CONTEXT

Surfactant nebulization (SN) may offer a safe alternative for surfactant administration in respiratory distress syndrome of preterm infants.

OBJECTIVE

To evaluate the efficacy of SN for the prevention of early intubation.

DATA SOURCES

Medline, Embase, The Cochrane Library, clinicaltrials.gov, published abstracts, and references of relevant articles were searched through March 23, 2021.

STUDY SELECTION

Randomized clinical trials of preterm infants <37 weeks’ gestation comparing SN with noninvasive respiratory support or intratracheal surfactant application.

DATA EXTRACTION

Two reviewers extracted data and assessed risk of bias from included studies separately and blinded. Data were pooled by using a fixed-effects model. Subgroups (gestational age, type of nebulizer, surfactant type, and dosage) were evaluated. Primary outcome was intubation rate at 72 hours after birth.

RESULTS

Nine studies recruiting 1095 infants met inclusion criteria. SN compared with standard care significantly reduced intubation rate at 72 hours after birth (226 of 565 infants [40.0%] vs 231 of 434 infants [53.2%]; risk ratio [RR]: 0.73, 95% confidence interval [CI]: 0.63–0.84; number needed to treat: 8; 95% CI: 5–14]). Prespecified subgroup analysis identified important heterogeneity: SN was most effective in infants ≥28 weeks' gestation (RR: 0.70, 95% CI: 0.60–0.82), with a pneumatically driven nebulizer (RR: 0.52, 95% CI: 0.40–0.68) and in infants receiving ≥200 mg/kg and animal-derived surfactant (RR: 0.63, 95% CI: 0.52–0.75). No differences in neonatal morbidities or mortality were identified.

LIMITATIONS

Quality of evidence was low owing to risk of bias and imprecision.

CONCLUSIONS

SN reduced the intubation rate in preterm infants with a higher efficacy for specific subgroups. There was no difference in relevant neonatal morbidities or mortality.

What’s Known on This Subject:

Respiratory distress syndrome in preterm infants is commonly treated by respiratory support and intratracheal surfactant application. Surfactant nebulization may offer a safe alternative for surfactant administration, but the efficacy is unknown.

What This Study Adds:

This meta-analysis, including >1000 preterm infants, reveals that surfactant nebulization reduces intubation rate in preterm infants and evaluates potential effect modifiers such as gestational age, nebulizer type and surfactant dose. Other relevant neonatal morbidities or mortality were comparable between groups.

Respiratory distress syndrome is the most common cause of respiratory failure in preterm infants.1  It is related to a primary surfactant deficiency leading to an unphysiologically high pulmonary resistance, increased work of breathing, and, in turn, the need for mechanical ventilation, which is a risk factor for the development of bronchopulmonary dysplasia (BPD).24 

Treatment strategies include respiratory support and exogenous surfactant administration.5,6  Although the benefit of surfactant has been widely investigated, the best route of surfactant application has not yet been determined.711  Surfactant is commonly instilled into the trachea, either by endotracheal intubation or by inserting a nasogastric tube into the trachea and removing it immediately after instillation (Minimally Invasive Surfactant Therapy). Minimally Invasive Surfactant Therapy may reduce volutrauma and airway inflammation,1214  but it still requires instrumentation of the airway and fluid instillation into the trachea. Airway instrumentation is painful and potentially injurious and may carry the risk of concomitant vasovagal reactions. Intratracheal surfactant instillation rapidly decreases cerebral blood flow,15  which may increase the risk of intraventricular hemorrhage (IVH).16 

Surfactant nebulization (SN) may offer a truly noninvasive alternative of surfactant application.17  In animal experiments, SN improved immediate cardiopulmonary1823  and neurologic outcomes,24  showed good lung deposition,25  and improved the homogeneity of aeration.26  Recent meta-analyses on the efficacy of SN included only 2 studies; these meta-analyses did not consider the largest trial to our knowledge27  or data from unpublished sources.28,29  If unpublished data are not considered for meta-analysis, trials with null or negative results may be underrepresented, thus potentially introducing systematic bias.30  Therefore, we aimed to perform a comprehensive systematic review and meta-analysis including data previously not sought.

