Guidelines for surfactant replacement therapy in neonates

Abstract

Surfactant replacement therapy (SRT) plays a pivotal role in the management of neonates with respiratory distress syndrome (RDS) because it improves survival and reduces respiratory morbidities. With the increasing use of noninvasive ventilation as the primary mode of respiratory support for preterm infants at delivery, prophylactic surfactant is no longer beneficial. For infants with worsening RDS, early rescue surfactant should be provided. While the strategy to intubate, give surfactant, and extubate (INSURE) has been widely accepted in clinical practice, newer methods of noninvasive surfactant administration, using thin catheter, laryngeal mask airway, or nebulization, are being adopted or investigated. Use of SRT as an adjunct for conditions other than RDS, such as meconium aspiration syndrome, may be effective based on limited evidence.

Decades of clinical trials and systematic reviews have established the unequivocal benefits of surfactant replacement therapy (SRT) for neonates with respiratory distress syndrome (RDS) (1–9). Irrespective of the strategy or product used, surfactant has been shown to decrease the need for ventilation support, risk of pulmonary air leak, mortality, and the combined outcome of death or bronchopulmonary dysplasia (BPD) at 28 days (10), without increasing adverse neurodevelopmental outcomes (11,12). However, there remain a number of questions related to how surfactant should be used in light of advances in other aspects of neonatal care, such as the use of noninvasive respiratory support from birth and the availability of new techniques for administering surfactant. This update is necessary to guide clinical practice in the current era.

METHODS OF STATEMENT DEVELOPMENT

A search of MEDLINE, including Epubs ahead of print, in-process, and other nonindexed citations (1946 to May 1, 2019), Embase (1974 to May 1, 2019), and the Cochrane Central Register of Controlled Trials (May 1, 2019) was performed, using the OVID interface. Search terms included the following: “surfactant,” “lung surfactant extract,” “artificial lung surfactant,” “respiratory tract agent,” “neonatal respiratory distress syndrome,” “respiratory distress syndrome, newborn” “hyaline membrane disease,” “newborn infant,” “pneumonia/or aspiration pneumonia,” “meconium aspiration,” “lung hemorrhage,” “respiratory tract intubation/or assisted ventilation,” “medical nebulizer,” “Less invasive*,” “Minimally invasive*,” and “laryngeal mask.” Reference lists of publications and guidelines were reviewed. All relevant Cochrane reviews were included.

The hierarchy of evidence from the Centre for Evidence-Based Medicine (CEBM) (Oxford Centre for Evidence-Based Medicine 2014: http://www.cebm.net) was applied to the publications identified. Recommendations are based on the format by Shekelle et al. (13).

PROPHYLACTIC VERSUS SELECTIVE SURFACTANT TREATMENT

Prophylactic use of surfactant refers to a strategy of providing exogenous surfactant at birth to infants at risk for RDS (9), with the aim of preventing severe RDS from developing. Selective use of surfactant refers to a strategy of providing exogenous surfactant to infants with established RDS. Both strategies have been shown to be effective, but with increasing use of continuous positive airway pressure (CPAP) in the delivery room stabilization of preterm infants, the benefit of prophylactic surfactant is being questioned (14–16).

While earlier trials without routine use of CPAP at birth showed significant benefits of prophylactic surfactant in reducing mortality and air leak in preterm infants, one systematic review (9) which included two recent clinical trials mandating routine use of CPAP in the delivery room (17,18) found that the benefit of prophylactic surfactant could no longer be demonstrated. Rather, this study observed a worrisome trend toward increasing mortality, BPD at 28 days and 36 weeks, and BPD or death at 36 weeks with the use of prophylactic surfactant. Also, in the three trials where rates of antenatal steroids exposure were high (>50%) (17–19), prophylactic surfactant was associated with a significant increase in BPD, BPD or death at 28 days, and a trend toward increasing mortality, BPD, and BPD or death (Level 1a evidence).

HOW SHOULD SURFACTANT BE USED IN PRETERM INFANTS ON NONINVASIVE RESPIRATORY SUPPORT FROM BIRTH?

