Surfactant therapy guided by tests for lung maturity in preterm infants at risk of respiratory distress syndrome

Abstract

Background

Administration of various exogenous surfactant preparations has been shown to decrease lung injury and pneumothorax and improve survival in very preterm infants with respiratory distress syndrome (RDS). There is no consensus on the threshold for surfactant administration, to allow timely intervention and avoid over‐treatment, also considering the invasiveness of the procedure and its cost. Rapid tests for lung maturity, which include the click test, lamellar body counts and stable microbubble test, might guide the identification of those infants needing surfactant administration.

Objectives

To assess the effects of surfactant treatment guided by rapid tests for surfactant deficiency in preterm infants at risk for or having RDS.

Comparison 1: In preterm infants at risk for RDS, does surfactant treatment guided by rapid tests for surfactant deficiency compared to prophylactic surfactant administration to all high‐risk infants minimize the need for surfactant treatment and prevent bronchopulmonary dysplasia and mortality?

Comparison 2: In preterm infants who require early respiratory support, does surfactant treatment guided by rapid tests for surfactant deficiency compared to surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria minimize the need for surfactant treatment and prevent bronchopulmonary dysplasia and mortality?

Search methods

We searched in October 2022 CENTRAL, PubMed, Embase and three additional trial registries. We also screened the reference lists of included studies and related systematic reviews for studies not identified by the database searches.

Selection criteria

We included randomized controlled trials (RCTs) and quasi‐RCTs evaluating rapid tests after birth for surfactant deficiency in infants at high risk of RDS or requiring respiratory support.

We specified two comparisons: 1)surfactant treatment guided by rapid tests for surfactant deficiency versus prophylactic surfactant administration to all high‐risk infants in extremely preterm (less than 28 weeks' gestation) and very preterm (28 to 32 weeks' gestation); 2)surfactant treatment guided by rapid tests for surfactant deficiency versus surfactant therapy provided to preterm infants (less than 37 weeks' gestation) with RDS diagnosed on clinical and radiologic criteria.

Data collection and analysis

We used standard Cochrane methods. We used the fixed‐effect model with risk ratio (RR) and risk difference (RD), with their 95% confidence intervals (CIs) for dichotomous data. Our primary outcomes were: neonatal mortality, mortality prior to hospital discharge, bronchopulmonary dysplasia and the composite outcome bronchopulmonary dysplasia or mortality. We used GRADE to assess the certainty of evidence.

Main results

We included three RCTs enrolling 562 newborn infants in this review.

No studies compared surfactant treatment guided by rapid tests for surfactant deficiency versus prophylactic surfactant administration to all high‐risk infants.

Comparing surfactant therapy guided by rapid tests for surfactant deficiency versus surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria.

No studies reported neonatal mortality. Compared with surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria, the evidence is very uncertain about the effect of surfactant treatment guided by rapid tests for surfactant deficiency on mortality prior to hospital discharge: RR 1.25, 95% CI 0.65 to 2.41, RD 0.01, 95% CI ‐0.03 to 0.05, 562 participants, 3 studies; I² for RR and RD = 75% and 43%, respectively; very low‐certainty evidence. Surfactant treatment guided by rapid tests for surfactant deficiency may result in little to no difference in bronchopulmonary dysplasia: RR 0.90, 95% CI 0.61 to 1.32, RD ‐0.02, 95% CI ‐0.08 to 0.04, 562 participants, 3 studies; I² for RR and RD = 0%; low‐certainty evidence. No studies reported the composite outcome bronchopulmonary dysplasia or mortality. Surfactant treatment guided by rapid tests for surfactant deficiency may result in little to no difference in surfactant utilization (RR 0.97, 95% CI 0.85 to 1.11, RD ‐0.02, 95% CI ‐0.10 to 0.06, 562 participants, 3 studies, I² for RR and RD = 63% and 65%, respectively, low‐certainty evidence), and any pneumothorax (RR 0.53, 95% CI 0.15 to 1.92, RD ‐0.01, 95% CI ‐0.04 to 0.01, 506 participants, 2 studies, I² for RR and RD = 0%, low‐certainty evidence) compared with surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria. No studies reported moderate to severe neurodevelopmental impairment.

We identified two large ongoing RCTs.

Authors' conclusions

No studies compared surfactant treatment guided by rapid tests for surfactant deficiency to prophylactic surfactant administration to all high‐risk infants. Low to very low‐certainty evidence from three studies is available on surfactant therapy guided by rapid tests for surfactant deficiency versus surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria. No studies reported neonatal mortality, the composite outcome 'bronchopulmonary dysplasia or mortality', or neurodevelopmental outcomes. Compared with surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria, the evidence is very uncertain about the effect of surfactant treatment guided by rapid tests for surfactant deficiency on mortality prior to hospital discharge. Surfactant treatment guided by rapid tests for surfactant deficiency may result in little to no difference in bronchopulmonary dysplasia, surfactant utilization and any pneumothorax.

The findings of the two large ongoing trials identified in this review are likely to have an important impact on establishing the effects of surfactant treatment guided by rapid tests for surfactant deficiency in preterm infants.

Plain language summary

What are the benefits and risks of using tests for lung maturation to assess if preterm newborns need to receive surfactant therapy to improve lung function?

Key messages

• Respiratory distress syndrome is a common condition in preterm infants, while the benefits of surfactant therapy guided by tests for lung maturation remain unclear.

• No studies reported neonatal death (first 28 days of life) or neurodevelopmental outcome. It is uncertain whether surfactant therapy guided by tests for lung maturation has an effect on death prior to hospital discharge. Surfactant treatment guided by rapid tests for surfactant deficiency may result in little to no difference in chronic lung disease of prematurity, known as bronchopulmonary dysplasia, need for surfactant treatment, or any pneumothorax, that is a collapsed lung.

• Studies are needed to compare surfactant treatment guided by rapid tests for surfactant deficiency to prophylactic surfactant administration (administration of surfactant before the onset of symptoms) in all high‐risk infants.

What are tests for lung maturity?

Surfactant is a complex mixture composed of proteins and phospholipids. The proteins aid in spreading and absorption at the lung surface, while lipids decrease the surface tension and thus prevent the collapse of the lung at the end of expiration, (that is when air leaves the lungs). Preterm infants are at risk of respiratory distress syndrome that occurs when their lungs have not developed properly. It is due to lack of surfactant, therefore surfactant administration is a procedure commonly performed in preterm infants. Up to now, there has been no consensus on the indicators and time for surfactant replacement therapy. Considering the invasiveness and cost, the aim is to allow timely intervention and avoid over treatment. Rapid tests for lung maturity (such as the click test, lamellar body counts and stable microbubble test) are based on measuring the concentration of pulmonary surfactant in any fluid. These tests can be performed on amniotic fluid, first fluid aspirated from the stomach or trachea (windpipe) soon after birth to assess the degree of surfactant deficiency. The use of rapid tests might guide the identification of infants needing surfactant administration.

What did we want to find out?

We wanted to find out if using tests for lung development in preterm infants was better than surfactant administration before the onset of respiratory distress syndrome (prophylactic surfactant administration) in all high‐risk infants or surfactant therapy provided to infants with respiratory distress syndrome diagnosed on clinical and radiologic criteria.

We also wanted to find out if using surfactant therapy guided by tests for lung maturity in preterm infants was associated with a decrease in negative outcomes, such as death, chronic lung disease of prematurity, or any collapsed lung. Chronic lung disease of prematurity is a major problem for preterm babies associated with both a higher death rate and worse outcomes among survivors. Persistent inflammation of the lungs due to long use of respirators for providing ventilation is the most likely cause of it. Surfactant administration can assist in weaning from mechanical ventilation, and therefore prevent neonates from developing chronic lung disease of prematurity.

What did we do?

We searched for studies that looked at surfactant therapy guided by different types of rapid tests for lung maturity compared with prophylactic surfactant administration in all high‐risk infants or surfactant therapy provided to infants with respiratory distress syndrome diagnosed on clinical and radiologic criteria.

We compared and summarized the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.

What did we find?

We found three studies that involved 562 preterm infants who either received surfactant treatment guided by rapid tests or by clinical and criteria and X‐ray or ultrasound images.

The main results of the review showed that it is very uncertain whether the surfactant therapy guided by rapid tests for surfactant deficiency compared with surfactant therapy provided to infants with respiratory distress syndrome diagnosed on clinical and radiologic criteria has an effect on death prior to hospital discharge.

Surfactant treatment guided by rapid tests for surfactant deficiency may result in little to no difference in chronic lung disease of prematurity, need for surfactant treatment and collapsed lung.

There are two large ongoing studies assessing ung ultrasound guided surfactant therapy (one study) and the evaluation of the lung function, together with clinical assessment for surfactant therapy (one study).

What are the limitations of the evidence?

We are not confident in the evidence because there are not enough studies to be certain about the results of our outcomes. Finally, not all the studies provided data about everything that we were interested in.

How up to date is this evidence?

The evidence is up‐to‐date to October 2022.

Summary of findings

Summary of findings 1. Surfactant treatment guided by rapid tests for surfactant deficiency versus surfactant therapy provided to preterm infants with respiratory distress syndrome diagnosed on clinical and radiologic criteria.

Surfactant treatment guided by rapid tests for surfactant deficiency versus surfactant therapy provided to preterm infants with respiratory distress syndrome diagnosed on clinical and radiologic criteria
Patient or population: preterm infants at risk of respiratory distress syndrome Setting: neonatal intensive care units Intervention: surfactant treatment guided by rapid tests Comparison: surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria
Outcomes	Relative effect (95% CI)	Anticipated absolute effects* (95% CI)			Certainty of the evidence (GRADE)	What happens
		Without Surfactant treatment guided by rapid tests	With Surfactant treatment guided by rapid tests	Difference
Neonatal mortality (mortality < 28 days of age) from any cause ‐ not reported	‐	‐			‐	This outcome was not reported
Mortality prior to hospital discharge № of participants: 562 (3 RCTs)	RR 1.25 (0.65 to 2.41) RD 0.01 (‐0.03 to 0.05)	Study population			⊕⊝⊝⊝ Very low 1 2	The evidence is very uncertain about the effect of surfactant treatment guided by rapid tests for surfactant deficiency on mortality prior to hospital discharge compared with surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria
		5.4%	6.7% (3.5 to 13)	1.3% more (1.9 fewer to 7.6 more)
Bronchopulmonary dysplasia № of participants: 562 (3 RCTs)	RR 0.90 (0.61 to 1.32) RD ‐0.02 (‐0.08 to 0.04)	Study population			⊕⊕⊝⊝ Low 2	Surfactant treatment guided by rapid tests for surfactant deficiency may result in little to no difference in bronchopulmonary dysplasia compared with surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria
		16.2%	14.6% (9.9 to 21.4)	1.6% fewer (6.3 fewer to 5.2 more)
Bronchopulmonary dysplasia or mortality ‐ not reported	‐	‐			‐	This outcome was not reported
Surfactant utilization № of participants: 562 (3 RCTs)	RR 0.97 (0.85 to 1.11) RD ‐0.02 (‐0.10 to 0.06)	Study population			⊕⊕⊝⊝ Low 1, 3	Surfactant treatment guided by rapid tests for surfactant deficiency may result in little to no difference in surfactant utilization compared with surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria
		60.8%	59.0% (51.7 to 67.5)	1.8% fewer (9.1 fewer to 6.7 more)
Any pneumothorax № of participants: 506 (2 RCTs)	RR 0.53 (0.15 to 1.92) RD ‐0.01 (‐0.04 to 0.01)	Study population			⊕⊕⊝⊝ Low 2	Surfactant treatment guided by rapid tests for surfactant deficiency may result in little to no difference in any pneumothorax slightly compared with surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria
		2.4%	1.3% (0.4 to 4.6)	1.1% fewer (2 fewer to 2.2 more)
Neurodevelopmental outcome at approximately two years' corrected age ‐ not reported	‐	‐			‐	This outcome was not reported
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RCT: randomized controlled trial; RD: risk difference; RDS: respiratory distress syndrome; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

¹ Downgraded one level for serious inconsistency (I² ≥ 50%, poor overlap of the CIs).

