# Surfactant treatment rate in very premature infants following change to less-invasive surfactant administration

Diane Gillot, Christophe Milési, Clémentine Combes, Vincent Brodeau, Arthur Gavotto, Gilles Cambonie

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## ► To cite this version:

Diane Gillot, Christophe Milési, Clémentine Combes, Vincent Brodeau, Arthur Gavotto, et al. | Surfactant treatment rate in very premature infants following change to less-invasive surfactant administration. European Journal of Pediatrics, 2025, 184 (9), pp.563. 10.1007/s00431-025-06406-z. hal-05215711

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# Surfactant treatment rate in very premature infants following change to less-invasive surfactant administration

Diane Gillot<fnref n="1" />, Christophe Milési<fnref n="1" />, Clémentine Combes<fnref n="1" />, Vincent Brodeau<fnref n="1" />, Arthur Gavotto<fnref n="1" />,<fnref n="2" />, Gilles Cambonie<fnref n="3" /> <fnref n="4" />

**Keywords:**

Bronchopulmonary dysplasia; Mechanical ventilation; Noninvasive ventilation; Premature infant; Pulmonary surfactants; Respiratory distress syndrome.

**E-mail** : * Gilles Cambonie

g-cambonie@chu-montpellier.fr

<footnote n="1">¹ Department of Neonatal Medicine, Pediatric Intensive Care and Pediatric Emergency Transport Service, Arnaud de Villeneuve Hospital, Montpellier University Hospital Centre, University of Montpellier, 371 Avenue du Doyen Gaston Giraud, Cedex 5, 34295, Montpellier, France.</footnote>

<footnote n="2">² PhyMedExp, CNRS, INSERM, University of Montpellier, Montpellier, France.</footnote>

<footnote n="3">³ Department of Neonatal Medicine, Pediatric Intensive Care and Pediatric Emergency Transport Service, Arnaud de Villeneuve Hospital, Montpellier University Hospital Centre, University of Montpellier, 371 Avenue du Doyen Gaston Giraud, Cedex 5, 34295, Montpellier, France. g-cambonie@chu-montpellier.fr.</footnote>

<footnote n="4">⁴ Pathogenesis and Control of Chronic Infection, INSERM UMR 1058, University of Montpellier, Montpellier, France. g-cambonie@chu-montpellier.fr.</footnote>
Abstract

This study investigates whether implementation of a less-invasive surfactant administration (LISA) protocol in a level IIb academic neonatal intensive care unit had an impact on the rate of infants treated with surfactant. This observational cohort study enrolled spontaneously breathing very premature infants, born < 33 weeks' gestational age (GA), with worsening respiratory distress syndrome despite support with continuous positive airway pressure and in need of surfactant replacement therapy. Data were collected over two 3-year periods, preceding (P1, 2013-2015) and following (P2, 2019-2021) implementation of a LISA protocol. Nine hundred and six neonates were studied, 412 (45%) born in P1 and 494 (55%) in P2, with comparable GA, birthweight, and severity score (CRIB-II). Administration technique was mainly conventional at P1 (85%) and LISA at P2 (75%). Surfactant treatment rate decreased from 54% (224/412) at P1 to 47% (233/494) at P2 (p = 0.04), notably in infants born at 28-32 weeks' GA (41 to 33%, OR [95% CI] 0.72 [0.53-0.99]). Among 23-32 weeks' GA infants, need for invasive mechanical ventilation decreased from 56% (231/412) at P1 to 23% (113/494) at P2 (OR 0.23 [0.17-0.31], p < 0.001). Mortality and survival without severe morbidity were comparable. Conclusion: Implementation of a LISA protocol in our level IIb NICU was associated with less surfactant use and lower exposure to invasive mechanical ventilation.
## Abbreviations

* BPD Bronchopulmonary dysplasia
* CMV Conventional mechanical ventilation
* CPAP Continuous positive airway pressure
* FiO2 Fraction of inspired oxygen
* GA Gestational age
* HFNC High-flow nasal cannula
* HFOV High-frequency oscillatory ventilation
* IMV Invasive mechanical ventilation
* INSURE Intubation, surfactant, and extubation
* LISA Less invasive surfactant administration
* LUS Lung ultrasonography
* NICU Neonatal intensive care unit
* NIV Noninvasive ventilation
* RDS Respiratory distress syndrome

## Introduction

Respiratory distress syndrome (RDS) is a common complication of premature birth that requires appropriate care to avoid early mortality and long-term morbidity. The current strategy to avoid severe RDS and its complications combines three key elements: prenatal administration of corticosteroids, early noninvasive ventilation (NIV) with continuous positive airway pressure (CPAP), and early rescue surfactant administration [1].

Surfactant administration has traditionally relied on endotracheal intubation and bolus delivery in infants supported by invasive mechanical ventilation (IMV). Other methods have more recently been proposed to avoid the need for or to reduce the duration of IMV, including the intubation and surfactant administration followed by immediate extubation (INSURE) procedure and less invasive surfactant administration (LISA) techniques. According to the 2022 European consensus guidelines on the management of acute neonatal RDS, LISA is the preferred mode of surfactant administration, provided that infants supported with CPAP are spontaneously breathing and clinicians are proficient in this technique [1].

Few studies have evaluated the impact of a more liberal non-invasive ventilation strategy in combination with the implementation of a LISA protocol on the rate of surfactant use. In Europe, use of LISA is most experienced and extensive in Germany. Within the German neonatal network, the increasing preference for LISA to administer surfactant was associated with an increasing rate of < 32 weeks' gestational age (GA) infants being treated [2, 3]. At the level of a single neonatal intensive care unit (NICU), however, if availability of a potentially more comfortable and less invasive method can incite a broader surfactant therapy, physician's insecurity or lack of confidence with this new technique can have a neutral or even opposite effect.

Our neonatal medicine department implemented a LISA protocol in 2017 [4]. The main objective of this study was to assess whether the transition to LISA influences the rate of surfactant treatment in very premature infants with RDS in a single center. Secondary objectives were to compare respiratory management and patients' outcomes.
# Material and methods

## Study design and patient population

This observational study was conducted in the NICU of Montpellier University Hospital Centre in France. All live born very premature infants (< 33 weeks' GA), born between January 01, 2013, and December 31, 2015, and between January 01, 2019, and December 31, 2021, actively managed in the delivery room of our hospital (in-born neonates) and admitted to the department were included. Infants with severe congenital anomalies were excluded. Perinatal data for each infant were collected prospectively in a database created in 2003 for neonates born < 33 weeks' GA and/or with a birthweight < 1500 g.

## Protocol applied during both periods

The surfactant administration policy for the treatment of RDS remained unchanged during the study periods. The treatment, poractant alfa at a dose of 200 mg/kg (Curosurf, Chiesi), was selected in patients with a fraction of inspired oxygen (FiO2) > 30% in neonates ≤ 26 weeks' GA or > 40% in neonates > 26 weeks' GA. A second dose was considered if FiO2 was > 30% within 2-6 h of the first dose. Premedication with ketamine or propofol was systematically considered before intubation or LISA, except for emergent intubation during resuscitation [4].