Should infants be intubated or not?

While studies have shown that avoidance of intubation and mechanical ventilation may contribute to reducing the rate of BPD (15,20), the question remains whether this new approach to respiratory care might deprive some infants of the proven benefits of expedient provision of exogenous surfactant (21). Verder et al. (22) were early advocates of the INSURE (INtubate, SURfactant, Extubate) technique. One of the first systematic reviews (23) to summarize evidence for the INSURE technique suggested that it may reduce need for mechanical ventilation and lower the incidence of BPD and air leak compared with delayed selective surfactant and ongoing mechanical ventilation. Subsequent to this review, several large trials have included CPAP use in the delivery room. They compared prophylactic surfactant via INSURE with CPAP use in the delivery room and provided surfactant via INSURE only to infants with clinical signs of RDS. Trial results have demonstrated that the latter strategy is safe and that it may reduce the number of infants intubated and given surfactant (18,19,24). A recent systematic review by Isayama et al. (25) compared INSURE with CPAP alone, and showed no statistically significant difference between the two strategies in altering the incidence of BPD or death at 36 weeks, BPD, death, air leak, severe intraventricular hemorrhage, neurodevelopmental impairment, and death or neurodevelopmental impairment. However, the relative risk estimates appear to trend in favour of INSURE over CPAP alone, particularly in the outcomes of BPD or death, BPD, and air leak. These studies suggest that use of nasal CPAP shortly after birth as the primary mode of respiratory support is an acceptable alternative to elective intubation and administration of prophylactic surfactant. However, the criteria for surfactant administration in infants initially supported by CPAP are less clear (Level 1a evidence).

One potential issue with INSURE is the perceived difficulty with extubation for selected infants, even without the influence of premedication. In a 2015 systematic review, pooled estimates from six randomized controlled trials showed that over 90% of infants were successfully extubated within one hour of INSURE (25). Risk factors associated with failure to extubate after INSURE include lower gestational age (GA), lower Apgar score at 5 minutes, and FiO₂>0.5 before surfactant (26). Concerns about lung injury remain, however, even with brief mechanical ventilation (27). Therefore, alternative modes of surfactant administration are needed and some of these are discussed below.

Early versus delayed surfactant

The timing of surfactant administration for preterm infants intubated for RDS was examined in one systematic review (8) that compared early (within the first 2 hours of age) to late surfactant administration (delayed until RDS was established, usually 2 hours or beyond). Meta-analyses of six randomized trials showed that early surfactant was associated with a significant decrease in mortality, BPD at 36 weeks, BPD or death at 36 weeks, and reduction in the risk of air leak, with no increase in the risk for pulmonary hemorrhage or severe intraventricular hemorrhage. Similar findings were noted in two trials of more preterm (<30 weeks GA) infants, showing the benefits of early surfactant in reducing mortality and BPD or death at 36 weeks (28,29). A number of studies comparing early to late surfactant, as defined by oxygen requirement thresholds, suggest that low (FiO₂ 0.30 to 0.50) versus high (FiO₂>0.55) thresholds incur more benefit by providing surfactant earlier—before the development of more severe RDS—without increasing the rate of intubation significantly (22,30,31). This finding held especially in infants born to mothers who received two doses of antenatal corticosteroids. In one systematic review published in 2007, analysis based on oxygen requirement criteria showed that a lower threshold (FiO₂≤0.45) for intubation and surfactant administration was associated with less air leak and BPD compared with an FiO₂ threshold >0.45 (23). Further, two large randomized trials that did not allow infants initially managed with CPAP to receive surfactant until an FiO₂ threshold of 0.6 was reached demonstrated higher rates of pneumothorax compared with those who were intubated and given surfactant early (24,32) (Level 1a evidence).

Use of surfactant before inter-facility transport of preterm infants was found to be associated with lower oxygen requirement during transport and shorter duration of ventilation support, compared with controls (33) (Level 4 evidence).

WHAT TYPE OF SURFACTANT IS PREFERABLE—NATURAL OR SYNTHETIC?