² Downgraded two levels for very serious imprecision: wide confidence of intervals overlapping the no‐difference line.

³ Downgraded one level for serious imprecision: confidence of intervals overlapping the no‐difference line.

Background

Description of the condition

Respiratory distress syndrome (RDS), previously known as hyaline membrane disease, occurs in newborns when pulmonary surfactant is deficient or dysfunctional (Avery 1959). Pulmonary surfactant is composed of both proteins and phospholipids. The phospholipids, primarily dipalmitoylphosphatidylcholine (DPPC), act to decrease the alveolar surface tension and thus prevent end‐expiratory atelectasis. The proteins aid in spreading and adsorption at the alveolar surface (Halliday 2008). Surfactant is made by type II pneumocytes and transported to the alveolar surface as lamellar bodies (Verder 2011). The maturation of type II pneumocytes occurs in the later stages of fetal development. Respiratory distress syndrome is thus primarily a disease of preterm infants. However, full‐term infants may present with RDS due to dysfunctional surfactant secondary to genetic mutations in genes such as surfactant protein B or C (SP‐B and SP‐C), or phospholipid transporter (ABCA3) (Wert 2009).

Infants with RDS present with early‐onset respiratory distress. Clinical signs often include intercostal retractions, grunting, and nasal flaring necessitating supplemental oxygen (Bancalari 2012). Further evaluation often reveals classic reticulogranular findings on a chest radiograph. However, such radiologic and clinical signs may be masked in infants who are quickly intubated and on ventilatory support. Furthermore, extremely low birth weight infants often present with similar signs of respiratory distress, although the underlining cause may not necessarily be due to surfactant deficiency, but rather poor postnatal adaptation, central respiratory depression, and lung inflammation secondary to chorioamnionitis (Bancalari 2012; Laughon 2009; Watterberg 1996). The diagnosis of RDS based on classic respiratory distress and radiographic evidence has resulted in significant diagnostic variation among providers (Fanaroff 2007; Stoll 2010).

There has been significant advancement in the treatment of RDS. Initial treatment focused on the administration of animal‐derived exogenous surfactant (Fujiwara 1980). Further research introduced synthetic surfactants. Research continues to address timing, frequency of dosing, and route of administration of exogenous surfactant. In addition to treatment with exogenous surfactant, maternal use of steroids during fetal development has been shown to promote fetal lung development and decrease the incidence of RDS once born (Robertson 1993). Advancement in respiratory support has allowed for early continuous distending pressure, which has decreased the need for prophylactic surfactant administration (Bahadue 2012; Chernick 1973). The rate of RDS among very low birthweight infants is more than 90% in infants born 27 to 29 weeks' gestational age (median 91.7%, interquartile range (IQR) 75 to 100) and approximately two thirds in infants born 30 to 32 weeks' gestational age (median 66.7%, IQR 41.7 to 88.9) (Vermont Oxford Network 2023).

Description of the intervention

Administration of various exogenous surfactant preparations has been shown to decrease lung injury and pneumothorax and improve survival (Jobe 1993; Soll 1997; Soll 1998). Surfactant products include animal‐derived surfactants, as well as protein‐ and non‐protein‐containing synthetic surfactants (Ardell 2015; Lasalvia 2017; Pfister 2007; Pfister 2009; Seger 2009).

Exogenous surfactant treatment strategies include prophylactic, early, or selective administration. Prophylactic administration is the immediate treatment of newborns at risk of RDS (Rojas‐Reyes 2012; Soll 2010). This could occur before (pre‐ventilatory) or after (post‐ventilatory) the first breath. Early administration is the use of exogenous surfactant in the first two hours of life for infants who are intubated for respiratory distress (Bahadue 2012; Stevens 2007). Selective treatment or rescue administration occurs only when the intubated newborn has developed symptoms of RDS (Rojas‐Reyes 2012). Such symptoms include an increased fraction of inspired oxygen (FiO₂) requirement (frequently defined as 0.4) or mean airway pressure greater than 7 cmH₂O.

Exogenous surfactant therapy is administered in several different ways. These include thin endotracheal tube, intrapartum pharyngeal instillation, INSURE (INtubation‐SURfactant‐Extubation), and minimally invasive surfactant therapy (MIST), also known as non‐invasive surfactant therapy (NIST) (Abdel‐Latif 2011; Abdel‐Latif 2012; Abdel‐Latif 2021).

There is a long history of using antenatal tests for surfactant deficiency to help plan timing of delivery. These include analysis of amniotic fluid for L/S ratio, concentration of phosphatidylglycerol (PG), rapid agglutination testing for anti‐PG antibodies, lamellar body count, and the now‐discontinued TDx‐Fetal Lung Maturity (FLM) II assay (surfactant‐to‐albumin ratio) (Yarbrough 2014). However, FLM testing utilization has steadily decreased (McGinnis 2008). This is thought to be secondary to improved fetal outcomes with increased use of antenatal steroids (McGinnis 2008).

Although several tests are available, testing for surfactant deficiency after delivery has been less widely utilized. The most prominent bedside tests are lamellar body counts, click test, and the stable microbubble test (Fiori 2004; Osborn 2000; Verder 2011). All three can be performed on amniotic fluid, first gastric aspirate, or tracheal aspirate soon after birth (Fiori 2004; Osborn 2000). The click test demonstrates high sensitivity (94%) and specificity (100%) utilizing tracheal aspirate in preterm infants (Skelton 1994), as well as high interobserver reliability (Osborn 1998). The stable microbubble test demonstrates lower sensitivity (57%) and specificity (96%) utilizing amniotic fluid just prior to delivery (Chida 1993). Lamellar body counts of gastric aspirates demonstrates moderate sensitivity (75%) and low specificity (72%) (Verder 2011). The lecithin‐to‐sphingomyelin (L/S) ratio and PG presence in amniotic fluid or tracheal aspirate has also been used (Merritt 1991; Verder 2017).

Surfactant is administered in about two thirds (median 67.9%, IQR 54.5 to 83.3) of infants born 27 to 29 weeks' gestational age and one third (median 30.2%,IQR 16.7 to 46.2) of infants born 30 to 32 weeks' gestational age (Vermont Oxford Network 2023).

How the intervention might work

While there has been significant advancement in the treatment of newborns who develop RDS, there is continued need to identify sooner those who would benefit from surfactant treatment without waiting for dramatic clinical signs of respiratory distress, as is the case with selective administration. Such an intervention would include the incorporation of rapid tests for lung maturity at the early stage of respiratory distress. However, this intervention is distinct from a conventional early administration protocol, as it considers lung maturity in addition to the need for respiratory support during the first two hours of life.

Alternatively, the rapid evaluation of lung maturity of neonates who are at high risk of developing RDS is also needed. This approach is distinct from the prophylactic surfactant administration of high‐risk infants, as it would allow for the option of not treating those who demonstrate sufficient lung maturity.

Why it is important to do this review

The administration of exogenous surfactant is not without harm. Examples include risks associated with instillation (bradycardia, hypoxemia, blockage of endotracheal tube), pulmonary hemorrhage, lung overdistension and hyperventilation (Lopez 2013). Hence, there is a desire to further limit administration only to neonates who are surfactant deficient and will benefit from surfactant administration, and spare those who are not deficient from the potential side effects.

Objectives

To assess the effects of surfactant treatment guided by rapid tests for surfactant deficiency in preterm infants at risk for or having respiratory distress syndrome (RDS).

Comparison 1: In preterm infants at risk for RDS, does surfactant treatment guided by rapid tests for surfactant deficiency compared to prophylactic surfactant administration to all high‐risk infants minimize the need for surfactant treatment and prevent bronchopulmonary dysplasia and mortality?

Comparison 2: In preterm infants who require early respiratory support, does surfactant treatment guided by rapid tests for surfactant deficiency compared to surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria minimize the need for surfactant treatment and prevent bronchopulmonary dysplasia and mortality?

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials (RCTs) and quasi‐RCTs and cluster‐RCTs that evaluate physiochemical tests for surfactant deficiency. We excluded cross‐over trials. Non‐randomized cohort studies were deemed not eligible for this review, given the fact of potential bias of confounding by indication or residual confounding influencing the results of studies with such designs (Fewell 2007; Kyriacou 2016).

Types of participants

Participants included in Comparison 1: prevention/prophylaxis: preterm infants at high risk of developing RDS include extremely preterm (less than 28 weeks' gestation) and very preterm (28 to 32 weeks' gestation), irrespective of need for respiratory support.

Participants included in Comparison 2: treatment of established disease: preterm infants who require early respiratory support including extremely preterm (less than 28 weeks' gestation), very preterm (28 to 32 weeks' gestation), and moderate‐to‐late preterm (32 to 37 weeks' gestation). Early respiratory support included utilization of supplemental oxygen, high flow nasal cannula, continuous positive airway pressure or assisted ventilation.

Excluded populations: term or late preterm infants with other causes of respiratory distress including meconium aspiration syndrome, pulmonary infection, acute respiratory distress syndrome, and congenital diaphragmatic hernia (Lopez 2013). We did not include these alternate applications of exogenous surfactant therapy in our review.

Types of interventions

We evaluated the utilization of rapid test after birth for surfactant deficiency in infants at high risk of RDS or requiring respiratory support.

Rapid tests included the click test (Osborn 2000), lamellar body counts (Verder 2011), and stable microbubble test (Fiori 2004), as well as any less common test insomuch as the test is able to assess surfactant deficiency in a reasonable time frame to inform clinical management.

Comparison 1: Intervention: surfactant treatment guided by rapid tests for surfactant deficiency; control: prophylactic surfactant administration to all high‐risk infants.

Comparison 2: Intervention: surfactant treatment guided by rapid tests for surfactant deficiency; control: surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria.

We included all methods of surfactant administration as well as all surfactant products utilized in the original research studies.

Types of outcome measures

Primary outcomes

1. Neonatal mortality (mortality < 28 days of age) from any cause.

2. Mortality prior to hospital discharge (from any cause).

3. Bronchopulmonary dysplasia (use of supplemental oxygen at 36 weeks' postmenstrual age in infants born before 32 weeks' gestation (Jobe 2001); or use of supplemental oxygen > 28 days of age in infants born after 32 weeks' gestation).

