Accepted Manuscript online: 2022-12-20 Article published online: 2023-02-15

THIEME
Clinical Opinion 211

Less Invasive Surfactant Administration:

A Viewpoint
Srinivasan Mani, MD1 Munmun Rawat, MD2

1 Department of Pediatrics, University of Toledo, Toledo, Ohio Address for correspondence Srinivasan Mani, Department of
2 Department of Pediatrics, University at Buffalo, Buffalo, New York Pediatrics, The University of Toledo, ProMedica Russell J. Ebeid
Children's Hospital, 2142 North Cove Boulevard, Toledo, OH 43606
Am J Perinatol 2024;41:211–227. (e-mail: drvazan@[Link]).

Abstract The standard of care in treating respiratory distress syndrome in preterm infants is
respiratory support with nasal continuous positive airway pressure or a combination of
continuous positive airway pressure and exogenous surfactant replacement. Endotra-
cheal intubation, the conventional method for surfactant administration, is an invasive
procedure associated with procedural and mechanical ventilation complications. The
INSURE (intubation, surfactant administration, and extubation soon after) technique is
an accepted method aimed at reducing the short-term complications and long-term
morbidities related to mechanical ventilation but does not eliminate risks associated
with endotracheal intubation and mechanical ventilation. Alternative methods of
Keywords surfactant delivery that can overcome the problems associated with the INSURE
► less invasive technique are surfactant through a laryngeal mask, surfactant through a thin intra-
surfactant tracheal catheter, and aerosolized surfactant delivered using nebulizers. The three
administration alternative methods of surfactant delivery studied in the last two decades have
► thin catheter advantages and limitations. More than a dozen randomized controlled trials have
technique aimed to study the benefits of the three alternative techniques of surfactant delivery
► aerosolized compared with INSURE as the control arm, with promising results in terms of reduction
surfactant in mortality, need for mechanical ventilation, and bronchopulmonary dysplasia. The
► minimally invasive need to find a less invasive surfactant administration technique is a clinically relevant
surfactant therapy problem. Before broader adoption in routine clinical practice, the most beneficial
► surfactant technique among the three alternative strategies should be identified. This review aims
administration to summarize the current evidence for using the three alternative techniques of
through laryngeal surfactant administration in neonates, compare the three techniques, highlight the
supraglottic airway knowledge gaps, and suggest future directions.

Key Points
• The need to find a less invasive alternative method of surfactant delivery is a clinically relevant problem.
• Clinical trials that have studied alternative surfactant delivery methods have shown promising results but are
inconclusive for broader adoption into clinical practice.
• Future studies should explore novel clinical trial methodologies and select clinically significant long term outcomes for
comparison.

received DOI [Link] © 2023. The Author(s).

September 5, 2022 10.1055/a-2001-9139. This is an open access article published by Thieme under the terms of the
accepted after revision ISSN 0735-1631. Creative Commons Attribution-NonDerivative-NonCommercial-License,
December 12, 2022 permitting copying and reproduction so long as the original work is given
accepted manuscript online appropriate credit. Contents may not be used for commercial purposes, or
December 20, 2022 adapted, remixed, transformed or built upon. ([Link]
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February 15, 2023 Thieme Medical Publishers, Inc., 333 Seventh Avenue, 18th Floor,
New York, NY 10001, USA
212 Less Invasive Surfactant Administration Mani, Rawat

Respiratory distress syndrome (RDS) is a disorder affecting In this review, we aim to summarize the current evidence
preterm infants due to pulmonary surfactant deficiency. This from randomized controlled trials (RCTs) and meta-analysis
condition’s standard treatment is respiratory support with for using the alternative techniques of surfactant adminis-
nasal continuous positive airway pressure (nCPAP) or a tration in neonates, compare the three well-studied techni-
combination of CPAP and exogenous surfactant replace- ques, highlight the knowledge gaps, and suggest future
ment.1 Surfactant is conventionally administered through directions.
the endotracheal tube.2,3
Endotracheal intubation for surfactant administration
Alternative Surfactant Delivery Methods
is an invasive procedure associated with procedural and
mechanical ventilation complications.4 The availability of The search for alternative methods that are less invasive than
health care personnel skilled in the neonatal airway is a the INSURE technique began in the early 2000s. Three
limiting factor that makes early surfactant administration important alternative methods can overcome the problems
difficult in resource-limited settings. Elective neonatal associated with the INSURE technique. These are (1) surfac-
endotracheal intubation for surfactant administration tant through a laryngeal mask, (2) surfactant through a thin
may require premedication, like sedatives and vagolytics.5 intratracheal catheter, and (3) aerosolized surfactant using
Despite using premedication, the infant may poorly toler- nebulizers.
ate the procedure of direct laryngoscopy with complica-
tions of autonomic disturbances manifesting as apnea,
Laryngeal Mask-Assisted Surfactant
bradycardia, hypoxemia, and systemic or intracranial
Delivery
hypertension.6
Even a short period of mechanical ventilation (<24 hours) The success of surfactant delivery feasibility through supra-
of the developing lung (late canalicular and saccular stages) glottic airway devices in preterm infants was first reported in
can result in volutrauma due to overdistension of the lung, 2004 (►Fig. 1).11 Following this, eight RCTs were conducted
barotrauma due to excessive pressure, atelectotrauma due to to compare the efficacy of surfactant administration through
cyclical recruitment and de-recruitment, biotrauma due to laryngeal mask or supraglottic airway (SALSA) against nCPAP
inflammation and oxidative stress, and rheotrauma due to without surfactant12,13 or INSURE technique surfactant de-
inappropriate airway flow.7,8 The long-term morbidities livery (►Table 1).14–19
associated with mechanical ventilation include bronchopul- The critical limitation of these trials is that they either did
monary dysplasia and poor neurodevelopmental outcomes.9 not report the prior sample size estimate or did not recruit
INSURE (intubation, surfactant administration, and extuba- enough participants to meet the calculated sample size. Six
tion soon after) is an accepted method aimed at reducing the out of eight clinical trials were single-center trials which
short-term complications and long-term morbidities related reduces the external validity of the results. Single-center
to mechanical ventilation, especially in extreme (<28.0 trials tend to show larger treatment effects than multicenter
weeks of gestational age [GA]) and very (<32.0 weeks of RCTs.20 The primary outcomes studied in most trials were
GA) preterm infants.10 The INSURE technique still carries the need for invasive mechanical ventilation (from 1 hour to
several risks associated with endotracheal intubation and 7 days) or improvement in oxygenation. However, the need
mechanical ventilation. for invasive mechanical ventilation cannot be automatically

Fig. 1 Surfactant delivery through LMA with the use of a syringe and 5 Fr catheter inserted into the LMA. (Image courtesy: Dr. Satyan
Lakshminrusimha, modified with permission).

