ABSTRACT
Objective
To compare the effectiveness of various surfactant administration methods.
Methods
We conducted an umbrella review of meta‐analyses conducted on randomized controlled trials. The search was conducted in March 2024 in four databases. Two authors screened the results and extracted the data. Review quality was assessed according to AMSTAR‐2. Traffic‐light plots were used to summarize the effectiveness of different administration methods.
Results
Nineteen meta‐analyses comprising 247 comparisons were included. The most evaluated method was less invasive surfactant administration (LISA), across 16 comparisons versus InSurE and intubation. LISA significantly reduced risks of bronchopulmonary dysplasia (BPD), BPD or death combined, mechanical ventilation, pneumothorax/air leaks, and intraventricular hemorrhage (IVH) versus intubation; it also lowered mortality versus InSurE and intubation. No IVH difference was seen between LISA and InSurE. Five comparisons (17 outcomes) assessed laryngeal mask airway (LMA) against intubation and InSurE. LMA reduced subsequent intubation or mechanical ventilation versus intubation. Findings on post‐surfactant FiO2 were inconsistent. No differences were observed in mortality, BPD (or death), IVH, additional surfactant needs, pneumothorax, patent ductus arteriosus, desaturation, reflux, procedure failure, bradycardia, or home oxygen use between LMA and intubation, nor in BPD outcomes versus InSurE.
Conclusion
Based on recent meta‐analyses, LISA appears to be the most effective and extensively evaluated surfactant administration method in head‐to‐head comparisons. Future research should clarify LMA's role and establish a definitive method hierarchy; currently, LISA remains the preferred choice when feasible.
Keywords: respiratory distress syndrome, surfactant, ventilation
1. Introduction
Respiratory distress syndrome (RDS) and its complications are major causes of morbidity in preterm infants. In 1959, it was recognized that RDS is a result of primary surfactant deficiency [1]. Over time, this acknowledgment has led to the development of surfactant replacement therapies [2]. Later on studies have shown that the administration of exogenous surfactant reduces mortality within preterm infants [3, 4]. This has led to exogenous surfactant therapy becoming a part of routine care within premature infants with RDS since the 1990s [1, 5]. Exogenous surfactant promotes better survival and healthier lung development by reducing the need for respiratory support and the rates of pneumothorax and mortality [6, 7]. It has become the most effective treatment for RDS [8, 9, 10]. Despite being necessary, the procedure of surfactant administration can lead to complications and cause damage to the lungs [9].
Surfactant can be administered using various techniques. Initially, surfactant was typically given via endotracheal tube instillation (ETT or commonly referred to as intubation), in which liquid surfactant is delivered as a single bolus through an endotracheal tube. To reduce the duration of mechanical ventilation associated with surfactant therapy, the InSurE technique (Intubation—Surfactant administration—Rapid Extubation) was later introduced. In this method, the neonate is first intubated, then given surfactant and subsequently extubated [11]. Both ETT and InSurE require intubation and in general involve mechanical ventilation (MV), and are therefore considered invasive methods [12].
Minimally invasive surfactant therapy (MIST) methods include several techniques: surfactant administration via a thin catheter (S‐TC) or less invasive surfactant administration (LISA), intrapharyngeal surfactant administration, surfactant administration via a laryngeal mask airway (LMA), and surfactant nebulization (SN) [13]. Both S‐TC and LISA involve surfactant instillation through a thin catheter while the infant breathes spontaneously [14, 15]. These methods require the maintenance of continuous positive airway pressure (CPAP) throughout the procedure, and MV cannot be provided while the catheter is in the trachea. Premedication practices associated with S‐TC and LISA vary but are generally lighter than those used for intubation to preserve spontaneous breathing. In this review, studies referring to S‐TC are included under the term LISA, as they are functionally considered equivalent methods.
In the LMA method, a laryngeal mask is first inserted, after which the surfactant is instilled through it [12]. Although the procedure requires placement of the device, it is technically less challenging than endotracheal intubation or LISA. Unlike LISA, ventilation is possible during the procedure when using an LMA, which may offer an advantage. However, the use of LMA in the smallest preterm infants has previously been limited by the lack of appropriately sized devices. Although smaller‐sized laryngeal masks have recently become available, their safety and efficacy remain to be fully established. In SN, the surfactant is administered in aerosolized form [13]. Neither of these methods include endotracheal intubation and they are therefore considered less invasive. The methods described above are all illustrated in Figure S1.
