Pulmonary alveoli are bubble shaped, with a high degree of curvature. The attraction between the molecules in the alveolar fluid of the moist inner surface of the alveoli generates surface tension and tends to make the alveoli collapse. Unchecked, this tendency would result in lung collapse. Surfactant greatly reduces the surface tension at the air–liquid interface in the alveoli and distal bronchioles. This prevents the alveoli from collapsing during expiration and promotes lung expansion during inspiration.

The main component responsible for decreasing the surface tension is DPPC. However it adsorbs very slowly to air–liquid interfaces and therefore requires surfactant proteins or other lipids to facilitate its adsorption. SP-B and SP-C enhance spreading of phospholipid in the airspaces. SP-B promotes phospholipid adsorption and induces the insertion of phospholipids into the monolayer, thus enhancing the formation of a stable surface film (Creuwels et al. 1997). SP-C enhances phospholipid adsorption, stimulates the insertion of phospholipids out of the subphase into the air–liquid interface, and may increase the resistance of surfactant to inhibition by serum proteins or by edema fluid (Creuwels et al. 1997; Griese 1999).

As the alveolar surface expands during inspiration, surfactant components insert from the hypophase (epithelial lining fluid) into the monolayer. At expiration the alveolar surface reduces and the monolayer is compressed, thereby squeezing out some surfactant proteins, unsaturated PC, and other lipids. By this mechanism, the monolayer comprises mainly of DPPC, the most important surface-tension-lowering component during compression (Zimmermann et al. 2005).

Surfactant also has a role in pulmonary host defense. SP-A and SP-D may play important roles in the defense against inhaled pathogens, and SP-A may have a regulatory function in the formation of the monolayer that lowers the surface tension (Creuwels et al. 1997).

The preterm infant with respiratory distress syndrome (RDS) has immaturity of the lungs, especially of the type II cells, and decreased synthesis of surfactant. This results in low amounts of surfactant in the alveoli (surfactant pool size of 2–10 mg/kg) (Zimmermann et al. 2005) that contains a lower percent of disaturated phosphatidylcholine species, less phosphatidylglycerol, and less of all the surfactant proteins than surfactant from a mature lung. Minimal surface tensions are also higher for surfactant from preterm than term infants (Nkadi et al. 2009). However, preterm infants may have increased recycling of surfactant when compared to term infants (Zimmermann et al. 2005).

Shortly after birth, infants with RDS develop tachypnea, grunting, nasal flaring, use of accessory muscles of respiration, intercostal or subcostal retractions, cyanosis, poor feeding, and apnea. A chest radiograph typically shows a diffuse reticulogranular “ground glass” opacification (the result of diffuse alveolar atelectasis) with superimposed air bronchograms (Nkadi et al. 2009). The lungs of infants who die from RDS show alveolar atelectasis, alveolar and interstitial edema, and diffuse hyaline membranes in distorted small airways (Nkadi et al. 2009). RDS is one of the most common causes of death and morbidity in preterm neonates. It occurs worldwide with a slight male predominance (Nkadi et al. 2009). Prenatal corticosteroids significantly reduce the incidence, severity, and mortality associated with RDS.

Surfactant dysfunction can develop secondary to a variety of other conditions that result in lung injury in neonates, such as meconium aspiration syndrome, pulmonary hemorrhage, and pneumonia.

In meconium aspiration syndrome, the mechanisms underlying surfactant inactivation are not fully understood, but it has been shown that meconium destroys the fibrillary structure of surfactant and decreases its surface adsorption rate (Nkadi et al. 2009). In vitro studies (Moses et al. 1991; Clark et al. 1987) and animal studies (Sun et al. 1993; Davey et al. 1993) have demonstrated that meconium inhibits surfactant function and is likely to be partially responsible for alveolar collapse in meconium aspiration syndrome. Components of meconium that may contribute to altered surfactant function include cholesterol, free fatty acids, bile salts, bilirubin, and proteolytic enzymes (Moses et al. 1991; Clark et al. 1987; Sun et al. 1993; Lieberman 1966). In particular, phospholipase-A2 (PLA2) in meconium has been found to inhibit the activity of surfactant in vitro in a dose-dependent manner, through the competitive displacement of surfactant from the alveolar film (Nkadi et al. 2009). PLA2 is also known to induce hydrolysis of DPPC, releasing free fatty acids and lyso-PC which damage the alveolar–capillary membrane and induce intrapulmonary sequestration of neutrophils (Nkadi et al. 2009).

In pulmonary hemorrhage, capillary filtrate builds up in the interstitial space and can burst through the pulmonary epithelium into the airspaces. Neutrophils are released following endothelial damage and they, in turn, express proteases, oxygen free-radicals, and cytokines. These free oxygen molecules damage the type II cells that produce surfactant proteins, thus inhibiting production of the proteins (Nkadi et al. 2009). Elastase, one of these proteases, damages and degrades SP-A, thereby inhibiting SP-A-mediated surfactant lipid aggregation and adsorption in vitro (Nkadi et al. 2009).

Acute respiratory distress syndrome (ARDS) is a significant cause of morbidity and mortality in all age groups following infection (the most common cause), hemorrhage, or other forms of lung injury. It is defined as a severe form of acute lung injury (ALI) and a syndrome of acute pulmonary inflammation. ALI/ARDS is characterized by sudden onset, impaired gas exchange, decreased static compliance, and a non-hydrostatic pulmonary edema (Nkadi et al. 2009). ARDS is characterized by an increase in the permeability of the alveolar–capillary barrier due to injury to the endothelium and/or alveolar lining cells. Damage to the alveolar type I cells leads to an influx of protein-rich edema fluid into the alveoli, as well as decreased fluid clearance from the alveolar space. Neutrophils are attracted into the airways by host bacterial and chemotactic factors and express enzymes and cytokines which further damage the alveolar epithelial cells (Nkadi et al. 2009). Type II epithelial cell injury leads to a decrease in surfactant production, with resultant alveolar collapse.

Mechanical ventilation in itself can worsen lung disease and effect surfactant function. The damage caused by mechanical ventilation can cause fluid, protein, and blood to leak into the airways, alveoli, and the lung interstitium, interfering with lung mechanics, inhibiting surfactant function, and promoting lung inflammation (Clark et al. 2001). Even a short period of mechanical ventilation can cause a decrease in lung compliance that is associated with a large influx of proteins into the alveolar space and with alterations in the pulmonary surfactant system (Veldhuizen et al. 2000). The changes of surfactant in these experiments are different from those seen in acute lung injury, indicating that they may represent an initial response to mechanical ventilation.

