When was surfactant discovered

The last 25 years have seen a large increase in basic science research on surfactants with determination of the structure and function of the four surfactant proteins probably being the most important advances. Future studies will focus on widening the indications for surfactant treatment, developing non-invasive means of administration and assessing the role of the newer synthetic surfactants. Abstract The first successful trial of surfactant treatment for respiratory distress syndrome RDS was reported in Substances Pulmonary Surfactants.

However, kinetics of surfactant phospholipid and protein synthesis and turnover can also be studied in vivo in infants by using the nonradioactive, stable isotopes 13 C and 2 H and analyzing serial tracheal aspirates with mass spectrometry.

The stable isotope method was used to demonstrate disruption of endogenous surfactant homeostasis in RDS, congenital diaphragmatic hernia, meconium aspiration pneumonia, genetic surfactant dysfunction diseases and other pathologic conditions, 21 , 22 , 23 , 24 but it can also assess the effects of exogenous surfactants in infants with RDS. Since the first studies of surfactant treatment for neonatal RDS in the s, several surfactant preparations have been tested and compared in clinical trials.

Currently, the only commercially available animal-derived surfactants are harvested either by lavage from bovine lungs such as calfactant, bovactant, bovine lipid extract surfactant or through mincing of porcine or bovine lung tissue, followed by centrifugation such as poractant alfa and beractant.

Commercially available animal-derived surfactant preparations differ in composition and concentration of PLs and proteins. Poractant alfa uses liquid chromatography to extract only polar lipids and contains the highest total concentrations of phospholipids and SP-B. The size of the first dose of surfactant may be more important for clinical response than the source of surfactant.

Older studies, before implementation of antenatal steroids and with other ventilation strategies, suggested that multiple doses of surfactant had additive effects in reducing complications such as pneumothorax. Recent guidelines do not recommend repeat doses routinely, but advise that a second and third dose should be given to infants with ongoing or progressing respiratory distress.

A meta-analysis by Singh et al. These results might suggest that the higher dose or concentration of phospholipids in poractant alfa may be important for optimal efficacy; however, there is a lack of dose-equivalent comparison groups to reliably answer this question, and there is the general flaw of meta-analyses that differences in indication and pattern of use at different centers may weaken the validity of results. Hence, it is not clear whether differing results are due to chemical composition, resistance to inactivation, or source of surfactant.

Recognizing the production limitations, costs and biological risks of animal-derived surfactants, many attempts have been made to produce synthetic surfactants for replacement therapy. A fully synthetic surfactant is appealing, because it eliminates concerns about the animal origin of mammalian surfactants, such as the potential risk of immunological or infectious side effects, and it also secures more predictable and consistent concentrations of all components in the surfactant preparation.

This second-generation synthetic surfactant was efficacious in treating RDS in preterm infants, 33 but proved to be inferior to animal-derived surfactants in randomized control trials, and was finally withdrawn from the market. Given the inferiority of protein-free synthetic surfactants, two third-generation synthetic surfactants lusupultide and lucinactant have been developed by adding functionally important proteins.

Lucinactant incorporated sinapultide KL4 acetate , a peptide analog mimicking SP-B, in a phospholipid mixture closer to human surfactant composition. Lucinactant has been evaluated against beractant and poractant alfa in two randomized trials and, although the second trial was stopped prematurely, the results suggest that it was safe, and outcome was comparable to animal-derived surfactants.

The drawbacks of the lucinactant preparation was its high viscosity at room temperature and a gel formulation, which required heating, mixing and subsequent cooling to body temperature before administration.

Also, the dose-equivalent volume was approximately 2. Surfaxin was withdrawn from the European market in , and production was completely stopped by the US manufacturer in Recently, CHF, a third-generation compound combining a 0.

In vivo stable isotope animal studies showed a considerable delay in catabolism and enhanced phospholipid recycling of CHF compared to poractant alfa. Surfactant consists of the two major subfractions called large aggregates LA and small aggregates SA. LA surfactant is able to lower alveolar surface tension, but SA surfactant is not surface active and is the metabolic product of the LA fraction.