American Journal of Perinatology Vol. 41 No. 2/2024 © 2023. The Author(s).

 Table 1 Clinical trials for laryngeal mask-assisted surfactant delivery

Citation Design Population Intervention/ Analysis/ Primary outcome Results Conclusion/comments

comparison sample
size
Attridge Single-center, pro- Inclusion: Calfactant (3 mL/kg.) Priori SS: 183 Need for mechani- CPAP vs. LMA: 23 Underpowered
et al 13 (2013) spective, unblind- 1. X-ray and clinical RDS administered through Enrolled: 26 cal ventilation vs. 8% (p ¼ 0.59) No significant difference
ed RCT at the 2. BW >1,200 g LMA in 2–4 aliquots ITT analysis detected in the primary
University of Vir- 3. <72 h old via a catheter with the 13 (LMA) group vs. 13 outcome
ginia, United 4. On nCPAP for at least tip midway down the (nCPAP group)
States 30 min with FiO2 -0.30– airway lumen.
0.60 nCPAP (comparison)
Exclusion:
1. Pneumothorax
2. Prior surfactant or in-
tubation
3. Congenital
anomaly
Sadeghnia Dual center RCT at Inclusion: Beractant (100 Priori SS: not a/A PO 2 before and i-gel vs. INSURE: Surfactant administration
et al14 (2014) the Shahid 1. BW  2 kg with RDS mg/kg) was adminis- reported. after surfactant Before surfactant using i-gel resulted in
Beheshti and Al- symptoms at birth or tered through i-gel 35 (i-gel) vs. mean (SD)-0.18 better oxygenation than
Zahra Hospitals, within 48 h (intervention) and by 35 (Insure) (0.03) vs. 0.19 the INSURE technique
Iran. 2. On bubble CPAP need- INSURE (0.04; p ¼ 0.39)
Randomization ing (comparison) After surfactant:
and Allocation: FiO2 0.3 for > 0.48 (0.08) vs.
not reported 30 min 0.43 (0.08)
Exclusion: (p ¼ 0.014)
1. Airway abnormalities 2.
Cardiothoracic
or craniofacial malforma-
tions, [Link] asphyxia
4. Air-leak syndromes
Pinheiro et al15 Single-center RCT Inclusion: Calfactant 3 mL/kg/ Priori SS: 78 (39 in Need for MV LMA vs. INSURE: Surfactant therapy
(2016) at Albany Medical 1. GA 290/7–366/7 wk dose each group) 30 vs. 77% (p  through an LMA de-
Center, United 2. Diagnosis of RDS 4. 48 h administered through 30 (LMA) vs. 31 0.001) creased the need for MV
States. of age size 1 LMA classic (INSURE) in newborns with moder-
Randomization: 3. On nCPAP 5 cm H2O using a 5 Fr catheter or ate RDS

American Journal of Perinatology

1:1 ratio within (with or without NIPPV) ETT compared with INSURE
two GA blocks 4. FiO2 0.30–0.60 to Premedication: Atro- with sedation
(<33 and  33 wk) maintain SpO2 pine (0.01 mg/kg) in

Vol. 41
using a computer- 88 to 95% the LMA group
ized algorithm. Exclusion: Atropine (0.01 mg/kg)
Allocation 1. Prior intubation or sur- and morphine (0.1
concealed by cleri- factant therapy mg/kg) in INSURE

No. 2/2024
cal staff in serially 2. BW < 1 kg group.
Less Invasive Surfactant Administration

numbered opaque 3. Major malformations

envelopes. 4. Apgar’s score  3 at
5 min
5. Pneumothorax
6. Severe RDS indicated
by FiO2 0.40–0.60

© 2023. The Author(s).

Mani, Rawat

(Continued)
213
 214

Table 1 (Continued)

Citation Design Population Intervention/ Analysis/ Primary outcome Results Conclusion/comments

comparison sample
size
Barbosa et al16 Prospective, un- Inclusion: Poractant 200 mg/kg Priori SS: 30 Reduction of oxy- LMA vs. ETT: 77 vs. LMA surfactant had
(2017) blinded single- 1. GA at birth 28–35 wk administered within Enrolled and analyzed: gen need to FiO2  77% (p ¼ 0.977) equivalent supplemental
center RCT at 2. BW 1 kg 8 h of age through size 48 0.30 at 3 h after oxygen need at 3 h com-
Maternidade 1 proseal LMA using 6 26 (LMA) vs. 22 (ETT) surfactant pared with ETT surfactant

American Journal of Perinatology

3. < 8 h of age
Unimed-BH in Belo 4. On nCPAP Fr catheter SS reduced after an
Horizonte, Brazil. 5. SA score > 4 or respira- ETT surfactant fol- interim analysis
Randomization: By tory frequency lowed by mechanical showed equivalence

Vol. 41
table of random >60 bpm or FiO2  ventilation (compari-
numbers. 0.40 son)
6. Clinical and X-ray diag- Premedication- Remi-
nosis of RDS fentanil and midazo-

No. 2/2024
Exclusion: lam bolus for ETT
Less Invasive Surfactant Administration

1. GA > 35 wk group.
2. Major congenital
anomalies
3. Prior intubation
4. Apgar’s score <3 at
5 min
5. Chorioamnionitis

© 2023. The Author(s).

Mani, Rawat

and/or ROM >18 h

Roberts et al12 Multicenter, pro- Inclusion: Poractant alfa 200 Priori SS estimate: Need for LMA vs. CPAP: 38 Surfactant via LMA de-
(2018) spective RCT 1. GA 280/7–356/7 wk mg/kg was adminis- 144 (72 per group) invasive MV in the vs. 64% (p ¼ 0.006) creased the rate of
All the centers 2. BW 1,250 g 3. Age tered Enrolled and analyzed: first 7 d of life invasive MV compared
were in the United 36 h via size 1 LMA Unique 103 with CPAP alone in pre-
States 4. On noninvasive respi- CPAP (comparison) Enrollment was termi- term infants with moder-
Randomization: ratory support (CPAP, nated after four years ate RDS
Computer-gener- NIPPV, or BiPAP) due to difficulty in re-
ated 5. Need for FiO2 0.30– cruitment
random numbers 0.40 for 30 min 50 (LMA group) vs. 53
stratified by study 6. CXR and clinical RDS. (CPAP group)
site and Exclusion:
GA at the time of 1. Prior MV or surfactant
enrollment administration
(280/7–316/7 wk 2. Major congenital
and 320/7–356/7 anomalies
wk) using random 3. Airway abnormality
blocks of 2, 4, and 4. Respiratory
6. distress because of
Allocation: non-RDS etiology
sequentially num- 5. Apgar’s score <5 at
bered, opaque, 5 min.
sealed
envelopes.
Gharehbaghi Single center RCT Inclusion: Beractant 100 mg/kg Priori SS estimate: not Reduction in LMA vs. INSURE: Surfactant via LMA is a
et al 17 (2018) at Al-Zahra hospi- 1. GA 33–37 wk and was given via size 1 reported patient’s FiO2 re- FiO2 before and safe and effective
tal, Tabriz. Iran BW  1,800 g LMA Enrolled and analyzed: quirement after surfactant in
 Table 1 (Continued)