In the adult lung, injuries due to mechanical ventilation occur primarily when the sum of the functional residual capacity (FRC) and tidal volume approach or exceed maximal lung volume (Dreyfuss and Saumon 1993). The preterm lung is particularly susceptible to injury by mechanical ventilation because of structural immaturity, and tidal volumes considered safe for the adult may approach the maximum lung volumes in the preterm lung (Wada et al. 1997). Initiation of ventilation in preterm lambs with high volumes causes lung injury and decreases the subsequent response to surfactant treatment (Wada et al. 1997).

In premature baboons, mechanical ventilation results in abnormal surfactant metabolism (Seidner et al. 1998). In the normal lung, large lipid arrays or large-aggregate forms of surfactant are the source of the surface film (Wright 1990). Small vesicles, primarily containing lipids, reenter the hypophase for recycling or catabolism. The amount of inactive vesicular forms increases with lung injury, and this increase is associated with a deterioration in lung mechanics.

Long-term ventilation of the lungs in immature preterm infants with respiratory distress leads to ventilator-induced lung injury and chronic lung disease. Ventilation of these infants not only interferes with alveolarization but also with the surfactant system. Ventilated preterm animals accumulated very large lipid pools in tissue, but alveolar pools stay relatively low indicating decreased secretion of newly synthesized saturated phosphatidylcholine and increased catabolism. These effects of both acute and long-term ventilation leave the preterm infant particularly susceptible to problems associated with surfactant deficiency and dysfunction.

These include the following:

These include the following:

Protein-free synthetic surfactants: There is one product in this category, colfosceril palmitate, cetyl alcohol, tyloxapol (Exosurf), and it consists of 85 % dipalmitoylphosphatidylcholine (DPPC), 9 % hexadecanol, and 6 % tyloxapol (a spreading agent). Another product in this category, pumactant (also known as artificial lung expanding compound, ALEC) is no longer manufactured (Halliday 2006) and was a 7:3 mixture of DPPC and phosphatidyl glycerol. These synthetic surfactants lack many of the components of animal-derived surfactant, particularly the hydrophobic surfactant proteins B and C.

Protein-containing synthetic surfactants: These surfactants contain synthetic phospholipids along with proteins (produced through peptide synthesis and recombinant technology) that attempt to mimic the function of either SP-B or SP-C. Of these, lucinactant (Surfaxin) contains dipalmitoylphosphatidylcholine, palmitoyl oleoylphosphatidyl glycerol, and palmitic acid (Cochrane et al. 1996, 1998) combined with a mimic of SP-B called sinapultide or KL4 peptide. KL4 is a 21-residue peptide comprised of repeated units of four hydrophobic leucine (L) residues, bounded by basic polar lysine (K) residues arranged in the following order: KLLLLKLLLLKLLLLKLLLLK. This structure resembles the repeating pattern of hydrophobic and hydrophilic residues in the C-terminal part of SP-B and stabilizes the phospholipid layer by interactions with the lipid heads and the acyl chains (Cochrane and Revak 1991). Another synthetic SP-B analog currently under testing is called dSP-B_1-25,which resembles the N-terminal segment of SP-B and when combined with synthetic phospholipids has shown some efficacy in animal studies.

Another type of synthetic protein-containing surfactant is called rSP-C surfactant or lusupultide (Venticute). It contains DPPC, palmitoyl oleoylphosphatidyl glycerol, palmitic acid, and calcium chloride (Hafner and Germann 2000; Spragg et al. 2000) combined with a recombinant SP-C analog (rSP-C), which is similar to the 34-amino acid human SP-C sequence, except that it contains cysteine (in place of phenylalanine) in positions 4 and 5 and contains isoleucine (instead of methionine) in position 32.

During surfactant replacement therapy, exogenous surfactants are given at doses between 10 and 20 times the usual pool sizes found in preterm infants with RDS, which approximates the pool size in term infants (Nkadi et al. 2009). The table summarizes the individual characteristics of each of these products, including the dosage, volume, and the recommended repeat dosing interval. All these products are administered intratracheally with each dose divided into multiple aliquots and should be administered according to the manufacturers’ recommendations (Table 28.1).

Many of the early surfactant trials studied the effects of surfactant treatment in preterm infants with clinical and/or radiologic features of RDS (rescue or treatment trials). Some of these studies used animal-derived surfactant and others used protein-free synthetic surfactant.

Rescue Therapy with Animal-Derived Surfactant: In a systematic review and meta-analysis of 13 randomized trials of animal-derived surfactant (Seger and Soll 2009), infants treated with surfactant had a rapid improvement in respiratory status (improved oxygenation and decreased need for ventilator support), as well as a significant decrease in the risk of (a) any air leak (typical RR 0.47, 95 % CI 0.39–0.58; typical ARD −0.16, 95 % CI −0.21 to −0.12), (b) pneumothorax (typical RR 0.42, 95 % CI 0.34–0.52; typical ARD −0.17, 95 % CI −0.21 to −0.13), and (c) pulmonary interstitial emphysema (typical RR 0.45, 95 % CI 0.37–0.55; typical ARD −0.20, 95 % CI −0.25 to −0.15). There was also a significant decrease in the risk of (a) neonatal mortality (typical RR 0.68, 95 % CI 0.57–0.82; typical ARD −0.09, 95 % CI −0.13 to −0.05), (b) mortality prior to hospital discharge (typical RR 0.63, 95 % CI 0.44–0.90; typical ARD −0.10, 95 % CI −0.18 to −0.03), and (c) bronchopulmonary dysplasia (BPD) or death at 28 days of age (typical RR 0.83, 95 % CI 0.77–0.90; typical ARD −0.11, 95 CI −0.16 to −0.06).

