urfactant replacement therapy is an established
effective and safe therapy for immaturity-related surfactant deficiency
[1]. Meta-analysis of randomized controlled trials (RCTs) has confirmed
that natural surfactant administration in preterm infants with RDS
reduces mortality, decreases the incidence of pulmonary air leak (pneumothorax
and pulmonary interstitial emphysema), and lowers the risk of
bronchopulmonary dysplasia (BPD) or death at 28 days of age [2].
Although RDS is characterized by the absence or
reduction of surfactant, there are other neonatal lung disorders in
which inadequate functional surfactant — either by inactivation or
inhibition of synthesis may be a prominent element of the
pathophysiology either by inactivation or inhibition of synthesis. These
include meconium aspiration syndrome (MAS), pulmonary hemorrhage,
pneumonia, congenital diaphragmatic hernia and BPD. The objective of
this review is to critically evaluate the role of surfactant replacement
therapy in neonatal respiratory conditions other than RDS.
Meconium Aspiration Syndrome
The pathophysiology of meconium aspiration syndrome
(MAS) is complex and multifactorial. Constituents of meconium,
especially bile salts, can inactivate surfactant. Inflammatory
mediators, such as cytokines and eicosanoids, can also inhibit
surfactant, as can the protein that leaks into the alveolar spaces [3].
Reduced pulmonary blood flow may cause pulmonary ischemia, with damage
to the type II cells and reduced surfactant production. Airway
obstruction may cause increased resistance and surfactant deficiency.
Parenchymal lung changes may require high ventilator support and
substantial supplemental oxygen, contributing to lung injury. Thus,
surfactant replacement to break this vicious cycle is an attractive
option. Two approaches have been attempted: surfactant replacement and
surfactant lavage.
Surfactant Replacement
Evidence
In a meta-analysis of four trials (n=326) [4],
surfactant replacement by bolus or slow infusion in infants with severe
MAS had no statistically significant effect on mortality [typical risk
ratio (RR) 0.98, 95% CI 0.41 to 2.39]. The risk of requiring
extracorporeal membrane oxygenation (ECMO) was significantly reduced in
a meta-analysis of two trials (n=208); [typical RR 0.64, 95% CI
0.46 to 0.9]. Findlay, et al. [5], in a trial of 40 term
neonates, reported a statistically significant reduction in the length
of hospital stay (mean difference -8 days, 95% CI -14 to -3 days). There
was no statistically significant reduction in duration of assisted
ventilation, duration of supplemental oxygen, air leaks, chronic lung
disease, need for oxygen at discharge or intraventricular hemorrhage.
Another meta-analysis incorporated eight RCTs of surfactant for MAS with
a total of 512 patients [6]. It reported that surfactant significantly
treatment reduced oxygenation index, increased arterial oxygen/alveolar
oxygen ratio, shortened hospitalization days and decreased mortality
rate. There was no statistical difference in the durations of mechanical
ventilation and oxygen therapy, and the incidences of air leaks,
pulmonary hemorrhage and intracranial hemorrhage between the two groups.
Surfactant Lavage
An alternative approach to treatment of MAS is the
technique of lung lavage. This takes advantage of the detergent-like
property of pulmonary surfactant, in which meconium might be solubilized
and literally "washed" from the lung. Thus, in addition to replenishing
the lung with functional surfactant, lavage might theoretically remove
particulate meconium and prevent some of the pathophysiology attributed
to obstruction and toxicity [7]. Surfactant lavage has been performed in
several animal and human studies, with an optimal total lavage fluid
volume of 15 to 30 mL/kg [8-12]. The surfactant was diluted in these
studies in physiological saline to obtain a final phospholipid
concentration of 5 mg/mL [13].
