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Animal-Derived Surfactants: Where Are We? the Evidence from Randomized, Controlled Clinical Trials

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Animal-Derived Surfactants: Where Are We? the Evidence from Randomized, Controlled Clinical Trials Journal of Perinatology (2009) 29, S38–S43 r 2009 Nature Publishing Group All rights reserved. 0743-8346/09 $32 www.nature.com/jp REVIEW Animal-derived surfactants: where are we? The evidence from randomized, controlled clinical trials R Ramanathan Division of Neonatal Medicine, Department of Pediatrics, Women’s and Children’s Hospital and Childrens Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA production of a surface-active agent, namely, surfactant. Surfactant Animal-derived surfactants, as well as synthetic surfactants, have been is the first drug developed specifically for treatment of preterm extensively evaluated in the treatment of respiratory distress syndrome neonates with RDS. Surfactant therapy has become the standard of (RDS) in preterm infants. Three commonly available animal-derived care in the management of RDS. Human surfactant is primarily surfactants in the United States include beractant (BE), calfactant (CA) and composed of dipalmitoylphosphatidylcholine (DPPC) and poractant alfa (PA). Multiple comparative studies have been performed surfactant proteins (SP), SP-A, SP-B, SP-C and SP-D. Among these using these three surfactants. Prospective as well as retrospective studies four surfactant proteins, two hydrophobic proteins, SP-B and SP-C, comparing BE and CA have shown no significant differences in clinical or play a crucial role in the adsorption and spread of the DPPC at the economic outcomes. Randomized, controlled clinical trials have shown that air–liquid interphase in the lungs. In addition, an antioxidant treatment with PA is associated with rapid weaning of oxygen and phospholipid, plasmalogen, has been shown to work synergistically ventilatory pressures, fewer additional doses, cost benefits and survival with surfactant-associated hydrophobic proteins in the spreading of advantage when compared with BE or CA. Recently, a study using an DPPC, thus maintaining lower surface tension and alveolar administrative database that included over 20 000 preterm infants has stability at the end of expiration.3,4 SP-A and SP-D are lectin shown a significant decrease in mortality and cost benefits in favor of PA, proteins that help to maintain sterility in the lung, whereas SP-B when compared with BE or CA. Differences in outcomes between these and SP-C help to maintain stability in the lung. None of the animal-derived surfactants may be related to a higher amount of surfactant preparations contain SP-A or SP-D. Natural, modified phospholipids and plasmalogens in PA. To date, animal-derived surfactants surfactants derived from bovine or porcine lungs contain different seem to be better than synthetic surfactants during the acute phase of RDS amounts of SP-B, SP-C and plasmalogens. Animal-derived as well and in decreasing neonatal mortality. Further studies are needed comparing as synthetic surfactants, which are completely devoid of SP-B, SP-C animal-derived surfactants with the newer generation of synthetic and plasmalogens, have been extensively evaluated in preterm surfactants. infants with RDS. Three animal-derived surfactant preparations Journal of Perinatology (2009) 29, S38–S43; doi:10.1038/jp.2009.31 used worldwide include beractant (BE) (Survanta, Abbott Keywords: preterm; respiratory distress syndrome; surfactant; animal Laboratories Inc., Columbus, OH, USA), calfactant (CA) (Infasurf, derived; synthetic; mortality Forest Laboratories, St Louis, MO, USA) and poractant alfa (PA) (Curosurf, Dey, LP, Napa, CA, USA). Synthetic surfactants that have been evaluated in comparative trials include colfosceril palmitate Introduction (Exosurf, Research Triangle Park, NC, USA), pumactant (ALEC, Significant advances in perinatal care have been achieved over the Britannia Pharmaceuticals, Crawley, UK) and lucinactant past three decades. Despite this, preterm birth rates continue to (Surfaxin, Discovery Laboratories, Doylestown, PA, USA). increase in the United States.1,2 Respiratory distress syndrome (RDS) is the leading cause of respiratory insufficiency and is a major cause of mortality and morbidity in preterm infants. Natural vs synthetic-surfactant studies Incidence of RDS is inversely proportional to gestational age at birth. Pathophysiology of RDS is characterized by insufficient Fourteen trials comparing animal-derived surfactants with synthetic surfactants have been published (Table 1).5–18 To date, Correspondence: Dr R Ramanathan, Division of Neonatal Medicine, Department of treatment with animal-derived surfactant preparations has been Pediatrics, Women’s and Children’s Hospital and Childrens Hospital Los Angeles, Keck School shown to result in