Rescue Therapy with Protein-Free Synthetic Surfactant: In a similar systematic review and meta-analysis of six randomized trials of protein-free synthetic surfactant treatment of established RDS (Soll 1998), surfactant therapy improved pulmonary gas exchange and decreased the requirement for ventilatory support. It also decreased the risk of (a) pneumothorax (typical RR 0.64, 95 % CI 0.55–0.76; typical ARD −0.09, 95 % CI −0.12 to −0.06), (b) pulmonary interstitial emphysema (typical RR 0.62, 95 % CI 0.54–0.71; typical ARD −0.12, 95 % CI −0.16 to −0.09), (c) patent ductus arteriosus (typical RR 0.90, 95 % CI 0.84–0.97; typical ARD −0.06, 95 % CI −0.10 to −0.02), (d) intraventricular hemorrhage (typical RR 0.88, 95 % CI 0.77–0.99; typical ARD −0.04, 95 % CI −0.08 to −0.00), (e) bronchopulmonary dysplasia (typical RR 0.75, 95 % CI 0.61–0.92; typical ARD −0.04, 95 % CI −0.06 to −0.01), (f) neonatal mortality (typical RR 0.73, 95 % CI 0.61–0.88; typical ARD −0.05, 95 % CI −0.07 to −0.02), (g) bronchopulmonary dysplasia or death at 28 days (typical RR 0.73, 95 % CI 0.65–0.83; typical ARD −0.06, 95 % CI −0.11 to −0.05), (h) mortality prior to hospital discharge (typical RR 0.79, 95 % CI 0.68–0.92; typical ARD −0.05, 95 % CI −0.07 to −0.02), and (i) mortality during the first year of life (typical RR 0.80, 95 % CI 0.69–0.94; typical ARD −0.04, 95 % CI −0.07 to −0.01). Treatment with synthetic surfactant increased the risk of apnea of prematurity (typical RR 1.20, 95 % CI 1.09–1.31; typical ARD 0.08, 95 % CI 0.04–0.12).

Several of the early trials of surfactant therapy also studied the effects of prophylactic surfactant in preterm infants at risk for developing RDS (i.e., before they had overt clinical features of RDS). Some of these studies used animal-derived surfactant and others used protein-free synthetic surfactant.

Prophylaxis with Animal-Derived Surfactant: A systematic review and meta-analysis of eight randomized trials (Soll and Özek 1997) found that prophylaxis with animal-derived surfactant lead to an initial improvement in respiratory status and a decrease in the risk of respiratory distress syndrome in infants. It also lead to a decrease in the risk of (a) pneumothorax (typical RR 0.35, 95 % CI 0.26–0.49; typical ARD −0.15, 95 % CI −0.20 to −0.11), (b) pulmonary interstitial emphysema (typical RR 0.46, 95 % CI 0.35–0.60; typical ARD −0.19, 95 % CI −0.25 to −0.13), (c) neonatal mortality (typical RR 0.60, 95 % CI 0.44–0.83; typical ARD −0.07, 95 % CI −0.12 to −0.03), and (d) bronchopulmonary dysplasia or death (typical RR 0.84, 95 % CI 0.75–0.93; typical ARD −0.10, 95 % CI −0.16 to −0.04).

Prophylaxis with Protein-Free Synthetic Surfactant: In a similar systematic review and meta-analysis of seven randomized trials (Soll and Özek 2010), protein-free synthetic surfactant prophylaxis leads to a variable improvement in the respiratory status and a decrease in respiratory distress syndrome in infants who receive prophylactic protein-free synthetic surfactant. It also leads to a decrease in the risk of (a) pneumothorax (typical RR 0.67, 95 % CI 0.50–0.90), (b) pulmonary interstitial emphysema (typical RR 0.68, 95 % CI 0.50–0.93), and (c) neonatal mortality (typical RR 0.70, 95 % CI 0.58–0.85). However, prophylactic protein-free synthetic surfactant administration was associated with an increase in the risk of patent ductus arteriosus (typical RR 1.11, 95 % CI 1.00–1.22) and an increase in the risk of pulmonary hemorrhage (typical RR 3.28, 95 % CI 1.50–7.16).

Many investigators believed that prophylactic administration of surfactant would be the most effective way to deliver surfactant based on the observation in animal studies that surfactant is distributed more uniformly and homogenously when it is administered into a fluid-filled lung (Jobe et al. 1984; Seidner et al. 1995) and the belief that administering surfactant into a previously unventilated or minimally ventilated lung will diminish acute lung injury. In animal models, even brief (15–30 min) periods of mechanical ventilation prior to surfactant administration have been shown to cause acute lung injury resulting in alveolar–capillary damage, leakage of proteinaceous fluid into the alveolar space, and release of inflammatory mediators (Ikegami et al. 1998; Jobe and Ikegami 1998a, b) and to decrease the subsequent response to surfactant replacement (Bjorklund et al. 1997; Rider et al. 1992). Surfactant-deficient animals who receive assisted ventilation develop necrosis and desquamation of the bronchiolar epithelium as early as 5 min after onset of ventilation (Nilsson et al. 1980).

Shortly after surfactant was approved for clinical use, eight randomized controlled trials compared the effects of prophylactic surfactant administration to surfactant treatment of established RDS (Bevilacqua et al. 1996, 1997; Dunn et al. 1991; Egberts et al. 1993; Kattwinkel et al. 1993; Kendig et al. 1991; Merritt et al. 1991; Walti et al. 1995). All these trials used animal-derived surfactant preparations. Trials varied whether surfactant was given before or after the onset of air breathing (pre- or post-ventilatory administration), but all administered surfactant before 15 min of age. The average time of administration of surfactant in the selective treatment groups ranged from 1.5 to 7.4 h. The results of the meta-analysis of the eight trials from a systematic review (Soll and Morley 2012) are summarized in Fig. 28.2.

Compared to surfactant treatment of established RDS, prophylactic administration of surfactant resulted in a decrease in the risk of pneumothorax (typical RR 0.62, 95 % CI 0.42–0.89; typical ARD −0.02, 95 % CI −0.04 to −0.01), a decrease in the risk of pulmonary interstitial emphysema (typical RR 0.54, 95 % CI 0.36–0.82; typical ARD −0.03, 95 % CI −0.04 to −0.01), a reduction in the risk of neonatal mortality (typical RR 0.61, 95 % CI 0.48–0.77; typical ARD −0.05, 95 % CI −0.07 to −0.02), and a trend towards a decrease in the risk of intraventricular hemorrhage (typical RR 0.92, 95 % CI 0.82–1.03; typical ARD −0.03, 95 % CI −0.06 to 0.01). Because of the greater risk of respiratory distress syndrome and mortality with decreasing gestational age, the benefits of prophylactic administration compared to selective administration were of greater magnitude. The meta-analysis demonstrates that compared to selective administration, prophylactic administration of animal-derived surfactant to infants less than 30 weeks gestation resulted in a greater reduction in neonatal mortality (typical RR 0.62, 95 % CI 0.49–0.78; typical ARD −0.06, 95 % CI −0.09 to −0.03) and a reduction in the combined outcome of bronchopulmonary dysplasia or death (typical RR 0.87, 95 % CI 0.77–0.97; typical ARD −0.05, 95 % CI −0.09 to −0.01).

