Fernando R. Moya

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.

Late versus early surgical correction for congenital diaphragmatic hernia in newborn infants

BACKGROUNDnCongenital diaphragmatic hernia, although rare (1 per 2-4,000 births), is associated with high mortality and cost. Opinion regarding the timing of surgical repair has gradually shifted from emergent repair to a policy of stabilization using a variety of ventilatory strategies prior to operation. Whether delayed surgery is beneficial remains controversial.nnnOBJECTIVESnTo summarize the available data regarding whether surgical repair in the first 24 hours after birth rather than later than 24 hours of age improves survival to hospital discharge in infants with congenital diaphragmatic hernia who are symptomatic at or immediately after birth.nnnSEARCH STRATEGYnSearch of MEDLINE (1966-2002), EMBASE (1978-2002) and the Cochrane databases using the terms congenital diaphragmatic hernia and surg*; citations search, and contact with experts in the field to locate other published and unpublished studies.nnnSELECTION CRITERIAnStudies were eligible for inclusion if they were randomized or quasi-randomized trials that addressed infants with CDH who were symptomatic at or shortly after birth, comparing early (<24 hours) vs late (>24 hours) surgical intervention, and evaluated mortality as the primary outcome.nnnDATA COLLECTION AND ANALYSISnData were collected regarding study methods and outcomes including mortality, need for ECMO and duration of ventilation, both from the study reports and from personal communication with investigators. Analysis was performed in accordance with the standards of the Cochrane Neonatal Review Group.nnnMAIN RESULTSnTwo trials met the pre-specified inclusion criteria for this review. Both were small trials (total n<90) and neither showed any significant difference between groups in mortality. Meta-analysis was not performed because of significant clinical heterogeneity between the trials.nnnREVIEWERS CONCLUSIONSnThere is no clear evidence which favors delayed (when stabilized) as compared with immediate (within 24 hours of birth) timing of surgical repair of congenital diaphragmatic hernia, but a substantial advantage to either one cannot be ruled out. A large, multicenter randomized trial would be needed to answer this question.

Postnatal dexamethasone therapy and cerebral tissue volumes in extremely low birth weight infants.

OBJECTIVE. Our goal was to relate postnatal dexamethasone therapy in extremely low birth weight infants (birth weight of ≤1000 g) to their total and regional brain volumes, as measured by volumetric MRI performed at term-equivalent age. METHODS. Among 53 extremely low birth weight infants discharged between June 1 and December 31, 2003, 41 had high-quality MRI studies; 30 of those infants had not received postnatal steroid treatment and 11 had received dexamethasone, all after postnatal age of 28 days, for a mean duration of 6.8 days and a mean cumulative dose of 2.8 mg/kg. Anatomic brain MRI scans obtained at 39.5 weeks (mean) postmenstrual age were segmented by using semiautomated and manual, pretested, scoring algorithms to generate three-dimensional cerebral component volumes. Volumes were adjusted according to postmenstrual age at MRI. RESULTS. After controlling for postmenstrual age at MRI, we observed a 10.2% smaller total cerebral tissue volume in the dexamethasone-treated group, compared with the untreated group. Cortical tissue volume was 8.7% smaller in the treated infants, compared with untreated infants. Regional volume analysis revealed a 20.6% smaller cerebellum and a 19.9% reduction in subcortical gray matter in the dexamethasone-treated infants, compared with untreated infants. In a series of regression analyses, the reductions in total cerebral tissue, subcortical gray matter, and cerebellar volumes associated with dexamethasone administration remained significant after controlling not only for postmenstrual age but also for bronchopulmonary dysplasia and birth weight. CONCLUSIONS. We identified smaller total and regional cerebral tissue volumes in extremely low birth weight infants treated with relatively conservative regimens of dexamethasone. These volume deficits may be the structural antecedents of neuromotor and cognitive abnormalities reported after postnatal dexamethasone treatment.

Randomized, controlled trial of slow versus rapid feeding volume advancement in preterm infants.

