RDS-NExT workshop: consensus statements for the use of surfactant in preterm neonates with RDS

Of the 15 HCPs contacted, 10 agreed to serve on the expert panel. Of these, 9 panelists completed the survey. All 11 panelists (10 plus the committee chair) participated in workshops 1 and 2. Two panelists were unable to attend workshop 3 due to scheduling conflicts, so absentee votes for these panelists were obtained via email. Names of participating panelists can be found in Supplementary Table B.

A total of 24 statements was discussed, refined, and voted on over the 3 workshops. Consensus was achieved on 20 statements. The original statements presented to the group, as well as the final statement and voting results, can be found in Supplementary Table C. The final consensus statements are listed below. They are followed by the panelists’ reasons for agreeing or disagreeing with the statements, as well as their limitations and applicability to clinical practice.

Section 1: Establishing RDS diagnosis and indicators for surfactant administration

Statement 1 (consolidated from original statements 1, 7, and 8; see Supplementary Table C): When the clinical decision has been made to administer surfactant, preterm infants with RDS should receive surfactant early (≤2 h of life), preferably within 1 h of life.

A review by Bahadue et al. concluded that early selective surfactant administration within the first 2 h of life (throughout this manuscript, life is used to denote extrauterine life) in neonates with RDS requiring assisted ventilation decreased the risk of mortality, acute pulmonary injury, and chronic lung disease compared to delayed treatment [16]. Some panelists expressed uncertainty about the 2 h limit. Variability in timing of treatment with surfactant replacement therapy and disease severity of patients included in clinical trials have left clinicians with uncertainty regarding the optimal timing of surfactant treatment [16]. Furthermore, a review that included more-recent trials demonstrating current clinical practice concluded that prophylactic use of surfactant, when compared to routine stabilization using continuous positive airway pressure (CPAP), does not improve clinical outcomes and may increase the risk of chronic lung disease or death [17].

Panelists also discussed the applicability of this statement to various patient populations, including neonates of ≥30 weeks’ gestational age (GA), extremely preterm infants (<28 weeks’ GA) and low birth weight neonates requiring CPAP.

Statement 2 (consolidated from original statements 2, 9, and 10; see Supplementary Table C): For preterm infants with RDS receiving positive pressure support, an elevated and increasing fraction of inspired oxygen (FiO2) is an important indicator of the need for surfactant treatment based on administration criteria; other clinical measures of respiratory distress and/or support, alone or in combination, may precede and preempt FiO2 as an indication of need for surfactant treatment.

There was a significant amount of discussion regarding identifying a specific FiO2 threshold for surfactant administration, as the evidence is inconsistent. The 2022 European Consensus Guidelines recommendations state that a FiO2 of >0.3 be used as a cutoff for surfactant administration for all babies with a clinical diagnosis of RDS, especially in the early phase of worsening disease [6]. Other studies have also utilized a FiO2 threshold of 0.3 [18, 19]; however, the populations included in studies supporting this cutoff are not generalizable to the entire population of neonates with RDS. The 0.3 FiO2 criterion was derived from observational studies (of CPAP failure, etc.) [18,19,20,21]. The need for a specific FiO2 threshold spurred much discussion among the group and resulted in the development of the surfactant indicator table (Table 1). Additional considerations included the type of support the infant is on, the surfactant delivery technique (invasive vs less invasive), clinical parameters, and differences in resources available, as per NICU level of care.

Table 1 Surfactant indicator table. Considerations for Surfactant Administration for RDSa (Need to fulfill at least 3 of 4 criteria).

The type of support the infant is on (e.g., CPAP vs mechanical ventilation) should be considered. The use of a lower threshold negates the work from the COIN and SUPPORT trials for noninvasive ventilation (NIV) alone, as these studies suggest that a substantial number of babies can be supported on CPAP and a higher level of oxygen [22, 23]. It must be recognized that a lower FiO2 criterion results in earlier treatment in babies with true surfactant deficiency; however, it also increases exposure to risks associated with surfactant administration in the subset of babies who would have never met treatment threshold if the FiO2 criteria were set higher.

This balance of risk vs benefit is also necessarily dependent on the risk profile associated with the different modes of surfactant administration. When administered via an endotracheal tube (ETT) followed by invasive mechanical ventilation (IMV), a higher FiO2 threshold may be more appropriate. A lower threshold may be more appropriate when an infant is on NIV and surfactant is administered and not followed by IMV, such as with less-invasive surfactant administration (LISA), INtubation-SURfactant-Extubation (INSURE), minimally invasive surfactant administration (MIST), or laryngeal mask airway (LMA) surfactant delivery. When the need for surfactant administration comes with a high likelihood of prolonged mechanical ventilation if an ETT is placed or a practitioner is not comfortable with the use of LISA and/or LMA to deliver surfactant, then a higher threshold of FiO2 may be preferred [14, 24].