4. Bronchopulmonary dysplasia or mortality (use of supplemental oxygen at 36 weeks' postmenstrual age in infants born before 32 weeks' gestation; or use of supplemental oxygen > 28 days of age in infants born after 32 weeks' gestation; any‐cause mortality).

Secondary outcomes

1. Surfactant utilization (number of infants receiving surfactant).

2. Any air leak syndromes (including pulmonary interstitial emphysema, pneumothorax, pneumomediastinum).

3. Any pneumothorax.

4. Pulmonary interstitial emphysema.

5. Any pulmonary hemorrhage.

6. Use of supplemental oxygen at 28 to 30 days of age.

7. Use of supplemental oxygen or death prior to 28 to 30 days of age.

8. Patent ductus arteriosus (treated pharmacologically (cyclooxygenase inhibitor, paracetamol) or surgically).

9. Any culture‐proven bacterial sepsis.

10. Any culture‐proven fungal sepsis.

11. Necrotizing enterocolitis (defined as Bell stage II or greater) (Bell 1978).

12. Intraventricular hemorrhage (any grade and severe (grade 3 to 4)) (Papile 1978).

13. Periventricular leukomalacia.

14. Retinopathy of prematurity (all grade and severe (stage 3 or greater)) (ICCROP 2005).

15. Length of hospital stay (days).

16. Moderate to severe neurodevelopmental impairment assessed at approximately two years corrected age (acceptable range 18 months to 28 months) including cerebral palsy, significant mental developmental delay (Bayley Scales of Infant Development Mental Developmental Index < 70) (Bayley 1993), legal blindness (< 20/200 visual acuity), and hearing deficit (aided or < 60 dB on audiometric testing). The composite outcome “neurodevelopmental impairment” was defined as having any one of the aforementioned deficits (modified from definitions of moderate‐to‐severe developmental delay) (Schmidt 2007). If data were available, we planned to report each component of moderate to severe neurodevelopmental impairment separately.

Search methods for identification of studies

The Cochrane Sweden Information Specialist developed a draft search strategy for PubMed (National Library of Medicine) in consultation with the review authors (Appendix 1). This strategy was peer‐reviewed by an Information Specialist using the PRESS Checklist (McGowan 2016a; McGowan 2016b). The PubMed strategy was translated, using appropriate syntax, for other databases.

A population filter developed by Cochrane Neonatal was used. The RCT search filter for Ovid MEDLINE as recommended by Cochrane Neonatal was adapted to the syntax of PubMed (NLM) and used to identify randomized and quasi‐randomized studies. Searches for eligible trials were conducted without language, publication year, publication type, or publication status restrictions.

Electronic searches

The following databases were searched in October 2022:

• Cochrane CENTRAL Register of Controlled Trials (CENTRAL), via Wiley (17 October 2022);

• PubMed (National Library of Medicine) (1946 to 17 October 2022);

• Embase.com, (Elsevier) (1974 to 17 October 2022).

Searching other resources

Trial registration records were identified (18 October 2022) using CENTRAL and by independent searches of:

• ISRCTN registry (https://www.isrctn.com);

• US NIH 1979 Institutes of Health Ongoing Trials Register ClinicalTrials.gov (clinicaltrials.gov);

• ICTRP‐‐World Health Organization International Clinical Trials Registry Platform (https://trialsearch.who.int/Default.aspx).

We screened the reference lists of included studies and related systematic reviews for studies not identified by the database searches.

We searched for errata or retractions for included studies published on PubMed (www.ncbi.nlm.nih.gov/pubmed).

Data collection and analysis

We collected information regarding the method of randomization, blinding, intervention, stratification, and whether the trial was single center or multicenter for each included study. We noted information regarding trial participants including gestational age, birthweight, sex. We analyzed the clinical outcomes noted above in Types of outcome measures.

Selection of studies

We downloaded all titles and abstracts retrieved by electronic searching to reference management software and removed duplicates. The remaining titles/abstracts were screened independently by three review authors (GS, FB, MM). After title and abstract review, two review authors (MM, GS) independently assessed the full text of the included studies. At any point in the screening process, disagreements between review authors were resolved by discussion or by a third review author (MB). Reasons for excluding studies during review of full texts were documented in the Characteristics of excluded studies table;. Reasons for exclusion were the absence of one or more PICO‐S elements (population, interventions, comparators, outcomes); where a study omitted more than one PICO‐S element, we documented only one. Where available, we collated multiple reports of the same study so that each study, rather than each report, is the unit of interest in the review. We also provided any information we could obtain about ongoing studies. We recorded the selection process in sufficient detail to complete a PRISMA flow diagram (Liberati 2009).

Data extraction and management

Three review authors (GS, FB, MM) independently extracted data using a data extraction form integrated with a modified version of the Cochrane Effective Practice and Organization of Care Group data collection checklist (Cochrane EPOC Group 2017). We piloted the form within the review team using a sample of included studies.

We extracted the following characteristics from each included study.

• Administrative details: study author(s); published or unpublished; year of publication; year in which study was conducted; presence of vested interest; details of other relevant papers cited.

• Study characteristics: study registration, study design type, study setting, number of study centers and location; informed consent; ethics approval, details of any 'run‐in' period (if applicable), completeness of follow‐up (e.g. greater than 80%).

• Participants: number randomized, number lost to follow‐up/withdrawn, number analyzed, mean gestational age (GA), GA age range, mean chronological age (CA), CA age range, sex, severity of condition, diagnostic criteria, inclusion criteria and exclusion criteria.

• Interventions: test for surfactant deficiency.

• Outcomes as mentioned above under Types of outcome measures.

We resolved any disagreements by discussion.

We described two ongoing studies identified by our search and documented available information such as the primary author, research question(s), methods, and outcome measures, together with an estimate of the reporting date and report them in the Characteristics of ongoing studies table.

We did not contact study investigators/authors for clarification as no queries arose, nor were additional data required. Two review authors (GS, FB) used Cochrane statistical software for data entry (RevMan Web 2023). We planned to replace any standard error of the mean (SEM) with the corresponding standard deviation (SD) but there was no such a case.

Assessment of risk of bias in included studies

Two review authors (GS, FB) independently assessed the risk of bias (low, high, or unclear) of all three included trials using the Cochrane risk of bias tool for the following domains (Higgins 2017).

1. Sequence generation (selection bias)

2. Allocation concealment (selection bias)

3. Blinding of participants and personnel (performance bias)

4. Blinding of outcome assessment (detection bias)

5. Incomplete outcome data (attrition bias)

6. Selective reporting (reporting bias)

7. Any other bias

We resolved any disagreements by discussion or by consulting a third assessor. See Appendix 2 for a more detailed description of risk of bias for each domain.

Measures of treatment effect

Dichotomous data

For dichotomous data we present results using risk ratios (RRs) and risk differences (RDs) with 95% confidence intervals (CIs). We planned to calculate the number needed to treat for an additional beneficial outcome (NNTB), or the number needed to treat for an additional harmful outcome (NNTH) with 95% CIs if there was a statistically significant reduction (or increase) in RD. There was no statistically significant reduction (or increase) in RD, and therefore we did not perform such analysis.

Continuous data

For continuous data, we planned to use mean difference (MD) when outcomes were measured in the same way between studies. We planned to use the standardized mean difference (SMD) to combine trials that measured the same outcome but used different methods. If studies reported continuous data as median and interquartile range (IQR) and the data passed the test of skewness, we planned to convert mean to median and estimate the standard deviation (SD) as IQR/1.35.

If data were not reported in a study in a format that could be entered directly into a meta‐analysis, we planned to convert them to the required format using the information inChapter 6 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022). There was no need to convert the data in a different format than reported by the studies' authors.

Unit of analysis issues

We planned to perform the primary analysis per individual randomized.

For cluster‐randomized trials, we planned to abstract information on the study design and unit of analysis for each study, indicating whether clustering of observations was present due to allocation to the intervention at the group level or clustering of individually‐randomized observations (e.g. patients within clinics). We planned to abstract available statistical information needed to account for the implications of clustering on the estimation of outcome variances such as design effects or intra‐cluster correlations (ICCs) and whether the study adjusted results for the correlations in the data. In cases where the study did not account for clustering, we planned to ensure that appropriate adjustments were made to the effective sample size following Cochrane guidance (Higgins 2022). Where possible, we planned to derive the ICC for these adjustments from the trial itself, or from a similar trial. If an appropriate ICC was unavailable, we planned to conduct sensitivity analyzes to investigate the potential effect of clustering by imputing a range of values of ICC. We did not include any cluster‐randomized trials.

If any trials had multiple arms that were compared against the same control condition that would be included in the same meta‐analysis, we planned either to combine groups to create a single pair‐wise comparison, or select one pair of interventions and exclude the others. We did not include any trial with multiple arms.

Dealing with missing data

Where feasible, we intended to carry out analysis on an intention‐to‐treat basis for all outcomes. Whenever possible, we planned to analyze all participants in the treatment group to which they were randomized, regardless of the actual treatment received. If we had identified important missing data (in the outcomes) or unclear data, we would have requested the missing data by contacting the original investigators. We would then have made explicit assumptions about any methods used to deal with missing data, and we might have performed sensitivity analyzes to assess how sensitive results were to reasonable changes in the undertaken assumptions. We did not address the potential impact of missing data on the findings of the review in the Discussion section as we did not identify any missing data.

Assessment of heterogeneity

We described the clinical diversity and methodological variability of the evidence narratively, and in Tables. The Tables include data on study characteristics such as design features, population characteristics, and intervention details.

To assess statistical heterogeneity, we planned to visually inspect forest plots and describe the direction and magnitude of effects and the degree of overlap between confidence intervals. We planned to consider the statistics generated in forest plots that measure statistical heterogeneity and to use the I² statistic to quantify inconsistency among the trials in each analysis. We planned also to consider the P value from the Chi² test to assess if this heterogeneity is significant (P < 0.1). If we had identified substantial heterogeneity we would have reported the finding and explored the possible explanatory factors using prespecified subgroup analysis.

We graded the degree of heterogeneity as:

• 0% to 40% might not represent important heterogeneity;

• 30% to 60% may represent moderate heterogeneity;

• 50% to 90% may represent substantial heterogeneity;

• more than 75% may represent considerable heterogeneity.

We used a rough guideline to interpret the I² value rather than a simple threshold, and our interpretation took into account an understanding that measures of heterogeneity (I² and Tau) were estimated with high uncertainty when the number of studies is small (Deeks 2022).

Assessment of reporting biases

We assessed reporting bias by comparing the stated primary outcomes and secondary outcomes and reported outcomes. Where study protocols were available, we compared these to the full publications to determine the likelihood of reporting bias. There were no studies using the interventions in a potentially eligible infant population but not reporting on any of the primary and secondary outcomes.

We planned to use the funnel plots to screen for publication bias where there were a sufficient number of studies (> 10) reporting the same outcome. If publication bias was suggested by a significant asymmetry of the funnel plot on visual assessment, we would have incorporated this in our assessment of the certainty of evidence (Egger 1997). We considered that if our review included few studies eligible for meta‐analysis, the ability to detect publication bias would be largely diminished, and we would simply note our inability to rule out possible publication bias or small‐study effects. This analysis was not performed as we included less than 10 studies.