In intubated infants, first-line respiratory support was conventional mechanical ventilation (CMV) in synchronized and volume-targeted mode. High-frequency oscillatory ventilation (HFOV) was used as a rescue mode of ventilation, in case of peak inspiratory pressure exceeding 22 cm H2O and FiO2 50% on CMV. In non-intubated infants, first-line respiratory support was nasal CPAP, set at 7 cm H2O. High flow nasal cannula (HFNC) was considered in infants with stable respiratory status with CPAP, initially from 1 to 2 h every 8 to 12 h, then gradually increased. Oxygen therapy was adjusted so that oxygen saturation (SpO2) was within a target range of 90 to 95% [5]. Rescue hydrocortisone administration was indicated for infants still requiring IMV for more than 14 days after birth [6].

## Change in respiratory care during the second period

LISA was performed according to the method described by Gopel et al. [7]. Implementation of LISA protocol was integrated into a policy aimed at avoiding tracheal intubation, based on the promotion of non-invasive ventilation. Early low-dose hydrocortisone was provided for infants born < 28 weeks' GA to reduce the risk of bronchopulmonary dysplasia (BPD). The dosing regimen followed the protocol described in the PREMILOC randomized trial, i.e., 1 mg/kg per day for 7 days, then 0.5 mg/kg per day for 3 days [8]. In addition, lung ultrasonography (LUS) practice was developed during this period, following the participation of the team's physicians in training courses [9], but did not influence the surfactant administration protocol for treating RDS.
## Outcomes

The primary endpoint was the number of infants treated with surfactant during the two study periods. The result was expressed according to the number of eligible infants < 33 weeks' GA during the period considered. Secondary endpoints included additional data on surfactant administration (guidance by lung ultrasonography (LUS), technique, timing and number of doses), respiratory management (need and duration of IMV and NIV), respiratory morbidity (bronchopulmonary hemorrhage, pneumothorax, severe bronchopulmonary dysplasia), death, and survival without severe morbidity.

## Definitions

The technique for surfactant administration was defined as follows: (i) conventional surfactant administration, when given via an endotracheal tube during mechanical ventilation; (ii) INSURE, when given via an endotracheal tube with a duration of mechanical ventilation of less than 1 h; and (iii) LISA, when given to a spontaneously breathing infant supported with CPAP, via a 5-French soft catheter placed in the trachea only for the time needed to give surfactant. Use of IMV, defined as endotracheal ventilation, was recorded at any time during hospitalization, regardless of reason and duration. Duration of IMV was defined as the cumulative duration of CMV and HFOV and duration of NIV as the cumulative duration of CPAP and HFNC.

Severe bronchopulmonary dysplasia (BPD) was defined at 36 weeks' GA as invasive positive pressure ventilation or the need for nasal CPAP, noninvasive positive pressure ventilation, or nasal cannula ≥ 3 L/min with FiO2 ≥ 30% to maintain SpO2 in the 90-95% range [10].

Severe morbidities included severe BPD, grade 3-4 intraventricular hemorrhage, cystic periventricular leukomalacia, stage 2-3 necrotizing enterocolitis, and grade III-V retinopathy of prematurity [11].

## Statistical analysis

Based on our surfactant annual use reported by the hospital pharmacy department, and assuming a 5-10% increase or decrease in this use following implementation of the protocol, the number of subjects required to demonstrate a significant difference was 400 per group, with a power of 80% and a two-sided p-value < 0.05. Considering the annual number of in-born infants admitted to the NICU, the recruitment period was set at 3 years for the two periods. As drafting of the LISA protocol was initiated in mid-2017, an 18-month washout period on both sides of the protocol was respected to take into account contamination risk.

Between periods, comparisons were made for qualitative variables using the chi-squared or Fisher test, as appropriate, and for quantitative variables using the Student or Wilcoxon-Mann-Whitney test, according to their distribution. In cases of significant difference, paired comparisons between subgroups of GA were made with Bonferroni method correction to account for the multiplicity of tests. Multivariate logistic regression analysis was performed to study the influence of covariates on the primary outcome. It included antenatal variables with a potential influence on surfactant treatment such as multiple pregnancy, maternal diabetes, main pregnancy complications, antenatal steroids, delivery mode, and neonatal data such as
gestational age, sex, birth weight z-score, Apgar score, and the two periods, before and after implementation of LISA protocol. The model was built using a stepwise procedure based on the likelihood ratio test (input and output thresholds = 0.20).

The adjusted odds ratios and their 95% confidence intervals were calculated. The quality of the model was assessed by the Hosmer–Lemeshow adequacy test. Statistical analysis was performed with SAS version 9 software (SAS Institute, Cary, NC). Values are expressed as numbers (%), medians (Q25, Q75), or means (• +/- SD); *p* < 0.05 was considered statistically significant.

# Results

## Population

Among the 966 in-born infants admitted to the NICU, 906 were eligible, including 412 (45%) born before (2013–2015) and 494 (55%) after (2019–2021) implementation of LISA protocol (Supplementary Fig. 1). Maternal gestational diabetes was more common in the second period. Exposure to antenatal corticosteroids was 97%, with a higher rate in the first period (99% vs 95%). Other perinatal characteristics were comparable (Table 1).

<table><caption>**Table 1** Perinatal characteristics of the patients before (2013–2015) and after (2019–2021) implementation of LISA protocol</caption><thead><tr><th></th><th>Pre-protocol; N=412</th><th>Post-protocol; N=494</th><th>p</th></tr></thead><tbody><tr><td>Antenatal</td><td></td><td></td><td></td></tr><tr><td>Multiple pregnancy, n (%)</td><td>151 (37)</td><td>161 (33)</td><td>0.21</td></tr><tr><td>Preeclampsia, n (%)</td><td>96 (23)</td><td>109 (22)</td><td>0.69</td></tr><tr><td>Diabetes, n (%)</td><td>4 (1.0)</td><td>7 (1.4)</td><td>0.76</td></tr><tr><td>Gestational diabetes, n (%)</td><td>22 (5.3)</td><td>67 (14)</td><td>&lt;10<sup>-3</sup></td></tr><tr><td>PROM, n (%)</td><td>120 (29)</td><td>146 (30)</td><td>0.94</td></tr><tr><td>Duration (days)</td><td>5.0 (2, 15)</td><td>5.0 (2, 13)</td><td>0.94</td></tr><tr><td>Antenatal corticosteroids, n (%)</td><td>406 (99)</td><td>469 (95)</td><td>0.005</td></tr><tr><td>Within 7 days before birth, n (%)</td><td>232 (56)</td><td>253 (51)</td><td>0.12</td></tr><tr><td>Birth</td><td></td><td></td><td></td></tr><tr><td>Cesarean delivery, n (%)</td><td>288 (70)</td><td>323 (65)</td><td>0.15</td></tr><tr><td>Female, n%</td><td>191 (46)</td><td>248 (50)</td><td>0.26</td></tr><tr><td>Gestational age, weeks</td><td>30.1 (27.6, 31.7)</td><td>30.0 (27.9, 31.7)</td><td>0.67</td></tr><tr><td>Gestational age distribution</td><td></td><td></td><td>0.59</td></tr><tr><td>23<sup>0</sup>–27<sup>6</sup> weeks, n (%)</td><td>110 (27)</td><td>124 (25)</td><td></td></tr><tr><td>28<sup>0</sup>–32<sup>6</sup> weeks, n (%)</td><td>302 (73)</td><td>370 (75)</td><td></td></tr><tr><td>Birthweight, g</td><td>1240 (920, 1540)</td><td>1250 (950, 1550)</td><td>0.68</td></tr><tr><td>Birthweight z-score</td><td>-0.14 (-0.91, 0.37)</td><td>-0.13 (-0.81, 0.44)</td><td>0.69</td></tr><tr><td>IUGR, n (%)</td><td>16 (3.9)</td><td>30 (6.1)</td><td>0.17</td></tr><tr><td>5-min Apgar score</td><td>9 (7, 10)</td><td>9 (7, 10)</td><td>0.90</td></tr><tr><td>CRIB-II</td><td>7 (4, 10)</td><td>7 (5, 10)</td><td>0.58</td></tr></tbody></table>

