Accepted Article

DR. IOANNIS BELLOS (Orcid ID : 0000-0001-5088-5458)

DR. AAKASH PANDITA (Orcid ID : 0000-0001-5890-0974)

Article type : Review Article

TITLE
Systematic review found that using thin catheters to deliver surfactant to preterm neonates
was associated with reduced bronchopulmonary dysplasia and mechanical ventilation
Raffaella Panza1, Nicola Laforgia1, Ioannis Bellos2 , Aakash Pandita3

1. Neonatology and Neonatal Intensive care unit, Department of Biomedical Science and
Human Oncology, “Aldo Moro” University of Bari, Bari 70124, Italy
2. Laboratory of Experimental Surgery and Surgical Research N.S. Christeas, Athens
University Medical School, National and Kapodistrian University of Athens, Greece.
3. Department of Neonatology, SGPGIMS, U.P, India.

Short title: Delivering surfactant using thin catheters

Correspondence: Dr. Aakash Pandita, Consultant Neonatology, SGPGIMS, U.P, India. Email id:
aakash.pandita@gmail.com

Abbreviations
BPD, bronchopulmonary dysplasia; CPAP, continuous positive airway pressure; INSURE,
intubation surfactant extubation; LISA, less invasive surfactant administration; MIST, minimally
invasive surfactant therapy; RCTs, randomised controlled trials;RDS, respiratory distress
syndrome; SURE, surfactant without endotracheal tube intubation.

This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process, which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1111/APA.15374
This article is protected by copyright. All rights reserved
Accepted Article
ABSTRACT
Aim: Surfactant delivery is a cornerstone for managing respiratory distress in preterm neonates,
but data on the best surfactant delivery methods have been conflicting.
Methods: A systematic literature review using the PubMed, Embase, Cochrane Library and Web
of Science databases identified papers published up to 5th November 2019. Additional studies
were identified from trial registries, conference proceedings and the reference lists of the selected
papers.
Results: We identified 15 studies covering 4,926 preterm infants. The randomised controlled trials
(RCTs) and observational studies both showed significant reductions in early intubation rates with
less invasive surfactant administration (LISA), which uses thinner catheters. The relative risk
(RR) was 0.63 and the 95% confidence interval (95% CI) was 0.55-0.72 (p <0.01), with an odds
ratio (OR) of 0.40 and 95% CI of 0.35-0.45 (p<0.0001). The collective results from the RCTs
revealed a significant decrease in bronchopulmonary dysplasia (BPD) rates in the LISA groups
(RR, 0.47; 95% CI 0.33-0.66; p< 0.01). These findings were consistent with the observational
studies (OR 0.47; 95% CI 0.43-0.52; p< 0.01).
Conclusion: Using thin catheters to delivery surfactant in comaprision to intubate surfactant
extubate (INSURE) to newborn preterm infants with respiratory distress was associated with a
reduced incidence of BPD and less need for mechanical ventilation.

This article is protected by copyright. All rights reserved

 Key notes
Accepted Article
 A systematic literature review up to 5th November 2019 focused on the best surfactant
delivery methods and identified 15 studies covering 4,926 preterm infants.
 The randomised controlled trials (RCTs) and observational studies both showed
significant reductions in early intubation rates with surfactant without endotracheal tube
intubation (SURE), which uses thinner catheters in comaprision to intubate surfactant
extubate (INSURE).
 In addition, the collective results from the RCTs revealed a significant decrease in
bronchopulmonary dysplasia rates in the LISA groups

Keywords
Bronchopulmonary dysplasia, less invasive surfactant administration, respiratory distress
syndrome, surfactant, thin catheters.

This article is protected by copyright. All rights reserved

 INTRODUCTION
Accepted Article
Respiratory distress syndrome (RDS) is the primary cause of respiratory insufficiency, mortality
and morbidity in preterm neonates. Together with mechanical ventilation, it plays a central role in
the pathophysiology of bronchopulmonary dysplasia (BPD), which remains a common morbidity
in preterm neonates(1). RDS is due to the lack of surfactant, which starts to synthesise at
approximately 20 weeks of gestation and reaches its peak from 36 weeks of gestation onwards(2).
Therefore, the incidence of RDS is inversely proportional to gestational age. It occurs in 60% of
infants born at less than 28 week of gestation and 30% of infants born between 28-34 weeks of
gestation(3). Early surfactant history was linked to surface tension. It dates back to 1765 when
Benjamin Franklin carried out his famous experiment calming the waves on a pond with a
teaspoon of oil(4). Before the intubation surfactant extubation technique (INSURE) was
developed, the majority of neonates with RDS were managed with mechanical ventilation as the
primary mode of respiratory support. Then in 1971 Dr Gregory(5) described the use of continuous
positive airway pressure (CPAP) for managing RDS, which was forgotten after a few years due to
the development of better ventilators(6,7). However, nasal CPAP enjoyed a renaissance after the
pioneering work by Verder et al in 1994(8). The authors demonstrated that using a combination of
CPAP and surfactant were associated with significant decreases in the need to provide mechanical
ventilation for preterm infant with RDS. Today, the main management plan for RDS is to secure
early delivery room nasal CPAP followed by early rescue surfactant. There is no role for
prophylactic surfactant(9–11). Exogenous surfactant replacement therapy rapidly improves
pulmonary gas exchange in preterm infants with RDS by maintaining the functional residual
capacity and decreasing the work of breathing(12). Traditionally, surfactant administration has
been performed through the endotracheal tube, either in mechanically-ventilated babies or in
babies supported with non-invasive ventilation using INSURE. The INSURE technique requires
intubation of the trachea and positive pressure ventilation, albeit for a relatively short time. This,
in turn, may still be associated with acute and chronic morbidities, including BPD(13). This
prompted research on alternative, and less invasive, surfactant administration techniques, which
principally aimed to avoid intubation and positive pressure ventilation. Surfactant delivery through
thin catheters has now gained popularity across the globe. These techniques are collectively
known as least invasive surfactant administration (LISA)14 or more appropriately surfactant
without endotracheal intubation (SURE)15. We have used the acronym SURE to simplify and
provide a uniform terminology. Our aim was to use a single term for all the surfactant delivery

This article is protected by copyright. All rights reserved

 methods that avoid endotracheal tube intubation and use thin catheters. These have also been
Accepted Article
called LISA, minimally invasive surfactant therapy (MIST)(16) and Take Care(17). Despite the
increasing number of observational and randomised controlled trials (RCTs) focusing on these
novel methods, there is still a lack of uniformity and consensus regarding the optimal mode of
surfactant delivery across the globe.

