Janusz Gadzinowski

A Multicenter, Randomized, Controlled Trial of Lucinactant Versus Poractant Alfa Among Very Premature Infants at High Risk for Respiratory Distress Syndrome

Background. Available therapeutic surfactants are either animal-derived or non–protein-containing synthetic products. Animal-derived surfactants contain variable amounts of surfactant apoproteins, whereas the older-generation synthetic products contain only phospholipids and lack surfactant proteins (SPs). Both decrease morbidity and mortality rates associated with respiratory distress syndrome (RDS) among preterm infants, compared with placebo. However, excess mortality rates have been observed with non–protein-containing synthetic surfactants, compared with the animal-derived products. Evidence suggests that synthetic surfactants consisting solely of phospholipids can be improved with the addition of peptides that are functional analogs of SPs. Lucinactant is a new synthetic peptide-containing surfactant that contains sinapultide, a novel, 21-amino acid peptide (leucine and lysine repeating units, KL4 peptide) designed to mimic human SP-B. It is completely devoid of animal-derived components. Objective. We hypothesized that the outcomes for premature infants treated with lucinactant and poractant alfa would be similar. Therefore, we compared lucinactant (Surfaxin; Discovery Laboratories, Doylestown, PA) with porcine-derived, poractant alfa (Curosurf; Chiesi Farmaceutici, Parma, Italy) in a trial to test for noninferiority. Methods. A total of 252 infants born between 24 and 28 weeks of completed gestation, with birth weights between 600 and 1250 g, were assigned randomly in a multicenter, multinational, noninferiority, randomized, controlled study to receive either lucinactant (n = 124) or poractant alfa (n = 128) within 30 minutes of life. The primary outcome was the incidence of being alive without bronchopulmonary dysplasia (BPD) through 28 days of age. Key secondary outcomes included death at day 28 and 36 weeks postmenstrual age (PMA), air leaks, neuroimaging abnormalities, and other complications related to either prematurity or RDS. An independent, international, data and safety monitoring committee monitored the trial. Results. The treatment difference between lucinactant and poractant alfa for survival without BPD through 28 days was 4.75% (95% confidence interval [CI]: −7.3% to 16.8%) in favor of lucinactant, with the lower boundary of the 95% CI for the difference, ie, −7.3%, being greater than the prespecified noninferiority margin of −14.5%. At 28 days, 45 of 119 infants given lucinactant were alive without BPD (37.8%; 95% CI: 29.1–46.5%), compared with 41 of 124 given poractant alfa (33.1%; 95% CI: 24.8–41.3%); at 36 weeks PMA, the rates were 64.7% and 66.9%, respectively. The corresponding mortality rate through day 28 for the lucinactant group was lower than that for the poractant alfa group (11.8% [95% CI: 6.0–17.6%] vs 16.1% [95% CI: 9.7–22.6%]), as was the rate at 36 weeks PMA (16% and 18.5%, respectively). There were no differences in major dosing complications. In addition, no significant differences were observed in the incidences of common complications of prematurity, including intraventricular hemorrhage (grades 3 and 4) and cystic periventricular leukomalacia (lucinactant: 14.3%; poractant alfa: 16.9%). Conclusions. Lucinactant and poractant alfa were similar in terms of efficacy and safety when used for the prevention and treatment of RDS among preterm infants. The ability to enhance the performance of a synthetic surfactant with the addition of a peptide that mimics the action of SP-B, such as sinapultide, brings potential advantages to exogenous surfactant therapy.

