Pulmonary surfactant is a fundamental substance in the mechanics
of the pulmonary system. It is found in all species that breathe
through lungs and, when absent, the fluid found between alveoli
and air increases surface tension, which exerts a collapsing force
over the alveoli. Surfactant creates an interface between water
molecules and the alveolar surface, reduces surface tension so
that it approaches zero at the end of expiration when the alveolar
surface is reduced, and, thus, avoids atelectasis.
In 1959, surfactant deficiency was shown to cause hyaline membrane
disease, also called respiratory distress syndrome (RDS) of the
Many attempts, unsuccessful at first, were made to produce exogenous
surfactants capable of replacing the endogenous production.
In 1972, Enhorning and Robertson started working with surfactant
extracts collected from adult rabbits and administered to premature
rabbit offspring. They demonstrated that surfactant improved the
pulmonary mechanical behavior of those animals (
After Fujiwara et al. (
published the first promising results of surfactant replacement
in RDS, this therapy has become a routine practice in premature
newborn units, and has completely changed the natural history
of this syndrome. Concurrently, great interest was directed to
a number of other potential uses of this therapy for other syndromes
and diseases associated with surfactant dysfunction.
During the 1980s, several studies confirmed the efficacy of both
natural and synthetic surfactants in the treatment and prevention
of RDS (
The main case-control studies investigating the prophylactic or
therapeutic use of surfactants were reviewed in two meta-analyses
They summarized the evident beneficial effects of surfactant therapy
on the natural clinical outcome of RDS. The most remarkable effects
were a reduction in mortality and in the occurrence of pneumothorax
and interstitial pulmonary emphysema.
Several commercial preparations became available for clinical
use in the beginning of the 1990s. Administration of surfactant
in RDS has become one of the main interventions conducted in neonatal
In the RDS of the newborn (NB), impairment of the surfactant
system is primarily caused by lack of endogenous production due
to lung immaturity. However, in other respiratory pathologies
found in preterm or term newborns, as well as in older children
and adults, there may be a reduction in surfactant function primarily
caused by the presence of several inhibiting substances in the
terminal airways. This reduction in surfactant function contributes
to the respiratory failure associated with the primary disease.
Several studies with experimental models or human subjects have
attempted to define the role of exogenous surfactant therapy in
these conditions, particularly in severe viral bronchiolitis,
meconium aspiration syndrome, bronchopneumonia, and acute respiratory
distress syndrome (ARDS). In spite of these attempts, precise
indications, real benefits, costs and administration modes are
still poorly defined.
Use of surfactant in the
The indication of surfactant therapy is unquestionable
when there is a diagnosis of hyaline membrane disease, or RDS
of the newborn (
In such cases, the difficulty lies in identifying the patients
that will require this therapy so that its use can be initiated
as early as possible.
The drug is usually administered in one 100mg/kg
dose, although a few studies recommend a different dosage. The
administration of an initial 200mg/kg dose - the estimated pool
of endogenous surfactant in the NB - of porcine surfactant (Curosurf@)
has been the object of studies, and results have shown some positive
effects in comparison with the usual dosage (
Additional 100 mg/kg doses may be administered if necessary.
The response to surfactant therapy may be affected
(reduced) because of other associated pathologies (persistent
pulmonary hypertension, pulmonary edema, meconium aspiration,
etc.), surfactant distribution, surfactant composition, management
of mechanical ventilation, or the moment when the therapy is administered.
This last variable has been the focus of the most important randomized
trials that have been conducted since 1992.
Surfactant therapy is generally indicated for preterm
newborns with an established diagnosis of RDS (therapeutic use),
or for patients at a very high risk of developing this syndrome
(prophylactic use). The therapeutic use of surfactant presupposes
a previous RDS diagnosis. The diagnosis is made, in practical
terms, by identification of clinical signs, progression of the
disease, and radiographic findings compatible with the syndrome.
As atelectasis is progressive in this syndrome, it often takes
some time for the diagnosis to be clearly defined. Radiographic
signs often become evident only when the syndrome has already
advanced significantly. Surfactant is, thus, only administered
when the clinical diagnosis is made.
The main advantage of the therapeutic approach is
that practically only newborns that actually require surfactant
are treated. However, when criteria to establish a diagnosis are
less stringent, more incorrect diagnoses are made and, therefore,
more unnecessary treatments are administered. This is the treatment
mode most frequently used for near-term newborns, for whom the
risk of lung immaturity and death are lower.
The other surfactant administration mode is prophylactic.