Preventilatory Versus Post-ventilatory Prophylactic Surfactant Administration: The initial studies using prophylactic surfactant administered the drug as an immediate bolus after intubating the infants rapidly after birth (i.e., “before the first breath”). This approach delays the initiation of neonatal resuscitation, including positive pressure ventilation, and is associated with a risk for surfactant delivery into the right main stem bronchus or esophagus. A randomized trial demonstrated that prophylaxis may be administered in small aliquots soon after resuscitation and confirmation of endotracheal tube position, with equivalent or greater efficacy (Kendig et al. 1998). Based on this trial, prophylactic surfactant should be administered after initial resuscitation of the infant at birth and administration prior to the “first breath” is unnecessary.

The trials mentioned above comparing the use of prophylactic surfactant to surfactant treatment of established RDS were all performed in an era when the use of maternal antenatal glucocorticoids was not as high as in the current era, where 90 % or more of mothers who deliver prematurely receive antenatal glucocorticoids. Also, in these trials, surfactant in the “rescue” group was given relatively late, between 1.5 and 7.4 h, after birth. There are no trials comparing the effects of prophylactic intubation and surfactant administration shortly after birth to infants at high risk of RDS (with intubation primarily performed to administer surfactant) to very early selective administration (e.g., at 30–60 min of life) in intubated infants with early RDS or respiratory insufficiency. Therefore, in current practice, the benefits of prophylactic surfactant demonstrated in these trials might not be as large. A strategy of surfactant prophylaxis subjects infants without RDS to unnecessary intubation and surfactant administration and also to the risk of ventilator-induced lung injury (Clark et al. 2001) (although admittedly some of these infants without RDS may still require intubation and ventilation for respiratory failure not due to RDS). In recent years, prophylactic surfactant administration to preterm infants at risk of RDS has been compared with the use of nasal CPAP (and attempting to avoid mechanical ventilation) as the primary method of respiratory management at birth. These studies are discussed in the next section.

Four large multicenter trials have evaluated the use of prophylactic or early surfactant administration to immediate stabilization on continuous distending pressure (SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network 2010; Vermont Oxford Network DRM Study Group et al. 2010; Sandri et al. 2010; Morley et al. 2008).

In the SUPPORT trial (SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network 2010), infants 24–27 weeks gestation were randomly assigned to intubation and surfactant treatment (within 1 h after birth) or to CPAP treatment initiated in the delivery room, with subsequent use of a “protocol-driven limited ventilation strategy.” The primary outcome, death, or bronchopulmonary dysplasia (defined as supplemental oxygen requirement at 36 weeks post-menstrual age) did not differ significantly between the CPAP group and the surfactant group (47.8 and 51.0 %, respectively; RR with CPAP, 0.95; 95 % CI, 0.85–1.05) after adjustment for gestational age, center, and familial clustering. The results were similar when bronchopulmonary dysplasia was defined according to the need for any supplemental oxygen at 36 weeks (rates of primary outcome, 48.7 and 54.1 %, respectively; RR with CPAP, 0.91; 95 % CI, 0.83–1.01). Infants who received CPAP treatment, as compared with infants who received surfactant treatment, less frequently required intubation or postnatal corticosteroids for bronchopulmonary dysplasia (P < 0.001), required fewer days of mechanical ventilation (P = 0.03), and were more likely to be alive and free from the need for mechanical ventilation by day 7 (P = 0.01). In secondary analyses, among infants 24 and 25 weeks gestation, there was a significant reduction in the risk of death in the CPAP group, as compared with the early-intubation group. The rate of death during hospitalization was 24 % versus 32 %, RR with CPAP, 0.74; 95 % CI 0.57–0.98. The rate of death at 36 weeks was 20 % versus 29 %, RR, 0.68; 95 % CI 0.5–0.92.

In the Delivery Room Management randomized trial conducted by the Vermont Oxford Network (Vermont Oxford Network DRM Study Group et al. 2010), three strategies were compared in infants at risk of RDS (preterm infants 26–29 weeks): prophylactic surfactant followed by a period of assisted ventilation, intubation with immediate surfactant treatment and rapid extubation to nasal CPAP (ISX), and early stabilization on nasal CPAP (NCPAP). The study was terminated prior to reaching the desired sample size. There were over 200 infants in each of the three study arms. No statistically significant differences were found between the three arms of the trial in the primary outcome of death or chronic lung disease (defined as supplemental oxygen requirement at 36 weeks post-menstrual age). The incidence of the primary outcome was 37 % in the prophylactic surfactant group, 29 % in the ISX group (RR with ISX compared to prophylactic surfactant 0.78, 95 % CI 0.59–1.03), and 31 % in the CPAP group (RR with CPAP compared to prophylactic surfactant 0.83, 95 % CI 0.64–1.09).

In the CURPAP trial (Sandri et al. 2010), infants 25–28 weeks gestation who were not intubated at birth were randomly assigned to prophylactic surfactant or nasal CPAP within 30 min of birth. There were no statistically significant differences between the two groups in the outcomes studied – need for mechanical ventilation in the first 5 days of life, death at 28 days of life, death at 36 weeks post-menstrual age, and the main morbidities of prematurity.

In the COIN trial (Morley et al. 2008), infants 25–28 weeks gestation who were breathing spontaneously but had developed respiratory distress were randomly assigned to CPAP or intubation and ventilation at 5 min after birth. Infants intubated before randomization and those not requiring respiratory support or oxygen were excluded. The primary outcome of death or chronic lung disease (defined as the need for oxygen treatment at 36 weeks gestational age) was not statistically different in infants assigned to receive intubation (39 %) compared with infants assigned to receive CPAP (34 %, odds ratio favoring CPAP, 0.80; 95 % CI 0.58–1.12). At 28 days, there was a lower risk of death or need for oxygen therapy in the CPAP group than in the intubation group (odds ratio, 0.63; 95 % CI 0.46–0.88; P = 0.006). There was little difference in overall mortality. In the CPAP group, 46 % of infants were intubated during the first 5 days, and the use of surfactant was halved. However, the incidence of pneumothorax was 9 % in the CPAP group, as compared with 3 % in the intubation group (P < 0.001). There were no other serious adverse events. The CPAP group had fewer days of ventilation.

The results of these trials suggest that in preterm infants at high risk of RDS, instead of routinely intubating and administering prophylactic surfactant immediately after birth, it is reasonable to try and initially stabilize such infants on nasal CPAP. This approach can avoid unnecessary intubation, unnecessary surfactant administration, and minimize ventilator-induced lung injury, while reducing healthcare costs and resource utilization. However, clinicians should closely monitor infants initially stabilized on CPAP to identify infants who have progressive respiratory failure, so that infants who require surfactant can be intubated and given surfactant as early as possible. Clinicians should also use information available prior to the birth of the infant to identify infants who are not likely to do well with initial stabilization on nasal CPAP, such as infants born to mothers who have not received antenatal glucocorticoids.