Previous reviews have shown that LISA is associated with greater safety, higher effectiveness, and fewer long‐term adverse outcomes compared to InSurE [16]. European, British, and Canadian guidelines recognize LISA as the preferred mode of surfactant delivery for preterm infants with RDS managed with CPAP [4, 7, 17, 18]. However, the use of LISA varies globally.
Surfactant nebulization is considered a truly non‐invasive method of surfactant delivery, as it does not require instrumentation of the airways. However, the technique presents technical challenges in achieving adequate surfactant deposition, and current studies have not demonstrated clear benefits in reducing the need for MV or in preventing BPD [19, 20].
The aim of this umbrella review was to provide an overview of the overall effectiveness and potential harms of different surfactant administration methods, and to identify the safest alternative based on the most recent evidence.
2. Methods
We performed an umbrella review of systematic reviews and meta‐analyses of randomized controlled trials comparing different surfactant administration methods.
2.1. Search Process
We searched PubMed, Scopus, Web of Science, and Cochrane in March 2024. We used the following search phrase: surfactant AND preterm AND meta‐analysis. We did not use any filters in the search process. Search results were then uploaded to Covidence software (Veritas Healthcare Inc., Victoria, Australia) for the screening process. Two authors screened the abstracts and full texts individually. Cases of disagreement were solved by reaching a mutual consensus or by consulting a third author.
2.2. Inclusion and Exclusion Criteria
We included meta‐analyses of randomized controlled trials focusing on surfactant administration in preterm neonates, defined as infants born before 37 weeks of gestation. No prespecified inclusion or exclusion criteria were applied regarding the outcomes or timing of the surfactant administration, as our aim was to extract all outcomes analyzed in the included reviews. We included meta‐analyses that compared surfactant administration techniques. The administration techniques are presented in Table S1.
We excluded meta‐analyses that compared, for example, surfactant treatment thresholds or surfactant versus non‐surfactant interventions. Non‐systematic reviews and those that did not perform a statistical synthesis of the included studies were also excluded. In addition, we excluded reviews that pooled observational and randomized studies without reporting the estimates separately. Studies published in other languages than English were excluded, as the databases we primarily searched contain predominately of English‐language literature.
2.3. Data Extraction
One author extracted the data, and another author validated the extracted data for integrity. The following information was extracted from the each included review: Authors, journal, publication year, inclusion criteria, patient population, effect estimates, statistical methods used, and evidence certainty assessments. Information on all outcomes was extracted. The extracted data is available in the supplementary materials.
2.4. Quality Appraisal and Reporting Guidelines
The quality of the studies included was assessed according to the AMSTAR‐2 tool. This review was reported according to the Preferred Reporting Items in Overviews of Reviews (PRIOR) guidelines, and the checklist is provided in the supplementary materials. We decided not to perform additional statistical analyses and instead systematically reported the effect estimates from the original reviews. The findings of this review have been presented in traffic‐light plots where green means that intervention was superior, yellow indicated no difference, and red mean that intervention group performed worse.
2.5. Protocol
The protocol for this review was registered to PROSPERO (ID CRD42024551405), and it is available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024551405.
3. Results
3.1. Search Results
After duplicate removal, a total of 326 abstracts and 29 full reports were further evaluated. Finally, 19 meta‐analyses with 247 statistical comparisons were included for this umbrella review [12, 15, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37] (Figure S1).
3.2. Study Characteristics
The meta‐analyses included were published between 2013 and 2024. The most assessed outcomes were mortality, BPD, IVH, and pneumothorax. The number of included RCTs in the reviews varied between 1 and 19. The quality of the included reviews was assessed according to AMSTAR‐2 as high in two reviews, moderate in four reviews, low in nine reviews, and critically low in four reviews. The domain specific rating is shown in Table S2. Complete list of the included studies and the complete extracted data has been provided in the Table S3.
3.3. Evidence Synthesis Methods
Of the included reviews, 13 primarily used risk ratios as measures of effectiveness, five primarily used odds ratios, and one primarily used mean differences. The most commonly applied statistical model was the Mantel‐Haenszel method, with both fixed‐effect and random‐effects models employed (Table S3).