This mode was suggested by experimental trials with animals that
revealed that immature, surfactant-deficient lungs acquired very
early pulmonary lesions secondary to ventilation (
Moreover, surfactant has been shown to distribute more evenly
when instilled in the airways right after birth, when the lungs
are still full of fluid ( ).
Prophylaxis has been used right after birth, before
the first ventilation or initial stabilization, and only minutes
after birth. If the purpose is to avoid lesions caused by surfactant
deficiency in newborns with lung immaturity, medication should
ideally be administered even before the first inspiration. However,
it has been suggested that immediate prophylaxis is not evidently
more beneficial than prophylaxis within 30 minutes of birth (
Another problem associated with the immediate use of surfactant,
that is, before the first inspiration, is that this procedure
may complicate the initial stabilization of the patient.
The high incidence of surfactant deficiency in very
immature newborns - less than 30 weeks' gestational age at birth,
for example - seems to justify a prophylactic approach to surfactant
use. When this preventive mode of administration is adopted, however,
many patients are unnecessarily treated and submitted to an invasive,
expensive procedure that has potential risks and undoubtedly causes
Several multi-center randomized clinical trials
have compared the prophylactic and therapeutic approaches (
In these studies, newborns less than 30 weeks' gestational age
at birth (6 studies) or less than 32 weeks (1 study) were randomly
chosen to receive either a prophylactic dose of surfactant or
surfactant therapy after a diagnosis was established.
Most of these studies reported improvement in respiratory
function and reduction in the incidence of RDS when the prophylactic
approach was adopted. A meta-analysis conducted by Sol and Morley
showed a reduction in the incidence of pneumothorax, pulmonary
interstitial emphysema, mortality, and the combination of death
and bronchopulmonary dysplasia; no complications were reported
with the use of prophylactic therapy (
Such strong evidence suggests that, of these two therapeutic approaches,
prophylaxis with surfactant is indicated for preterm newborns
less than 30 weeks' gestational age at birth (some other researchers
suggest 28 weeks). Patients that need intubation and mechanical
ventilation immediately after birth are probably the ones that
benefit the most from this procedure. In cases of surfactant deficiency,
there is evidence of lesions secondary to positive pressure ventilation
after only a few minutes ( ).
Waiting longer and delaying surfactant administration seems to
be an inappropriate choice. However, it is unclear whether patients
that are born well, with effective natural ventilation, even if
at less than 30 weeks' gestational age, should receive the same
treatment. The prophylactic medication for preterm newborns without
early signs of severe disease, and for whom there is a significant
lower incidence of RDS, may not bring significant benefits. No
clinical studies have used any criterion other than gestational
age to investigate prophylactic treatment.
However, prophylaxis, or very early treatment, with
exogenous surfactant should ideally be administered upon confirmation
of surfactant deficiency. The chance of obtaining an accurate
diagnosis, available either before or right after birth, should
benefit patients at risk of developing RDS. However, 100% accurate
tests for this purpose are not available. A logical approach for
preterms born at 30 or 32 weeks' gestational age would be the
use of a test with a close to 100% sensitivity, so that no, or
practically no, patient that would eventually develop RDS would
fail to receive surfactant as early as possible. If such test
had a good specificity, it would significantly reduce the number
of patients iatrogenically treated with surfactant .
The therapeutic approach in a group of patients
with high prevalence of the disease does not make any sense if
no test is available to identify RDS accurately right after birth.
Perhaps the only justifiable reason for a therapeutic approach
in patients born at less than 30 weeks' gestational age would
be cost reduction. Such cost reduction would be less significant
if the decision to adopt this approach were based on test results.
The analysis of these concepts has given rise to
renewed interest in older rapid tests to determine surfactant
function by means of examination of the amniotic fluid and the
newborn's tracheal or gastric aspirates (
Of these tests, the stable microbubble test (SMT) seems to be
the most promising as its sensitivity and specificity are good
Its performance takes less than 10 minutes, and the basic equipment
required is a common microscope and a slide graduated in millimeters.
Besides SMT, another test, the lamellar body count,
has been evaluated. Lamellar bodies are corpuscles containing
endogenous surfactant. The purpose of this test is the same -
to take only a few minutes to screen patients for very early use
of surfactant. This test can be performed in blood cell analyzers
available in clinical laboratories. A meta-analysis study has
shown that this test results are similar or even better than results
of tests that measure the lecithin/sphyngomyelin ratio (
It is likely that SMT and/or lamellar body counts
will soon become widely used in delivery rooms and/or neonatal
intensive care units to help decide about the use of exogenous
While the efficacy of exogenous surfactant is well
established in the treatment of RDS of the newborn, the role of
this therapy is still unclear in other diseases or syndromes in
which surfactant function is impaired.