better clinical response during the acute phase of Medicine, University of Southern California, 1240, North Mission Road, Room L-919, Los Angeles, CA 90033, USA. of RDS as evidenced by rapid weaning of inspired oxygen, mean E-mail: [email protected] airway pressure and lower air leaks when compared with treatment Animal-derived surfactants R Ramanathan S39 Table 1 Summary of 14 trials comparing animal-derived surfactants with synthetic surfactants for RDS in preterm infants Trials (n ¼ 14) Surfactant Number of Type Patients Results patients 5 Horbar et al. Beractant vs colfosceril 617 Treatment 500–1500 g Beractant: lower 0–72 h FiO2 and MAP palmitate 6 Alvarado et al. Beractant vs colfosceril 66 Treatment <1500 g Beractant: decreased duration of PPV, O2, LOS palmitate Pearlman et al.7 Beractant vs colfosceril 121 Treatment Any with No differences in any outcomes palmitate RDS Sehgal et al.8 Beractant vs colfosceril 41 Treatment 600–1750 g No differences in any outcomes palmitate 9 VON Beractant vs colfosceril 1296 Treatment 501–1500 g Beractant: lower FiO2 at 72 h, lower 0–72 h MAP, fewer air leaks palmitate 10 Hudak et al. Calfactant vs colfosceril 1126 Treatment All with RDS Calfactant: lower 0–72 h FiO2 and MAP, fewer air leaks palmitate 11 Hudak et al. Calfactant vs colfosceril 846 Prophylaxis <29 weeks Calfactant: less RDS, lower 0–72 h FiO2 and MAP, fewer air leaks, palmitate more intraventricular hemorrhage Modanlou Beractant vs colfosceril 122 Treatment <1500 g Beractant: lower FiO2, MAP and OI et al.12 palmitate da Costa et al.13 Beractant vs colfosceril 89 Treatment <37 weeks, No difference palmitate 1000 g 14 Rollins et al. Poractant alfa vs colfosceril 66 Treatment All with RDS Poractant alfa: lower FiO2, and improved a/A ratio palmitate Kukkonen Poractant alfa vs colfosceril 228 Treatment All with RDS Poractant alfa: lower FiO2, and MAP et al.15 palmitate Ainsworth Poractant alfa vs pumactant 212 Treatment <30 weeks Poractant alfa: decreased mortality (trial stopped after interim et al.16 analysis) Moya et al.17 Lucinactant vs colfosceril 1294 Prophylaxis 600–1250 g Lucinactant more effective than colfosceril palmitate and similar to palmitote vs beractant beractant Sinha et al.18 Lucinactant vs poractant alfa 252 Prophylaxis 600–1250 g Non-inferiority trial, early trial closure, original sample size 496, no differences in any outcomes Abbreviations: RDS, respiratory distress syndrome; FiO2, fraction of inspired oxygen; MAP, mean airway pressure; PPV, positive pressure ventilation; LOS, length of stay; OI, oxygenation index. with synthetic preparations. Furthermore, neonatal mortality has compared two different synthetic preparations, bronchopulmonary also been shown to be lower among infants treated with a porcine- dysplasia was significantly lower with lucinactant therapy when derived surfactant when compared with those treated with compared with colfosceril palmitate. In this prophylaxis trial, BE pumactant, a synthetic preparation.16 Ainsworth et al.16 compared was included as a reference arm. A total of 1294 preterm infants, the porcine-derived surfactant, PA, with pumactant. This trial was weighing 600 to 1250 g, were included; 509 infants received stopped by the data and safety monitoring committee, because colfosceril palmitate, 527 received lucinactant and 258 infants mortality assumed greater importance than the primary outcome. received BE, within 20 to 30 min of birth. Even though the trial Mortality was significantly lower (14.1 vs 31%, P ¼ 0.006; odds was designed as a prophylaxis trial, investigators allowed up to ratio 0.37; 95% confidence interval [0.18, 0.76]) in the PA-treated 30 min for administration of surfactants. This is because of the fact infants. This difference was sustained after adjusting for gestational that lucinactant is a gel at both room and body temperature, and age, birth weight, gender, center, plurality and use of antenatal had to be warmed in a special warming cradle to 44 1C for 15 min. steroids. This was the first randomized, controlled trial that showed In all earlier, randomized, controlled prophylaxis trials, surfactant a survival advantage for an animal-derived surfactant preparation was typically administered within 10 to 15 min of birth. In the true over that for a synthetic surfactant. However, survival advantage sense, this trial17 is an early rescue trial. Furthermore, comparison was a secondary endpoint in this trial. The incidence of of outcomes between BE and lucinactant was of secondary interest, bronchopulmonary dysplasia was not different with either and this trial was not powered to detect efficacy against BE. Despite animal-derived or synthetic surfactants. In the only trial17 that these limitations, there were no differences in the 14 variables that Journal of Perinatology Animal-derived surfactants R Ramanathan S40 Table 2 Composition of animal-derived
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