Paediatrics & Child Health, 2021, 35–41

doi: 10.1093/pch/pxaa116
Position Statement

Position Statement

Guidelines for surfactant replacement therapy in neonates

Eugene H. Ng, Vibhuti Shah
Canadian Paediatric Society, Fetus and Newborn Committee, Ottawa, Ontario
Correspondence: Canadian Paediatric Society, 100–2305 St Laurent Blvd, Ottawa, Ontario K1G 4J8. E-mail info@cps.ca,
website www.cps.ca

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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.

Abstract
Surfactant replacement therapy (SRT) plays a pivotal role in the management of neonates with res-
piratory 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 pre-
term 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 sur-
factant 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.

Keywords: Bronchopulmonary dysplasia; Neonates; Noninvasive ventilation; Preterm infants; Respiratory

distress syndrome; Surfactant

Decades of clinical trials and systematic reviews have es- METHODS OF STATEMENT
tablished the unequivocal benefits of surfactant replace- DEVELOPMENT
ment therapy (SRT) for neonates with respiratory distress
A search of MEDLINE, including Epubs ahead of print, in-process,
syndrome (RDS) (1–9). Irrespective of the strategy or
and other nonindexed citations (1946 to May 1, 2019), Embase
product used, surfactant has been shown to decrease
(1974 to May 1, 2019), and the Cochrane Central Register of
the need for ventilation support, risk of pulmonary air
Controlled Trials (May 1, 2019) was performed, using the OVID
leak, mortality, and the combined outcome of death or
interface. Search terms included the following: “surfactant,” “lung
bronchopulmonary dysplasia (BPD) at 28  days (10),
surfactant extract,” “artificial lung surfactant,” “respiratory tract agent,”
without increasing adverse neurodevelopmental out-
“neonatal respiratory distress syndrome,” “respiratory distress syn-
comes (11,12). However, there remain a number of ques-
drome, newborn” “hyaline membrane disease,” “newborn infant,”
tions related to how surfactant should be used in light of
“pneumonia/or aspiration pneumonia,” “meconium aspiration,”
advances in other aspects of neonatal care, such as the
“lung hemorrhage,” “respiratory tract intubation/or assisted venti-
use of noninvasive respiratory support from birth and the
lation,” “medical nebulizer,” “Less invasive*,” “Minimally invasive*,”
availability of new techniques for administering surfac-
and “laryngeal mask.” Reference lists of publications and guidelines
tant. This update is necessary to guide clinical practice in
were reviewed. All relevant Cochrane reviews were included.
the current era.

Received: May 24, 2019; Accepted: October 18, 2019

© Canadian Paediatric Society 2021. Published by Oxford University Press on behalf of the Canadian Paediatric Society. 35
All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
36 Paediatrics & Child Health, 2021, Vol. 26, No. 1

The hierarchy of evidence from the Centre for Evidence- prophylactic surfactant via INSURE with CPAP use in the deli-
Based Medicine (CEBM) (Oxford Centre for Evidence-Based very room and provided surfactant via INSURE only to infants
Medicine 2014: http://www.cebm.net) was applied to the with clinical signs of RDS. Trial results have demonstrated that
publications identified. Recommendations are based on the the latter strategy is safe and that it may reduce the number of
format by Shekelle et al. (13). infants intubated and given surfactant (18,19,24). A recent sys-
tematic review by Isayama et al. (25) compared INSURE with
CPAP alone, and showed no statistically significant difference
PROPHYLACTIC VERSUS SELECTIVE
between the two strategies in altering the incidence of BPD or
SURFACTANT TREATMENT death at 36 weeks, BPD, death, air leak, severe intraventricular
Prophylactic use of surfactant refers to a strategy of providing hemorrhage, neurodevelopmental impairment, and death or
exogenous surfactant at birth to infants at risk for RDS (9), with neurodevelopmental impairment. However, the relative risk
the aim of preventing severe RDS from developing. Selective estimates appear to trend in favour of INSURE over CPAP
use of surfactant refers to a strategy of providing exogenous alone, particularly in the outcomes of BPD or death, BPD, and