Data synthesis

Where studies were sufficiently similar, we performed meta‐analysis analysis using Review Manager Web (RevMan Web 2023). For categorical outcomes, we calculated the typical estimates of RR and RD, each with its 95% CI; for continuous outcomes, we planned to calculate the MD or the SMD, each with its 95% CI. We used a fixed‐effect model to combine data where it is reasonable to assume that studies were estimating the same underlying treatment effect. If we had judged meta‐analysis to be inappropriate, we would have analyzed and interpreted individual trials separately. As there was evidence of clinical heterogeneity, we planned to explain this based on the different study characteristics and subgroup analyzes.

Subgroup analysis and investigation of heterogeneity

We planned to interpret tests for subgroup differences in effects with caution given the potential for confounding with other study characteristics and the observational nature of the comparisons. See Section 10.11.2 Cochrane handbook version six. In particular, subgroup analyzes with fewer than five studies per category are unlikely to be adequate to ascertain valid differences in effects and are not highlighted in our results. If subgroup comparisons were possible, we planned to conduct stratified meta‐analysis and a formal statistical test for interaction to examine subgroup differences that could account for effect heterogeneity (e.g., Cochran’s Q test, meta‐regression) (Borenstein 2013). However, this was not necessary in our review.

Given the potential differences in the intervention effectiveness related to gestational age, disease severity, type of rapid test, timing of testing and treatment, exposure to antenatal steroids, surfactant preparation, discussed in the Background section, we planned to conduct subgroup comparisons to see if tests for lung maturity are more effective for the treatment of RDS in newborn infants.

We planned to carry out the following subgroup analyzes of factors that may contribute to heterogeneity in the effects of the intervention:

• gestational age: term infants (very preterm infants, i.e. less than 32 weeks' gestation; extremely preterm infants, i.e. less than 28 weeks' gestation);

• disease severity (need for assisted ventilation, need for FiO₂ > 0.4);

• type of rapid test;

• timing of testing and treatment;

• exposure to antenatal steroids;

• surfactant preparation.

We planned to use the main outcomes in subgroup analyzes if there were enough studies reporting to support valid subgroup comparisons (at least five studies per subgroup). As only three studies were included in this review we did not perform subgroup analysis.

Sensitivity analysis

Had we identified substantial heterogeneity, we would have conducted sensitivity analysis to determine if the findings were affected by the inclusion of only those trials 1) considered to have used adequate methodology with a low risk of bias (selection, performance and reporting bias); 2) with the right characteristics of participants (e.g. infants in some RCTs meet the age range criteria of the review). We would have reported the results of sensitivity analyses for primary outcomes only.

Given that there is no formal statistical test that can be used for sensitivity analysis, we planned to provide informal comparisons between the different ways of estimating the effect under different assumptions. Changes in the P values should not be used to judge whether there was a difference between the main analysis and sensitivity analysis, since statistical significance may have been lost with fewer studies included. We planned to report sensitivity analysis results in tables rather than forest plots.

We did not perform sensitivity analysis.

Summary of findings and assessment of the certainty of the evidence

We used the GRADE approach, as outlined in the GRADE Handbook (Schünemann 2013), to assess the certainty of evidence for the following outcomes where reported.

1. Neonatal mortality (mortality < 28 days of age) from any cause.

2. Mortality prior to hospital discharge (from any cause).

3. Bronchopulmonary dysplasia (use of supplemental oxygen at 36 weeks' postmenstrual age in infants born before 32 weeks' gestation; or use of supplemental oxygen > 28 days of age in infants born after 32 weeks' gestation).

4. Bronchopulmonary dysplasia or mortality (use of supplemental oxygen at 36 weeks' postmenstrual age in infants born before 32 weeks' gestation; or use of supplemental oxygen > 28 days of age in infants born after 32 weeks' gestation; any‐cause mortality).

5. Surfactant utilization (number of infants receiving surfactant).

6. Any pneumothorax.

7. Neurodevelopmental outcome at approximately two years' corrected age (acceptable range 18 months to 28 months) including: cerebral palsy, significant mental developmental delay (Bayley Scales of Infant Development Mental Developmental Index < 70) (Bayley 1993), legal blindness (< 20/200 visual acuity), and hearing deficit (aided or < 60 dB on audiometric testing). The composite outcome “neurodevelopmental impairment” was defined as having any one of the aforementioned deficits (modified from definitions of moderate‐to‐severe developmental delay) (Schmidt 2007).

Two review authors (GS, MB) independently assessed the certainty of the evidence for outcomes 2, 3, 5 and 6. Outcomes 1, 4, and 7 were not reported by any of the included studies. We considered evidence from randomized controlled trials (RCTs) as high certainty, downgrading the evidence one level for serious (or two levels for very serious) limitations based upon the following: design (risk of bias), consistency across studies, directness of the evidence, precision of estimates, and presence of publication bias. We used GRADEpro GDT Guideline Development Tool to create a Table 1to report the certainty of the evidence.

The GRADE approach resulted in an assessment of the certainty of a body of evidence in one of the following four grades.

• High: we are very confident that the true effect lies close to that of the estimate of the effect.

• Moderate: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.

• Low: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.

• Very low: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Results

Description of studies

Results of the search

Searches identified a total of 10,083 references, after removing 612 duplicates, 9470 search results were available for screening. Of these, 9470 were processed using Cochrane's Screen4Me (Figure 1). Screen4Me identified 4878 references as non‐RCTs (76 records excluded by Crowd Known assessment; 1922 records excluded by RCT Classifier; 2880 records excluded by Cochrane Crowd). Covidence de‐duplicated 709 records (among the 4591 which passes the Screen4Me process).

1.

Screen4Me summary diagram

The remaining 3854 records were screened by the authors. We excluded 3849 based on title and abstract and reviewed six full ‐texts. We included three studies (Characteristics of included studies), excluded one study (Characteristics of excluded studies), and identified two ongoing studies (one identified post hoc) (Characteristics of ongoing studies). Details are provided in Figure 2.

2.

Prisma flow chart

Included studies

We included three studies (enrolling 562 newborn infants) and all of them were performed in neonatal intensive care units (NICUs) (Osborn 2000; Rodriguez‐Fanjul 2020; Verder 2013). One of them included preterm infants born before 37 weeks of gestation (Osborn 2000), one below 32 weeks of gestational age (Rodriguez‐Fanjul 2020), and one below 30 weeks of gestational age (Verder 2013). The three included studies were pooled only in Comparison 2. ‐ surfactant treatment guided by rapid tests versus surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria.

Surfactant was administered in two of included studies (Rodriguez‐Fanjul 2020; Verder 2013), in the intervention group, also if infants met the same criteria as in the control group ‐ increasing need for oxygen. Criteria for the second dose of surfactant were the same in the study carried out by Osborn 2000. Different studies assessed surfactant therapy based on the results of different tests for lung maturity: click test (Osborn 2000), lamellar body counts (Verder 2013), and lung ultrasound score (LUS) (Rodriguez‐Fanjul 2020). Different types of surfactant: poractant alfa (Rodriguez‐Fanjul 2020;Verder 2013), and beractant (Osborn 2000), ‐ were administered by different methods: intubate surfactant extubate(NSURE) (Verder 2013), to the endotracheal tube during mechanical ventilation (Osborn 2000), and ess invasive surfactant administration LISA (Rodriguez‐Fanjul 2020).

One study was conducted in Denmark and Sweden (Verder 2013), one in Spain (Rodriguez‐Fanjul 2020), and one in Australia (Osborn 2000). Both Osborn 2000 and Rodriguez‐Fanjul 2020 reported no external funding. Verder 2013 reported funding from Chiesi Farmaceutici, Takeda‐Nycomed, and the Medical Research Foundation, Region Zealand, Denmark.

Excluded studies

We excluded one study (NCT04775459), as it was not a randomized. This is an observational study with 60 participants conducted in a neonatal intensive care unit (NICU) in France, comparing the outcomes of preterm infants below 33 weeks of gestation treated with surfactant before and after the introduction of a rapid test based on lung ultrasound score (LUS). There are no results published and no external funding reported.

Studies awaiting classification

There are no studies awaiting classification.

Ongoing studies

We identified two ongoing studies matching the inclusion criteria of this review (NCT05198375; REMEDIES), both of which are randomized, multicenter studies with a large sample size. (NCT05198375 is proposing to enroll 668 newborn infants, while REMEDIES will have 458 participants). Each study is using a different test for the intervention group, and the gestational age of included infants is different (lung ultrasound and 25+0 to 29+6 weeks for NCT05198375 and oscillatory mechanics and 27 to 33 weeks for REMEDIES). We are anticipating that these large studies will bring valuable new data and clarity to the subject when completed.

Please see Characteristics of ongoing studies

Risk of bias in included studies

The overall risk of bias assessment for each study, including all domain evaluations and justifications for judgment, is displayed in the risk of bias section (Characteristics of included studies), on the right side of all forest plots and Figure 3; Figure 4.

3.

Risk of bias graph

4.

Risk of bias summary

Allocation

All three included studies specified the random sequence generation and had a low risk of selection bias (Osborn 2000; Rodriguez‐Fanjul 2020; Verder 2013). One study did not specify the allocation concealment (Rodriguez‐Fanjul 2020) and was judged as having an unclear risk of bias. The remaining two studies had low risk of bias (Osborn 2000; Verder 2013).

Blinding

All three included studies were not blinded, or did not mention blinding of participants and personnel (performance bias), leading to high risk of performance bias. However, it should be considered that blinding does not affect mortality, or diagnosis of bronchopulmonary dysplasia (BPD), pneumothorax or retinopathy of prematurity (ROP), limiting the risk of dealing with biased findings for these outcomes. It can affect surfactant utilization due to the nature of the intervention.

Incomplete outcome data

All three included studies had low risk for attrition bias.

Selective reporting

One study (Osborn 2000), had unclear risk of reporting bias as no protocol was available. In the remaining two studies no discrepancies were identified between the protocol and the final manuscript (Rodriguez‐Fanjul 2020; Verder 2013).

Other potential sources of bias

All three included studies had low risk of other potential sources of bias.

Effects of interventions

See: Table 1

Comparison 1: Surfactant treatment guided by rapid tests for surfactant deficiency versus prophylactic surfactant administration to all high‐risk infants

None of the three included studies were included in this comparison.

Comparison 2: Surfactant treatment guided by rapid tests for surfactant deficiency versus surfactant therapy provided to infants with respiratory digress syndrome (RDS) diagnosed on clinical and radiologic criteria

Three studies (562 preterm infants) were included in this comparison (Osborn 2000; Rodriguez‐Fanjul 2020; Verder 2013). See Table 1.

Primary outcomes

Neonatal mortality (mortality < 28 days of age) from any cause

No studied reported this outcome.

Mortality prior to hospital discharge (from any cause)

All three studies reported this outcome (Osborn 2000; Rodriguez‐Fanjul 2020; Verder 2013). The evidence is very uncertain about the effect of surfactant treatment guided by rapid tests for surfactant deficiency on mortality prior to hospital discharge compared with surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria (risk ratio (RR) 1.25, 95% confidence interval (CI) 0.65 to 2.41, risk difference (RD) 0.01, 95% CI ‐0.03 to 0.05, 562 participants, 3 studies; I² for RR and RD = 75 and 43%, respectively; very low‐certainty evidence; Analysis 1.1).