Anionic polymers such as dextran and hyaluronan have the property of enhancing and restoring interface adsorption of surfactant LA. Endogenous and animal-derived surfactants supplemented with hyaluronan showed enhanced resistance to inactivation by meconium, cholesterol or serum, offering the potential for clinical improvements in secondary surfactant deficiencies due to ARDS, pulmonary hemorrhage or aspiration.

Due to its adsorption and spreading characteristics, surfactant is a potential vehicle for airway-targeted medications. It was used as an alternative to systemic steroids in the prevention and treatment of BPD, but no benefit could be demonstrated for the latter.

Cochrane Database Syst. However, the unusually high incidence of BPD in their study population may limit the value of their conclusion. Different modes of surfactant administration have been studied with regard to impact on mechanical properties of the lung and gas exchange.

The standard approach to administer surfactant is instillation via the endotracheal tube ETT in the mechanically ventilated infant with RDS. This allows rapid surfactant bolus application, resulting usually in a more homogenous surfactant distribution, compared to slow infusion of surfactant, as evidenced from animal studies.

Surfactant obviously needs a few minutes to dissipate into the typical monolayer along bronchial and alveolar surfaces, which is essential for its physicochemical properties.

However, an immediate change of resistance and the risk of disturbed blood pressure and heart rate, as well as bronchus obstruction, remain unsolved problems 49 , 52 , 53 , 54 ; so, in individual cases slow surfactant infusion might be preferable. Since mechanical ventilation is associated with barotrauma and increased risk for ventilator-associated infections, noninvasive modes to administer surfactant were sought to minimize need for endotracheal intubation or duration of mechanical ventilation.

This approach uses short acting sedatives for intubation allowing extubation to noninvasive respiratory support right after surfactant administration. Since the studies by Verder et al. Reversal of sedation or use of very short acting sedatives allow for rapid return to spontaneous breathing. More recently LISA was introduced, and this technique was adopted quickly into clinical practice.

Both newer modes of surfactant therapy have proven to reduce the duration of invasive mechanical ventilation. Several randomized trials showed an effectivity at least equivalent to the classical approach with intubation and mechanical ventilation. Surfactant has been given into the pharynx before the first breath, 64 via laryngeal mask 65 or by nebulization 66 either experimentally or in small trials.

Deposition of a satisfactory dose is the main challenge hampering these approaches. However, with new technical developments, these techniques may play a role in the future.

Consistent with animal data human studies have clearly shown that antenatal corticosteroid ANS treatment has significant beneficial effects on the outcome of preterm infants, reducing incidence and severity of RDS, but also mortality as one of the most important effects.

Animal models have shown that ANS accelerate lung maturation by thinning of the walls between the alveolar and vascular compartment and by speeding up maturation of the surfactant producing type II pneumocytes. Furthermore, ANS treatment enhances the effect of exogenous surfactant on these outcomes and on lung function.

Mortality is reduced, but there is no effect on neurodevelopmental outcome, and rate of BPD is reduced only in single studies. The most important effect of exogenous surfactant is lowering of the alveolar surface tension thereby improving lung volume, lung mechanics and gas exchange.

However, the effect of exogenous surfactant on these outcomes may differ between patients, and several factors impacting the response to exogenous surfactant have been identified. The timing of surfactant treatment after birth can also impact its efficacy. Several meta-analyses have shown that delaying surfactant treatment after birth will have a negative impact on its efficacy. However, it is important to mention that these negative effects of delayed surfactant treatment have mainly been observed in trials using invasive mechanical ventilation as initial strategy for respiratory support after birth.

Nowadays, many centers have adopted noninvasive ventilation as the primary mode postnatally, and studies have shown that delaying surfactant treatment under these circumstances does not have a negative effect on its efficacy, when compared with primary invasive respiratory support combined with early prophylactic surfactant treatment.

Secondary surfactant deficiency from surfactant inactivation may occur with aspiration syndrome, pulmonary hemorrhage, pneumonia or ARDS. An aspiration syndrome may be due to ingestion of meconium, 72 blood, 73 milk 74 or bile 75 into the lung. Part of the deleterious effects of meconium aspiration syndrome is exerted by inactivation of alveolar surfactant and activation of severe inflammation causing pneumonitis.