METHODS
A detailed search for eligible studies was performed using the PubMed, Embase, Cochrane
Library and Web of Science databases. We searched for all relevant papers published in English
up to 5th November 2019. The following medical subject headings were used: pulmonary
surfactants, respiratory distress syndrome, newborn, infant, newborn, neonate. Proper Boolean
operators AND and OR were also included to make the search as comprehensive as possible.
Additional studies were identified from trial registries, conference proceedings and the reference
lists of the selected papers. The literature search was carried out by 2 authors and identified 169
manuscripts.
Studies were held eligible if they were either observational studies or RCTs reporting clinical
outcomes among neonates with RDS treated with methods of administering surfactant via thin
catheter (nasogastric tube or angiocath) without intubation in comparison with surfactant delivery
via endotracheal tube. We excluded papers that reported on other alternative methods of surfactant
administration (i.e. laryngeal mask, nebulization or pharyngeal instillation) and single-arm studies
without control group.
Once the criteria had been applied the majority of them was excluded for not meeting the pre-
defined criteria and thus there were 19 papers retrieved to assess for eligibility. Then, having
studied the titles and abstracts, one was excluded as it was concerning use on laryngeal mask for
surfactant administration(18). There were 18 papers that underwent a review of the full text. Of
these: 1 was excluded because it evaluated exclusively the effects of different ventilation modes
during MIST procedure(19), and 2 were excluded because they reported either on diaphragmatic
activity(20) or on cerebral autoregulation(21) during the procedure. As a result, 15 manuscripts
finally were selected for this review.

RESULTS

This article is protected by copyright. All rights reserved

 This review evaluated the results of 15 studies, including six RCTs(15,17–21),
Accepted Article seven
observational studies(14,22–27) and two feasibility studies(16,28) (Table 1). Of these 15 studies,
three used data from the German Neonatal Network, which reflects the actual clinical practice in
more than 50 neonatal intensive care units across the country(14,22,23). These studies used a
matched-pair analysis in which each baby treated with the LISA technique was paired with a baby
from a historic cohort, using similar significant characteristics, such as gestational age and Apgar
scores. The studies presented in this review provide collective data from 4926 newborn infants
who received surfactant by the LISA/SURE technique. The inclusion criteria varied slightly in
each study (Table 1). The three studies based on the German Neonatal Network, enrolled very low
birth weight newborns, whereas the remaining studies used gestational age as the inclusion
criteria(15-17,21,24–28). Most of these studies assessed neonates below 32-34 weeks of gestation.
However, Teig et al, Kribs et al and Klebermass-Schrehof et al enrolled extremely preterm
neonates with lower gestational ages of 23-28+6, 23-26+6, and 23–27 weeks,
respectively(19,26,27). All the studies, except one (27), administered exogenous surfactant
replacement therapy according to a targeted approach based on the inspired fraction of oxygen,
CPAP requirements and the severity of RDS. The timing of surfactant varied from less than two to
24 hours of life (Table 1).
Procedure
Different techniques for surfactant delivery using thin catheters have been reported across the
globe (Table 2). All the authors stated that they used natural formulations of either bovine or
porcine surfactant at a dose of 100-200 mg/kg. However, the administration procedure and the
chosen devices varied among centres.

Kribs et al described a method using a 4F end-hole soft feeding tube marked with a wax pencil
approximately 1.5cm above one end(19). The newborn infant continued to receive nasal CPAP
during the procedure and Magill forceps were used during direct laryngoscopy to instill the
surfactant. The surfactant was introduced over 30 to 120 seconds by mini-boluses. This LISA
technique is widely used across Germany(19).

Dargaville et al conceptualised the so-called Hobart method, commonly known as the MIST
technique(28). In contrast to the method used by Kribs et al(19), this was performed with a semi-
rigid 16G vascular catheter, namely an angiocath that was 130mm in length. The catheter was

This article is protected by copyright. All rights reserved

 prepared with a marker pen by marking a point that indicated the desired depth of insertion
Accepted Article
beyond the vocal cords such, as 1.0cm for 25–26 weeks, 1.5cm for 27–28 weeks and 2.0cm for
29–34 weeks of gestation. During the procedure, CPAP was withdrawn. The authors did not use
Magill forceps. The exogenous surfactant was administered as a single bolus for 25–28 weeks of
gestation and as two boluses 10 seconds apart for 29–34 weeks. CPAP was resumed immediately
after surfactant administration(28).

Kanmaz et al described the Take Care procedure, in which exogenous surfactant was administered
through a 5F, flexible, sterile nasogastric tube cut at depth of 33cm from the catheter hub(17).
The desired depths of insertion beyond the vocal cords were comparable to those suggested for the
MIST method (28). CPAP support was continued during direct laryngoscopy and exogenous
surfactant was administered as a single bolus for 30 to 60 seconds without using any forceps(17).

In the largest RCT to date, Pandita et al reported another improved technique, referred to as
SURE(15). After direct laryngoscopy, a 16G angiocath or a 6F feeding tube was directly inserted
through the vocal cords to the desired depth with the hand. CPAP was continued throughout the
procedure and bovine lipid extract surfactant suspension, at a dose of 135 mg/kg, was given as a
single bolus over 60 to 90 seconds(15).

The vast majority of the studies (n=13) did not use any premedication before the procedure.
However, the Avoiding Mechanical Ventilation trial used sedation in 26% of the infants in the
LISA group(21). More recently, Dargaville et al suggested the administration of sucrose as an
alternative option for premedication(24).

Main outcomes
Most of the studies showed that LISA/SURE reduced the need for mechanical ventilation, ranging
from 7.2% to 42% in treated infants (14-18,20–22,24-28). However, Kribs et al reported a higher
rate of mechanical ventilation (74.8%) in the LISA group and this was probably due to the
extremely low gestational age (< 26+6 weeks) of the treated neonates(19). When pooled together,
the results from the RCTs in Table 1 showed a significant reduction in early intubation rates in the
LISA/SURE group (relative risk, 0.63; 95% CI 0.55-0.72; p<0.01). Similarly, the observational
studies in Table 1 showed lower rates of intubation in the first few days of life in the LISA/SURE

This article is protected by copyright. All rights reserved

 group (odds ratio, 0.40; 95% CI 0.35-0.45; p<0.0001). Interestingly, an observational study using
Accepted Article
a matched-pairs design with more than 1,000 infants showed that this result was reproducible in
clinical practice outside the specific trial setting(14). Furthermore two studies reported that
oxygen requirements, and the duration of respiratory support, were reduced with the LISA/SURE
methods(15,24).
However, the effect of LISA/SURE on the incidence of BPD remains controversial. While some
authors found a statistically significant reduction in BPD rates, others reported a similar incidence
of BPD to historical cohorts(14,24,25). The collective results from RCTs in Table 1 show a
significant decrease in BPD rates in the LISA/SURE group (relative risk, 0.47; 95% CI 0.33-0.66;
p<0.0001). This result was consistent to with the results from the observational studies reported in
Table 1 (odds ratio, 0.47; 95% CI 0.43 0.52; p<0.01).

