Gastric Aspirate Phosphatidylcholine Species in Preterm Neonates Receiving Aerosolized Surfactant.

OBJECTIVE: To characterize phosphatidylcholine (PC) molecular species in serial gastric aspirates as biomarkers for lung maturity, delivery of aerosolized surfactant (AS), and need for intubation. METHODS: In a phase II clinical trial of aerosolized surfactant in preterm neonates with respiratory distress syndrome receiving noninvasive ventilation, infants received a maximum of 2 doses of nebulized beractant. Gastric aspirates were collected before and after each dose and were analyzed for PCs using liquid chromatography mass spectrometry. RESULTS: Of 149 infants enrolled, gastric aspirates were obtained before (n = 91) and after (n = 94) dose 1, and before (n = 56) and after (n = 57) dose 2 of nebulized beractant. The mean ± SD values of birthweight, gestational age, and age at collection of baseline gastric aspirate were 1.7 ± 0.6 kg, 31.7 ± 2.8 weeks, and 5.5 ± 1.7 hours, respectively. The most abundant PC in beractant and gastric aspirates was PC(16:0/16:0). Advancing gestational age and number of antenatal corticosteroid doses predicted increased gastric aspirate PC(16:0/16:0), whereas maternal diabetes predicted a decrease. Several PCs increased significantly (P < .05) after nebulized beractant, consistent with effective aerosol delivery. Infants who received intubation within 72 hours of birth were more likely to have lower PC(16:0/16:0) levels in baseline gastric aspirates compared with those who did not (P = .024). CONCLUSIONS: PC molecular species in gastric aspirates of preterm neonates are potentially novel and precise biomarkers to assess lung maturity, aerosol delivery, and need for endotracheal intubation.

Early histological changes of bronchopulmonary dysplasia and pulmonary hypertension may precede clinical diagnosis in preterm infants.

Bronchopulmonary Dysplasia (BPD), the commonest complication of prematurity, is defined by treatment with oxygen for ≥28 days. Pulmonary hypertension (PH) often coexists with BPD and is associated with increased mortality. In 42 autopsies, histological changes of BPD and PH were demonstrated in 25 % and 65 % respectively of preterm infants <28 days of age, highlighting the need for early diagnosis and treatment.

Chronic Inflammatory Placental Lesions Correlate With Bronchopulmonary Dysplasia Severity in Extremely Preterm Infants.

OBJECTIVE: Correlation of BPD with placental pathology is important for clarification of the multifactorial pathogenesis of BPD; however, previous reports have yielded varying results. We report placental findings in no/mild BPD compared to moderate/severe BPD, and with and without pulmonary hypertension (PH). METHODS: Eligible infants were 230/7-276/7 weeks gestational age. BPD was defined by the need for oxygen at ≥28 days with severity based on need for respiratory support at ≥36 weeks. Acute and chronic inflammatory placental lesions and lesions of maternal and fetal vascular malperfusion were examined. RESULTS: Of 246 eligible infants, 146 (59%) developed moderate/severe BPD. Thirty-four (23%) infants developed PH, all but 1 being in the moderate/severe BPD group. Chronic deciduitis (32% vs 16%, P = .003), chronic chorioamnionitis (23% vs 12%, P = .014), and ≥ 2 chronic inflammatory lesions (13% vs 3%, P = .007) were more frequent in the moderate/severe BPD group. Development of PH was associated with placental villous lesions of maternal vascular malperfusion (30% vs 15%, P = .047). CONCLUSIONS: The association of chronic inflammatory placental lesions with BPD severity has not been previously reported. This supports the injury responsible for BPD as beginning before birth in some neonates, possibly related to cytokines associated with these chronic inflammatory lesions.

Aerosolized Beractant in neonatal respiratory distress syndrome: A randomized fixed-dose parallel-arm phase II trial.