Evidence
In a recent meta-analysis of surfactant lavage, lung
lavage with diluted surfactant was shown to be beneficial to infants
with MAS in terms of reduction in composite outcome of death or use of
ECMO (RR 0.33, 95% CI 0.11 to 0.96; n=88) [14]. Additional
controlled clinical trials of lavage therapy should be conducted to
confirm this effect, to refine the method of lavage, and to compare
lavage with other approaches including surfactant bolus therapy [14]. In
a study of newborn lambs with respiratory failure and pulmonary
hypertension induced by MAS, gas exchange and lung compliance were
improved by lung lavage with dilute surfactant but not by bolus
treatment [15]. Till further robust evidence is available, lung lavage
with surfactant in MAS should be considered as an experimental therapy.
In infants with MAS, if ECMO is not available, surfactant administration
may reduce the severity of respiratory illness, mortality and decrease
the number of infants with progressive respiratory failure requiring
support with ECMO.
Recent Developments
Henn, et al. [16] assessed the effect of
surfactant administration in 21 newborn pigs, preceded or not by
bronchoalveolar lavage (BAL) with dilute surfactant, on pulmonary
function in experimental severe MAS. BAL with dilute surfactant,
followed by an additional dose of surfactant, produced significant
improvements in arterial blood gases and pulmonary mechanics as compared
with a single dose of surfactant.
A synthetic surfactant (CHF5633), containing SP-B and
SP-C analogs, was tested in 26 newborn pigs for resistance to meconium
inactivation in comparison to poractant alfa.
Surfactant was inactivated in both groups 6 hours
after meconium instillation, but CHF5633 was more resistant than
poractant alfa in terms of lipid peroxidation. This study indicates that
CHF5633 may be as efficient as poractant alfa in experimental MAS [17].
In a recent study by Mikolka, et al. [18],
budesonide was added into surfactant preparation curosurf to enhance
efficacy of the surfactant therapy in experimental model of MAS.
Combined therapy improved gas exchange, and showed a longer-lasting
effect than surfactant-only therapy. In conclusion, budesonide
additionally improved the effects of exogenous surfactant in
experimental MAS.
Pneumonia
Surfactant inactivation may be associated with
pneumonia [19,20]. Facco, et al. [21] studied kinetics
of surfactant’s major component, disaturated-phosphatidylcholine (DSPC),
in neonatal pneumonia and concluded that DSPC half-life and pool size
were markedly impaired in neonatal pneumonia, and that they inversely
correlated with the degree of respiratory failure. In a small randomized
trial of surfactant rescue therapy, the subgroup of infants with sepsis
showed improved oxygenation and a reduced need for ECMO compared with a
similar group of control infants [19]. Newborn infants with pneumonia or
sepsis receiving rescue surfactant also demonstrated improved gas
exchange compared with infants without surfactant treatment [20].
Pulmonary Hemorrhage
Experimental data suggest that the molecular
components involved in pulmonary haemorrhage can biophysically
inactivate endogenous lung surfactant, and exogenous surfactant
replacement may be capable of reversing this process even in the
continued presence of inhibitor molecules [22,23].
Evidence
In two clinical studies, the mean oxygenation index
improved in preterm and term infants who received surfactant following
clinically significant pulmonary hemorrhage, with no clinical
deterioration in any patient [24,25]. Case reports have also described
the successful use of surfactant treatment after idiopathic [26] or
iatrogenic [27] pulmonary hemorrhage. However, a recent systematic
review [28] found no randomized or quasi-randomized trials evaluating
the effects of surfactant in pulmonary hemorrhage in neonates,
suggesting the need for such trials.
Recent Developments
A recent study evaluated the impact of surfactant
upon in-vitro clot formation in order to assess the role of
surfactant in the pathogenesis of pulmonary haemorrhage. The presence of
surfactant impairs coagulation in vitro hence conferring greater
risk of pulmonary haemorrhage in extremely preterm infants [29]. Bozdađ,
et al. [30], in an RCT compared efficacy of two natural
surfactants (poractant alfa and beractant) for pulmonary haemorrhage in
42 very low-birth-weight (VLBW) infants. They concluded that both
natural surfactants improved oxygenation, and the type of surfactant did
not seem to have any effect on BPD and mortality rates in these
patients.