Surfactant, no matter which form, has been shown to be efficacious in the treatment of RDS. Surfactant is a complex structure that is mainly composed of dipalmitoylphosphatidylcholine (DPPC) and surfactant protein (SP-) A, B, C, and D (34). SP-B and SP-C are two hydrophobic proteins that play important roles in adsorption and distribution of DPPC. A plethora of systematic reviews since the late 1990s have summarized the vast literature on the many clinical trials comparing effects of different types of surfactant.

Synthetic surfactants

First-generation synthetic surfactants are composed of DPPC without surfactant proteins, and they are less effective in reducing ventilation support, pneumothorax, and mortality compared with animal-derived surfactants (4). The only second-generation synthetic surfactant ever tested in infants is lucinactant (Surfaxin), which contains two phospholipids, a fatty acid, and a hydrophobic synthetic peptide to mimic SP-B (KL4). Lucinactant was withdrawn from the market in 2015 preceding trials of its aerosolized form (34). A phase II trial of a third-generation synthetic surfactant that includes DPPC and analogs of SP-B and SP-C (CHF5633) is currently underway.

Animal-derived surfactants

A wide variety of animal-derived or natural surfactants are available for use, and many clinical trials have been conducted to compare the efficacy of different preparations. One systematic review of 13 randomized controlled trials associated administering animal-derived surfactant to infants with established RDS with significant improvement in oxygenation, ventilation requirements, and reduction of air leak, mortality before hospital discharge, and in death or BPD at 28 days, compared with placebo (6). Another systematic review included 16 trials comparing different animal-derived surfactants (7). While the two types of bovine surfactant preparations were comparable in reducing death or BPD, meta-analysis showed that porcine surfactant was more effective than bovine surfactant in reducing mortality before discharge, death or BPD at 36 weeks, and need for re-dosing. In the subgroup analyses, the benefit of porcine surfactant was only observed when given in the higher dose (>100 mg/kg) range. One recent trial (35) comparing bovine lipid extract surfactant to porcine minced lung extract (poractant) in 87 preterm infants <32 weeks GA who required surfactant within 48 hours of age, found that poractant was more effective in reducing duration of supplemental oxygen and appeared to trend toward less BPD in survivors. However, a trend toward increased mortality associated with the use of poractant was also noted, although these deaths were not respiratory-related.

In summary, animal-derived and the newer generation synthetic surfactants are both effective for treating RDS and improving survival without BPD. When comparing different animal-derived surfactants, emerging evidence suggests that porcine minced lung extract, especially in higher dose, may be superior to bovine surfactant for improving acute respiratory status and reducing mortality or BPD in infants with RDS (Level 1a evidence).

DOSING AND RE-DOSING SURFACTANT

Generally accepted practice at the present time is to repeat doses of surfactant only when there is evidence of ongoing RDS based on ventilation and oxygen requirements. Kattwinkel et al. (36) studied the effects of re-dosing at low (FiO₂>0.3 and still requiring intubation) versus high (FiO₂>0.4 and needing mean airway pressure >7 cm H₂O) thresholds, both at least 6 hours after the first dose. Their results suggested that delaying re-dosing of surfactant until the infant requires escalated respiratory support is acceptable, except when RDS is complicated by sepsis or perinatal hypoxic-ischemic injury. Moreover, the size of the initial dose might be an important factor to consider in this context. One study involving poractant (37) showed that a higher initial dose (200 mg/kg) was more effective in reducing oxygen requirement, need for re-dosing, and mortality by 36 weeks corrected GA. Poractant is the only product that is concentrated enough to create such a high dose in a reasonable intratracheal volume (38) (Level 1b evidence).

NEWER TECHNIQUES OF SURFACTANT ADMINISTRATION

One meta-narrative review in 2014 of less-invasive surfactant administration (LISA) methods (specifically thin catheter, laryngeal mask airway (LMA), pharyngeal route, and nebulization), demonstrated that there is growing clinical interest in techniques that avoided mechanically ventilating infants with RDS (39).