The primary objective of this meta-analysis was to determine the effectiveness of SN versus standard care in preventing intubation among preterm infants. The secondary objectives were to assess potential effect modifiers of the primary outcome and effects on relevant neonatal morbidities.

This meta-analysis was conducted in accordance with the methods delineated in the Cochrane Handbook for Systematic Reviews of Interventions, version 6.2.31  Reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline.32  The protocol for this meta-analysis was registered on PROSPERO (CRD42020175625) and published elsewhere.33 

We conducted a comprehensive literature search in the following electronic databases: Medline, Embase and The Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials) without language restrictions. In addition, we searched for ongoing or unpublished trials in ClinicalTrials.gov, and we reviewed the reference lists of relevant articles, abstracts and conference proceedings (Pediatric Academic Societies, Society for Pediatric Research, European Society for Pediatric Research 1990–2020) when available. The final search was conducted on March 23, 2021.

All randomized controlled trials (RCTs) and quasi-RCTs enrolling preterm infants (<37 weeks’ gestation) in which researchers compared SN with any control group (ie noninvasive respiratory support, no respiratory support or intratracheal surfactant application) were included. Observational studies were excluded.

The primary outcome was intubation rate at 72 hours after birth. Secondary outcomes included peridosing events (bradycardia, desaturation, emesis), short-term efficacy (changes in peripheral oxygen saturation [Spo2] and arterial carbon dioxide [Paco2] at 1, 2, and 3 hours after nebulization; fraction of inspired oxygen [Fio2], Spo2/Fio2 ratio and mean airway pressure [MAP] at 1, 24, 48, and 72 hours after nebulization; and changes in electrolyte levels at 24 hours after nebulization), and longer-term efficacy (number of hours on mechanical ventilation during hospitalization and intubation rate during hospitalization) as well as death and major neonatal morbidities (blood-culture positive sepsis before 36 weeks postmenstrual age; any air leak (pneumothorax or pulmonary interstitial emphysema); grade 3 or 4 IVH34 ; any stage of retinopathy of prematurity (ROP)35 ; necrotizing enterocolitis (NEC) stage 2 or higher36 ; pulmonary hemorrhage; moderate or severe BPD, defined as oxygen requirement at 36 weeks’ postmenstrual age; and impaired neurodevelopment, defined as a Bayley Scales of Infant and Toddler Development, third edition composite motor or cognitive score of >2 SD below the mean).37 

Two reviewers (V.D.G. and J.T.) independently assessed titles and abstracts to determine the eligibility of all studies identified in the search. Reviewers extracted full texts of potentially eligible studies and studies in which abstract and title contained insufficient information to determine eligibility. Disagreements were resolved by consensus, if necessary, through referral to a third reviewer (C.M.R.).

For each included study, the following details were recorded: contributing authors, publication date (in case of online registries, publication date of results), study design, start and end of recruitment, inclusion and exclusion criteria, number of participants assigned randomly and analyzed in each group, type of nebulizer, type and dose of surfactant, timing of surfactant application, whether a repeat application was possible, demographic characteristics of participants, and details of reported outcomes. We contacted authors of primary studies for 3 consecutive months to provide any missing outcome information as well as patient data by gestational weeks for the primary outcome. For articles in different languages, we contacted the primary author and the national Cochrane center for assistance with data extraction.

Two reviewers (V.D.G. and J.T.) assessed the risk of bias (ROB) of eligible studies using the Revised Cochrane risk-of-bias tool for randomized trials.38  A score (low risk, high risk, or some concerns) was assigned to 6 domains of potential bias (randomization process, deviations from the intended interventions, missing outcome data, measurement of the outcomes, selective reporting, and other bias). Disagreements between reviewers were resolved by consensus after discussion, if necessary, through referral to a third reviewer (C.M.R.). The strength of evidence was assessed by using the Grading of Recommendations Assessment, Development and Evaluation method. We aimed to assess reporting and publication bias by examining funnel plot asymmetry.

