Research

Original Investigation

Minimally Invasive Surfactant Administration

in Preterm Infants
A Meta-narrative Review
Kiran More, MD, FRACP; Pankaj Sakhuja, MD; Prakesh S. Shah, MSc, MD, FRCPC

Supplemental content at
IMPORTANCE Surfactant administration by minimally invasive methods that allow for jamapediatrics.com
spontaneous breathing might be safer and more effective than administration with
endotracheal intubation and mechanical ventilation; however, the efficacy and safety of
minimally invasive methods have not been reviewed.

OBJECTIVE To conduct a meta-narrative review of the efficacy and safety of minimally

invasive surfactant administration using a thin catheter, aerosolization, a laryngeal mask
airway, and pharyngeal administration in preterm infants with or at risk for respiratory
distress syndrome.

DATA SOURCES We searched the PubMed, EMBASE, Cochrane, and CINAHL databases,
published journals, and conference proceedings from inception to June 30, 2013.

STUDY SELECTION Randomized clinical trials or observational studies of preterm infants who
were given surfactant for respiratory distress syndrome by minimally invasive methods.

DATA EXTRACTION AND SYNTHESIS An overall meta-narrative review was conducted

encompassing the evolution of noninvasive surfactant therapy. Risk ratios and 95%
confidence intervals are reported when appropriate.

MAIN OUTCOMES AND MEASURES Chronic lung disease diagnosed by the need for oxygen
therapy at a postmenstrual age of 36 weeks, need for mechanical ventilation within the first
72 hours of birth, need for mechanical ventilation any time during the hospital stay, and
adverse events associated with administration of surfactant by various methods.

RESULTS We included 10 studies (6 randomized and 4 observational) of 3081 neonates. Thin

catheter administration was evaluated in 6 studies (2 randomized and 4 observational);
aerosolization, in 2 randomized studies; and laryngeal mask and pharyngeal administration, in
1 observational study each. The meta-narrative review confirmed the slow evolution and
challenges of the different modes of administration, with thin catheter administration being
the most studied intervention. Two randomized studies of surfactant administration using a Author Affiliations: Department of
thin catheter revealed no significant difference in the outcome of bronchopulmonary Neonatology, Hospital for Sick
dysplasia but a potential reduction in the need for mechanical ventilation within 72 hours of Children, Toronto, Ontario, Canada
(More); Department of Paediatrics,
birth when compared with standard care.
King Hamad University Hospital,
Busaiteen, Kingdom of Bahrain
CONCLUSIONS AND RELEVANCE Surfactant administration via a thin catheter may be an (Sakhuja); Department of Paediatrics,
efficacious and potentially safe method; however, further studies are needed. Further studies Mount Sinai Hospital, Toronto,
Ontario, Canada (Shah); Department
are also needed for other methods of minimally invasive surfactant administration. of Paediatrics, University of Toronto,
Toronto, Ontario, Canada (Shah);
Institute of Health Policy,
Management and Evaluation,
University of Toronto, Toronto,
Ontario, Canada (Shah).
Corresponding Author: Prakesh S.
Shah, MSc, MD, FRCPC, Department
of Paediatrics, Mount Sinai Hospital,
Ste 19-231F, 600 University Ave,
JAMA Pediatr. 2014;168(10):901-908. doi:10.1001/jamapediatrics.2014.1148 Toronto, ON M5G 1X5, Canada
Published online August 4, 2014. (pshah@mtsinai.on.ca).

