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Dizdar et al., 2011


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Dizdar et al., 2011

  1. 1. Original Article A Randomized, Controlled Trial of Poractant Alfa versus Beractant in the Treatment of Preterm Infants with Respiratory Distress Syndrome Evrim Alyamac Dizdar, M.D. 1 Fatma Nur Sari, M.D. 1 Cumhur Aydemir, M.D. 1 Omer Erdeve, M.D. 1 Nurdan Uras, M.D. 1 Ugur Dilmen, M.D. 1 Teaching Hospital, Ankara, Turkey. Am J Perinatol Abstract Keywords ► ► ► ► beractant poractant alfa preterm respiratory distress syndrome ► surfactant Address for correspondence and reprint requests Evrim Alyamac Dizdar, M.D., Neonatal Intensive Care Unit, Zekai Tahir Burak Maternity and Teaching Hospital, 06111 Hamamonu, Ankara, Turkey (e-mail: We prospectively evaluated the differences in clinical responses and short-term outcomes in preterm infants with respiratory distress syndrome (RDS) treated with poractant alfa or beractant. Premature infants with RDS were randomized to poractant alfa or beractant treatment between July 2008 and June 2009. Patients were followed until 40 weeks of corrected gestational age or death. The fraction of inspired oxygen (Fio2) after surfactant treatment, need for repeat doses, and duration of respiratory support and hospitalization were evaluated between groups. Sixty-one infants received poractant alfa and 65 received beractant. Significantly more patients in the beractant group required !2 doses of surfactant compared with the poractant alfa group (31% versus 12%, p ¼ 0.023). Extubation rate within the first 3 days after surfactant administration was higher in the poractant alfa group than in the beractant group (81% versus 55.9%, p ¼ 0,004). Posttreatment Fio2 requirement in the poractant alfa group was significantly lower than in the beractant group on days 1, 3, and 5. Overall mortality and morbidities were similar between groups. Survival free of bronchopulmonary dysplasia (BPD) at the end of study period was 78.7% and 58.5% in poractant alfa and beractant groups, respectively (p ¼ 0.015). Our study confirms the rapid onset of action, less need for redosing, rapid extubation, and higher survival free of BPD in preterm infants treated with poractant alfa. Respiratory distress syndrome (RDS) is an important cause of mortality and morbidity in preterm infants, despite the major advances in perinatal care and increasing use of antenatal steroids to accelerate lung maturity. RDS occurs in almost 50% of preterm infants born at <30 weeks’ gestation.1 The biochemical abnormality in RDS is insufficient production of surfactant, which leads to poor compliance of lungs, inadequate gas exchange, and need for high ventilatory pressures. Surfactant therapy has been available since the 1980s and is well known to improve lung function and to reduce morbidity and mortality in newborns with or at risk for RDS.2 Surfactant is mainly composed of dipalmitoylphosphatidylcholine (DPPC) and surfactant proteins (SPs), SP-A, SP-B, SP-C and SP-D. Among the SPs, the lipid soluble SPs, namely, SP-B and SP-C, play a major role in rapid adsorption and spreading of DPPC at the air–liquid interphase, resulting in lower surface tension. Beside SPs, plasmalogen is an antioxidant phospholipid component of surfactant that has been shown to act synergistically with SP-B in the adsorption and spreading of DPPC.3 There are two types of surfactants—animal derived and synthetic—that are free of proteins. Randomized controlled trials have shown that received April 21, 2011 accepted after revision July 5, 2011 Copyright © 2012 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. DOI 10.1055/s-0031-1295648. ISSN 0735-1631. Downloaded by: Hacettepe University. Copyrighted material. 1 Neonatal Intensive Care Unit, Zekai Tahir Burak Maternity and Serife Suna Oguz, M.D. 1