1.1. Analysis.

Comparison 1: Surfactant treatment guided by rapid tests versus surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria., Outcome 1: Mortality prior to hospital discharge

Bronchopulmonary dysplasia (BPD)

Three studies reported this outcome (Osborn 2000; Rodriguez‐Fanjul 2020; Verder 2013). Surfactant treatment guided by rapid tests for surfactant deficiency may result in little to no difference in bronchopulmonary dysplasia (BPD) compared with surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria (RR 0.90, 95% CI 0.61 to 1.32, RD ‐0.02, 95% CI ‐0.08 to 0.04, 562 participants, 3 studies; I² for RR and RD = 0%; low‐certainty evidence; Analysis 1.2).

1.2. Analysis.

Comparison 1: Surfactant treatment guided by rapid tests versus surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria., Outcome 2: Bronchopulmonary dysplasia

Bronchopulmonary dysplasia (BPD) or mortality

No studied reported this outcome.

Secondary outcomes

Surfactant utilization (number of infants receiving surfactant)

All three studies reported this outcome (Osborn 2000; Rodriguez‐Fanjul 2020; Verder 2013). Surfactant treatment guided by rapid tests for surfactant deficiency may result in little to no difference in surfactant utilization (number of infants receiving surfactant) compared with surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria (RR 0.97, 95% CI 0.85 to 1.11, RD ‐0.02, 95% CI ‐0.10 to 0.06, 562 participants, 3 studies, I² for RR and RD = 63% and 65%, respectively, low‐certainty evidence; Analysis 1.3).

1.3. Analysis.

Comparison 1: Surfactant treatment guided by rapid tests versus surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria., Outcome 3: Surfactant utilization (number of infants receiving surfactant)

Any pneumothorax

Two studies reported this outcome (Osborn 2000; Verder 2013). Surfactant treatment guided by rapid tests for surfactant deficiency may result in little to no difference in any pneumothorax slightly compared with surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria (RR 0.53, 95% CI 0.15 to 1.92, RD ‐0.01, 95% CI ‐0.04 to 0.01, 506 participants, 2 studies, I² for RR and RD = 0%, low‐certainty evidence; Analysis 1.4).

1.4. Analysis.

Comparison 1: Surfactant treatment guided by rapid tests versus surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria., Outcome 4: Any pneumothorax

Retinopathy of prematurity (ROP) (all grades)

Two studies reported this outcome (Osborn 2000; Verder 2013). Surfactant treatment guided by rapid tests for surfactant deficiency may result in little to no difference in retinopathy of prematurity (all grade) compared with surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria (RR 0.80, 95% CI 0.45 to 1.43, RD‐0.02, 95% CI ‐0.06 to 0.03, 506 participants, 2 studies, I² for RR and RD = 0%, very low‐certainty evidence; Analysis 1.5).

1.5. Analysis.

Comparison 1: Surfactant treatment guided by rapid tests versus surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria., Outcome 5: Retinopathy of prematurity (all grades)

No studies reported: other air leak syndromes than pneumothorax; pulmonary interstitial emphysema; any pulmonary hemorrhage; use of supplemental oxygen at 28 to 30 days of age; use of supplemental oxygen or death prior to 28 to 30 days of age; patent ductus arteriosus (treated pharmacologically (cyclo‐oxygenase inhibitor, paracetamol) or surgically); any culture‐proven bacterial sepsis; any culture‐proven fungal sepsis; necrotizing enterocolitis (defined as Bell stage II or greater); intraventricular hemorrhage (any grade and severe (grade 3 to 4)); periventricular leukomalacia; severe retinopathy of prematurity (stage 3 or greater); length of hospital stay (days); cerebral palsy; moderate to severe neurodevelopmental impairment.

Discussion

Summary of main results

We evaluated the benefits and harms of surfactant therapy guided by tests for lung maturity in preterm infants at risk of respiratory distress syndrome (RDS). Three studies (Osborn 2000; Rodriguez‐Fanjul 2020; Verder 2013), compared surfactant therapy guided by rapid tests for surfactant deficiency with surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria. No studies compared surfactant treatment guided by rapid tests with prophylactic surfactant administration to all high‐risk infants.

No studies reported neonatal mortality (mortality < 28 days of age) from any cause, the composite outcome 'bronchopulmonary dysplasia or mortality', or moderate to severe neurodevelopmental impairment. The evidence is very uncertain about the effect of surfactant treatment guided by rapid tests for surfactant deficiency on mortality prior to hospital discharge compared with surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria. Surfactant treatment guided by rapid tests for surfactant deficiency may result in little to no difference in bronchopulmonary dysplasia (BPD), surfactant utilization and any pneumothorax compared with surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria.

Overall completeness and applicability of evidence

For thisreview, we included three studies which are investigating the surfactant therapy guided by rapid tests for surfactant deficiency compared to surfactant therapy provided to infants with RDS diagnosed using clinical and radiologic criteria. We found great heterogeneity between the three studies, which were conducted at significant distance in time (2000, 2013, 2020), using different tests, and different type of surfactant (poractant and beractant in two studies and one study, respectively). The number of included infants ranged from 56 (Rodriguez‐Fanjul 2020) to 380 (Verder 2013).

Neonatal mortality was not reported by any of the included studies. Regarding our pre‐specified outcomes, compared with surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria, the evidence is very uncertain about the benefit of surfactant treatment guided by rapid tests on mortality prior to hospital discharge, and it may result in little to no evidence regarding bronchopulmonary dysplasia (BPD), surfactant utilization and any pneumothorax.

We also identified two ongoing randomized, multicentric studies matching the inclusion criteria of this review, with large sample sizes (458 and 668 preterm infants (NCT05198375; REMEDIES). These studies y will use lung ultrasound and oscillatory mechanics, respectively to investigate the surfactant therapy guided by rapid tests compared to surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria. They are both proposing to report a considerable array of outcomes, so we are anticipating that, upon publication, these ongoing studies will bring more clarity and better evidence.

Certainty of the evidence

Following the GRADE approach, the overall certainty of the evidence for the reported outcomes for surfactant therapy guided by tests for lung maturity is very low to low (See Table 1).

The four reported outcomes (mortality prior to hospital discharge, bronchopulmonary dysplasia, surfactant utilization and any pneumothorax) were downgraded (one or two levels) for serious to very serious imprecision: the confidence of intervals was wide and overlapping the no‐difference line. The outcomes mortality prior to hospital discharge and surfactant utilization were also downgraded (one level) because inconsistency was substantial (I² = 75%).

We did not use funnel plots to evaluate publication bias because there were fewer than 10 studies that met the inclusion criteria of this Cochrane Review.

Potential biases in the review process

Throughout the review process, we adhered to the protocols and procedures endorsed by Cochrane and the MECIR standards to alleviate any potential procedural bias. There were deviations from the original protocol (Kearl 2018). However, this was done to update the methods section of this review to the latest template used by Cochrane Neonatal, to ensure the optimal methodology (see Differences between protocol and review). We did not apply any language restrictions. It is unlikely that the literature search missed relevant trials. In addition, the review authors carefully investigated all publications, including previous systematic reviews, to cross‐reference and add studies where appropriate. We are confident that this systematic review summarizes all the presently available evidence from randomized studies comparing surfactant therapy guided by tests for lung maturity in preterm infants at risk of respiratory distress syndrome.

Agreements and disagreements with other studies or reviews

A systematic review evaluated the accuracy of biochemical and lung function tests performed within three hours from birth for predicting surfactant need in preterm infants undergoing non‐invasive respiratory support (Lavizzari 2022). The review included click test, the stable microbubble test, the lamellar body count on gastric aspirates, and the forced oscillation technique. Eight studies were included, however the accuracy estimates were not pooled in a meta‐analysis due to the heterogeneity of the study characteristics (Lavizzari 2022).

The multicenter non‐RCT (Raimondi 2021), evaluated whether lung ultrasound score (LUS) can predict the need for surfactant replacement therapy. The authors concluded that LUS is a reliable measure of the need for surfactant therapy, regardless of gestational age. The accuracy of LUS increased when combined with oxygen saturation to FiO₂ ratio. A double‐blinded prospective study compared LUS with chest X‐ray for prediction of the severity of RDS, need for surfactant and continuous positive airway pressure (CPAP) failure (Vardar 2021). The LUS score showed a correlation with the need for total surfactant doses and predicted the need for surfactant therapy in the mild RDS group with 93% sensitivity and 100% specificity.

Authors' conclusions

Implications for practice.

No studies compared surfactant treatment guided by rapid tests for surfactant deficiency versus prophylactic surfactant administration to all high‐risk infants. Low to very low‐certainty evidence from three studies is available on surfactant therapy guided by rapid tests for surfactant deficiency versus surfactant therapy provided to infants with respiratory distress syndrome (RDS) diagnosed on clinical and radiologic criteria. No studies reported neonatal mortality, the composite outcome 'bronchopulmonary dysplasia (BPD) or mortality', or neurodevelopmental outcomes. Compared with surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria, the evidence is very uncertain about the effect of surfactant treatment guided by rapid tests for surfactant deficiency on mortality prior to hospital discharge. Surfactant treatment guided by rapid tests for surfactant deficiency may result in little to no difference in bronchopulmonary dysplasia, surfactant utilization and any pneumothorax.

The findings of the two large ongoing trials identified in this review are likely to have an important impact on establishing the effects of surfactant treatment guided by rapid tests for surfactant deficiency in preterm infants.

Implications for research.

Randomized controlled trials on surfactant treatment guided by rapid tests should report long‐term outcomes, such as respiratory function and morbidity at school age. This is of utmost importance as fraction of inspired oxygen (FiO₂₎ has been reported to be a poor predictor for surfactant administration (Branagan 2023). Considering the uncertain balance of benefits and harms, data on cost‐effectiveness of different approaches of surfactant administration are needed to assess the effectiveness of rapid tests. If surfactant treatment guided by rapid tests will be shown to be effective both in terms of clinical and cost‐effectiveness outcomes, further studies should aim to evaluate its availability and utility in middle‐ and low‐ income countries.

History

Protocol first published: Issue 11, 2018

Appendices

Appendix 1. Search strategy

Information specialists: Maria Björklund, Krister Aronsson

Affiliation: Lund University, Faculty of Medicine, Library & ICT, Sweden

Date of search: 17 October 2022
No publication date limitations or language limitations were used.