Citation Design Population Intervention/ Analysis/ Primary outcome Results Conclusion/comments

comparison sample
size
Randomization 2. Clinical and X-ray signs Or ETT 50 following surfac- mean (SD) ¼ 0.60 alternative to surfactant
and Allocation: of RDS After surfactant ther- 25 (LMA) vs. 25 tant (0.12) vs. 0.57 therapy via ETT
Computer-gener- Exclusion: apy, LMA and ETT were (INSURE) administration (0.12) and 0.42
ated numbers in 1. Apgar’s score <4 at 5 removed and infants (0.15) vs. 0.36
sealed opaque min were placed on CPAP (0.10; (p < 0.001)
envelopes. 2. Major congenital Premedication:
anomalies INSURE group only—
3. Pneumonia Fentanyl (1–2 µg/kg)
4. Pneumothorax
18
Amini et al Single-center pro- Inclusion: Poractant α 2.5 Priori SS estimate: not Need for RDS-re- LMA vs. INSURE: Early surfactant via LMA
(2019) spective, open-la- 1. GA <37 wk mL/kg/dose was given reported lated MV 23.3 vs. 20% and ETT is equally effec-
bel RCT conducted 2. BW 1,200 g via size 1 LMA or via Enrolled and analyzed: (p ¼ 0.75) tive with no significant
at Tehran Univer- 3. Diagnosis of RDS in ETT by INSURE 60 (30 in each group) differences in the adverse
sity of Medical < 2 h of life [Link] for Premedication: IN- 30 (LMA) vs. 30 outcomes
Sciences, Tehran, CPAP 5 cm H2O with SURE group only— (INSURE)
Iran. FiO2 0.30–0.60 morphine (0.1 mg/kg)
Randomization: Exclusion:
Computer-gener- 1. Prior intubation [Link]-
ated random jor malformations 3.
numbers mean BP < 40 mm Hg
Allocation con- 4. Apgar’s score 3 at 5
cealment: conse- min
cutive opaque 5. FiO2 need > 0.60
envelopes 6. Pneumothorax 7. Ap-
nea requiring assisted
ventilation.
Gallup et al19 Single-center RCT Inclusion: Calfactant Priori SS estimate: Failure of surfac- LMA vs. INSURE: Surfactant therapy via
(2022) conducted at 1. GA 270/7-366/7 wk and 3 mL/kg (105 mg/kg 130 (65 in each group) tant therapy de- 20 vs. 29% LMA is noninferior to IN-
Albany Medical BW >800 g phospholipid) was Randomized and ana- fined as (p ¼ 0.311) SURE technique
Center, United 2. RDS needing CPAP given via size 1 LMA lyzed: 1. Need for inva-
States. >5 cm H20, or NIPPV Unique or via ETT by 93 sive mechanical
Randomization and FiO2 0.30–0.60 for INSURE 51 (LMA group) vs. 42 ventilation (or)

American Journal of Perinatology

and allocation: >2 hours within Premedication: (ETT group) 2. Need for >2
Computer-based 48 hours of birth. LMA group: atropine doses of surfac-
stratified block Exclusion: (0.01 mg/kg) only tant therapy

Vol. 41
randomization 1. Pneumothorax ETT group: 3. Need for FiO2
1:1 allocation for 2. Prior intubation Atropine and remifen- >0.60
the first half of the 3. Major malformations tanil (2 µg/kg) 4. Need for
study, followed by 4. Apgar’s score <3 at the second dose
2:1 5 min of life or of surfactant

No. 2/2024
Less Invasive Surfactant Administration

Concealment: encephalopathy within 8 hours

opaque sealed
envelopes

Abbreviations: a/A PO2, arterial-to-alveolar oxygen tension ratio; BW, birth weight; BP, blood pressure; BW, birth weight; CPAP, continuous positive airway pressure; ETT, endotracheal tube; FiO2, fraction of
inspired oxygen; GA, gestational age; INSURE, intubation, surfactant administration, and extubation soon after; LMA, laryngeal mask airway; MV, mechanical ventilation; nCPAP, nasal continuous positive airway
pressure; NIPPV, nasal intermittent positive pressure ventilation; RCT, randomized controlled trial; RDS, respiratory distress syndrome; SA, Silverman-Andersen score; SD, standard deviation; SS, sample size.

© 2023. The Author(s).

Mani, Rawat
215
216 Less Invasive Surfactant Administration Mani, Rawat

Fig. 2 Surfactant delivery through a intratracheal 4 Fr catheter inserted with the help of magill forceps and laryngoscope (Image courtesy: Dr.
Satyan Lakshminrusimha, modified with permission).

