Journal of Perinatology (2009) 29, S23–S28 r 2009 Nature Publishing Group All rights reserved. 0743-8346/09 $32 www.nature.com/jp REVIEW Synthetic surfactants: where are we? Evidence from randomized, controlled clinical trials F Moya1,2 1Department of Neonatology, New Hanover Regional Medical Center, Wilmington, NC, USA and 2Department of Pediatrics, University of North Carolina, Chapel Hill, NC, USA were shown in that meta-analysis or in any individual trials The benefits of exogenous synthetic or animal-derived surfactants for comparing these surfactants. None of these surfactant comparison prevention or treatment of respiratory distress syndrome (RDS) are well trials reported outcomes beyond the initial stay in the neonatal established. Data from head-to-head trials comparing animal-derived intensive care unit (NICU). surfactants primarily with the synthetic surfactant colfosceril suggest that Multiple studies have shown that synthetic surfactants lacking the major clinical advantages afforded by the presence of surfactant protein SP-B and SP-C fail to lower surface tension in vitro, whereas (SP)-B and SP-C in animal-derived preparations relate to faster onset of animal-derived surfactants can reduce it to an extent somewhat action, a reduction in the incidence of RDS when used prophylactically, and directly related to their SP content.3,4 The absence of SP-B seems to a lower incidence of air leaks and RDS-related deaths. However, no benefits be particularly important as animals or humans lacking SP-B in terms of overall mortality or BPD have been shown in these head-to-head because of a genetic mutation develop a fatal form of respiratory comparisons. Findings from trials of a new-generation synthetic surfactant failure during the neonatal period.5,6 In contrast, individuals with containing a peptide that mimics SP-B, as well as their follow-up study mutations in SP-C develop interstitial lung disease as adults rather suggest that its administration improves short-term clinical outcomes than respiratory disease during the neonatal period.7 compared with colfosceril and results in survival through 1 year of age, The purpose of this review is to summarize the results from which is at least comparable, if not perhaps superior, to that seen with published randomized trials comparing animal-derived with animal-derived surfactants. synthetic surfactants devoid of proteins and to review the evidence Journal of Perinatology (2009) 29, S23–S28; doi:10.1038/jp.2009.26 from clinical trials of a new-generation synthetic surfactant that 8 Keywords: surfactant; respiratory distress syndrome; bronchopulmonary contains phospholipids and a peptide that mimics SP-B. For a dysplasia; infant/newborn summary of all published head-to-head comparison trials of surfactants, including comparisons between animal-derived surfactants, the reader is referred to the recent review by Moya and Maturana.9 Introduction Animal-derived surfactants from bovine or porcine sources currently in clinical use contain various phospholipids and variable quantities of surfactant proteins (SP)-B and -C, whereas currently Composition of commonly used surfactants available synthetic surfactants contain only phospholipids and no The main characteristics and components of the most studied and surfactant proteins.1 Although synthetic surfactants have potential used synthetic and animal-derived surfactants are found in safety advantages over animal-derived products, they seem to be Table 1. The amount of phospholipids administered per dose of clinically inferior to animal-derived surfactants. This assertion is surfactant is quite variable and ranges from 50 to 200 mg kg–1. based primarily on the results of a meta-analysis of 11 controlled The volume of each dose and interval for administration trials comparing these two classes of surfactants, which showed a recommended by the various manufacturers are also different. marginally significant lower mortality and a lower risk of Colfosceril and pumactant contain no SPs. Animal-derived pneumothorax plus more rapid weaning with animal-derived surfactants differ in their contents of SP-B and SP-C.3 Calfactant surfactants compared with synthetic surfactants.2 However, no (Infasurf, Forest Laboratories, Inc., St Louis, MO, USA) contains the reductions in the incidence of bronchopulmonary dysplasia (BPD) highest concentration of SP-B on a weight basis, followed by poractant (Curosurf, Chiesi Farmaceutici, Parma, Italy). Beractant Correspondence: Dr F Moya, Department of Neonatology, New Hanover Regional Medical Center, 2131 South 17th Street, Wilmington, NC 28402-9025, USA. (Survanta, Ross Products Division, Abbott Laboratories, Columbus, E-mail: [email protected] OH, USA) has the lowest content of SP-B of these