901

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 Research Original Investigation
N
eonatal respiratory distress syndrome (RDS) is asso-
ciated with high mortality and morbidity in preterm
infants. Surfactant therapy for RDS has been a major
achievement in the care of the preterm newborn.1,2 Surfac-
tant administration traditionally requires endotracheal intu-
bation and mechanical ventilation for a certain period. This
exposure to artificial ventilation, no matter how brief, is
responsible for mechanical (volutrauma and barotrauma) and
inflammatory mediator–induced (biotrauma) responses in
neonates that set the stage for chronic inflammatory pro-
cesses leading to bronchopulmonary dysplasia (BPD).3 The
use of noninvasive approaches such as nasal continuous
positive airway pressure (CPAP) without use of exogenous
surfactant has increased.4 However, nasal CPAP may lead to
pneumothorax in high-risk, surfactant-deficient preterm
infants.5 Moreover, conflicting results in terms of reduction
in BPD with early nasal CPAP compared with intubation have
been noted.5-7
To counter the effects of mechanical ventilation and opti-
mize benefits of early surfactant administration,8 the innova-
tive approach of intubation, surfactant administration during
brief mechanical ventilation, and extubation (the INSURE
technique) was introduced by Victorin et al.9 This concept
became popular. 10,11 The INSURE technique, however,
involves intubation with a brief period of apparent loss of
spontaneous breathing by infants. Subsequently, less invasive
modifications of the INSURE method for delivering surfactant
to avoid even brief intubation and mechanical ventilation
have been conceptualized, implemented, and empirically
evaluated with the aim of reducing intubation-related compli-
cations and improving the success of nasal CPAP after surfac-
tant administration. These modifications include intratra-
cheal surfactant instillation with the help of a thin catheter
(eg, nasogastric tube or vascular catheter),12-17 aerosolized
administration,18-20 pharyngeal administration,21 and laryn-
geal mask airway (LMA)–guided administration.22-24 All of
these techniques have the underlying premise of administer-
ing surfactant while maintaining spontaneous breathing but
have produced variable success. Many centers around the
world have adopted some of these practices based on prelimi-
nary results.
Our objective was to perform a meta-narrative review
encompassing the conceptualization, implementation, and
evaluation of the efficacy and safety of minimally invasive
methods of surfactant administration in preterm infants
with or at risk for RDS with the potential for meta-analysis
of studies comparing similar interventions. The INSURE
technique has been well studied in a Cochrane review by
Stevens et al25 and moreover involves brief loss of spontane-
ous breathing, so it was not included in our meta-narrative
review.
Methods
We used the method described by Greenhalgh et al26 to con-
duct this meta-narrative review27 and planned traditional
methods for conducting meta-analyses when appropriate. This
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Minimally Invasive Surfactant Administration
method is used when various techniques or interventions on
a theme have been conceptualized differently and has been
studied by different research groups over time.27 In this meta-
narrative review, we sought to identify and evaluate different
techniques of surfactant administration while the infant is
breathing spontaneously and then to synthesize them by means
of an overarching narrative. Review of search, study selec-
tion, data extraction, risk of bias assessment, and analyses were
performed by two of us (K.M. and P.S.) independently, and dis-
crepancies were resolved by discussion and arbitration by the
third author (P.S.S.).
Guiding Principles
A preliminary review of the literature identified 4 different
methods of surfactant administration. We evaluated the evo-
lution, safety, and efficacy of the following methods:
1. Thin catheter administration
2. Aerosolized or nebulized route
3. LMA-guided administration
4. Pharyngeal route
Scoping of the Literature
After extensive discussion, we developed and finalized search
terms in consultation with an experienced librarian. Initial
searches were led by prior knowledge, content experts’ pub-
lications, and review of nonsystematic reviews. We searched
the PubMed, EMBASE, Cochrane, and CINAHL databases from
inception until June 30, 2013. We used database-specific terms
without language restrictions. The reference lists of identi-
fied studies, key review articles, and conference proceedings
of the annual meetings of the Pediatric Academic Society (2008-
2013) were searched (details are available in the eMethods in
the Supplement).
Mapping Phase
The next steps involved mapping the various approaches ac-
cording to theoretical construct, concept development, and
methodologic implementation. The following factors were cen-
tral to the development of this phase. First, we considered the
type of participants and interventions. We included studies of
preterm infants (gestational age, <37 weeks) who received sur-
factant for RDS or received prophylactic surfactant because
they were considered at risk for RDS. Surfactant administra-
tion for term infants was not included. Second, we consid-
ered the type of studies. We restricted this review to random-
ized clinical trials (RCTs) and observational studies with
concurrent or historical controls. Case reports, case series, let-
ters to editors, editorials, review articles, and commentaries
were read to identify theoretical background, concept devel-
opment, and progress but were not included in the synthesis.
Duplicate reports were excluded. Third, we considered out-
comes, including efficacy and safety. Efficacy outcomes in-
cluded BPD or chronic lung disease diagnosed by the need for
oxygen at a postmenstrual age of 36 weeks and the need for
mechanical ventilation within the first 72 hours of birth. Safety
outcomes included adverse events during interventions, such
as bradycardia, desaturation, apnea, pneumothorax, and pul-
monary hemorrhage.
jamapediatrics.com
 Minimally Invasive Surfactant Administration Original Investigation Research