Kribs et al and Gopel et al also reported a lower incidence of intraventricular haemorrhage with
LISA(14,19). Nonetheless, a significant decrease in intraventricular haemorrhage rates in the
LISA/SURE population was exclusively observed in the observational (Table 1), when pooled
together (odds ratio 0.46; 95% CI 0.41-0.52; p<0.01). Conversely, decreases in intraventricular
haemorrhage were not confirmed by the pooled RCTs (relative risk 0.73; 95% CI 0.44-1.20; p<
0.22) (Table 1). Alarmingly, Härtel et al reported an increased risk of focal intestinal perforation
in a subset of infants born at 23–24 weeks of gestational age who received LISA (odds ratio 1.49
(95% CI 1.14–1.95), p=0.002)(23). However, this finding was not reported by other studies and
requires further evaluation. In addition, Teig et al assessed 52% of discharged infants for
neurodevelopmental outcomes at a corrected age of 36 months. The authors reported an
improvement in the Mental Developmental Index (89 versus 98, p=0.16) and Physical
Developmental Index (83 versus 91, p=0.03) compared to historical controls(26). Unpublished
data from the five-year follow-up by the German Neonatal Network of infants who received LISA
suggested better lung function. Furthermore, the authors reported better neurodevelopmental
outcomes and intellectual properties using the Wechsler Preschool and Primary Scale of
Intelligence score in infants that received surfactant via LISA. However, the studies were non-
randomised and this means that selection bias cannot be ruled out. In addition, Bayley scores
differed widely between the different participating centres. Therefore, one team of investigators is
carrying out the ongoing follow up of the Kribs study. They are blinded to the study allocation of

This article is protected by copyright. All rights reserved

 the neonate’s treatment group and travel to the different study sites, so that investigators and
Accepted Article
equipment are identical for all infants(29).

Feasibility and safety

LISA/SURE procedures require specific training and should only be performed by neonatologists
or neonatal fellows that are specifically trained and familiar with the technique. The success rates
for the method are reported to be high(28). Surfactant reflux, desaturations, bradycardia and need
for manual ventilation have been reported with LISA/SURE. These complications were observed
in <10% to >30% across different trials(15,16,20). They were reported more frequently in
relatively mature premature infants when CPAP was discontinued during the procedure(20,24,28).
However, the use of thin diameter tubes, and the slow installation of surfactant while the CPAP
device stays in place, are likely to reduce the complications described above(29).

DISCUSSION
This review found the LISA/SURE techniques were associated with a decreased need for
mechanical ventilation and reductions in the incidence of BPD. According to the 2019 European
guidelines on the management of RDS, LISA should be the preferred mode of surfactant
delivery(30). Similar benefits were documented by previously published meta-analysis(31,32).
Furthermore, another network meta-analysis found LISA to be most beneficial(33). However,
there were various inbuilt biases in most of these studies. A number of factors need to standardised
before planning such trials. These are the antenatal steroid coverage, mode and initial setting of
noninvasive respiratory support, the criteria for giving surfactant, the type and dose of the
surfactant, the use of caffeine, the type of care, nutrition and the ventilation criteria (Table 3). The
gestational age and birth weight criteria for inclusion were also different among the published
studies. Furthermore, BPD has rarely been studied as a primary outcome in such trials, because of
the need for a larger sample size(34). Over the years, the incidence of BPD has remained the
same, despite good antenatal steroid coverage, use of caffeine, non-invasive ventilation and other
possible preventive measures. However, LISA/SURE is one such measure which has shown
promising results(31–33). The terminology is still confounding and somewhat misleading, since,
in real-life settings, LISA and MIST are often used interchangeably, despite having some major
differences. Moreover, newer, less invasive techniques are being introduced, such as those
employing laryngeal mask airway and nebulised surfactant, which is, in fact, the actual least

This article is protected by copyright. All rights reserved

 invasive method(35–37). Hence, the term SURE was introduced to encompass previously
Accepted Article
described methods like LISA/MIST and Take Care techniques(15). Furthermore, an editorial by
Pandita et al proposed a novel classification, the first of its kind for surfactant delivery methods
(Figure 1), to clarify these points(38). Studies assessing the effectiveness of LISA/SURE
techniques in neonates on heated humidified high-flow therapy are lacking and this may be of
relative importance, especially to centres that rely on this non-invasive ventilation mode(39,40).
This aspect, together with the urgent need for standardisation of practice and clear indications,
may account for the patchy uptake of this technique in some countries(41). Most of the authors in
our review opted out of administering premedication before the procedure, as it may have
interfered with cardiovascular function and the respiratory effort, both of which may be essential
for this method to work. However, more evidence is needed to get a clear picture. Nevertheless,
Dekker et al have conducted a study, published in 2018, that assesed the effectiveness of
intravenous propofol during MIST procedure in infants between 26 and 36 weeks of
gestational(42). The authors concluded that low-dose sedation increased comfort during the
procedure in preterm infants, but the need for transient non-invasive ventilation was also increased
in the sedation group. Therefore, some of the issues that need to be answered are premedication,
the dose of surfactant, use of caffeine, use with high flow, pain, physiological responses and
implementation protocols. A large international trial that evaluated MIST in preterm infants born
at 25-28 weeks of gestation is ongoing and may provide more answers(43). Furthermore,
nebulised and laryngeal mask airway may be the preferred mode of surfactant delivery if the
logistics involved are answered and countered appropriately.

CONCLUSION
Providing surfactant therapy via thin catheters in comaprision to intubate surfactant extubate
(INSURE) resulted in a reduced need for mechanical ventilation in neonates with RDS requiring
surfactant. It also decreased the incidence of BPD in this population.