animal-derived Synthetic surfactants F Moya S24 Table 1 Main characteristics of surfactants commonly used or studied in neonates Surfactant Family Main Proteins Phospholipid Suggested dose Phospholipid phospholipids concentration (mg mlÀ1) (ml kgÀ1) per dose (mg kgÀ1) Colfosceril Synthetic DPPC No 13.5 5 67.5 Pumactant Synthetic DPPC, PG No 40 1.2 100 Beractant Animal-derived (bovine) DPPC, PG SP-B/SP-C 25 4 100 Calfactant Animal-derived (bovine) DPPC, PG SP-B/SP-C 35 3 105 Poractant Animal-derived (porcine) DPPC, PG SP-B/SP-C 80 1.25/2.5 100/200 Lucinactant Peptide-containing DPPC, POPG KL4 as SP-B 30 5.8 175 synthetic Abbreviations: DPPC, dipalmitoylphosphatidylcholine; PG, phosphatidylglycerol; POPG, palmitoyloleylphosphatidylglycerol; SP-B, surfactant protein B; SP-C, surfactant protein C. surfactants. The content of the SP-B mimic in lucinactant recent lucinactant prophylaxis trial comparing this surfactant with (Surfaxin, Discovery Laboratories, Warrington, PA, USA) is colfosceril, in which infants were also randomized to beractant in a discussed later. 2:2:1 scheme.10–15 A major advantage of these studies lies in the fact that several thousand infants have been included. A major limitation in the design of these studies is that none of them were Controlled trials comparing non-protein-containing masked, except for the comparison included within the lucinactant synthetic with animal-derived surfactants trial. Moreover, the use of antenatal steroids in all but the Since the advent of exogenous surfactant therapy, several lucinactant trials was <40%, reflecting the time when they were animal-derived but only two synthetic surfactants devoid of SPs have conducted. The cumulative results show that overall mortality was been used clinically, namely colfosceril (Exosurf, GlaxoSmithKline, 18.4% for beractant and 20.9% for colfosceril (relative risk (RR) Brentford, UK) and pumactant (artificial lung expanding 0.89, 95% CI 0.75 to 1.05). Only the incidence of pneumothorax compound, Britannia Pharmaceuticals Ltd, Redhill, Surrey, was reduced using beractant versus colfosceril when used for England). Over the past decade and a half, there have been many treatment of RDS (RR 0.61, 95% CI 0.47 to 0.78) with a number randomized trials comparing these two major classes of surfactants, needed to treat (NNT) of 21, but not for prophylaxis of RDS. No although most have used a treatment rather than a prophylactic changes in need for supplemental oxygen at 36 weeks were noted approach. Soll and Blanco2 conducted a widely quoted systematic (23.5 versus 25.6%, respectively). Nonetheless, those trials for review of 11 trials comparing animal-derived surfactants with treatment of RDS in which ventilatory settings were reported synthetic surfactants. Seven of ten of the trials included in that showed more rapid reductions of supplemental oxygen and review compared colfosceril with beractant, two trials compared it ventilatory pressures among infants given beractant, which with calfactant and one trial with poractant alfa. Only one trial averaged about 7% lower FiO2 and 0.7 cm H2O lower mean airway compared the only other synthetic surfactant used clinically, pressure over the first 48 h. It should be noted that, when pumactant, with poractant. These authors concluded that both types colfosceril was compared with beractant using a prophylactic of surfactants are effective in the treatment and prevention of approach, a secondary comparison in one of the lucinactant trials, respiratory distress syndrome (RDS). However, they also concluded beractant reduced the incidence of RDS at 24 h (33.3 versus 47.2%, that, when taken together, use of animal-derived surfactants respectively), but did not result in less overall deaths, deaths due to 15 resulted in fewer deaths, greater early improvement in the RDS or other complications. requirement for ventilatory support and a lower overall incidence of Collectively, these data show that beractant has clinical pneumothorax than synthetic products containing only advantages such as less pneumothorax and more rapid weaning phospholipids. No advantages in terms of reduction in the incidence over colfosceril mainly when used for treatment of RDS, although of BPD were described in this systematic review or in any of the it is also more effective in prevention of RDS than colfosceril. individual trials included in it. In addition, a small but significant No benefits in terms of overall mortality or BPD have been shown. increase in the incidence of intraventricular hemorrhage (IVH) among infants treated with animal-derived surfactants was reported. Colfosceril versus calfactant There have been only two trials comparing colfosceril and Colfosceril versus beractant calfactant, one for prophylaxis and one for