construed as a failure of surfactant therapy because preterm invasive surfactant administration (LISA) or minimally inva-
diseases like a hemodynamically significant patent ductus sive surfactant therapy (MIST), with the standard delivery
arteriosus, congenital pneumonia, early pulmonary hyper- method through an endotracheal tube (►Table 2).23–30 One
tension, perinatal asphyxia, and apnea of prematurity can RCT compared surfactant delivery by a thin catheter tech-
lead to invasive mechanical ventilation or contribute to the nique with the continuation of CPAP alone without
outcome in varying proportions. surfactant.31
A meta-analysis including five of seven RCTs found that Six out of the nine RCTs were multicenter trials. Two
surfactant administration through laryngeal mask airway studies included only very preterm infants, and three includ-
(LMA) reduces the need for invasive mechanical ventilation ed only extremely preterm infants. Two studies included a
compared with nCPAP alone without any surfactant or combination of both. Six trials studied the LISA technique
surfactant delivery by INSURE.21 The meta-analysis showed using a porcine surfactant, and three RCTs used a bovine
that surfactant delivery via LMA is associated with a reduc- surfactant. Seven trials used either a feeding tube or a
tion in oxygen requirement compared with nCPAP alone and vascular catheter for surfactant administration. Three trials
increased oxygen requirement compared with INSURE in 1 to used Magill forceps, and one used ophthalmic forceps to
6 hours after treatment. However, this meta-analysis did not guide the catheter through the vocal cords. Two RCTs used a
find evidence supporting SALSA for reducing mortality or narrow-bore vascular catheter (16-gauge Angiocath, Becton
short-term morbidities like pneumothorax, bronchopulmo- Dickinson, Sandy, UT), of which one trial also used a propri-
nary dysplasia, intraventricular hemorrhage, and length of etary semirigid catheter called LISAcath (Chiesi Farmaceutici
hospital stay. None of the trials investigated long-term SpA, Parma, Italy) for endotracheal instillation of surfactant.
neurodevelopmental outcomes. The heterogeneity in the These catheters can be inserted endotracheally using a
type of surfactant used, the type of LMA device, and the laryngoscope without Magill forceps by the Hobart meth-
premedication use in the control arm (INSURE group) of od.32 Three studies used atropine as premedication for the
these trials provides low-quality evidence, which limits our procedure. One study did not use any premedication. Other
ability to make meaningful conclusions regarding its routine studies did not report premedication use specifically.
use in clinical practice All the clinical trials that studied the LISA technique have
reported the prior sample size estimation except one study.
Six studies enrolled enough participants to meet the sample
Thin Intratracheal Catheter-Assisted
size. Two studies did not fulfill the sample size requirement.
Surfactant Delivery
Six of the nine clinical trials evaluated the need for invasive
Kribs et al in 2007 demonstrated the feasibility and safety of mechanical ventilation as the primary outcome. Five of them
the surfactant administration by intratracheal catheter in specifically looked at the need for invasive mechanical
extremely preterm infants up to the limits of viability (23 ventilation within 72 hours. Three studies had bronchopul-
weeks GA).22 In this study, a 0.04 Charrière catheter was monary dysplasia at 36 weeks as their primary outcome. Of
clamped with Magill forceps at an angle of 120 degree and the three studies, one evaluated death or bronchopulmonary
inserted into the trachea using a laryngoscope to deliver the dysplasia (BPD) at 36 weeks as a composite outcome, and
liquid surfactant (see ►Fig. 2). Eight RCTs compared surfac- another studied survival without BPD and death as two
tant administration using a thin catheter, also known as less different outcomes.

American Journal of Perinatology Vol. 41 No. 2/2024 © 2023. The Author(s).

 Table 2 Clinical trials for thin intratracheal catheter-assisted surfactant delivery

Citation Design Population Intervention/ Analysis/ Primary outcome Results Conclusion

comparison sample
size
Göpel et al23 Multicenter unblinded Inclusion: Infants on CPAP with Priori SS estimate: 105 Need for MV or pCO2 Thin catheter vs. Stan- Surfactant via thin
(2011) RCT at 12 NICUs (level 1. GA 26–286/7 wk a FiO2 > 0.30 in each group >65 mm Hg or FiO2 dard treatment: catheter reduces the
3) in 2. BW < 1.5 kg received surfactant Enrolled and analyzed: > 0.60, or both, for 28 vs. 46% need for MV
Germany Exclusion: (100 mg/kg) using 220 more than 2 h be- (p ¼ 0·008)
Randomization: RITA 1. Lethal malformations 2.5–5 Fr catheter 108 (Thin catheter tween 25 and 72 h of
(v1.2) 1:1 ratio with 2. Surfactant without in- placed in the trachea group) vs. 112 (stan- age
variable block sizes tubation before enroll- using Magill forceps dard treatment group)
Allocation: sequentially ment and laryngoscope
numbered, sealed, Enrolled all infants, Standard treatment
opaque envelopes irrespective of their re- included Surfactant
stratified by center spiratory via ETT followed by
and multiple birth status MV
statuses Sedation and analge-
sia
were used at the dis-
cretion of each neo-
natologist.
Atropine (5 μg/kg)
was optional
25
Kanmaz et al Single-center RCT con- Inclusion A 5F catheter was Priori SS estimate: Need for invasive MV Thin catheter vs. IN- Surfactant via thin
(2013) ducted GA <32 wk with RDS by inserted beyond the 100 in each group in the first 72 h of life SURE: catheter reduces the
in the NICU of Zekai clinical, chest X-ray and vocal cords and por- Enrolled and analyzed: 30 vs. 45% need and duration of
Tahir Burak blood gas parameters on cine surfactant 200 (p ¼ 0.02) MV in very low birth
Maternity Teaching nCPAP with  0.4 FiO2 in 100 mg/kg was ad- 100 (thin catheter weight infants
Hospital, Turkey the first 2 h of life ministered in the in- group) vs. 100 (INSURE
Randomization and Al- Exclusion tervention group group)
location: 1. Major INSURE group (com-
Sequentially numbered congenital anomalies parison)
sealed opaque 2. Need for PPV or intuba- No premedication
envelopes stratified by tion
GA in the delivery room
3. Infants not resuscitated

American Journal of Perinatology

by trial
investigators
Mirnia et al24 Multicenter RCT con- Inclusion 5F feeding Priori SS estimate – not Primary outcome not TEC vs. INSURE: TEC was effective in

Vol. 41
(2013) ducted in the NICU of GA 27–32 wk tube was guided reported identified 19 vs. 22% treating RDS
three university hospi- on nCPAP needed FiO2 through 1–2 cm be- Enrolled and analyzed – Need for MV at 72 h (p ¼ 0.6) Mortality was signifi-
tals in Tabriz, Isfahan >30% for establishing low the vocal cords 136 Mortality 9.3 vs. 15.7% (p ¼ 0.01) cantly decreased in the
and Mashhad, Iran SpO2 >85% and needed and 66 (thin endotracheal BPD 7.5% vs. 7.1% TEC group

No. 2/2024
surfactant poractant α 200 mg/ catheter (TEC) group) (p ¼ 0.9)
Less Invasive Surfactant Administration

Exclusion kg was given over 1–3 V. 70 (INSURE group)

1. 5 min Apgar score < 6 min
2. Congenital INSURE group: Same
dose of surfactant
(Continued)

© 2023. The Author(s).