Acknowledgments
We are grateful for the support of the families and of the colleagues of our NICUs.

Funding
This study did not receive any funding.

This article is protected by copyright. All rights reserved

Accepted Article
Competing interests
The authors have no conflicts of interest to declare.

This article is protected by copyright. All rights reserved

 References
Accepted Article
1. Blencowe H, Vos T, Lee AC, Philips R, Lozano R, Alvarado MR, et al. Estimates of
neonatal morbidities and disabilities at regional and global levels for 2010: introduction,
methods overview, and relevant findings from the Global Burden of Disease study. Pediatr
Res 2013; 74:4–16. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24366460
2. Ma CC-H, Ma S. The role of surfactant in respiratory distress syndrome. Open Respir Med
J 2012; 6:44–53. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22859930
3. Warren JB, Anderson JM. Core Concepts: Respiratory Distress Syndrome. Neoreviews
2009; 10:e351–61. Available from:
http://neoreviews.aappublications.org/cgi/doi/10.1542/neo.10-7-e351
4. Clements JA, Avery ME. Lung surfactant and neonatal respiratory distress syndrome. Am J
Respir Crit Care Med 1998; 157.
5. Gregory G, Kitterman J, Phibbs R, Tooley W, Hamilton W. Treatment of the Idiopathic
Respiratory-Distress Syndrome With Continuous Positive Airway Pressure. N Engl J Med
1971; 284:1333–40.
6. Victorin LH, Deverajan L V., Curstedt T, Robertson B. Surfactant replacement in
spontaneously breathing babies with hyaline membrane disease - a pilot study. Neonatology
1990; 58:121–6. Available from:
https://pubmed.ncbi.nlm.nih.gov/2279046/?from_single_result=Surfactant+replacement+in
+spontaneously+breathing+babies+with+hya-+line+membrane+disease+–
+a+pilot+study.&expanded_search_query=Surfactant+replacement+in+spontaneously+brea
thing+babies+with+hya-+
7. Verder H, Agertoft L, Albertsen P, Christensen NC, Curstedt T, Ebbesen F, et al. Surfactant
treatment of newborn infants with respiratory distress syndrome primarily treated with nasal
continuous positive air pressure. A pilot study. Ugeskr Laeger 1992; 154:2136–9. Available
from: http://www.ncbi.nlm.nih.gov/pubmed/1509593
8. Verder H, Albertsen P, Robertson B, Greisen G, Lundstrom K, Jacobsen T, et al. Surfactant
therapy and nasal continuous positive airway pressure for newborns with respiratory
distress syndrome. N Engl J Med 1994; 331:1051–5. Available from:
https://pubmed.ncbi.nlm.nih.gov/8090164/?from_sort=pubdate&from_term=Verder+H&fro
m_cauthor_id=9925870&from_pos=5
9. Stevens TP, Blennow M, Myers EW, Soll R. Early surfactant administration with brief

This article is protected by copyright. All rights reserved

Accepted Articleventilation vs. selective surfactant and continued mechanical ventilation for preterm infants
with or at risk for respiratory distress syndrome [Internet]. Cochrane Database of
Systematic Reviews. John Wiley & Sons, Ltd; 2007. Available from:
http://doi.wiley.com/10.1002/14651858.CD003063.pub3
10. Rojas-Reyes MX, Morley CJ, Soll R. Prophylactic versus selective use of surfactant in
preventing morbidity and mortality in preterm infants. In: Cochrane Database of Systematic
Reviews John Wiley & Sons, Ltd; 2012. Available from:
http://doi.wiley.com/10.1002/14651858.CD000510.pub2
11. Bahadue FL, Soll R. Early versus delayed selective surfactant treatment for neonatal
respiratory distress syndrome. Cochrane Database Syst Rev 2012. Available from:
http://doi.wiley.com/10.1002/14651858.CD001456.pub2
12. Bhutani VK, Bowen FW, Sivieri EM. Postnatal changes in pulmonary mechanics and
energetics of infants with respiratory distress syndrome following surfactant treatment. In:
Biology of the Neonate 2005. p. 323–31. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/15985755
13. Fischer HS, Buhrer C. Avoiding Endotracheal Ventilation to Prevent Bronchopulmonary
Dysplasia: A Meta-analysis. Pediatrics 2013; 132:e1351–60. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/24144716
14. Göpel W, Kribs A, Härtel C, Avenarius S, Teig N, Groneck P, et al. Less invasive
surfactant administration is associated with improved pulmonary outcomes in
spontaneously breathing preterm infants. Acta Paediatr 2015; 104:241–6. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/25474712
15. Jena SR, Bains HS, Pandita A, Verma A, Gupta V, Kallem VR, et al. Surfactant therapy in
premature babies: SurE or InSurE. Pediatr Pulmonol 2019:1–6. Available from:
http://dx.doi.org/10.1002/ppul.24479
16. Dargaville PA, Aiyappan A, Cornelius A, Williams C, De Paoli AG. Preliminary evaluation
of a new technique of minimally invasive surfactant therapy. Arch Dis Child - Fetal
Neonatal Ed 2011; 96:F243–8. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/20971722
17. Kanmaz HG, Erdeve O, Canpolat FE, Mutlu B, Dilmen U. Surfactant Administration via
Thin Catheter During Spontaneous Breathing: Randomized Controlled Trial. Pediatrics
2013; 131:e502–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23359581

