Portal de Periódicos da CAPES

The fascinating story of surfactant

2017; Wiley; Volume: 53; Issue: 4 Linguagem: Inglês

10.1111/jpc.13500

1440-1754

Henry L. Halliday,

Congenital Diaphragmatic Hernia Studies

The story of surfactant probably began in 1929 when Kurt von Neergaard, a German-born Physiologist working in Switzerland filled a porcine lung with an isotonic gum solution ‘to eliminate surface tension of the air tissue interfaces’.1 After expanding the lung with air and liquid, he concluded that ‘a lower surface tension would be useful for the respiratory mechanism’ and that ‘Surface tension as a force counteracting the first breath of the newly born should be investigated further’. Unfortunately, von Neergaard did not follow his own advice and it was Peter Gruenwald, a Pathologist working in New York who 18 years later repeated these experiments with the lungs of stillborn infants.2 Gruenwald stated ‘The resistance to aeration is due to surface tension which counteracts the entrance of air’ and he showed that surface active substances reduced the pressure needed for aeration. Of interest Peter Gruenwald later was a teacher of Mary Ellen Avery who was to play a major role in understanding the pathogenesis of respiratory distress syndrome (RDS). Prior to that, in the early 1950s, Richard Pattle in England,3 Charles Macklin in Canada4 and John Clements at the US Army Chemical Center in Maryland, USA5 were studying the effects of nerve gases on the lungs. Each in their own way contributed greatly to understanding the importance of surfactant. It is remarkable that three men working on chemical warfare projects in three countries in the 1950s came to similar conclusions independently (see Fig. 1). The next step was to show that hyaline membrane disease, now called RDS, was caused by abnormal surface tension in the lungs. Mary Ellen Avery was a research fellow in Jere Mead's laboratory in Boston, with Clement Smith as her clinical supervisor. Mel was so impressed with Clements’ studies in 1957 that she visited him in Edgewood to learn about the surface film Wilhelmy balance and adapt it to study lung extracts from newborn infants who had died soon after birth. Figure 2 is from the original publication in 1959, showing surface tension in dynes/cm on the vertical axis plotted against birthweight on the horizontal axis.6 Babies dying of hyaline membrane disease (closed circles) had mean minimal surface tensions of about 30 dynes/cm compared with about 8 dynes/cm for those who died of other causes (open circles). Avery and Mead concluded ‘Hyaline membrane disease is associated with absence or late appearance of some substances which in normal subjects render the internal surface capable of attaining a low surface tension when lung volume is decreased’. Despite knowledge of the cause of RDS as early as 1959, clinicians were reluctant to accept that surfactant deficiency was the major problem to be overcome and as a result progress to develop a cure proceeded slowly until a tragic event occurred. In 1963, President John Fitzgerald Kennedy and his wife Jacqueline Bouvier Kennedy were involved in a sad chapter of the history of surfactant. On 7 August 1963, just 4 years after Mead and Avery's seminal research on pathogenesis of RDS, Patrick Bouvier Kennedy, third child of President and Jackie Kennedy was born at 35 weeks after a placental abruption. Tragically, he died 2 days later from hyaline membrane disease despite state-of-the-art care in Boston. An obituary in the New York Times noted the absence of any specific treatment for hyaline membrane disease. This event helped focus attention on RDS. Within a year trials with synthetic surfactants had begun. Developmental work on surfactant phospholipids by Marshall Klaus and his colleagues in San Francisco7 allowed the first trials with synthetic surfactants to be conducted in Canada and Singapore, with publications in 19648 and 1967.9 Alas, the results were not good; both studies used nebulised dipalmitoylphosphatidylcholine (DPPC) with no apparent beneficial effects. The study of Jacqueline Chu and colleagues (including John Clements, Marshall Klaus and Bill Tooley) in Singapore left the authors so disillusioned that they entitled their paper ‘Neonatal Pulmonary Ischemia’ implying that the underlying cause of RDS was low pulmonary blood flow rather than surfactant deficiency.9 We now know that phospholipids on their own lower surface tension in vitro but proteins are necessary for the rapid spreading and adsorption needed for efficacy in vivo. Also, nebulisation was not an effective method of delivering surfactant to the lungs. About 2 years later, in 1969, an important