Selection and Appraisal Phase Figure 1. Flow Diagram Describing Study Selection for Inclusion
We extracted data on conceptual modeling, theoretical con- in Meta-narrative Review
struct, and implementation strategies in the form of study de-
sign, patient characteristics, and outcomes. We contacted the 2128 Records identified through 34 Additional records identified
principal authors of studies included in this review for clari- database searching through other sources
fications and/or additional data when needed.
For appraisal of evidence in randomized studies, we used 2015 Records after
duplicates removed
the Cochrane Handbook’s risk of bias assessment tool.28 For
observational studies, the risk of bias in selection, exposure
assessment, outcome assessment, attrition, and confound- 2015 Records screened 1985 Records excluded
ing factors was assessed using the Newcastle-Ottawa Scale.29
30 Full-text articles 20 Full-text articles excluded
Analysis and Synthesis Phase assessed for eligibility 6 Case series
6 Not meeting inclusion
Two methods of synthesis were applied. First, a narrative criteria
account of each method of surfactant administration was 10 Studies included in 2 Overlap of data
meta-review and 6 Review articles/others
described. This description included detailing the historical qualitative synthesis
aspects of each method, eventual concept modifications, and
later comparative evaluations. This narrative was used as the
main frame of this review. Second, a quantitative summary Thin catheter/ Aerosolized LMA-guided Pharyngeal
was planned as traditional meta-analysis in the absence of sig- NG tube administration administration administration
administration 2 RCTs 1 RCT 1 RCT
nificant clinical heterogeneity. Because conceptual and meth- 2 RCTs and 4
odologic differences exist between RCTs and observational observational trials
studies, we did not combine information from RCTs and
observational studies in a single statistical analysis. This LMA indicates laryngeal mask airway; NG, nasogastric; and RCT, randomized
hybrid method allowed for exploration of the full spectrum of clinical trial.
the underlying construct of minimally invasive surfactant
administration.
studies13,30,37,38 in different gestational age groups has dem-
onstrated improving success over time as their learning curve
improved. This technique has been adopted increasingly and
Results was tested further in another observational study17 and 2
Selection and Appraisal Phase RCTs.12,16 Dargaville et al15 introduced a modified thin cath-
The results of the literature search, the study selection log, and eter technique by using a semirigid vascular catheter in 25 pre-
the number of studies are reported in Figure 1. The baseline term infants with gestational ages of 25 to 34 weeks. More re-
characteristics of the 10 studies selected12,14,16-18,30-34 under sults were reported after the study was extended to 2 more
each method of surfactant administration, which include a total centers.38
of 3081 neonates, are described in Table 1. We excluded 20 stud- This method of less invasive surfactant administration by
ies, and the reasons for exclusion are given in the eTable in the thin catheter or vascular catheter has been studied in 4 com-
Supplement. The timeline of the evolution of different meth- parative observational studies14,17,30,31 and 2 RCTs12,16 in-
ods of surfactant administration is described in Figure 2. cluded in our meta-narrative review, encompassing a total of
2631 neonates. In the included studies, surfactant was admin-
Risk of Bias Among Included Studies istered as rescue therapy after meeting predefined respira-
The risk of bias assessment among the included RCTs12,16,18,32-34 tory criteria except for the study by Klebermass-Schrehof et
and cohort studies14,17,30,31 is reported in Table 2 and Table 3, al,17 in which surfactant was administered prophylactically to
respectively. Most studies had low to moderate risk of bias all extremely premature infants (gestational age, 23-27 weeks)6
(score, 6-8 of a total 10). Most bias stemmed from selection of in the intervention group.
control subjects and lack of adjustment for confounders. The
results of our appraisal of the evolution and efficacy of the Evidence From Observational Studies
methods of surfactant administration of interest are de-
scribed below. Efficacy | Kribs13 compared outcomes after surfactant admin-
istration via a thin catheter with those of a historical cohort
Method 1: Thin Catheter who received standard care. In the first study of 64 extremely
The use of a thin catheter for surfactant administration was low-birth-weight infants by Kribs et al,14 the investigators dem-
first described in 1992 by Verder et al36 in 6 of 34 infants in a onstrated the feasibility of using this new technique. They
pilot study of neonates primarily treated with nasal CPAP. Kribs found no significant reduction in the need for mechanical ven-
et al14 reported the first quantitative assessment of the out- tilation or BPD. In a subsequent historical comparative study,
come of surfactant instillation using a thin, flexible intratra- Kribs et al30 described a significant reduction in BPD and the
cheal catheter in a feasibility study. Since then, a series of need for mechanical ventilation within 72 hours (Table 1). On