Mani, Rawat
217
 218

Table 2 (Continued)

Citation Design Population Intervention/ Analysis/ Primary outcome Results Conclusion

comparison sample
size
malformations and through ETT
congenital heart Premedication: Atro-
disease pine 5 µg/kg before
intubation

American Journal of Perinatology

Bao et al27 (2015) Single-center RCT in the Inclusion 16G, 130 mm Angio- Priori SS estimate - 60 Need for intubation LISA vs. INSURE: LISA in spontaneously
Women’s Hospital 1. GA 28–32 wk cath, infants in each group. and MV within 72 h. 17 vs. 23.3% breathing infants on
NICUs, Zhejiang Uni- 2. Signs of RDS needing BD, Sandy, Utah, Enrolled and analyzed: (p ¼ 0.44) nCPAP is an alternative

Vol. 41
versity, China nCPAP 7 cm H2O and United States, was 90 for surfactant therapy
FiO2 0.3 (280/7–296/7 marked at 1.5 cm 47(LISA group) vs. 43 avoiding
wk gestation) or 0.35 (28–29 wk) or 2 cm (INSURE group)
(300/7–326/7 wk) to (30–32 wk) and using

No. 2/2024
maintain SpO2 at 85– direct laryngoscopy
Less Invasive Surfactant Administration

95% the catheter was

Exclusion inserted beyond the
1. Prior intubation vocal cords surfac-
2. Congenital anomalies tant was given at a
affecting respiratory standard
function. dose over 3–5 min.
Infants were contin-

© 2023. The Author(s).

Mani, Rawat

ued
on nCPAP throughout
the procedure.
INSURE group - Sur-
factant via ETT
Mohammadi RCT at 2 NICUs in the Inclusion 4F feeding tube Priori SS estimate: 34 Need for MV within CATH vs. INSURE: Surfactant administra-
Zadeh et al28 tertiary care hospitals GA < 34 wk and marked 1.5 cm above Enrolled and analyzed: 72 h of birth. 10.5 vs. 15.8% tion via a thin intratra-
(2015) affiliated with Isfahan BW 1–1.8 kg with signs of the tip was inserted 38 (p ¼ 0.99) cheal catheter has
University of Medical RDS within the first h of life using Magill forceps 19 (CATH group) 19 vs. similar feasibility, effi-
Sciences, Isfahan, Iran. and need for surfactant and laryngoscope, (ET group) cacy, and safety as IN-
Randomization and Al- after 30 min of nCPAP and poractant alfa SURE technique
location: Exclusion was injected into the
Using cards provided in 1. Maternal chorioamnio- trachea over 1–3 min.
consecutively num- nitis nCPAP was continued
bered, opaque, and 2. Apgar’s score  4 at 5 during and after the
sealed envelopes min procedure
3. Congenital anomalies In the ETT group, the
4. Invasive MV at birth same dose of surfac-
5. Need for MV for more tant was adminis-
than a few minutes after tered using INSURE
Surfactant technique.
Premedication: intra-
venous atropine
(0.025 mg/kg)
 Table 2 (Continued)

Citation Design Population Intervention/ Analysis/ Primary outcome Results Conclusion

comparison sample
size
Kribs et al26 Multicenter, random- Inclusion A laryngoscope and a Priori SS estimate: Survival without BPD LISA vs. ETT: Surfactant via LISA
(2015) ized clinical parallel- 1. GA Magill forceps were 87 infants in each Death 67.3 vs. 58.7% technique was not
group study conducted 230/7–266/7 wk used to group (p ¼ 0.20) superior to surfactant
at 13 level III NICUs in 2. Spontaneous breathing, intubate a 4F catheter Enrolled and analyzed: 9.3 vs. 11.5% via ETT, followed by MV
Germany age 10 to 120 min up to the 1.5 cm 211 (p ¼ 0.59) concerning survival
Randomization and Al- Exclusion mark. After removing 107 (LISA group) vs. without BPD in ex-
location: 1. Prenatally diagnosed the laryngoscope 104 (ETT group) tremely preterm
1:1 ratio with variable severe underlying dis- 100 mg/kg of porac- infants (23–26 wk).
block sizes using ease tant alfa was instilled
serially numbered opa- 2. Primary cardiopulmo- over 30 to 120 sec-
que, sealed envelopes nary failure onds. CPAP was con-
3. Enrolled in any other tinued after the
interventional trial intervention.
In the control group,
infants were intu-
bated, MV was initi-
ated, and surfactant
was given via ET.
MV was
weaned as soon as
possible according to
the center’s standard
practice.
Halim et al29 Single-center RCT in the Inclusion 6F nasogastric tube Priori SS estimate: Need for invasive LISA vs. INSURE: LISA technique was
(2019) NICU of Pakistan Insti- 1. GA 34 wk was inserted 1–2 cm 43 infants in each mechanical 30 vs. 60% more effective than IN-
tute of Medical Scien- 2. Clinical and radiological past the vocal cords group ventilation (p ¼ 0.003) SURE in preventing the
ces, Islamabad, evidence of RDS treated under direct visuali- Enrolled and analyzed: need for invasive me-
Pakistan with CPAP zation using a laryn- 100 chanical ventilation
Randomization and Al- Exclusion goscope.100 mg/kg 50 (LISA group) vs. 50
location: 1. Major congenital mal- of beractant was ad- (INSURE group)
Random numbers using formations ministered while
a web-based randomi- 2. Intubation at birth CPAP was continued.

American Journal of Perinatology

zation tool INSURE Surfactant
(Comparison)
Premedication:

Vol. 41
not reported
Han et al30 (2020) Multicenter RCT at Inclusion 5F gastric tube was Priori SS estimate: Development of MISA V. EISA: Minimally invasive sur-
eight level III 1. GA < 316/7 wk inserted 1 cm past 130 infants in each bronchopulmonary 19.2 vs. 25.9% factant administration
NICUs in Beijing, Tian- 2. On NCPAP the vocal cords using group dysplasia (MV or (p ¼ 0.17) was not superior to en-

No. 2/2024
jin, and Hebei province, 3. Signs of a 10 cm ophthalmic Enrolled and analyzed: CPAP or FiO2 > 0.3 at dotracheal surfactant
Less Invasive Surfactant Administration

China respiratory distress with forceps and laryngo- 298 36 wk CGA) delivery concerning a
Randomization and Al- FiO2 >0.4 for SpO2 scope.70–100 mg/kg 151 (MISA group) vs. reduction in BPD
location: >85% of calf pulmonary 147 (EISA group)
Sequentially numbered 4. Surfactant need surfactant was ad-
opaque sealed within 6 h of life ministered while con-
Exclusion tinuing CPAP.

© 2023. The Author(s).