Values are numbers (%) or medians (Q25, Q75)

LISA less invasive surfactant administration, PROM premature rupture of membranes > 24 h, IUGR intrauterine growth restriction, according to Olsen et al. [12]. CRIB-II critical risk index for babies-II (https://sfar.org/score/s2/crib22.php)

## Surfactant administration

Surfactant treatment rate decreased in the second period, from 54 to 47% (OR [95% CI] 0.75 [0.58–0.97], *p* = 0.04), driven by a lower rate in infants born at 28–32 weeks’ GA (41 to 33%, OR [95% CI] 0.72 [0.53–0.99], *p* = 0.04), and notably those at 28 and 29 weeks’ GA (77 to 58%, OR [95% CI] 0.42 [0.23–0.78], *p* = 0.008) (Fig. 1). Oxygen requirements before
treatment and timing of administration were comparable. LUS before surfactant administration was only performed during the second period. The implementation of the protocol had a significant impact on the administration technique, mainly conventional before (85%) and LISA after (75%) (Table 2). In the multivariate analysis, absence of antenatal steroids within 7 days before birth, cesarean delivery, male sex, 5-min Apgar score, gestational age, and the pre-protocol period were significantly associated with increased odds of surfactant treatment (Table 3). The area under the ROC curve of the model was 0.88 (95% CI 0.78–0.96), with a chi-squared value of the Hosmer–Lemeshow goodness-of-fit test equal to 5.66 (p = 0.69).

<figure><img src="image_3.png" /><figcaption>**Table 2** Surfactant treatment before (2013–2015) and after (2019–2021) implementation of LISA protocol</figcaption></figure>

<table><thead><tr><th rowspan="2">Infants treated</th><th>Pre-protocol</th><th>Post-protocol</th><th rowspan="2">p</th></tr><tr><th>N=412</th><th>N=494</th></tr></thead><tbody><tr><td>23<sup>0</sup>–27<sup>6</sup> weeks, n (%)</td><td>101/110 (92)</td><td>111/124 (90)</td><td>0.65</td></tr><tr><td>28<sup>0</sup>–32<sup>6</sup> weeks, n (%)</td><td>123/302 (41)</td><td>122/370 (33)</td><td>0.04</td></tr><tr><td>23<sup>0</sup>–32<sup>6</sup> weeks, n (%)</td><td>224/412 (54)</td><td>233/494 (47)</td><td>0.04</td></tr><tr><td>Infants requiring > 1 dose</td><td>28 (7)</td><td>46 (9)</td><td>0.18</td></tr><tr><td><strong>Administration</strong></td><td><strong>N=224</strong></td><td><strong>N=233</strong></td><td></td></tr><tr><td>Timing after birth (min)</td><td>28 (18, 37)</td><td>29.5 (10, 55)</td><td>0.39</td></tr><tr><td>23<sup>0</sup>–27<sup>6</sup> weeks</td><td>20 (14, 28)</td><td>26 (13, 40)</td><td>0.04</td></tr><tr><td>28<sup>0</sup>–32<sup>6</sup> weeks</td><td>33 (25, 53)</td><td>30 (10, 90)</td><td>0.05</td></tr><tr><td>FiO<sub>2</sub> before (%)</td><td>50 (40, 70)</td><td>45 (35, 80)</td><td>0.14</td></tr><tr><td>LUS before, n%</td><td>0 (0)</td><td>98 (42)</td><td>&lt; 10<sup>-3</sup></td></tr><tr><td><strong>Technique</strong></td><td><strong>CSA</strong></td><td><strong>ISE</strong></td><td><strong>LISA</strong></td><td><strong>CSA</strong></td><td><strong>ISE</strong></td><td><strong>LISA</strong></td></tr><tr><td>23<sup>0</sup>–27<sup>6</sup> weeks, n (%)</td><td>92 (91)</td><td>8 (8)</td><td>1 (1)</td><td>40 (36)</td><td>2 (2)</td><td>69 (62)</td><td>&lt; 10<sup>-3</sup></td></tr><tr><td>28<sup>0</sup>–32<sup>6</sup> weeks, n (%)</td><td>99 (80)</td><td>23 (19)</td><td>1 (1)</td><td>11 (9)</td><td>5 (4)</td><td>106 (87)</td><td>&lt; 10<sup>-3</sup></td></tr><tr><td>23<sup>0</sup>–32<sup>6</sup> weeks, n (%)</td><td>191 (85)</td><td>31 (14)</td><td>2 (1)</td><td>51 (22)</td><td>7 (3)</td><td>175 (75)</td><td>&lt; 10<sup>-3</sup></td></tr></tbody></table>

Values are numbers (%) or medians (Q25, Q75)

LISA less invasive surfactant administration, LUS lung ultrasonography, CSA conventional surfactant administration, ISE intubation, surfactant, and extubation

*Bonferroni method correction
<table><caption>**Table 3** Variables associated with surfactant treatment. Multivariate logistic regression analysis</caption><thead><tr><th></th><th>OR</th><th>95% CI</th><th>p</th></tr></thead><tbody><tr><td>Absence of antenatal steroids within 7 days before birth</td><td>2.56</td><td>1.77-3.71</td><td>&lt;0.001</td></tr><tr><td>Cesarean delivery</td><td>2.42</td><td>1.62-3.60</td><td>&lt;0.001</td></tr><tr><td>Male sex</td><td>1.46</td><td>1.03-2.08</td><td>0.033</td></tr><tr><td>5-min Apgar score &lt;7</td><td>2.24</td><td>1.35-3.72</td><td>0.002</td></tr><tr><td>GA (per 1 week' GA decrement)</td><td>2.23</td><td>2.00-2.48</td><td>&lt;0.001</td></tr><tr><td>Pre-protocol period</td><td>1.64</td><td>1.15-2.33</td><td>0.006</td></tr></tbody></table>