Clinical parameters should also be considered. However, work of breathing (WOB) is very subjective and has not been studied alone.

Differences in access to resources as per NICU level of care and how elevation (altitude) of the NICU site impacts FiO2 requirement need to be considered as well.

Statement 3. Chest x-ray (CXR) confirmation for RDS diagnosis is suggested but not required prior to surfactant administration.

CXRs can be useful to rule out pneumothorax; however, a CXR may not be available during transport or when resources are limited (e.g., night shift) and could cause delays in surfactant administration. Recent approaches with no radiation exposure, such as lung ultrasound, do not require CXR for confirmation of the diagnosis of RDS [25,26,27,28,29,30,31].

Statement 4. The most important predictors for determining the need for surfactant in preterm infants with RDS are GA, FiO2 requirement and clinical signs and symptoms with supporting investigations (e.g., CXR, blood gases).

The biggest predictor for RDS is GA [32,33,34]; however, the biggest predictor for noninvasive ventilation failure is FiO2 [18,19,20].

Statement 5. A second or third dose of surfactant may be necessary for ongoing RDS depending on clinical factors (e.g., lack of improvement, FiO2 requirement, increased WOB, or continued need for mechanical ventilation).

Limited data exist around indications or outcomes for repeat doses [35,36,37]. Findings from a review by Soll et al. suggest that infants with ongoing respiratory insufficiency who received multiple doses of surfactant had better clinical outcomes than those who received single dosing [38]. Repeat doses, in accordance with manufacturer’s guidelines, may be necessary in some situations and should not be discouraged or delayed, if clinically indicated.

Statement 6. Based on current data, GA alone should not be the sole criterion for surfactant administration.

The decision to administer surfactant should not be based on GA alone. No data exist for dosing solely based on GA; however, the younger the GA of the infant, the higher the risk for RDS and noninvasive respiratory support failure [39]. RCTs comparing initial stabilization on CPAP vs intubation in babies born at <28 weeks’ GA demonstrate that a significant majority (~50–70%) of those managed on CPAP will receive surfactant [22, 40]. Results from a German study are comparable [41].

As discussed in Statement 2, the risk-benefit profile of the mode of administration should be considered. Specifically, surfactant administered via ETT, followed by exposure to IMV potentially carries a higher risk profile than administration via LISA, MIST, INSURE, or LMA [42]. Meta-analyses suggest that LISA is superior to the INSURE technique in terms of avoidance of BPD and IVH [41]. Furthermore, the GA of the baby independently modifies the risk profile associated with mode of administration. For example, chronic lung disease affects lower GA infants at higher rates [43]. Given the relationship between IMV and chronic lung disease [44], the risk of adverse outcomes increases among lower GA infants administered surfactant via ETT followed by IMV. A recently published article showed that LISA in the delivery room is routine practice in Germany for infants <27 weeks’ GA [45]. There is an ongoing single-center study to evaluate delivery room LISA vs NICU LISA [46].

Additionally, extremely early GA should be considered, as infants at 22–23 weeks’ gestation have almost universally been shown to fail CPAP [47].

Statement 7 (originally 11; see Supplementary Table C): Additional studies are needed to assess the role of lung ultrasound and clinical respiratory scoring as adjunct tools in determining the need for surfactant administration for non-intubated infants with RDS.

Although more popular in Europe, use of lung ultrasound is becoming more commonplace in the US [48,49,50]. An early high lung ultrasound score correlates with the need for surfactant administration in preterm neonates with RDS [51]. Lung ultrasound score has also been correlated with oxygenation status and may help predict bronchopulmonary dysplasia (BPD) [52].

Many methods to assess the severity of respiratory distress exist, including Downes’ score [53], Silverman Anderson [54], and the Respiratory Severity Score; there is no consensus on which is the ideal scoring system [55,56,57]. Use of these tools should not delay therapy.

Statement 8 (originally 12; see Supplementary Table C): Barriers to the timely administration of surfactant may be due to limited availability of appropriately skilled staff and/or resources (e.g., delay in diagnosing RDS and timely transport to a regional center).

Barriers to timely surfactant administration include limited availability of appropriately skilled staff (ability to intubate, familiarity with less-invasive methods of surfactant administration) and/or resources (equipment and surfactant medication), as well as delays in diagnosing RDS (need for confirmatory radiological exams, transport to a regional center) [58].