We performed the primary meta-analysis using a fixed-effects model because we assumed a common underlying treatment effect a priori. A random-effects model was used for confirmatory analysis of the primary outcome. Aggregate data of individual studies were analyzed. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated for each study and for the combined effect of the meta-analysis, by using the Mantel-Haenszel method.39  The Higgins I2 index was used to assess heterogeneity across studies.38  Meta-analysis was performed by using RevMan, version 5.4.40 

We conducted sensitivity analyses (1) restricted to high-quality studies (with low ROB) to account for potential methodologic heterogeneity, (2) restricted to articles published in peer-reviewed journals, and (3) restricted to studies using the same prespecified definitions for our primary and secondary outcomes.

Subgroup analyses were performed for our primary outcome to assess prespecified sources of clinical heterogeneity33 : gestational age (GA; infants <28 vs ≥28 completed weeks’ GA); birth weight (<1250 vs ≥1250 g); type of nebulizer (capillary versus pneumatically driven versus vibrating membrane); surfactant dose (<200 mg/kg surfactant versus ≥200 mg/kg, based on current guidelines for surfactant administration5 ); surfactant type (animal-derived versus synthetic); timing of surfactant (prophylactic versus selective41 ); and the effect of repeat nebulization. We aimed to perform meta-regression analysis to explore the effect of proposed sources of heterogeneity in case of >10 included studies, in keeping with recent suggestions.31,42 

The search yielded 2477 records. Full-text review was performed for 25 studies. Nine trials with 1095 infants were included in this meta-analysis (Fig 1).27,4350  Results were extracted from the published full texts of 3 studies,27,43,46  from the English abstracts of 2 studies published in Chinese,44,45  and from the results of 4 studies posted in official trial registries4750  (see Table 1 for study characteristics and Supplemental Table 3 for definitions of study outcomes). The study by Guo et al originally consisted of 3 groups, with infants in the third group being intubated and mechanically ventilated without the application of surfactant.44  Because the inclusion of this control group would have systematically biased the analysis of our primary outcome and this procedure is not common practice, this additional control group was not regarded in this analysis.

FIGURE 1

Preferred Reporting Items for Systematic Reviews and Meta-analyses flowchart for the inclusion of studies.

FIGURE 1

Preferred Reporting Items for Systematic Reviews and Meta-analyses flowchart for the inclusion of studies.

