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\begin{document}

\title{Surfactant Administration in Preterm babies (28-36 weeks) with
Respiratory Distress Syndrome: LISA vs InSurE, an Open-Label Randomized
Controlled Trial}



\author[1]{Aradhana Mishra}%
\author[1]{Amol Joshi}%
\author[1]{Atul Londhe}%
\author[1]{Laxmikant Deshmukh}%
\affil[1]{Government Medical College Aurangabad}%


\vspace{-1em}



  
  \date{May 29, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
\textbf{ABSTRACT} INtubation- SURfactant-Extubation (InSurE) approach is
traditional method of surfactant delivery in preterm neonates with
Respiratory Distress Syndrome (RDS). Newer, Less Invasive Surfactant
Administration(LISA) techniques lessen the need for mechanical
ventilation and its adverse consequences. Evidence on the favourable
effects of LISA can't be extrapolated from developed to developing
countries. Aim of Study is to compare the effectiveness of InSurE and
LISA. \textbf{Objectives:} Primary outcome was to find need of
intubation and mechanical ventilation within 72 hrs of birth. Neonates
were followed until discharge/death for adverse events and
complications. \textbf{Material \& Methods}: Open-label RCT was
conducted at tertiary neonatal intensive care unit. Preterm neonates
with diagnosis of RDS were randomized in two groups (InSurE or LISA) to
receive surfactant soon after birth. \textbf{Results:} Total of 150
neonates were analysed (75 in each group). Insignificant Statistical
difference was seen in the need for intubation and mechanical
ventilation within 72 h of birth between the two groups {[}InSurE, 30
(40\%) and LISA, 30(40\%), relative risk 1.0, 95\% confidence interval
0.68--1.48{]}. 12\% (n=9, LISA group) \& 14.6\% (n=11 InSurE group) had
adverse events during the procedure. Also, we observed insignificant
statistical difference in the rates of major complications or duration
of respiratory support, hospital stay \& mortality. \textbf{Conclusion}:
: LISA and InSurE are equally effective for surfactant administration in
the treatment of RDS, when NIPPV is the primary mode of respiratory
support. More RCTs are required to compare the efficacy \& long-term
outcomes of LISA with InSurE. Keywords- Intubation, Mechanical
Ventilation, NIPPV.%
\end{abstract}%



\sloppy


\textbf{INTRODUCTION}

Respiratory distress syndrome (RDS), one of the most common respiratory
illness in preterm infants, is mainly due to the lack of pulmonary
surfactant, leading to atelectasis, ventilation-perfusion (V/Q)
mismatch, and often resulting in neonatal morbidity and mortality (1,2).
Since the early 1990s, Surfactant replacement therapy (SRT) for RDS has
been a standard of care across neonatal intensive care units (NICU) (3).
Along with invasive ventilation, it plays a vital role in the
pathophysiology of bronchopulmonary dysplasia (BPD), which remains
common morbidity in preterm neonates (4,5). Nasal continuous positive
airway pressure (nCPAP) is frequently used for RDS to decrease the
incidence of acute lung injury. The combination of Surfactant therapy
with nCPAP for alveolar recruitment has transformed the management of
RDS(6). The classical InSurE technique introduced by Verder et al.
(1990) involving Intubation, Surfactant administration with brief
positive pressure ventilation, and Extubation, along with nCPAP has been
the standard of care for RDS(7). To avoid intubation for delivering
surfactant in preterm infants with RDS, less invasive surfactant
administration (LISA) ,also known as minimally invasive surfactant
therapy (MIST) techniques have been described (8--10). LISA came into
focus by attaining surfactant delivery while maintaining spontaneous
breathing and avoiding the need for endotracheal tube intubation even
for a split second(11). LISA technique has been suggested as the
preferred way of surfactant administration to preterm infants with RDS
as an alternative to InSurE(12--14).