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 Research Original Investigation Minimally Invasive Surfactant Administration

Table 1. Characteristics of Included Studies

Design and Comparison Participants and
Source Population Treatment Intervention Results
Method 1: Administration of Surfactant via Thin Catheter
Kribs et al,14 Nonrandomized feasibility ET instillation 29 I and 34 C; FIo2, BPD: 14% I vs 15% C (NS);
2007 study; ELBW infants with >0.4: 100 mg/kg mortality: 12% I vs 35% C
GA, 23-27 wk surfactant (P = .025)
Kribs et al,30 Prospective cohort study; ET instillation 319 I and 1222 C MV in first 72 h: 29% I vs 53%
2010 VLBW infants or GA, C (P < .001); BPD: 11% I vs
<31 wk 18% C (P = .004)
Göpel et al,12 RCT; VLBW infants or GA, CPAP followed 108 I and 112 C MV on day 2-3: RR, 0.68 (95%
2011 26-286 wk, age <12 h by ET instillation CI, 0.42-0.88); MV at any
time: RR, 0.42 (95% CI,
0.31-0.59); BPD: RR,
0.62 (95% CI, 0.27-1.40)
Dargaville et al,31 Nonrandomized study Routine CPAP 38 I and 41 C: GA, MV at 72 h, GA, 25-28 wk: OR,
2013 (historical controls); GA, and ET 25-28 wk; 23 I and 0.21 (95% CI, 0.08-0.55); MV
25-34 wk, age, <24 h instillation 56 C: GA, 29-34 wk at 72 h, GA, 29-34 wk: OR
0.34 (95% CI, 0.11-1.0); BPD:
29% I vs 29% C (P = .85)
Klebermass- Nonrandomized study CPAP, ET 224 I and 182 C MV need at 3 d: 23% I vs 52% C
Schrehof et al,17 (historical controls); instillation (P < .001); BPD: 16% I vs 12%
2013 GA, 23-27 wk, at birth C (NS)
Kanmaz et al,16 RCT; GA, <32 wk; INSURE method 100 C and 100 I MV within 72 h: 30% I vs 45%
2013 age, <72 h (porcine surfactant, C (P = .02) (reported); MV at
100 mg/kga) any time: 40% I vs 49% C Abbreviations:
(P = .08); BPD: 10% I vs 20% C BPD, bronchopulmonary dysplasia;
(P = .009)
BW, birth weight; C, comparison;
Method 2: Surfactant Administration via Aerosolb CPAP, continuous positive airway
Berggren et al, 18
RCT; GA, 27-36 wk; CPAP 16 C and 16 I Need for MV: 38% C vs 31% I pressure; ELBW, extremely low birth
2000 randomized at 2-36 h; (porcine surfactant, (NS); BPD: 12.5% C vs 0% I weight; ET, endotracheal;
FIo2 >0.4 480 mga) (NS) FIo2, fraction of inspired oxygen;
Minocchieri RCT; GA, 29-33 wk; FIo2, CPAP N = 64; I (porcine Need for intubation in the first GA, gestational age; I, intervention;
et al,32 2013 0.22-0.30 in first 6 h surfactanta) vs C 72 h: RR, 0.56 (95% CI, INSURE, intubation, surfactant
after birth 0.34-0.93); BPD: no administration during brief
difference (numbers not given) mechanical ventilation, and
Method 3: Surfactant Administration via LMA extubation; LMA, laryngeal mask
airway; MV, mechanical ventilation;
Attridge et al,33 RCT; BW, ≥1200 g; ET instillation 13 I (calfactant MV need within 96 h:
2013 age at inclusion, ≤72 h surfactant, 3 mL/kg) RR, 1.0 (95% CI, 0.25-4.07) NS, not significant; OR, odds ratio;
and 13 C RCT, randomized clinical trial;
RDS, respiratory distress syndrome;
Method 4: Surfactant Administration via Nasopharyngeal Instillation
RR, relative risk; VLBW, very low birth
Ten Centre Study RCT; GA, 25-29 wk Saline 43 I and 32 C: 25-26 Mortality: 19% I vs 30% C weight.
Group,34 1987 wk; 116 I and 117 C: (P < .01); respiratory support a
27-29 wk in first 10 d: I group, 19 h less Indicates Curosurf (Chiesi USA, Inc).
in >30% oxygen (P < .05) and b
Indicates CPAP plus nebulized
20 h less ventilation (P < .05)
surfactant.