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TABLE 1

Description of Included Studies

StudySourceSettingNGAInterventionControl GroupPrimary Outcome(s)Findings
Berggren 200043  Full text Single-center 32 <36 0/7 SN over 3 h, 2–36 h after birth, using a jet nebulizer with 480 mg animal-derived surfactant. Repeat application not possible. nCPAP, 3–5 cm H2Not specified No beneficial effects of SN 
Guo 200744  Abstract Not specified 32 Not specified Not specified Intratracheal Surfactant, not further specified Not specified SN may improve oxygenation 
Chang 201245  Abstract N/A 63 Not specified Not specified Intratracheal Surfactant, not further specified Not specified SN may improve lung aeration 
NCT02074059 201747  Registry Multicenter 80 29-34 6/7 SN over 15–75 min, 90 min after birth, using a capillary nebulizer with an ascending dose 25–150 mg/kg synthetic surfactant. Repeat application not possible. nCPAP, no level specified Peridosing events, mortality, changes in Spo2, electrolytes None specified 
NCT02528318 201948  Registry Multicenter 48 26-28 6/7 SN over 30–60 min, <20 h after birth, using a capillary nebulizer with an ascending dose 50–100 mg/kg synthetic surfactant. Repeat application possible. nCPAP, 5–7 cm H2Peridosing events, air leak None specified 
Minocchieri 201946  Full text Single-center 64 29-33 6/7 SN over 20–30 min, <4 h after birth, using a vibrating membrane nebulizer with a dose of 200 mg/kg animal-derived surfactant. Repeat application possible. nCPAP, 5–8 cm H2Intubation rate at 72 h after birth, duration of MV Early SN may reduce the need for intubation 
Cummings 202027  Full text Multicenter 401 <37 0/7 SN over 1 h, 1–12 h after birth, using a pneumatically driven nebulizer with a dose of 210 mg/kg animal-derived surfactant. Repeat application possible. Any nasal respiratory support (nCPAP, NIPPV, HFNC) Intubation rate at 72 h after birth SN reduced intubation rate by nearly one-half 
EUCTR-004547-36 202150  Registry Multicenter 162 28-32 6/7 SN over 20–30 min, 1–12 h after birth, using a vibrating membrane nebulizer with an ascending dose 200-600mg/kg animal-derived surfactant. Repeat application possible. nCPAP, 5–8 cm H2Intubation rate at 72 h after birth None specified 
NCT02636868 202149  Registry Multicenter 213 28-32 6/7 SN over 25–50 min, <20 h after birth, using a capillary nebulizer with an ascending dose 40–80 mg/kg synthetic surfactant. Repeat application possible. nCPAP, 5–7 cm H2Respiratory failure or death within 72 h after birth None specified 
StudySourceSettingNGAInterventionControl GroupPrimary Outcome(s)Findings
Berggren 200043  Full text Single-center 32 <36 0/7 SN over 3 h, 2–36 h after birth, using a jet nebulizer with 480 mg animal-derived surfactant. Repeat application not possible. nCPAP, 3–5 cm H2Not specified No beneficial effects of SN 
Guo 200744  Abstract Not specified 32 Not specified Not specified Intratracheal Surfactant, not further specified Not specified SN may improve oxygenation 
Chang 201245  Abstract N/A 63 Not specified Not specified Intratracheal Surfactant, not further specified Not specified SN may improve lung aeration 
NCT02074059 201747  Registry Multicenter 80 29-34 6/7 SN over 15–75 min, 90 min after birth, using a capillary nebulizer with an ascending dose 25–150 mg/kg synthetic surfactant. Repeat application not possible. nCPAP, no level specified Peridosing events, mortality, changes in Spo2, electrolytes None specified 
NCT02528318 201948  Registry Multicenter 48 26-28 6/7 SN over 30–60 min, <20 h after birth, using a capillary nebulizer with an ascending dose 50–100 mg/kg synthetic surfactant. Repeat application possible. nCPAP, 5–7 cm H2Peridosing events, air leak None specified 
Minocchieri 201946  Full text Single-center 64 29-33 6/7 SN over 20–30 min, <4 h after birth, using a vibrating membrane nebulizer with a dose of 200 mg/kg animal-derived surfactant. Repeat application possible. nCPAP, 5–8 cm H2Intubation rate at 72 h after birth, duration of MV Early SN may reduce the need for intubation 
Cummings 202027  Full text Multicenter 401 <37 0/7 SN over 1 h, 1–12 h after birth, using a pneumatically driven nebulizer with a dose of 210 mg/kg animal-derived surfactant. Repeat application possible. Any nasal respiratory support (nCPAP, NIPPV, HFNC) Intubation rate at 72 h after birth SN reduced intubation rate by nearly one-half 
EUCTR-004547-36 202150  Registry Multicenter 162 28-32 6/7 SN over 20–30 min, 1–12 h after birth, using a vibrating membrane nebulizer with an ascending dose 200-600mg/kg animal-derived surfactant. Repeat application possible. nCPAP, 5–8 cm H2Intubation rate at 72 h after birth None specified 
NCT02636868 202149  Registry Multicenter 213 28-32 6/7 SN over 25–50 min, <20 h after birth, using a capillary nebulizer with an ascending dose 40–80 mg/kg synthetic surfactant. Repeat application possible. nCPAP, 5–7 cm H2Respiratory failure or death within 72 h after birth None specified 

HFNC, high-flow nasal cannulae; MV, mechanical ventilation; N/A, not applicable; NIPPV, noninvasive intermittent positive pressure ventilation; NIV, noninvasive respiratory support.

The assessment of potential sources of bias is presented in Supplemental Table 4. There were some concerns regarding the randomization process and potential deviations from the intended interventions for 2 studies, EUCTR-004547-36 and NCT02074059.47,50  There were 4 and 8 postrandomization exclusions lacking explanation in EUCTR-004547-3650  and NCT02636868,49  respectively, resulting in some concerns regarding missing outcome data. There were some concerns regarding the measurement of the outcome for the study by Cummings et al, NCT02074059, and NCT02528318, because lack of blinding and no criteria for the decision to intubate.27,4350  The study by Berggren et al was not preregistered.43  Several trials were terminated early: Minocchieri et al because insufficient funding,46  and all trials from study registries because of sponsor decision.4750  In the study by Cummings et al, the initial inclusion criterion of a minimal Fio2 of 0.25 was removed 4 months into recruitment, and consent was obtained from the parents of 187 infants but the infants were subsequently not randomly assigned.27  Overall, the only study with a low ROB assessment was the study by Minocchieri et al.46  With only 9 included studies, we did not evaluate funnel plot asymmetry to assess publication bias.31 