A Multicenter, Randomized, Masked, Comparison Trial of Lucinactant, Colfosceril Palmitate, and Beractant for the Prevention of Respiratory Distress Syndrome Among Very Preterm Infants

Background and Objective. Evidence suggests that synthetic surfactants consisting solely of phospholipids can be improved through the addition of peptides, such as sinapultide, that mimic the action of human surfactant protein-B (SP-B). A synthetic surfactant containing a mimic of SP-B may also reduce the potential risks associated with the use of animal-derived products. Our objective was to compare the efficacy and safety of a novel synthetic surfactant containing a functional SP-B mimic (lucinactant; Discovery Laboratories, Doylestown, PA) with those of a non–protein-containing synthetic surfactant (colfosceril palmitate; GlaxoSmithKline, Brentford, United Kingdom) and a bovine-derived surfactant (beractant; Abbott Laboratories, Abbott Park, IL) in the prevention of neonatal respiratory distress syndrome (RDS) and RDS-related death. Methods. We assigned randomly (double-masked) 1294 very preterm infants, weighing 600 to 1250 g and of ≤32 weeks gestational age, to receive colfosceril palmitate (n = 509), lucinactant (n = 527), or beractant (n = 258) within 20 to 30 minutes after birth. Primary outcome measures were the rates of RDS at 24 hours and the rates of death related to RDS during the first 14 days after birth. All-cause mortality rates, bronchopulmonary dysplasia (BPD) rates, and rates of other complications of prematurity were prespecified secondary outcomes. Primary outcomes, air leaks, and causes of death were assigned by an independent, masked, adjudication committee with prespecified definitions. The study was monitored by an independent data safety monitoring board. Results. Lucinactant reduced significantly the incidence of RDS at 24 hours, compared with colfosceril (39.1% vs 47.2%; odds ratio [OR]: 0.68; 95% confidence interval [CI]: 0.52–0.89). There was no significant difference in comparison with beractant (33.3%). However, lucinactant reduced significantly RDS-related mortality rates by 14 days of life, compared with both colfosceril (4.7% vs 9.4%; OR: 0.43; 95% CI: 0.25–0.73) and beractant (10.5%; OR: 0.35; 95% CI: 0.18–0.66). In addition, BPD at 36 weeks postmenstrual age was significantly less common with lucinactant than with colfosceril (40.2% vs 45.0%; OR: 0.75; 95% CI: 0.56–0.99), and the all-cause mortality rate at 36 weeks postmenstrual age was lower with lucinactant than with beractant (21% vs 26%; OR: 0.67; 95% CI: 0.45–1.00). Conclusions. Lucinactant is a more effective surfactant preparation than colfosceril palmitate for the prevention of RDS. In addition, lucinactant reduces the incidence of BPD, compared with colfosceril palmitate, and decreases RDS-related mortality rates, compared with beractant. Therefore, we conclude that lucinactant, the first of a new class of surfactants containing a functional protein analog of SP-B, is an effective therapeutic option for preterm infants at risk for RDS.

Differences in rates and short-term outcome of live births before 32 weeks of gestation in Europe in 2003: results from the MOSAIC cohort.

OBJECTIVES. Advances in perinatal medicine increased survival after very preterm birth in all countries, but comparative population-based data on these births are not readily available. This analysis contrasts the rates and short-term outcome of live births before 32 weeks of gestation in 10 European regions. METHODS. The Models of Organizing Access to Intensive Care for Very Preterm Births (MOSAIC) study collected prospective data on all very preterm births in 10 European regions covering 494463 total live births in 2003. The analysis sample was live births between 24 and 31 weeks of gestation without lethal congenital anomalies (N = 4908). Outcomes were rates of preterm birth, in-hospital mortality, intraventricular hemorrhage grades III and IV or cystic periventricular leukomalacia and bronchopulmonary dysplasia. Mortality and morbidity rates were standardized for gestational age and gender. RESULTS. Live births between 24 and 31 weeks of gestation were 9.9 per 1000 total live births with a range from 7.6 to 13.0 in the MOSAIC regions. Standardized mortality was doubled in high versus low mortality regions (18%–20% vs 7%–9%) and differed for infants ≤28 weeks of gestation as well as 28 to 31 weeks of gestation. Morbidity among survivors also varied (intraventricular hemorrhage/periventricular leukomalacia ranged from 2.6% to ≤10% and bronchopulmonary dysplasia from 10.5% to 21.5%) but differed from mortality rankings. A total of 85.2 very preterm infants per 10000 total live births were discharged from the hospital alive with a range from 64.1 to 117.1; the range was 10 to 31 per 10000 live births for infants discharged with a diagnosis of neurologic or respiratory morbidity. CONCLUSIONS. Very preterm mortality and morbidity differed between European regions, raising questions about variability in treatment provided to these infants. Comparative follow-up studies are necessary to evaluate the impact of these differences on rates of cerebral palsy and other disabilities associated with preterm birth.