3.4. Mortality
Mortality was assessed in 16 comparisons of LISA versus intubation. Three comparisons reported lower mortality in the LISA group compared to InSurE group, and one found lower mortality in the LISA compared to intubation. Four reviews found no mortality difference between LISA and InSurE, and eight reviews found no mortality difference between LISA and intubation. None of these studies reported higher mortality in the LISA group compared to InSurE or intubation (Table 1).
Table 1.
Traffic‐light plot to compare the LISA method to the more invasive methods: the InSurE method and intubation.
| Comparison | Study | Death | BPD | BPD or death | Need for intubation or MV at any time | IVH | PH | ROP | NEC | Additional surfactant needed | pneumothorax/air leak | PDA | Desaturation/hypoxemia | Surfactant reflux | PVL | Failure of procedure on the first attempt | Bradycardia |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| LISA vs. InSurE | Yeung 2023 | ||||||||||||||||
| Bellos 2021 | |||||||||||||||||
| Abdel‐Latif 2021 | |||||||||||||||||
| Kesler 2022 | |||||||||||||||||
| Lau CSM 2017 | |||||||||||||||||
| Isayama 2016 | |||||||||||||||||
| Silveira 2024 | |||||||||||||||||
| Luna 2022 | |||||||||||||||||
| LISA vs. intubation | Rigo 2016 | ||||||||||||||||
| Abdel Latif 2021 | |||||||||||||||||
| Yeung 2023 | |||||||||||||||||
| Aldana‐Aguirre 2017 | |||||||||||||||||
| Wu 2021 | |||||||||||||||||
| Cao 2020 | |||||||||||||||||
| Isayama 2016 | |||||||||||||||||
| Wu 2017 | |||||||||||||||||
| Luna 2022 | |||||||||||||||||
| Kesler 2022 |
Note: Green color indicates that the LISA method was better, yellow indicates no difference between the methods, red indicates that the more invasive method (listed in the table) was better. Gray color indicates that this outcome was not assessed.
Mortality was also assessed in three reviews comparing LMA and intubation; none found a mortality difference between these methods (Table 2).
Table 2.
Traffic‐light plot to compare LMA to the more invasive methods: intubation and InSurE.
| Comparison | Study | Death | BPD | BPD or death | Need for intubation or MV at any time | IVH | Air leak | Additional surfactant needed | PNX | PDA | Desaturation/hypoxemia | Surfactant reflux | Failure of procedure on the first attempt | Brady‐cardia | Ventilation failed | Post‐surfactant FiO2 | Apnea during the intervention | Use of home oxygen |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| LMA vs. intubation | Schmölzer 2013 | |||||||||||||||||
| AlAli 2022 | ||||||||||||||||||
| Calevo 2019 | ||||||||||||||||||
| Abdel‐Latif 2024 | ||||||||||||||||||
| LMA vs. InSure | Isayama 2016 |
Note: Green color indicates that LMA was better, yellow indicates no difference between the methods, red indicates that the more invasive method (listed in the table) was better. Gray color indicates that this outcome was not assessed.
One review comparing InSurE and intubation found no difference in mortality (Table 3).
Table 3.
Traffic‐light plot to compare InSurE and intubation.
| Comparison | Study | Death | BPD | Death or BPD | IVH | Pneumothorax |
|---|---|---|---|---|---|---|
| InSurE vs. intubation | Isayama 2016 |
Note: Yellow color indicates no difference between the methods.
3.5. Bronchopulmonary Dysplasia
BPD was assessed in 16 comparisons of LISA versus InSurE or intubation. Three comparisons between LISA and InSurE reported a lower risk of BPD in the LISA group, and four found no difference. Five comparisons reported a lower BPD risk with LISA when compared to intubation, and four comparisons found no difference between these two methods (Table 1).
One review comparing LMA and InSurE reported no difference in BPD incidence (Table 2).
3.6. Bronchopulmonary Dysplasia or Death
All five comparisons between LISA and InSurE reported a lower combined risk of BPD or death in the LISA group. Four comparisons between LISA and intubation reported a lower combined risk of BPD and death in the LISA group (Table 1).