Blood components like hemoglobin, entering the lung either with sangineous amnion fluid or following pulmonary hemorrhage, rapidly inactivate surfactant causing secondary surfactant deficiency and severe decline in lung function. Disturbance of surfactant homeostasis in the presence of chorioamnionitis or pneumonia results from inactivation of surfactant with leakage of plasma proteins into the airspaces and influx of inflammatory cells causing cytokine release and inflammation.

Surfactant is frequently needed in inflammation processes, like chorioamnionitis, pneumonia or ARDS. However, while the role of surfactant therapy is well established to improve gas exchange and reduce mortality in primary surfactant deficiency in the preterm infant, its role in surfactant inactivation through inflammation is less clear: response is more unpredictable and often slower; also repeated doses of surfactant may be needed.

Mechanical ventilation of preterm infants is associated with volutrauma and hyperoxia, leading to lung damage. This triggers an inflammation process, which activates cellular response and release of cytokines and proteases, harbingers of BPD.

This sequence of injury can be attenuated or even abrogated by surfactant administration. Animal data suggest that large tidal volumes Vt delivered shortly after birth during respiratory support of preterm lambs have a negative impact on surfactant response.

Animal studies have also shown that injurious invasive mechanical ventilation increases conversion of SA to LA surfactant, which leads to leakage of proteins into the alveolar space and reduces surfactant function. Applying so-called lung-protective ventilation strategies can attenuate this process. Lack of surfactant, due to premature birth, hampers constant lung expansion, so continuous distending pressure from intermittent mandatory ventilation IMV or CPAP and administration of exogenous surfactant is required.

A homogenous distribution across the whole compartment of terminal bronchioli and alveoli would be optimal; however, surfactant will not reach areas, which are filled with debris or are collapsed, so a certain distending pressure is required immediately before and after surfactant administration. Unless surfactant is given via a side port of the ETT during continuous ventilation or CPAP, surfactant administration usually requires disconnection of the patient from the ventilator for a short period of time, during which alveoli will collapse.

So a static distending pressure via ventilation bag to re-open the lung and facilitate distribution of surfactant into the periphery after disconnection may be advantageous. Immediate increase in oxygenation, following surfactant administration, is probably the result of increased FRC, not of altered lung mechanics, 84 so FiO 2 is always the first parameter of ventilation, which can be reduced.

The subsequent ventilation most often requires increased peak inspiratory pressure PIP to yield at least minimum ventilation in the first minutes after surfactant treatment 53 , 54 or to overcome the frequent phenomenon of total bronchial obstruction. Positive end-expiratory pressure PEEP must be high enough to keep alveoli open during expiration, and from the clinical perspective PIP must be high enough to yield visible chest expansions after surfactant administration.

To some extent ventilation modes with volume guarantee may help to overcome the problem of rapidly changing lung mechanics after surfactant, resulting in changing Vt, but PIP must be set high enough.

At this time point frequency can eventually be increased. For effective and lung-protective ventilation in these most vulnerable preterm infants, the time-resolved mechanics of the inspiratory and expiratory part of the ventilation cycle should be taken into consideration. In this respect total bronchial and bronchiolar resistance and local bronchiolar and alveolar compliance are the most important determinants.

In animal and human studies surfactant administration leads to immediate changes in hemodynamics. In a dose-dependent manner mean arterial blood pressure decreases after surfactant, due to systemic vasodilation, but can be partly compensated by an increase in cardiac output.

On the other hand, these effects are difficult to distinguish from effects resulting from the frequently observed increase in pCO 2 , leading in particular to cerebral vasodilation and a decrease of left-to-right-shunt across the PDA after increase of pulmonary vascular resistance. These parameters can be measured only indirectly, but differences in timing of measurement, surfactant dose and persistence of PDA may also lead to varying results.

Over 50 years of basic research on surfactant biology and homeostasis have yielded one of the greatest breakthroughs in neonatology, surfactant replacement therapy, which has led to a spectacular increase in survival, pushing back the boundaries of premature viability, and improving short- and long-term morbidity of preterm infants.

However, translation of basic research into clinical applications remains often challenging, due to the complexity and extreme sensitivity of the surfactant system, the lack of clinically applicable assays and techniques, and the fragility of the premature infant. Translational research efforts, which aim at closing this gap, hold the potential for future advances, which may go well beyond prematurity and the neonatal period.