Rates of Bronchopulmonary Dysplasia in Very Preterm Neonates in Europe: Results from the MOSAIC Cohort

Background: A considerable local variability in the rate of bronchopulmonary dysplasia (BPD) has been recorded previously. Objectives: The objectives of the present study were to describe regional differences in the rate of BPD in very preterm neonates from a European population-based cohort and to further delineate risk factors. Methods: 4,185 survivors to 36 weeks’ postmenstrual age of 4,984 live-born infants born at 24+0–31+6 weeks’ gestation in 2003 (the MOSAIC cohort) in 10 European regions were enrolled using predefined structured questionnaires. Results: Overall median gestational age of preterms without BPD was 30 weeks (range 23–31), median birth weight 1,320 g (range 490–3,150) compared with 27 weeks (23–31) and 900 g (370–2,460) in those with BPD. The region-specific crude rate of BPD ranged from 10.2% (Italian region) to 24.8% (UK Northern region). Maternal hypertension, immaturity, male gender, small for gestational age, Apgar <7 and region of care were associated with an increased incidence of BPD on multivariate analysis. Conclusion: A wide variability of BPD between European regions may be explained by different local practices; the strongest association however was with degree of immaturity.

Termination of pregnancy among very preterm births and its impact on very preterm mortality: results from ten European population-based cohorts in the MOSAIC study.

Objective  To study the impact of terminations of pregnancy (TOP) on very preterm mortality in Europe.

Use of evidence based practices to improve survival without severe morbidity for very preterm infants: results from the EPICE population based cohort

Objectives To evaluate the implementation of four high evidence practices for the care of very preterm infants to assess their use and impact in routine clinical practice and whether they constitute a driver for reducing mortality and neonatal morbidity. Design Prospective multinational population based observational study. Setting 19 regions from 11 European countries covering 850 000 annual births participating in the EPICE (Effective Perinatal Intensive Care in Europe for very preterm births) project. Participants 7336 infants born between 24+0 and 31+6 weeks’ gestation in 2011/12 without serious congenital anomalies and surviving to neonatal admission. Main outcome measures Combined use of four evidence based practices for infants born before 28 weeks’ gestation using an “all or none” approach: delivery in a maternity unit with appropriate level of neonatal care; administration of antenatal corticosteroids; prevention of hypothermia (temperature on admission to neonatal unit ≥36°C); surfactant used within two hours of birth or early nasal continuous positive airway pressure. Infant outcomes were in-hospital mortality, severe neonatal morbidity at discharge, and a composite measure of death or severe morbidity, or both. We modelled associations using risk ratios, with propensity score weighting to account for potential confounding bias. Analyses were adjusted for clustering within delivery hospital. Results Only 58.3% (n=4275) of infants received all evidence based practices for which they were eligible. Infants with low gestational age, growth restriction, low Apgar scores, and who were born on the day of maternal admission to hospital were less likely to receive evidence based care. After adjustment, evidence based care was associated with lower in-hospital mortality (risk ratio 0.72, 95% confidence interval 0.60 to 0.87) and in-hospital mortality or severe morbidity, or both (0.82, 0.73 to 0.92), corresponding to an estimated 18% decrease in all deaths without an increase in severe morbidity if these interventions had been provided to all infants. Conclusions More comprehensive use of evidence based practices in perinatal medicine could result in considerable gains for very preterm infants, in terms of increased survival without severe morbidity.