Figure 2. Timeline for Evolution of Techniques for Surfactant Administration While Maintaining Spontaneous Breathing

Method Source Gopel et al,12 2011a

Kanmaz et al,16 2013a
Dargaville et al,31 2013
Thin catheter Verder et al,36 Kribs et al,14 Kribs et al,30 Klebermass-Schrehof
administration 1992 2007 2010 et al,17 2013

Aerosolized Jorch et al,39 Berggren et al,18 Minocchieri et al,32

administration 1997 2000a 2013

LMA-guided Trevisanauto et al,22 Attridge et al,33

administration 2005 2013

Pharyngeal Ten Centre Study Dambeanu et al,35 Kattwinkel et al,21

administration Group,34 1987 1997 2004

1985 1990 1995 2000 2005 2010 2013

Year

LMA indicates laryngeal mask airway.

a
Indicates randomized clinical trial.

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 Minimally Invasive Surfactant Administration Original Investigation Research

Table 2. Risk of Bias Assessment for Included Randomized Clinical Trials

Bias
Selection
Random Performance: Detection: Attrition:
Sequence Allocation Blinding of Participant Blinding of Outcome Incomplete Selective Other
Source Generation Concealment and Personnel Assessment Outcome Data Reporting Sources Overall
Kanmaz et al,16 Low risk Low risk Low risk Low risk Low risk Low risk Unclear Low risk
2013 risk
Minocchieri Low risk Low risk High risk Low risk Low risk Unclear risk Unclear Moderate
et al,32 2013 risk risk
Göpel et al,12 Low risk Low risk High risk Low risk Low risk Unclear risk High risk Moderate
2011 risk
Attridge et al,33 Low risk Low risk High risk High risk Low risk Low risk High risk Moderate
2013 risk
Berggren et al,18 Low risk Low risk High risk High risk Low risk Unclear risk High risk High risk
2000
Ten Centre Study Low risk Low risk Low risk Low risk Low risk Low risk High risk Moderate
Group,34 1987 risk

Table 3. Risk of Bias Assessment for Included Cohort Studies

Selectiona Outcomec
Demonstration Comparability Study
Selection That Outcome of Cohorts Controls Follow-up
Representa- of the of Interest Was on the Basis for Any Long Enough
tiveness of the Nonexposed Ascertainment Not Present at of the Design Additional Assessment for Outcomes Overall
Source Exposed Cohort Cohort of Exposure Start of Study or Analysisb Factor of Outcome to Occur Scored
Kribs et al,14 1 1 1 1 1 0 1 1 7
2007
Kribs et al,30 1 1 1 1 1 0 1 1 7
2010
Dargaville 1 1 1 1 1 0 1 1 7
et al,31 2013
Klebermass- 1 1 1 1 1 0 1 1 7
Schrehof
et al,17 2013
a
Indicates a maximum of 4 points.
b
Indicates a maximum of 2 points.
c
Indicates a maximum of 3 points.
d
Indicates a maximum of 9 points.