Congenital Diaphragmatic Hernia (CDH)
Pulmonary hypoplasia and pulmonary hypertension are
the hallmarks of CDH, but morphologic and biochemical immaturity of the
lung have also been noted, and exogenous surfactant as adjuvant
treatment for the severe respiratory distress associated with this
disease is an attractive concept. Data from human studies in CDH are
conflicting. In human fetuses with CDH, amniotic fluid lecithin to
sphingomyelin (L/S) ratios and phosphatidylglycerol (PG) levels have
been inconsistent; some investigators have found normal values and
others document values suggestive of lung immaturity [31-35]. Moreover,
surfactant phosphatidylcholine synthesis and pool size do not appear to
be altered by CDH, although turnover of phosphatidylcholine is faster in
CDH, possibly due to increased catabolism and/or recycling [36]. Of the
few studies that have examined surfactant proteins (SP) expression in
CDH, data are available only for SP-A. The concentration of SP-A in
tracheal aspirates of infants with CDH has been shown to be either
unchanged [37] or reduced [38] by CDH.
Evidence
There have been no multicenter randomized trials of
surfactant for respiratory failure due to CDH. In two retrospective
analyses of patients in the CDH Study Group, surfactant treatment did
not improve outcomes [39], and was associated with increased ECMO use, a
higher incidence of chronic lung disease, and lower survival [40]. In
preterm infants with CDH, the usage of surfactant was associated with a
lower survival rate [41].
Recent Developments
Janssen, et al. [42] studied endogenous
surfactant metabolism in the most severe CDH patients who required ECMO.
These patients have a decreased surfactant phosphatidylcholine synthesis
that may be part of the pathogenesis of severe pulmonary insufficiency
and has a negative impact on weaning from ECMO. Cogo, et al. [43]
measured DSPC and SP-B concentration in tracheal aspirates and their
synthesis rate in infants with CDH compared to infants without lung
disease. Infants with CDH had a lower rate of synthesis of SP-B and less
SP-B in tracheal aspirates. In these infants, partial SP-B deficiency
could contribute to the severity of respiratory failure and its
correction might represent a therapeutic goal [43].
Bronchopulmonary Dysplasia (BPD)
BPD describes the end product of a multitude of
injuries and exposures to the preterm lung occurring prenatally,
perinatally, and postnatally. The etiology of BPD is multifactorial, and
involves derangements in multiple aspects of lung function (for example,
surfactant production), repair from injury (for example, elastin
deposition), and growth and development (for example, alveologenesis).
These derangements of normal development are likely mediated, in part,
by chronic inflammation that develops in the immature lung exposed to
repetitive ventilator stretch with oxygen-enriched gas, often
complicated by infection [44]. Surfactant dysfunction (defined as
elevation in the values of minimum surface tension in vitro)
occurs in a high proportion (43-76%) of preterm infants who remain
intubated and ventilated at 1-2 weeks of age [45-47]. Infants are twice
as likely to develop surfactant dysfunction during episodes of
respiratory deterioration or infection, and higher minimum surface
tension is directly correlated with an index of lung disease severity
[45,46]. In these ventilated preterm infants, elevated minimum surface
tension as measured in tracheal aspirates was associated with altered
lipid composition, lower total protein in the surfactant fraction, and
markedly lower content of surfactant proteins B and C. SP-B content had
the strongest correlation with surface tension and was inversely related
[45]. Similar findings relating SP-B content to surfactant dysfunction
have been described in acute lung injury, thereby supporting the
validity of using SP-B content as an indicator of surfactant function
[48]. Heavy isotope labeling studies of intubated infants with BPD have
demonstrated altered surfactant phospholipid pools and reduced recycling
of alveolar surfactant phospholipids [49,50].
Evidence
There is limited data evaluating late surfactant
therapy for premature infants who require continuing ventilatory support
beyond one week of life. Pandit, et al. [51] found that FiO
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