Infasurf Research Articles

Health Economics and Outcomes of Surfactant Treatments for Respiratory Distress Syndrome Among Preterm Infants in US Level III/IV Neonatal Intensive Care Units.

To compare length of stay (LOS), costs, mechanical ventilation (MV), and mortality in preterm infants treated in the Neonatal Intensive Care Unit (NICU) with beractant (BE), calfactant (CA), and poractant alfa (PA) for Respiratory Distress Syndrome (RDS). This study evaluated preterm infants born between 2010 and 2013 with RDS diagnosis, gestational age of 25 to 36 weeks, birthweight of ≥500 g, and age of ≤2 days on first surfactant administration. Multivariable regression was used to evaluate all NICU outcomes. Of 13,240 infants meeting the study criteria, 4136 (31.2%) received BE, 2502 (18.9%) received CA, and 6602 (49.9%) received PA. Adjusted analyses estimated similar mean LOS (BE 26.7 days, CA 27.8 days, and PA 26.2 days) and hospital costs (BE: $50,929; CA: $50,785; and PA: $50,212). Compared to PA, BE and CA were associated with greater odds of MV use on day 3 (OR = 1.56 and 1.60, respectively) and day 7 (OR = 1.39 and 1.28, respectively; all p < 0.05). Adjusted NICU mortality was significantly higher only with CA vs PA (OR = 1.51; p = 0.015). Adjusted NICU LOS and costs were similar among BE, CA, and PA. Infants receiving PA were less likely to be on MV at 3 and 7 days, and PA treatment was associated with lower odds of NICU mortality when compared to CA.

PS-280 Surface Film Fromationin VitroBy Infant And Therapeutic Surfactants: Role Of Surfactant Protein B

Background Essential surfactant properties include transfer to gas-liquid interface, reduction of surface tension and film replenishment during respiratory cycles. Objective To compare component-specific film formation properties of infant and therapeutic surfactants. Design/methods Using a multiwell fluorescence assay, we compared maximal fluorescence (Max), time to reach Max (tMax) and phospholipid concentration for ½ maximal signal (½Max) for calfactant (CAL), poractant (POR), beractant (BER), colfosceryl palmitate (COL), with surfactant from immature infants with RDS. Dose-response studies were performed for addition of SP-B, albumin and budesonide. Results Max and ½Max values for CAL were higher/similar to those of rat surfactant. There were significant differences between CAL and other therapeutic surfactants for Max (CAL >COL >POR >BER) whereas ½Max were similar except for COL. In surfactant from 39 infant tracheal aspirates, ½Max was inversely correlated with SP-B content (p = 0.001). Addition of SP-B to samples with low endogenous content ( Conclusions This assay reveals differences in film formation efficiency for therapeutic surfactants reflecting differences in SP-B content and lipid composition. Film formation by infant surfactant is strongly influenced by SP-B content. The findings support the key physiological role of SP-B and the safety of surfactant as anti-inflammatory drug vehicle.

Response to Cummings

We would like to thank Dr Cummings for giving us the opportunity to explain our study results. Results from nine randomized, controlled, trials (RCTs),1, 2, 3, 4, 5, 6, 7, 8, 9 including the one that has been just published (e-pub ahead of print) by Dizdar et al.9 and meta-analyses10, 11, 12 comparing animal-derived surfactants, namely, poractant alfa (PA), beractant (BE), bovactant (BO) and/or calfactant (CA), have consistently shown faster weaning of oxygen and mean airway pressure, less need for redosing, fewer days on oxygen and mechanical ventilation, shorter length of stay (LOS) as well as survival advantage in babies treated with PA. These advantages with PA over BE, CA or BO are likely related to major biological and/or biochemical differences between these animal-derived surfactant preparations. PA contains the highest amount of phospholipids when compared with BE or CA. Higher amount of phospholipids has been shown to downregulate oxidative functions in monocytes and confer better anti-inflammatory properties.13 In addition, bacterial growth in different surfactant preparations is influenced by microbial species and the composition and dose of the surfactant. PA was bactericidal in a dose-dependent fashion and differed from BE and BO, a surfactant preparation similar to CA.14 PA contains the highest amount of plasmalogens (PL) when compared with BE.15 BO contains the lowest amount of PL.15 PL are anti-oxidant phospholipids and presence of higher amounts of PL in the tracheal aspirates from pre-term infants has been shown to be associated with a lower risk for bronchopulmonary dysplasia (BPD).16 Also, the amount of surfactant-associated protein B (SP-B) is highest in PA when compared with BE or CA. SP-B is the most important SP in helping the phospholipids to rapidly adsorb at the air–liquid interphase and in decreasing surface tension. Furthermore, the phospholipid molecular species of PA is much closer to that of human surfactant.17, 18

Animal-derived surfactants: where are we? The evidence from randomized, controlled clinical trials

