Laplace was the first to formulate that the external and internal pressures applied to an air bag are inversely proportional to the radius of the air bag and proportional to twice the surface tension (ST). The excess pressure inside a liquid surface is determined by its curvature and tension according to Laplace's equation. A major function of PS is to reduce ST at the air-water interface of the terminal airways, thereby decreasing the tendency for alveolar collapse by Laplace's law.10 In 1929, Von Neergaard11 studied PS function in the porcine lung and demonstrated that a lower ST would be useful for the respiratory mechanism. In 1946, Thannhauser et al.12 showed that the lung contains unusually large amounts of dipalmitoylphosphatidylcholine (DPPC); however, at the time, the association between DPPC and the surface-active properties of the alveolar wall was not known. In 1947, Gruenwald13 reported that resistance to aeration is caused by ST interfering with the entrance of the air, and surface-active substances were shown to reduce the pressure required for lung aeration. In the 1950s, Clements14 and Macklin15 experimentally demonstrated that PS influences the ST in lung volume.

As the pathophysiological mechanism in RDS, the lack of PS in actual clinical practice was first described by Avery and Mead1 in 1959. They found that the lungs of a neonate who died of RDS had a higher ST than those of neonates who died of non-RDS causes, and it was related to the absence or late emergence of some substances that render the internal surface capable of obtaining a low ST when the lung volume decreases in normal subjects. This was the first research to identify the cause of RDS. In 1963, Patrick Bouvier Kennedy, son of John F. Kennedy, former President of the United States, was born with RDS and a birth weight of only 1,860 g at 34 weeks of gestation; he died on the third day of life. The case was highlighted by the media, ultimately leading to the establishment of a large research support system in the United States for RDS research and therapeutic drug development. In fact, this provided significant momentum to the development of artificial therapeutic PS drugs in the 1980s.16

In a clinical study in 1965, Chu17 used nebulized DPPC as a spray method for the first time, but aerosolized DPPC was not effective and might worsen the clinical course of RDS. Due to the failure of this experiment, studies investigating artificial PS supplementation fell dormant for a while. In the 1970s, however, Enhörning and Robertson18 and Adams et al.19 reported that a natural PS formulation was effective in animal models of RDS. This had a significant impact on the basis for future preparations of PS. In the meantime, as PS studies continued, in 1973, King et al.20 described surfactant proteins (SPs), in addition to PLs, as structural components of PS, which play key roles in physical surface properties. In the 1980s, Hallman et al.21 described the administration of PS preparations isolated from human amniotic fluid.

Based on these studies, Fujiwara et al.,2 who were studying PS in the United States with the Adams team, returned to Japan and extracted PS from bovine lungs in 1980. They administered artificial PS in a formulation called surfactant-TA, a reconstituted PS supplement containing PLs, to 10 neonates with RDS (mean gestational age, 30 weeks; mean birth weight, 1,500 g). This was the first report to describe the successful use of an artificial PS preparation in the clinic and was a landmark contribution to the field.2 Fujiwara then won the Virginia Apgar Award, a neonatal research award from the American Academy of Pediatrics, and the King Faizal Medical Prize in Saudi Arabia for his work. Meanwhile, in Stockholm (Sweden), Bengt Robertson teamed up with Tore Curstedt to produce a porcine surfactant that they named after themselves: Curstedt–Robertson surfactant or “Curosurf.” This surfactant was isolated and produced from porcine lungs and underwent an additional preparation and purification step involving liquid gel chromatography.22

PS preparations are roughly categorized as natural PS preparations extracted from animals, such as cows or pigs, and synthetic preparations combining PLs alone or PLs with synthetic PS proteins. Natural products include Surfacten^®, Survanta^® (generic name as Beractant, AbbVie Inc., North Chicago, IL, USA), BLES^® (generic name as CLSE, BLES Biochemicals Inc., London, Canada), Infasurf^®, Alveofact^® (generic name as Bovactant, Boehringer-Ingelheim Pharma, Ingelheim, Germany), and Curosurf^®. Surfacten^® and Survanta^® are derived from modified bovine minced lung surfactant extracts with added DPPC, tripalmitoylglycerol, and palmitic acid. BLES^®, Infasurf^®, and Alveofact^® are bovine lung lavage surfactant extracts obtained using chloroform–methanol extraction. Curosurf^® is a porcine minced lung surfactant extract obtained using chloroform–methanol extraction and liquid-gel chromatography.2223 All natural PS preparations contain SP-B and CP-C, but the minced lung surfactants extracts (Survanta^® and Curosurf^®) contain less than 10% of the SP-B found in the lung lavage surfactant extracts (Infasurf^®, Alveofact^®, and BLES^®).24