This article is protected by copyright. All rights reserved

 18.
Accepted ArticleHalim A, Shirazi H, Riaz S, Gul SS, Ali W. Less invasive surfactant administration in
preterm infants with respiratory distress syndrome. J Coll Physicians Surg Pakistan 2019;
29:226–30. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30823947
19. Kribs A, Roll C, Göpel W, Wieg C, Groneck P, Laux R, et al. Nonintubated surfactant
application vs conventional therapy in extremely preterm infants: A randomized clinical
trial. JAMA Pediatr 2015; 169:723–30. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/26053341
20. Bao Y, Zhang G, Wu M, Ma L, Zhu J. A pilot study of less invasive surfactant
administration in very preterm infants in a Chinese tertiary center. BMC Pediatr 2015;
15:21. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25885964
21. Göpel W, Kribs A, Ziegler A, Laux R, Hoehn T, Wieg C, et al. Avoidance of mechanical
ventilation by surfactant treatment of spontaneously breathing preterm infants (AMV): an
open-label, randomised, controlled trial. Lancet 2011; 378:1627–34. Available from:
https://www.sciencedirect.com/science/article/pii/S0140673611609860
22. Langhammer K, Roth B, Kribs A, Göpel W, Kuntz L, Miedaner F. Treatment and outcome
data of very low birth weight infants treated with less invasive surfactant administration in
comparison to intubation and mechanical ventilation in the clinical setting of a cross-
sectional observational multicenter study. Eur J Pediatr 2018; 177:1207–17. Available
from: http://www.ncbi.nlm.nih.gov/pubmed/29808237
23. Härtel C, Paul P, Hanke K, Humberg A, Kribs A, Mehler K, et al. Less invasive surfactant
administration and complications of preterm birth. Sci Rep 2018; 8. Available from:
www.nature.com/scientificreports
24. Dargaville PA, Ali SKM, Jackson HD, Williams C, De Paoli AG. Impact of Minimally
Invasive Surfactant Therapy in Preterm Infants at 29-32 Weeks Gestation. Neonatology
2017; 113:7–14. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28922658
25. Tomar RS, Ghuliani R, Yadav D. RETRACTED ARTICLE: Effect of Surfactant Therapy
Using Orogastric Tube for Tracheal Catheterization in Preterm Newborns with Respiratory
Distress. Indian J Pediatr 2017; 84:257–61. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/28050683
26. Teig N, Weitkämper A, Rothermel J, Bigge N, Lilienthal E, Rossler L, et al. Observational
Study on Less Invasive Surfactant Administration (LISA) in Preterm Infants. Z Geburtshilfe
Neonatol 2015; 219:266–73.

This article is protected by copyright. All rights reserved

 27.
Accepted ArticleKlebermass-Schrehof K, Wald M, Schwindt J, Grill A, Prusa A-R, Haiden N, et al. Less
Invasive Surfactant Administration in Extremely Preterm Infants: Impact on Mortality and
Morbidity. Neonatology 2013; 103:252–8. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/23446061
28. Dargaville PA, Aiyappan A, De Paoli AG, Kuschel CA, Kamlin COF, Carlin JB, et al.
Minimally-invasive surfactant therapy in preterm infants on continuous positive airway
pressure. Arch Dis Child Fetal Neonatal Ed 2013; 98:F122-6. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/22684154
29. Herting E, Härtel C, Göpel W. Less invasive surfactant administration (LISA): chances and
limitations. Arch Dis Child - Fetal Neonatal Ed 2019:fetalneonatal-2018-316557.
30. Sweet DG, Carnielli V, Greisen G, Hallman M, Ozek E, Te Pas A, et al. European
Consensus Guidelines on the Management of Respiratory Distress Syndrome - 2019
Update. Neonatology 2019; 115:432–50.
31. Aldana-Aguirre JC, Pinto M, Featherstone RM, Kumar M. Less invasive surfactant
administration versus intubation for surfactant delivery in preterm infants with respiratory
distress syndrome: a systematic review and meta-analysis. Arch Dis Child - Fetal Neonatal
Ed 2017; 102:F17–23. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27852668
32. Rigo V, Lefebvre C, Broux I. Surfactant instillation in spontaneously breathing preterm
infants: a systematic review and meta-analysis. Eur J Pediatr 2016; 175:1933–42.
Available from:
https://pubmed.ncbi.nlm.nih.gov/27678511/?from_single_result=Surfactant+instillation+in
+spontaneously+breathing+preterm+infants%3A+a+systematic+review+and+meta-
analysis&expanded_search_query=Surfactant+instillation+in+spontaneously+breathing+pr
eterm+infan
33. Isayama T, Iwami H, McDonald S, Beyene J. Association of Noninvasive Ventilation
Strategies With Mortality and Bronchopulmonary Dysplasia Among Preterm Infants: A
Systematic Review and Meta-analysis. JAMA 2016; 316:611–24. Available from:
http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.10708
34. De Luca D, Shankar-Aguilera S, Centorrino R, Fortas F, Yousef N, Carnielli VP. Less
invasive surfactant administration: a word of caution. Lancet Child Adolesc Heal 2020;
4:331–40. Available from: http://www.ncbi.nlm.nih.gov/pubmed/32014122
35. Minocchieri S, Berry CA, Pillow JJ. Nebulised surfactant to reduce severity of respiratory

This article is protected by copyright. All rights reserved

Accepted Articledistress: A blinded, parallel, randomised controlled trial. Arch Dis Child Fetal Neonatal Ed
2019; 104:F313–9. Available from: http://fn.bmj.com/lookup/doi/10.1136/archdischild-
2018-315051
36. Roberts KD, Brown R, Lampland AL, Leone TA, Rudser KD, Finer NN, et al. Laryngeal
Mask Airway for Surfactant Administration in Neonates: A Randomized, Controlled Trial.
J Pediatr 2018; 193:40-46.e1. Available from:
https://linkinghub.elsevier.com/retrieve/pii/S0022347617313227
37. Vannozzi I, Ciantelli M, Moscuzza F, Scaramuzzo RT, Panizza D, Sigali E, et al. Catheter
and Laryngeal Mask Endotracheal Surfactant Therapy: the CALMEST approach as a novel
MIST technique. J Matern Neonatal Med 2017; 30:2375–7. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/27780385
38. Pandita A, Panza R. SURE or INSURE. Pediatr Pulmonol 2020; 55.
39. Zivanovic S, Scrivens A, Panza R, Reynolds P, Laforgia N, Ives KN, et al. Nasal High-
Flow Therapy as Primary Respiratory Support for Preterm Infants without the Need for
Rescue with Nasal Continuous Positive Airway Pressure. Neonatology 2019; 115:175–81.
Available from: http://www.ncbi.nlm.nih.gov/pubmed/30513521
40. Di Mauro A, Capozza M, Cotugno S, Tafuri S, Bianchi FP, Schettini F, et al. Nasal high
flow therapy in very low birth weight infants with mild respiratory distress syndrome: A
single center experience. Ital J Pediatr 2017; 43:1–8.
41. Bhayat S, Kaur A, Premadeva I, Reynolds P, Gowda H. Survey of less Invasive Surfactant
Administration in England, slow adoption and variable practice. Acta Paediatr
2019:apa.14995. Available from: http://www.ncbi.nlm.nih.gov/pubmed/31471992
42. Dekker J, Lopriore E, van Zanten HA, Tan RNGB, Hooper SB, te Pas AB. Sedation during
minimal invasive surfactant therapy: a randomised controlled trial. Arch Dis Child - Fetal
Neonatal Ed 2018; 104:fetalneonatal-2018-315015. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/30068669
43. Dargaville PA, Kamlin COF, De Paoli AG, Carlin JB, Orsini F, Soll RF, et al. The
OPTIMIST-A trial: evaluation of minimally-invasive surfactant therapy in preterm infants
25–28 weeks gestation. BMC Pediatr 2014; 14:213. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/25164872