[Population block‐ Cochrane Neonatal standard search filter, as presented https://neonatal.cochrane.org/Literature‐Search‐Filters‐for‐Neonatal‐Reviews ]

#1 "Infant, Newborn"[Mesh] OR "Intensive Care, Neonatal"[Mesh] OR "Intensive Care Units, Neonatal"[Mesh] OR "Gestational Age"[Mesh]
709880 records
#2 (babe[Text Word] OR babes[Text Word] OR baby*[Text Word] OR babies[Text Word] OR gestational age*[Text Word] OR infant*[Text Word] OR infantile[Text Word] OR infancy[Text Word] OR low birth weight[Text Word] OR low birthweight[Text Word] OR neonat*[Text Word] OR neo‐nat*[Text Word] OR newborn*[Text Word] OR new born[Text Word] OR newly born[Text Word] OR premature[Text Word] OR pre‐mature[Text Word] OR pre‐matures[Text Word] OR prematures[Text Word] OR prematurity[Text Word] OR pre‐maturity[Text Word] OR preterm[Text Word] OR preterms[Text Word] OR pre term*[Text Word] OR preemie[Text Word] OR preemies[Text Word] OR premies[Text Word] OR premie[Text Word] OR VLBW[Text Word] OR VLBWI[Text Word] OR VLBW‐I[Text Word] OR VLBWs[Text Word] OR LBW[Text Word] OR LBWI[Text Word] OR LBWs[Text Word] OR ELBW[Text Word] OR ELBWI[Text Word] OR ELBWs[Text Word] OR NICU[Text Word] OR NICUs[Text Word])
1798130 records
#3 #1 OR #2[Neonatal filter]
1798130 records

#4 Pulmonary Surfactants[MeSH]
11267 records
#5 ((surfactant*[Text Word] OR phospholipids[Text Word] OR lecithin[Text Word] OR sphingomyelin[Text Word] OR lung‐surfactant*[Text Word] OR exosurf[Text Word] OR dipalmitoylphosphatidylcholine[Text Word] OR survanta[Text Word] OR beractant[Text Word] OR curosurf[Text Word] OR poractant[Text Word] OR Lucinactant[Text Word])

OR

intrapartum pharyngeal instillation[Text Word] OR INSURE[Text Word] OR MIST[Text Word] OR NIST[Text Word]
192835 records
#6 #4 OR #5 [Intervention terms Surfactant]
192835 records
[Study design block‐ Cochrane Neonatal standard RCT filter with modification including cluster‐randomized studies, otherwise as presented https://neonatal.cochrane.org/Literature‐Search‐Filters‐for‐Neonatal‐Reviews ]

#7 randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized [tiab] OR placebo [tiab] OR drug therapy [sh] OR randomly [tiab] OR trial [tiab] OR groups [tiab]
=5552641 records
#8 quasirandom*[tw] OR quasi‐random*[tw] OR cluster random*[tw] OR cluster‐random*[tw] OR randomi*[tw] OR randomly[tw]
1270477 records
#9 control group*[tw]
=540918
#10 #7 OR #8 OR #9
5765152 records
#11 (animals [mh] NOT humans [mh])
=5050697 records
#12 #10 NOT #11
5024804 records

[Combination search]
#13 #3 AND #6 AND #12
3647 records

Annotations:
The MeSH term Surface‐active agents was also searched initially but lead to irrelevant results‐ The search focuses on pulmonary surfactants.

Embase.com (Elsevier, 1947‐present)

Date of search: 17 October 2022

No publication date limitations or language limitations were used

[Population block‐ Cochrane Neonatal standard search filter, as presented https://neonatal.cochrane.org/Literature‐Search‐Filters‐for‐Neonatal‐Reviews ]

#1

('newborn'/exp OR 'prematurity'/exp OR 'newborn intensive care'/exp OR 'newborn care'/exp OR gestational) AND 'age'/exp
=94501 records
#2
babe:ti,ab,kw OR babes:ti,ab,kw OR baby*:ti,ab,kw OR babies:ti,ab,kw OR ‘gestational age*’:ti,ab,kw OR infant*:ti,ab,kw OR infantile:ti,ab,kw OR infancy:ti,ab,kw OR 'low birth weight':ti,ab,kw OR 'low birthweight':ti,ab,kw OR neonat*:ti,ab,kw OR 'neo‐nat*':ti,ab,kw OR newborn*:ti,ab,kw OR ‘new born*’:ti,ab,kw OR 'newly born':ti,ab,kw OR premature:ti,ab,kw OR 'pre mature':ti,ab,kw OR 'pre matures':ti,ab,kw OR prematures:ti,ab,kw OR prematurity:ti,ab,kw OR 'pre maturity':ti,ab,kw OR preterm:ti,ab,kw OR preterms:ti,ab,kw OR ‘pre term*’:ti,ab,kw OR preemie:ti,ab,kw OR preemies:ti,ab,kw OR premies:ti,ab,kw OR premie:ti,ab,kw OR vlbw:ti,ab,kw OR vlbwi:ti,ab,kw OR 'vlbw i':ti,ab,kw OR vlbws:ti,ab,kw OR lbw:ti,ab,kw OR lbwi:ti,ab,kw OR lbws:ti,ab,kw OR elbw:ti,ab,kw OR elbwi:ti,ab,kw OR elbws:ti,ab,kw OR nicu:ti,ab,kw OR nicus:ti,ab,kw
=1282690 records
#3
#1 OR #2[Neonatal filter]
=1314998 records

#4

'lung surfactant'/exp OR 'phospholipid'/exp OR 'sphingomyelin'/exp OR 'dipalmitoylphosphatidylcholine'/exp OR 'beractant'/exp OR 'poractant'/exp OR 'lucinactant'/exp
=237310 records

#5
surfactant*:ti,ab,kw OR phospholipids:ti,ab,kw OR lecithin:ti,ab,kw OR sphingomyelin:ti,ab,kw OR 'lung surfactant*':ti,ab,kw OR exosurf:ti,ab,kw OR dipalmitoylphosphatidylcholine:ti,ab,kw OR survanta:ti,ab,kw OR beractant:ti,ab,kw OR curosurf:ti,ab,kw OR poractant:ti,ab,kw OR lucinactant:ti,ab,kw OR 'intrapartum pharyngeal instillation':ti,ab,kw OR insure:ti,ab,kw OR mist:ti,ab,kw OR nist:ti,ab,kw
=178569 records

#6
#4 OR #5[Intervention terms surfactant]
=344218 records

#7
random*:ti,ab,kw OR placebo:ti,ab,kw OR 'drug therapy':ti,ab,kw
=2024342 records

#8
quasirandom*:ti,ab,kw OR 'quasi random*':ti,ab,kw OR randomi*:ti,ab,kw OR randomly:ti,ab,kw OR 'cluster random*':ti,ab,kw
=1510319 records

#9
((controlled NEAR/7 study):ti,ab,kw) OR ((controlled NEAR/7 design):ti,ab,kw) OR ((controlled NEAR/7 trial):ti,ab,kw)
=430688 records

#10
(control NEAR/2 group*):ti,ab,kw
=820815 records

#11
#7 OR #8 OR #9 OR #10
=2660893 records

#12
('animals'/exp OR 'invertebrate'/exp OR 'animal experiment' OR 'animal model' OR 'animal tissue' OR nonhuman) AND ('human'/exp OR human OR 'human cell'/exp OR 'human cell')
=26002839 records

#13
'animals'/exp OR 'invertebrate'/exp OR 'animal experiment' OR 'animal model' OR 'animal tissue' OR nonhuman
=32975572 records

#14
#13 NOT #12 [Animal Exclusion‐https://community‐cochrane‐org/sites/default/files/uploads/inline‐files/Embase%20animal%20filter.pdf]
=6972733 records

#15
#11 NOT #14 [Filter: RCT‐EMBASE]
=2282517 records

Combination search

#16
#3 AND #6 AND #15
=2086 records

#17
#16 AND [embase]/lim NOT ([embase]/lim AND [medline]/lim)
=610 records
CENTRAL via Cochrane Library online, Wiley, Issue 10 of 12, October 2022)

#1 MeSH descriptor: [Infant, Newborn] explode all trees 
17700 records

#2 MeSH descriptor: [Intensive Care, Neonatal] explode all trees 
352 records

#3 MeSH descriptor: [Intensive Care Units, Neonatal] explode all trees

868 records

#4 MeSH descriptor: [Gestational Age] explode all trees

2788 records

#5 (babe OR babes OR baby* OR babies OR gestational age OR infant OR infantile OR infancy OR low birth weight OR low birthweight OR neonat* OR neo‐nat* OR newborn* OR new born OR newly born OR premature OR pre‐mature OR pre‐matures OR prematures OR prematurity OR pre‐maturity OR preterm OR preterms OR pre term OR preemie OR preemies OR premies OR premie OR VLBW OR VLBWI OR VLBW‐I OR VLBWs OR LBW OR LBWI OR LBWs OR ELBW OR ELBWI OR ELBWs OR NICU OR NICUs):ti,ab,kw

111175 records

#6 1# OR #2 OR #3 OR #4 OR #5

1284579 records [Neonatal filter]

#7 MeSH descriptor: [Pulmonary Surfactants] explode all trees

573 records

#8 (surfactant* OR phospholipids OR lecithin OR sphingomyelin OR lung‐surfactant* OR exosurf OR dipalmitoylphosphatidylcholine OR survanta OR beractant OR curosurf OR poractant OR Lucinactant):ti,ab,kw

4565 records

#9 (intrapartum pharyngeal instillation OR INSURE OR MIST OR NIST):ti,ab,kw

1085 records

#10 #7 OR #8 OR #9 [Intervention terms surfactant]

5511 records

#12 #6 AND #10

4436 records

Of which 4355 are trials

EbscoHost, inception to present)

Date of search: 17 October 2022

No publication date limitations or language limitations were used.

#1 (MH "Infant, Newborn+")

157549 records

#2 (MH "Intensive Care, Neonatal+")

6468 records

#3 (MH "Intensive Care Units, Neonatal")

15582 records

#4 (MH "Gestational Age")

23210 records

#5 TI ( babe OR babes OR baby* OR babies OR gestational age OR infant OR infantile OR infancy OR low birth weight OR low birthweight OR neonat* OR neo‐nat* OR newborn* OR new born OR newly born OR premature OR pre‐mature OR pre‐matures OR prematures OR prematurity OR pre‐maturity OR preterm OR preterms OR pre term OR preemie OR preemies OR premies OR premie OR VLBW OR VLBWI OR VLBW‐I OR VLBWs OR LBW OR LBWI OR LBWs OR ELBW OR ELBWI OR ELBWs OR NICU OR NICUs babe OR babes OR baby* OR babies OR gestational age OR infant OR infantile OR infancy OR low birth weight OR low birthweight OR neonat* OR neo‐nat* OR newborn* OR new born OR newly born OR premature OR pre‐mature OR pre‐matures OR prematures OR prematurity OR pre‐maturity OR preterm OR preterms OR pre term OR preemie OR preemies OR premies OR premie OR VLBW OR VLBWI OR VLBW‐I OR VLBWs OR LBW OR LBWI OR LBWs OR ELBW OR ELBWI OR ELBWs OR NICU OR NICUs ) OR AB ( babe OR babes OR baby* OR babies OR gestational age OR infant OR infantile OR infancy OR low birth weight OR low birthweight OR neonat* OR neo‐nat* OR newborn* OR new born OR newly born OR premature OR pre‐mature OR pre‐matures OR prematures OR prematurity OR pre‐maturity OR preterm OR preterms OR pre term OR preemie OR preemies OR premies OR premie OR VLBW OR VLBWI OR VLBW‐I OR VLBWs OR LBW OR LBWI OR LBWs OR ELBW OR ELBWI OR ELBWs OR NICU OR NICUs )

282641 records

#6 #1 OR #2 OR #3 OR #4 OR #5 [Neonatal filter]