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surfactant to infants with established RDS. Both strategies have air leak. These studies suggest that use of nasal CPAP shortly
been shown to be effective, but with increasing use of conti- after birth as the primary mode of respiratory support is an
nuous positive airway pressure (CPAP) in the delivery room acceptable alternative to elective intubation and administration
stabilization of preterm infants, the benefit of prophylactic sur- of prophylactic surfactant. However, the criteria for surfactant
factant is being questioned (14–16). administration in infants initially supported by CPAP are less
While earlier trials without routine use of CPAP at birth clear (Level 1a evidence).
showed significant benefits of prophylactic surfactant in redu- One potential issue with INSURE is the perceived difficulty
cing mortality and air leak in preterm infants, one systematic with extubation for selected infants, even without the influence
review (9) which included two recent clinical trials manda- of premedication. In a 2015 systematic review, pooled esti-
ting routine use of CPAP in the delivery room (17,18) found mates from six randomized controlled trials showed that over
that the benefit of prophylactic surfactant could no longer be 90% of infants were successfully extubated within one hour
demonstrated. Rather, this study observed a worrisome trend of INSURE (25). Risk factors associated with failure to extu-
toward increasing mortality, BPD at 28 days and 36 weeks, and bate after INSURE include lower gestational age (GA), lower
BPD or death at 36 weeks with the use of prophylactic surfac- Apgar score at 5 minutes, and FiO2>0.5 before surfactant (26).
tant. Also, in the three trials where rates of antenatal steroids Concerns about lung injury remain, however, even with brief
exposure were high (>50%) (17–19), prophylactic surfactant mechanical ventilation (27). Therefore, alternative modes of
was associated with a significant increase in BPD, BPD or death surfactant administration are needed and some of these are dis-
at 28 days, and a trend toward increasing mortality, BPD, and cussed below.
BPD or death (Level 1a evidence).
Early versus delayed surfactant
The timing of surfactant administration for preterm infants
HOW SHOULD SURFACTANT BE USED IN
intubated for RDS was examined in one systematic review (8)
PRETERM INFANTS ON NONINVASIVE that compared early (within the first 2 hours of age) to late
RESPIRATORY SUPPORT FROM BIRTH? surfactant administration (delayed until RDS was established,
Should infants be intubated or not? usually 2 hours or beyond). Meta-analyses of six randomized
While studies have shown that avoidance of intubation and trials showed that early surfactant was associated with a signi-
mechanical ventilation may contribute to reducing the rate of ficant decrease in mortality, BPD at 36 weeks, BPD or death at
BPD (15,20), the question remains whether this new approach 36 weeks, and reduction in the risk of air leak, with no increase
to respiratory care might deprive some infants of the pro- in the risk for pulmonary hemorrhage or severe intraventricular
ven benefits of expedient provision of exogenous surfactant hemorrhage. Similar findings were noted in two trials of more
(21). Verder et  al. (22) were early advocates of the INSURE preterm (<30 weeks GA) infants, showing the benefits of early
(INtubate, SURfactant, Extubate) technique. One of the first surfactant in reducing mortality and BPD or death at 36 weeks
systematic reviews (23) to summarize evidence for the INSURE (28,29). A number of studies comparing early to late surfactant,
technique suggested that it may reduce need for mechanical as defined by oxygen requirement thresholds, suggest that low
ventilation and lower the incidence of BPD and air leak com- (FiO2 0.30 to 0.50) versus high (FiO2>0.55) thresholds incur
pared with delayed selective surfactant and ongoing mechani- more benefit by providing surfactant earlier—before the deve-
cal ventilation. Subsequent to this review, several large trials lopment of more severe RDS—without increasing the rate of
have included CPAP use in the delivery room. They compared intubation significantly (22,30,31). This finding held especially
Paediatrics & Child Health, 2021, Vol. 26, No. 1 37

in infants born to mothers who received two doses of antena- with placebo (6). Another systematic review included 16 trials
tal corticosteroids. In one systematic review published in 2007, comparing different animal-derived surfactants (7). While the
analysis based on oxygen requirement criteria showed that a two types of bovine surfactant preparations were comparable
lower threshold (FiO2≤0.45) for intubation and surfactant in reducing death or BPD, meta-analysis showed that porcine
administration was associated with less air leak and BPD com- surfactant was more effective than bovine surfactant in redu-
pared with an FiO2 threshold >0.45 (23). Further, two large cing mortality before discharge, death or BPD at 36 weeks,
randomized trials that did not allow infants initially managed and need for re-dosing. In the subgroup analyses, the bene-
with CPAP to receive surfactant until an FiO2 threshold of 0.6 fit of porcine surfactant was only observed when given in the
was reached demonstrated higher rates of pneumothorax com- higher dose (>100 mg/kg) range. One recent trial (35) com-
pared with those who were intubated and given surfactant early paring bovine lipid extract surfactant to porcine minced lung
(24,32) (Level 1a evidence). extract (poractant) in 87 preterm infants <32 weeks GA who
Use of surfactant before inter-facility transport of preterm required surfactant within 48 hours of age, found that porac-
infants was found to be associated with lower oxygen require- tant was more effective in reducing duration of supplemental