nCPAP has been a part of the standard of care in managing preterms with
RDS. Although it reduces the need for invasive mechanical
ventilation(IMV), there is substantial evidence of nCPAP failure as high
as 35-50\%(6,15,16). Hence, nasal intermittent positive pressure
ventilation (NIPPV) can be a better option as it delivers time cycled
peak inspiratory pressure (PIP) above Positive End Expiratory Pressure
(PEEP), thereby delivering higher mean airway pressure at nasal
interface compared to nCPAP(17). Evidence from the literature suggests
that NIPPV as primary mode of respiratory support has lower rates of
failure and need for IMV(18--21).

There is limited data about the feasibility and efficacy of LISA from
developing countries. Moreover, hardly very few RCTs have been published
comparing LISA vs InSurE using NIPPV as a primary mode of respiratory
support. This prospective open-label RCT was planned to study the
comparative efficacy of LISA with InSurE in preterm (28-36 weeks of
gestation) with RDS using NIPPV as a primary mode of respiratory
support.

The primary objective was to find need of intubation and mechanical
ventilation within 72 hrs of birth. Neonates were followed until
discharge/death for adverse events and complications.

\textbf{MATERIAL AND METHODS}

This prospective, single-centre, open-label, randomized controlled trial
was conducted in neonatal intensive care unit (NICU, Level 3) at
tertiary care teaching hospital in western India.

Inclusion Criteria: Spontaneously breathing preterm neonates between 28
to 36 weeks of gestation diaginosed with RDS were enrolled in the study.

Exclusion Criteria: newborns with a major congenital malformation
(congenital heart disease, congenital diaphragmatic hernia,
tracheoesophageal fistula, choanal atresia, cleft palate, malformation
of the upper airway, Pierre-Robin sequence \emph{etc} ) severe perinatal
asphyxia requiring PPV or poor respiratory effort requiring intubation
in the delivery room were excluded from the study.

Sample size: One previous study(22) showed, 40\% of infants in InSurE
group required intubation in the first 72 h of life. To decrease the
need of IMV with LISA to 20\% (Power of 80 percent and alpha error of
0.05) we estimated a sample size of 75 in each group. Data analysis was
done by using SPSS software version 19. qualitative data were expressed
as frequency/ percentage. Quantitative data was stated as mean (S.D) and
median (IQR). Chi-square test and Fisher's exact test were used to
compare qualitative variables. Z test and Mann-Whitney U test were used
for quantitative variables. P value \textless{} 0.05 was considered
significant.

Institutional ethics committee (IEC) approval was taken and written
informed consent was taken from the parents before the procedure.
Written informed consent was taken from the parents before the procedure
at the time of enrollment before randomization. Trial registered with
Clinical Trial Registry India (CTRI/2022/01/039147).

Study protocol: RDS was diagnosed clinically in preterm babies based on
the need for supplemental oxygen or respiratory support, clinical signs
of tachypnea, retractions, grunting, and,or chest x-ray suggestive of
RDS (low volume lung, bilateral reticulogranular pattern) in the initial
hours of life. Premies with RDS were initially stabilized, and put on
respiratory support in the form of NIPPV with initial settings of PIP
15-16 cm of H2O, PEEP of 6-8 cm of H2O, rate of 40 min, and FiO2
{[}Oxygen fraction in inspired air{]} adjusted to achieve a target
saturation of 90 to 95\% with use of the Sophie (Fritz Stephan GMBH,
Germany) or Fabian (Acutronic Medical System, Switzerland) ventilator.
Snugly fitting appropriate size binasal prongs were used as the
interface for NIPPV. Surfactant was given after randomization by either
LISA or InSurE technique to patients requiring FiO2 of more than 30\%
and PEEP more than 6cm of H2O to maintain target saturation of
90-95\%(14).