When a preterm infant has respiratory distress syndrome that is initially managed with CPAP or with supplemental oxygen through a hood, is it better to intubate him early, administer surfactant and extubate within an hour after brief mechanical ventilation, or to wait and see if the infant develops significant respiratory insufficiency, and if he does, only then intubate, give surfactant, and wean him off the ventilator gradually? Six randomized controlled clinical trials addressed this question and are summarized in a systematic review (Stevens Timothy et al. 2007). The rapid (within one hour) extubation attempted in these trials contrasts with the traditional approach – developed when surfactant therapy was first used – of keeping an infant on mechanical ventilation after surfactant administration, weaning ventilator support gradually as the pulmonary status improved, and extubating the infant from low ventilator settings. This approach of rapid extubation followed immediately by the use of nasal CPAP has been called “INSURE” (INtubate, SURfactant, Extubate to CPAP) and is intended to prevent ventilator-induced lung injury than can result from even brief periods of mechanical ventilation (Donn and Sinha 2006; Schmolzer et al. 2008). The six randomized trials, all of which are trials of “rescue” surfactant administration, are summarized in a systematic review (Stevens Timothy et al. 2007). Most of these studies included infants with a gestation of 35 weeks and below and a birth weight of 2,500 g and below. Many of the infants in these studies were between 32 and 35 weeks (few were extremely premature). In these studies of infants with signs and symptoms of RDS, intubation and early surfactant therapy followed by extubation to nasal CPAP (NCPAP) compared with later selective surfactant administration was associated with a lower incidence of mechanical ventilation (typical RR 0.67, 95 % CI 0.57–0.79; typical ARD −0.19, 95 % CI −0.26 to −0.11), air leak syndromes (typical RR 0.52, 95 % CI 0.28–0.96; typical ARD −0.04, 95 % CI −0.08 to 0.00), and BPD (typical RR 0.51, 95 % CI 0.26–0.99; typical ARD −0.08, 95 % CI −0.15 to −0.01). A larger proportion of infants in the early surfactant group received surfactant than in the selective surfactant group (typical RR 1.62, 95 % CI 1.41–1.86; typical ARD 0.38, 95 % CI 0.30–0.47). The number of surfactant doses per patient was significantly greater among patients randomized to the early surfactant group (WMD 0.57 doses per patient, 95 % CI 0.44–0.69). In stratified analysis by FiO₂ at study entry, a lower threshold for treatment (FiO₂ ≤ 0.45) resulted in lower incidence of air leak (typical RR 0.46 and 95 % CI 0.23–0.93; typical ARD −0.05, 95 % CI −0.10 to −0.01) and BPD (typical RR 0.43, 95 % CI 0.20–0.92; typical ARD −0.10, 95 % CI −0.19 to −0.02). A higher treatment threshold (FiO₂ > 0.45) at study entry was associated with a higher incidence of patent ductus arteriosus requiring treatment (typical RR 2.15, 95 % CI 1.09–4.13; typical ARD 0.12, 95 % CI 0.02–0.21). In another recent randomized trial (Rojas et al. 2009), infants 27–31 weeks gestation with RDS who were randomly assigned within the first hour of life either to intubation, very early surfactant, extubation, and nasal continuous positive airway pressure required less ventilation and had a lower incidence of mortality and air leaks (pneumothorax and pulmonary interstitial emphysema) than infants assigned to nasal continuous airway pressure alone. These data suggest that for a preterm infant with RDS who is not on mechanical ventilation (and is being managed on CPAP or an oxygen hood), early intubation at a low FiO₂ threshold (FiO₂ < 0.45), surfactant administration, and rapid extubation to CPAP decreases the risk of needing mechanical ventilation, BPD, and air leak syndrome, although it results in more surfactant use. Whether the same INSURE approach should be followed when prophylactic surfactant therapy is used is not clear due to lack of evidence.

Preterm infants who do not receive prophylaxis and subsequently develop RDS should be treated with surfactant as soon as possible. This strategy is supported by many of the same arguments that support prophylactic surfactant administration as well as by clinical trials. Four randomized controlled trials (European Exosurf Study Group 1992; Gortner et al. 1998; Konishi et al. 1992; The OSIRIS Collaborative Group 1992), including the largest randomized trial conducted in neonatology (the OSIRIS trial), have evaluated early versus delayed selective surfactant administration. The results of these trials are summarized in a systematic review (Yost and Soll 2000). In these trials, early administration of surfactant consisted of administration of the first dose within the first 30 min to the first 2 h of life. Two of these studies used animal-derived surfactants and two used protein-free synthetic surfactant. The results of the meta-analysis of these studies are summarized in Fig. 28.3.

Early selective treatment resulted in a decrease in the risk of pneumothorax (typical RR 0.70, 95 % CI 0.59–0.82; typical ARD −0.05, 95 % CI −0.08 to −0.03), a decrease in the risk of pulmonary interstitial emphysema (typical RR 0.63, 95 % CI 0.43–0.93; typical ARD −0.06, 95 % CI −0.10 to −0.01), a decrease in the risk of chronic lung disease (requirement for supplemental oxygen at 36 weeks gestation, typical RR 0.70, 95 % CI 0.55–0.88; typical ARD −0.03, 95 % CI −0.05 to −0.01) and a decrease in the risk of neonatal mortality (typical RR 0.87, 95 % CI 0.77–0.99; typical ARD −0.03, 95 % CI −0.06 to 0.00). Therefore preterm infants who do not receive prophylactic surfactant and subsequently develop clinical features of RDS should receive the first dose of surfactant as early as possible. Outborn infants are at highest risk of delayed administration. Tertiary referral units accepting outborn infants should attempt to develop systems to ensure that surfactant is administered as early as possible to these infants, either by the transporting team or, if appropriate, by the referring hospital. In inborn infants, delays in administration of surfactant occur if other admission procedures such as line placement, radiographs, and nursing procedures are allowed to take precedence over surfactant dosing soon after birth. Surfactant administration should be given priority over such admission procedures.