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ment during transport and shorter duration of ventilation sup- oxygen and appeared to trend toward less BPD in survivors.
port, compared with controls (33) (Level 4 evidence). However, a trend toward increased mortality associated with
the use of poractant was also noted, although these deaths were
not respiratory-related.
WHAT TYPE OF SURFACTANT IS In summary, animal-derived and the newer generation syn-
PREFERABLE—NATURAL OR SYNTHETIC? thetic surfactants are both effective for treating RDS and
Surfactant, no matter which form, has been shown to be effica- improving survival without BPD. When comparing different
cious in the treatment of RDS. Surfactant is a complex structure animal-derived surfactants, emerging evidence suggests that
that is mainly composed of dipalmitoylphosphatidylcholine porcine minced lung extract, especially in higher dose, may
(DPPC) and surfactant protein (SP-) A, B, C, and D (34). SP-B be superior to bovine surfactant for improving acute respira-
and SP-C are two hydrophobic proteins that play important tory status and reducing mortality or BPD in infants with RDS
roles in adsorption and distribution of DPPC. A  plethora of (Level 1a evidence).
systematic reviews since the late 1990s have summarized the
vast literature on the many clinical trials comparing effects of DOSING AND RE-DOSING SURFACTANT
different types of surfactant.
Generally accepted practice at the present time is to repeat
doses of surfactant only when there is evidence of ongoing RDS
Synthetic surfactants
based on ventilation and oxygen requirements. Kattwinkel et al.
First-generation synthetic surfactants are composed of DPPC
(36) studied the effects of re-dosing at low (FiO2>0.3 and still
without surfactant proteins, and they are less effective in
requiring intubation) versus high (FiO2>0.4 and needing mean
reducing ventilation support, pneumothorax, and morta-
airway pressure >7 cm H2O) thresholds, both at least 6 hours
lity compared with animal-derived surfactants (4). The only
after the first dose. Their results suggested that delaying re-do-
second-generation synthetic surfactant ever tested in infants
sing of surfactant until the infant requires escalated respiratory
is lucinactant (Surfaxin), which contains two phospholipids, a
support is acceptable, except when RDS is complicated by
fatty acid, and a hydrophobic synthetic peptide to mimic SP-B
sepsis or perinatal hypoxic-ischemic injury. Moreover, the size
(KL4). Lucinactant was withdrawn from the market in 2015
of the initial dose might be an important factor to consider in
preceding trials of its aerosolized form (34). A phase II trial of
this context. One study involving poractant (37) showed that
a third-generation synthetic surfactant that includes DPPC and
a higher initial dose (200 mg/kg) was more effective in redu-
analogs of SP-B and SP-C (CHF5633) is currently underway.
cing oxygen requirement, need for re-dosing, and mortality by
36 weeks corrected GA. Poractant is the only product that is
Animal-derived surfactants concentrated enough to create such a high dose in a reasonable
A wide variety of animal-derived or natural surfactants are avai- intratracheal volume (38) (Level 1b evidence).
lable 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 adminis-
NEWER TECHNIQUES OF SURFACTANT
tering animal-derived surfactant to infants with established ADMINISTRATION
RDS with significant improvement in oxygenation, ventila- One meta-narrative review in 2014 of less-invasive surfac-
tion requirements, and reduction of air leak, mortality before tant administration (LISA) methods (specifically thin cathe-
hospital discharge, and in death or BPD at 28 days, compared ter, laryngeal mask airway (LMA), pharyngeal route, and
38 Paediatrics & Child Health, 2021, Vol. 26, No. 1

nebulization), demonstrated that there is growing clinical inte- Laryngeal mask airway

rest in techniques that avoided mechanically ventilating infants A number of studies have reported the use of LMA for surfac-
with RDS (39). tant administration in higher GA (29 to 35 weeks) preterm
infants, demonstrating that this method is feasible and, com-
Less-invasive surfactant administration and minimally pared with surfactant given via ETT, may achieve better oxyge-
invasive surfactant treatment nation and lower need for invasive ventilation (53–57). The
Administering surfactant through a thin catheter instead of latter observation, however, may be confounded by the fact that
an endotracheal tube (ETT) may combine the avoidance of LMA insertion does not require premedication, while INSURE
mechanical ventilation with the benefits of early surfactant does. A  new approach using the LMA to guide a catheter for
(40). LISA was first described by Verder et al. (41) as placing a LISA or MIST has been described and shown to be feasible wit-
small catheter in the trachea with a Magill forceps under direct hout overt adverse effect (58) (Level 2b evidence).
laryngoscopy, while the infant continues on CPAP support.
LISA is part of a complete strategy that also includes avoidance Pharyngeal surfactant