No premedication was used in either group. Non-pharmacological measures
like swaddling and nesting were done to comfort the baby during the
procedures. Repeat surfactant was given after 6-12 hours by the same
technique if the patient continued to have FiO2 requirement more than
30\% with significant respiratory distress. In either group, NIPPV
failure was considered and infants were mechanically ventilated if they
had any of the following: severe respiratory distress with SAS [?] 7, FiO2
requirement [?] 0.6 on NIPPV, Arterial blood pH \textless{}7.2, pCO2 [?] 60
mmHg, or significant apnea and hemodynamic instability. Weaning from
NIPPV to O2 by NC was considered if the baby did not show any sign of
respiratory distress or apnea for 24hrs with setting of PIP: 12-14cm of
H2O, PEEP:4-5cm of H2O and FiO2 \textless{}30\%.

The detail of each technique is described below:

LISA: The procedure was performed by two trained residents and a staff
nurse for assistance. A sterile(gamma/ETO Sterilized) 5Fr (Single lumen,
Infant feeding tube GS-4008-ROMSONS) feeding tube was used for
delivering surfactant and desired tip to lip distance was decided as per
nasotragal length plus 1 cm (NTL+1 cm). Surfactant (beractant) 100mg/kg
was prefilled in a 5 to 10 ml syringe under aseptic precaution, and an
additional 1 mL of air was drawn up, taking into consideration the dead
volume of the tube. Direct laryngoscopy was performed and a feeding tube
was inserted to the desired depth (1-2 cm below vocal cords) without
using Magill forceps. After placing the tube, the laryngoscope was
removed and surfactant was administered slowly over 60-120 seconds, and
then the catheter was removed immediately. NIPPV was continued
throughout the procedure. Patients were given manual breaths or PPV in
case of apnea/bradycardia.

InSurE: Patients were intubated with an appropriate sized endotracheal
tube (ETT) ,and surfactant was administered through a sterile 5Fr
feeding tube passing through the ETT followed by PPV using an
appropriately sized self-inflating resuscitation bag. Babies were
extubated after a few minutes and continued on NIPPV support.

Randomization: Infants were randomly assigned to LISA and InSurE group
with 1:1 allocation ratio using online computer-generated sequential
random numbers, and concealment was done using serially numbered opaque
sealed envelopes. Blinding was not done because of the nature of
intervention in treatment groups.

Interventions: Asynchronised NIPPV was used as primary mode of
respiratory support in both the groups. As servo-controlled oxygen
delivery was not available, FiO2 was controlled manually. Aside from the
experimental intervention, the groups recieved similar treatment.

The primary outcome of the study, was to evaluate the need for IMV
(Invasive Mechanical Ventilation) within the first 72 hours of birth.
Babies were followed until discharge/death for a secondary outcome which
included intraventricular hemorrhage (IVH), hemodynamically significant
patent ductus arteriosus (hsPDA), necrotizing enterocolitis (NEC),
retinopathy of prematurity (ROP), and BPD. Also, duration of invasive
ventilation, non invasive respiratory support, oxygen by nasal cannula,
need for repeat surfactant doses, length of hospital stay, and adverse
events during surfactant administration were recorded. For diagnosing
IVH, cranial ultrasound was performed first within 48-72 hours, and then
on day7 and 14 of birth. The diagnosis of BPD referred to the
requirement of respiratory support at 36 weeks of gestation(23).