Objectives. To determine whether infants who are fed initially and advanced at 30 mL/kg per day (intervention) take fewer days to get to full feedings than those who are fed initially and advanced at 20 mL/kg per day (control), without increasing their incidence of feeding complications and necrotizing enterocolitis (NEC). We also examined whether these infants regain birth weight earlier, have fewer days of intravenous fluids, and a have shorter hospital stay. Methods. A randomized, controlled, single-center trial was conducted in a Neonatal Intensive Care Unit of a community-based county hospital in Houston, Texas. Infants between 1000 and 2000 g at birth, gestational age ≤35 weeks, and weight appropriate for gestational age were allocated randomly to feedings of expressed human milk or Enfamil formula starting and advanced at either 30 mL/kg per day or 20 mL/kg per day. Infants remained in the study until discharge or development of stage ≥IIA NEC. Results. A total of 155 infants were enrolled: 72 infants in the intervention group and 83 in the control group. Infants in the intervention group achieved full-volume feedings sooner (7 vs 10 days, median), regained birth weight faster (11 vs 13 days, median), and had fewer days of intravenous fluids (6 vs 8 days, median). Three infants in the intervention group and 2 control infants developed NEC for an overall incidence of 3.2% (relative risk: 1.73; 95% confidence interval: 0.30–10.06). Conclusion. Among infants between 1000 and 2000 g at birth, starting and advancing feedings at 30 mL/kg per day seems to be a safe practice and results in fewer days to reach full-volume feedings than using 20 mL/kg per day. This intervention also leads to faster weight gain and fewer days of intravenous fluids.

A New Liquid Human Milk Fortifier and Linear Growth in Preterm Infants

OBJECTIVES: To evaluate the growth, tolerance, and safety of a new ultraconcentrated liquid human milk fortifier (LHMF) designed to provide optimal nutrients for preterm infants receiving human breast milk in a safe, nonpowder formulation. METHODS: Preterm infants with a body weight ≤1250 g fed expressed and/or donor breast milk were randomized to receive a control powder human milk fortifier (HMF) or a new LHMF for 28 days. When added to breast milk, the LHMF provided ∼20% more protein than the control HMF. Weight, length, head circumference, and serum prealbumin, albumin, blood urea nitrogen, electrolytes, and blood gases were measured. The occurrence of sepsis, necrotizing enterocolitis, and serious adverse events were monitored. RESULTS: This multicenter, third party–blinded, randomized controlled, prospective study enrolled 150 infants. Achieved weight and linear growth rate were significantly higher in the LHMF versus control groups (P = .04 and 0.03, respectively). Among infants who adhered closely to the protocol, the LHMF had a significantly higher achieved weight, length, head circumference, and linear growth rate than the control HMF (P = .004, P = .003, P = .04, and P = .01, respectively). There were no differences in measures of feeding tolerance or days to achieve full feeding volumes. Prealbumin, albumin, and blood urea nitrogen were higher in the LHMF group versus the control group (all P < .05). There was no difference in the incidence of confirmed sepsis or necrotizing enterocolitis. CONCLUSIONS: Use of a new LHMF in preterm infants instead of powder HMF is safe. Benefits of LHMF include improvements in growth and avoidance of the use of powder products in the NICU.

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.

A pilot, randomized, controlled clinical trial of lucinactant, a peptide-containing synthetic surfactant, in infants with acute hypoxemic respiratory failure.