The evaluation of therapy results in the NB is complicated
because the differential diagnosis of pulmonary disease may be
difficult to establish in some situations. Quantitative surfactant
deficiency may accompany and even be part of the pathophysiology
of some clinical entities that are not routinely associated with
surfactant deficiency. An example of such a situation is the case
of respiratory problems in term or near-term newborns with a clinical
and radiological diagnosis of transient tachypnea of the newborn
(TTN) or meconium aspiration syndrome (MAS). Low levels of phosphatidylglycerol
have been found in tracheal aspirates (
and in amniotic fluid ( )
in TTN, and low surfactant protein levels in MAS ( ).
Therefore, it may be difficult to know whether a positive response
to surfactant therapy is due to resolution of inhibition, by quantitative
replacement for the syndrome under treatment, or to an associated
RDS that cannot be easily ruled out.
Surfactant use has been investigated for use in
MAS, one of the main clinical syndromes of the newborn. Meconium
is a potent surfactant inhibitor. Therefore, it is logical to
consider surfactant replacement in severe MAS.
Sun et al. (
treated term newborn rabbits with exogenous porcine surfactant
(200 mm/kg) after induced meconium aspiration, and reported improved
oxygenation and lung compliance. There was a decrease in the mean
airway pressure necessary for adequate oxygenation.
conducted a multicenter study with a population of 328 term newborns
(who have MAS more often than preterms) with severe respiratory
failure. The pathology described was compatible with MAS in a
high percentage of the patients, and no reduction in complications
was observed after surfactant treatment, although the percentage
of patients that needed extracorporeal membrane oxygenation (ECMO)
Some non-randomized studies have shown a slight
improvement in oxygenation for most newborns with respiratory
failure due to meconium aspiration who were treated with surfactant
Findlay et al. ( )
conducted a randomized study and reported better oxygenation,
lower incidence of pneumothorax, faster control of persistent
lung hypertension, and less need of ECMO in newborns that received
up to four 15-mg/kg doses of surfactant administered in about
20 minutes every 6 hours.
A meta-analysis conducted by Soll and Dargaville
revealed that surfactant administration reduces the need of ECMO
for newborns with MAS and moderate to severe respiratory failure
Lung lavage with diluted surfactants is another
form, still experimental, of use of this medication. This technique
seems to be more efficient in increasing the removal of substances
such as meconium than pure saline solution, and to reduce the
effect of surfactant removal from the lungs caused by saline solution.
This therapeutic mode has been studied in animal models of meconium
aspiration syndrome (
and acute respiratory distress syndrome ( ),
and its effects seem to be positive. Lam and Yeung published results
of a preliminary study that revealed a significant improvement
in the lung function of six newborns with severe MAS treated with
tracheobronchial lavage with 15 ml/kg diluted surfactant (5mg/100
ml saline solution) administered in 2 ml aliquots ( ).
Wiswell et al. ( )
have more recently published results of a multicenter randomized
study with 15 newborns with severe MAS treated with artificial
surfactant bronchoalveolar lavage, and 7 control patients treated
according to standard care. They reported positive trends, though
not statistically significant, for treated newborns to be weaned
from mechanical ventilation earlier and to have better oxygenation
These results demonstrate a clear need for further
studies to accurately define indications and adequate administration
modes of surfactant in newborns with severe meconium aspiration.
New surfactants with protein preservation or the addition of molecules
that may block or minimize surfactant-inhibiting activity may
determine a significant improvement in the prognosis of severe
Pneumonia and sepsis affect surfactant function
in different ways - the damage to the alveolocapillary barrier
permits the flooding of the alveoli with plasma proteins and other
blood products that are well-known inhibitors of surfactant activity
Lesions to type II cells impair the production and secretion of
surfactant, and phospholipases secreted by bacteria are also capable
of inhibiting the reduction in surface tension ( ).
Clinical experience in using exogenous surfactants
in pneumonia of the newborn is still limited. Many times the patients
are premature, and RDS may also be present. The radiographic patterns
for Streptococcus agalactie pneumonia may be very similar
to those for RDS. Some studies with a small number of patients
have shown an improvement in oxygenation ( ),
and a reduction in airway mean pressure and in the need for oxygenation
in treated newborns ( ).
