Introduction: Less invasive surfactant application (LISA) is associated with improved short-term outcomes in preterm infants. Data on LISA eligibility and success for infants <28 weeks of gestation are lacking. Methods: Preterm infants <28 weeks of gestation who were born and actively treated in our tertiary care center in 2018 were included in the retrospective study. We assessed baseline characteristics, delivery room (DR) management, LISA success and complications, and short-term outcome. Results: In total, 57 infants received LISA in the DR. LISA eligibility was 73% at 22 weeks, 88% at 23 weeks, and >90% at gestational ages >24 weeks. LISA was successful in 63% of infants. LISA failure was associated with increased risk for high-grade IVH (OR 17.88), death (OR 10.94), and a reduced chance for survival without complications (OR 8.75). Conclusion: Our report justifies LISA as a mode for surfactant application in preterm infants. It contributes to the call for studies to define risk factors for LISA failure.

A growing body of evidence from both, observational and randomized controlled trials conducted worldwide, has demonstrated the safety, efficacy, and benefits of less invasive surfactant application (LISA) for preterm infants [1, 2]. Compared to surfactant application after intubation, LISA reduced duration of mechanical ventilation, mortality, and major complications [1, 2]. However, most infants <28 weeks of gestation are considered ineligible for the LISA procedure and are regularly intubated in the delivery room (DR) [3, 4]. Furthermore, although LISA failure has been repeatedly associated with lower gestational age (GA) and higher preprocedural inspired fraction of oxygen (FiO2) [5, 6], the risk factors for LISA failure are not well defined.

In our center, LISA was implemented as early as 2004 [7] and has been the preferred method of surfactant application for preterm infants from 22 weeks of gestation [8] for almost 20 years. We conducted an extensive retrospective analysis of all preterm infants treated in 2018 to evaluate LISA eligibility and to identify factors associated with LISA failure.

All inborn infants with GA between 22 0/7 and 27 6/7 who were actively treated in 2018 were included in the retrospective analysis. The study was approved by the Ethics Committee of the University of Cologne (Approval Number 19-1504).

LISA is part of an extensive care bundle that aims at avoidance of mechanical ventilation within the first 72 h of life [7]. A stepwise increasing positive end-expiratory pressure (PEEP) strategy with high PEEP levels is applied to establish spontaneous breathing. In infants with lack of respiratory drive, we used nasal high frequency oscillatory ventilation (nHFOV) before and/or after LISA to avoid intubation and mechanical ventilation. According to our local protocol, infants <28 weeks receive LISA in the DR in a quasi-prophylactic approach regardless of the required FiO2. For the first surfactant dose, we aim for 200 mg/kg but apply the full volume of the respective vial (1.5 or 3 mL containing 80 mg/mL surfactant). For subsequent surfactant doses, we aim for 100 mg/kg. All infants received a loading dose of 20 mg/kg caffeine in the DR. Atropine and/or sedatives/analgesics were administered at the discretion of the attending neonatologists.

We assessed baseline characteristics, antenatal steroids, clinical chorioamnionitis, mode of delivery, DR management, surfactant dose, and periprocedural complications for LISA. Mild desaturation was defined as drop in oxygen saturation to a minimum of 80%. Bradycardia was defined as decrease of heart rate to a minimum of 60 bpm. Apnea regularly preceded bradycardia, so both entities were combined. LISA failure was defined as intubation within 72 h after birth. We evaluated short-term complications (pneumothorax needing thoracentesis, intraventricular hemorrhage [IVH] >grade 2, moderate or severe bronchopulmonary dysplasia [BPD], surgery for necrotizing enterocolitis, surgery or peritoneal drainage for focal intestinal perforation, retinopathy of prematurity requiring treatment), death, and the combined outcome of death or occurrence of a severe complication.

Statistics

Statistical analysis was performed using IBM SPSS Statistics 29 for Windows (IBM Corp, New York, NY, USA). Variables are described as median (IQR), mean ± standard deviation, or absolute and relative frequencies. Differences between groups were compared by t test for normally distributed data, Wilcoxon-Mann-Whitney or Kruskal-Wallis test for other metric data, or Fisher´s exact test for categories. A two-sided p value <0.05 was defined as significant. All analyses were regarded as explorative. Bonferroni correction was used in multiple testing. Logistic regression was used to assess the effect of LISA failure on clinical outcome parameters. We performed a univariate logistic regression analysis identifying potential complications associated with LISA failure. Subsequently, we included all factors with a p value <0.05 in a multivariate forward stepwise regression model to identify independent risk factors.