Usefulness of cardiac troponin T and echocardiography in the diagnosis of hypoxic myocardial injury of full-term neonates.

Background: Perinatal asphyxia constitutes a significant problem influencing neonatal mortality and morbidity. Objectives: The aim of the present work was to provide evidence of the usefulness of cardiac troponin T (cTnT) and echocardiographic investigations in the diagnosis of heart damage in full-term infants after intrauterine hypoxia. Material and Methods: The subjects were 39 asphyxiated and 44 term infants without fetal anoxia. Quantitative determinations of cTnT were performed between 12 and 24 h of life. Two-dimensional Doppler and color Doppler studies were performed at the bedside. We evaluated fractional shortening (FS), cardiac output (CO), cardiac index (CI), tricuspid (TI) and mitral (MI) insufficiency. Results: Asphyxiated infants presented increased cTnT (mean 0.141 ± 0.226 vs. 0.087 ± 0.111ng/ml; p < 0.01) and TI (38.5 vs. 11.4% of population; p < 0.05) compared to healthy infants. CO, CI and FS remained in the same range. Conclusions: We found cTnT to be the most useful among accessible diagnostic tools used in post-hypoxic heart damage in neonates. The data from our relatively small population study suggest a cTnT value of >0.1 ng/ml as a reliable marker of myocardial injury in neonates. Further study should be performed to generate a receiver-operator characteristic curve to discover what the cut-off level should be.

One-Year Follow-up of Very Preterm Infants Who Received Lucinactant for Prevention of Respiratory Distress Syndrome: Results From 2 Multicenter Randomized, Controlled Trials

BACKGROUND. The benefits of exogenous surfactants for prevention or treatment of respiratory distress syndrome are well established, but there is a paucity of long-term follow-up data from surfactant-comparison trials. OBJECTIVE. We sought to determine and compare survival and pulmonary and neurodevelopmental outcomes through 1 year corrected age of preterm infants who received lucinactant and other surfactants in the SELECT (Safety and Effectiveness of Lucinactant Versus Exosurf in a Clinical Trial) and STAR (Surfaxin Therapy Against Respiratory Distress Syndrome) trials individually and, secondarily, from analysis using combined data from these 2 trials. METHODS. All infants from both trials who were randomly assigned to administration of lucinactant (175 mg/kg), colfosceril palmitate (67.5 mg/kg), beractant (100 mg/kg), or poractant alfa (175 mg/kg) were prospectively followed through 1 year corrected age, at which point masked assessment of outcomes was performed for surviving infants. One-year survival was a key outcome of interest. Other parameters assessed included rates of rehospitalization and respiratory morbidity and gross neurologic status. Data were analyzed by comparing the different surfactants within each trial and, in secondary analysis, combining data from both trials to compare lucinactant versus the animal-derived surfactants (beractant and poractant) used in these trials. Survival rates over time were compared by using the Wilcoxon test for survival through 1 year corrected age and logistic regression for comparison of fixed time points. The latter analyses were performed by using the prespecified approach, where loss to follow-up or withdrawal of consent was imputed as a death, and also using raw data. Other outcomes were analyzed by using the Cochran-Mantel-Haenszel test or logistic regression for categorical data, and analysis of variance on ranks was used for continuous data. RESULTS. Very few cases were lost to follow-up in either trial (29 of 1546 enrolled in both trials [1.9%]). In the primary analysis of the SELECT trial comparing lucinactant to either colfosceril or beractant, there were no significant differences in the proportion of infants who were alive through 1 year corrected age. Fixed-time-point estimates of mortality at 1 year corrected age imputing loss to follow-up as a death were 28.1% for lucinactant, 31.0% for colfosceril, and 31.0% for beractant. By using raw data without imputing loss to follow-up as a death, mortality estimates at 1 year corrected age were computed to be 26.6%, 29.1%, and 28.3%, respectively. In the primary analysis of the STAR trial, significantly more infants treated with lucinactant were alive through 1 year corrected age compared with those who received poractant alfa. Fixed time estimates of mortality at 1 year corrected age imputing loss to follow-up as a death were 19.4% for lucinactant and 24.2% for poractant. These estimates using raw data that did not impute loss to follow-up as a death were 18.6% and 21.9%, respectively. In the combined analysis, survival through 1 year corrected age was higher for infants in the lucinactant group versus that of the infants in the animal-derived surfactants (beractant and poractant) group. The fixed-time-point estimates of mortality at 1 year corrected age imputing loss to follow-up as a death for lucinactant and animal-derived surfactants were 26.0% and 29.4%, respectively. However, the 1-year-corrected-age estimates using combined raw data were 24.6% for the lucinactant group and 26.7% for the animal-derived surfactant group. The incidence of postdischarge rehospitalizations, total number of rehospitalizations, incidence of respiratory illnesses, and total number of respiratory illnesses were generally similar among those in the treatment groups. Neurologic status at 1 year corrected age was essentially similar between infants who received lucinactant and those who received all other surfactants used in these 2 trials. CONCLUSIONS. Findings from this 1-year follow-up of both lucinactant trials indicate that this new peptide-based synthetic surfactant is at least as good, if not superior, to animal-derived surfactants for prevention of respiratory distress syndrome and may be a viable alternative to animal-derived products.