More recently, the role of surfactant proteins A and D, which
are not found in surfactants commercially available, has become
evident in the defense against infection. The addition of these
proteins to exogenous surfactants, as well as their use to carry
specific antibodies into the lungs, may well become an important
advancement in the treatment of neonatal pneumonia in the near
Surfactant therapy has also been studied for other
neonatal clinical entities, such as pulmonary hypoplasia and diaphragmatic
hernia. Some positive, though transient, effects have been reported.
Further studies should be conducted for an objective evaluation
of this therapy in these cases.
Summing up, surfactant therapy of the newborn for
conditions other than RDS is still controversial, and questions
about its use even in RDS remain to be answered. It is important,
moreover, to point out that RDS also occurs in patients born at
37 or 38 weeks' gestational age. Therefore, the fact that the
patient was a term newborn does not rule out this diagnosis.
Surfactant therapy should, thus, be considered for
newborns with severe respiratory failure on the first days of
life even if the diagnosis is not RDS. Clinical results are many
times surprising. One of the main problems for the indication
of surfactant therapy in these cases is the cost of the medication,
but it should be kept in mind that other expensive therapies,
such as nitric oxide, might be avoided if surfactant is used.
Moreover, surfactant therapy is generally very safe.
Use of surfactant after the neonatal period
Changes in the surfactant system can be observed
in pediatric as well as adult patients in several situations.
Inhibition is the most common cause of these changes, but a decrease
in production may also occur in certain situations. One of the
greatest difficulties in the study of potential indications of
surfactant therapy is the high cost of this medication. Such costs
are directly proportional to the patient's weight.
Positive clinical responses have been reported for
patients with respiratory failure due to different etiologies
at times other than the neonatal period. However, the experience
in using surfactant in such situations is still limited. The expectation
remains that new products, more resistant to inhibition, may be
developed in the coming years, and bring about better results.
Severe viral bronchiolitis
Severe viral bronchiolitis is the most frequent
lung infection in infants, and is caused by the respiratory syncytial
virus in 70-80% of the cases.
Clinical progression is usually benign, but this
disease may lead to hospitalization in some special situations.
A number of patients will develop severe acute respiratory failure,
have to be hospitalized in pediatric intensive care units, and
require invasive ventilation. Patients more susceptible to severe
clinical conditions are those that have bronchopulmonary dysplasia.
Lesions of the type II pneumocyte lead to a qualitative
surfactant dysfunction, which contributes to alveolar collapse
and an increase in capillary permeability, thus further impairing,
by inactivation, surfactant functional activity (
Surfactant therapy in this disease has been proposed
because of its potential to stabilize terminal bronchioles and
alveoli and to improve gas exchanges.
Lucchetti et al. (2
and in ventilator parameters, and a reduction in length of time
of invasive ventilation support and hospitalization.
conducted a randomized study with infants with acute viral bronchiolitis,
and showed an improvement in oxygenation, decrease in PaCO
Vitola et al. (2 of 60-80 mmHg. The use of surfactant
(Exosurf Glaxo - 50 mmHg) was followed by an improvement in ventilation
and a reduction in the parameters used for that patient.
have described the use of surfactant in a patient with severe
acute viral bronchiolitis who needed high ventilation parameters
to keep a PaO
Data in the literature are scarce but promising
in terms of the use of surfactants for severe bronchiolitis as
an adjuvant therapy, particularly in chronic pneumopathy, such
as in patients with bronchopulmonary dysplasia.
The pathogenic activity of viruses, bacteria and
fungi may cause abnormalities in the different fractions - proteins
and phospholipids - that compose surfactant. Also, a reduction
in surfactant production may be observed in the presence of inflammation
and intense edema of the lower airways.
Improvement in hypoxemia in adults has been reported
as well as in newborns with severe pulmonary conditions caused
by group B Streptococci. ( ).
Data are still not enough to justify any indication of surfactant
therapy in this disease.
Acute Respiratory Distress Syndrome (ARDS)
Ranieri and Slutsky have provided classical descriptions
of lesions caused by mechanical ventilation, such as the increase
in epithelial and endothelial pulmonary permeability and the consequent
change in surfactant production.
Several studies with bronchoalveolar lavage have
demonstrated quantitative changes in alveolar surfactant in ARDS.