This article is protected by copyright. All rights reserved

Accepted Article
Authors Type of Population Intervention Technique Surfactant Results Other
study And Comparison considerations

Jena el al.17 Multicentri 350 infants (175 babies in
c RCT each group)
≤34 weeks
RDS (FiO2 more than 30%
on CPAP of 6 cm H2O to
maintain saturation
between 90% and 95%)
First 6 hours of life
Surfactant administartion SurE: 16G Angiocath Neosurf (bovine lipid extract Significant reduction in the need for MV in the SurE Only 50 neonates
either by SurE or InSurE (Desilet; Vygon) or surfactant suspension) at 135 group (19% vs 40%, p <0.01; risk ratio [RR]= 0.49 [0.34‐ with a gestation of
technique feeding tube of 6 Fr mg/kg given as a single bolus 0.69]). less than 28 weeks.
prepared by over 60 to 90 seconds and the Duration of oxygen therapy, BPD, NEC, and duration of
marking a point tracheal catheter was NICU stay was significantly less in the SurE group.
indicating the immediately withdrawn
desired depth of
insertion beyond
the vocal cords.
Direct laryngoscopy.
No Magill forceps
and no
premedication.

Halim et al.24 Single 100 infants (50 babies in Surfactant administartion LISA: 6 Fr Survanta 100 mg/Kg delivered LISA patients had significantly less need of mechanical Pre-natal steroids
center RCT each group) either by LISA or INSURE nasogastric tube within 1-3 minutes in small ventilation {30% vs. 60%; p-value <0.05}. The median were given to 38
<34 weeks technique Direct laryngoscopy aliquots duration of mechanical ventilation was 40 hours (IQR 75) patients (76%) in
RDS (requiring FiO2 >0.4 on Catheter was in LISA and 71 hours (IQR 62) in INSURE group. Median LISA and 30 patients
nasal CPAP) passed 1-2 cm past FiO2 reduction was 30 (IQR 30) in LISA group and 25 (IQR (60%) in INSURE
First 12 hours of life the vocal cords 10) in INSURE group, p-value <0.05. There was no group.
significant difference in mortality, hospital stay and
complications.

This article is protected by copyright. All rights reserved

Accepted Article
Langhammer et Cross- 296 VLBW babies with Surfactant administration LISA: thin end-hole Surfactant (poractant alfa or The need for mechanical ventilation was significantly Infants of the
al.18 sectional need for intensive care either by LISA or catheter marked. beractant) at the recommended higher in the control group (86% vs 34%; p < 0.001) treatment group
observation Inborn, or admitted within intubation methods Direct laryngoscopy. dosage was applied slowly LISA-treated infants required significantly less mechanical received surfactant
al study the first 24 h of life (148 Magill forceps are ventilation during hospital stay (p <0.001) and days with via LISA or via LISA
German LISA group vs 148 used to grasp the supplemental oxygen (p = 0.03). Analgesics and sedatives and intubation.
Neonatal intubation group) catheter. were used less often during the stay (p < 0.001). Infants who
Network Surfactant administration Infants treated with LISA had significantly lower rates of received surfactant
(GNN) within 2 hours from birth bronchopulmonary dysplasia (p = 0.003). via LISA and
intubation were
more immature and
their
birth weight was
lower.

Härtel et al.20 Cohort 1214 infants never Surfactant administration Not specified Not specified LISA was superior to intubation for clinical and culture- LISA was associated
study received surfactant either by LISA or ETT confirmed sepsis, pneumonia, higher grade IVH, PVL, with an increased
German 2624 VLBWI LISA method ROP, Patent Ductus arteriosus (PDA) surgery risk for focal
Neonatal 3695 VLBWI had intestinal
Network surfactant via ETT MV not included in outcomes perforation. [FIP;
(GNN) OR 1.49 (95% CI:
1.14–1.95), p =
0.002].
Dargaville et al.25 Retrospecti 37 infants MIST group Epoch 1 (pre-MIST) vs MIST: Hobart Poractant alfa (100-200 mg/kg) In Epoch 2 there was a reduction in the proportion of
ve 29-32 weeks Epoch 2 (MIST) method was instilled in 2-3 boluses over infants failing CPAP (from 14% in epoch 1 to
observation RDS (FiO2 ≥ 0.35 on CPAP ≥ 15-30 sec 7.2% in epoch 2, p = 0.027), and a substantial
al study 7 cm H2O) Sucrose was used reduction in the incidence of pneumothorax (from 8.0 to
First 24 hours of life for premedication at 2.4%, p < 0.01 ).
the discretion of The need for MV was lower in epoch 2, with an average
operator. Narcotic of 0.43 days of intubation per infant.
analgesia and No differences in other outcomes, including mortality,

This article is protected by copyright. All rights reserved

Accepted Article
atropine were not BPD, death or BPD, and severe IVH.
used.
Tomar et al.26 Single 64 infants MIST group Historic cohort (INSURE) vs Modified MIST: Survanta (100 mg/kg) in 30–45 s No differences in the requirement of intubation and Retracted article
center 24-34 weeks modified MIST cohort sterile orogastric mechanical ventilation (MV) in the first 72 h (p > 0.40)
prospective RDS (FiO2 > 0.4 on nasal tube (5 Fr, Lifeline, but the duration of MV and continuous positive airway
observation CPAP) India) was inserted pressure (CPAP) were significantly shorter in modified
al study First 2 hours of life through the vocal MIST group (p< 0.001). Other neonatal morbidities and
cords under mortality rates were similar in either of the groups.
standard direct
laryngosopy with
Miller 00 blades.
No sedation or
atropine.
Teig et al.21 Single 53 infants LISA group Period 1 (pre-LISA) vs n.a. n.a. In Period 2, 66% of the preterm infants needing 52% of discharged
center 23+0 and 28+6 weeks Period 2 (LISA) surfactant were treated by LISA. In this period, less need infants were
retrospecti RDS for MV during the first 72 hours of life (42 vs. 77%, assessed for
ve p<0.0005) and overall (55 vs. 77%, p=0.02) was observed. neurodevelopmenta
observation The median duration of mechanical ventilation was 2 vs. l outcome at
al study 3 days (p=0.056). Survival without BPD was 68% in period corrected age of 3
1 and 74% in period 2 (p=0.29). years.
Mental
Developmental
Index (89 vs. 98,
p=0.16) and Physical
Developmental
Index (83 vs. 91,
p=0.03) at 3 years
improved between
the 2 periods.
22
Kribs et al. Multicentri 211 infants (107 LISA Surfactant administration LISA: 4F end hole Surfactant (poractant alfa) 100 Intubation rate was lower in LISA group (80 infants LISA did not