observation in New Zealand was reported.10 Graham Liggins, an Obstetrician working in Auckland, infused glucocorticoids into pregnant sheep to try to prevent preterm labour and by serendipity he noticed that the immature lambs did not die soon after birth from RDS but survived.10 With his co-researcher Ross Howie, a Paediatrician, he later performed an important randomised controlled trial to show that maternal betamethasone given to women at risk of preterm birth reduced rates of RDS and neonatal mortality, at least in part by stimulating surfactant synthesis. This seminal paper was published in 197211 and it eventually led to acceptance of prenatal corticosteroids as a major contribution to improved perinatal care. In the same year, 1972, in Stockholm, Goran Enhorning, another Obstetrician, and Bengt Robertson, a Paediatric Pathologist, showed that preterm rabbits treated with natural surfactant did not die soon after birth.12 In 1973, they also showed that pharyngeal deposition rather than tracheal instillation of natural surfactant was effective13 in reducing mortality from RDS, but over 40 years later this is still not a recognised method of surfactant administration. Tetsuro Fujiwara in the 1970s was working in Forrest Adams’ laboratory in California14 but before US studies in humans could begin Fujiwara returned to Japan and in 1980 published in the Lancet the results of administration of Surfactant-TA to 10 preterm infants.15 These were relatively mature infants with a mean gestation of 30 weeks and mean birthweight over 1500 g. Within a short time, mean arterial oxygen tension had increased from about 45–210 torr and chest radiographs also improved. Nine of the 10 infants developed a patent ductus arteriosus and 2 died but natural surfactant (in this case bovine-derived) was launched as a treatment for RDS in 198015 (see Fig. 3). Meanwhile in Belfast, we had developed a synthetic surfactant containing DPPC and high density lipoprotein and had tested it prophylactically on 100 preterm babies of less than 34 weeks’ gestation.16 Our results were somewhat disappointing and we were considering the next steps to take when I met Colin Morley who had developed his own synthetic surfactant (ALEC or pumactant) with Alec Bangham in Cambridge.17 He was interested in our results and helped us analyse the outcome for a sub-group of infants of 25–29 weeks’ gestation. Figure 4 shows neonatal mortality in four studies – the old and new Cambridge studies, the Belfast and the Nottingham – surfactant treated infants had lower death rates than controls in all four trials. In our study we had only 36 infants of 25–29 weeks’ gestation so our trial was under-powered to show a difference in this important sub-group.16 Colin suggested that I should contact Bengt Robertson in Stockholm and compare our surfactant with a natural product. Meanwhile in Stockholm, Bengt Robertson with his expertise in in vitro and in vivo testing of surfactants had teamed up with Tore Curstedt, a Clinical Chemist, with an interest in isolation of phospholipids and proteins.18 Together they produced a porcine surfactant which they named after themselves – Curstedt – Robertson surfactant or Curosurf for short. This surfactant was unique in that, apart from being produced from pig rather than cow lungs, it went through an additional preparation step of liquid gel chromatography leaving only polar lipids and SP-B and SP-C with a phospholipid concentration of 80 mg/mL18 (see Fig. 5). I spent November 1984 in Stockholm comparing our synthetic surfactant Turfsurf with Curosurf, both in vitro and in Bengt's 27-day fetal rabbit model. The 27-day fetal rabbits were given surfactant or saline and ventilated using a multiple chamber, constant pressure whole body plethysmograph developed by Burkhard Lachmann and Bengt Robertson and later modified by Bo Sun (see Fig. 6). Curosurf was clearly better than Turfsurf in treating experimental RDS.19 Whilst I was in Stockholm, I also witnessed the treatment with Curosurf of very preterm twins who had severe RDS, and the white creamy mixture literally turned these blue babies pink within minutes. The chest x-ray also dramatically improved within a very short time from a white-out to almost clear lung fields20 (see Fig. 7). This led us to design and undertake the first randomised controlled trial of Curosurf, made exclusively in Stockholm by Tore Curstedt and not by a drug company at that time. We randomised preterm infants with severe RDS (mean inspired oxygen 80%) and mean age 10 hours to treatment with a single dose of 200 mg/kg Curosurf or treatment with mechanical ventilation alone (control group). We found significant reductions