the contrary, Dargaville et al31 reported a reduction in me-
chanical ventilation at 72 hours but no difference in BPD using
the thin catheter technique. A slightly modified approach was
used by Klebermass-Schrehof et al.17 They used high-flow CPAP
delivered initially by facial mask followed by nasopharyngeal
tube, followed in turn by administration of surfactant via a thin
catheter inserted with help of laryngoscope and Magill for-
ceps without any premedication. They reported significant re-
duction in mechanical ventilation at days 1 and 3 and in the
first week of life but no significant difference in BPD between
the study group and controls (Table 1). Two studies17,31 re-
ported outcomes for extremely premature infants (gesta-
tional age, <28 weeks) and showed that thin catheter inter-
vention can also be useful by reducing early need for
mechanical ventilation, but no difference in BPD was identi-
fied. However, the number of infants with younger gesta-
tional ages described in these studies remains small.
Safety | All 4 observational studies14,17,30,31 reported few epi-
sodes of bradycardia or desaturations during the procedure,
requiring a temporary halt in the procedure or the use of posi-
tive pressure ventilation. The study by Dargaville et al31 was
an exception, with episodes of bradycardia of longer than 10
seconds occurring in 39% of infants with gestational ages of
25 to 28 weeks. None of the studies reported any significant
harm with any of the techniques.
Evidence From RCTs
Efficacy | Two RCTs12,16 have evaluated the thin catheter inter-
vention. Kanmaz et al16 compared the INSURE method with
intratracheal surfactant administration using nasogastric tub-
ing as a catheter in 200 preterm newborn infants. They de-
scribed a reduction in the need for mechanical ventilation at
72 hours in the thin catheter group. The incidence of BPD was
also relatively low in the intervention group (Table 1). Göpel
et al12 compared the standard method of care with surfactant
administration via a thin catheter in 220 very-low-birth-
weight neonates with gestational ages of less than 29 weeks
and reported a reduction in the need for mechanical ventila-
tion in the intervention group. Kanmaz et al16 reported a sig-
nificant reduction in the incidence of BPD (P = .009) in the in-
tervention vs control groups; however, we could not reproduce
the results from the numbers given in their study (P = .08).