OR odds ratio, CI confidence interval

of high oxygen demand [16]. Surfactant treatment was provided early, in the first 30 min after birth. Implementation of the LISA protocol had opposite effects on this timing according to gestational age, as it increased in infants born at 23-27 weeks' GA and decreased in infants born at 28-32 weeks' GA. Regardless of the gestational age group, this timing may seem fast for a selective treatment strategy but is in line with an organization allowing administration

## Respiratory management and patients' outcome

Among the 124 infants born < 28 weeks' GA after implementation of the protocol, 113 (91%) received a full dosage regimen of early low-dose hydrocortisone. Rescue hydrocortisone treatment was administered to 34 (31%) infants in the first period, and nine (7%) infants in the second (p < 0.001). Use of IMV was less frequent after implementation of the protocol, from 56 to 23% (OR [95% CI] 0.23 [0.17-0.31], p < 0.001), and this result applied in the different GA categories. Durations of IMV (p < 0.001) and oxygen therapy (p = 0.003) were shorter in the second period. In contrast, NIV duration was longer (p < 0.001), resulting in a higher GA at weaning from all respiratory support (p < 0.001) (Table 4).

<table><caption>**Table 4** Respiratory management before (2013-2015) and after (2019-2021) implementation of LISA protocol</caption><thead><tr><th></th><th>Pre-protocol; N = 412</th><th>Post-protocol; N = 494</th><th>p</th></tr></thead><tbody><tr><td>Invasive mechanical ventilation, n (%)</td><td></td><td></td><td></td></tr><tr><td>-23<sup>0</sup>-32<sup>6</sup> weeks, n (%)</td><td>231 (56)</td><td>113 (23)</td><td>&lt;0.001</td></tr><tr><td>-23<sup>0</sup>-27<sup>6</sup> weeks, n (%)</td><td>106/110 (96)</td><td>81/124 (65)</td><td>&lt;0.001</td></tr><tr><td>23<sup>0</sup>-25<sup>6</sup> weeks, n (%)</td><td>49/49 (100)</td><td>45/49 (92)</td><td>0.11</td></tr><tr><td>26<sup>0</sup>-27<sup>6</sup> weeks, n (%)</td><td>57/61 (93)</td><td>36/75 (48)</td><td>&lt;0.001</td></tr><tr><td>-28<sup>0</sup>-32<sup>6</sup> weeks, n (%)</td><td>125/302 (41)</td><td>32/370 (9)</td><td>&lt;0.001</td></tr><tr><td>High-frequency oscillatory ventilation, n (%)</td><td>75 (18)</td><td>68 (14)</td><td>0.08</td></tr><tr><td>Invasive mechanical ventilation (days)*</td><td></td><td></td><td></td></tr><tr><td>-23<sup>0</sup>-32<sup>6</sup> weeks, mean (SD); median (IQR)</td><td>2.5 (±6.7); 1 (0, 22.5)</td><td>1.7 (±6.0); 0 (0, 0)</td><td>&lt;0.001</td></tr><tr><td>-23<sup>0</sup>-27<sup>6</sup> weeks, mean (SD); median (IQR)</td><td>7.0 (±10.4); 2.1 (0.5, 8.5)</td><td>6.6 (±10.6); 2.0 (0, 7)</td><td>0.04</td></tr><tr><td>23<sup>0</sup>-25<sup>6</sup> weeks, mean (SD); median (IQR)</td><td>11.1 (±12.9); 6.0 (2, 16)</td><td>11.4 (±12.7); 6.3 (4, 14)</td><td>0.61</td></tr><tr><td>26<sup>0</sup>-27<sup>6</sup> weeks, mean (SD); median (IQR)</td><td>3.2 (±5.2); 0.8 (0.2, 4)</td><td>2.4 (±6.0); 0 (0, 3)</td><td>&lt;0.001</td></tr><tr><td>-28<sup>0</sup>-32<sup>6</sup> weeks, mean (SD); median (IQR)</td><td>0.7 (±3.2); 0 (0, 0.2)</td><td>0.2 (±0.8); 0 (0, 0)</td><td>&lt;0.001</td></tr><tr><td>Oxygen (days), mean (SD); median (IQR)</td><td>11.0 (±19.3); 1 (0, 14)</td><td>8.7 (±16.7); 1 (0, 6)</td><td>0.003</td></tr><tr><td>Continuous positive airway pressure (days)</td><td>12 (±15); 5 (1.9, 19)</td><td>17 (±19); 7 (2, 33)</td><td>&lt;0.001</td></tr><tr><td>High-flow nasal cannula (days)</td><td>10 (±11); 5 (0.7, 17)</td><td>9 (±8); 6 (2, 14)</td><td>0.16</td></tr><tr><td>Noninvasive ventilation (days)</td><td>23 (±24); 11 (4, 36)</td><td>26 (±22); 20 (6.2, 40)</td><td>&lt;0.001</td></tr><tr><td>Postmenstrual age when spontaneous breathing without ventilatory assistance was established (weeks' GA)**</td><td>33.5 (1.8); 33.1 (32.1, 34.4)</td><td>34.4 (1.8); 34.1 (33, 35.6)</td><td>&lt;0.001</td></tr><tr><td>mean (SD); median (IQR)</td><td></td><td></td><td></td></tr><tr><td>Bronchopulmonary hemorrhage, n (%)</td><td>17 (4)</td><td>18 (6)</td><td>0.73</td></tr><tr><td>Pneumothorax, n%</td><td>6 (1)</td><td>9 (2)</td><td>0.89</td></tr></tbody></table>

Values are numbers (%) or means (± SD) and medians (IQR)

LISA less invasive surfactant administration

*0 day was assigned to infants who did not require IMV

**Spontaneous ventilation is defined as absence of invasive mechanical ventilation (conventional mechanical ventilation or high-frequency oscillatory ventilation) or noninvasive ventilation (continuous positive airway pressure or high-flow nasal cannula)
The second period was associated with a reduced rate of severe BPD. Rates of death and survival without severe morbidity were comparable (Table 5).

<table><caption>**Table 5** Outcomes before (2013–2015) and after (2019–2021) implementation of LISA protocol</caption><thead><tr><th></th><th>Pre-protocol;<br>N=412</th><th>Post-protocol;<br>N=494</th><th>P</th></tr></thead><tbody><tr><td>Outcome</td><td></td><td></td><td></td></tr><tr><td>Severe bronchopulmonary dysplasia, n (%)</td><td>77 (19)</td><td>64 (13)</td><td>0.03</td></tr><tr><td>Grade 3–4 intraventricular hemorrhage, n (%)</td><td>26 (6)</td><td>41 (8)</td><td>0.32</td></tr><tr><td>Cystic periventricular leukomalacia, n (%)</td><td>4 (1)</td><td>8 (2)</td><td>0.34</td></tr><tr><td>Stage 2–3 necrotizing enterocolitis, n (%)</td><td>22 (5)</td><td>19 (4)</td><td>0.36</td></tr><tr><td>Grade III–V retinopathy of prematurity, n (%)</td><td>8 (2)</td><td>8 (2)</td><td>0.91</td></tr><tr><td>Death, n (%)</td><td>36 (9)</td><td>48 (10)</td><td>0.70</td></tr><tr><td>Survival without severe morbidity, n (%)</td><td>276 (67)</td><td>344 (70)</td><td>0.43</td></tr><tr><td colspan="4">Values are numbers (%)</td></tr><tr><td colspan="4">LISA less invasive surfactant administration</td></tr></tbody></table>

Discussion

In this single-center study, implementation of LISA protocol was associated with a reduction in surfactant therapy to very premature infants. Other changes in respiratory management were observed, as a decreased use of IMV and increased duration of overall respiratory support, in addition to an increased use of low-dose hydrocortisone.