These barriers may not be an issue for NICUs providing level III or higher care; however, it is unknown how often surfactant is delayed in other settings, as data do not exist.

Section 2: Surfactant administration methods and techniques

Statement 9 (originally 13; see Supplementary Table C): Surfactant can be administered using equipment based on the provider’s experience/skill level, preference, and institutional practice.

The type of equipment used for surfactant administration may influence procedure duration, number of attempts, accuracy of dose delivery, and need to interrupt the delivery of positive pressure during the procedure; however, no RCTs have been performed to determine the optimal delivery method. Designing such a trial would be difficult and would require consideration of the environment, the skill level of the operator, and the target patient population. Kribs et al. report findings from a non-blinded study that compared outcomes among infants who received surfactant via a thin endotracheal catheter during CPAP-assisted spontaneous breathing (LISA; intervention group) vs those who received surfactant after conventional endotracheal intubation during mechanical ventilation (control group) [59]. The primary outcome, survival without BPD, was not demonstrated; however, some of the secondary endpoints (rates of successful application and number of attempts, duration of mechanical ventilation, etc.) demonstrated important safety benefits associated with LISA administration. Infants who received surfactant via the LISA method were less frequently intubated (80 infants [74.8%] vs 103 [99.0%]; P < 0.001) and required fewer days of mechanical ventilation compared to those in the control group. The groups had a similar number of surfactant doses per infant and more than 1 attempt for successful surfactant administration was needed in 27% of the infants in both groups [59]. In a consensus guideline for LISA, Reynolds et al. concluded that LISA can be a safe method, with the potential to improve outcomes for premature neonates [60]. In a recent RCT, MIST therapy compared with sham (control) treatment did not significantly reduce the incidence of the primary composite outcome of death or BPD, though the incidence of BPD was significantly lower in the MIST group (P = 0.03) [61]. Further, a meta-analysis comparing different surfactant strategies concluded that administration of surfactant via thin catheter, compared with ETT administration, was associated with a reduced risk of BPD/death, fewer patients intubated in the first 72 h, and reduced incidence of morbidities and in-hospital mortality [62]. The above data suggest that treatment with surfactant via thin catheter may be preferable to ETT administration; however, additional studies of adequate size and power are needed to confirm these findings [62]. Furthermore, given subgroup differences observed in some of the RCTs referenced above, whether the protective effect of LISA/MIST varies across GA strata remains to be determined.

Statement 10 (originally 14; see Supplementary Table C): Routine repositioning during surfactant administration may not improve the distribution of surfactant relative to maintaining the infant supine; repositioning may increase the risk of device malposition.

There are no RCTs comparing response with repositioning of the infant during surfactant administration. Uncertainty exists around distribution of surfactant within the lungs and safety concerns arise with the repositioning of a critically ill infant. In a recent survey of US HCPs, 44% turn or reposition the infant during surfactant administration [63]. Manufacturer guidelines are available as they relate to infant positioning [64,65,66].

Preclinical data in a lamb model demonstrate that 1 aliquot of exogenous surfactant administered via the ETT distributes evenly without repositioning. There are data for 4 vs 2 doses, with no differences seen [67]; however, similar data in humans do not exist.

Statement 11 (originally 15; see Supplementary Table C): Surfactant can be administered as a single bolus or divided aliquots, based on provider preference, mode of administration, manufacturer recommendation, and clinical considerations.

Some centers may defer to manufacturer recommendations, which recommend using multiple aliquots [64,65,66]. There was an RCT comparing 2 aliquots vs 4 aliquots of Survanta®. It showed no major differences [68]; however, the studies were conducted more than 20 years ago and may not be applicable to current NICU populations. In a recent survey of US HCPs, 50% said they use 2 aliquots; 32%, a single bolus dose; 7%, >2 aliquots; and 11% reported “other” [63]. The rationale most often provided for using the single bolus dose was tolerability and maintaining the infant in a neutral position. For providers who use 2 aliquots, historical practice was most frequently noted, with tolerability being second most common rationale. HCPs who reported “other” mentioned type of surfactant used, location, GA/weight, and clinical presentation in determining how to administer surfactant. Bolus administration of surfactant is preferred when given via the ETT; using the LISA approach, surfactant administration can usually to be completed in <1 min, though it might require more time if apnea/bradycardia/surfactant reflux occur [8, 69, 70].

Statement 12 (originally 16; see Supplementary Table C): When using the INSURE technique to administer surfactant, infants should be extubated as soon as possible.