Mani, Rawat

(Continued)
219
 220

Table 2 (Continued)

Citation Design Population Intervention/ Analysis/ Primary outcome Results Conclusion

comparison sample
size
envelopes were used 1. Delivery room INSURE Surfactant
for the 1:1 assignment intubation (comparison)
2. Major Premedication: none
congenital malforma-

American Journal of Perinatology

tions
3. Death or transfer
4. Enrolled in other studies

Vol. 41
5 Repeat dose of
surfactant via ETT in
first 72 h

No. 2/2024
Dargaville et al31 Multicenter RCT at 33 Inclusion: A 16-gauge vascular Priori SS estimate: 606 Composite of death MIST vs. CPAP MIST technique of sur-
(2021) tertiary-level NICUs in catheter, or a propri- Enrolled and analyzed: prior to 36 wk PMA or 43.6 vs. 49.6% factant delivery
Less Invasive Surfactant Administration

[Link] 250/7–286/7 wk
11 countries 2. Inborn at a study center etary catheter (LISA- 485 BPD assessed at 36 (RR, 0.87; 95% CI, 0.74– did not cause a statisti-
Randomization and Al- and admitted to the cath), was inserted 241 (MIST group) vs. wk (oxygen 1.03, p ¼ 0.1) cally significant reduc-
location: NICU via direct laryngosco- 244 (control group) requirement) tion in the composite
Permuted block ran- 3. On CPAP/ NIPPV without py into the trachea to outcome of death or
domization with strati- prior intubation with a instill surfactant bronchopulmonary
fication using a CPAP level of 5–8 cm (200 mg/kg of porac- dysplasia.

© 2023. The Author(s).

Mani, Rawat

computer-generated H2O and requiring FIO2 tant alfa). CPAP was

code linked to a corre- of 0.30 within the first applied throughout
sponding opaque 6 h of life the procedure
sealed envelope Exclusion: Control (sham treat-
1:1 group assignment 1. Serious congenital ment):
Blinding: A screen was anomaly Transient reposition-
used to blind clinicians 2. Imminent need for ing with CPAP
and parents intubation Premedication:
Atropine, 25% su-
crose (optional)

Abbreviations: BW, birth weight; BPD, bronchopulmonary dysplasia; CI, confidence interval; CPAP, continuous positive airway pressure; EISA, endotracheal intubation surfactant administration; ETT, endotracheal
tube; FiO2, fraction of inspired oxygen; GA, gestational age; INSURE, intubate-surfactant-extubate; LISA, less invasive surfactant administration; MISA, minimally invasive surfactant administration; MIST,
minimally invasive surfactant therapy; MV, mechanical ventilation; NICU, neonatal intensive care unit; NIPPV, nasal intermittent positive pressure ventilation; PMA, postmenstrual age; PPV, positive pressure
ventilation; RCT, randomized controlled trial; RDS, respiratory distress syndrome; RITA, randomization in treatment arms; RR, relative risk; SS, sample size; TEC, thin endotracheal catheter.
 Less Invasive Surfactant Administration Mani, Rawat 221

Subsequently, a meta-analysis of six out of nine trials at the nasal interface leading to decreased deposition in the
showed that in preterm infants receiving nCPAP as the lungs could be a reason for the loss of efficacy.
respiratory support, the intratracheal catheter technique
for surfactant delivery compared with endotracheal intuba-
Comparison of Three Alternative Methods
tion was beneficial in terms of reduction in the composite
with INSURE
outcome of death or BPD at 36 weeks, BPD at 36 weeks among
survivors, and the need for mechanical ventilation with a Three alternative methods of surfactant delivery studied in the
trend toward lower rates of air leaks.33 last two decades have both advantages and limitations when
compared with each other (►Table 4). A recent network meta-
analysis compared their efficacy with INSURE.40 Sixteen RCTs
Noninvasive Surfactant Delivery by
and 20 observational studies with a large sample size
Aerosolization
(n ¼ 13,234) were included in the analysis. The primary out-
Early attempts to study surfactant delivery by aerosolization comes analyzed were mortality (n ¼ 12,155), the need for
through a jet nebulizer in an RCT showed no difference in the mechanical ventilation (n ¼ 5,961), and BPD (n ¼ 10,993).
arterial/alveolar PO2 and the need for mechanical ventila- The sample’s median GA and birth weights were 29 weeks 6
tion.34 The authors of this study felt that the failure of days (interquartile range [IQR]: 28 weeks 1 days–31 weeks)
effective aerosolized surfactant delivery could be the reason and 1,289 g (IQR: 1,040.8–1,622.5). Compared with the IN-
for their negative results. Finer et al showed the feasibility SURE method, surfactant delivery via a thin catheter alone and
and safety of aerosolized delivery of Aerosurf, a peptide- not SALSA or nebulization showed a significant decrease in
containing synthetic surfactant by nCPAP, to preterm infants mortality, need for mechanical ventilation (MV), and BPD. The
at risk for RDS using a clinically approved vibrating mem- significance of the difference in mortality and BPD seen with
brane nebulizer called Aeroneb Pro.35 Following this, an RCT the thin catheter method was lost when RCTs alone were
using aerosolized surfactant (poractant alfa) through a new- included for analysis. The main limitations of this study are the
generation vibrating membrane nebulizer called eFlow neo- pooling of the results from RCTs and observational studies, the
natal showed that early postnatal administration of nebu- exclusion of three RCTs involving SALSA as the interven-
lized surfactant might reduce the need for intubation in tion,17–19 two RCTs studying thin catheter technique,29,31
preterm infants with mild RDS (►Table 3).36 and one RCT comparing nebulized surfactant with usual
Among the two strata of preterm infants (29.0–31.6 and care,37 and lack of adequate representation of extremely
32.0–33.6 weeks of GA) studied in this trial, the nebulized preterm infants (<28 weeks) in the sample.
surfactant aided the successful establishment of noninvasive
support in the 32.0 to 33.6 weeks of group alone. This study’s
Conclusion
results were limited by the single-center enrollment and small
sample size (n ¼ 32/group). A recently published multicenter The need to find a LISA technique is a clinically relevant
pragmatic RCT including 457 infants (23–41 weeks of GA) used problem. The three alternative methods, namely surfactant
a modified Solarys nebulizer to deliver aerosolized surfactant delivery through (1) laryngeal mask, (2) thin intratracheal
into the mouth (►Fig. 3).37 The study has reported an approx- catheter, and (3) aerosolization, have shown promising
imately 50% reduction in the need for subsequent intubation results in clinical trials. Before broader adoption in routine
for liquid surfactant administration. This difference was not clinical practice, we must identify the most beneficial tech-
consistent among infants born at various GA strata, especially nique among the three alternative strategies. There is no RCT
extreme preterm infants. A single-center phase 2 trial investi- comparing these three techniques. An essential challenge of
gated four dosing schedules of beractant α delivered using two conducting well-designed RCT is the recruitment of partic-
nebulizers, compared the data between three gestational ipants. A multicenter RCT with a multiarm, multistage
strata, and found that aerosolized surfactant therapy is feasible (MAMS) design will be one way to move forward. MAMS
without serious adverse outcomes.38 trial design provides the benefit of a smaller sample size,
A multicenter RCT enrolled spontaneously breathing pre- shorter duration, lower cost, and a shared control arm.41
term infants (28.0–32.6 weeks of GA) with mild-to-moderate The recent RCTs, which have studied outcomes like death
RDS to investigate the safety, tolerability, and efficacy of and BPD rather than the need for invasive mechanical
nebulized poractant alfa, a porcine surfactant in comparison ventilation, have shown that equipoise still exists between
with nCPAP alone.39 After the interim evaluation of the first the alternative methods of surfactant delivery and nCPAP
120 randomized neonates, the trial was terminated prema- alone. So, future trials should have four arms comparing the
turely because the nebulized surfactant was found to have three surfactant delivery methods simultaneously with a
negligible efficacy in the study population. The authors control arm of nCPAP without surfactant. Those trials should
analyzed the randomized infants and found that the nebu- study the composite outcome of death or respiratory mor-
lized surfactant did not reduce the likelihood of intubation bidity as the primary outcome and report the adverse effects
within 72 hours of life compared with CPAP alone. Although of each modality of surfactant delivery, other short-term
the trial was conceptualized based on robust preclinical data, morbidities, and long-term neurodevelopmental outcomes.
it could not be translated to clinical efficacy. The authors Such trials can be resource intensive during the initial
speculate that significant surfactant aerosol loss due to a leak phases, but they might have the potential to provide