Mechanics of Breathing after Surgical Ligation of Patent Ductus arteriosus in Newborns with Respiratory Distress Syndrome

The aim of the study was to detect changes in pulmonary function following ligation of a patent ductus arteriosus (PDA). Pulmonary function was recorded in 16 newborns (birth weight 1,081 ± 166 g, gestational age 27.6 ± 1.7 weeks) before and after ligation. No change in resistance of airways or mean airway pressure was observed. We found an increase in dynamic compliance (Cdyn) of 77% (p < 0.01), in tidal volume (TV) of 29% (p = 0.004), and in minute ventilation (MV) of 17% (p < 0.01) after the procedure. We demonstrated that pulmonary function improves after surgical ligation of the PDA. Because of considerable variation in intubated and spontaneously breathing premature newborns, we recommend the analysis of three main parameters: Cdyn, TV and MV for estimation of pulmonary mechanics in these infants.

Predictors of successful extubation of preterm low-birth-weight infants with respiratory distress syndrome.

Objective: The aim of the study was to measure pulmonary mechanics in infants with respiratory distress syndrome before extubation and to correlate pulmonary function values with successful extubation. Design: Clinical study. Setting: Neonatal intensive care unit. Patients: Fifty-one infants (birth weight, 1158.6 ± 150.6 g; gestational age, 29.1 ± 2.0 wks). Interventions: Ventilation and daily ventilatory management. Measurements and Main Results: Of the 51 infants studied, 35 (60.8%) were successfully extubated, whereas 16 (39.2%) required reintubation and mechanical ventilation within 72 hrs after extubation. All patients met the clinical and biochemical criteria for extubation. Variables of artificial ventilation before extubation were minimal in all the studied cases (Fio2 ≤0.4, inspiratory pressure ≤20 cm H2O, ventilatory rate, ≤10/min). Pulmonary mechanics were measured before extubation using a noninvasive, mobile VenTrak measuring station. Results: Significant differences in pulmonary function values between the groups were found. Lower resistance of airways and work of breathing and higher dynamic compliance, tidal volume, and minute ventilation before extubation were associated with successful extubation. Conclusion: On the average, tidal volume values of >6 mL/kg, minute ventilation of >309 mL/kg/min, work of breathing of <0.172 J/L, dynamic compliance of ≥1 mL/cm H2O/kg, and resistance of airways of ≤176 cm H2O/L/sec predicted successful extubation. We recommend measurement of pulmonary function as an assessment tool in determining readiness for extubation.