Objective:To explore the application and treatment efficacy of less invasive surfactant administration (LISA) and nasal high-frequency oscillation ventilation (nHFOV) in very low and extremely low birth weight preterm infants with neonatal respiratory distress syndrome (NRDS).Methods:A total of 85 very low and extremely low birth weight preterm infants with gestational age ranging between 27-32 weeks who were diagnosed with NRDS in the Second Affiliated Hospital of Zhengzhou University from July 2018 to October 2019 were enrolled.After being stratified by gestational age of >27-29 weeks, >29-30 weeks, >30-31 weeks, >31-32 weeks, the neonates were divided into the LISA group (40 cases) and the intubation-surfactant-extubation (INSURE) group (45 cases) by the random envelope method.The LISA group was subdivided into the continuous positive airway pressure (CPAP) group (25 cases) and the nHFOV group (15 cases) by the same method.The patients in the INSURE group were infused with pulmonary surfactant (PS) through the endotracheal tube under positive airway pressure, and then treated with CPAP after extubation.The patients in the LISA group were first treated with CPAP and injected with PS through the gastric tube.After removing the gastric tube, the patients in the CPAP group were given CPAP-assisted ventilation, while the patients in the nHFOV group were given nHFOV-assisted ventilation or mechanical ventilation if nHFOV-assisted ventilation failed.The feasibility of LISA technology and nHFOV was observed, and the adverse reactions, mechanical ventilation, oxygen duration, hospital stay and the incidence of NRDS complications in different groups of the patients were compared.Results:(1) The mechanical ventilation rate (5.0% vs.22.2%), the incidence of broncho-pulmonary dysplasia (BPD) (20.0% vs.42.2%) and the incidence of periventricular leukomalacia (PVL) (12.5% vs.42.2%) in the LISA group were significantly lower than those in the INSURE group (all P<0.05). There were no statistically significant differences in total oxygen duration, hospitalization duration, intraventricular he-morrhage (IVH), retinopathy of prematurity (ROP), and necrotizing enterocolitis (NEC) between the LISA group and the INSURE group (all P>0.05). (2) There was no significant difference in adverse reactions between the LISA group and the INSURE group as well as between the CPAP group and the nHFOV group (all P>0.05). (3) The younger the gestational age at birth, the higher the incidence of NRDS complications.Patients in the LISA group had a lower incidence of NPDS complications than patients of the same gestational age in the INSURE group, but the diffe-rence was not statistically significant (all P>0.05). (4) There was no significant difference in the mechanical ventilation rate and the incidence of BPD, IVH, PVL, NEC and ROP complications between the CPAP group and the nHFOV group (all P>0.05). Conclusions:In the treatment of very low and extremely low birth weight preterm infants with NRDS at the gestational age of 27-32 weeks, LISA technology is a safe and effective PS delivery method, which can reduce the mechanical ventilation rate and the incidence of BPD and PVL.The nHFOV can be used as an initial model for respiratory support of NRDS preterm infants with very low and ultra-low birth weight.LISA combined with nHFOV is applicable to the treatment of preterm infants with NRDS.