The implementation of the LISA protocol was followed by a substantial change in practices among the team's physicians. According to our protocol, the LISA method was dedicated to infants born between 25 and 30 weeks' GA [4]. However, our results show that it has become the reference method in the department to administer surfactant to very preterm infants, regardless of their gestational age. Minimally invasive techniques, such as LISA, may be prioritized because of perceived advantages, such as fewer adverse effects and reduced exposure to IMV. Although these approaches also have side effects, including desaturation, bradycardia, and surfactant reflux, some surveys show the clinician preference for their use [13–15].

The high threshold value for FiO2 before surfactant administration relates to the wide distribution of gestational ages in our sample. Nevertheless, we observed a trend toward a decrease in the second period, probably based on the recently reported risk of CPAP failure in case of high oxygen demand [16]. Surfactant treatment was provided early, in the first 30 min after birth. Implementation of the LISA protocol had opposite effects on this timing according to gestational age, as it increased in infants born at 23–27 weeks' GA and decreased in infants born at 28–32 weeks' GA. Regardless of the gestational age group, this timing may seem fast for a selective treatment strategy but is in line with an organization allowing administration in the delivery room at both periods [17]. Treatment selectivity was much more marked after 26 weeks' GA. The wide use of surfactant in extremely premature infants is consistent with observational [18] and interventional studies [19] and represents a marker of active management of these newborns [20].

Trials comparing prophylactic and selective use of surfactant have found that approximately twice as many infants at risk of respiratory distress will receive surfactant using the prophylactic approach [21]. This difference persisted in subsequent trials that included a majority of infants exposed to antenatal steroids and used CPAP shortly after birth to support
infants randomized in the selective treatment group [22]. Studies conducted over the past decade have focused on comparing less/minimally invasive surfactant administration in infants receiving NIV with INSURE or stabilization with CPAP alone. Meta-analysis of these trials shows a comparable rate of infants requiring multiple doses of surfactant, but the rate of infants treated by at least one dose in each group is not reported [23]. The decreased rate of surfactant use we observed in the post-protocol period may therefore seem counterintuitive. While we considered this assumption in our calculation of the number of subjects needed, we expected that the availability of a less invasive intervention would be an incentive for a more broad treatment [24]. Our center has transitioned to the application of less invasive ventilation strategies since 2010. The results, reported exclusively in extremely preterm infants managed in our department between 2003 and 2017, have shown increased use of surfactant and NIV and a marked reduction in IMV duration [5]. The reduction in surfactant use after implementation of LISA protocol may have been influenced by the confidence gained in the effectiveness of NIV in treating neonatal RDS, particularly in newborns between 28 and 32 weeks' GA.

The use of LUS varies across European NICUs. It is most commonly performed by neonatologists, particularly to guide surfactant administration [25]. LUS can predict surfactant requirement with comparable accuracy in extremely preterm or late preterm infants [26, 27]. In these studies, however, surfactant administration was based on oxygen requirements, not on ultrasound. According to the literature, LUS is currently the most appropriate tool to personalize treatment of RDS [28, 29]. Further randomized controlled trials are needed to compare the relevance of echography guided or predefined FiO2 thresholds for surfactant therapy.

Metaanalyses show that less/minimally invasive surfactant administration in very preterm infants at risk of RDS reduces the need for intubation [30], including in infants < 29 weeks' GA [23]. Our results showed that this reduction applied also to extremely preterm infants, which is consistent with the data reported in the gestation stratum 25-26 weeks in a recent randomized clinical trial [31]. We also found a shorter duration of IMV and oxygen therapy during the second period, but this result is mitigated by a longer duration of NIV. Other studies in very premature infants have noted this evolution, underpinned by the development of respiratory assistance devices, characterized by shorter invasive respiratory assistance but a prolonged duration of NIV [32]. Our experience in this area suggests that clinicians maintain NIV beyond respiratory failure in order to facilitate growth and to assist infants in the transition to active bottle or breast feeding [5]. While GA at weaning from all respiratory support was higher in the second period, the lower incidence of severe BPD suggests that IMV and its duration are critical intermediaries in the development of injury to the preterm lung [33].

Our study has several limitations. The perinatal characteristics of the populations differed in antenatal corticosteroid exposure, which was more frequently administered in the first period, and gestational diabetes, which was more frequent in the second period. In contrast to our results, these differences should have increased the risk of severe RDS requiring surfactant treatment during the second period. The time interval between the two periods may also be a source of changes in clinical practices. According to our protocol, FiO2 threshold for surfactant administration did not change, but the European consensus guidelines has probably influenced the respiratory management of the most premature infants. INSURE has recently undergone a standardized definition that cannot be applied to our study, although several aspects of our practice meet the proposed standards [34]. LUS was used only in the second
study period, and this practice may have contributed to the reduction in surfactant use during
the second period. However, our surfactant administration strategy did not include this tool, as
the protocol for the treatment of RDS remained unchanged. In addition, the use of LUS was
not systematic in neonatal RDS, and the results, in terms of score, were not recorded strictly,
particularly in infants not treated with surfactant. Finally, early low-dose hydrocortisone was
administered to infants born < 28 weeks' GA during the second period only, which prevents
any conclusion on the decreased incidence of severe BPD after implementation of a LISA
protocol in our NICU. As for any retrospective study, the suggested relationships between
implementation of the protocol and patient outcomes are hypothetical, and this requires great
caution when interpreting the results of our study.

In conclusion, implementation of a LISA protocol in our NICU was widely and rapidly
adopted by physicians, with ages initially targeted. This change in practice was associated
with less surfactant use and less exposure to IMV.

Authors’ contributions

All authors contributed to the study conception and design. Material preparation and data
collection were performed by D.G. and G.C. Data analysis was performed by C.C. The first
draft of the manuscript was written by D.G., C.M., and G.C. V.B. and A.G. critically revised
the report and made substantial contributions to the final manuscript. All authors read and
approved the final manuscript.

Data availability

Data will be available upon reasonable request from the corresponding author, for research
purposes and respective all relevant regulations.

Declarations

Ethics approval This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the institutional review board of Montpellier University Hospital (IRBMTP- 2023-01396).