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 Research Original Investigation
Because of apparent clinical heterogeneity between study
groups and the method for selection for outcome assess-
ment, we have not conducted a meta-analysis with these data.
We presented them for comparative evaluation in eFigure 1 in
the Supplement.
Safety | Kanmaz et al16 reported that bradycardia and desatu-
ration rates were similar in both groups in their study; how-
ever, they observed that surfactant reflux during administra-
tion via a thin catheter was significantly higher than in the
INSURE group (21% vs 10%; P = .002). Twelve percent of in-
fants had severe apnea lasting 20 seconds and bradycardia
(<100 beats/min) requiring positive-pressure ventilation with
a T-piece device during surfactant administration via a thin
catheter. Göpel et al12 reported episodes of bradycardia and sig-
nificant desaturation in 5% of the neonates in their interven-
tion group.
Method 2: Aerosolized or Nebulized Route
Aerosolized surfactant was evaluated in animal studies in the
early 1990s; however, the first human study was published in
1997 by Jorch et al,39 who conducted an uncontrolled multi-
center feasibility study in 20 infants. Since then, this method
has been tested in 2 RCTs.18,32 Arroe et al40 conducted an un-
controlled observational study in preterm infants and dem-
onstrated no benefits from nebulized surfactant. Finer et al41
conducted a feasibility study and suggested that aerosolized
surfactant was well tolerated and might reduce the need for
endotracheal intubation. No adverse effects were reported
apart from transient desaturation.
Berggren et al18 compared infants treated with aerosol-
ized surfactant with control infants who did not receive sur-
factant and reported no difference in the need for mechani-
cal ventilation or incidence of BPD. Minocchieri et al 32
conducted an RCT of aerosolized porcine surfactant (Curo-
surf; Chiesi USA, Inc) vs CPAP alone and demonstrated a de-
crease in the need for intubation in the first 72 hours; how-
ever, they found no difference in the incidence of BPD.
Method 3: LMA-Guided Administration
The first attempt at surfactant instillation using an LMA was
described in a case series of 8 infants by Trevisanuto et al22 with
limited demonstrable benefits. This method was subse-
quently tested in 1 RCT of 26 newborns by Attridge et al33 who
reported that surfactant administration via an LMA resulted
in a reduction in the mean fraction of inspired oxygen require-
ment for 12 hours after the intervention; however, no signifi-
cant difference was reported in the subsequent need for me-
chanical ventilation or BPD (Table 1). Adverse events reported
included hypoxia and bradycardia during surfactant admin-
istration, laryngospasm, and malposition of the LMA.33
Method 4: Pharyngeal Route
The first trial of nasopharyngeal surfactant administration
was conducted by the Ten Centre Study Group in 1987 in 328
infants. 34 A decrease in the severity of RDS, the use of
mechanical ventilation in the first 10 days, and incidence of
mortality were observed (Table 1). However, with the theo-
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Minimally Invasive Surfactant Administration
retical uncertainty about the amount of surfactant that actu-
ally gets delivered into the trachea, this approach has only
been investigated further in a small case series by Kattwinkel
et al.21
Synthesis Phase
We found significant clinical heterogeneity among included
studies with differences in study design, gestational age, spe-
cific surfactant products, and indication of therapy, so meta-
analysis was not performed. In addition, the standard care
mentioned in the control group varied between studies, as in-
dicated in Table 1. The data from Kanmaz et al16 and Göpel et
al12 were included for comparison but not for meta-analysis
owing to clinical heterogeneity.
Bronchopulmonary Dysplasia
We found no statistically significant reduction in BPD in both
studies12,16 in which infants underwent analysis on an inten-
tion-to-treat basis (eFigure 1 in the Supplement). We caution
that Kanmaz et al16 reported a treatment effect (P = .05) in fa-
vor of surfactant administration via a thin catheter, a result that
we could not reproduce using the published numbers.
Need for Mechanical Ventilation Within 72 Hours of Birth
Göpel et al12 reported the reduction in the need for mechani-
cal ventilation from 25 to 72 hours of birth. Kanmaz et al16 de-
scribed a significant reduction in mechanical ventilation within
72 hours of birth for the intervention group compared with the
INSURE group (eFigure 2 in the Supplement).
Discussion
To our knowledge, this review is the first systematic meta-
narrative to examine various minimally invasive methods of
surfactant administration while maintaining spontaneous
breathing in the preterm infant with or at risk for RDS. This re-
view of 10 studies (a combination of RCTs and observational
studies) indicates a growing interest in such methods of sur-
factant administration. Current evidence suggests that admin-
istration via a thin catheter is a feasible, potentially effective,
and safe method of minimally invasive surfactant adminis-
tration. Meta-analysis was not conducted in lieu of signifi-
cant heterogeneity between studies. We found synchrony in
the results from observational studies and RCTs for thin cath-
eter use and neonatal outcomes. The thin catheter method may
also be safe and effective in infants born at an extreme gesta-
tional age of less than 28 weeks. On the other hand, adminis-
tration by an aerosolized, a pharyngeal, or an LMA-guided route
was not shown to be beneficial to neonatal outcomes in a small
series of studies. From the safety perspective, all described
methods were well tolerated except for the occurrence of short-
lasting events such as bradycardia and desaturations that re-
verted back quickly with minor interventions.
Bronchopulmonary dysplasia described in the presurfac-
tant era was mainly the consequence of barotrauma and the
toxic effects of oxygen administration. Thus, approaches to
minimize mechanical damage to the lungs were developed with
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 Minimally Invasive Surfactant Administration Original Investigation Research