Seven studies with 999 infants were included in the primary outcome analysis. Overall, 226 of 565 infants randomly assigned to SN (40.0%) versus 231 of 434 infants randomly assigned to control groups (53.2%) were intubated within the first 72 hours after birth (RR: 0.73, 95% CI: 0.63–0.84; number needed to treat to benefit: 8, 95% CI: 5–14) (Fig 2A). Heterogeneity was I2 = 70%. Confirmatory analyses using the random-effects model revealed a consistent RR of 0.77 with a borderline 95% CI (0.58–1.01).

FIGURE 2

Fixed-effects meta-analysis of the primary outcome, intubation rate at 72 hours after birth. A, Including all studies; B, including only studies with identical outcome definitions. aStudy excluded in sensitivity analysis (B): Guo et al44  (no time frame for intubation) and NCT0263686849  (intubation or worsening respiratory status) (see Supplemental Table 3). M–H, Mantel-Haenszel method.

FIGURE 2

Fixed-effects meta-analysis of the primary outcome, intubation rate at 72 hours after birth. A, Including all studies; B, including only studies with identical outcome definitions. aStudy excluded in sensitivity analysis (B): Guo et al44  (no time frame for intubation) and NCT0263686849  (intubation or worsening respiratory status) (see Supplemental Table 3). M–H, Mantel-Haenszel method.

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Sensitivity analysis using studies with a low ROB was restricted to a single study revealing a significant reduction in the need for intubation (RR: 0.57, 95% CI: 0.35–0.91)].46  Restricting analysis to peer-reviewed published studies resulted in 2 studies with 465 infants, also revealing a reduction in the need for intubation (RR: 0.53, 95% CI: 0.42–0.67). Sensitivity analysis using only studies with reliable data on intubation rate included 5 studies and 754 infants with similar results compared with our primary analysis (fixed-effects, RR: 0.68, 95% CI: 0.58–0.80; Fig 2B).

There was no significant variability in effect sizes between GA groups (I2 = 54%, P = .11), but there was significant variability between different nebulizers (I2 = 81%, P = .001) as well as between different surfactant doses and surfactant types (analyzed together, as all studies using <200 mg/kg also used synthetic surfactant; I2 = 85%, P = .002).

The effectiveness of SN was greatest in infants ≥28 weeks' gestation (5 studies; RR: 0.70, 95% CI: 0.60–0.82), for pneumatically driven nebulizers (1 study; RR: 0.52, 95% CI: 0.40–0.68), and in infants receiving ≥200 mg/kg and animal-derived surfactant (on the basis of 3 studies; RR: 0.625, 95% CI: 0.52–0.75), see Fig 3A3C. The vibrating membrane nebulizer showed borderline effectiveness in the prevention of early intubation (2 studies; RR: 0.78, 95% CI 0.61–1.00).

FIGURE 3

Subgroup analyses for intubation rate at 72 hours after birth. GA (A), nebulizer type (B), and dose as well as type of surfactant (C, on the basis of the same studies). a Study included infants between 26 0/7 and 28 6/7 weeks' gestation. M–H, Mantel-Haenszel method.

FIGURE 3

Subgroup analyses for intubation rate at 72 hours after birth. GA (A), nebulizer type (B), and dose as well as type of surfactant (C, on the basis of the same studies). a Study included infants between 26 0/7 and 28 6/7 weeks' gestation. M–H, Mantel-Haenszel method.

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There were insufficient data available for subgroup analyses based on birth weight and repeat application, and prophylactic nebulization was not performed in any study. With only 9 included studies, we did not perform meta-regression analysis.

