Jan Mazela

An Open Label, Pilot Study of Aerosurf® Combined with nCPAP to Prevent RDS in Preterm Neonates

BACKGROUND Nasal continuous positive airway pressure (nCPAP) is an accepted mode of respiratory support for preterm infants with respiratory insufficiency. To avoid potential sequelae of endotracheal (ET) intubation and mechanical ventilation, prophylactic aerosolization of surfactant delivered via nCPAP has been attempted with limited success. METHODS To determine the feasibility and safety of prophylactic aerosolization of a peptide-containing synthetic surfactant, Aerosurf® (lucinactant for inhalation) was delivered by nCPAP to preterm infants at risk for respiratory distress syndrome (RDS). Neonates were enrolled into treatment group 1 (Aerosurf retreatment separated by at least 3 h) or treatment group 2 (Aerosurf retreatment separated by at least 1 h). A vibrating membrane nebulizer Aeroneb Pro® was used to aerosolize 20 mg/mL Aerosurf. All neonates received the initial 3-h treatment, and three retreatments were permitted within 48 h based on clinical response. RESULTS Seventeen infants were enrolled. Aerosurf was well tolerated, with transient desaturations observed during dosing without bradycardia or hypotension. Variability in output rates of the Aeroneb Pro was observed leading to different average dispensed drug volumes per treatment per patient. All infants survived; 29.4% required subsequent ET surfactant replacement therapy, 23.5% were diagnosed with RDS at 24 h, and 11.8% with bronchopulmonary dysplasia (BPD) at 28 days of life. Mean FiO₂ was 0.4 at baseline, and 0.32 at 4 h posttreatment. CONCLUSIONS Aerosurf can be safely administered via nCPAP in preterm infants at risk for RDS and may provide an alternative to surfactant administration via an ET tube. Further studies are required to evaluate this delivery approach.

Characteristics of Neonatal Units That Care for Very Preterm Infants in Europe: Results From the MOSAIC Study

OBJECTIVES. We sought to compare guidelines for level III units in 10 European regions and analyze the characteristics of neonatal units that care for very preterm infants. METHODS. The MOSAIC (Models of Organising Access to Intensive Care for Very Preterm Births) project combined a prospective cohort study on all births between 22 and 31 completed weeks of gestation in 10 European regions and a survey of neonatal unit characteristics. Units that admitted ≥5 infants at <32 weeks of gestation were included in the analysis (N = 111). Place of hospitalization of infants who were admitted to neonatal care was analyzed by using the cohort data (N = 4947). National or regional guidelines for level III units were reviewed. RESULTS. Six of 9 guidelines for level III units included minimum size criteria, based on number of intensive care beds (6 guidelines), neonatal admissions (2), ventilated patients (1), obstetric intensive care beds (1), and deliveries (2). The characteristics of level III units varied, and many were small or unspecialized by recommended criteria: 36% had fewer than 50 very preterm annual admissions, 22% ventilated fewer than 50 infants annually, and 28% had fewer than 6 intensive care beds. Level II units were less specialized, but some provided mechanical ventilation (57%) or high-frequency ventilation (20%) or had neonatal surgery facilities (17%). Sixty-nine percent of level III and 36% of level I or II units had continuous medical coverage by a qualified pediatrician. Twenty-two percent of infants who were <28 weeks of gestation were treated in units that admitted fewer than 50 very preterm infants annually (range: 2%–54% across the study regions). CONCLUSIONS. No consensus exists in Europe about size or other criteria for NICUs. A better understanding of the characteristics associated with high-quality neonatal care is needed, given the high proportion of very preterm infants who are cared for in units that are considered small or less specialized by many recommendations.

Obstetric interventions for babies born before 28 weeks of gestation in Europe: results of the MOSAIC study.

Objective  To describe obstetric intervention for extremely preterm births in ten European regions and assess its impact on mortality and short term morbidity.

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.

Aerosol delivery to ventilated newborn infants: historical challenges and new directions.

There are several aerosolized drugs which have been used in the treatment of neonatal respiratory illnesses, such as bronchodilators, diuretics, and surfactants. Preclinical in vitro and in vivo studies identified a number of variables that affect aerosol efficiency, including particle size, aerosol flows, nebulizer choice, and placement. Nevertheless, an optimized aerosol drug delivery system for mechanically ventilated infants still does not exist. Increasing interest in this form of drug delivery requires more controlled and focused research of drug/device combinations appropriate for the neonatal population. In the present article, we review the research that has been conducted thus far and discuss the next steps in developing the optimal aerosol delivery system for use in mechanically ventilated neonates.

Evolution of pulmonary surfactants for the treatment of neonatal respiratory distress syndrome and paediatric lung diseases

This review documents the evolution of surfactant therapy, beginning with observations of surfactant deficiency in respiratory distress syndrome, the basis of exogenous surfactant treatment and the development of surfactant‐containing novel peptides patterned after SP‐B. We critically analyse the molecular interactions of surfactant proteins and phospholipids contributing to surfactant function.