Less-invasive surfactant administration and minimally invasive surfactant treatment

Administering surfactant through a thin catheter instead of an endotracheal tube (ETT) may combine the avoidance of mechanical ventilation with the benefits of early surfactant (40). LISA was first described by Verder et al. (41) as placing a small catheter in the trachea with a Magill forceps under direct laryngoscopy, while the infant continues on CPAP support. LISA is part of a complete strategy that also includes avoidance of positive pressure ventilation, use of antenatal steroids, early use of CPAP, and caffeine administration in the delivery room (40). One recent systematic review of LISA versus INSURE included six trials of preterm infants between 23 and <34 weeks GA with RDS. This study demonstrated that LISA results in less need for mechanical ventilation, and in reduced death or BPD at 36 weeks, and reduced BPD at 36 weeks, in survivors (42). Another systematic review compared mechanical ventilation with various noninvasive ventilation strategies in preterm infants (<33 weeks GA) with RDS in the first 24 hours postbirth. Compared with mechanical ventilation or CPAP alone, LISA was the noninvasive strategy associated with the lowest likelihood of death or BPD at 36 weeks (43) (Level 2b evidence).

Dargaville et al. modified the LISA technique by using a more rigid adult vascular catheter (thus avoiding Magill forceps), known as minimally invasive surfactant treatment (MIST) or the Hobart procedure. Two observational trials of the MIST method (44,45) showed similar results to LISA, and a larger trial is currently underway (46).

Regarding the type of surfactant used, most trials of MIST and LISA used poractant (47) to minimize the volume of instillation. A recent trial comparing LISA to ETT administration of beractant, a modified bovine lung surfactant (4 mL/kg in preterm infants 26 to 32 weeks with RDS) reported similar effect of LISA in reducing the need for mechanical ventilation, although a high rate of surfactant reflux (66%) was reported (48). One recent cohort study on the experience of LISA using bovine lipid extract surfactant (5 mL/kg in preterm infants ≥28 weeks GA) reported no serious adverse events, including surfactant reflux (49). Concerns have also been raised regarding the loss of surfactant in feeding tubes, which could be as high as two times that from an ETT (50,51). One study reporting on 2-year outcomes in preterm infants <32 weeks GA given surfactant by LISA compared with INSURE showed no difference in respiratory morbidities, sensorineural deficits, or adverse neurodevelopmental issues (52).

Laryngeal mask airway

A number of studies have reported the use of LMA for surfactant administration in higher GA (29 to 35 weeks) preterm infants, demonstrating that this method is feasible and, compared with surfactant given via ETT, may achieve better oxygenation and lower need for invasive ventilation (53–57). The latter observation, however, may be confounded by the fact that LMA insertion does not require premedication, while INSURE does. A new approach using the LMA to guide a catheter for LISA or MIST has been described and shown to be feasible without overt adverse effect (58) (Level 2b evidence).

Pharyngeal surfactant

Pharyngeal surfactant administration allows distribution of surfactant to the air–fluid interface during spontaneous breathing. One large randomized controlled trial comparing pharyngeal surfactant to saline placebo found significant reduction in mortality, severity of RDS, and ventilation requirement (59). However, study results were confounded by a significant number of infants from both groups who required subsequent intubation and surfactant, making it difficult to draw definite conclusions regarding the benefit of this approach of surfactant administration (Level 2b evidence).

Nebulization

The only truly noninvasive method of SRT is via nebulization. However, the effect of nebulized surfactant depends on a number of important factors, including optimal particle size (0.5 to 2.0 µm), stability of the substance after nebulization, and the loss of particles in relation to an effective dose (47). Earlier clinical studies using jet nebulizers (60,61) did not show significant clinical benefits. One feasibility study of nebulized lucinactant used vibrating perforated membrane nebulizers (62), and demonstrated safety, tolerability, and some evidence of clinical effect with early treatment. A newer device can deliver higher doses of surfactant to the newborn’s lungs (63), and a recent study (64) of preterm infants with mild RDS, randomized to bubble CPAP with or without aerosolized poractant, showed reduced requirement for intubation in the higher GA subgroup (32⁰ to 33⁶ weeks) in favour of nebulization (Level 1b evidence).