In total, 67 preterm infants with a GA from 22 0/7 to 27 6/7 weeks were born and actively treated in 2018. Of these, 65 (97%) received surfactant in the DR. Two infants did not receive surfactant because they died despite active care within the first hour of life. Among those who received surfactant in the DR, LISA was used in 57 (88%) of infants compared to 8 (12%) who received surfactant after intubation. Infants who were intubated differed significantly from the LISA group regarding median Apgar scores at 1 (4 vs. 6, p < 0.001), 5 (5 vs. 7, p < 0.001), and 10 (6 vs. 8, p < 0.001) minutes. The eligibility rate for LISA was 73% at 22 weeks of gestation, 88% at 23 weeks of gestation, and >90% at GAs greater than 24 weeks of gestation. Overall, LISA was successful in 36/57 (63%) infants. Baseline characteristics of both, infants successfully treated with LISA and LISA failure, are presented in Table 1 and did not differ significantly between groups.

Table 1.

Comparison of baseline characteristics

Baseline characteristics
LISA success (n = 36)LISA failure (n = 21)p value
GA, median [IQR], weeks 25 [23–26] 25 [23–26] 0.643 
GA 22/23 weeks, N (%) 11 (31) 7 (33) 1.000 
GA 24/25 weeks, N (%) 9 (25) 9 (42) 0.238 
GA 26/27 weeks, N (%) 16 (44) 5 (24) 0.159 
Birthweight, median [IQR], g 753 [574–977] 706 [535–900] 0.408 
Male, N (%) 23 (64) 18 (86) 0.126 
C-section, N (%) 34 (94) 21 (100) 0.526 
Antenatal steroids, N (%) 31 (86) 17 (81) 0.696 
Apgar score, median [IQR] 6 [5–7] 6 [5–7] 0.690 
5 min 7 [6–8] 8 [7–8] 0.375 
10 min 8 [8–9] 8 [8–9] 0.823 
Clinical chorioamnionitis, N (%) 17 (47) 12 (57) 0.585 
Baseline characteristics
LISA success (n = 36)LISA failure (n = 21)p value
GA, median [IQR], weeks 25 [23–26] 25 [23–26] 0.643 
GA 22/23 weeks, N (%) 11 (31) 7 (33) 1.000 
GA 24/25 weeks, N (%) 9 (25) 9 (42) 0.238 
GA 26/27 weeks, N (%) 16 (44) 5 (24) 0.159 
Birthweight, median [IQR], g 753 [574–977] 706 [535–900] 0.408 
Male, N (%) 23 (64) 18 (86) 0.126 
C-section, N (%) 34 (94) 21 (100) 0.526 
Antenatal steroids, N (%) 31 (86) 17 (81) 0.696 
Apgar score, median [IQR] 6 [5–7] 6 [5–7] 0.690 
5 min 7 [6–8] 8 [7–8] 0.375 
10 min 8 [8–9] 8 [8–9] 0.823 
Clinical chorioamnionitis, N (%) 17 (47) 12 (57) 0.585 

One in two infants developed periprocedural complications, predominantly mild desaturation, but none of the complications were associated with LISA failure. Infants with LISA failure received surfactant significantly later (at 45 vs. 38 min, p = 0.011) and more infants (11 vs. 4) required a second dose of surfactant (p < 0.001, Table 2). The second dose was administered by re-LISA in 6 infants and after intubation in 9 infants. LISA failure was associated with an increased risk of high-grade IVH (p < 0.001), death (p = 0.022), and the combined outcome of death or occurrence of a severe complication (p < 0.001, Table 3). In a linear regression model (Table 4) including these significant factors, LISA failure significantly increased the risk of high grade IVH (OR 16.22).

Table 2.