Parra, E. Composition, structure and mechanical properties define performance of pulmonary surfactant membranes and films. Lipids , — Suri, L. Adaptation to low body temperature influences pulmonary surfactant composition thereby increasing fluidity while maintaining appropriately ordered membrane structure and surface activity.

Acta , — Nogee, L. A mutation in the surfactant protein B gene responsible for fatal neonatal respiratory disease in multiple kindreds. A combined action of pulmonary surfactant proteins SP-B and SP-C modulates permeability and dynamics of phospholipid membranes. Peca, D. Clinical and ultrastructural spectrum of diffuse lung disease associated with surfactant protein C mutations.

ABCA3, a key player in neonatal respiratory transition and genetic disorders of the surfactant system. McCarthy, C. Statin as a novel pharmacotherapy of pulmonary alveolar proteinosis.

Clements, J. Surface phenomena in relation to pulmonary function. Physiologist 5 , 11—28 Stichtenoth, G.

Surface tension of airway aspirates withdrawn during neonatal resuscitation reflects lung maturity. PubMed Google Scholar. Bhatia, R. Neonatology , — Vieira, A. Lamellar body count and stable microbubble test on tracheal aspirates from infants for the diagnosis of respiratory distress syndrome. Care Med. Ravasio, A. High-throughput evaluation of pulmonary surfactant adsorption and surface film formation. Lipid Res. Danhaive, O.

Surface film formation in vitro by infant and therapeutic surfactants: role of surfactant protein B. The adjusted ORs demonstrate an approximate halving the odds of developing severe RDS, neonatal mortality and BPD in day survivors favoring prophylaxis. In Walti and colleagues using the same database of three trials demonstrated significant reductions in intraventricular hemorrhage IVH in the prophylaxis group.

Three criteria can be used to help develop a protocol for surfactant treatment: type of surfactant, timing of treatment and the dose of phospholipids required. Current evidence favors the use of natural surfactants rather than the old protein-free synthetic surfactants, and it is too soon to say whether the new synthetic surfactants have a role to play and none is currently approved for treatment of the newborn.

The dose of surfactant needed may depend upon timing, severity of illness and whether or not prenatal steroids were given. For gestational ages less than 27 or 28 weeks prophylaxis in the delivery suite would seem to be indicated based upon the currently available evidence. For these immature infants an attempt to extubate to CPAP should be made soon after transfer to the neonatal unit and this is usually possible in infants with gestational ages over 24 weeks.

The presence of chest X-ray appearances of RDS help to determine the need for early treatment. Are there benefits of introducing a policy of early or prophylactic surfactant treatment into a neonatal unit? An observational study from Belfast addressed this question. This study compared outcomes of extremely low gestational age 23 weeks to 27 weeks neonates between and at the Regional Neonatal Unit, Royal Maternity Hospital, Belfast.

This may have accounted for some of the need for increased oxygen supplementation. Any true increase in CLD is likely to have been of the milder variety as length of stay in hospital remained similar in the two eras median 47 versus 44 days Table 7. However, with improved early neonatal care and increased survival neonatologists have to care for more babies with CLD and, therefore, this remains one of the biggest problems to be solved in neonatal practice.

Surfactant was the first drug developed solely for treatment of neonates. Its use has been a major advance in neonatology during the past 25 years. Prophylactic or very early treatment with a natural surfactant seems to give the best results for very preterm infants at risk of developing RDS.

Long-term follow-up studies have not identified any increases in major neurodevelopmental or pulmonary sequelae in surviving infants. Von Neergaard K. Neue auffassungen uber einen grundbegriff der atemmechanik. Die retraktionskraft der lunge, abhangig von der oberflachenspannung in den alveolen. Z Gesamt Exp Med ; 66 : — Article Google Scholar. Gruenwald P.

Surface tension as a factor in the resistance of neonatal lungs to aeration. Am J Obstet Gynecol ; 53 : — Pattle RE. Properties, function and origin of the alveolar lining layer. Nature ; : — Clements JA. Dependence of pressure-volume characteristics of lungs on intrinsic surface active material. Am J Physiol ; : Google Scholar. Surface tension of lung extracts. Proc Soc Exp Biol Med ; 95 : — Macklin CC. The pulmonary alveolar mucoid film and the pneumonocytes.