This article is protected by copyright. All rights reserved

Accepted Article
NINSAPP trial c RCT group vs 104 control either via LISA or after catheter marked mg/kg was instilled by hand [74.8%] vs 103 [99.0%]; p < 0.001) and LISA infants increase survival
group) conventional endotracheal with a wax pencil during 30 to 120 seconds by required fewer days of mechanical ventilation. without BPD but
23+0-26+6 weeks intubation during approximately 1.5 mini-boluses. BPD was diagnosed in 72 (67.3%) infants in the LISA was associated with
RDS (FiO2 >0.3) mechanical ventilation cm above one end. group compared with 61 (58.7%) infants in the control increased survival
First 2 hours of life (control group) Magill forceps are group (p <0.19). The reduction in absolute risk was 8.6% without major
used to grasp the (95% CI, -5.0% to 21.9%; p = 0.20). complications.
catheter. Significant reductions were seen in pneumothorax (p
No sedation or = 0.04) and severe IVH (p = 0.02), and the combined
analgesia. survival without severe adverse events was increased in
the intervention group (P = 0.02; absolute risk reduction,
14.9; 95% CI, 1.4 to 28.2).
27
Bao et al. Single 90 infants (LISA group, Surfactant administration LISA: 16G Angiocath Surfactant (poractant alfa - Surfactant was successfully administered in 100% babies None
center RCT n=47; via ETT (intubation group) marked to indicate Curosurf, Chiesi Farmaceutici, using the conventional approach and in 97% of babies
Intubation group, n=43) or via catheter while on desired depth of Parma, Italy) at a dose of 200 using LISA. The duration of both MV and nCPAP was
28–32 weeks age nCPAP (LISA group) insertion. Direct mg/kg in 5 boluses or more over significantly shorter in LISA group, when compared with
RDS (FiO2 ≧30% in babies laryngoscopy to 3-5 min. intubation group (p = 0.03). No significant differences in
28+0-29+6 weeks’ or insert the vascular both the rate of MV in the first 72 hours and mean
≧0.35 in babies 30+0– catheter beyond the duration of oxygen requirement. There were also no
32+6 weeks’ who were on vocal cords. differences in the mortality or in the incidence of BPD,
nCPAP ≧7 cm H2O) No sedation. IVH, ROP and NEC, or in the duration of respiratory
First 2 hours of life support.
19
Göpel et al. Cross- 1103 infants (LISA group) LISA group vs control LISA method: n.a. LISA infants had lower rates of mechanical ventilation None
sectional VLBW group (matching controls) https://www.youtu (41% versus 62%, p<0.001), postnatal dexamethasone
observation First 12 hours of life be.com/watch?v=O treatment (p<0.001), BPD (p=0.001) and BPD or death
al study UvgJ57FQR8 (p<0.001) than the controls.
German
Neonatal
Network
(GNN)
28
Dargaville et al. Multicentri 61 infants MIST group vs historical MIST: A 16G Surfactant (poractant alfa, 100 or Surfactant was successfully administered via MIST in all None

This article is protected by copyright. All rights reserved

Accepted Article
c feasibility 25-32 weeks’ controls Angiocath (BD, 200 mg/kg Curosurf ) cases. Rapid and sustained reduction in FiO2. For infants
study RDS (CPAP pressure ≥7 cm Sandy, Utah, USA) at 25-28 weeks’ gestation, need for MV <72 h decreased
H2O and FiO2 ≥0.3 if 25–28 marked to indicate after MIST compared with controls (32% vs 68%; OR 0.21,
weeks’ gestation, n=38 or desired depth of 95% CI 0.083 to 0.55), with a similar trend at 29-32 weeks
≥0.35 if 29–32 weeks, insertion (25–26 (22% vs 45%; OR 0.34, 95% CI 0.11 to 1.1). Duration of
n=23) weeks: 1 cm, 27–28 ventilation and incidence of BPD were similar, but infants
First 24 hours of life weeks: 1.5 cm, 29– receiving MIST had a shorter duration of oxygen therapy.
32 weeks: 2 cm).
Direct laryngoscopy.
No premedication
29
Kanmaz et al. Single 200 infants (100 in each Take Care group vs INSURE Take Care: A 5F, Porcine surfactant (Curosurf; Failure of the first attempt was recorded in 18% of None
center RCT group) group flexible, sterile Chiesi Farmaceutici, Parma, Italy) patients in the Take Care group and 10% in the InSurE
<32 weeks nasogastric tube at 100mg/kg in 1 bolus in 30 to group and the difference was not statistically significant
RDS (FiO2 >0.4 on nCPAP) prepared by 60 seconds (p = 0.07).
First 2 hours of life shortening at 33-cm MV requirement in the first 72 hours of life was
depth from the significantly lower in the Take Care group when
catheter hub. compared with the INSURE group (p = 0.02).
Desired depths of Mean duration of both nCPAP and MV were significantly
insertion beyond shorter in the Take Care group (p values 0.006 and 0.002,
the vocal cords for respectively).
preterm infants BPD rate was significantly lower among the infants
with 25 to 26, treated with the Take Care technique (relative risk -0.27,
27 to 28, and 29 to 95% confidence interval -0.1 to -0.72)
32 weeks GA were
1.0, 1.5, and 2.0 cm,
respectively.16
Direct laryngoscopy.
No premedication.
Dargaville et al.30 Non- 25 infants MIST group vs historical MIST: Porcine surfactant In all cases, surfactant was successfully administered and None
randomised 25-34+6 weeks controls 16G Angiocath, BD, (Curosurf, Chiesi Farmaceutici, CPAP re-established. Coughing (32%) and bradycardia

