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Surfactant Preparations for Preterm Infants with Respiratory Distress Syndrome: Past, Present, and Future

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Surfactant Preparations for Preterm Infants with Respiratory Distress Syndrome: Past, Present, and Future Review article Korean J Pediatr 2019;62(5):155-161 Korean J Pediatr 2019;62(5):155-161 https://doi.org/10.3345/kjp.2018.07185 pISSN 1738-1061•eISSN 2092-7258 Korean J Pediatr Surfactant preparations for preterm infants with respiratory distress syndrome: past, present, and future Ga Won Jeon, MD, PhD Department of Pediatrics, Inje University Busan Paik Hospital, Inje University College of Medicine, Busan, Korea Following the first successful trial of surfactant replacement therapy for preterm infants with respiratory Corresponding author: Ga Won Jeon, MD, PhD distress syndrome (RDS) by Fujiwara in 1980, several animal-derived natural surfactants and synthetic Department of Pediatrics, Inje University Busan Paik Hospital, Inje University College of Medicine, surfactants have been developed. Synthetic surfactants were designed to overcome limitations of 75 Bokji-ro, Busanjin-gu, Busan 47392, Korea natural surfactants such as cost, immune reactions, and infections elicited by animal proteins con- Tel: +82-51-890-6497 tained in natural surfactants. However, first-generation synthetic surfactants that are protein-free Fax: +82-51-895-7785 have failed to prove their superiority over natural surfactants because they lack surfactant protein (SP). E-mail: [email protected] https://orcid.org/0000-0002-8206-9727 Lucinactant, a second-generation synthetic surfactant containing the SP-B analog, was better or at least as effective as the natural surfactant, suggesting that lucinactant could act an alternative to natural Received: 16 October, 2018 surfactants. Lucinactant was approved by the U. S. Food and Drug Administration in March 2012 as the Revised: 8 January, 2019 fifth surfactant to treat neonatal RDS. CHF5633, a second-generation synthetic surfactant containing Accepted: 8 February, 2019 SP-B and SP-C analogs, was effective and safe in a human multicenter cohort study for pre term infants. Many comparative studies of natural surfactants used worldwide have reported different efficacies for different preparations. However, these differences are believed to due to site variations, not actual differences. The more important thing than the composition of the surfactant in improving outcome is the timing and mode of administration of the surfactant. Novel synthetic surfactants containing syn- thetic phospholipid incorporated with SP-B and SP-C analogs will potentially represent alternatives to natural surfactants in the future, while improvement of treatment modalities with less-invasive or non- invasive methods of surfactant administration will be the most important task to be resolved. Key words: Pulmonary surfactants, Preterm infant, Newborn respiratory distress syndrome, Calfactant, Poractant alfa Introduction The first successful trial of surfactant replacement therapy in preterm infants with respiratory distress syndrome (RDS) was reported by Fujiwara et al.1) using surfactant-TA in 1980. Surfactant-TA (Surfacten, Tokyo Tanabe Co, Tokyo, Japan) is a modified minced bovine lung surfactant extract that contains surfactant protein (SP)-B and SP-C with dipalmitoyl phospha- tidyl-choline (DPPC), tripalmitin, and palmitic acid. Surfactant-TA can improve neonatal morbidity such as pneumothorax, intracranial hemorrhage, bronchopulmonary dysplasia (BPD), and mortality of preterm infants associated with RDS.2) Copyright © 2019 by The Korean Pediatric Society Various animal-derived natural surfactants, first-generation synthetic surfactants, and second-generation synthetic surfactants have been developed. However, individual neonatal This is an open-access article distributed under the terms of the Creative Commons Attribution Non- intensive care units use different surfactants. Various natural surfactants and synthetic Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/) which permits unrestricted non- surfactants will be compared from the past to present in this review. In addition, better commercial use, distribution, and reproduction in any preparations or mode of administration of surfactants will be sug gested to improve outcome of medium, provided the original work is properly cited. https://doi.org/10.3345/kjp.2018.07185 155 Jeon GW • Surfactants for preterm infants preterm infants. Table 1. Surfactants used in clinical trials Animal-derived natural surfactants Minced lung extracts Surfacten (surfactant-TA) bovine Composition and functions of pulmonary surfactants Survanta (beractant) bovine Curosurf (poractant alfa) porcine The function of pulmonary surfactants is essentially to lower sur - Lung lavage extracts bLES (CLSE) calf face tension, thus preventing collapse of alveoli at