There was no effect of SN on relevant neonatal morbidities and mortality in the overall data set or in sensitivity analyses with clearly defined outcomes (Table 2). No researchers reported Bayley Scales of Infant and Toddler Development, third edition values concurring with our prespecified definition. Researchers in 1 study reported neurodevelopmental outcomes at 24 months to be similar between infants who received nebulized surfactant and infants receiving nasal continuous positive airway pressure (nCPAP) (Supplemental Table 5).50 

TABLE 2

Fixed-Effects Meta-Analysis of RR of Key Secondary Outcomes

OutcomeOverallSensitivity AnalysisExcluded Studies
N StudiesN InfantsCombined Effect
RR (95% CI)
PI2, %N studiesN infantsCombined Effect
RR (95% CI)
PI2, %
Death 1000 0.89 (0.30 to 2.65) .83 1000 0.89 (0.30 to 2.65) .83 — 
BPD (oxygen need at 36 wk PMA) 998 0.99 (0.74 to 1.32) .96 33 435 0.72 (0.39 to 1.35) .31 45 Cummings et ala; EUCTR-004547-36b 
Severe IVH (grade ≥3)34  994 0.65 (0.29 to 1.44) .29 465 0.20 (0.02 to 4.08) .29 N/A Berggren et alc; NCT02074059c; NCT02528318c; NCT02636868c; EUCTR-004547-36d 
Air leak 1000 1.03 (0.69 to 1.52) .90 1000 1.03 (0.69 to 1.52) .90 — 
Pulmonary hemorrhage 904 0.48 (0.14 to 1.68) .25 904 0.48 (0.14 to 1.68) .25 — 
Sepsis 904 0.90 (0.58 to 1.38) .62 58 401 0.56 (0.17 to 1.89) .35 N/A NCT02074059d; NCT02528318d; NCT02636868d; EUCTR-004547-36d 
Any ROP35  423 0.76 (0.37 to 1.54) .44 423 0.76 (0.37 to 1.54) .44 — 
NEC (≥ stage 2)36  968 1.13 (0.49 to 2.63) .78 465 1.48 (0.25 to 8.75) .67 N/A NCT02074059e; NCT02528318e; NCT02636868e; EUCTR-004547-36d 
OutcomeOverallSensitivity AnalysisExcluded Studies
N StudiesN InfantsCombined Effect
RR (95% CI)
PI2, %N studiesN infantsCombined Effect
RR (95% CI)
PI2, %
Death 1000 0.89 (0.30 to 2.65) .83 1000 0.89 (0.30 to 2.65) .83 — 
BPD (oxygen need at 36 wk PMA) 998 0.99 (0.74 to 1.32) .96 33 435 0.72 (0.39 to 1.35) .31 45 Cummings et ala; EUCTR-004547-36b 
Severe IVH (grade ≥3)34  994 0.65 (0.29 to 1.44) .29 465 0.20 (0.02 to 4.08) .29 N/A Berggren et alc; NCT02074059c; NCT02528318c; NCT02636868c; EUCTR-004547-36d 
Air leak 1000 1.03 (0.69 to 1.52) .90 1000 1.03 (0.69 to 1.52) .90 — 
Pulmonary hemorrhage 904 0.48 (0.14 to 1.68) .25 904 0.48 (0.14 to 1.68) .25 — 
Sepsis 904 0.90 (0.58 to 1.38) .62 58 401 0.56 (0.17 to 1.89) .35 N/A NCT02074059d; NCT02528318d; NCT02636868d; EUCTR-004547-36d 
Any ROP35  423 0.76 (0.37 to 1.54) .44 423 0.76 (0.37 to 1.54) .44 — 
NEC (≥ stage 2)36  968 1.13 (0.49 to 2.63) .78 465 1.48 (0.25 to 8.75) .67 N/A NCT02074059e; NCT02528318e; NCT02636868e; EUCTR-004547-36d 

Including all studies with available data (varying definitions) on the left and sensitivity analyses using only studies in which the definition of the outcome concurred with our prespecified definition on the right. N/A, not applicable; PMA, postmenstrual age; —, no studies excluded.

a

Defined as oxygen need at 28 d after birth, irrespective of GA.

b

Defined as oxygen need at 36 wk PMA for infants <32 wk gestation and as oxygen need ≥28 d for infants ≥32 wk gestation.59 

c

Defined as any grade IVH.34 

d

Unclear definition.

e

Defined as any stage NEC.36  For all definitions of outcomes in each study, see Supplemental Table 3.