\par\null

Fig. 1 CONSORT flow chart

\textbf{RESULTS}

A total of 150 neonates were randomized to one of the two groups of LISA
and InSurE (Fig. 1). Baseline characteristics were comparable in both
groups (Table 1). The mean gestational Age was 31.4 weeks (\selectlanguage{ngerman}±0.53 SD),
whereas the mean birth weight of the population was 1243.94g (± 212.60
SD). All the babies were followed till discharge/death. Table.2 depict
Primary and secondary outcomes. We observed statistically insignificant
difference in the need for intubation within 72 h of birth between the
InSurE and LISA group {[}Relative Risk(RR) of 1.0, 95\% of Confidence
Interval(CI) 0.68--1.47).Complications like IVH, hsPDA, Pneumothorax,
BPD, LOS, NEC, and ROP were more in the InSurE group, however, the
difference was statistically insignificant. There was no difference in
requirement of the second dose of surfactant between two groups. Also,
difference was statistically insignificant in the duration of need for
NIPPV,mechanical ventilation and supplemental oxygen. Adverse events
during the procedure such as transient desaturation/bradycardia were
more in the InSurE group but the P-value was not significant.
Furthermore, insignificant statistical difference was seen in the
duration of hospital stay and survival outcome among the two groups.

TABLE -1.Baseline characteristics of study groups\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
Indicators\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
LISA (n=75)\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
InSURE (n=75)\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
P-value\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Gestational Age (weeks), Mean \selectlanguage{ngerman}± SD\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
31.41\selectlanguage{ngerman}±0.30\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
31.36 \selectlanguage{ngerman}± 0.69\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.57*\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Gestational age group\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
28 to \textless{} 32 weeks, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
49\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
50\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.90**\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
32 to \textless{} 34 weeks, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
23\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
23\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
[?] 34 weeks, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
03\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
02\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
SGA n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
32\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
35\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.74***\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
AGA n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
43\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
40\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
LGA n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
00\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
00\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Birth weight, g, Mean \selectlanguage{ngerman}± SD\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1226 (\selectlanguage{ngerman}±176)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1261.5 (\selectlanguage{ngerman}±244)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.30*\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Birth weight group\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
ELBW (\textless{}1000 g)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
08\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
09\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.49**\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
VLBW (1000--1499 g)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
59\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
62\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
LBW (1500--2499 g)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
08\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
04\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Gender\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Male, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
39\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
41\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.87***\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Female, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
36\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
34\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
APGAR Score, Median (IQR)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1 min\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
5(4-6)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
5(5-6)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.25\#\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
5 min\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
7(7-8)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
8(7-8)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.56\#\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Mode of delivery\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Vaginal, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
55(73.33\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
52(69.33\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.71***\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Caesarean, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
20(26.66\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
23(30.66\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Antenatal steroids\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Complete course, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
22 (29.33\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
21 (28 \%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.98**\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Incomplete course, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
37 (49.33\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
38(50.66\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Not received, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
16(21.33\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
16(21.33\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Antenatal complications\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
GDM, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
03\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
02\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.97**\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
PIH\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
29\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
32\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
ECLAMPSIA\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
05\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
04\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
APH\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
16\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
15\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
PPROM\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
24\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
22\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
MAX PEEP before surfactant, Median (IQR)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
7 (6-7)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
7 (6-7)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.87\#\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Age at surfactant therapy (hrs), Mean \selectlanguage{ngerman}± SD\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2.98 \selectlanguage{ngerman}± 0.70\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2.8 \selectlanguage{ngerman}± 0.79\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.13*\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
SAS Score before surfactant, Median (IQR)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
5(5-6)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
5 (5-6)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.89\#\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

InSurE, intubate-surfactant-extubate; LISA, less invasive surfactant
administration; n, number; g, grams; SD, standard deviation; ELBW,
extremely low birth weight; VLBW, very low birth weight; LBW, low birth
weight; SGA, small for gestational age; AGA, appropriate for gestational
age; LGA, large for gestational age; PPROM preterm premature rupture of
membrane; GDM gestational diabetes mellitus; APH antepartum hemorrhage;
PIH pregnancy-induced hypertension; IQR, interquartile range.