Characteristics of the LISA procedure

LISA procedure
LISA success (n = 36)LISA failure (n = 21)p valueOR [95% CI]
LISA with nHFOV, N (%) 3 (8.3) 3 (14) 0.657 N/A 
Surfactant dose, median [IQR], mg/kg 175 [106–340] 185 [111–271] 0.599 N/A 
Timing of surfactant, median [IQR], min 38 [30–45] 45 [40–61] 0.011 1.05 [1.01–1.10] 
Second surfactant dose, N (%) 4 (11) 11 (52) <0.001 8.77 [2.28–33.33] 
Second surfactant dose [IQR], mg/kg 132 [102-132] 148 [91–262] <0.001 N/A 
Any LISA complication, N (%) 21 (58) 10 (47) 0.582 N/A 
Desaturation, N (%) 15 (42) 6 (29) 0.399 N/A 
Apnea/bradycardia, N (%) 6 (17) 5 (24) 0.503 N/A 
Surfactant reflux, N (%) 5 (14) 4 (19) 0.707 N/A 
Increase of flow/FiO2, N (%) 17 (47) 6 (29) 0.257 N/A 
PPV/intubation, N (%) 1 (2.8) 2 (9.5) 0.548 N/A 
Atropine 14 (39) 14 (67) 0.097 N/A 
Analgesics/sedatives 2 (5.6) 2 (9.5) 0.626 N/A 
LISA procedure
LISA success (n = 36)LISA failure (n = 21)p valueOR [95% CI]
LISA with nHFOV, N (%) 3 (8.3) 3 (14) 0.657 N/A 
Surfactant dose, median [IQR], mg/kg 175 [106–340] 185 [111–271] 0.599 N/A 
Timing of surfactant, median [IQR], min 38 [30–45] 45 [40–61] 0.011 1.05 [1.01–1.10] 
Second surfactant dose, N (%) 4 (11) 11 (52) <0.001 8.77 [2.28–33.33] 
Second surfactant dose [IQR], mg/kg 132 [102-132] 148 [91–262] <0.001 N/A 
Any LISA complication, N (%) 21 (58) 10 (47) 0.582 N/A 
Desaturation, N (%) 15 (42) 6 (29) 0.399 N/A 
Apnea/bradycardia, N (%) 6 (17) 5 (24) 0.503 N/A 
Surfactant reflux, N (%) 5 (14) 4 (19) 0.707 N/A 
Increase of flow/FiO2, N (%) 17 (47) 6 (29) 0.257 N/A 
PPV/intubation, N (%) 1 (2.8) 2 (9.5) 0.548 N/A 
Atropine 14 (39) 14 (67) 0.097 N/A 
Analgesics/sedatives 2 (5.6) 2 (9.5) 0.626 N/A 
Table 3.

Short-term complications of prematurity of infants with LISA success and LISA failure

Short-term complications of prematurity
LISA success (n = 36)LISA failure (n = 21)p valueOR [95% CI]
Pneumothorax with drainage, N (%) 2 (5.5) 4 (19) 0.179 N/A 
IVH >grade 2, N (%) 3 (8.3) 13 (62) <0.001 17.88 [4.09–78.05] 
Moderate/severe BPD, N (%) 5 (14) 3 (14) 1.000 N/A 
Surgery for NEC, N (%) 2 (5.5) 2 (9.5) 0.620 N/A 
Surgery/drainage for FIP, N (%) 7 (19) 9 (43) 0.073 N/A 
ROP requiring treatment, N (%) 1 (2.8) 1 (2.8) 1.000 N/A 
Death, N (%) 1 (2.8) 5 (24) 0.022 10.94 [1.18–101.41] 
Death or severe complication, N (%) 7 (19) 6 (29) <0.001 8.75 [2.56–29.95] 
15 (71) 
Short-term complications of prematurity
LISA success (n = 36)LISA failure (n = 21)p valueOR [95% CI]
Pneumothorax with drainage, N (%) 2 (5.5) 4 (19) 0.179 N/A 
IVH >grade 2, N (%) 3 (8.3) 13 (62) <0.001 17.88 [4.09–78.05] 
Moderate/severe BPD, N (%) 5 (14) 3 (14) 1.000 N/A 
Surgery for NEC, N (%) 2 (5.5) 2 (9.5) 0.620 N/A 
Surgery/drainage for FIP, N (%) 7 (19) 9 (43) 0.073 N/A 
ROP requiring treatment, N (%) 1 (2.8) 1 (2.8) 1.000 N/A 
Death, N (%) 1 (2.8) 5 (24) 0.022 10.94 [1.18–101.41] 
Death or severe complication, N (%) 7 (19) 6 (29) <0.001 8.75 [2.56–29.95] 
15 (71) 

NEC, necrotizing enterocolitis; FIP, focal intestinal perforation.

Table 4.