  2. 2. Poractant Alfa versus Beractant in the Treatment of RDS Dizdar et al. animal-derived surfactants are better than synthetic surfactants during the acute phase of RDS, with lower mortality in favor of animal-derived surfactants. At present, there is no synthetic surfactant available for the treatment of RDS in preterm infants. Animal-derived surfactants are produced from bovine or porcine lungs and contain different amounts of DPPC, SP-B, SP-C, and plasmalogens. Three animal-derived surfactant preparations commonly used worldwide include beractant (BE), calfactant (CA), and poractant alfa (PA). BE is a minced bovine lung extract and contains 84% phospholipids and 1.5 mol% plasmalogens. CA is a lavage preparation from bovine lung and contains more SP-B and phospholipids than BE. PA is a concentrated, minced porcine surfactant that contains pure polar lipids and the highest amount of plasmalogens (3.8 mol%).3,4 Four randomized controlled clinical trials comparing BE and CA have shown no significant differences in the need for redosing, short- or long-term outcomes, or mortality.5,6 In one study, treatment with CA was associated with faster weaning from respiratory support when compared with BE, and a statistically significant reduction in mortality was shown in another study in the BE-treated group in infants with birth weight <600 g.5 Given the significant differences in composition and biochemical properties between BE and PA, we aimed to evaluate whether there were any differences in the efficacy and shortterm outcomes between these two animal-derived surfactants in a large population of preterm patients with RDS. followed until 40 weeks of corrected gestational age or death. Posttreatment Fio2 values, duration of intubation, nasal continuous positive airway pressure (CPAP) ventilation, supplemental O2 support, total respiratory support (the sum of mechanical ventilation days þ nasal CPAP days þ O2 support days), and total duration of hospitalization were recorded and compared between the two groups. The groups were also compared regarding the following NICU-related complications diagnosed within 40 weeks of corrected gestational age: pneumothorax, patent ductus arteriosus (PDA), intraventricular hemorrhage (IVH), pulmonary hemorrhage, sepsis, bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), and death. This prospective randomized study was performed in Zekai Tahir Burak Maternity Teaching Hospital Neonatal Intensive Care Unit (NICU). Infants were eligible for the study when the following inclusion criteria were met: gestational age <37 weeks, clinical and radiological diagnosis of RDS within 6 hour of birth, fraction of inspired oxygen (Fio2) !0.30 to maintain oxygen saturation by pulse oximeter of 88 to 96%. Infants with congenital heart and lung diseases or abdominal wall pathology were excluded. Patients were randomized to receive either 100 mg/kg BE or 200 mg/kg PA via the endotracheal tube for the initial dose. Additional doses of surfactant were given if the infant required ventilator support and if Fio2 !0.30 was required to maintain the oxygen saturation !88% by pulse oximetry. Retreatment with 100 mg/kg of BE or PA per dose was performed in accordance with the manufacturer’s drug package insert. Informed parental consent was obtained for all study infants. The study was approved by the institutional review board of the hospital and financially supported by Hospital Research Foundation. The cost of the drugs were 380$ for 120 mg/1.5 mL vial of PA and 392$ for 800 mg/8 mL vial of BE. Patient characteristics including gestational age, gender, birth weight, presence of perinatal asphyxia, Apgar scores, and maternal risk factors including prenatal steroid administration, preterm prolonged rupture of membranes, chorioamnionitis, preeclampsia, route of delivery, and multiple pregnancy were collected for all infants. Patients were American Journal of Perinatology RDS was defined clinically as the presence of tachypnea with retractions, nasal flaring, expiratory grunting, and cyanosis in room air and with chest radiograph that showed diffuse reticulogranular opacities and air bronchogram. BPD was diagnosed by using the U.S. National Institutes of Health diagnostic criteria for BPD.7 Sepsis was defined as presence of clinical signs of systemic infection with positive blood culture. IVH was graded according to the classification of Papile and coworkers.8 PDA was considered significant if the patency of the ductus was confirmed