Nonintubated Surfactant Application vs Conventional Therapy in Extremely Preterm Infants: A Randomized Clinical Trial

JAMA Pediatr. 2015 Aug;169(8):723-30. doi: 10.1001/jamapediatrics.2015.0504.


Importance: 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 participants: The 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 measures: Survival without BPD at 36 weeks' gestational age.

Results: Of 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.

Trial registration: Identifier: ISRCTN64011614.

Publication types

  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catheterization
  • Continuous Positive Airway Pressure
  • Female
  • Follow-Up Studies
  • Humans
  • Infant, Extremely Premature*
  • Infant, Newborn
  • Intubation, Intratracheal
  • Male
  • Pulmonary Surfactants / administration & dosage*
  • Treatment Outcome


  • Pulmonary Surfactants

Associated data

  • ISRCTN/ISRCTN64011614