Binary logistic regression analysis of LISA failure

Factors associated with LISA failureOdds ratio [95% CI]p value
IVH >grade 2 16.22 [1.42–185.82] 0.025 
Death 7.04 [0.36–137.10] 0.198 
Death or severe complication 0.93 [0.09–9.78] 0.953 
1.07 [0.10–11.1] 
Factors associated with LISA failureOdds ratio [95% CI]p value
IVH >grade 2 16.22 [1.42–185.82] 0.025 
Death 7.04 [0.36–137.10] 0.198 
Death or severe complication 0.93 [0.09–9.78] 0.953 
1.07 [0.10–11.1] 

In a highly skilled setting with a focus on avoidance of mechanical ventilation in the DR, 85% of infants <28 weeks and >90% for infants between 24 and 28 weeks were eligible for LISA. This is remarkable because the largest LISA trial [3] so far that included preterm infants between 25 and 28 weeks and was conducted in 33 centers worldwide reported LISA eligibility for only one in two infants. Moreover, in the randomized controlled NINSAPP trial [9], that included infants from 23 to 26 weeks, LISA eligibility in the attending centers varied between 40 and 90% (unpublished data). Of note, our center reported 79% LISA eligibility in infants born <24 weeks of gestation [8]. A recent meta-survey summarized LISA eligibility data from Europe, Australia, North America, and Asia. Although many centers planned to implement LISA, three out of four were skeptical about using LISA in infants <26 weeks of gestation [4]. Interestingly, insufficient training and experience, rather than lack of evidence, was seen as the main barrier.

LISA is not a stand-alone intervention but embedded in a complex care bundle. Lung recruitment strategies [7, 10, 11] play an important role in establishing spontaneous breathing. Furthermore, different respiratory support strategies can be used to avoid intubation in infants with insufficient respiratory drive. A recent meta-analysis described a significant reduction in the need for intubation and mechanical ventilation in preterm infants with respiratory distress syndrome treated with nHFOV compared to nasal CPAP [12]. Data on infants <28 weeks are lacking, but a protocol for a RCT comparing nasal CPAP and nHFOV as the primary respiratory support was published recently [13].

Compared to intubation, LISA improves survival without major complications. This is increasingly recognized and reflected in current European and North American recommendations [14, 15]. Intriguingly, the beneficial effects of LISA, such as the reduction of severe IVH, were predominately observed in extremely immature infants [9, 16]. Looking only at data of very immature preterm infants with GA <28 weeks, LISA was associated with a reduced risk of all-cause death, BPD, and BPD or death [16]. In addition, studies consistently reported a significant reduction of high-grade IVH [9, 17]. Our results support these findings. The high rate of survival without severe complication is particularly remarkable as one in three infants were born at less than 24 weeks.

Consistent with our findings, LISA failure has been reported to increase the risk for adverse short-term outcomes [18]. However, we could not confirm an association of LISA failure with lower GA. Of note, we observed a high rate of pneumothorax in the LISA failure group. An explanation for this finding may be the use of high PEEP levels in the DR. If these are followed by an inadequate surfactant effect, there is a high risk of lung overdistension and air leaks. A similar effect of overdistension may occur in the intestinal tract and cause the high rate of focal intestinal perforation.

Interestingly, infants with LISA failure were more likely to require a second dose of surfactant compared to infants with LISA success. This may indicate a subgroup of infants who, for reasons to be determined, have more severe respiratory distress syndrome and are at a higher risk for respiratory failure. These infants probably need repeat surfactant doses to prevent LISA failure. Of note, the first surfactant dose was comparable in both groups and within the range that was not associated with LISA failure [19].

The main limitation of our study is the restriction to a single center with high LISA expertise. Therefore, our results are not easily generalizable to other settings. However, LISA was associated with low mortality and a high rate of survival without major complications. This justifies considering LISA as a mode for surfactant application in preterm infants regardless of GA. As LISA failure has been associated with adverse outcomes, two pressing questions need to be addressed. What is the best way to prevent LISA failure and how do we identify infants at risk? Our findings contribute to the call for well-defined RCTs to evaluate LISA in extremely immature infants.

The study protocol was reviewed and approved by the Ethics Committee of the University of Cologne (Approval Number 19-1504). Written informed consent was obtained from the participants’ parent/legal guardian/next of kin to participate in the study.

The authors have no conflicts of interest to declare.

The study was not supported by any sponsor or funder.

Dr. Mehler had primary responsibility for protocol development and writing the manuscript. Mrs. Fastnacht participated in data acquisition and analysis. Drs. Kribs and Kuehne participated in the development of the protocol and analytical framework for the study and contributed to the writing of the manuscript. Dr. Klein supervised the design of the study, performed the final data analyses, and contributed to the writing of the manuscript.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

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