by the echocardiogram with ductal size >2 mm and left atrial diameter/ aortic root ratio of >1.5 together with left ventricular enlargement. NEC was classified according to the classification of Bell and colleagues.9 An experienced ophthalmologist confirmed the diagnosis of ROP by using international classification of ROP.10 Statistical Analyses The primary outcome of our study was Fio2 at 24 hours postgestation. It was determined that 51 patients per group were necessary to detect a 10% difference in Fio2 at 24 hours postgestation between surfactant groups, with an α of 0.05 and a power of 0.80. Descriptive analysis was performed for demographic and clinical characteristics of the patients. Student t test or Mann-Whitney U test was used for comparison of numeric variables between two groups, and chi-square test was used for comparison of ratios between the groups. Spearman test was used for correlation analysis. Statistical analysis was performed with SPSS software version 13.0 (SPSS Inc., Chicago, IL), and statistical significance was set at p < 0.05. Results A total of 126 preterm infants with RDS were included in the study. Sixty-five infants received BE, and 61 infants received PA. Patient characteristics are shown in ►Table 1. There were no significant differences between the patient groups with regards to gestational age, birth weight, gender, Apgar scores, mode of delivery, maternal age, or antenatal steroid administration rates. More patients in the PA group were born from multiple-birth pregnancies. More patients in the BE group Downloaded by: Hacettepe University. Copyrighted material. Patients and Methods Study Definitions
  3. 3. Poractant Alfa versus Beractant in the Treatment of RDS Dizdar et al. Table 1 Patient Characteristics (n ¼ 126) Poractant Alfa (n ¼ 61) Beractant (n ¼ 65) p Gestational age (wk), median (range) 28 (25–36) 28 (23–36) NS Birth weight (g), median (range) 1165 (620–2290) 1080 (510–2750) NS Male gender, n (%) 31 (51%) 42 (65%) NS Apgar score at 1 min, median (range) 5 (1–7) 4 (1–7) NS Apgar score at 5 min, median (range) 7 (3–9) 7 (2–9) NS Surfactant treatment, n (%) One dose Two doses Three doses 54 (88%) 7 (12%) — 45 (69%) 18 (28%) 2 (3%) Maternal age (y), median (range) 27 (19–40) 29 (18–40) 0.023 NS 52 (85%) 51 (78%) NS Multiple pregnancy, n (%) 33 (54%) 21 (32%) 0.011 Antenatal steroid use, n (%) 37 (63%) 33 (51%) NS Preeclampsia, n (%) 3 (5%) 9 (14%) NS required !2 doses of surfactant compared with PA group (31% versus 12%, respectively, p ¼ 0.023). Mean Fio2 requirement in the PA-treated group was significantly lower than in the BE-treated group on days 1, 3, and 5 but was similar on days 7, 14, and 28 (►Fig. 1). Extubation rate within the first 3 days after surfactant administration was higher in the PA group than in the BE group (81% versus 55.9%, p ¼ 0.004). Overall mortality was similar between the groups. Other follow-up outcomes including BPD rates, duration of intubation, days on nasal CPAP, O2 supplementation and total respiratory support, hospitalization period, and development of complications such as pneumothorax, pulmonary hemorrhage, ROP, sepsis, NEC, and IVH were also similar between the two groups (►Tables 2 and 3). Survival free of BPD at the end of the study period was 78.7% versus 58.5% in PA- and BEtreated groups, respectively (p ¼ 0.015). Figure 1 Post surfactant mean fraction of inspired oxygen (Fio2 ) requirement in patients treated with beractant and poractant alfa (PA). Mean Fio 2 requirement was less in the PA-treated group on days 1, 3, and 5 (p < 0.05). Error bars denote range. Discussion In this study, we found that treatment with PA was associated with lower Fio2 requirements within the first 5 days in infants with RDS as well as higher rates of extubation within the first 3 days compared with BE. The need for additional doses was significantly less among the infants treated with PA compared with those treated with BE. Survival free of BPD was significantly higher in the PA group than in the BE group, although the study was not powered to detect differences in this outcome. No differences in mortality or other outcomes were seen between the two groups. Although