The overall numbers of surfactant doses (including intratracheal surfactant) and MAP at 48 and 72 hours postrandomization were higher in the intervention group than in the control group, but no difference in the total hours of mechanical ventilation and MAP at 1 and 24 hours postnebulization (on the basis of 1 study, Supplemental Table 6) was detected. No data were available on changes in Spo2, Fio2, and electrolytes after nebulization, and peridosing events were available only for the intervention group.

Quality of evidence was downgraded to “low” because of ROB and inconsistency for the primary outcome and because of ROB and imprecision for secondary outcomes (Supplemental Table 7).

In this meta-analysis, we demonstrated that SN in preterm infants reduced the intubation rate at 72 hours after birth with high heterogeneity between studies. Part of the heterogeneity could be explained by prespecified subgroup analyses: SN was most effective in infants ≥28 completed weeks' gestation and when a pneumatically driven nebulizer and ≥200 mg/kg animal-derived surfactant were used. There were no effects on neonatal morbidities and mortality and no adverse reactions to SN.

To our knowledge, this was the first meta-analysis on the efficacy of SN to include data from unpublished sources such as clinicaltrials.gov. Together with the different sample sizes between studies, the inclusion of unpublished data introduced a high heterogeneity into the data set, partly explaining why the CI was just crossing the 1 when using a random-effects model. Interestingly, all 4 studies presented in online study registries reported null results. Publishing negative or null results is essential to prevent systematic bias.30  Even with the inclusion of these unpublished data, SN was still found to decrease the intubation rate by approximately one-fourth, even after accounting for dissimilarities in outcome definition. Early intubation is an important outcome but not essential to parents and health care providers.51  Having demonstrated the effectiveness of SN on this short-term outcome, larger studies investigating the effect on critical outcomes such as mortality or BPD are warranted.

To explain the heterogeneity in the primary outcome, we performed prespecified subgroup analyses. We demonstrated that various factors modified the effect size, including GA, type of nebulizer, and type and dose of surfactant. The pneumatically driven nebulizer used in the study by Cummings et al27  was most effective, but the results were based on an unblinded study only. Replication in a double-blinded fashion would be essential before clinical application could be recommended. Vibrating membrane nebulizers seemed less effective, but evaluation may have been more reliable, because 1 of the respective studies was blinded.46,50  One advantage over other types of nebulizers is the short duration of nebulization with this device.19,46  Studies using a capillary nebulizer revealed no efficacy.4749  These studies also used synthetic surfactant and doses below the recommended dose of 200 mg/kg.5  Therefore, it is difficult to disentangle whether the lack of effectiveness is due to the type of nebulizer or the type and dose of surfactant. The delivery of nebulized surfactant to the alveoli remains challenging and the underlying principles of potential benefits are still unclear.52  However, our meta-analysis provides clinical evidence that using at least 200 mg/kg animal-derived surfactant and either a pneumatically driven or a vibrating membrane nebulizer may be beneficial.

Infants with a GA ≥28 completed weeks seemed to benefit more than infants <28 weeks. Despite efforts to increase the use of noninvasive respiratory support,79  many extremely preterm infants still require intubation.1  Insufficient lung deposition may have precluded effectiveness of SN in these highly surfactant-deficient infants.25,53  The refinement of currently available nebulizers or nebulization via different interfaces (eg, nasopharyngeal tube or laryngeal mask) may improve efficacy in this population. However, this needs to be tested in further clinical trials.

