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.

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.

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.

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].

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.

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.

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].

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].

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.

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]. Bozdað, 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.

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.

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].

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].

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].

An ongoing trial multi-center, blinded, randomized controlled clinical trial (NCT01022580) aims to evaluate the effects of booster doses of exogenous surfactant in addition to iNO on the outcome of survival without BPD at post-menstrual age of 36 weeks in extremely low gestational age infants.

Evidence demonstrating the utility of surfactant replacement therapry across the varied spectrum of neonatal respiratory disorders other than RDS exists, but there still remains a paucity of high-quality RCTs to recommend routine incorporation into clinical practice. Considering the evidence in support of surfactant replacement therapry as an effective management strategy in infants with MAS, large multicentric trials comparing bolus route and lung lavage route should be conducted. The outcomes should include short- and long-term clinical outcomes and any adverse effects. In addition, future studies should focus on carefully designed RCTs of surfactant replacement therapy in term or late preterm infants with proven bacterial pneumonia. In addition, experimental studies exploring the pharmacokinetics, optimal dose and dosing interval, concentration, method of delivery and duration of treatment regimen in each of these conditions are needed to further optimize neonatal outcomes.

Contributors: BJ: Literature search, Initial draft and final draft; NSK and RN: Literature search and manuscript writing.

Funding: None; Competing interests: None stated.

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