exposure to oxygen is essential for the survival of infants with RDS, it may result in oxidative stress and development of chronic lung disease, which may lead to substantial mortality and morbidity in preterm infants.11 Therefore, faster weaning of oxygen is crucial to reduce lung injury in preterm infants. Surfactant treatment is the standard of care in the treatment of RDS and effectively reduces associated morbidity and mortality. In a meta-analysis conducted by the Committee of the Fetus and Newborn of the American Academy of Pediatrics, attributed reductions in the mortalities of RDS patients to surfactant were as follows: odds ratios of 0.6 for agents of animal origin and 0.7 for those of synthetic origin when administered with prophylactic intent, and 0.67 for agents of animal origin and 0.73 for those of synthetic origin when administered as rescue therapies.12 Animal-derived surfactants have been demonstrated to result in a greater improvement in the severity of RDS compared with synthetic surfactants in clinical trials. Therefore, natural surfactants are used during the acute phase of RDS almost exclusively.13 There are significant differences in the composition, phospholipid and plasmalogen content, SP content, viscosity, volume of administration, and onset of action among the different animal-derived surfactants. These American Journal of Perinatology Downloaded by: Hacettepe University. Copyrighted material. Cesarean section, n (%)
  4. 4. Poractant Alfa versus Beractant in the Treatment of RDS Dizdar et al. Table 2 Pulmonary and Other Outcomes Poractant Alfa (n ¼ 61) Beractant (n ¼ 65) p Extubation within first 3 d (%) 81 55.9 0.004 Reintubation for respiratory distress within first 14 d (%) 24.5 38.8 NS 4.8 (10.5) 4.2 (4.3) NS NCPAP (d) 5.9 (13.6) 4.7 (4.7) NS O2 by hood (d) 2.0 (4.5) 3.1 (3.9) NS Free O2 supplementation (d) 7.8 (11.7) 9.3 (15.0) NS Total respiratory support (d) 20.1 (27.3) 20.7 (21.5) NS Dopamine infusion (d) 6.6 (6.1) 8.0 (7.17) NS Day 1 Fio2 60.5 (14.2) 67.4 (15.0) 0.031 Day 3 Fio2 43.9 (18.5) 58.6 (19.7) 0.001 Day 5 Fio2 36.5 (16.7) 44.2 (15.9) 0.044 Day 7 Fio2 30.5 (12.2) 34.2 (12.5) NS Day 14 Fio2 25.3 (8.7) 28.7 (11.1) NS Day 28 Fio2 24,2 (7.7) 24,3 (10.0) NS Initiation of oral feeding (d) 2.24 (0.9) 2.38 (1.6) NS Initiation of full feeding (d) 17.5 (9.2) 22.3 (16.2) NS Days of hospitalization 37.7 (24.4) 40.1 (30.9) NS 9.8 20 NS Mortality rate (%) Ã Data are mean (standard deviation) unless noted otherwise. Fio2, fraction of inspired oxygen; NCPAP, nasal continuous positive airway pressure. properties are likely the reason for the differences in outcomes seen in comparative clinical trials. PA contains the highest amount of phospholipids distributed in the lowest volume (80 mg/mL) and highest amount of plasmalogens (3.8%). Plasmalogens are antioxidant phospholipids that help to protect against oxidative stress, which is very important in preterm infants with low antioxidant activity.13 BE contains 84% phospholipids and 1.5% plasmalogens. PA contains more SP-B and less SP-C compared with BE.3 Five randomized controlled trials comparing BE and PA have been published since 1995.2,14–17 In a pilot study comparing PA (200 mg/kg for the first dose) and BE (100 mg/kg for the first dose), Speer et al showed treatment with PA resulted in faster weaning of oxygen and lower requirement of peak inspiratory pressure and mean airway pressure 24 hours after administration.14 Baroutis et al showed that infants treated with PA 100 mg/kg/dose had a shorter ventilator course, required oxygen for fewer days, and had a shorter length of stay in hospital than infants treated with BE 100 mg/kg/dose.15 Ramanathan et al showed faster weaning of oxygen and fewer doses with PA treatment when compared with BE.2 In addition, they found that mortality decreased from 11% in infants <32 weeks treated with BE (100 mg/kg) to 3% in infants treated with the higher initial dose of PA (200 mg/kg). This improvement in mortality is likely related to the larger initial dose of PA, rather than to an intrinsic difference in the properties of the surfactant itself. In the study by Malloy et al, preterm infants with RDS (n ¼ 58) Table 3 Adverse Outcomes Poractant Alfa (n ¼ 61) Beractant (n ¼ 65) p Pneumothorax 7.1% 4.9% NS Pneumonia 7.1% 13.3% NS Pulmonary hemorrhage 7.1% 6.5% NS Intraventricular hemorrhage 22% 13,8% NS Patent ductus arteriosus 54.9% 70.6% NS Sepsis 43.6% 57.1% NS Necrotizing enterocolitis 13.5% 5.6% NS BPD-free survival 78.7% 58.5% 0.015 All data are (%). BPD, bronchopulmonary dysplasia. American Journal of Perinatology Downloaded by: Hacettepe University. Copyrighted material. Ventilation (d)