Consent to participate

In accordance with the French law relating to observational research (Decree n° 2016-1537 of November 16, 2016), an information note was sent to the parents, informing them on the objectives of the research and inviting them to report to the main investigator

(Pr G Cambonie) if they were opposed to the participation of their infant.

Consent for publication

Not applicable.
## Conflict of interest

The authors declare no competing interests.

## References

1. Sweet DG, Carnielli VP, Greisen G et al (2023) European consensus guidelines on the management of respiratory distress syndrome: 2022 update. Neonatology 120:3–23. https://doi.org/10.1159/000528914

2. Gopel W, Kribs A, Hartel C et al (2015) Less invasive surfactant administration is associated with improved pulmonary outcomes in spontaneously breathing preterm infants. Acta Paediatr 104:241–246. https://doi.org/10.1111/apa.12883

3. Herting E, Hartel C, Gopel W (2019) Less invasive surfactant administration (LISA): chances and limitations. Arch Dis Child Fetal Neonatal Ed 104:F655–F659. https://doi.org/10.1136/archdischiId-2018-316557

4. Brotelande C, Milesi C, Combes C, Durand S, Badr M, Cambonie G (2021) Premedication with ketamine or propofol for less invasive surfactant administration (LISA): observational study in the delivery room. Eur J Pediatr 180:3053–3058. https://doi.org/10.1007/s00431-021-04103-1

5. Habas F, Durand S, Milesi C, Mesnage R, Combes C, Gavotto A, Picaud JC, Cambonie G (2020) 15-year trends in respiratory care of extremely preterm infants: contributing factors and consequences on health and growth during hospitalization. Pediatr Pulmonol 55:1946–1954. https://doi.org/10.1002/ppul.24774

6. Cambonie G, Mesnage R, Milesi C, Rideau A, Veyrac C, Picaud JC (2009) Hydrocortisone treatment for severe evolving bronchopulmonary dysplasia and cerebral haemodynamics. Arch Dis Child Fetal Neonatal Ed 94:F154–F155

7. Gopel W, Kribs A, Ziegler A et al (2011) Avoidance of mechanical ventilation by surfactant treatment of spontaneously breathing preterm infants (AMV): an open-label, randomised, controlled trial. Lancet 378:1627–1634. https://doi.org/10.1016/S0140-6736(11)60986-0

8. Baud O, Maury L, Lebail F et al (2016) Effect of early low-dose hydrocortisone on survival without bronchopulmonary dysplasia in extremely preterm infants (PREMILOC): a double-blind, placebo-controlled, multicentre, randomised trial. Lancet. https://doi.org/10.1016/S0140-6736(16)00202-6

9. Singh Y, Tissot C, Fraga MV et al (2020) International evidence-based guidelines on point of care ultrasound (POCUS) for critically ill neonates and children issued by the POCUS working group of the European Society of Paediatric and Neonatal Intensive Care (ESPNIC). Crit Care 24:65. https://doi.org/10.1186/s13054-020-2787-9
10. Higgins RD, Jobe AH, Koso-Thomas M et al (2018) Bronchopulmonary dysplasia: executive summary of a workshop. J Pediatr 197:300-308. https://doi.org/10.1016/j.jpeds. 2018.01.043

11. Durrmeyer X, Marchand-Martin L, Porcher R, Gascoin G, Roze JC, Storme L, Favrais G, Ancel PY, Cambonie G; Hemodynamic EPIPAGE 2 Study Group (2017) Abstention or intervention for isolated hypotension in the first 3 days of life in extremely preterm infants: association with short-term outcomes in the EPIPAGE 2 cohort study. Arch Dis Child Fetal Neonatal Ed 102:490-496. https://doi.org/10.1136/archd-ischi-ld-2016-312104

12. Olsen IE, Groveman SA, Lawson ML, Clark RH, Zemel BS (2010) New intrauterine growth curves based on United States data. Pediatrics 125:e214-e224. https://doi.org/10. 1542/peds.2009-0913

13. Rite Gracia S, Aguera Arenas JJ, Ginovart Galiana G, Rodriguez Revuelta MJ (2024) Management of respiratory distress syndrome in moderate/late preterm neonates: a Delphi consensus. Anales de Pediatria (English Edition) 101:319-330. https://doi.org/10. 1016/j.anpede.2024.10.003

14. Shetty S, Tolentino D, Lau C, Duffy D, Greenough A (2025) Changes in practice of less-invasive surfactant administration (LISA) in United Kingdom neonatal units. Acta Paediatr 114:393-397. https://doi.org/10.1111/apa.17446

15. Maiwald CA, Franz AR, Poets CF, Springer L; LISA-Survey-Team Germany (2025) Less invasive surfactant administration in preterm infants in tertiary neonatal intensive care units in Germany: a survey. Neonatology 122:46-55. https://doi.org/10.1159/000539302

16. Hartel C, Kribs A, Gopel W, Dargaville P, Herting E (2024) Less invasive surfactant administration for preterm infants - state of the art. Neonatology 121:584-595. https://doi. org/10.1159/000540078

17. Cambonie G, Theret B, Badr M, Fournier P, Combes C, Picaud JC, Gavotto A (2022) Birth during on-call period: impact of care organization on mortality and morbidity of very premature neonates. Front Pediatr. https://doi.org/10.3389/fped.2022.977422

18. Ancel PY, Goffinet F; EPIPAGE-2 Writing Group (2015) Survival and morbidity of preterm children born at 22 through 34 weeks' gestation in France in 2011: results of the EPIPAGE-2 cohort study. JAMA Pediatr 169:230-238. https://doi.org/10.1001/jamapediat rics.2014.3351

19. SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network (2010) Early CPAP versus surfactant in extremely preterm infants. N Engl J Med 362:1970-1979. https://doi.org/10.1056/NEJMo a0911783

20. Rysavy MA, Li L, Bell EF et al (2015) Between-hospital variation in treatment and outcomes in extremely preterm infants. N Engl J Med 372:1801-1811. https://doi.org/10.1056/NEJMo a1410689
21 Soll RF, Morley CJ (2001) Prophylactic versus selective use of surfactant in preventing morbidity and mortality in preterm infants. Cochrane Database Syst Rev 2:CD000510. https://doi.org/10.1002/14651858. CD000510

22. Schmolzer GM, Kumar M, Pichler G, Aziz K, O'Reilly M, Cheung PY (2013) Non-invasive versus invasive respiratory support in preterm infants at birth: systematic review and meta-analysis. BMJ 347:f5980. https://doi.org/10.1136/bmj.f5980

23. Yeung TY, Zhou Q, Kanmaz Kutman HG, Pandita A, Philippopoulos E, Jasani B (2023) Surfactant delivery via thin catheter in preterm infants: a systematic review and meta-analysis. PLoS One 18:e0284792. https://doi.org/10.1371/journ.al.pone.0284792

24. Glaser K, Bamat NA, Wright CJ (2023) Can we balance early exogenous surfactant therapy and non-invasive respiratory support to optimise outcomes in extremely preterm infants? A nuanced review of the current literature. Arch Dis Child Fetal Neonatal Ed 108:554–560. https://doi.org/10.1136/archd.ischi ld-2022-324530