Plasma proteins that migrate into the alveoli also inactivate
surfactant. Surfactant will thus undergo inhibition or change
its optimal structural composition - changes in phospholipids
or proteins - due to the action of inflammatory mediators that
are knowingly present in ARDS. Surfactant will be incorporated
into the hyaline membrane, and there will be changes in the synthesis
and release of surfactant due to lesions in type II pneumocytes.
In 1996, Anzueto et al. (
published a randomized controlled study with 725 patients with
ARDS who were administered aerosolized surfactant. They reported
no improvement in gas exchanges (oxygenation) or in survival.
The aerosolized form of surfactant administration adopted in their
study was criticized because only 5% of the administered dose
reaches the alveoli in this administration form.
Lopez-Herce, in 1999 (
published results of a study with 20 children (13 with ARDS and
7 with cardiopathy) and reported a significant improvement in
the PaO2/FiO2 ratio in the oxygenation index after surfactant
use in 10 of the 13 patients with ARDS. The same effect was not
observed for patients with cardiopathies. Those authors discussed
the possible beneficial effects of early use and of tracheal instillation
of the medication.
Willson and Zaritsky, in 1999 (
studied 42 children with ARDS, 21 treated with surfactant and
21 controls. They used one dose of exogenous surfactant and obtained
an improvement in the oxygenation and ventilation indices in the
group of children treated with surfactant. This group needed ventilation
support for 4.2 days less than controls, and were weaned earlier.
Mortality rate was 11.9%.
Data in the literature about adult patients favors
the use of surfactant as there were fewer patients with negative
Commercial Surfactants Available
Several surfactants are offered for clinical use
worldwide. Surfactants commercialized in more recent years in
Brazil are made from porcine lung extract (Curosurf®), bovine
lung extract (Survanta®), bovine lung lavage (Alveofact®),
or are synthetic surfactants (Exosurf®). The first three contain
surfactant proteins B and C, but proteins A and D are eliminated
during the preparation process. The synthetic surfactant contains
associated proteins. All are efficient in the treatment of RDS,
but natural surfactants have been shown to be more advantageous
than synthetic ones. Soll and Blanco conducted an updated review
of the efficiency of these two types of surfactants. They concluded
that patients treated with natural surfactants have a faster improvement
of ventilation parameters, less air escape, and lower mortality
The studies reviewed reported a higher incidence of ventricular
hemorrhage, but not when only the most severe hemorrhages were
taken into consideration. Those authors suggested that natural
surfactants are better than synthetic ones in the treatment of
Several attempts to improve synthetic surfactants
have been made by the addition of surfactant proteins, and a change
in results may be seen in a few years. Table 1 shows the characteristics
of the most common surfactants found in Brazil.
Surfactants are administered through an endotracheal
tube, which must be adequately positioned. The medication is instilled
in one or more aliquots, with the patient in supine position or
in different positions, according to recommendations provided
by each laboratory. The increase in the number of aliquots may
not make much difference (
but the recommendations follow protocols that were used for testing
each product. However, some commercial surfactants are too diluted,
and the administration in one single aliquot may temporarily impair
ventilation. Surfactants may be administered through a line passed
through the endotracheal tube or directly into the endotracheal
tube, and there does not seem to be any difference between these
urfactant should be warmed before administration
by holding its container between the hands. The endotracheal tube
should be disconnected from the respirator, and the instillation
should be fast, accomplished in less than 30 seconds; the patient
should be immediately reconnected to the respirator. It may also
be administered through systems for which there is no possibility
of disconnection. Heart beat and transcutaneous saturation should
be monitored during the procedure. Aspiration of the endotracheal
tube should be avoided in the first six hours after administration.
Ventilation parameters and oxygen inspiratory fraction should
be adjusted according to the changes observed immediately after
Administration by means of nebulization has been
attempted in some occasions, and has shown to have some beneficial
effects in studies with animals. However, no aerosolized administration
mode has been shown to be a good alternative for the administration
through instillation, although its main benefit would be to avoid
tracheal intubation (
Table 1 -
Characteristics of surfactants currently available in the Brazilian
Other aspects, such as ventilation techniques and
alveolar recruiting, in conjunction with surfactant therapy, may
also have an impact in the results of this therapy.
Exogenous surfactant therapy should be further investigated,
even for its use in RDS. In current clinical practice, meconium
aspiration and respiratory failure are indications for the possible
use of exogenous surfactant, especially in the first two days
of life. After the first days of life, indications are not as
Surfactants may still be improved, particularly
to resist inhibition, and other forms of uses in diseases other
than RDS should be developed. This topic seems extremely promising
as a research field.