Lucinactant attenuates pulmonary inflammatory response, preserves lung structure, and improves physiologic outcomes in a preterm lamb model of RDS

Background:Acute inflammatory responses to supplemental oxygen and mechanical ventilation have been implicated in the pathophysiological sequelae of respiratory distress syndrome (RDS). Although surfactant replacement therapy (SRT) has contributed to lung stability, the effect on lung inflammation is inconclusive. Lucinactant contains sinapultide (KL4), a novel synthetic peptide that functionally mimics surfactant protein B, a protein with anti-inflammatory properties. We tested the hypothesis that lucinactant may modulate lung inflammatory response to mechanical ventilation in the management of RDS and may confer greater protection than animal-derived surfactants.Methods:Preterm lambs (126.8 ± 0.2 SD d gestation) were randomized to receive lucinactant, poractant alfa, beractant, or no surfactant and studied for 4 h. Gas exchange and pulmonary function were assessed serially. Lung inflammation biomarkers and lung histology were assessed at termination.Results:SRT improved lung compliance relative to no SRT without significant difference between SRT groups. Lucinactant attenuated lung and systemic inflammatory response, supported oxygenation at lower ventilatory requirements, and preserved lung structural integrity to a greater degree than either no SRT or SRT with poractant alfa or beractant.Conclusion:These data suggest that early intervention with lucinactant may more effectively mitigate pulmonary pathophysiological sequelae of RDS than the animal-derived surfactants poractant alfa or beractant.

Aerosolized KL4 surfactant improves short-term survival and gas exchange in spontaneously breathing newborn pigs with hydrochloric acid-induced acute lung injury.

Surfactant therapy may be beneficial in acute lung injury (ALI). In spontaneously breathing newborn pigs with ALI supported with continuous positive airway pressure (CPAP), we evaluated the hypothesis that aerosolized KL4 surfactant (AERO KL4S) would provide a similar therapeutic effect as intratracheal KL4 surfactant (ETT KL4S) when compared to controls.

Pulmonary Distribution of Lucinactant and Poractant Alfa and Their Peridosing Hemodynamic Effects in a Preterm Lamb Model of Respiratory Distress Syndrome

Tracheal instillation of surfactant to premature newborns improves their survivability but may transiently obstruct airways resulting in undesirable acute effects on cerebral blood flow (CBF) and oxygenation. The acute peridosing hemodynamic effects of surfactant administration may be avoided by minimizing the volume of surfactant administered, but smaller surfactant volumes may also result in less even distribution of surfactant throughout the lung. These experiments were undertaken to compare responses to two surfactants with different dose volumes (porcine-derived poractant alfa, 2.5 mL/kg vs peptide-based synthetic lucinactant, 5.8 mL/kg) given to newly delivered lambs at 85% gestation. Both surfactants resulted in similar improvements in blood gas values, a doubling of dynamic compliance, increases in brain tissue oxygen tension, and stable blood pressure with no significant change in CBF. Distribution of surfactant throughout the lungs was more uniform with lucinactant than poractant alfa when assessed by labeled microspheres. We conclude that improvements in lung mechanics, gas exchange, and changes in CBF are comparable for a porcine-derived and peptide-containing synthetic surfactant, despite instilled volumes differing by 2-fold. Intrapulmonary distribution of surfactant is more uniform after a larger volume is instilled.

Association of Short Antenatal Corticosteroid Administration-to-Birth Intervals With Survival and Morbidity Among Very Preterm Infants: Results From the EPICE Cohort

Importance Administration-to-birth intervals of antenatal corticosteroids (ANS) vary. The significance of this variation is unclear. Specifically, to our knowledge, the shortest effective administration-to-birth interval is unknown. Objective To explore the associations between ANS administration-to-birth interval and survival and morbidity among very preterm infants. Design, Setting, and Participants The Effective Perinatal Intensive Care in Europe (EPICE) study, a population-based prospective cohort study, gathered data from 19 regions in 11 European countries in 2011 and 2012 on 4594 singleton infants with gestational ages between 24 and 31 weeks, without severe anomalies and unexposed to repeated courses of ANS. Data were analyzed November 2016. Exposure Time from first injection of ANS to delivery in hours and days. Main Outcomes and Measures Three outcomes were studied: in-hospital mortality; a composite of mortality or severe neonatal morbidity, defined as an intraventricular hemorrhage grade of 3 or greater, cystic periventricular leukomalacia, surgical necrotizing enterocolitis, or stage 3 or greater retinopathy of prematurity; and severe neonatal brain injury, defined as an intraventricular hemorrhage grade of 3 or greater or cystic periventricular leukomalacia. Results Of the 4594 infants included in the cohort, 2496 infants (54.3%) were boys, and the mean (SD) gestational age was 28.5 (2.2) weeks and mean (SD) birth weight was 1213 (400) g. Mortality for the 662 infants (14.4%) unexposed to ANS was 20.6% (136 of 661). Administration of ANS was associated with an immediate and rapid decline in mortality, reaching a plateau with more than 50% risk reduction after an administration-to-birth interval of 18 to 36 hours. A similar pattern for timing was seen for the composite mortality or morbidity outcome, whereas a significant risk reduction of severe neonatal brain injury was associated with longer administration-to-birth intervals (greater than 48 hours). For all outcomes, the risk reduction associated with ANS was transient, with increasing mortality and risk for severe neonatal brain injury associated with administration-to-birth intervals exceeding 1 week. Under the assumption of a causal relationship between timing of ANS and mortality, a simulation of ANS administered 3 hours before delivery to infants who did not receive ANS showed that their estimated decline in mortality would be 26%. Conclusions and Relevance Antenatal corticosteroids may be effective even if given only hours before delivery. Therefore, the infants of pregnant women at risk of imminent preterm delivery may benefit from its use.