the end of expira- Infasurf (calfactant) calf tion. The surfactant is composed of a complex mixture of ap proxi- Alveofact (SF-RI1) bovine mately 90% lipids and 10% proteins. These lipids include 80%–90% Amniotic fluid extracts Human surfactant phospholipids, 5% neutral lipids, and cholesterol. The phos pholipids Synthetic surfactants are mainly composed of 80% phosphatidyl-choline, 5%–10% First generation synthetic surfactants Exosurf (colfosceril palmitate) phosphatidyl-glycerol (PG), and other phospholipids. Major surface- (protein-free) ALEC (pumactant) active phospholipids that can lower surface tension include DPPC Belfast surfactant (Turfsurf) and PG.3,4) Second generation synthetic surfactants Surfaxin (lucinactant) SPs are composed of 2 hydrophobic proteins, SP-B and SP-C, and (protein-containing) Venticute (rSP-C surfactant) 2 hydrophilic proteins, SP-A and SP-D. SP-B and SP-C play signifi- ALEC, artificial lung-expanding compound; CLSE, calf lung surfactant extract. cant roles in the adsorption and spread of DPPC to stabilize alveoli. Phospholipids incorporated with SP-B and SP-C and packaged with lamellar bodies are secreted into the airspace. Phospholi pids layers Reading, UK) (Table 1). called surface films are formed at the air-liquid interface and SP-B and SP-C also help stabilize this surface film during respiration. 2. Comparison of first-generation synthetic surfactant with natu- DPPC can adsorb to the air-liquid interface of alveoli through hydro- ral surfactant philic head groups with affinity to water and with the hydrophobic Multiple studies have been conducted to compare natural surfac- tail toward air, thus reducing surface tension.5) tants with protein-free, first-generation synthetic surfactants (Table The surfactant storage pool in term newborn infants is 100 mg/ 2). Soll and Blanco reviewed 11 randomized controlled trials (RCTs) kg whereas that in preterm infants is 4–5 mg/kg at birth. Thus, exo- (from 1975 to 2000) and compared protein-free synthetic surfac- genous surfactant replacement therapy in preterm infants is crucial tants with natural surfactants.8) Protein-free synthetic sur factants until endogenous surfactant levels are sufficient to stabilize the failed to lower surface tension whereas natural surfactants reduced alveoli and reduce surface tension.6) the requirement for ventilator support, the risk of pneumo thorax, and the risk of mortality.8) Protein-free synthetic surfactants have been associated with increased mortality with greater risk of pneu- First-generation synthetic surfactant mothorax than animal-derived surfactants. The inferiority of protein- free synthetic surfactants might be attributable to the ab sence of 1. Composition of protein-free first-generation synthetic surfac- SP-B and SP-C, resulting in failure to lower surface tension. tants Ardell et al.9) reviewed 15 RCTs (from 1975 to 2014) comparing The benefits of exogenous surfactants for preterm infants with protein-free synthetic surfactants to natural surfactants. Greater RDS are well established. However, animal-derived natural surfac- early improvement in the requirement of a ventilator, fewer cases of tants have limitations such as their elevated costs and limited pro- pneumothorax, and fewer deaths have been associated with natural duction due to animal availability. In addition, they contain animal surfactants. This superiority of natural surfactants over protein-free proteins that may be potentially immunogenic and infectious. synthetic surfactants was directly related to their SP-B and SP-C Therefore, synthetic surfactants have been developed to overcome content. Finally, protein-free, first-generation synthetic surfactants these limitations of natural surfactants. Synthetic surfactants are have been removed from the market, as the superiority over natural manufactured with fewer production limitations. In addition, they surfactants could not be demonstrated. do not contain immunogens or pro-inflammatory mediators that cause BPD and animal-borne infections because they are free of 7) animal proteins. First-generation synthetic surfactants contained Natural surfactants phospholipids only without SPs. Commonly used protein-free, first-generation synthetic surfactants were colfosceril palmitate 1. Composition of animal-derived natural surfactants (Exosurf, GlaxoSmithKline, Brentford, UK) and pumactant (ALEC, Beractant (Survanta, Abbott Laboratories, Abbott Park, IL, USA) artificial lung expanding compound, Britannia Pharmaceuticals Ltd., is used in Western regions such as the United States and Europe 156 https://doi.org/10.3345/kjp.2018.07185 Korean J Pediatr 2019;62(5):155-161 instead of surfactant-TA. Beractant is similar to surfactant-TA. It is a modified minced bovine lung surfactant extract with SP-B, SP- 2. Comparison of animal-derived natural surfactants C, DPPC, tripalmitin, and palmitic acid. Several natural
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