American Journal of Perinatology Vol. 41 No. 2/2024 © 2023. The Author(s).

 222

Table 3 Clinical trials for surfactant delivery by aerosolization

Citation Design Population Intervention/ Analysis/sample size Outcomes Results Conclusion

comparison
Berggren Multicenter RCT was Inclusion A jet nebulizer (Aiolos Priori SS estimate – Need for MV Nebulized surfactant No beneficial effects of
et al34 (2000) conducted at six 1. GA <36 wk Karlstad, Sweden) was not reported group vs. CPAP group aerosolized surfactant
NICUs in Sweden 2. Age 2–36 h used to generate sur- Enrolled–34 infants 37.5 vs. 31.3% were demonstrated in this
Randomization and 3. Clinically and radio- factant aerosol and Analyzed–32 infants trial with a small sample
Allocation: Random- logically diagnosed was administered via 16 (nebulized surfac- size
ized using sealed progressive RDS the CPAP equipment tant group) vs. 16

American Journal of Perinatology

envelopes 4. Arterial/alveolar into the nostril. Dose - (CPAP group)
oxygen tension ra- 480 mg dry weight of
tio 0.15–0.22 poractant α

Vol. 41
5. FiO2 > 0.4 needed CPAP alone with no
to maintain SaO2 aerosols (control
85–95%. group)
6. No evident lung or

No. 2/2024
cardiovascular mal-
formation
Less Invasive Surfactant Administration

Exclusion
Not fulfilling the in-
clusion criteria
Minocchieri Single-center blinded Inclusion A customized vibrat- Priori SS estimate–70 Need for intubation Nebulized surfactant Nebulized surfactant in
et al36 (2019) RCT conducted in ter- 1. GA 290/7–336/7 wk ing membrane neb- (35 patients/group) within the first 72 h vs. CPAP alone the first 4 h of life reduced
tiary NICU in Western 2. Age < 4 h ulizer (eFlow neonatal Randomized and ana- 34.4 vs. 68.8% the need for intubation

© 2023. The Author(s).

Mani, Rawat

Australia 3. Clinical signs of nebulizer system, PARI lyzed: 64 (RR [95% CI]: 0.526 within the first 72 h in the
Randomization and mild-to-moderate Pharma, Starnberg) 32 in Nebulized sur- [0.292–0.950]) study population
Allocation: RDS requiring CPAP was used to adminis- factant group vs. 32 in
Computer-generated 5–8 cm H2O ter poractant alfa CPAP group
block stratified ran- 4. FiO2 requirement 200 mg/kg body Intention to treat
domization was used 0.22–0.30 to main- weight. analysis
with opaque sealed tain SpO2 86–94% Control – nasal bubble
sequentially num- Exclusion CPAP alone without
bered envelopes. [Link] intubation or surfactant.
Stratification was surfactant
based on GA: 290/7–- 2. Known pneumo-
316/7 wk and 320/7–- thorax
336/7 wk 3. Cardiorespiratory
instability
4. Cardiothoracic mal-
formation
5. Chromosomal
aberrations.
Cummings Multicenter RCT con- Inclusion The aerosol group re- Priori SS estimate Need for endotracheal Aerosol group vs. Aerosolized calfactant
et al37 (2020) ducted in 22 level Cohort 1 ceived 6 mL/kg ¼ 458 (229 patients intubation and liquid usual care group 26 administration reduces
three or four NICUs in 1. Nonintubated and body weight of 35 per group) surfactant administra- vs. 50% the need for intubation
the United States not received prior mg/mL calfactant Randomized and ana- tion within the first 4 d (p < 0.001) and liquid surfactant in-
Randomization and surfactant. suspension, 210 mg lyzed ¼ 457 stillation in infants with
Allocation: 2. Age >1 h but <12 h phospholipids/kg 230 in the aerosol mild-to-moderate RDS
Moses-Oakford algo- of life body weight, group vs. 227 in the during the first 4 d of life
rithm was used to 3. Suspected or con- through a modified usual care group
generate sequential firmed RDS Solarys nebulizer.
 Table 3 (Continued)

Citation Design Population Intervention/ Analysis/sample size Outcomes Results Conclusion

comparison
randomization codes. requiring nCPAP, Usual care group – Intention to treat
Two different codes HFNC, or NIV. determined as appro- analysis
were used to recruit Cohort 2 priate by the physician
two cohorts. 1. Age <24 h
2. Received liquid sur-
factant by 1 h of
age
3. Extubated to nasal
respiratory support
Exclusion
1. Congenital anomaly
2. Hypotension with
metabolic acidosis
(base deficit > 10
meq/L)
3. Hypoxemia (SpO2
<88%) or hyper-
capnia (paCO2 
60 mm Hg)
4. Grade 3 or 4 IVH or
acute hypoxic-is-
chemic
encephalopathy
Sood et al38 Single-center Phase II Inclusion: Nebulized beractant Priori SS estimate: 30 Four primary out- Dose I vs. Dose II vs. Aerosolized surfactant
(2021) RCT at a level III NICU 1. GA 240/7–366/7 with was administered in each dosing sched- comes: Dose III vs. Dose IV: therapy is feasible without
in the United States RDS through two types of ule 1. Safety 8 vs. 21% vs. 11 vs. any serious adverse out-
and 2. On noninvasive re- nebulizers (MiniHeart Randomized A. Surfactant reflux 13% comes. Short-term effica-
Computer-generated spiratory support Lo-Flo jet nebulizer and analyzed: 2. Feasibility (p < 0.05) cy was better
stratified block ran- with FiO2 25%, (WestMed) or the 149 3. Impact of different Data for primary out- than historical
domization assigned PEEP 4 cm H2O or AeroNeb Solo (Aero- dosing schedules comes 2 and 3 com- controls
patients to 4 groups at flow rate 2 LPM gen) vibrating mesh 4. Efficacy pared between three
a [Link] ratio for 8 h in the 1st nebulizer) attached to defined as the need for GA strata
24 h of life the inspiratory limb of intubation within 72 h Study was not pow-

