This single-center prospective cohort study was conducted in the neonatal intensive care unit (NICU) of the hospital over a 2-year period. We included 20 preterm infants born at 25 to 29 weeks of gestation or with a birth weight of less than 1,250 g, who received prophylactic pulmonary surfactant (200 mg/kg Curosurf, Chiesi Pharmaceuticals, Parma, Italy) by tracheal catheterization (5-French gastric tube) while applying nasal CPAP without endotracheal intubation between January 1, 2015 and December 31, 2016 (LISA group). We compared them to the INSURE group (historical control) of 20 infants managed in our hospital with prophylactic surfactant treatment via the INSURE method between January 1, 2013 and December 31, 2014. The eligible INSURE group was matched to a case by gestational age (within ±7 days) and birth weight (within ±250 g). The inclusion criteria of the LISA and INSURE groups were: (1) preterm infants with 25 to 29 weeks of gestation or with a birth weight of less than 1,250 g; (2) preterm infants born in the hospital and admitted to the NICU; and (3) primary use of nasal CPAP (5 to 8 cm H₂O, Infant Flow SiPAP, CareFusion, San Diego, CA, USA) for respiratory support. The exclusion criteria were: (1) infants who were transferred from another hospital; (2) infants who required persistent positive pressure ventilation (PPV) in the delivery room during initial resuscitation; (3) infants who were diagnosed with chromosomal abnormalities; and (4) infants who were diagnosed with multiple congenital anomalies. The LISA group was treated with a prophylactic surfactant through a sterile 5-French gastric tube while applying nasal CPAP. This procedure was performed as described by Gopel et al. [14] study. The INSURE group was treated with prophylactic surfactant using the INSURE method. When FiO₂ ≥0.6, pH <7.20, and PaCO₂ >65 mm Hg or recurrent apnea requiring PPV or CPAP setting of FiO₂ ≥0.6, peak end-expiratory pressure (PEEP) >8 cm of H₂O to maintain SpO₂ 90% to 95%, invasive ventilation was applied after endotracheal intubation. Infants were extubated and weaned to nasal CPAP when they had minimal or no signs of respiratory difficulty and MV settings of PIP ≤15 cm H₂O, PEEP ≤5 cm H₂O, rate ≤20 rate per min, and FiO₂ ≤0.3. If the infant continued to require FiO₂ >0.4 and PEEP >8 cm H₂O after 6 h of initial SRT to maintain SpO₂ 90% to 95%, the second dose of surfactant (100 mg/kg Curosurf) was administered by the LISA or INSURE method.

The primary outcomes of our study included the need for MV at 72 hours after birth or during hospitalization due to failure of non-invasive respiratory support, failure of the procedure on the first attempt, and requirement of an additional dose of surfactant. The secondary outcomes included the presence of bradycardia or reflux during SRT, MV duration, nasal CPAP duration, heated humidified high-flow nasal cannula (HHHFNC) duration, and hospital stay duration. Additionally, patent ductus arteriosus (PDA) requiring treatment, necrotizing enterocolitis (NEC, greater than grade 2) [15], intraventricular hemorrhage (IVH, higher than grade 2) [16], cystic periventricular leukomalacia, retinopathy of prematurity (ROP) [17], culture-proven sepsis, pulmonary hemorrhage, pneumothorax, death, bronchopulmonary dysplasia (BPD) [18], and composite outcomes of death or BPD were investigated.

Clinical characteristics were compiled prospectively from the LISA group and retrospectively from the INSURE group. Demographic data, including gestational age, birth weight, type of delivery, sex, multiple births, maternal age, antenatal steroid use, oligohydramnios, premature rupture of membranes (PROMs ≥18 hours), histologic chorioamnionitis, maternal diabetes, maternal hypertension, small for gestational age (SGA), Apgar score (1- and 5-minute), need for oxygen supplementation in the delivery room, and need for PPV support in the delivery room, were collected. Data on treatment during hospitalization were also collected. Thereafter, the results were compared between groups using statistical analysis.

Continuous variables were analyzed using Student’s t-test or Mann–Whitney U-test. Categorical variables were analyzed using the chi-squared test or Fisher’s exact test. All analyses indicated that the P-value was statistically significant at P<0.05. Continuous data are expressed as median (interquartile range [IQR]) or mean±standard deviation, and dichotomous data are expressed as number (%). Additionally, multivariate logistic regression analysis was performed for all the statistically significant variables in the univariate analysis to adjust for the effect of LISA on known confounding variables (gestational age, SGA, sex, multiple births, and use of antenatal steroids). Statistical analysis was performed using the IBM SPSS software version 25.0 for Windows (IBM Co., Armonk, NY, USA).

From January 1, 2015 to December 31, 2016, 30 preterm infants, 25 to 29 weeks of gestation, or with a birth weight of less than 1,250 g, were treated with prophylactic SRT. Five neonates who required persistent PPV after birth and five who refused to provide consent to their parents, were excluded from the study. Twenty spontaneously breathing preterm infants managed with prophylactic SRT with the LISA method using a 5-French gastric tube were enrolled in the LISA group. From January 1, 2013, to December 31, 2014, 35 preterm infants, at 25 to 29 weeks of gestation, or with a birth weight of less than 1,250 g, were treated with prophylactic SRT via endotracheal intubation. Eight neonates who required persistent PPV after birth during initial resuscitation and seven neonates who did not match gestational age and birth weight, were excluded from this study. Twenty spontaneously breathing preterm infants who were treated with prophylactic SRT according to the INSURE method via an endotracheal tube were enrolled in the INSURE group (Figure 1).

Comparisons of the clinical characteristics between the two groups are shown in Table 1. There were no statistically significant differences between the groups in terms of gestational age, birth weight, type of delivery, sex, maternal age, multiple births, antenatal steroids use, maternal diabetes, maternal hypertension, SGA, oligohydramnios, PROM, histologic chorioamnionitis, Apgar scores at -1 and 5 minute, oxygen supplementation or PPV in the delivery room, baseline concentration of inspired oxygen, and baseline capillary blood gas analysis.

In the univariate analysis, the LISA group had a significantly lower likelihood of receiving MV within 72 hours after birth (P=0.019) or during hospitalization (P=0.025) than the INSURE group. However, there were no significant differences in the second dose of surfactant use and failure on the first attempt using the LISA or INSURE method. The frequency of bradycardia during SRT was significantly lower in the LISA group than in the control group (P=0.031). The median duration of MV (0 days vs. 6 days, P=0.038) was shorter in the LISA group than in the INSURE group. In contrast, the median duration of nasal CPAP, MV+nasal CPAP, HHHFNC, and MV+nasal CPAP+HHHFNC were not significantly different between the two groups (Table 2, Figure 2). In the multivariate analysis, prophylactic SRT with LISA was associated with a significantly lower likelihood of receiving MV during hospitalization (odds ratio [OR], 0.029; 95% confidence interval [CI], 0.001 to 0.938; P=0.046) and a decreased incidence of bradycardia during SRT (OR, 0.020; 95% CI, 0.001 to 0.535; P=0.020) as compared to the INSURE method.

There were no significant differences in neonatal morbidities (pneumothorax, PDA, NEC, ROP laser, IVH, culture-proven sepsis, BPD, mortality, composite outcome of BPD and mortality, and hospital stay) between the two groups (Table 3).