Many of the initial trials of surfactant therapy tested a single dose of surfactant. However, surfactant may become rapidly metabolized and functional inactivation of surfactant can result from the action of soluble proteins and other factors in the small airways and alveoli (Jobe and Ikegami 1993). Administering repeat doses of surfactant can overcome such inactivation. The results of two randomized controlled trials that compared multiple dosing regimens to single-dose regimens of animal-derived surfactant extract for treatment of established respiratory distress syndrome (Dunn et al. 1990; Speer et al. 1992) have been evaluated in a systematic review (Soll and Özek 2009). In one study (Dunn et al. 1990), after the initial dose of bovine lipid extract surfactant, infants assigned to the multiple-dose group could receive up to three additional doses during the first 72 h of life if they had a respiratory deterioration, provided they had shown a positive response to the first dose and a pneumothorax had been eliminated as the cause of the respiratory deterioration. In the other study (Speer et al. 1992), infants in the multiple-dose group received additional doses of poractant at 12 and 24 h after the initial dose if they still needed supplemental oxygen and mechanical ventilation. Approximately 70 % of the infants randomized to the multiple-dose regimen received multiple doses.

The meta-analysis supports a decreased risk of pneumothorax associated with multiple dose surfactant therapy (typical RR 0.51, 95 % CI 0.30–0.88; typical ARD −0.09, 95 % CI −0.15 to −0.02). There was also a trend towards decreased mortality (typical RR 0.63, 95 % CI 0.39–1.02; typical ARD −0.07, 95 % CI −0.14 to 0.00). No differences were detected in other clinical outcomes. No complications associated with multiple-dose treatment were reported in these trials. In a third study, in which protein-free synthetic surfactant was used in a prophylactic manner, the use of two doses of surfactant in addition to a prophylactic dose lead to a decrease in mortality, respiratory support, necrotizing enterocolitis, and other outcomes when compared to a single prophylactic dose (Corbet et al. 1995). In the OSIRIS trial, which used protein-free synthetic surfactant, a two-dose treatment schedule was found to be equivalent to a treatment schedule permitting up to four doses of surfactant.

The use of a higher threshold for retreatment with surfactant appears to be as effective as a low threshold and can lead to significant savings in costs of the drug. The criteria for administration of repeat doses of surfactant were investigated in two studies that both used animal-derived surfactant. In one study (Dunn et al. 1991), the retreatment criteria compared were an increase in the fraction of inspired oxygen by 0.1 over the lowest baseline value (standard retreatment) versus a sustained increase of just 0.01 (liberal retreatment). There were no differences in complications of prematurity or duration of respiratory support. However, short-term benefits in oxygen requirement and degree of ventilator support were noted in the liberal retreatment group.

In another study (Kattwinkel et al. 2000), retreatment at a low threshold (FiO₂ > 30 %, still requiring endotracheal intubation) was compared to retreatment at a high threshold (FiO₂ > 40 %, mean airway pressure >7 cm H₂O). Again, there were minor short-term benefits to using a low threshold with no differences in major clinical outcomes. However, in a subgroup of infants with respiratory distress syndrome complicated by perinatal compromise or infection, infants in the high-threshold group had a trend towards higher mortality than the low-threshold group. Based on current evidence, it appears appropriate to use persistent or worsening signs of respiratory distress syndrome as criteria for retreatment with surfactant. A low threshold for repeat dosing should be used for infants with RDS who have perinatal depression or infection.

Comparison of Animal-Derived and Protein-Free Synthetic Surfactants: Although both protein-free synthetic and animal-derived surfactants are effective, their composition differs. Animal-derived surfactant extracts contain surfactant-specific proteins that aid in surfactant adsorption and resist surfactant inactivation (Kuroki and Voelker 1994; Possmayer 1990). Eleven randomized trials have compared the effects of animal-derived and protein-free synthetic surfactants in the treatment or prevention of RDS (Ainsworth et al. 2000; Alvarado et al. 1993; da Costa et al. 1999; Horbar et al. 1993b; Hudak et al. 1996, 1997; Kukkonen et al. 2000; Modanlou et al. 1997; Pearlman et al. 1993; Sehgal et al. 1994; Neonatal 1996). A total of over 4,500 infants were studied in these trials. A systematic review of these trials is available (Soll and Blanco 2001). The results of the meta-analysis are summarized in Fig. 28.4.

Compared to protein-free synthetic surfactant, treatment with animal-derived surfactant extracts resulted in a significant reduction in the risk of pneumothorax (typical RR 0.63, 95 % CI 0.53–0.75; typical ARD −0.04, 95 % CI −0.06 to −0.03) and the risk of mortality (typical RR 0.87, 95 % CI 0.76–0.98; typical ARD −0.02, 95 % CI −0.05 to 0.00). Natural surfactant extract is associated with a marginal increase in the risk of intraventricular hemorrhage (typical RR 1.09, 95 % CI 1.00–1.19; typical ARD 0.03, 95 % CI 0.00–0.06), but no increase in grade 3 to 4 intraventricular hemorrhage (typical RR 1.08, 95 % CI 0.92–1.28; typical ARD 0.01, 95 % CI −0.01 to 0.03). The meta-analysis also supports a marginal decrease in the risk of bronchopulmonary dysplasia or mortality associated with the use of natural surfactant preparations (typical RR 0.95, 95 % CI 0.90–1.01; typical ARD −0.03, 95 % CI −0.06 to 0.00).

In addition to these benefits, animal-derived surfactants have a more rapid onset of action, allowing ventilator settings and inspired oxygen concentrations to be lowered more quickly than with protein-free synthetic surfactant (Horbar et al. 1993b; Hudak et al. 1996; Modanlou et al. 1997; Rollins et al. 1993; Choukroun et al. 1994). A comparison of physical properties and the results of animal studies also suggest that animal-derived surfactants have advantages over protein-free synthetic surfactants (Halliday 1996). These properties are attributed to the presence of the surfactant proteins SP-B and SP-C in animal-derived surfactants (Hall et al. 1992a).

The use of animal-derived surfactant preparations should be favored in most clinical situations, as their use results in greater clinical benefits than protein-free synthetic surfactants. However, all animal-derived surfactants have to be refrigerated for storage. The protein-free synthetic surfactant colfosceril is available as a lyophilized powder that is to be stored at below 30 °C in a dry place (not to be frozen) and reconstituted with sterile water before use. Therefore in situations where refrigeration is a problem (as in developing countries), it may be more practical to use colfosceril than animal-derived surfactants.

