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Treatment of respiratory distress syndrome in premature infants with continuous positive airway pressure (CPAP) preserves surfactant and keeps the lung open but is insufficient in severe surfactant deficiency. Traditional surfactant administration is related to short periods of positive pressure ventilation and implies the risk of lung injury. CPAP with surfactant but without any positive pressure ventilation may work synergistically. This randomized trial investigated a less invasive surfactant application protocol (LISA).OBJECTIVE To test the hypothesis that LISA increases survival without bronchopulmonary dysplasia (BPD) at 36 weeks' gestational age in extremely preterm infants. DESIGN, SETTING, AND PARTICIPANTSThe Nonintubated Surfactant Application trial was a multicenter, randomized, clinical, parallel-group study conducted between April 15, 2009, and March 25, 2012, in 13 level III neonatal intensive care units in Germany. The final follow-up date was June 21, 2012. Participants included 211 of 558 eligible (37.8%) spontaneously breathing preterm infants born between 23.0 and 26.8 weeks' gestational age with signs of respiratory distress syndrome. In an intention-to-treat design, infants were randomly assigned to receive surfactant either via a thin endotracheal catheter during CPAP-assisted spontaneous breathing (intervention group) or after conventional endotracheal intubation during mechanical ventilation (control group). Analysis was conducted from September 6, 2012, to June 20, 2013.INTERVENTION LISA via a thin catheter. MAIN OUTCOMES AND MEASURESSurvival without BPD at 36 weeks' gestational age. RESULTSOf 211 infants who were randomized, 104 were randomized to the control group and 107 to the LISA group. Of the infants who received LISA, 72 (67.3%) survived without BPD compared with 61 (58.7%) of those in the control group. The reduction in absolute risk was 8.6% (95% CI, −5.0% to 21.9%; P = .20). Intervention group infants were less frequently intubated (80 infants [74.8%] vs 103 [99.0%]; P < .001) and required fewer days of mechanical ventilation. Significant reductions were seen in pneumothorax (5 of 105 intervention group infants [4.8%] vs 13 of 103 12.6%]; P = .04) and severe intraventricular hemorrhage (11 infants [10.3%] vs 23 [22.1%]; P = .02), and the combined survival without severe adverse events was increased in the intervention group (54 infants [50.5%] vs 37 [35.6%]; P = .02; absolute risk reduction, 14.9; 95% CI, 1.4 to 28.2).CONCLUSIONS AND RELEVANCE LISA did not increase survival without BPD but was associated with increased survival without major complications. Because major complications are related to lifelong disabilities, LISA may be a promising therapy for extremely preterm infants.

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Almost half of all preterm births are caused or triggered by an inflammatory process at the feto-maternal interface resulting in preterm labor or rupture of membranes with or without chorioamnionitis (“first inflammatory hit”). Preterm babies have highly vulnerable body surfaces and immature organ systems. They are postnatally confronted with a drastically altered antigen exposure including hospital-specific microbes, artificial devices, drugs, nutritional antigens, and hypoxia or hyperoxia (“second inflammatory hit”). This is of particular importance to extremely preterm infants born before 28 weeks, as they have not experienced important “third-trimester” adaptation processes to tolerate maternal and self-antigens. Instead of a balanced adaptation to extrauterine life, the delicate co-regulation between immune defense mechanisms and immunosuppression (tolerance) to allow microbiome establishment is therefore often disturbed. Hence, preterm infants are predisposed to sepsis but also to several injurious conditions that can contribute to the onset or perpetuation of sustained inflammation (SI). This is a continuing challenge to clinicians involved in the care of preterm infants, as SI is regarded as a crucial mediator for mortality and the development of morbidities in preterm infants. This review will outline the (i) role of inflammation for short-term consequences of preterm birth and (ii) the effect of SI on organ development and long-term outcome.

Non-invasive ventilation and especially the application of continuous positive airway pressure (CPAP) has become standard for the treatment of premature infants with respiratory problems. However, CPAP failure may occur due to respiratory distress syndrome, that is, surfactant deficiency. Less invasive surfactant administration (LISA) aims to provide an adequate dose of surfactant while the infant is breathing spontaneously, thus avoiding positive pressure ventilation support. Using a thin catheter for surfactant application allows infants to maintain function of the glottis and continue spontaneous breathing, whereas the INtubate-SURfactant-Extubate (INSURE) procedure is connected with sedation/analgesia, regular intubation and a (brief) period of positive pressure ventilation. Individual studies and meta-analyses summarised in this review point in the direction that LISA is more effective than standard treatment or INSURE both in terms of short-term (avoidance of mechanical ventilation) and long-term (intracerebral haemorrhage and bronchopulmonary dysplasia) outcomes. Open questions include exact treatment thresholds for different gestational ages, the usefulness of devices/catheters that have recently been purpose-built for the LISA technique and especially the question of analgesia/sedation during the procedure. The current technology still demands laryngoscopy with all its unpleasant effects for infants. Therefore, studies with pharyngeal surfactant deposition immediately after delivery, the use of laryngeal airways for surfactant administration and attempts to nebulise surfactant are under way. Finally, LISA is not simply an isolated technical procedure for surfactant delivery but rather part of a comprehensive non-invasive approach supporting the concept of a gentle transition to the extrauterine world enabling preterm infants to benefit from the advantages of spontaneous breathing.