  5. 5. PA, poractant alfa; BE, beractant; BPD, bronchopulmonary dysplasia. Dizdar et al Dizdar et al. who were treated with PA had a lower Fio2 requirement than those treated with BE within the first 48 hours following surfactant administration.16 This study extended the findings of improved oxygenation following treatment with PA up to 48 hours, whereas the earlier studies reported improvements in oxygenation up to 6 or 24 hours after surfactant administration.2,14 A meta-analysis of these two trials showed an odds ratio for mortality of 0.31 (95% confidence interval 0.010 to 0.98).18 Recently, Fujii et al compared BE and PA in 52 preterm infants with RDS and showed that treatment with PA was associated with faster weaning of oxygen and lower mean airway pressure requirement to maintain adequate oxygenation. Significantly higher proportion of infants were extubated in the PA-treated group 48 and 72 hours after surfactant administration.17 Interestingly, they also found a lower incidence of PDA and air leaks among the PA-treated infants.19 Our findings also showed lower oxygen need in infants treated with PA within the first 5 days. Mean Fio2 requirements were similar on days 7, 14, and 28. Extubation rate within the first 3 days after surfactant administration, which is a marker of early recovery, was also higher in the PA-treated group than in the BE-treated group. Mortality rate was similar in our study in the two groups. However, we found survival free of BPD to be higher in the PA group than in the BE group. As BPD is defined as the need for oxygen at 36 weeks’ postmenstrual age and >28 days of age, infants who die within this period are excluded when determining BPD rates. This may result in exclusion of a subgroup with high frequency of respiratory problems and high risk of developing BPD if they lived longer. Therefore, we believe that “survival free of BPD” is a more rational outcome, and we showed that PA is more efficacious in this regard. A meta-analysis of randomized trials comparing these surfactants also showed a mortality difference (odds ratio 0.35; 95% confidence interval 0.13 to 0.92).18 However, the numbers of patients were relatively small, and the recent American Academy of Pediatrics recommendations state: ‘‘It is unclear whether significant differences in clinical outcomes exist among the available [animalderived surfactant] products.”12 Infants needed lower additional doses in the PA-treated group when compared with the infants in the BE-treated group in the two trials reported before.2,16 In our study, 88% of infants treated with PA required only one dose of surfactant. The PA-treated group required less additional doses of surfactant compared with the BE-treated group. Ramanathan et al2 explained this finding due to the larger initial dose of PA compared with BE in their study. We also used 200 mg/kg PA initially in our study. Caution should be exercised when interpreting our results in comparison with other randomized studies of BE and PA. Although not statistically significant, differences in the baseline characteristics of the treatment groups in our study might have influenced the results given the small sample size and should be noticed as a limitation. Second, although our study and all the previous studies comparing BE and PA included preterm infants with RDS, baseline demographics differed significantly among the studies; for instance, median American Journal of Perinatology Downloaded by: Hacettepe University. Copyrighted material. 