Objective: Inhibition of surfactant function and abnormal surfactant synthesis lead to surfactant dysfunction in children with acute hypoxemic respiratory failure. We evaluated whether intratracheal lucinactant, a synthetic, peptide-containing surfactant, was safe and well-tolerated in infants with acute hypoxemic respiratory failure, and assessed its effects on clinical outcomes. Methods and Main Results: Infants ⩽2 yrs of age with acute hypoxemic respiratory failure were enrolled in a phase II, double-blind, multinational, placebo-controlled randomized trial across 36 pediatric intensive care units. Infants requiring mechanical ventilation with persistent hypoxemia meeting acute lung injury criteria were randomized to receive intratracheal lucinactant (175 mg/kg) or air placebo. One retreatment was allowed 12–24 hrs after initial dosing if hypoxemia persisted. Peri-dosing tolerability of intratracheal lucinactant and adverse experiences were assessed. Mechanical ventilation duration was analyzed using analysis of variance. The Cochran–Mantel–Haenszel test was used for categorical variables. We enrolled 165 infants (84 lucinactant; 81 placebo) with acute hypoxemic respiratory failure. There were no significant differences in baseline subject characteristics, with the exception of a lower positive end-expiratory pressure and higher tidal volume in placebo subjects. The incidence of transient peri-dosing bradycardia and desaturation was significantly higher in the lucinactant treatment group. There were no statistical differences between groups for other adverse events or mortality. Oxygenation improved in infants randomized to receive lucinactant as indicated by fewer second treatments (67% lucinactant vs. 81% placebo, p = .02) and a trend in improvement in partial pressure of oxygen in arterial blood to fraction of inspired oxygen from eligibility to 48 hrs after dose (p = .06). There was no significant reduction in duration of mechanical ventilation with lucinactant (geometric least square means: 4.0 days lucinactant vs. 4.5 days placebo; p = .254). In a subset of infants (n = 22), the duration of mechanical ventilation in children with acute lung injury (partial pressure of oxygen in arterial blood to fraction of inspired oxygen >200) was significantly shorter with lucinactant (least square means: 2.4 days lucinactant vs. 4.3 days placebo; p = .006). Conclusions: In mechanically ventilated infants with acute hypoxemic respiratory failure, treatment with intratracheal lucinactant appeared to be generally safe. An improvement in oxygenation and a significantly reduced requirement for retreatment suggests that lucinactant might improve lung function in infants with acute hypoxemic respiratory failure.

Surfactant for respiratory distress syndrome: Are there important clinical differences among preparations?

Purpose of review Respiratory distress syndrome is the leading cause of mortality and morbidity among infants born prematurely. The disorder arises from the developmental and biochemical abnormalities associated with preterm delivery. The decreased number of type II alveolar pneumocytes results in absent or reduced surfactant production, which leads to alveolar instability and a tendency to collapse during expiration and increased work of breathing necessitating the institution of supplemental oxygen therapy and positive pressure mechanical ventilation. Recent findings Exogenous surfactant replacement therapy has been shown to be effective in the treatment of neonatal respiratory distress syndrome and has become a standard of care in neonatal intensive care units. A number of controversies still exist over a number of issues, however, such as the comparative effectiveness of one surfactant preparation over another, timing of administration, dosing volumes and short versus long-term benefits. Furthermore, the emergence of a newer generation of synthetic, peptide-containing surfactants has opened a new era in surfactant therapy which may have implications for future practice and research. Summary This paper discusses these developments and analyses the effectiveness of surfactant therapy against respiratory distress syndrome by appraising the evidence produced from published trials and systemic reviews.

Reintubation and risk of morbidity and mortality in preterm infants after surfactant replacement therapy

Background: In preterm infants at risk for RDS, reintubation following surfactant replacement therapy and successful extubation may be associated with poor clinical outcomes. Methods: Initial extubation, reintubation, mortality, and major morbidity rates associated with prematurity from two surfactant trials utilizing lucinactant, colfosceril palmitate, beractant, and poractant alfa were compared for reintubated infants versus infants who were not reintubated, and among treatment groups.

Surfactant-replacement therapy for respiratory distress syndrome in the preterm and term neonate: congratulations and corrections.

To the Editor. —nnWe would like to express our congratulations to Dr Engle and the American Academy of Pediatrics Committee on Fetus and Newborn on the publication of their clinical report “Surfactant-Replacement Therapy for Respiratory Distress in the Preterm and Term Neonate.” Overall, this document was comprehensive in scope yet sufficiently detailed and referenced to provide practical, evidence-based guidance to the clinician who renders neonatal care. However, the attempt to summarize information from so many studies has led to inaccurate statements that, if left uncorrected, are misleading.nnThe report stated that “[w]hen compared with infants receiving the animal-derived surfactants beractant and poractant alfa, infants receiving lucinactant were found to have similar rates of mortality and morbidity from respiratory distress syndrome [RDS].”1 One of the studies cited in connection with this statement is the Safety and Effectiveness of Lucinactant Versus Exosurf in a Clinical Trial of RDS in Premature Infants (SELECT) study. …