Lancet ; i : — Obladen M. History of surfactant up to Biol Neonate ; 87 : — Avery ME, Mead J. Surface properties in relation to atelectasis and hyaline membrane disease. Am J Dis Child ; 97 : — CAS Google Scholar. Microaerosol administration of synthetic beta-gamma-dipalmitoyl-L-alpha-lecithin in the respiratory distress syndrome. A preliminary report. Can Med Assoc J ; 90 : 55— Neonatal pulmonary ischemia: clinical and physiologic studies. Pediatrics ; 40 : — Enhorning G, Robertson B.

Lung expansion in the premature rabbit fetus after tracheal deposition of surfactant. Pediatrics ; 50 : 58— Pharyngeal deposition of surfactant in the premature rabbit fetus. Biol Neonate ; 22 : — Effects of tracheal instillation of natural surfactant in premature lambs. Clinical and autopsy findings. Pediatr Res ; 12 : — Artificial surfactant therapy in hyaline membrane disease. Lancet ; i : 55— Structural and functional characterization of porcine surfactant isolated by liquid-gel chromatography.

Prog Resp Res ; 25 : — Halliday HL. Overview of clinical trials comparing natural and synthetic surfactants. Biol Neonate ; 67 suppl 1 : 32— Prophylactic treatment of very premature infants with human surfactant.

N Engl J Med ; : — History of surfactant from Soll RF. Prophylactic natural surfactant extract for preventing morbidity and mortality in preterm infants. Prophylactic synthetic surfactant for preventing morbidity and mortality in preterm infants. Synthetic surfactant for respiratory distress syndrome in preterm infants. Cochrane database. Syst Rev ; 3 : CD Multiple versus single dose natural surfactant extract for severe neonatal respiratory distress syndrome. Early versus delayed selective surfactant treatment for neonatal respiratory distress syndrome.

Prophylactic versus selective use of surfactant in preventing morbidity and mortality in preterm infants. Soll RF, Blanco F. Natural surfactant extract versus synthetic surfactant for neonatal respiratory distress syndrome. Early surfactant treatment with brief ventilation versus selective surfactant and continued mechanical ventilation for preterm infants with or at risk of respiratory distress syndrome.

A randomized, multicenter masked comparison trial of poractant alfa Curosurf versus beractant Survanta in the treatment of respiratory distress syndrome in preterm infants. Am J Perinatol ; 21 : — Comparison of Infasurf calf lung surfactant extract to Survanta beractant in the treatment and prevention of respiratory distress syndrome.

Pediatrics ; : 31— Comparison of Infasurf calfactant and Survanta beractant in the prevention and treatment of respiratory distress syndrome. Pediatrics ; : — Comparative evaluation of the respiratory and circulatory responses after instillation of two bovine surfactant preparations.

Pediatr Res ; 45 : A abstract Pharmacokinetics of bovine surfactant in neonatal respiratory distress syndrome. Randomised clinical trial of two treatment regimens of natural surfactant preparations in neonatal respiratory distress syndrome. A randomised trial comparing beractant and poractant treatment in neonatal respiratory distress syndrome. Acta Paediatr ; 94 : — Differences in mortality among infants treated with three different natural surfactants for respiratory distress syndrome.

Neonatology ; 91 : A multicenter, randomised, masked, comparison trial of lucinactant, colfosceril palmitate, and beractant for the prevention of respiratory distress syndrome among very preterm infants.

A multicenter, randomised, controlled trial of lucinactant versus poractant alfa among very premature infants at high risk for respiratory distress syndrome. Halahakoon CW. A study of cerebral function following surfactant treatment for respiratory distress syndrome MD thesis, Queen's University, Belfast, Comparison of three treatment regimens of natural surfactant preparations in neonatal respiratory distress syndrome.

Eur J Pediatr ; : — Collaborative European Multicenter Study Group. Surfactant replacement therapy for severe neonatal respiratory distress syndrome: an international randomized clinical trial.