PURPOSE: There is increasing research into novel techniques of administering surfactant to preterm infants (PTIs) with respiratory distress syndrome (RDS) receiving non-invasive respiratory support (NIRS). Although aerosolized surfactant (AS) is promising in PTIs receiving NIRS, the optimal surfactant dose and formulation, drug-device combination and patient profile is not known. The objective of this randomized clinical trial was to investigate the feasibility, safety, efficacy and impact of four dosing schedules of AS using two nebulizers in PTIs with RDS stratified by gestational age (GA). METHODS: PTIs with RDS receiving pre-defined NIRS for ≤8 h were assigned to 4 A S dosing schedules and 2 nebulizers within three GA strata (I = 240/7-286/7, II = 290/7-326/7, III = 330/7-366/7 weeks). There was no contemporaneous control group; at the recommendation of the Data Monitoring Committee, data was collected retrospectively for control infants. RESULTS: Of 149 subjects that received AS, the median age at initiation of the 1st dose and duration was 5.5 and 2.4 h respectively. There were 29 infants in stratum I, and 60 each in strata II and III. Of infants <32 weeks GA, 94% received caffeine prior to AS. Fifteen infants (10%) required intubation within 72 h; the rates were not significantly different between GA strata, dosing schedules and nebulizers for infants who received aerosolized surfactant. Compared to retrospective controls, infants who received AS were less likely to need intubation within 72 h in both the intention-to-treat (32% vs. 11%) and the per-protocol (22% vs. 10%) analyses (p < 0.05) with GA stratum specific differences. AS was well tolerated by infants and clinical caregivers. Commonest adverse events included surfactant reflux from nose and mouth (18%), desaturations (11%), and increased secretions (7%). CONCLUSIONS: We have demonstrated the feasibility, absence of serious adverse events and short-term efficacy of four dosing schedules of AS in the largest Phase II clinical trial of PTIs 24-36 weeks' GA with RDS receiving NIRS (ClinicalTrials.gov NCT02294630). The commonest adverse events noted were surfactant reflux and desaturations; no serious adverse effects were observed. Infants who received AS were less likely to receive intubation within 72 h compared to historical controls. AS is a promising new therapy for PTIs with RDS.

Early prediction of moderate to severe bronchopulmonary dysplasia in extremely premature infants.

BACKGROUND: Bronchopulmonary Dysplasia (BPD) is the commonest morbidity in extremely preterm infants (PTIs). Risk factors for BPD have been described in the era before the widespread availability of non-invasive ventilation (NIV) in the delivery room (DR). The objective of this study is to identify risk factors for Moderate/Severe BPD in an era of widespread availability of NIV in the DR. METHODS: Detailed antenatal and postnatal data were abstracted for PTIs, 230/7-276/7 weeks GA. Multivariate logistic regression and classification and regression tree analyses (CART) identified predictors for the primary outcome of Moderate/Severe BPD. RESULTS: Of 263 eligible infants, 59% had Moderate/Severe BPD. Moderate/Severe BPD was significantly associated with birthweight, gender, DR intubation and surfactant compared to No/Mild BPD. Of infants not intubated in the DR, 40% with No/Mild BPD and 80% with Moderate/Severe BPD received intubation by 48 hours (p < 0.05). Infants with Moderate/Severe BPD received longer duration of oxygen and mechanical (MV). On logistic regression, birthweight, gender, oxygen concentration, cumulative duration of oxygen and MV, surfactant, and blood transfusions predicted Moderate/Severe BPD. Both CART analysis and logistic regression showed duration of oxygen and MV to be the most important predictors for Moderate/Severe BPD. CONCLUSIONS: In an era of increasing availability of NIV in the DR, lower birthweight, male gender, surfactant treatment, blood transfusions and respiratory support in the first 2-3 weeks after birth predict Moderate/Severe BPD with high sensitivity and specificity. The majority of these infants received intubation within 48 hours of birth (97%). These data suggest that early failures of NIV represent opportunities for improvement of NIV techniques and of non-invasive surfactant to avoid intubation in the first 48 hours. Furthermore, these risk factors may allow earlier identification of infants most likely to benefit from interventions to prevent or decrease severity of BPD.