Comparison of Animal-Derived and Protein-Containing Synthetic Surfactants: Clinical trials have compared the effects of synthetic surfactants containing peptides to animal-derived surfactant preparations. These synthetic surfactants do not have the theoretical concerns associated with animal-derived surfactants, namely, transmission of microorganisms, exposure to animal proteins and inflammatory mediators, susceptibility to inactivation, and inconsistent content (Engle and Committee on Fetus and Newborn 2008). Lucinactant, the synthetic surfactant containing an analog of SP-B, sinapultide, was compared with beractant in SELECT, a multicenter masked randomized trial of surfactant prophylaxis in infants 24–32 weeks gestation (Moya et al. 2005). Lucinactant was also compared with poractant in STAR, a multicenter randomized trial of surfactant prophylaxis in infants 24–28 weeks gestation that was structured as a non-inferiority trial (Sinha et al. 2005). A meta-analysis of these two studies (Pfister et al. 2007) found no significant differences in outcomes between lucinactant and the comparison animal-derived surfactant in mortality at 36 weeks post-menstrual age (typical RR 0.81, 95 % CI 0.64–1.03), chronic lung disease at 36 weeks post-menstrual age (typical RR 0.99, 95 % CI 0.84–1.18), the composite outcome of mortality or chronic lung disease at 36 weeks post-menstrual age (typical RR 0.96, 95 % CI 0.82–1.12), or in other respiratory outcomes. A decreased risk of necrotizing enterocolitis, a secondary outcome, was noted in infants receiving lucinactant (typical RR 0.60, 95 % CI 0.42–0.86; typical RD −0.06, 95 % CI −0.10 to −0.01).

However, both trials of lucinactant described above had multiple methodologic problems (Kattwinkel 2005) that undermine their validity, and at present there is no clear evidence of the equivalence or superiority of lucinactant over any animal-derived surfactant product (Halliday 2006). While these newer surfactants show promise, further research is required to elucidate their role in the prevention or treatment of RDS.

Comparison of Protein-Containing Versus Protein-Free Synthetic Surfactants: In the SELECT trial (Moya et al. 2005; Pfister Robert et al. 2009), the randomized trial of lucinactant mentioned above where it was compared with beractant, it was also compared to colfosceril. Compared to infants receiving colfosceril, infants receiving lucinactant had less RDS (39 % vs 47 %) and less RDS-related mortality (4.7 % vs 9.4 %, RR 0.50, 95 % CI 0.32–0.80). All-cause mortality at 36 weeks post-menstrual age was not significantly different (21 % for lucinactant vs 24 % for colfosceril). A trend towards a reduction in BPD or death at 36weeks post-menstrual age was associated with lucinactant treatment when compared to colfosceril (RR 0.88, 95 % CI 0.77–1.01).

Comparison of Different Types of Bovine Surfactants: Two randomized trials, both from the same group of investigators, have compared the efficacy and adverse effects of different bovine surfactant products. In a comparison of beractant (Survanta) and calf lung surfactant extract (Infasurf) (Bloom et al. 1997), there were no differences detected between the two groups in the frequency of air leaks, complications associated with dosing, complications of prematurity, mortality, or survival without chronic lung disease. However, some differences were noted among subgroups of infants. Among infants treated for established respiratory distress syndrome, those who received calf lung surfactant extract had a significantly longer interval between doses, a lower inspired oxygen concentration, and a lower mean airway pressure in the first 48 h of life than infants treated with beractant. Among infants in whom these surfactants were administered in a preventive manner, mortality in infants with a birth weight <600 g was significantly higher with calf lung surfactant extract than with beractant. In a second report (Bloom et al. 2005) that included two separate trials – a prophylaxis trial and a treatment trial – the trials were halted prematurely due to recruitment problems and hence had inconclusive results with no demonstrated differences in outcomes between the two products. Thus, there is no evidence of the superiority of one bovine preparation over the other.

Comparison of Porcine and Bovine Surfactants: Five studies comparing surfactant treatment of established moderate to severe RDS with poractant versus beractant have been published (Baroutis et al. 2003; Speer et al. 1995; Malloy et al. 2005; Halahakoon 1999; Ramanathan et al. 2004).

A meta-analysis of these studies (Halliday 2005) found that compared to beractant, poractant treatment led to a significant reduction in neonatal mortality (typical RR 0.57, 95 % CI 0.34–0.96). The dose of beractant was uniformly 100 mg/kg across all five studies. When only studies that used a 100 mg/kg dose of poractant were considered, the reduction in mortality was not statistically significant (typical RR 0.82, 95 % CI 0.44–1.58), emphasizing the fact that the most significant effect on mortality was seen with a 200 mg/kg dose of poractant (typical RR 0.29, 95 % CI 0.10–0.79). Two of these five studies (Speer et al. 1995; Ramanathan et al. 2004) also reported more rapid improvement in oxygenation with poractant compared to beractant. The difference in outcomes described above between poractant and beractant may well be related to the dose of phospholipids and not to other characteristics of the products. There are no studies to determine whether poractant, especially in a 100 mg/kg dose, is superior to beractant when surfactant is dosed for prophylaxis.

Several factors have been reported by various authors to be associated with a poor response to surfactant therapy, either in terms of immediate pulmonary response or in terms of later morbidity and mortality. These factors include high total fluid and colloid intake in the first days of life (Hallman et al. 1993), a low mean airway pressure relative to the FiO₂ (Hallman et al. 1993), the presence of an additional pulmonary disorder such as infection (Segerer et al. 1991) and perinatal asphyxia, other complications of prematurity (Konishi et al. 1992), high fraction of inspired oxygen requirement at entry (had a negative impact on a/APO2 6 and 24 h after treatment), lower birth weight, male sex, outborn status, and high airway pressure requirement at entry (Collaborative European Multicentre Study Group 1991). Low birth weight, low Apgar score, and initial disease severity were associated with an increased mortality (Herting et al. 1992).

A high pulmonary resistance prior to therapy was associated with a poor response to therapy at 24 and 48 h (Wallenbrock et al. 1992). In addition, the immediate response to surfactant therapy itself has been reported to be a significant prognostic indicator for mortality and morbidity (Kuint et al. 1994). In animal studies, poor response to surfactant has been associated with delayed administration (Seidner et al. 1995) and the leakage of proteinaceous fluid into the alveolar spaces. Within some multicenter trials, significant differences in outcomes of surfactant-treated infants have been noted between participating hospitals (Collaborative European Multicentre Study Group 1991; Herting et al. 1992), suggesting that variations in patient care practices have an important influence on the outcomes of surfactant-treated infants.

As noted earlier, observational studies have demonstrated a decrease in mortality and morbidity for such infants after the introduction of surfactant therapy. However, racial differences in this decline in mortality have been reported. In one study, the overall neonatal mortality for black very low birth weight infants did not change after the introduction of surfactant therapy (Hamvas et al. 1996), and in another study, declines in neonatal mortality risks caused by respiratory distress syndrome and all respiratory causes were greater for non-Hispanic white VLBW infants than for black VLBW infants (Ranganathan et al. 2000). While such racial differences have been noted at a population level, the role of racial factors in the response pattern of individual infants with respiratory distress syndrome to exogenous surfactant therapy is unknown.