345732 records

#7 (MH "Pulmonary Surfactants") 
1726 records

#8 TI ( surfactant* OR phospholipids OR lecithin OR sphingomyelin OR lung‐surfactant* OR exosurf OR dipalmitoylphosphatidylcholine OR survanta OR beractant OR curosurf OR poractant OR Lucinactant ) OR AB ( surfactant* OR phospholipids OR lecithin OR sphingomyelin OR lung‐surfactant* OR exosurf OR dipalmitoylphosphatidylcholine OR survanta OR beractant OR curosurf OR poractant OR Lucinactant )

6806 records

#9 TI ( intrapartum pharyngeal instillation OR INSURE OR MIST OR NIST ) OR AB ( intrapartum pharyngeal instillation OR INSURE OR MIST OR NIST )

1505 records

#10 #7 OR #8 OR #9 [Intervention terms surfactant]

8614 records

#11 PT randomized controlled trial

147260 records

#12 TI controlled clinical trial OR AB controlled clinical trial

57541 records

#13 TX randomized OR placebo OR drug therapy OR randomly OR trial OR groups

2904062 records

#14 TX quasirandom OR quasi‐random OR cluster random OR cluster‐random OR random*

797544 records

#15 TX control group*

823387 records

#16 MH animals NOT MH humans

97952 records

#17 #11 OR #12 OR #13 OR #14 OR #15

2974198 records

#18 #17 NOT #16 [study design filter]

2935835 records

#19 #6 AND #10 AND #18

1470 records

Number of records from databases (before deduplication)

10082 records

Trial Registries

ClinicalTrials.gov (US National Library of Medicine)

Date of search: 18 October 2022

Other terms

(lung OR pulmonary) AND surfactant AND (infant OR preterm OR neonate OR premature OR newborn OR baby OR preterm)

248 records

International Clinical Trials Registries Platform Search Portal, ICTRP (World Health Organization)

Date of search: 18 October 2022

Search function on start page

(lung OR pulmonary) AND surfactant AND (infant OR preterm OR neonate OR premature OR newborn OR baby OR preterm)

52 records for 49 trials

ISRCTN registry (BioMed Central/SpringerNature)

Date of search: 18 October 2022

Advanced search

(lung OR pulmonary) AND surfactant AND (infant OR preterm OR neonate OR premature OR newborn OR baby OR preterm)

16 records (csv file)

Number of records from trial registries

313 records

Number of records after deduplication EndNote (if RCTs/trials, going to Screen4Me)

EndNote indicates 3005 duplicates

Appendix 2. 'Risk of bias' tool

1. Sequence generation (checking for possible selection bias). Was the allocation sequence adequately generated?

For each included study, we categorized the method used to generate the allocation sequence as:

1. low risk (any truly random process e.g. random number table; computer random number generator);

2. high risk (any non‐random process e.g. odd or even date of birth; hospital or clinic record number); or

3. unclear risk.

2. Allocation concealment (checking for possible selection bias). Was allocation adequately concealed?

For each included study, we categorized the method used to conceal the allocation sequence as:

1. low risk (e.g. telephone or central randomization; consecutively numbered sealed opaque envelopes);

2. high risk (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth); or

3. unclear risk.

3. Blinding of participants and personnel (checking for possible performance bias). Was knowledge of the allocated intervention adequately prevented during the study?

For each included study, we categorised the methods used to blind study participants and personnel from knowledge of which intervention a participant received. Blinding was assessed separately for different outcomes or class of outcomes. We categorized the methods as:

1. low risk, high risk or unclear risk for participants; and

2. low risk, high risk or unclear risk for personnel.

4. Blinding of outcome assessment (checking for possible detection bias). Was knowledge of the allocated intervention adequately prevented at the time of outcome assessment?

For each included study, we categorized the methods used to blind outcome assessment. Blinding was assessed separately for different outcomes or class of outcomes. We categorized the methods as:

1. low risk for outcome assessors;

2. high risk for outcome assessors; or

3. unclear risk for outcome assessors.

5. Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations). Were incomplete outcome data adequately addressed?

For each included study and for each outcome, we described the completeness of data including attrition and exclusions from the analysis. We noted whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomized participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported or supplied by the trial authors, we re‐included missing data in the analyses. We categorized the methods as:

1. low risk (< 20% missing data);

2. high risk (≥ 20% missing data); or

3. unclear risk.

6. Selective reporting bias. Are reports of the study free of suggestion of selective outcome reporting?

For each included study, we described how we investigated the possibility of selective outcome reporting bias and what we found. For studies in which study protocols were published in advance, we compared prespecified outcomes versus outcomes eventually reported in the published results. If the study protocol was not published in advance, we contacted study authors to gain access to the study protocol. We assessed the methods as:

1. low risk (where it is clear that all of the study's prespecified outcomes and all expected outcomes of interest to the review have been reported);

2. high risk (where not all the study's prespecified outcomes have been reported; one or more reported primary outcomes were not prespecified outcomes of interest and are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported); or

3. unclear risk.

7. Other sources of bias. Was the study apparently free of other problems that could put it at a high risk of bias?

For each included study, we described any important concerns we had about other possible sources of bias (for example, whether there was a potential source of bias related to the specific study design or whether the trial was stopped early due to some data‐dependent process). We assessed whether each study was free of other problems that could put it at risk of bias as:

1. low risk;

2. high risk; or

3. unclear risk.

If needed, we explored the impact of the level of bias through undertaking sensitivity analyses.

Data and analyses

Comparison 1. Surfactant treatment guided by rapid tests versus surfactant therapy provided to infants with RDS diagnosed on clinical and radiologic criteria.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Mortality prior to hospital discharge	3	562	Risk Ratio (M‐H, Fixed, 95% CI)	1.25 [0.65, 2.41]
1.2 Bronchopulmonary dysplasia	3	562	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.61, 1.32]
1.3 Surfactant utilization (number of infants receiving surfactant)	3	562	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.85, 1.11]
1.4 Any pneumothorax	2	506	Risk Ratio (M‐H, Fixed, 95% CI)	0.53 [0.15, 1.92]
1.5 Retinopathy of prematurity (all grades)	2	506	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.45, 1.43]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Osborn 2000.

Study characteristics
Methods	Randomized controlled trial
Participants	126 infants (70 males, 56 females) of born < 37 weeks’ gestation, enrolled in Australia, between July 1997 and November 1998. Inclusion criteria Infants born < 37 weeks of gestation Intubated and ventilated Required fraction oxygen saturation ≥ 25% and mean airway pressure ≥ 7 cm H2O to obtain an oxygen saturation between 90% and 95% Exclusion criteria Major congenital abnormality Infants considered to be unlikely to survive Had previous surfactant therapy Parents refused consent Click test group (n = 63; mean GA 28.6 SD 3.4 weeks; mean BW 1332 SD 613 g) Control group (n = 63; mean GA 28.8 SD 3.5 weeks; mean BW 1308 SD 559 g)
Interventions	Intervention ‐ surfactant administration guided by negative result of click test performed on a specimen of tracheal aspirate. Control ‐ surfactant administration guided by clinical and early chest radiograph diagnoses of RDS. Infants with severe respiratory distress in the control group (FiO2 ≥ 0.6 or peak inspiratory pressure ≥ 25 cm H2O; or both) were eligible to receive surfactant before a chest radiograph. Further doses of surfactant for both groups were given if clinically indicated (FiO2 ≥ 0.25 and MAP ≥ 7 cm H2O)
Outcomes	Primary outcomes Time from birth to first surfactant therapy Use of exogenous surfactant Use of nitric oxide Use of oscillatory ventilation Days intubated Days in oxygen Discharge home on oxygen Days in hospital Secondary outcomes Mortality Air leak Chronic lung disease ‐ oxygen at 36 weeks’ postmenstrual age Intraventricular hemorrhage (all grades) Retinopathy (all) Necrotizing enterocolitis
Funding	Not reported
Notes	Declarations of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "computer‐generated sequence"
Allocation concealment (selection bias)	Low risk	Quote: "numbered, opaque, sealed envelopes"
Blinding of participants and personnel (performance bias) All outcomes	High risk	Due to the nature of the study
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Blinding of assessors not reported
Incomplete outcome data (attrition bias) All outcomes	Low risk	Reasons for exclusion are provided, outcomes are listed in the methods section
Selective reporting (reporting bias)	Unclear risk	No protocol found
Other bias	Low risk	No other sources of bias found

Rodriguez‐Fanjul 2020.

Study characteristics
Methods	Randomized controlled trial
Participants	56 newborns (31 males, 25 females), enrolled in Spain, between January 2019 and March 2020. Inclusion criteria Infants born < 32 weeks of gestation Respiratory distress syndrome Lung images that support the diagnosis (non‐mandatory) Exclusion criteria Lack of informed consent Chromosomal abnormalities Complex congenital malformations Signs of early‐onset septic shock Mechanical ventilation Patients who received surfactant in the delivery room Ultrasound group (n = 29; median GA 30+1 weeks IQR 28+4 –31+3 weeks; median BW 1500 g IQR 1058 – 1808 g) Control group (n = 27; median GA 30+2 weeks IQR 28+2 –31+4 weeks; median BW 1520 g IQR 1245 – 1795 g)
Interventions	Intervention ‐ surfactant administration guided by a LUS score (> 8) or FiO2 threshold (> 30% in patients with a GA of < 28+6 weeks 40% in patients whose GA was > 29+0), or both Control ‐ surfactant administration guided by a FiO2 threshold (> 30% in patients with a GA of < 28+6 weeks 40% in patients whose GA was > 29+0) alone
Outcomes	Primary outcomes Earlier surfactant therapy (within the first 3 hours of life) Secondary outcomes Oxygen exposure in early life SpO2/FiO2 ratio after surfactant therapy Need for mechanical ventilation (defined as mechanical ventilation during the first 3 days of life) Duration of invasive and non‐invasive ventilation Ventilator‐free days Duration of supplemental oxygen requirements Length of stay in the NICU Bronchopulmonary dysplasia
Funding	Quote: "There is no external funding source"
Notes	LUS score was performed for patients in both group, and was not blinded for neonatologist assistant. Declarations of interest: (quote:) "The authors declare that they have no conflicts of interest or financial relationship with any organization"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "random” function in the MS‐Excel® programme. A binary sequence of random numbers was generated following a balanced block sampling (Friedman procedure)"
Allocation concealment (selection bias)	Unclear risk	Quote: "The principal investigator assigned participants to interventions based on the randomised list." Allocation concealment not described
Blinding of participants and personnel (performance bias) All outcomes	High risk	Due to the nature of the study
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Blinding of outcome assessors not described
Incomplete outcome data (attrition bias) All outcomes	Low risk	Outcomes reported as in the methods section, reasons for exclusion are provided
Selective reporting (reporting bias)	Low risk	Protocol found and published, all outcomes mentioned in the protocol were reported
Other bias	Low risk	No other sources of bias

Verder 2013.

