:9961001.
3. Avery ME, Mead J. Surface properties in relation to atelectasis
and hyaline membrane disease. Am J Dis Child 1959;97:517-23.
4. Fujiwara T, Maeta H, Chida S, Morita T, Watabe Y, Abe T.
Artificial surfactant therapy in hyaline membrane disease. Lancet
1980;1:55-9.
5. Soll RF, Blanco F. Natural surfactant extract versus synthetic
surfactant for neonatal respiratory distress syndrome [review].
Cochrane Database of Syst Rev 2001;(2):CD000144.
6. Soll RF, Morley CJ. Prophylactic versus selective use of
surfactant in preventing morbidity and mortality in preterm
infants [review]. Cochrane Database of Syst Rev 2001;(2);
CD000511.
7. Soll RF. Multiple versus single dose natural surfactant extract
for severe neonatal respiratory distress syndrome [review].
Cochrane Database of Syst Rev 2000;(2):CD000141.
8. Shelley SA, Paciga JE, Balis JU. Lung surfactant phospholipids
in different animal species. Lipids 1984;19:857-62.
9. Goerke J. Pulmonary surfactant: functions and molecular
composition. Biochim Biophys Acta 1998;1408:79-89.
10. LeVine AM, Kurak KE, Wright JR, Watford WT, Bruno MD,
Ross GF, et al. Surfactant protein A (SP-A) binds group B
streptococcus enhancing phagocytosis and clearance from lungs
of surfactant protein A deficient mice. Am J Respir Cell Mol
Biol 1999;20(2):279-86.
11. Cockshutt AM, Weitz J, Possmeyer F. Pulmonary surfactantassociated protein A enhances the surface activity of lipid extract
surfactant and reverses inhibition by blood proteins in vitro.
Biochemistry 1990;29:8424-9.
Exogenous surfactant therapy... - Rebello CM et alii
12. Nogee LM, Garnier G, Dietz HC, Singer L, Murphy AM,
deMello DE, et al. A mutation in the surfactant protein B gene
responsible for fatal respiratory disease in multiple kindreds. J
Clin Invest 1994;93:1860-3.
13. Nogee LM, DeMello DE, Dehner LP, Colten HR. Deficiency of
pulmonary surfactant protein B in congenital alveolar proteinosis.
N Engl J Med 1993;328:406-10.
14. Suzuki Y, Fujita Y, Kogishi K. Reconstitution of tubular myelin
from synthetic lipids and proteins associated with pig pulmonary
surfactant. Am Rev Respir Dis 1989;140:75-81.
15. Glasser SW, Burhans MS, Korfhagen TR, Sly PD,
Ross GF, Ikegami M, et al. Generation of an SP-C Deficient
mouse by targeted gene inactivation. Am J Respir Crit Care Med
2000;161:A43.
16. Crouch EC. Structure, biologic properties and expression of
surfactant protein D (SP-D). Biochim Biophys Acta 1998;
1408:278-89.
17. Gail DB, Steinkamp H, Massaro D. Interspecies variation in lung
lavage and tissue saturated phosphatidylcholine. Respir Physiol
1978;33:289-97.
18. Pre J, Perret G, Bladier D. Lecithin content estimate of human
alveolar lining layer: comparison with mouse, rat and rabbit.
Comp Biochem Physiol 1983;76A:393-5.
19. Rebello CM, Jobe AH, Eisele JW, Ikegami M. Alveolar and
tissue surfactant pool size in humans. Am J Respir Crit Care Med
1996;154:625-8.
20. Hallman M, Merritt TA, Pohjavuori M, Gluck L. Effect of
surfactant substitution on lung effluent phospholipids turnover,
pool size and the relationship to severity of respiratory failure.
Pediatr Res 1986;20:1228-35.
21. Jobe AH, Ikegami M, Sarton-Miller I. Surfactant metabolism of
newborn lamb lungs in vivo. J Appl Physiol 1980;49:1091-8.
22. Ito Y, Ruud AWV, Yao LJ, MacCaig LA, Bartlett AJ, Lewis JF.
Ventilation strategies affect surfactant aggregate conversion in
acute lung injury. Am J Respir Crit Care Med 1997;155:493-9.
23. Ikegami M, Ikegami M. Surfactant metabolism. Semin Perinatol
1993;17:233-40.
24. Ikegami, M. Surfactant inactivation. In: Boyton BR, Carlo WA,
Jobe AH, editores. New Therapies for Neonatal Respiratory
Failure. New York: Cambridge University Press; 1994.p.36-48.
25. Seeger W, Gunther A, Thede C. Differential sensitivity to
fibrinogen inhibition of SP-C vs SP-B based surfactants. Am J
Physiol 1992;261:L286-91.
26. Yukitake K, Brown CL, Schlueter MA, Clements JA, Hawgood
S. Surfactant apoprotein A modifies the inhibitory effect of
plasma proteins on surfactant activity in vivo. Pediatr Res 1995;
37:21-5.
27. Rebello CM, Ikegami M, Polk DH, Jobe AH. Postnatal lung
responses and surfactant function after fetal or maternal
corticosteroid treatment of preterm lambs. J Appl Physiol 1996;
80:1674-9.