Nebulization was performed as a treatment of respiratory distress syndrome after the initial stabilization phase in all studies, precluding subgroup analysis based on timing. Because surfactant efficacy decreases with increasing postnatal age,54  we speculate that prophylactic nebulization may be more effective. Early nebulization may decrease shear forces and inflammatory processes starting from the first inflation,55,56  thus potentially attenuating BPD development. An ongoing RCT investigating the efficacy of SN on early lung aeration may soon provide some insight into this pathophysiological assumption.57 

We could not show any effect of SN on relevant secondary outcomes, such as BPD, IVH, or death, neither in primary nor in sensitivity analyses using only studies with prespecified outcome definitions. Because mechanical ventilation is associated with BPD,58  one would expect a decrease in BPD rate. Additionally, high-grade IVH may occur because of rapid changes in cerebral blood flow,16  which may be less pronounced during SN than during intratracheal surfactant instillation.15  However, the number of included infants may be insufficient to assess these outcomes. Furthermore, high methodologic and clinical heterogeneity may have been additional contributing factors for the lack of clinical efficacy. Effect directions for BPD, IVH, and mortality were in favor of SN. Only a few data on 2-year neurodevelopmental outcomes were available, which indicated neither benefit nor harm. Overall, there were no adverse effects of SN in this large meta-analysis, indicating that this is a safe method of surfactant administration. On the basis of our results, methodologically sound trials are now warranted to examine the effect of SN on critical outcomes.

We acknowledge the limitations of our study: First, we included only 9 trials with just >1000 infants in this meta-analysis, leading to a high degree of imprecision. However, for our primary outcome intubation rate at 72 hours after birth, imprecision was not as pronounced, with a narrow CI and a relatively high number of events. This strengthened the core message of our meta-analysis. Additionally, a sample size of >1000 preterm infants is not often achieved. Second, there was high heterogeneity in the assessment of the primary outcome, which reduces the strength of evidence. We could explain some but not all of the heterogeneity by detailed subgroup analyses. These data provide new avenues for potential future research that should then focus on relevant longer-term outcomes in which data are still insufficient to draw final conclusions. Third, we did not perform funnel plot analysis to assess publication bias. However, we included data from published and unpublished sources and found 7 additional trials not included in previous meta-analyses.28,29  Fourth, the short-term nature of the original studies precluded meta-analysis of long-term outcomes. Finally, there was a high ROB for all but 1 study, mostly because of lack of blinding. Further well-designed trials are warranted to determine the true effect of SN.

In this pooled analysis including 1095 preterm infants, we provide evidence that SN may reduce intubation rate at 72 hours after birth. This effect was only present in infants ≥28 completed weeks' gestation, using a pneumatically driven nebulizer and using ≥ 200mg/kg animal-derived surfactant. There were no detectable adverse or additional positive short- and long-term effects of SN. Because of ROB and inconsistency or imprecision, strength of evidence was downgraded to low for all outcomes. Further well-designed trials with relevant long-term outcomes are needed before this technique can be recommended.

We thank Prof Jim Cummings for the provision of detailed data from his study for this meta-analysis.

FUNDING: Dr Gaertner was supported by a Start-Up Grant of the European Society for Pediatric Research. Dr Thomann was supported by a Filling The Gap Grant of the University of Zurich. The other authors received no external funding. The funders had no influence on data analysis and writing the manuscript.

Dr Gaertner conceptualized and designed the study, reviewed the literature, extracted the data for meta-analysis, performed the risk of bias assessment, wrote the initial draft of the manuscript and reviewed and revised the manuscript; Dr Thomann reviewed the literature, extracted the data for meta-analysis, performed the risk of bias assessment and reviewed and revised the manuscript; Dr Bassler helped interpret the data and critically reviewed the manuscript for important intellectual content; Dr Rüegger conceptualized and designed the study, coordinated and supervised data collection, and critically reviewed the manuscript for important intellectual content; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

VDG and JT report that they had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All data used and/or analyzed during the current study are available from the manuscripts or registries of the included studies. Individual patient data were not available to the authors.

BPD

bronchopulmonary dysplasia

CI

confidence interval

Fio2

fraction of inspired oxygen

GA

gestational age

IVH

intraventricular hemorrhage

MAP

mean airway pressure

nCPAP

nasal continuous positive airway pressure

NEC

necrotizing enterocolitis stage 2 or higher

Paco2

arterial carbon dioxide

PRISMA

Preferred Reporting Items for Systematic Reviews and Meta-analyses

RCT

randomized controlled trials

ROB

risk of bias

ROP

retinopathy of prematurity

RR

risk ratio

SN

Surfactant nebulization

Spo2

peripheral oxygen saturation

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.