Study characteristics
Methods	Randomized controlled trial
Participants	380 infants (235 males, 145 females) born at 24 – 29 weeks’ gestation, enrolled in Denmark and Sweden, between March 2007 and April 2011. Inclusion criteria Less than 1.5 hours of age Gestational age of 24 weeks 0 days to 29 weeks 6 days Gastric aspirate was obtained ≤ 45 minutes after birth Exclusion criteria Intubated infants Presence of lethal malformations Ruptured membranes > 3 weeks with risk of lung hypoplasia If prenatally therapeutic infusion was given in the amniotic cavity Gastric aspirate unavailable or contaminated by meconium or pus Lamellar body counts group (n = 192; median GA 28.1 weeks IQR 27.0 – 29.1 weeks; median BW 1073 g IQR 876 – 1254 g) Control group (n = 188; median GA 28.3 weeks IQR 27.3 – 29.1 weeks; median BW 1070 g IQR 921 – 1249 g)
Interventions	Intervention ‐ surfactant administration guided by Lamellar body counts (LBC) on gastric aspirate or increasing need for oxygen (LBC was < 8000/μl or a/APO2 was < 0.36 and decreasing more than 30 minutes), or both Control ‐ surfactant administration guided by an increasing need for oxygen (a/APO2 was < 0.36 and decreasing more than 30 minutes) alone
Outcomes	Primary outcomes Mechanical ventilation or death within the first 5 days of life Secondary outcomes: a/APO2 at 6 hours of age Mechanical ventilation before discharge Death before discharge Days on supplemental oxygen Days on mechanical ventilation or nCPAP Pneumothorax Pulmonary hemorrhage Patent ductus arteriosus Necrotizing enterocolitis Requirement for surfactant treatment Need for oxygen at 28 days of life Incidence of BPD (defined as need for oxygen treatment at 36 weeks’ gestation) Intraventricular hemorrhage Cystic periventricular leucomalacia Retinopathy of prematurity
Funding	Quote: "The study was supported by Chiesi Farmaceutici, Takeda‐Nycomed, and the Medical Research Foundation, Region Zealand, Denmark"
Notes	In 44 cases among 192 randomized to intervention group Lamellar body counts could not be measured due to various reasons. Declarations of interest: (quote:) "The authors have no conflicts of interest to disclose"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomisation was stratified according to GA (24 – 25 and 26 – 29 weeks) and center, and performed by telephone balanced in random blocks of 2, 4 or 6 infants."
Allocation concealment (selection bias)	Low risk	Quote: "telephone based"
Blinding of participants and personnel (performance bias) All outcomes	High risk	Due to the nature of the study
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "Clinical outocmes were assessed by personel which were aware of allocation, however study quite strictly define outcomes what made them less biased by subjective judgement and unblidned design of the study."
Incomplete outcome data (attrition bias) All outcomes	Low risk	Outcomes reported as in the methods section, reasons for exclusion are provided
Selective reporting (reporting bias)	Low risk	Protocol found and published, all outcomes mentioned in the protocol were reported
Other bias	Low risk	No other sources of bias

a/APO₂: arterial alveolar oxygen tension ratio; BPD: bronchopulmonary dysplasia; BW: birth weight; cm: centimeters; FiO₂: fraction of inspired oxygen g: gram GA: gestational age; H₂O: water; IQR: interquartile range; LBC: lamellar body counts; LUS: lung ultrasound score; MAP: mean airway pressure; n: number; nCPAP: Nasal continuous positive airway pressure; NICU: neonatal intensive care unit; RDS: Respiratory distress syndrome; SD: standard deviation; SpO₂: oxygen saturation; μl: microliter

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
NCT04775459	Not a randomized trial

Characteristics of ongoing studies [ordered by study ID]

NCT05198375.

Study name	Lung ultrasound guided surfactant therapy in preterm infants (LUNG Study)
Methods	Multicenter, randomized controlled trial
Participants	The total number of enrolled infants will be 668 (334 per arm) Inclusion criteria In‐born infants at 25+0‐29+6 weeks of gestational age Spontaneously breathing at birth but requiring noninvasive respiratory support with nCPAP at a pressure of 6 ‐ 8 cmH2O to maintain an SpO2 between 90% and 95% Parental consent has been obtained Exclusion of causes of respiratory failure other than RDS Exclusion criteria Endotracheal intubation in the delivery room for resuscitation or insufficient respiratory drive according to European guidelines Prolonged premature rupture of membranes for more than 3 days Presence of major congenital malformations or chromosomal anomalies Hydrops fetalis Inherited disorders of metabolism Administration of surfactant before performing the LUS Other respiratory diseases than RDS
Interventions	Decision to administer surfactant when LUS > 8 on nCPAP (pressure 6 ‐ 8 cmH20) to maintain preductal SpO2 between 90% and 95%. The LUS group will receive surfactant administration as rescue therapy in case of LUS < or = 8 but FiO2 > 0.30 on nCPAP (pressure 6 ‐ 8 cmH20) to maintain preductal SpO2 between 90% and 95%
Outcomes	Primary outcome BPD or death reduction Primary endpoint will be the difference in proportion of infants with BPD (defined as Bancalari, Jobe 2001), or death in the group managed with LUS compared to the control group. Secondary outcomes Proportion of infants treated "early" (before 3 hours of life) versus late Age in minutes at the first surfactant administration Need of mechanical ventilation in the first 3 days of life Maximal FiO2 value before surfactant treatment FiO2/SpO2 ratio before surfactant treatment Duration of non‐invasive and invasive respiratory support (O2 therapy included) Proportion of infants needed to receive multiple doses of surfactant Duration of hospitalization Occurrence of BPD using multiple definitions Proportion of infants with patent ductus arteriosus treated pharmacologically, surgically or both Proportion of infants with pneumothorax Proportion of infants with retinopathy of prematurity Proportion of infants with intraventricular hemorrhage > or = grade 3 Proportion of infants with periventricular leukomalacia Proportion of infants with necrotizing enterocolitis > stage 2 Use of systemic postnatal steroids Mortality Pulmonary hemorrhage
Starting date	5 April 2022 Estimated Study Completion Date: 31 July 2024
Contact information	Iuri Corsini, MD, 003903557946468, corsiniiuri@gmail.com Carlo Dani, Prof, 003903557946468, cdani@unifi.it
Notes

REMEDIES.

Study name	REMEDIES (respiratory mechanics for delivering individualized exogenous surfactant): "A randomized controlled trial of oscillatory mechanics versus oxygenation‐based criteria for surfactant therapy"
Methods	Multicenter, randomized controlled trial
Participants	Planned sample size: 458 newborn infants. Inclusion criteria: Gestational age ≥ 27+0 and < 33+0 weeks Spontaneously breathing infants, requiring non‐invasive respiratory support Inborn Written parental consent obtained Administration of Caffeine bolus 20 mg/kg IV or by mouth as per standard care. Exclusion criteria: infants will be ineligible for the study if presenting: major congenital anomalies; need of intubation in delivery suite or early at the admission in neonatal intensive care unit; surfactant therapy prior to the study entry; severe birth asphyxia; respiratory failure secondary to conditions other that RDS as identified by lung imaging (air leaks, lung malformations…); any clinical condition which may place the infants at undue risk as deemed by clinicians; participation to trials with competitive outcomes or likely to have an impact on the primary outcome of the study outborn patients
Interventions	Surfactant administration following lung mechanics assessment by the Forced oscillation and clinical assessment. Evaluation at 4 hours and 24 hours after birth. Surfactant administration following clinical assessment only. Clinical evaluation (4 hours and 24 hours after birth): If clinical criteria for surfactant are matched (FiO2 ≥ 0.30 and CPAP of at least 6 cmH2O to target SpO2 91% ‐ 95%) the infants receive surfactant. Surfactant (Poractant alfa, 200 mg/kg ET) administered via the LISA technique or INSURE
Outcomes	Primary outcome: overall number of days of respiratory support. Secondary outcomes Time at first surfactant administration (in hours) Days of non‐invasive respiratory support Days of invasive respiratory support Number of patients intubated and mechanically ventilated Number of patients receiving multiple surfactant doses Days on supplemental oxygen Total cumulative oxygen exposure computed as the time integral of the FiO2 values Number of infants receiving more than 28 days of respiratory support Number of infants developing BPD according to the definition by NICHD 2016 (Higgins 2018) Number of infants developing air leaks Number of infants developing prematurity associated complications (severe intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, sepsis, retinopathy of prematurity, patent ductus arteriosus requiring pharmacological or surgical treatment) Number of infants discharged home with oxygen or respiratory support Days to achieve full enteral feeding (160 mL/kg/day of milk intake) Days of hospitalization Number of infants receiving postnatal steroids
Starting date	2023; Closing of Enrollment: May 2025
Contact information	Dr. Anna Lavizzari, anna.lavizzari@gmail.com
Notes	Submitted for registration in clinicaltrials.gov (personal communication with Dr. Anna Lavizzari)

BPD: Bronchopulmonary dysplasia; cm: centimeter; CPAP: Continuous Positive Airway Pressure; ET: endotracheal;FiO₂ : fraction of inspired oxygen; H₂O: water; INSURE: intubate surfactant extubate; IV: intravenously; kg: kilogram; LISA: Less invasive surfactant administration; mg: milligrams; mL: milliliters; NICHD: Eunice Kennedy Shriver National Institute of Child Health and Human Development; : Respiratory distress syndrome; SpO₂: Saturation of Peripheral Oxygen

Differences between protocol and review

We made the following changes to the published protocol (Kearl 2018)

1. We updated the methods section of this review to the latest template used by Cochrane Neonatal, to ensure the optimal methodology.

2. Leslie Young co‐authored the protocol (Kearl 2018) but not the review

3. Greta Sibrecht, Franciszek Borys, Mihai Morariu and Matteo Bruschettini co‐authored the review but not the protocol (Kearl 2018)

Contributions of authors

GS: contributed to writing and editing, made an intellectual contribution to, advised on, approved the final version prior to submission.

CRK, FB and MM: developed, contributed to writing and editing, made an intellectual contribution to, advised on, approved the final version prior to submission.

MB: made an intellectual contribution to; advised on; approved the final version of the review prior to submission.

RS: made an intellectual contribution to; advised on; approved the final version of the review prior to submission; is a guarantor of the review.

Sources of support

Internal sources

• Institute for Clinical Sciences, Lund University, Lund, Sweden

  MB is employed by this organization

External sources

• Vermont Oxford Network, USA

  Vermont Oxford Network is a not‐for‐profit voluntary collaboration of Neonatal Intensive Care Units dedicated to improving newborn care throughout the world. Vermont Oxford Network supports administrative needs of Cochrane Neonatal.

• National Institute for Health Research, UK

  Editorial support for Cochrane Neonatal has been funded by a UK National Institute of Health Research Grant (NIHR) Cochrane Programme Grant (13/89/12). The views expressed in this publication are those of the authors and not necessarily those of the National Health Service (NHS), the NIHR, or the UK Department of Health.

• Region Skåne, Skåne University Hospital, Lund University and Region Västra Götaland, Sweden

  Cochrane Sweden is supported from Region Skåne, Skåne University Hospital Lund University and Region Västra Götaland

Declarations of interest

GS has no relevant interests to declare.

CRK has no relevant interests to declare.

FB has no relevant interests to declare.

MM has no relevant interests to declare.

MB is an Associate Editor for Cochrane Neonatal. However, he had no involvement in the editorial processing of this review.

Roger Soll is the Co‐ordinating Editor of Cochrane Neonatal (therefore the review was seen and edited by other members of the editorial team). He received a grant from the Gerber Foundation to update reviews on interventions for pain and discomfort.

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