Lung recruitment before surfactant administration in extremely preterm neonates with respiratory distress syndrome (IN-REC-SUR-E): a randomised, unblinded, controlled trial.

BACKGROUND: The importance of lung recruitment before surfactant administration has been shown in animal studies. Well designed trials in preterm infants are absent. We aimed to examine whether the application of a recruitment manoeuvre just before surfactant administration, followed by rapid extubation (intubate-recruit-surfactant-extubate [IN-REC-SUR-E]), decreased the need for mechanical ventilation during the first 72 h of life compared with no recruitment manoeuvre (ie, intubate-surfactant-extubate [IN-SUR-E]). METHODS: We did a randomised, unblinded, controlled trial in 35 tertiary neonatal intensive care units in Italy. Spontaneously breathing extremely preterm neonates (24 + 0 to 27 + 6 weeks' gestation) reaching failure criteria for continuous positive airway pressure within the first 24 h of life were randomly assigned (1:1) with a minimisation algorithm to IN-REC-SUR-E or IN-SUR-E using an interactive web-based electronic system, stratified by clinical site and gestational age. The primary outcome was the need for mechanical ventilation in the first 72 h of life. Analyses were done in intention-to-treat and per-protocol populations, with a log-binomial regression model correcting for stratification factors to estimate adjusted relative risk (RR). This study is registered with ClinicalTrials.gov, NCT02482766. FINDINGS: Of 556 infants assessed for eligibility, 218 infants were recruited from Nov 12, 2015, to Sept 23, 2018, and included in the intention-to-treat analysis. The requirement for mechanical ventilation during the first 72 h of life was reduced in the IN-REC-SUR-E group (43 [40%] of 107) compared with the IN-SUR-E group (60 [54%] of 111; adjusted RR 0·75, 95% CI 0·57-0·98; p=0·037), with a number needed to treat of 7·2 (95% CI 3·7-135·0). The addition of the recruitment manoeuvre did not adversely affect the safety outcomes of in-hospital mortality (19 [19%] of 101 in the IN-REC-SUR-E group vs 37 [33%] of 111 in the IN-SUR-E group), pneumothorax (four [4%] of 101 vs seven [6%] of 111), or grade 3 or worse intraventricular haemorrhage (12 [12%] of 101 vs 17 [15%] of 111). INTERPRETATION: A lung recruitment manoeuvre just before surfactant administration improved the efficacy of surfactant treatment in extremely preterm neonates compared with the standard IN-SUR-E technique, without increasing the risk of adverse neonatal outcomes. The reduced need for mechanical ventilation during the first 72 h of life might facilitate implementation of a non-invasive respiratory support strategy. FUNDING: None.

Neonatal respiratory support strategies for the management of extremely low gestational age infants: an Italian survey.

BACKGROUND: We aimed to survey Delivery Room and Neonatal Intensive Care Unit (NICU) respiratory strategies dedicated to the extremely low gestational age newborn (ELGAN - GA < 28 wks) in Italy. METHODS: A questionnaire was sent to 113 Italian level III centres. A lead physician and a nurse with expertise in mechanical ventilation (MV) were identified in each unit to answer. Information about those aspects of ventilatory support considered by center's staff as needing improvement was also collected. RESULTS: A 100% response rate was obtained. In the Delivery Room, sustained lung inflation was performed in 74.8% of centres, and 89.2% used NCPAP. For ELGANs who need invasive MV, conventional MV was the most used strategy. Volume-targeted ventilation and High-frequency oscillatory ventilation (HFOV) were considered as primary mode in < 30% of centres. Among non-invasive strategies, NCPAP was the most utilized, followed by BiPAP, High-flow nasal cannula and nasal intermittent positive pressure ventilation. Nurses more commonly recorded in the nursing charts the ventilator's setting parameters rather than measured ones. HFOV and non-invasive ventilation were the most quoted aspects of neonatal ventilation felt as to be improved. CONCLUSION: The routine respiratory support practices in Italy showed marked variations among units. Focused interventions are largely required to improve clinical practice.

Serum levels of seven cytokines in premature ventilated newborns: correlations with old and new forms of bronchopulmonary dysplasia.