SURFACTANT FOR RESPIRATORY CONDITIONS OTHER THAN RDS

Meconium aspiration syndrome and neonatal pneumonia

In meconium aspiration syndrome (MAS), SRT may ameliorate respiratory distress caused, in part, by natural surfactants being rendered inactive by meconium and plasma protein. There may also be a role for surfactant lavage, to remove meconium particles from an infant’s airways. One systematic review (65) included three small trials of surfactant diluted with saline to varying concentrations and used for lavage in term and late-preterm infants with MAS. No difference in mortality, need for extracorporeal membrane oxygenation (ECMO), development of pneumothorax, duration of ventilation, or length of stay, was demonstrated. However, surfactant lavage was associated with reducing the combined outcomes of death or need for ECMO (Level 2b evidence). Another systematic review (66) examined the role of SRT in MAS, and while it again showed no difference in mortality, air leak, duration of ventilation, and duration of supplemental oxygen, a significant decrease in the need for ECMO was evident (Level 2b evidence). For neonatal pneumonia, some clinicians may choose to administer surfactant based on similar principles, but there is no evidence to date to support the practice (67) (Level 5 evidence).

Pulmonary hemorrhage

One systematic review (68) of surfactant administration to term and preterm infants with pulmonary hemorrhage did not include a clinical trial. However, two small observational studies have suggested that administering surfactant after pulmonary hemorrhage may improve infant oxygenation index (69,70). Of note, pulmonary hemorrhage can also be a complication of surfactant therapy (71) (Level 4 evidence).

SUMMARY OF RECOMMENDATIONS

Based on the best available evidence, surfactant replacement in newborns can be recommended as follows:

1. In neonatal care settings where CPAP is routinely used to stabilize preterm infants, and when the rate of antenatal corticosteroid administration has been high (>50%), prophylactic surfactant is no longer recommended (Grade A).

2. Noninvasive respiratory support (e.g., CPAP) should be provided to preterm infants with RDS from birth. Early surfactant should be provided for newborns with increasing severity of RDS, demonstrated by escalating or sustained levels of oxygen requirement and other clinical or radiological indications (72) (Grade B).

3. Infants with RDS whose oxygen requirements exceed FiO₂ of 0.5 should receive SRT (Grade A).

4. Intubated infants with RDS should receive exogenous surfactant before inter-facility transport (Grade B).

5. Repeated dosing of surfactant should be provided to infants only when there is evidence of ongoing moderate to severe RDS (Grade A).

6. For spontaneously breathing infants on CPAP with RDS, noninvasive methods of surfactant administration, such as LISA or MIST, are preferable. Factors such as clinician experience, optimal dosage, volume, and the types of surfactant available must be considered to optimize delivery method (Grade B).

7. Surfactant replacement for infants with MAS or pulmonary hemorrhage may be considered at clinicians’ discretion (Grade B).

All Canadian Paediatric Society position statements and practice points are reviewed regularly and revised as needed. Consult the Position Statements section of the CPS website www.cps.ca/en/documents for the most current version. Retired statements are removed from the website.

CANADIAN PAEDIATRIC SOCIETY FETUS AND NEWBORN COMMITTEE

Members: Nicole Anderson MD (Resident Member), Heidi Budden MD (Board Representative), Mireille Guillot MD (Resident member), Leonora Hendson MD, Thierry Lacaze-Masmonteil MD, PhD (past Chair), Brigitte Lemyre MD, Souvik Mitra MD, Michael R. Narvey MD (Chair), Vibhuti Shah MD

Liaisons: Radha Chari MD, The Society of Obstetricians and Gynaecologists of Canada; James Cummings MD, Committee on Fetus and Newborn, American Academy of Pediatrics; William Ehman MD, College of Family Physicians of Canada; Danica Hamilton RN, Canadian Association of Neonatal Nurses; Roxanne Laforge RN, Canadian Perinatal Programs Coalition; Chantal Nelson PhD, Public Health Agency of Canada; Eugene H. Ng MD, CPS Neonatal-Perinatal Medicine Section

Principal authors: Eugene H. Ng MD, Vibhuti Shah MD