This article is protected by copyright. All rights reserved

Accepted Article
feasibility RDS (supported with CPAP, Sandy, Utah, USA Parma, Italy) at 100 mg/kg in one (44%) were transiently noted, and 44% received positive
study with early enrolment of prepared by bolus (25–28 weeks) or pressure inflations. There was a clear surfactant effect,
25-28-week infants, n=11 marking a point two boluses 10 s apart (29–34 with lower FiO2 after MIST (p<0.01), and a modest
at any CPAP pressure and indicating weeks) reduction in CPAP pressure.
FiO2, and enrolment of 29- the desired depth of Adverse outcomes were few: intubation within 72 h
34-week infants, n=14 at insertion beyond (n=3), pneumothorax (n=1), chronic lung disease (n=3)
CPAP pressure ≥7 cm H2O the vocal cords and death (n=1), all in the 25-28-week group. Outcome
and FiO2 ≥0.35) with a marker pen was otherwise favourable in both gestation groups, with
First 24 hours of life (for infants 25–26: 1 a trend towards reduction in intubation in the first 72 h
cm, in the 25-28-week infants compared with historical
27–28 weeks: 1.5 controls.
cm and 29–34
weeks: 2
cm). No
premedication
31
Göpel et al. RCT 220 infants (108 LISA vs LISA group vs standard LISA: thin catheter Surfactant at 100 mg/kg On day 2 or 3 after birth, less infants in the intervention Premedication used
AMV trial 112 intubation group) intubation group (diameter 2·5–5 bodyweight was instilled group were mechanically ventilated compared to the in 26% infants of the
26-28+6 weeks and VLBW french) placed intratracheally for 1–3 min. standard treatment group (p=0.008). 36 (33%) infants in LISA group
RDS (FiO2 > 0.30 on CPAP) in the trachea with the intervention group were mechanically ventilated
First 12 hours of life use of Magill during their stay in the hospital compared with 82 (73%)
forceps with direct in the standard treatment group (p<0.0001). The
laryngoscopy. intervention group had significantly fewer median days
Sedation and on mechanical ventilation, (0 days. IQR 0–3 vs 2 days, 0–
analgesia 5) and a lower need for oxygen therapy at 28 days
at the discretion of (p=0.032) compared with the standard treatment group.
neonatologist. No differences for mortality and serious adverse events.
Klebermass- Single 224 infants (LISA group) LISA group vs historical LISA: thin gastric Porcine surfactant (200 mg/kg LISA was tolerated by 94% of all infants. 68% of infants Prophylactic
23
Schrehof K et al. center 23–27 weeks’ GA cohort (elective feeding tube 4F Curosurf, Chiesi, Parma, Italy) stayed on CPAP on day 3. The rate of mechanical surfactant
prospective Prophylactic surfactant intubation) inserted in the over 2–5 min ventilation was 35% within the first week and 59% during
observation therapy at 20–30 min after trachea with help of the entire hospital stay. Compared to historical controls,

This article is protected by copyright. All rights reserved

Accepted Article
al study birth Magill’s forceps and LISA group showed higher survival rates (75.8 vs. 64.1%)
visualized via direct and significantly less IVH (28.1 vs. 45.9%), severe IVH
laryngoscopy. (13.1 vs. 23.9%) and cystic periventricular leukomalacia
No premedication. (1.2 vs. 5.6%); conversely, PDA (74.7 vs. 52.6%) and ROP
(40.5 vs. 21.1%) occurred significantly more often in LISA
group. Compared to VONN data, LISA group showed
significantly less chronic lung disease (20.6 vs. 46.4%),
severe cerebral lesions (IVH 3/4 + cystic PVL; 9.4 vs.
16.1%) and ROP (all grades) (40.5 vs. 56.5%); only PDA
(74.7 vs. 63.1%) and severe ROP (> grade 2) (24.1 vs.
14.1%) occurred significantly more often in LISA cohort.

This article is protected by copyright. All rights reserved

Accepted Article
Method Device Magill forceps Ongoing nCPAP Bolus
LISA Thin feeding tube Yes Yes Mini-boluses 30-120’’
MIST Semi-rigid Angiocath No No One bolus (25-28 wk)
Two boluses (29-34
wk)
Take Care Thin feeding tube No Yes One bolus 30-60’’
Sure Angiocath or feeding No Yes One bolus 60-90’’
tube
nCPAP: nasal continuous positive airway pressure
LISA: least invasive surfactant administration
MIST: minimally invasive surfactant technique
SURE: surfactant without endotracheal tube intubation

Table 2: Comparison between different surfactant administration techniques using thin

catheters

This article is protected by copyright. All rights reserved

Accepted Article Study Criteria

Jena et al.(15) 1. CPAP >7cm of H2O and FiO2 >0.70 to maintain target
SaO2 of 90-95%
2. Persistent respiratory acidosis (pH <7.2 and/or PCO2 >60
mmHg
3. Recurrent apnoea requiring positive pressure ventilation
despite the caffeine
Kribs et al. 1. FiO2 >0.45 for more than 2 hours during CPAP to obtain a
NINSAPP(19) PaO2 >45mmHg
2. Respiratory acidosis with pH <7.15
3. Severe apnoea during CPAP despite the caffeine
Kanmaz et al.(17) 1. CPAP >7cm of H2O and/or FiO2 >0.60 to maintain target
SaO2 of 85-92%
2. Sustained respiratory acidosis (pH <7.2)
3. Recurrent apnoea requiring positive pressure ventilation
Göpel et al. AMV 1. pCO2 >65mm Hg and/or FiO2 >0.60 for more than 2 hours
trial(21) on day 2 or 3 after birth
CPAP: continuous positive airway pressure
SaO2: arterial oxygen saturation
FiO2: fraction of inspired oxygen
pCO2: partial pressure of carbon dioxide
PaO2: arterial oxygen pressure

Table 3: Intubation criteria used during major studies of surfactant delivery using thin
catheters

This article is protected by copyright. All rights reserved

 apa_15374_f1.docx

Figure 1. Proposed classification of surfactant delivery techniques (Pandita’s Classification)

Accepted Article ↓
Surfactant delivery methods

↓ ↓ ↓

↓ ↓ ↓
Invasive techniques Minimally invasive techniques Least invasive technique

INSURE ↓ ↓ ↓
SURE LMA CALMEST Nebulization
(using thin catheters)

INSURE: Intubation SURfactant Extubation

SURE: SURfactant without ET intubation (Includes previously described LISA/MIST/Take Care)
LMA: Laryngeal mask airway
CALMEST: Catheter and laryngeal mask endotracheal surfactant therapy

Figure 1: Pandita’s classification for surfactant administration techniques

This article is protected by copyright. All rights reserved