American Journal of Perinatology

Exclusion: the noninvasive respi- of aerosolized ered for efficacy.
1. Unstable infants ratory support in four surfactant Efficacy was com-
requiring immedi- fixed doses pared with historical

Vol. 41
ate intubation Dose Schedule I: Sur- controls
2. Pneumothorax 3. vanta dose 100
Prior receipt of sur- mg/kg; dilution
factant 12.5 mg /

No. 2/2024
4. Serious congenital mL
Less Invasive Surfactant Administration

malformations Dose Schedule II: Sur-

5. Death anticipat- vanta dose 100
ed within 3 d. mg/kg; dilution 8.3
mg/mL
Dose Schedule III:
Survanta dose 200
mg/kg; dilution

© 2023. The Author(s).

Mani, Rawat

(Continued)
223
 224

Table 3 (Continued)

Citation Design Population Intervention/ Analysis/sample size Outcomes Results Conclusion

comparison
12.5 mg/
mL
Dose Schedule IV:
Survanta dose 200

American Journal of Perinatology

mg/kg; dilution
8.3 mg/
mL

Vol. 41
Dani et al39 Multicenter, open-la- Inclusion A vibrating membrane Priori SS estimate: Respiratory failure Group 1 vs. Group 3: Nebulized surfactant did
(2022) bel, [Link] 280/7–326/7 nebulizer (investiga- 252 (84 infants in each within 72 h 57 vs. 58% (p ¼ 0.926) not decrease the likeli-
RCT was conducted in 2. mild to moderate tional eFlow Neos, group) Group 2 vs. group 3: hood of respiratory failure
34 centers in six Euro- RDS PARI Randomized and ana- 49 vs. 58% (p ¼ 0.39) within the first 72 h of life

No. 2/2024
pean countries. 3. On nCPAP 5–8 cm Pharma GmbH) was lyzed: compared with CPAP
Less Invasive Surfactant Administration

Randomization and H2O with connected close to 126 alone

Allocation: FiO2 0.25–0.40 the patient between 42 (group 1) vs. 41
Computer-based bal- Exclusion: the nasal prongs (group 2) vs. 43
anced block randomi- 1. Intubation and the connection of (group 3)
zation scheme within 1 h after birth the ventilator circuit
2. Surfactant use be- to deliver poractant α
fore study in two doses - 200

© 2023. The Author(s).

Mani, Rawat

entry mg/kg (group 1)

3. RDS not secondary and 400 mg/kg (group
to surfactant defi- 2)
ciency Group 3: CPAP only
4. Severe asphyxia without surfactant
5. Major congenital
abnormalities 6.
PROM (>21 d) 7. Air
le-
ak
8. IVH  grade III
9. Hemodynamic
instability

Abbreviations: CI, confidence interval; FiO2, fraction of inspired oxygen; GA, gestational age; HFNC, high-flow nasal cannula; IVH, intraventricular hemorrhage; MV, mechanical ventilation; nCPAP, nasal continuous
positive airway pressure; NICU, neonatal intensive care unit; NIV, noninvasive ventilation; PEEP, positive end-expiratory pressure; PROM, prolonged rupture of membranes; RCT, randomized controlled trial; RDS,
respiratory distress syndrome; RR, relative risk; SS, sample size.
 Less Invasive Surfactant Administration Mani, Rawat 225

Fig. 3 Aerosolized surfactant delivered with the help of a modified Solarys nebulizer resembling a pacifier (Image courtesy: Dr. Satyan
Lakshminrusimha, modified with permission).

Table 4 Comparison of alternative methods of surfactant delivery

Alternative methods Laryngeal mask Thin catheter Aerosolization

of surfactant delivery
Advantages 1. Avoids complications due to direct 1. Can be used in the extremely 1. Truly a noninvasive strategy for
laryngoscope preterm infants surfactant delivery
2. Availability of the device in the NICU 2. Avoids PPV for surfactant ad- 2. Allows concurrent use of CPAP
3. Familiarity with the use of the device ministration 3. Avoids direct laryngoscopy and
among NICU providers. 3. Reduces the need for intuba- PPV
4. Ability to treat apnea/hypoxemia tion and mechanical ventila- 4. Some evidence for the reduced
(potential complication of surfactant tion in preterm infants need for intubation and me-
administration) with PPV - potential 4. Some evidence for a reduction chanical ventilation
complication of surfactant in BPD/mortality 5. No premedication is required
administration
Disadvantages 1. Interruption of CPAP during the pro- 1. Need direct laryngoscopy with 1. Optimal dose of surfactant for the
cedure the associated risks nebulization route is unknown
2. Need for PPV to disperse the surfac- 2. Need availability and use of 2. Deposition of a significant fraction
tant through the lungs. Magill forceps of the aerosolized dose in the
3. Cannot be used in extremely preterm 3. Need training and providers upper airways
infants with advanced skills. 3. Lack of an effective nebulizer to
4. Lack of evidence for a reduction in BPD 4. May need premedication aerosolize surfactant
5. Lack of evidence regarding the 4. Lack of evidence for use in severe
long-term neurodevelopmen- RDS
tal outcome 5. Data on the effect on BPD and
NDO is unavailable

Abbreviations: BPD, bronchopulmonary dysplasia; CPAP, continuous positive airway pressure; NDO, neurodevelopmental outcome; NICU, neonatal
intensive care unit; PPV, positive pressure ventilation; RDS, respiratory distress syndrome.

definitive data to make recommendations for standardized Acknowledgment

surfactant delivery techniques. We thank Dr. Satyan Lakshminrusimha, MD (Professor
and Chair of Pediatrics, UC Davis), and Ms. Sylvia Gugino,
Conflict of Interest MA (Senior Research Support Specialist, University at
None declared. Buffalo), for helping with the figures.

American Journal of Perinatology Vol. 41 No. 2/2024 © 2023. The Author(s).

226 Less Invasive Surfactant Administration Mani, Rawat

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