25. Alonso-Ojembarrena A, Ehrhardt H, Cetinkaya M et al (2024) Use of neonatal lung ultrasound in European neonatal units: a survey by the European Society of Paediatric Research. Arch Dis Child Fetal Neonatal Ed 109:660–664. https://doi.org/10.1136/archd.ischi ld-2024-327068

26. De Martino L, Yousef N, Ben-Ammar R, Raimondi F, Shankar-Aguilera S, De Luca D (2018) Lung ultrasound score predicts surfactant need in extremely preterm neonates. Pediatrics 142:e20180463. https://doi.org/10.1542/peds.2018-0463

27. De Luca D, Bonadies L, Alonso-Ojembarrena A et al (2024) Quantitative lung ultrasonography to guide surfactant therapy in neonates born late preterm and later. JAMA Netw Open 7:e2413446. https://doi.org/10.1001/jamanetwor.kopen.2024.13446

28. De Luca D, Autilio C, Pezza L, Shankar-Aguilera S, Tingay DG, Carnielli VP (2021) Personalized medicine for the management of RDS in preterm neonates. Neonatology 118:127–138. https://doi.org/10.1159/000513783

29. Chidini G, Raimondi F (2024) Lung ultrasound for the sick child: less harm and more information than a radiograph. Eur J Pediatr 183:1079–1089. https://doi.org/10.1007/s00431-023-05377-3

30. Abdel-Latif ME, Davis PG, Wheeler KI, De Paoli AG, Dargaville PA (2021) Surfactant therapy via thin catheter in preterm infants with or at risk of respiratory distress syndrome. Cochrane Database Syst Rev 5:CD011672. https://doi.org/10.1002/14651858.CD011672.pub2

31. Dargaville PA, Kamlin COF, Orsini F et al (2021) Effect of minimally invasive surfactant therapy vs sham treatment on death or bronchopulmonary dysplasia in preterm infants with respiratory distress syndrome: the OPTIMIST-A randomized clinical trial. JAMA 326:2478–2487. https://doi.org/10.1001/jama.2021.21892
32. Doyle LW, Carse E, Adams AM, Ranganathan S, Opie G, Cheong JLY; Victorian Infant Collaborative Study Group (2017) Ventilation in extremely preterm infants and respiratory function at 8 years. N Engl J Med 377:329-337. https://doi.org/10.1056/NEJMo1700827

33. Jobe AH (2015) Animal models, learning lessons to prevent and treat neonatal chronic lung disease. Front Med 2:49. https://doi.org/10.3389/fmed.2015.00049

34. Fortas F, Loi B, Centorrino R, Regiroli G, Ben-Ammar R, Shankar-Aguilera S, Yousef N, De Luca D (2022) Enhanced INSURE (ENSURE): an updated and standardised reference for surfactant administration. Eur J Pediatr 181:1269-1275. https://doi.org/10.1007/s00431-021-04301-x
**Conflict of interest statement**

Declarations. Ethics approval: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the institutional review board of Montpellier University Hospital (IRB-MTP-2023-01396). Consent to participate: In accordance with the French law relating to observational research (Decree n° 2016-1537 of November 16, 2016), an information note was sent to the parents, informing them on the objectives of the research and inviting them to report to the main investigator (Pr G Cambonie) if they were opposed to the participation of their infant. Consent for publication: Not applicable. Conflict of interest: The authors declare no competing interests.
References

1. Sweet DG, Carnielli VP, Greisen G et al (2023) European consensus guidelines on the management of respiratory distress syndrome: 2022 update. Neonatology 120:3–23. https://doi.org/10.1159/000528914 - DOI - PubMed

2. Göpel W, Kribs A, Härtel C et al (2015) Less invasive surfactant administration is associated with improved pulmonary outcomes in spontaneously breathing preterm infants. Acta Paediatr 104:241–246. https://doi.org/10.1111/apa.12883 - DOI - PubMed

3. Herting E, Härtel C, Göpel W (2019) Less invasive surfactant administration (LISA): chances and limitations. Arch Dis Child Fetal Neonatal Ed 104:F655–F659. https://doi.org/10.1136/archdischild-2018-316557 - DOI - PubMed

4. Brotelande C, Milési C, Combes C, Durand S, Badr M, Cambonie G (2021) Premedication with ketamine or propofol for less invasive surfactant administration (LISA): observational study in the delivery room. Eur J Pediatr 180:3053–3058. https://doi.org/10.1007/s00431-021-04103-1 - DOI - PubMed

5. Habas F, Durand S, Milési C, Mesnage R, Combes C, Gavotto A, Picaud JC, Cambonie G (2020) 15-year trends in respiratory care of extremely preterm infants: contributing factors and consequences on health and growth during hospitalization. Pediatr Pulmonol 55:1946–1954. https://doi.org/10.1002/ppul.24774 - DOI - PubMed

6. Cambonie G, Mesnage R, Milési C, Rideau A, Veyrac C, Picaud JC (2009) Hydrocortisone treatment for severe evolving bronchopulmonary dysplasia and cerebral haemodynamics. Arch Dis Child Fetal Neonatal Ed 94:F154–F155 - PubMed

7. Göpel W, Kribs A, Ziegler A et al (2011) Avoidance of mechanical ventilation by surfactant treatment of spontaneously breathing preterm infants (AMV): an open-label, randomised, controlled trial. Lancet 378:1627–1634. https://doi.org/10.1016/S0140-6736(11)60986-0 - DOI - PubMed

8. Baud O, Maury L, Lebail F et al (2016) Effect of early low-dose hydrocortisone on survival without bronchopulmonary dysplasia in extremely preterm infants (PREMILOC): a double-blind, placebo-controlled, multicentre, randomised trial. Lancet. https://doi.org/10.1016/S0140-6736(16)00202-6 - DOI - PubMed

9. Singh Y, Tissot C, Fraga MV et al (2020) International evidence-based guidelines on point of care ultrasound (POCUS) for critically ill neonates and children issued by the POCUS working group of the European Society of Paediatric and Neonatal Intensive Care (ESPNIC). Crit Care 24:65. https://doi.org/10.1186/s13054-020-2787-9 - DOI - PubMed - PMC

10. Higgins RD, Jobe AH, Koso-Thomas M et al (2018) Bronchopulmonary dysplasia: executive summary of a workshop. J Pediatr 197:300–308. https://doi.org/10.1016/j.jpeds.2018.01.043 - DOI - PubMed - PMC

11. Durrmeyer X, Marchand-Martin L, Porcher R, Gascoin G, Roze JC, Storme L, Favrais G, Ancel PY, Cambonie G; Hemodynamic EPIPAGE 2 Study Group (2017) Abstention or intervention for isolated hypotension in the first 3 days of life in extremely preterm infants: association with short-term outcomes in the EPIPAGE 2 cohort study. Arch Dis Child Fetal Neonatal Ed 102:490–496. https://doi.org/10.1136/archdischild-2016-312104 - DOI