No significant differences have been reported in the long-term neurodevelopmental outcomes of infants treated with surfactant compared to those treated with placebo, either with protein-free synthetic surfactant (Corbet et al. 1995; Morley and Morley 1990; Courtney et al. 1995) or animal-derived surfactant (Hoekstra et al. 1994; Robertson et al. 1992; Dunn et al. 1988; Ferrara et al. 1991; Vaucher et al. 1988; Wagner et al. 1995; Ware et al. 1990).

Compared to infants treated with placebo, infants treated with surfactant in the neonatal period have been reported to have either improved (Abbasi et al. 1993; Pelkonen et al. 1998; Yuksel et al. 1993) or equivalent (Couser et al. 1993; Gappa et al. 1999; Walti et al. 1992) results on pulmonary function testing. Some studies have reported a lower frequency of subsequent clinical respiratory disorders in surfactant-treated infants compared to placebo (Vaucher et al. 1988; Sell et al. 1995), while others have reported no difference (Robertson et al. 1992; Morley and Morley 1990; Dunn et al. 1988; Abbasi et al. 1993) or a trend towards an increase in allergic manifestations (Ware et al. 1990).

No significant differences have been reported in weight or height outcomes between surfactant- and placebo-treated infants on follow-up (Corbet et al. 1995; Robertson et al. 1992; Courtney et al. 1995; Ware et al. 1990; Abbasi et al. 1993; Pelkonen et al. 1998; Gappa et al. 1999; Sell et al. 1995).

Two studies compared the long-term outcomes of infants treated with prophylactic surfactant to those treated with a “rescue” strategy. In one, there were no differences at school age in neurodevelopmental outcome or in the results of pulmonary function testing between the two groups, though infants who had received prophylactic surfactant showed fewer clinical pulmonary problems than those that received rescue treatment (Sinkin et al. 1998). In another study, in which there was significant loss of infants to follow-up (and therefore a high likelihood of attrition bias), the mean scores on the Bayley scales of infant development at 12 months adjusted age were higher in the rescue group than in the prophylactic group (Vaucher et al. 1993).

In non-controlled studies of human infants with meconium aspiration syndrome, improved oxygenation has been reported with exogenous surfactant therapy (Auten et al. 1991; Halliday et al. 1996; Khammash et al. 1993). A randomized trial in infants greater than 34 weeks gestation (including infants with MAS) with severe respiratory failure on extracorporeal membrane oxygenation (ECMO) showed that infants treated with beractant had improved lung function, a shorter duration of ECMO, and fewer complications after ECMO (Lotze et al. 1993).

Four randomized trials (Lotze et al. 1998; Findlay et al. 1996; Chinese Collaborative Study Group for Neonatal Respiratory Diseases 2005; Maturana et al. 2005) have studied the effect of animal-derived surfactant in term infants with meconium aspiration syndrome and are included in a systematic review. In these trials, surfactant therapy was administered as a continuous infusion over 20 min (Findlay et al. 1996) or as a bolus. The meta-analysis of these four trials (El Shahed et al. 2007) showed a decreased need for extracorporeal membrane oxygenation with surfactant therapy (typical RR 0.64, 95 % CI 0.46–0.91; typical ARD −0.17, 95 % CI −0.30 to −0.04). One trial reported a reduction in the length of hospital stay (mean difference −8 days (95 % CI −14 to −3 days)). There were no statistically significant effects on mortality (typical RR 0.98 (95 % CI 0.41–2.39), typical ARD 0.00 (95 % CI −0.05 to 0.05)) or other outcomes (duration of assisted ventilation, duration of supplemental oxygen, pneumothorax, pulmonary interstitial emphysema, air leaks, chronic lung disease, need for oxygen at discharge, or intraventricular hemorrhage).

In summary, infants with severe meconium aspiration syndrome are likely to benefit from treatment with animal-derived surfactants. Multiple doses are usually required in such infants. Only animal-derived surfactants have been tested in human clinical trials in this setting. Each dose should be administered cautiously, with close cardiac, respiratory, and oxygen saturation monitoring, because surfactant can aggravate preexisting airway obstruction from meconium and transient oxygen desaturation and endotracheal tube obstruction have been reported with bolus administration in nearly one-third of infants (Lotze et al. 1998).

Investigators have also attempted to treat MAS by lavaging the airways with diluted surfactant solutions in order to wash out residual meconium (Dargaville et al. 2007; Wiswell et al. 2002; Hung et al. 2006; Lista et al. 2006; Gadzinowski et al. 2008). When this approach was tested in a randomized trial with a small number of babies, there were no statistically significant differences in clinical outcomes, although there was a trend towards reduction in the combined outcome of death or need for ECMO (Dargaville et al. 2010).

Surfactant dysfunction is well described in acute lung injury (Willson et al. 2008). Therefore, surfactant replacement has been proposed as a treatment for patients with acute lung injury and the acute respiratory distress syndrome (ARDS), which, although more common in adults and older children, can occur in term neonates (Faix et al. 1989; Pfenninger et al. 1991). Exogenous surfactant therapy has been attempted in ARDS in adults but the results of clinical trials have not been promising (Anzueto et al. 1996; Gregory et al. 1997a). There are no randomized trials of exogenous surfactant therapy specifically for ARDS in neonates, but in older children with acute respiratory failure, surfactant use decreased mortality and duration of ventilation (Willson et al. 1999; Duffett et al. 2007). Because of this, and based on the pathophysiologic, clinical, and radiologic similarities between RDS and ARDS, it is reasonable to provide exogenous surfactant therapy to term infants with clinical and radiologic features of ARDS (severe respiratory failure with pulmonary opacification and air bronchograms on chest radiographs). The use of surfactant in ARDS is discussed in detail in Sect. 28.2.

There are reports (single-case reports or case series) of the use of exogenous surfactant therapy in human infants for the management of pulmonary hemorrhage (Pandit et al. 1995; Amizuka et al. 2003) and neonatal pneumonia (Auten et al. 1991; Robertson 1996; Herting et al. 2000; Fetter et al. 1995). However, the efficacy of surfactant in these conditions is uncertain and its routine use in these conditions cannot be recommended. Surfactant therapy for infants with congenital diaphragmatic hernia has also been attempted (Bos et al. 1991; Lotze et al. 1994; Glick et al. 1992; Lally et al. 2004; Van Meurs and Congenital Diaphragmatic Hernia Study Group 2004) but actually resulted in worse outcomes and therefore is not recommended.