Current synthetic products without SPs are mixtures of various surface-active PLs and spreading agents.25 These products include ALEC^® (generic name, Pumactant; Britannia Pharmaceuticals Ltd., Berkshire, UK) and Exosurf^®, which have been used in the past and are no longer manufactured due to lack of natural surfactant components, particularly the hydrophobic SP-B and C.25 Synthetic products containing SPs generated through peptide synthesis and recombination technology function similar to the SP-B and C of native human surfactant.26 These products include Surfaxin^® (generic name as Lucinactant, Discovery Laboratories, Warrington Township, PA, USA), which contains a chemically synthesized SP-B peptide called sinapultide (also known as KL4 peptide) combined with PLs and palmitic acid, and Venticure^® (generic name as rSP-C Surfactant, Byk Gulden, Konstanz, Germany), which contains a recombinant SP-C combined with PLs and palmitic acid. However, clinical trials with these products were discontinued.2728

In Korea, foreign PS preparations have been imported and used since 1991. The composition and characteristics of these preparations are summarized in Table 1. Since 1991, Surfacten^® has been a component of readjusted natural PS from minced bovine lung extract with DPPC, tripalmitoylglycerol and palmitic acid, and contains SP-B, and -C. Imports have been discontinued since 2018, and are no longer available. Exosurf^®, used from 1991 to 2008, was a synthetic PS of DPPC with 9% hexadecanol and 6% tyloxapol, which was not effective due to lack of SPs, and its production was discontinued in 2008. Curosurf^®, imported from 2003, is a natural PS from minced porcine lung DPPC, subjected to chloroform–methanol extraction, purified by liquid-gel chromatography, and contains SP-B and -C, and is currently in use. Infasurf^®, imported from 2007, had a short period of interruption and was imported again from 2017, is a natural PS from bovine lung lavage extract subjected to chloroform methanol extraction and contains SP-B, and -C. Newfactan^®, a domestic product developed in Korea and used since 1996, has the same components as Surfacten^®.

The Korean Society of Neonatology has hosted or sponsored numerous symposiums and seminars on PS replacement therapy (Table 2).72930 Since 1989, there have been many national and international communications on PS replacement therapy.

Before the formal importation of PS preparations into Korea in 1991, reports of pilot trials included those by Namgung et al.,31 in 1989, which involved eight cases, and Park et al.32 in 1991, involving six cases. After formal importation of PS preparations, the reports of outcomes of PS replacement therapy came from nationwide collective studies (total RDS patients who were admitted to the neonatal intensive care unit and who underwent PS replacement therapy without distinction according to birth weight), including those by Bae et al.33 in 1993 (60 patients in 16 hospitals), Bae et al.34 in 1997 (1,066 patients in 64 hospitals), Bae et al.35 in 2004 (1,596 patients in 62 hospitals), Bae et al.36 in 2009 (1,921 patients in 57 hospitals), and Bae et al.37 in 2011 (3,160 patients in 72 hospitals); the exception to these nationwide multicenter studies was one single-hospital study. Table 3 summarizes the results of these reports. The mortality rate for each year was 40.0% in 1990/1991, 28.7% in 1996, 18.7% in 2002, 14.3% in 2007, and 10.1% in 2010, clearly demonstrating the significant reduction in mortality. In 2014, Kim et al.38 published a report of nationwide research of early prophylactic and late selective use in RDS, showing that early prophylactic use was more effective than late selective use. Shim et al.8 reported changes in the survival rates of VLBWI and ELBWI in Korea before and after the introduction of PS. As shown in Fig. 1, the introduction of PS in 1991 contributed to improved survival rate, and the survival rates for 2010–2014 were reported to be 84.8% in VLBWI and 69.6% in ELBWI. Chung and Bae9 compared the survival rates of VLBWI and ELBWI in the KNN data in 2015 with data from western developed countries. Fig. 2 reveals that the levels were similar to those in the United States and Taiwan, which were slightly below those in Japan, Canada, Australia, New Zealand, and Europe.

There have been changes in the ways PS is administered. One focus of current research is the use of less invasive approaches. Tracheal intubation has been performed for PS administration in most premature babies; however, it is now known that positive pressure ventilation should be avoided as much as possible to minimize lung injury.39 The less invasive surfactant application (LISA) protocol developed by Kribs et al.40 preserves spontaneous breathing and avoids mechanical ventilation. It allows spontaneous breathing by combining PS administration and continuous positive airway pressure (CPAP). PS is delivered during CPAP via a thin catheter. In Korea, some studies have suggested that the early application of CPAP for RDS treatment is effective and can reduce the occurrence of lung injury via the Intubate-SURfactant-Extubation technique. However, there has been little research on LISA.4142

In 1991, the first imported PS preparations were not initially covered by insurance in Korea. Insurance started covering single doses in February 1992 and multiple doses in October 2007.5 Since January 2011, early PS replacement therapy (early prophylactic therapy, which is administered within 2 hours of birth in very preterm infants to prevent RDS, has already been proven to improve the prognosis in other countries) started to be covered by insurance.5 The criteria for early treatment are as follows: premature babies with a birth weight < 1,250 g or a gestational age < 30 weeks, and a single administration within 2 hours after birth. Recent changes in the standard of insurance benefits for neonatal RDS in Korea are described in Table 4.