28. Shardonofsky FR, Sato J, Bates JHT. Quasi-static pressurevolume hysteresis in the canine respiratory system in vitro. J
Appl Physiol 1990;68:2230-6.
29. Goldsmith LS, Greenspan JS, Rubenstein SD, Wolfson MR,
Shaffer TH. Immediate improvement in lung volume after
exogenous surfactant: alveolar recruitment versus increased
distention. J Pediatr 1991;119(3):424-8.
30. Alexander J, Milner AD. Lung volume and pulmonary blood
flow measurements following exogenous surfactant. Eur J Pediatr
1995;154:392-7.
31. Hamdan AH, Shaw NJ. Changes in pulmonary artery pressures
during the acute phase of respiratory distress syndrome treated
with three different types of surfactant. Pediatr Pulmonol
1998;25:191-5.
Exogenous surfactant therapy... - Rebello CM et alii
32. 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 RDS
[review]. Cochrane Database of Syst Rev 2002;(2): CD003063.
33. Jobe AH, Ikegami M. Protein permeability abnormalities in the
preterm. In: Effros RM, Chang HK, editores. Lung Biology in
Health & Disease. Fluid and solute transport in the airspaces of
the lung. New York: Mascel Dekker Inc.; 1994.p.335-55.
34. Ikegami M, Adams FH, Towers B, Osher AB. The quantity of
natural surfactant necessary to prevent the respiratory distress
syndrome in premature lambs. Pediatr Res 1980;14:1082-5.
35. King RJ, Clements JA. Surface active materials from dog lung.
II Composition and physiological correlation. Am J Physiol
1972;223:715-9.
36. Fujiwara T. Surfactant replacement in neonatal RDS. In:
Robertson B, Van Golde LMG, Batemburg JJ, editores. Pulmonary
surfactant. Amsterdam: Elsevier Science Publishers; 1984.
p.480-503.
37. Henry MD, Rebello CM, Ikegami M, Jobe AH, Langenback EG,
Davis JM. Ultrasonic nebulized in comparison with instilled
surfactant treatment of preterm lambs. Am J Respir Crit Care
Med 1996;154:366-75.
38. Jobe AH, Ikegami M, Jacobs H, Jones S. Surfactant and pulmonary
blood flow distributions following treatment of premature lambs
with natural surfactant. J Clin Invest 1984;73:848-56.
39. Broadbent R, Fok TF, Dolovich M. Chest position and pulmonary
deposition of surfactant in surfactant depleted rabbits. Arch Dis
Child Fetal Neonatal Ed 1995;72:F84-F89.
40. Zola EM, Gunkel JH, Chan RK, Lim MO, Knox I, Feldman BH,
et al. Comparison of three dosing procedures for administration
of bovine surfactant to neonates with respiratory distress
syndrome. J Pediatr 1993;122:453-9.
41. Raju TNK, Langenberg P. Pulmonary hemorrhage and exogenous
surfactant therapy: a metaanalysis. J Pediatr 1993;123:603-10.
42. Garland J, Buck R, Weinberg M. Pulmonary hemorrhage risk in
infants with a clinically diagnosed patent ductus arteriosus: a
retrospective cohort study. Pediatrics 1994;94:719-23.
43. Hafner D, Germann PG, Hauschke D. Comparison of rSP_C
surfactant with natural and synthetic surfactants after late
treatment in a rat model of acute respiratory distress syndrome.
Br J Pharmacol 1998;124:1083-90.
44. Spragg RG, Smith RM, Harris K, Lewis J, Hafner D, Germann
P. Effect of recombinant SP-C surfactant in a porcine lavage
model of acute lung injury. J Appl Physiol 1999;88:674-81.
45. Beers MF, Fisher AB. Surfactant protein C: a review of its unique
properties and metabolism. Am J Physiol 1992;263: 151-60.
46. Davis AJ, Jobe AH, Hafner D, Ikegami M. Lung function in
premature lambs and rabbits with a recombinant SP-C surfactant.
Am J Respir Crit Care Med 1998;157:553-9.
47. Hafner D, Germann PG. Additive effects of phosphodiesterase4 inhibition on effects of rSP-C surfactant. Am J Respir Crit Care
Med 2000;161(5):1495-500.
48. Hafner D, Germann PG. Dexamethasone enhances the activity of
rSP-C surfactant but not of exosurf in a rat model of the acute
lung injury. J Pharmacol Toxicol Methods 1999;42(1):39-48.
49. Germann PG, Kemkowski J, Hauschke D, Steinhilber W, Hafner
D. Intratracheally applied rSP-C surfactant exhibits no
anaphylactic shock reactions in a guinea pig model of acute lung
hypersensitivity. Exp Toxicol Pathol 1999;51(6):495-505.
50. Walmrath D, De Vaal JB, Bruining HA, Kilian JG, Papazian L,
Hohlfeld J, et al. Treatment of ARDS with a recombinant SP-C
(rSP-C) based synthetic surfactant. Am J Respir Crit Care Med
2000;161:A379.