3.7. Need for MV
The need for MV or reintubation was assessed in 14 comparisons between LISA and InSurE or intubation. Thirteen of these reported a lower need for MV or reintubation in the LISA group. One comparison found no difference between LISA and intubation (Table 1).
The need for MV or reintubation was assessed in three reviews comparing LMA and intubation. All threereported a reduced need in the LMA group (Table 2).
Duration of MV was assessed in review which compared nebulized surfactant to invasive surfactant administration.
It reported nebulized surfactant treatment as a possible alternative (Table 4). However, the outcomes were limited in the review.
Table 4.
Traffic‐light plot to compare SN to invasive surfactant administration.
| Comparison | Study | SpO2 level 1 h after treatment | A/APaO2 level 1 h after treatment | Duration of mechanical ventilation |
|---|---|---|---|---|
| Nebulized vs. invasive surfactant administration | Rong 2020 |
Note: Green color indicates that SN was better, yellow indicates no difference between the methods.
3.8. Pneumothorax
Pneumothorax or other air leaks were analyzed in 16 comparisons between LISA and InSurE intubation. Three comparisons reported a lower risk of pneumothorax in the LISA group compared to intubation, and one comparison reported a lower risk of pneumothorax in the LISA group when compared to InSurE. Twelve comparisons found no difference between the methods (Table 1).
3.9. Intraventricular Hemorrhage
IVH was assessed in 13 comparisons between LISA and InSurE or intubation. Three comparisons reported a lower risk of IVH in the LISA group compared to intubation. None of the reviews found a difference in the risk of IVH with LISA compared to InSurE (Table 1).
Two reviews assessed the IVH risk between LMA and intubation and found no difference between the methods (Table 2).
One review comparing InSurE and intubation also found no difference in IVH risk (Table 3).
3.10. Necrotizing Enterocolitis
Seven comparisons assessed the risk of NEC between LISA and InSurE or intubation. Two comparisons reported a lower risk of NEC in the LISA group compared to InSurE. Four comparisons between LISA and intubation found no difference between the methods (Table 1).
3.11. Surfactant Reflux
The risk of surfactant reflux was assessed in five reviews. Three comparing LISA and intubation (Table 1), and two comparing LMA and intubation (Table 2). All three studies assessing the LISA method reported a higher risk of surfactant reflux in the LISA group. No difference was found between LMA and intubation.
4. Discussion
Based on the findings from 19 meta‐analyses, the LISA method appears to be the safest approach to surfactant administration. Within these meta‐analyses, LISA was also the most frequently assessed method. LISA was clearly found to be a better alternative than InSurE or intubation in terms of mortality, the risk of BPD, the combined risk of BPD or death, and the need for MV.
Of the 16 outcomes collected from reviews comparing LISA with InSurE and intubation, only three outcomes suggested LISA as the less favorable option. One study reported a higher risk of hypoxemia in the LISA group compared to intubation [15], one study reported a higher risk of bradycardia in the LISA group [15], and three studies found a higher risk of surfactant reflux in the LISA group compared to intubation [21, 22, 27]. However, the surfactant reflux is an expected finding, as LISA catheters are not designed to seal the airway in the vocal cords, unlike endotracheal tubes, which provide a tighter seal.
The remaining 14 outcomes either favored LISA or showed no significant difference between the methods. These findings support the conclusion that LISA is an effective and safe method of surfactant delivery while being less invasive than techniques requiring intubation. This is consistent with the 2022 European Consensus guidelines on the Management of RDS, which recommend LISA as the preferred method of surfactant administration [38]. A previous umbrella review reported that LISA would benefit over INSURE against BPD, however, other surfactant administration methods or outcomes were not considered [39].
One review compared InSurE and intubation and found them to be equal in terms of mortality, BPD, IVH, and pneumothorax [31]. Both methods require endotracheal intubation and have been shown to be less favorable than LISA in separate comparisons. Therefore, they should be avoided when LISA is a feasible option. However, LISA requires the presence of spontaneous breathing and sufficient respiratory drive at the time of administration. Therefore, it may not be feasible in all clinical situations—particularly in very preterm or unstable infants. In such cases, alternative methods, including intubation‐based techniques or LMA, may still be necessary.