12. Olsen IE, Groveman SA, Lawson ML, Clark RH, Zemel BS (2010) New intrauterine growth curves based on United States data. Pediatrics 125:e214–e224. https://doi.org/10.1542/peds.2009-0913 - DOI - PubMed
13. Rite Gracia S, Agüera Arenas JJ, Ginovart Galiana G, Rodríguez Revuelta MJ (2024) Management of respiratory distress syndrome in moderate/late preterm neonates: a Delphi consensus. *Anales de Pediatría* (English Edition) 101:319-330. https://doi.org/10.1016/j.anpede.2024.10.003 - DOI - PubMed

14. Shetty S, Tolentino D, Lau C, Duffy D, Greenough A (2025) Changes in practice of less-invasive surfactant administration (LISA) in United Kingdom neonatal units. *Acta Paediatr* 114:393-397. https://doi.org/10.1111/apa.17446 - DOI - PubMed

15. Maiwald CA, Franz AR, Poets CF, Springer L; LISA-Survey-Team Germany (2025) Less invasive surfactant administration in preterm infants in tertiary neonatal intensive care units in Germany: a survey. *Neonatology* 122:46-55. https://doi.org/10.1159/000539302 - DOI

16. Härtel C, Kribs A, Göpel W, Dargaville P, Herting E (2024) Less invasive surfactant administration for preterm infants - state of the art. *Neonatology* 121:584-595. https://doi.org/10.1159/000540078 - DOI - PubMed

17. Cambonie G, Theret B, Badr M, Fournier P, Combes C, Picaud JC, Gavotto A (2022) Birth during on-call period: impact of care organization on mortality and morbidity of very premature neonates. *Front Pediatr*. https://doi.org/10.3389/fped.2022.977422 - DOI - PubMed - PMC

18. Ancel PY, Goffinet F; EPIPAGE-2 Writing Group (2015) Survival and morbidity of preterm children born at 22 through 34 weeks' gestation in France in 2011: results of the EPIPAGE-2 cohort study. *JAMA Pediatr* 169:230-238. https://doi.org/10.1001/jamapediatrics.2014.3351 - DOI

19. SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network (2010) Early CPAP versus surfactant in extremely preterm infants. *N Engl J Med* 362:1970-1979. https://doi.org/10.1056/NEJMoa0911783 - DOI - PMC

20. Rysavy MA, Li L, Bell EF et al (2015) Between-hospital variation in treatment and outcomes in extremely preterm infants. *N Engl J Med* 372:1801-1811. https://doi.org/10.1056/NEJMoa1410689 - DOI - PubMed - PMC

21. Soll RF, Morley CJ (2001) Prophylactic versus selective use of surfactant in preventing morbidity and mortality in preterm infants. *Cochrane Database Syst Rev* 2:CD000510. https://doi.org/10.1002/14651858.CD000510 - DOI

22. Schmölzer GM, Kumar M, Pichler G, Aziz K, O'Reilly M, Cheung PY (2013) Non-invasive versus invasive respiratory support in preterm infants at birth: systematic review and meta-analysis. *BMJ* 347:f5980. https://doi.org/10.1136/bmj.f5980 - DOI - PubMed - PMC

23. Yeung TY, Zhou Q, Kanmaz Kutman HG, Pandita A, Philippopoulos E, Jasani B (2023) Surfactant delivery via thin catheter in preterm infants: a systematic review and meta-analysis. *PLoS One* 18:e0284792. https://doi.org/10.1371/journal.pone.0284792 - DOI - PubMed - PMC

24. Glaser K, Bamat NA, Wright CJ (2023) Can we balance early exogenous surfactant therapy and non-invasive respiratory support to optimise outcomes in extremely preterm infants? A nuanced review of the current literature. *Arch Dis Child Fetal Neonatal Ed* 108:554-560. https://doi.org/10.1136/archdischild-2022-324530 - DOI - PubMed

25. Alonso-Ojembarrena A, Ehrhardt H, Cetinkaya M et al (2024) Use of neonatal lung ultrasound in European neonatal units: a survey by the European Society of Paediatric Research. *Arch Dis Child Fetal Neonatal Ed* 109:660-664. https://doi.org/10.1136/archdischild-2024-327068 - DOI - PubMed
26. De Martino L, Yousef N, Ben-Ammar R, Raimondi F, Shankar-Aguilera S, De Luca D (2018) Lung ultrasound score predicts surfactant need in extremely preterm neonates. Pediatrics 142:e20180463. https://doi.org/10.1542/peds.2018-0463 - DOI - PubMed

27. De Luca D, Bonadies L, Alonso-Ojembarrena A et al (2024) Quantitative lung ultrasonography to guide surfactant therapy in neonates born late preterm and later. JAMA Netw Open 7:e2413446. https://doi.org/10.1001/jamanetworkopen.2024.13446 - DOI - PubMed - PMC

28. De Luca D, Autilio C, Pezza L, Shankar-Aguilera S, Tingay DG, Carnielli VP (2021) Personalized medicine for the management of RDS in preterm neonates. Neonatology 118:127-138. https://doi.org/10.1159/000513783 - DOI - PubMed

29. Chidini G, Raimondi F (2024) Lung ultrasound for the sick child: less harm and more information than a radiograph. Eur J Pediatr 183:1079-1089. https://doi.org/10.1007/s00431-023-05377-3 - DOI - PubMed

30. Abdel-Latif ME, Davis PG, Wheeler KI, De Paoli AG, Dargaville PA (2021) Surfactant therapy via thin catheter in preterm infants with or at risk of respiratory distress syndrome. Cochrane Database Syst Rev 5:CD011672. https://doi.org/10.1002/14651858.CD011672.pub2 - DOI - PubMed

31. Dargaville PA, Kamlin COF, Orsini F et al (2021) Effect of minimally invasive surfactant therapy vs sham treatment on death or bronchopulmonary dysplasia in preterm infants with respiratory distress syndrome: the OPTIMIST-A randomized clinical trial. JAMA 326:2478-2487. https://doi.org/10.1001/jama.2021.21892 - DOI - PubMed

32. Doyle LW, Carse E, Adams AM, Ranganathan S, Opie G, Cheong JLY; Victorian Infant Collaborative Study Group (2017) Ventilation in extremely preterm infants and respiratory function at 8 years. N Engl J Med 377:329-337. https://doi.org/10.1056/NEJMoa1700827 - DOI

33. Jobe AH (2015) Animal models, learning lessons to prevent and treat neonatal chronic lung disease. Front Med 2:49. https://doi.org/10.3389/fmed.2015.00049 - DOI

34. Fortas F, Loi B, Centorrino R, Regiroli G, Ben-Ammar R, Shankar-Aguilera S, Yousef N, De Luca D (2022) Enhanced INSURE (ENSURE): an updated and standardised reference for surfactant administration. Eur J Pediatr 181:1269-1275. https://doi.org/10.1007/s00431-021-04301-x - DOI - PubMed