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of positive pressure ventilation, use of antenatal steroids, early Pharyngeal surfactant administration allows distribution of
use of CPAP, and caffeine administration in the delivery room surfactant to the air–fluid interface during spontaneous brea-
(40). One recent systematic review of LISA versus INSURE thing. One large randomized controlled trial comparing pha-
included six trials of preterm infants between 23 and <34 weeks ryngeal surfactant to saline placebo found significant reduction
GA with RDS. This study demonstrated that LISA results in in mortality, severity of RDS, and ventilation requirement
less need for mechanical ventilation, and in reduced death or (59). However, study results were confounded by a significant
BPD at 36 weeks, and reduced BPD at 36 weeks, in survivors number of infants from both groups who required subsequent
(42). Another systematic review compared mechanical ven- intubation and surfactant, making it difficult to draw definite
tilation with various noninvasive ventilation strategies in pre- conclusions regarding the benefit of this approach of surfactant
term infants (<33 weeks GA) with RDS in the first 24 hours administration (Level 2b evidence).
postbirth. Compared with mechanical ventilation or CPAP
alone, LISA was the noninvasive strategy associated with the Nebulization
lowest likelihood of death or BPD at 36 weeks (43) (Level 2b The only truly noninvasive method of SRT is via nebulization.
evidence). However, the effect of nebulized surfactant depends on a num-
Dargaville et al. modified the LISA technique by using a more ber of important factors, including optimal particle size (0.5 to
rigid adult vascular catheter (thus avoiding Magill forceps), 2.0  µm), stability of the substance after nebulization, and the
known as minimally invasive surfactant treatment (MIST) or loss of particles in relation to an effective dose (47). Earlier
the Hobart procedure. Two observational trials of the MIST clinical studies using jet nebulizers (60,61) did not show signi-
method (44,45) showed similar results to LISA, and a larger ficant clinical benefits. One feasibility study of nebulized luci-
trial is currently underway (46). nactant used vibrating perforated membrane nebulizers (62),
Regarding the type of surfactant used, most trials of MIST and demonstrated safety, tolerability, and some evidence of
and LISA used poractant (47) to minimize the volume of ins- clinical effect with early treatment. A newer device can deliver
tillation. A recent trial comparing LISA to ETT administra- higher doses of surfactant to the newborn’s lungs (63), and a
tion of beractant, a modified bovine lung surfactant (4 mL/ recent study (64) of preterm infants with mild RDS, rando-
kg in preterm infants 26 to 32 weeks with RDS) reported mized to bubble CPAP with or without aerosolized poractant,
similar effect of LISA in reducing the need for mechanical showed reduced requirement for intubation in the higher GA
ventilation, although a high rate of surfactant reflux (66%) subgroup (320 to 336 weeks) in favour of nebulization (Level
was reported (48). One recent cohort study on the expe- 1b evidence).
rience 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
SURFACTANT FOR RESPIRATORY
have also been raised regarding the loss of surfactant in fee- CONDITIONS OTHER THAN RDS
ding tubes, which could be as high as two times that from Meconium aspiration syndrome and neonatal
an ETT (50,51). One study reporting on 2-year outcomes pneumonia
in preterm infants <32 weeks GA given surfactant by LISA In meconium aspiration syndrome (MAS), SRT may ameliorate
compared with INSURE showed no difference in respiratory respiratory distress caused, in part, by natural surfactants being
morbidities, sensorineural deficits, or adverse neurodevelop- rendered inactive by meconium and plasma protein. There
mental issues (52). may also be a role for surfactant lavage, to remove meconium
Paediatrics & Child Health, 2021, Vol. 26, No. 1 39

particles from an infant’s airways. One systematic review (65) factant available must be considered to optimize delivery
included three small trials of surfactant diluted with saline to method (Grade B).
varying concentrations and used for lavage in term and late-pre- 7. Surfactant replacement for infants with MAS or pulmon-
term infants with MAS. No difference in mortality, need for ary hemorrhage may be considered at clinicians’ discretion
extracorporeal membrane oxygenation (ECMO), development (Grade B).
of pneumothorax, duration of ventilation, or length of stay, was
demonstrated. However, surfactant lavage was associated with Acknowledgements
reducing the combined outcomes of death or need for ECMO
This position statement was reviewed by the Community Paediatrics
(Level 2b evidence). Another systematic review (66) examined
Committee of the Canadian Paediatric Society.
the role of SRT in MAS, and while it again showed no diffe- Funding: There are no funders to report for this submission.
rence in mortality, air leak, duration of ventilation, and duration Potential Conflicts of Interest: All authors: No reported conflicts of in-
of supplemental oxygen, a significant decrease in the need for terest. All authors have submitted the ICMJE Form for Disclosure of
ECMO was evident (Level 2b evidence). For neonatal pneu- Potential Conflicts of Interest. Conflicts that the editors consider rele-

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monia, some clinicians may choose to administer surfactant vant to the content of the manuscript have been disclosed.
based on similar principles, but there is no evidence to date to
support the practice (67) (Level 5 evidence). References
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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

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Health Agency of Canada; Eugene H. Ng MD, CPS Neonatal-Perinatal Medicine Section
Principal authors: Eugene H. Ng MD, Vibhuti Shah MD