9.8 versus 20 15 versus 28 63 versus 51 51 versus 65 28 versus 28 1165 versus 1080 PA 200 versus BE 13 versus 18 35 versus 50 100 versus 96 48 versus 74 27.1 versus 26.7 930 versus 900 19 versus 23 0 versus 10 34 versus 37 69 versus 79 48 versus 45 29.6 versus 29.3 1394 versus 1408 PA 200 versus BE PA 200 versus BE Fujii et al 17 Malloy et al 16 3 versus 12.5 12.5 versus 11.4 14.8 versus 15.4 26 versus 31 42 versus 37 33 versus 55 59 versus 38 28.7 versus 29.2 28.8 versus 28.9 PA 200 versus BE Baroutis et al15 1233 versus 1180 PA 200 versus BE Speer et al14 1095 versus 1082 3 versus 6 versus 8 50 versus 49 versus 50 82 versus 76 versus 85 58 versus 61 versus 56 28.8 versus 28.7 versus 28.7 1148 versus 1151 versus 1187 PA 100 versus PA 200 versus BE Ramanathan et al2 Gestational age, wk (Mean) Birth Weight, g (Mean) Table 4 Patient Characteristics and BPD/Death Rates in Randomized Studies of PA versus BE Gender (% Male) Antenatal Steroid (%) BPD (%) Death (%) Poractant Alfa versus Beractant in the Treatment of RDS
  6. 6. birth weight was $900 g in the study of Fujii et al 17 versus $1200 g in the study of Baroutis et al 15 versus $1100 g in our study. Malloy et al’s study 16 and ours had broader ranges of birth weight and gestational age compared with the remaining studies, and this might lead to heterogeneity as a source of bias. Other demographics and related clinical outcomes including gender distribution, antenatal steroid use, and rates of death and BPD also differed significantly between study groups (►Table 4). This heterogeneity might be secondary to the differences in patient characteristics as well as intercenter differences, as demonstrated by Ambalavanan et al, who found that center differences were significantly associated with BPD/death rates even after correction for clustered infant-level variables.20 In summary, our data indicate that preterm infants with RDS treated with PA have a more favorable outcome regarding lower oxygen need and faster weaning from mechanical ventilation as shown by higher extubation rate within 3 days of surfactant treatment compared with BE. Survival rates were similar. This study and the previous studies consistently delineate some clinical benefit with the use of PA over BE. However, larger studies are necessary to confirm the impact on BPD and/or mortality as a primary outcome between the different animal-derived surfactants. Dizdar et al. 5 6 7 8 9 10 11 12 13 Acknowledgments We would like to thank to Zekai Tahir Burak Maternity Teaching Hospital Research Foundation for financial support and Professor Rangasamy Ramanathan for his thoughtful contributions to our study. 14 15 16 References 1 Horbar JD, Wright LL, Soll RF, et al; National Institute of Child Health and Human Development Neonatal Research Network. A multicenter randomized trial comparing two surfactants for the treatment of neonatal respiratory distress syndrome. J Pediatr 1993;123;757–766 2 Ramanathan R, Rasmussen MR, Gerstmann DR, Finer N, Sekar K; North American Study Group. 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 2004;21;109–119 3 Ramanathan R. Animal-derived surfactants: where are we? The evidence from randomized, controlled clinical trials. J Perinatol 2009;29( Suppl 02):S38–S43 4 Rüdiger M, Tölle A, Meier W, Rüstow B. Naturally derived commercial surfactants differ in composition of surfactant lipids and in American Journal of Perinatology 17 18 19 20 surface viscosity. Am J Physiol Lung Cell Mol Physiol 2005;288; L379–L383 Bloom BT, Kattwinkel J, Hall RT, et al. Comparison of Infasurf (calf lung surfactant extract) to Survanta (beractant) in the treatment and prevention of respiratory distress syndrome. Pediatrics 1997;100;31–38 Bloom BT, Clark RH; Infasurf Survanta Clinical Trial Group. Comparison of Infasurf (calfactant) and Survanta (beractant) in the prevention and treatment of respiratory distress syndrome. Pediatrics 2005;116;392–399 Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001;163;1723–1729 Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. 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Intercenter differences in bronchopulmonary dysplasia or death among very low birth weight infants. Pediatrics 2011;127;e106–e116 Downloaded by: Hacettepe University. Copyrighted material. Poractant Alfa versus Beractant in the Treatment of RDS