an increasing trend toward use of noninvasive ventilation tech-
niques such as early nasal CPAP. Large randomized trials such
as the COIN (Continuous Positive Airway Pressure or Intuba-
tion at Birth) trial5 and the Surfactant Positive Airway Pres-
sure and Pulse Oximetry Randomised Trial (SUPPORT)6 have
demonstrated that early use of nasal CPAP is a safe and effi-
cacious alternative to intubation and prophylactic surfactant
administration. However, these trials did not show a signifi-
cant reduction in BPD.
For infants to benefit from surfactant therapy followed
by noninvasive ventilation, use of the INSURE technique
increased.9-11,39 The INSURE method, however, requires intu-
bation and brief mechanical ventilation, which in a preterm
neonate can cause significant hemodynamic instability,
including hypoxia, bradycardia, blood pressure fluctuation,
and an increase in intracranial pressure, and can trigger
pulmonary and systemic inflammation owing to apparent
asynchrony.42-44 Indeed, BPD results from the interaction of
many factors such as prolonged mechanical ventilation and
colonization of the airway with pathogens that may trigger an
inflammatory cascade.3 Although the overall incidence of BPD
has not been substantially modified by surfactant therapy, the
severity of BPD has been reduced.44
The lack of a reduction in the overall incidence of BPD af-
ter surfactant administration is likely owing to a reduction in
mortality, but it could also be due to the need for surfactant
administration with a period of endotracheal intubation and
exposure to barotrauma. Thus, attempts to evolve surfactant
therapy into a minimally invasive technique that can be used
while the infant is breathing spontaneously were initiated. At-
tempts at aerosolizing surfactant or administering it via an LMA
have indicated that these methods are potentially feasible.
However, the delivery of surfactant to the alveoli is highly un-
reliable, and aerosolization of surfactant is still a technical chal-
lenge owing to the particle size and the small airways of pre-
term neonates.45 The thin catheter technique appears to be
safer because it allows an infant to maintain spontaneous
breathing and ensures administration of surfactant into the tra-
chea in reasonable amounts.
This technique might have an equal appeal in resource-
rich and resource-poor settings. However, it requires patience
and skill. Despite being minimally invasive, the technique still
involves the use of a laryngoscope and a maneuver to visual-
ize the vocal cords in a relatively awake infant, which might
be perceived as equally traumatic, especially in hands of
untrained individuals. One of the major issues in mastering
this skill will be achieving success while avoiding the need for
sedatives and analgesics. Thus, other opportunities to keep
infants comfortable during this time need to be identified.
Furthermore, the application of different surfactant types and
volumes using this technique needs to be assessed. The
amount of surfactant lost and the need for repeated adminis-
tration of surfactant owing to loss during the procedure also
needs careful attention. The learning curve described by Kribs
et al13,30,37,38 is a perfect example of the understanding and
realization of the challenges one might face while attempting
this approach.
Conclusions
Overall, this meta-narrative review comprehensively summa-
rizes the methodologic details, effectiveness, and safety of the
different methods of surfactant administration while main-
taining spontaneous breathing. However, the RCTs were lim-
ited in their description of the individual methods and
included small samples. Observational studies37,38 had larger
samples but they were not looking at the specific question of
thin catheter instillation vs intubation as a method of surfac-
tant administration. The choice of surfactant also differed
between the studies, thus affecting generalizability. In addi-
tion, none of the studies evaluated early childhood neurode-
velopmental outcomes. Further, large RCTs are required to
assess the neonatal and childhood outcomes of infants
treated with early stabilization by CPAP followed by selective
surfactant administration by thin catheter compared with
those of infants treated with intubation as the method of sur-
factant administration.

ARTICLE INFORMATION Canadian Institutes of Health Research to conduct REFERENCES

Accepted for Publication: May 27, 2014.
Published Online: August 4, 2014.
doi:10.1001/jamapediatrics.2014.1148.
Author Contributions: Drs More and Shah had full
access to all the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: All authors.
Acquisition, analysis, or interpretation of data:
Sakhuja, Shah.
Drafting of the manuscript: More, Sakhuja.
Critical revision of the manuscript for important
intellectual content: Sakhuja, Shah.
Statistical analysis: More, Shah.
Study supervision: Shah.
Conflict of Interest Disclosures: None reported.
Funding/Support: Dr Shah is the recipient of an
Applied Research Chair Award in Reproductive and
Child Health Services and Policy Research from the
research projects involving maternal and child health.
Role of the Sponsor: The funding source had no
role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Additional Information: This study is registered with
the PROSPERO International Prospective Register of
Systematic Reviews (http://www.crd.york.ac.uk
/PROSPERO/). Identifier: CRD42013004455.
Additional Contributions: Wolfgang Göpel, MD,
provided additional data for inclusion in this review
from his study. Elizabeth Uleryk, BA, MLS, Hospital
for Sick Children, helped in conducting searches for
this project. Ruth Warre, PhD, from the Maternal-
Infant Care Research Centre, Mount Sinai Hospital,
provided editorial support. The Maternal-Infant
Care Research Centre is supported by the Ministry
of Health and Long-term Care, Ontario, Canada.
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