Jornal de Pediatria - Vol. 78, Supl.2, 2002 S225
51. Cochrane CG, Revak SD. Surfactant lavage treatment in a model
of respiratory distress syndrome. Chest. 1999 Jul;116 Suppl
1:85-86.
52. Cochrane CG, Revak SD, Merritt TA, Heldt GP, Hallman M,
Cunningham MD, et al. The efficacy and safety of KL4-surfactant
in preterm infants with respiratory distress syndrome. Am J
Respir Crit Care Med 1996;153(1):404-10.
53. Krause M, Olsson T, Law AB, Parker RA, Lindstrom DP,
Sundell HW, et al. Effect of volume recruitment on response of
surfactant treatment in rabbits with lung injury. Am J Respir Crit
Care Med 1997;156:862-6.
54. Krause MF, Hoehn T. Enhancement of surfactant effect by a
mechanical volume recruitment maneuver depends on the lungs
preexisting distension. Biol Neonate 1998;73:320-9.
55. Krause MF, Jakel C, Haberstroh J, Schulte-Monting J, Leititis J,
Orlowska-Volk M. Alveolar recruitment promotes homogeneous
surfactant distribution in a piglet model of lung injury. Pediatr
Res 2001;50:34-43.
56. Michna J, Jobe AH, Ikegami M. Positive end-expiratory pressure
preserves surfactant function in preterm lambs. Am J Respir Crit
Care Med 1999;160:634-9.
57. Ogawa A, Brown CL, Schlueter MA, Benson BJ, Clements JA,
Hawgood S. Lung function, surfactant apoprotein content, and
level of PEEP in prematurely delivered rabbits. J Appl Physiol
1994;77:1840-9.
58. Sun B, Cursted T, Song GW, Robertson B. Surfactant improves
lung function and morphology in newborn rabbits with meconium
aspiration. Biol Neonate 1993;63:96-104.
59. Halliday HL, Speer CP, Robertson B. Treatment of severe
meconium aspiration syndrome with porcine surfactant. Eur J
Pediatr 1996;155:1047-51.
60. Lotze A, Mitchell BR, Bulas DI, Zola EM, Shalwitz RA, Gunkel
JH. Multicenter study of surfactant (beractant) use in the treatment
of term infants with severe respiratory failure. J Pediatr
1998;132:40-47.
61. Findlay RD, Taeusch HW, Walter FJ. Surfactant replacement
therapy for meconium aspiration syndrome. Pediatrics
1996;97:48-52.
62. Baughman RP, Sternberg RI, Hull W, Buchsbaum JA Whitsett J.
Decreased surfactant protein A in patients with bacterial
pneumonia. Am Rev Respir Dis 1993;147:653-7.
63. Brehmer U, Jorch G. Surfactant therapy in severe neonatal
respiratory failure – multicenter study III. Surfactant therapy in
41 premature infants under 34 weeks with suspected congenital
infection (case-control analysis). Klin Padiatr 1993;205:78-82.
64. Mikawa K, Maekawa N, Nishina K, Takao Y, Yaku H, Obara H.
Selective intrabronchial instillation of surfactant in a patient
with pneumonia: a preliminary report. Eur Respir J 1993;6:1563-6.
65. Herting E, Gefeller O, Land M, van Sonderen L, Harms K,
Robertson B. Surfactant treatment of neonates with respiratory
failure and group B streptococcal infection. Pediatrics
2000;106(5):957-64.
66. Glick PL, Stannard VA, Leach CL, Rossman J, Hosada Y, Morin
FC, et al. Pathophysiology of congenital diaphragmatic hernia
II: the fetal lamb CDH model is surfactant deficient. J Pediatr
Surg 1992;27:382-8.
67. Glick PL, Stannard VA, Leach CL, Rossman J, Hosada Y, Morin
FC, et al. Pathophysiology of congenital diaphragmatic hernia
III: Exogenous surfactant therapy for the high risk neonate with
CDH. J Pediatr Surg 1992;27:866.
68. Keer MH, Paton JY. Surfactant protein levels in severe respiratory
syncytial virus infection. Am J Respir Crit Care Med 1999;159(4
Pt 1):1115-8.
S226 Jornal de Pediatria - Vol. 78, Supl.2, 2002
69. Luchetti M, Casiraghi G, Valsecchi R, Galassini E, Marraro G.
Porcine-derived surfactant treatment of severe bronchiolitis.
Acta Anaesthesiol Scand 1998;42:805-10.
70. Anzueto A, Baughman RP, Guntupalli KK, Weg JG, Wiedemann
HP, Raventos AA, et al. Aerosolized surfactant in adults with
sepsis-induced acute respiratory distress syndrome. N Engl J
Med 1996;334:1417-21.
71. Matthay MA. The acute respiratory distress syndrome. N Engl J
Med 1996;334:1469-70.
Exogenous surfactant therapy... - Rebello CM et alii
Correspondence:
Dr. Celso M. Rebello
Av. Dr. Enéas de Carvalho Aguiar, 647
CEP 05403-900 – São Paulo, SP, Brazil
Phone: +55 (11) 3066.7360
E-mail: [email protected]