OBJECTIVE: In addition to the previous classification of chronic lung disease (CLD) O2 dependency at 36 weeks of postmenstrual age, a new definition of CLD has recently been proposed: new bronchopulmonary-dysplasia (BPD). This uses total duration of O2 supplementation and positive pressure requirements to delineate three degrees of severity (mild, moderate, and severe) according to the respiratory status at 36 weeks postmenstrual age. We analyzed the balance of serum proinflammatory and profibrotic/angiogenic cytokine concentrations in relation to CLD and the new BPD definition. DESIGN AND SETTING: Descriptive study in a third-level neonatal ICU. PATIENTS: Thirty-one preterm neonates with a gestational age of 24-29 weeks were studied to evaluate their serum cytokine concentration; they were previously enrolled in a randomized clinical trial to compare the effects of high-frequency oscillatory ventilation vs. intermittent mandatory ventilation in terms of pulmonary mechanics and lung cytokines. Serum samples were collected on days 1, 3, and 5 after birth until extubation to detect the levels of three proinflammatory cytokines plus four profibrotic/angiogenic cytokines, and correlations were examined to old CLD and new BPD. Ventilation treatments were distributed homogeneously between the groups and did not interfere with the results presented here. RESULTS AND CONCLUSIONS: Old CLD development, mainly corresponding to the moderate/severe forms of new BPD, was associated with increased proinflammatory and profibrotic/angiogenic cytokines, while mild forms of new BPD were characterized only by increases in profibrotic/angiogenic cytokines, suggesting a different balance of two pathogenic mechanisms in different phases of the disease.

HFOV in premature neonates: effects on pulmonary mechanics and epithelial lining fluid cytokines. A randomized controlled trial.

OBJECTIVE: Ventilation strategies for preterm neonates may influence the severity of pulmonary dysfunction and later development of chronic lung disease. The objective of this report is to compare the effects of high-frequency oscillatory ventilation (HFOV) versus synchronized intermittent mandatory ventilation (sIMV) from the points of views of biochemical and functional variables. DESIGN: Randomized controlled trial. SETTING: Third level NICU. PATIENTS AND PARTICIPANTS: Forty preterm neonates with a gestational age of 24-29 weeks were randomly assigned to one of the two above-mentioned ventilation strategies within 30 min from birth. MEASUREMENTS AND RESULTS: At 1, 3, 5, and 7 days, the babies were monitored by means of ventilator indices, pulmonary function, and eight pro-inflammatory or anti-inflammatory cytokines measured in bronchoalveolar lavage fluid. The neonates assigned to the HFOV procedure benefited from early and sustained improvement in pulmonary mechanics and gas exchange-significantly higher dynamic respiratory compliance values, significantly lower expiratory airway resistance and oxygenation index values-with earlier extubation as compared to the neonates assigned to sIMV treatment, and showed significantly lower transforming growth factor-beta1 concentrations in bronchoalveolar lavage fluid. CONCLUSIONS: The results of this randomized clinical trial support the hypothesis that early and exclusive use of HFOV, combined with optimum volume strategy, has a beneficial effect during the acute phase of lung injury.

Effects of early dexamethasone therapy on pulmonary fibrogenic mediators and respiratory mechanics in preterm infants.

Corticosteroid administration may prevent chronic lung disease in premature newborns, perhaps by modulating the synthesis of various cytokines, including those involved in fibrogenic processes. This study analyses the levels of three fibrogenic cytokines, namely vascular endothelial growth factor, transforming growth factor-beta 1 and basic fibroblast growth factor in tracheobronchial aspirate fluids collected from 20 premature newborns randomly assigned to the early dexamethasone group or to the control group. Furthermore, pulmonary function tests were performed on days 0 and 2 following the start of therapy. The results show that early corticosteroid administration reduces transforming growth factor-beta 1 and basic fibroblast growth factor levels, and abolishes the spontaneous vascular endothelial growth factor increase observed in untreated patients, concomitantly with significant improvement of dynamic lung compliance and shorter duration of the intubation period in the treated group of patients. Significant correlations were observed between the levels of transforming growth factor-beta 1 and vascular endothelial growth factor, indicating that the production of both these cytokines is coordinated. Finally, transforming growth factor-beta 1 ratios (day 2/day 0), representing early variations of the cytokine levels, were significantly different between treated and untreated subjects and correlated with the dynamic lung compliance ratios and the extubation day, suggesting that the downmodulation of some fibrogenic mediators may be involved in the mode of action of dexamethasone.