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
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36
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 conti-
nuous positive airway pressure (CPAP) in the delivery room
stabilization of preterm infants, the benefit of prophylactic sur-
factant is being questioned (14–16).
While earlier trials without routine use of CPAP at birth
showed significant benefits of prophylactic surfactant in redu-
cing mortality and air leak in preterm infants, one systematic
review (9) which included two recent clinical trials manda-
ting 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 surfac-
tant. 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 pro-
ven 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 com-
pared with delayed selective surfactant and ongoing mechani-
cal ventilation. Subsequent to this review, several large trials
have included CPAP use in the delivery room. They compared
Paediatrics & Child Health, 2021, Vol. 26, No. 1
prophylactic surfactant via INSURE with CPAP use in the deli-
very 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 sys-
tematic 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
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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 esti-
mates 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 extu-
bate 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 dis-
cussed 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 signi-
ficant 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 deve-
lopment of more severe RDS—without increasing the rate of
intubation significantly (22,30,31). This finding held especially
Paediatrics & Child Health, 2021, Vol. 26, No. 1
in infants born to mothers who received two doses of antena-
tal 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 com-
pared 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 com-
pared 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 require-
ment during transport and shorter duration of ventilation sup-
port, 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 effica-
cious 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 morta-
lity 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 avai-
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-
tering animal-derived surfactant to infants with established
RDS with significant improvement in oxygenation, ventila-
tion requirements, and reduction of air leak, mortality before
hospital discharge, and in death or BPD at 28 days, compared
37
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 redu-
cing mortality before discharge, death or BPD at 36 weeks,
and need for re-dosing. In the subgroup analyses, the bene-
fit of porcine surfactant was only observed when given in the
higher dose (>100 mg/kg) range. One recent trial (35) com-
paring 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 porac-
tant was more effective in reducing duration of supplemental
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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 syn-
thetic 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 respira-
tory 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-do-
sing 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 redu-
cing 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 surfac-
tant administration (LISA) methods (specifically thin cathe-
ter, laryngeal mask airway (LMA), pharyngeal route, and
38
nebulization), demonstrated that there is growing clinical inte-
rest 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 ven-
tilation with various noninvasive ventilation strategies in pre-
term 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 ins-
tillation. A recent trial comparing LISA to ETT administra-
tion 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 expe-
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
have also been raised regarding the loss of surfactant in fee-
ding 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 neurodevelop-
mental issues (52).
Paediatrics & Child Health, 2021, Vol. 26, No. 1
Laryngeal mask airway
A number of studies have reported the use of LMA for surfac-
tant administration in higher GA (29 to 35 weeks) preterm
infants, demonstrating that this method is feasible and, com-
pared with surfactant given via ETT, may achieve better oxyge-
nation 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 wit-
hout overt adverse effect (58) (Level 2b evidence).
Pharyngeal surfactant
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Pharyngeal surfactant administration allows distribution of
surfactant to the air–fluid interface during spontaneous brea-
thing. One large randomized controlled trial comparing pha-
ryngeal 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 num-
ber 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 signi-
ficant clinical benefits. One feasibility study of nebulized luci-
nactant 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, rando-
mized 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
Paediatrics & Child Health, 2021, Vol. 26, No. 1
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-pre-
term 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 diffe-
rence 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 pneu-
monia, 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 sur-
factant 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 cor-
ticosteroid administration has been high (>50%), prophy-
lactic 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 sur-
factant should be provided for newborns with increasing
severity of RDS, demonstrated by escalating or sustained
levels of oxygen requirement and other clinical or radio-
logical 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 sur-
factant 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 sur-
39
factant available must be considered to optimize delivery
method (Grade B).
7. Surfactant replacement for infants with MAS or pulmon-
ary hemorrhage may be considered at clinicians’ discretion
(Grade B).
Acknowledgements
This position statement was reviewed by the Community Paediatrics
Committee of the Canadian Paediatric Society.
Funding: There are no funders to report for this submission.
Potential Conflicts of Interest: All authors: No reported conflicts of in-
terest. All authors have submitted the ICMJE Form for Disclosure of
Potential Conflicts of Interest. Conflicts that the editors consider rele-
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vant to the content of the manuscript have been disclosed.
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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