Animal-derived surfactants, as well as synthetic surfactants, have been extensively evaluated in the treatment of respiratory distress syndrome (RDS) in preterm infants. Three commonly available animal-derived surfactants in the United States include beractant (BE), calfactant (CA) and poractant alfa (PA). Multiple comparative studies have been performed using these three surfactants. Prospective as well as retrospective studies comparing BE and CA have shown no significant differences in clinical or economic outcomes. Randomized, controlled clinical trials have shown that treatment with PA is associated with rapid weaning of oxygen and ventilatory pressures, fewer additional doses, cost benefits and survival advantage when compared with BE or CA. Recently, a study using an administrative database that included over 20,000 preterm infants has shown a significant decrease in mortality and cost benefits in favor of PA, when compared with BE or CA. Differences in outcomes between these animal-derived surfactants may be related to a higher amount of phospholipids and plasmalogens in PA. To date, animal-derived surfactants seem to be better than synthetic surfactants during the acute phase of RDS and in decreasing neonatal mortality. Further studies are needed comparing animal-derived surfactants with the newer generation of synthetic surfactants.

Surfactant liquid and black foam film formation and stability in vitro and correlative conditions in vivo

We studied foam film formation by three preparations that are used as surfactant replacement therapy by injection into the lungs of neonatal infants with surfactant insufficiency (“respiratory distress syndrome”). The preparations contain either all putative hydrophobic components of the normal surfactant system (prepared from bovine lung lavage, Infasurf (IN); prepared from minced bovine lung tissue, Survanta (SU)) or a single component of the system, dipalmitoylphosphatidylcholine (Exosurf Neonatal (EX)). Foam film formation is relevant directly to normal surfactant structure and function in vivo in the neonatal period (Pediatr. Res. 12 (1978) 1070–1076). We assessed morphology and stability of liquid to black film formation and its dependence on substrate concentration C, adsorption time, temperature T, “capillary pressure” P c, film drainage time τ 0–1 and black film formation times τ 1–2. We found that (1) in contrast with the other preparations, IN regularly formed stable black films at the lowest C (“threshold C” C t) under all conditions of T (22 and 37°C) and P c (0.3, 0.4, 1.2 and 2.4 × 10 3 dyn cm −2), (2) EX also formed black films but differed from IN in that C t was higher, film integrity required a longer adsorption time and black film formation was blocked (instability) at P c values of 1.2 and 2.4 × 10 3 dyn cm −2 and (3) SU did not form black films but instead formed slowly (long τ 0–1 and τ 1–2), at relatively high C t, viscosity-dependent inhomogeneous atypical (“rheological”) films containing aggregates of material in the preparation. Extrapolation to in-vivo conditions of C, T and P c indicates that both IN and SU (but not EX) may form stable foam films in situ, that film formation by IN is the more efficient process and that stable surfactant foam films, formed naturally in vivo, are consistent with both the in-vitro characteristics described here and correlative lung function in vivo.

Rapid in vitro tests of surfactant film formation: advantages of the Exerowa black film method.

Based on our research, the natural configuration of surfactant from birth through adulthood takes the form of intraalveolar bubbles. Thus, bubble film analysis would seem to be the specific in vitro testing method for lung surfactant. In the present study we report a battery of five in vitro tests for assessing structural and functional properties of surfactant bubbles and bubble films from hydrophobic extracts, namely, the therapeutic surfactants Survanta (SU) and Infasurf (IN) (full strength and diluted to 3 mg phospholipid/mL) and from aqueous extracts from rabbit lung lavage at 3 mg phospholipid/mL (SAM). Each substrate was assessed by: 1) Shake test: stable bubbles from SU, IN, and SAM (50/50, v/v in 95% ethanol) covered the peripheral surfaces, indicating positive response; bubble production by IN and SAM always exceeded SU; 2) Click test: bubble clicking began immediately in all preparations except for undiluted SU, in which the onset of clicking was delayed more than 40 sec; 3) Pattle's stability test: diameters of SU, IN, and SAM bubbles were unchanged for more than 20 min in aerated solution, indicating stable very low surface tension; 4) bubble generation by gas dispersion from a single capillary: full-strength concentration of SU and IN produced relatively large bubbles-bubble rate (number/min) and size were comparable; all SU bubbles rupture in < 25 min, whereas IN bubbles were stable for > 30 min; and 5) Exerowa black film method: in contrast with each of the preceding methods for studying intact bubbles, the Exerowa method focuses on the contact between bubble films and permits direct observation of film formation and determination of film structure. Stable black films were formed spontaneously by both IN (full strength and diluted) and SAM. Conversely, SU (full strength) formed no black films but stable rheological films. Diluted SU films ruptured in 50% of trials. Since methods 1, 2, and 3 were nondiscriminatory and method 4 produced unphysiologically large bubbles for most mammals, we concluded that the black film method of Exerowa is the most discriminating of the tests studied here. It provides a unique visual record of foam film formation and stability and clearly defines differences relative to both the nature and concentration of the preparations.