The AAP guidelines do not give a time recommendation for extubation after surfactant administration via INSURE – just that it should be rapid [5]. The experts agreed that the most likely protective effect gained through administration via INSURE is limited IMV exposure. Some centers do not specify when to extubate after surfactant administration after the INSURE procedure has been completed. If premedications were used with the INSURE technique, such as sedative and/or paralyzing agents, this may influence timing of extubation after surfactant has been administered.

Statement 13 (originally 17; see Supplementary Table C): For spontaneously breathing infants with RDS on CPAP for whom the decision to give surfactant has been made, less-invasive methods of surfactant administration may be appropriate alternatives to the INSURE technique.

In a network meta-analysis, Isayama et al. reported that the use of LISA was associated with a lower likelihood of the primary outcome of death or BPD than was mechanical ventilation or nasal CPAP alone. INSURE was associated with a lower likelihood of death or BPD than was mechanical ventilation or nasal CPAP alone. Ranking probabilities supported LISA as the best among all strategies for all outcomes assessed. INSURE tied with nasal intermittent positive pressure ventilation as the second-best strategy to prevent death or BPD [71]. However, the authors judged the quality of evidence of the meta-analysis to be low because the sample size of all included studies did not reach the optimal information size [71]. The limitations of the OPTIMIST-A trial comparing MIST vs CPAP and the LMA vs INSURE trials must be acknowledged [61, 72]. A consensus guideline from the UK has suggested that LISA has the potential to “improve outcomes” for preterm infants with RDS [60]. Although promising, these reports are not definitive and may not be applicable in certain GA categories. The consensus of this expert panel was that a single approach does not fit all NICU sites/scenarios. At the current time, the choice of delivery method should be made with careful consideration of the environment, resources available, operator experience, and patient characteristics, including GA and degree of illness. The clinician caring for the infant should choose which method of surfactant administration is most appropriate. It is likely that additional studies will further inform this practice.

Statement 14 (originally 18; see Supplementary Table C): For preterm infants with RDS with adequate respiratory effort on CPAP (not requiring IMV), LISA/MIST are appropriate less-invasive options for surfactant administration based on provider experience and institutional practice.

There is emerging evidence for LISA/MIST modes of administration of surfactant to be considered preferential [14, 45, 71, 73, 74]. It is important to note that most studies of these modes of surfactant delivery included early treatment at relatively low thresholds for administration (e.g., FiO2 of 0.3) and they have not been studied for rescue delivery in unstable neonates.

A meta-analysis of 6 RCTs comparing surfactant administration utilizing LISA vs standard endotracheal administration showed a reduction in the composite outcome of death or BPD, BPD among survivors, and need for mechanical ventilation at 72 h and at any time during the NICU course. There were no differences found in death or other neonatal morbidities. Three of the six studies included patients <28 weeks, with one including 23-week preterm infants [75].

Statement 15 (originally 19; see Supplementary Table C): Surfactant administration via supraglottic airway devices (e.g., LMA) may benefit certain populations of preterm infants and is a promising method of surfactant administration.

A study by Roberts et al. found that infants of 28 0/7–35 6/7 weeks gestational age and with birth weights ≥1250 g who received surfactant via LMA had a decreased rate of intubation and mechanical ventilation compared with controls (38% vs 64%; OR: 0.30 [95% CI, 0.13–0.70]; P = 0.006) [72]. A recent meta-analysis of 6 RCTs found that administering surfactant via LMA was associated with decreased FiO2 requirement, decreased intubation, and decreased mechanical ventilation [76]. A recent study comparing LMA to INSURE in infants of 27–36 weeks’ gestation and weighing >800 g found surfactant therapy via LMA was non-inferior to INSURE for efficacy and that LMA administration decreased early failures, possibly by avoiding adverse effects of premedication, laryngoscopy, and intubation [77]. Notably, both groups received atropine premedication while only the INSURE group received remifentanil premedication.

Statement 16 (originally 20; see Supplementary Table C): More data are required to evaluate the use of the promising technique of aerosol administration of surfactant.

Although aerosolization is the most noninvasive of all methods of surfactant administration, studies have historically been unable to show improvement in respiratory status [78,79,80,81,82,83]. A recent study was the first to show benefit, with a reduction in intubation and surfactant via endotracheal instillation of nearly one-half (26% in the aerosol group and 50% in the usual care group; P < 0.0001) [84]. There is currently no US Food and Drug Administration–approved device available.

Statement 17 (originally 21; see Supplementary Table 

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