Five reviews assessed the use of LMA compared to intubation or InSurE [12, 25, 30, 31, 34]. A total of 17 outcomes were analyzed, and overall, the safety profiles of the compared methods were similar. The most notable difference was in the need for MV, which was lower in the LMA group compared to intubation in all three relevant reviews [12, 25, 30]. Thus, LMA appears to be a safer alternative to intubation.
Notably, none of the studies compared LISA directly with LMA. While this umbrella review clearly favored LISA over intubation and InSurE, LMA did not show as strong superiority when compared to the same invasive methods. However, it is important to note the risk of procedural failure in the LISA method. LISA requires laryngoscopy and visualization of the vocal cords and therefore requires skilled practitioners [40]. LMA, in turn, is perceived as easier to position [41] and has a lower incidence of adverse events during administration [40]. These differences highlight the distinct advantages and limitations of each method.
Ongoing studies, such as the SURFSUP trial [42], are expected to provide further evidence comparing these techniques and may help clarify their roles in clinical practice.
This umbrella review also compared nebulized vs invasive surfactant administration. However, only one review addressed this topic, and it did not assess outcomes such as mortality, BPD. Therefore, meaningful comparison between nebulization and other administration methods was not possible in this review.
4.1. Future Research
Future studies should focus on minimally invasive surfactant administration techniques. In particular, direct comparisons between LISA and LMA are needed to determine the safer alternative. The development of surfactant nebulization also holds a promise for improving safety in the treatment and prevention of RDS.
New surfactant administration methods are also under investigation. One such method, InRecSurE—an adaptation of the InSurE method that includes a lung recruitment maneuver ‐ has been shown in a single RCT to reduce the need of MV in 72 h of life in one RTC [43]. However, a 2‐year follow‐up found no significant differences between InRecSurE and InSurE in terms of mortality, neurodevelopmental outcomes, or respiratory infections [44]. An ongoing RTC is currently evaluating whether the InRecSurE method is safer than LISA.
4.2. Strengths and Limitations
This umbrella review is currently the largest and most comprehensive synthesis of evidence on different surfactant administration methods to date. However, the main limitation lies in the quality of the studies included: only two out of nineteen systematic reviews or meta‐analyses were rated as high quality, while most were rated as low or very low. Furthermore, only a minority of the reviews assessed the certainty of the evidence, limiting the strength of the conclusions: the overall confidence in the effect estimates varied mostly between very low and low. Another limitation is the lack of statistical pooling, as we relied on the effect estimates reported in the original reviews.
5. Conclusion
This umbrella review found that, based on the latest systematic reviews and meta‐analyses, LISA is currently the most compared and safest surfactant administration method. The risks of BPD or death as well as the need for MV are consistently lower with LISA compared to intubation or the InSurE method. Accordingly, the LISA method is the preferred method in clinical practice when feasible. The LMA method represents a promising alternative, but current evidence is insufficient to determine, whether it is comparable to LISA. Further comparative studies are needed to establish the optimal approach to minimally invasive surfactant administration.
Author Contributions
I.K. had the initial idea. A.H., I.K. and K.R. performed study selection. A.H. and I.K. performed data extraction and analyses. P.K. provided insights to analyses. A.H. wrote the initial draft. P.K., K.R., and I.K. commented and revised the manuscript. All authors approved the manuscript to be submitted.
Funding
The authors have nothing to report.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Figure S1: PRISMA flowchart of the study selection process.
Table S1: Surfactant administration methods assessed in this article. Adapted from sources 12,23,24,33,46.
Table S2: AMSTAR‐2 ratings of the included reviews.
Table S3: All extracted data and outcomes from the included studies
Supporting File
Acknowledgments
Open access publishing facilitated by Ita‐Suomen yliopisto, as part of the Wiley ‐ FinELib agreement.
Data Availability Statement
The data that supports the findings of this study are available in the supporting information of this article All data available in the supplementary materials alongside the submission.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1: PRISMA flowchart of the study selection process.
Table S1: Surfactant administration methods assessed in this article. Adapted from sources 12,23,24,33,46.
Table S2: AMSTAR‐2 ratings of the included reviews.
Table S3: All extracted data and outcomes from the included studies
Supporting File
Data Availability Statement
The data that supports the findings of this study are available in the supporting information of this article All data available in the supplementary materials alongside the submission.