in pulmonary air leaks, neonatal mortality and death or bronchopulmonary dysplasia (BPD) in treated infants.21 Subsequent trials studied single versus multiple doses, early versus late surfactant treatment, use of CPAP and surfactant and comparisons with other surfactant preparations.22, 23 For the first few studies in the 1980s and 1990s mortality fell from 50% in controls to 30% with single dose treatment to about 10% with multiple doses, but remember this was late rescue treatment more than 30 years ago, a far cry from today's practice. Many surfactant preparations have been used in clinical trials including: the original protein-free synthetic surfactants – pumactant (ALEC), colfosceril palmitate (Exosurf) and the Belfast surfactant (Turfsurf) which was never commercially produced; the natural (minced lung extract) surfactants – Surfactant-TA (Fujiwara's surfactant), beractant (Survanta) – the north American version of Surfactant-TA with added DPPC, tripalmitin and palmitic acid and poractant alfa (Curosurf); and the natural (lung lavage extract) surfactants – calf lung surfactant extract or bLES used in Canada, calfactant (Infasurf) in the USA and bovactant (Alveofact) used in parts of Europe. Amniotic fluid extract was a very interesting surfactant studied by Allen Merritt and Mikko Hallman – it contained some SP-A in addition to SP-B and SP-C and appeared to be very effective.22 However, it was withdrawn from clinical use once the risk of HIV contamination became apparent. Some new synthetic surfactants containing protein analogues, including CHF5633, have recently been studied.18 Surfactant was the first drug developed solely for treatment of neonates; a major breakthrough in neonatal medicine in the past 35 years. Surfactant reduced both neonatal mortality and pulmonary air leaks by about 50%. Its introduction was also associated with a 6% reduction in infant mortality in the USA. Prophylactic or very early treatment with a natural surfactant seemed to give the best results for very preterm infants although recent trials suggest early CPAP is also effective. Follow-up studies showed no increase in adverse neuro-developmental or pulmonary sequelae. Currently, three surfactant preparations are licensed for use in Europe: beractant, bovactant and poractant alfa whereas there are four in the USA: beractant, calfactant, lucinactant and poractant alfa. All but lucinactant are derived from animal lungs.24 Recently, guidelines for surfactant treatment have been updated in Europe24 and the USA.25 The present indications for surfactant therapy may be summarised as: treatment of RDS; prophylaxis of RDS, although early CPAP is probably just as effective in most cases; surfactant may help in meconium aspiration syndrome (MAS)26 or neonatal pneumonia,25 improving oxygenation and reducing need for extracorporeal membrane oxygenation; other indications are largely experimental. Not all our problems in neonatology have been solved and those continuing include – prevention and management of chronic lung disease or BPD, determining the limits of viability for optimal survival without significant disability, providing appropriate neonatal care in the developing world and finally putting the patient (and family) first in all our care decisions. What does the future hold? New generation synthetic surfactants with protein analogues which are cheaper to produce and more resistant to inactivation will continue to be developed and tested in preterm babies.18 As inactivation of surfactant may be a key feature in pathogenesis of neonatal pneumonia, MAS and adult RDS, these new surfactants may have a role in their management. Nebulisation and/or atomisation will continue to be developed as means of non-invasive administration of surfactant, and drug delivery directly to the lungs using surfactant may become commonplace and an effective way of reducing BPD. The fascinating story of surfactant also involved names such as Charles Cochrane, Ted Egan, Lou Gluck, Mikko Hallman, Sam Hawgood, Alan Jobe, Walker Long, Allen Merritt, Bob Notter, Michael Obladen, Rod Phibbs, Fred Possmayer, Ola Saugstad, Don Shapiro, Barry Smith, Roger Soll, Christian Speer, Bo Sun, Bill Taeusch, Jeff Whitsett and many others. Although only the latter part of this story occurred during my clinical lifetime it was an honour to have been involved in some small way. The story, however, is not over as we enter the era of altering the survival of preterm infants into survival without long-term disabilities. The author would like to thank Tore Curstedt from the Karolinska Institute, Stockholm who provided material for some of the figures reproduced in this viewpoint article.