The benefits of exogenous surfactants for preterm infants with RDS are well established. However, animal-derived natural surfactants have limitations such as their elevated costs and limited production due to animal availability. In addition, they contain animal proteins that may be potentially immunogenic and infectious. Therefore, synthetic surfactants have been developed to overcome these limitations of natural surfactants. Synthetic surfactants are manufactured with fewer production limitations. In addition, they do not contain immunogens or pro-inflammatory mediators that cause BPD and animal-borne infections because they are free of animal proteins [7]. First-generation synthetic surfactants contained phospholipids only without SPs. Commonly used protein-free, first-generation synthetic surfactants were colfosceril palmitate (Exosurf, GlaxoSmithKline, Brentford, UK) and pumactant (ALEC, artificial lung expanding compound, Britannia Pharmaceuticals Ltd., Reading, UK) (Table 1).

Multiple studies have been conducted to compare natural surfactants with protein-free, first-generation synthetic surfactants (Table 2). Soll and Blanco reviewed 11 randomized controlled trials (RCTs) (from 1975 to 2000) and compared protein-free synthetic surfactants with natural surfactants [8]. Protein-free synthetic surfactants failed to lower surface tension whereas natural surfactants reduced the requirement for ventilator support, the risk of pneumothorax, and the risk of mortality [8]. Protein-free synthetic surfactants have been associated with increased mortality with greater risk of pneumothorax than animal-derived surfactants. The inferiority of protein-free synthetic surfactants might be attributable to the absence of SP-B and SP-C, resulting in failure to lower surface tension.

Ardell et al. [9] reviewed 15 RCTs (from 1975 to 2014) comparing protein-free synthetic surfactants to natural surfactants. Greater early improvement in the requirement of a ventilator, fewer cases of pneumothorax, and fewer deaths have been associated with natural surfactants. This superiority of natural surfactants over protein-free synthetic surfactants was directly related to their SP-B and SP-C content. Finally, protein-free, first-generation synthetic surfactants have been removed from the market, as the superiority over natural surfactants could not be demonstrated.

Beractant (Survanta, Abbott Laboratories, Abbott Park, IL, USA) is used in Western regions such as the United States and Europe instead of surfactant-TA. Beractant is similar to surfactant-TA. It is a modified minced bovine lung surfactant extract with SP-B, SP-C, DPPC, tripalmitin, and palmitic acid. Several natural surfactants have become available from various manufacturers following the synthesis of surfactant-TA. Calfactant (Infasurf, ONY Inc., Amherst, NY, USA) was derived from calf lung lavage extract, while poractant alfa (Curosurf, Chiesi Farmaceutici, Parma, Italy) was synthesized from minced porcine lung extract.

After beractant was approved by the U.S. Food and Drug Administration (FDA) in July 1991, calfactant was approved in July 1998, followed by poractant alfa in November 1999. These agents differ in their preparation, SP concentration, phospholipid concentration, and volume of administration (Table 3). The concentration of SP- B is the highest in calfactant, followed by that in poractant alfa, while the concentration of SP-B is the lowest in beractant [7]. The concentration of phospholipid is the highest in poractant alfa. Volumes of administration per kilogram of body weight for beractant, calfactant, and poractant alfa are 4 mL, 3 mL, and 2.5 mL (initial dose)/1.25 mL (subsequent dose), respectively.

There have been various comparative studies evaluating natural surfactants (Table 2). Results differ from center to center. In 1997, Bloom et al. [10] reported that there were no significant differences in the incidence of pneumothorax, mortality, or survival without BPD between calfactant and beractant, although calfactant seemed to have a longer duration of treatment effect than beractant. Calfactant was approved by the U.S. FDA the following year. Ramanathan et al. [11] compared the efficacy and safety of poractant alfa and beractant in preterm infants with RDS (3 groups: 100 mg/kg of poractant alfa, 200 mg/kg of poractant alfa, and 100 mg/kg of beractant). Mortality, redosing of surfactant, and oxygen supplements were significantly reduced in the 200 mg/kg of poractant alfa group than in the 100 mg/kg of poractant alfa or beractant groups. Several years later, Ramanathan [12] reviewed 8 trials comparing natural surfactants and concluded that poractant alfa was associated with lower mortality, less redosing of surfactant, and oxygen supplement compared to calfactant or beractant. However, these differences may be related to the higher amount of phospholipids and plasmalogens present in 200 mg/kg of poractant alfa group.

Singh et al. [13] reviewed 5 RCTs to compare the efficacy of a porcine surfactant (poractant alfa) and bovine surfactants (beractant and calfactant). There were significant reductions in mortality and redosing requirement of surfactants in high-dose 200 mg/kg of poractant alfa, but not in low-dose poractant alfa. There were no differences between the porcine surfactant and bovine surfactants.

Trembath et al. [14] reported that pneumothorax, mortality, and BPD were similar for beractant, calfactant, and poractant alfa. They proposed that the previously described differences in outcomes between surfactants might be due to study site variations and not to actual differences in efficacy.

Because of the wide range of differences in the efficacy of natural surfactants, Singh et al. [15] conducted a systematic review of 16 RCTs comparing natural surfactants. Seven treatment trials and 2 prevention trials comparing a bovine lung lavage surfactant (calfactant) to a modified bovine minced lung surfactant (beractant) were reported. There were no differences in death or chronic lung disease in the prevention or treatment trials. There were no differences in outcomes between the bovine lung lavage surfactant (calfactant) and the porcine minced lung surfactant (poractant alfa). There have been 9 treatment trials comparing a modified bovine minced lung surfactant (beractant) to a porcine minced lung surfactant (poractant alfa). Mortality, oxygen requirement, redosing need, and patent ductus arteriosus (PDA) requiring treatment were higher in beractant-treated patients than in poractant alfa-treated patients. However, mortality and oxygen requirement decreased only with high-dose (200 mg/kg) poractant alfa.

CHF5633 is the first synthetic surfactant containing analogs of both SP-B and SP-C. Sato and Ikegami treated preterm lambs with CHF5633, survanta, or air [23]. All lambs treated with air died of respiratory difficulty. The CHF5633 group had a faster initial response of tidal volume than the survanta group. The CHF5633 group had a higher compliance than the survanta group at 20 minutes and 300 minutes of age, with a higher lung volume at 10 cmH₂O, than the survanta group. Alveoli were uniformly expanded in the CHF5633 group, somewhat atelectatic in the survanta group, and atelectatic in the air group based on hematoxylin and eosin staining. Inflammatory mediators such as interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor alpha mRNA expression levels were not significantly different between the CHF5633 and survanta groups. The authors concluded that CHF5633 was effective in treating preterm lambs with surfactant deficiency [23].

Sweet et al. [24] conducted a first-in-human multicenter cohort study with CHF5633 in 40 preterm infants (27⁺⁰ to 33⁺⁶ weeks of gestation) diagnosed with RDS from 12 European centers in the United Kingdom, Czech Republic, and Germany. Both mean airway pressure and FiO₂ improved rapidly and were sustained. There was no systemic absorption or immunogenicity supported by undetectable peptides or antibodies. There were no significant adverse events associated with CHF5633, except for one episode of endotracheal tube obstruction with 200 mg/kg of CHF5633. The authors concluded that both 100 and 200 mg/kg of CHF5633 were effective and safe for preterm infants with RDS. However, larger RCTs with more preterm infants are needed to support this result.