*Z test.; ** Chi-Square Test ; ***Fisher's exact test; \#Mann--Whitney
U-test

TABLE -2. Outcome variables of the study group\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
Primary outcome\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
LISA (n=75)\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
InSURE (n=75)\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
RR (95\% CI)\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
P-value\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Intubation within 72h of birth, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
30(40\%)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
30(40\%)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1.0 (0.68~to~1.48)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\textgreater{}0.99***\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Secondary outcomes (Major complications) n (\%)
\emph{\textsuperscript{\textbf{CT}}}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
IVH\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
07\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
09\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.9418 (0.49 -- 1.50)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\textgreater{}0.99***\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
BPD\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
06\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
09\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.85 (0.41 -- 1.43)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.79***\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
hsPDA\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
28\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
30\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1.07 (0.75 -- 1.47)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.74***\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
NEC\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
03\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
04\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.92 (0.33 -- 1.68)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\textgreater{}0.99***\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Pneumothorax\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
01\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
02\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.50 (0.04 -- 5.40)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.99***\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
LOS\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
27\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
30\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1.038 (0.72 -- 1.43)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.87***\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
ROP\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
08\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
10\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.96 (0.51 -- 1.49)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\textgreater{}0.99***\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Median (IQR) duration of MV (days)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
6.5 (5.5-7)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
6.25 (5.5-7)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
--\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.40\#\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Median (IQR) duration of non-invasive respiratory support (days)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
6 (5-6)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
6(5.25-6.5)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
--\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.50\#\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Median (IQR) Duration of Supplemental Oxygen\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
5(3-11)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
5(3-14)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
--\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.90\#\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Repeat dose of surfactant, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
13 (17.33\%)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
11 (14.66\%)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
--\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.82**\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Adverse events during surfactant administration\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Transient desaturation/ bradycardia), n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
9 (12\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
11 (14.66\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
--\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.63**\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Regurgitation, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
4 (5.33\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
3 (4\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
--\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.69**\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Median (IQR) length of hospital stay (days)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
30.5(22-39)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
26 (18.5-41)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
--\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.56\#\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Survival n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
54 (72\%)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
52 (69.33\%)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
1.07 (0.76 -1.57)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
0.86***\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

InSurE, intubate-surfactant-extubate; LISA, less invasive surfactant
administration; RR, relative risk; 95\% CI, 95\% confidence interval; n,
number; IVH, intraventricular hemorrhage; BPD, bronchopulmonary
dysplasia; hsPDA, hemodynamically significant patent ductus arteriosus;
NEC, necrotizing enterocolitis; ROP, retinopathy of prematurity; d,
days; IQR, interquartile range.

** Chi-Square Test test; ***Fisher's exact test.; \#Mann--Whitney U-test

\textbf{DISCUSSION}

In this open-label RCT, we compared the newer less invasive surfactant
administration technique with the traditional, more invasive method of
surfactant instillation, InSurE. The population included spontaneously
breathing preterm babies between 28 to 34 weeks of gestation with RDS
using NIPPV as a primary mode of ventilation. A less invasive approach
was proven to be equally effective with no significant difference in the
need for mechanical ventilation within 72hours of birth between the two
groups. We found insignificant statistical difference in~duration of
ventilation, oxygen therapy, length of hospital stay, major
complications, adverse events, or~mortality between the two groups.

InSurE has been the traditional method of surfactant administration.
However, a brief period of invasive ventilation in this technique may
also cause lung injury, so less invasive methods (LISA) came into the
field. Following an initial pilot trial by Verder et al.(24), several
variations have been conducted and published over years using different
types of catheters for intratracheal administration of surfactant with
or without Magill forceps(25--28). Over the years LISA has been
increasingly used in different parts of the world. Few studies have been
reported from India.

As with our study, several other trials(27--34) found no significant
difference between the InSurE and LISA groups about the need for
intubation within 72 hours of birth. Mohammadizadeh, et al.(28)
Conducted a multicentre RCT~~in Iran among 38 preterm babies below 34
weeks gestational age and found insignificant difference in the need for
intubation within first 72 hours of life. Similar findings were seen in
a single-centre RCT from china by Bao et al(27). However, various
studies(22,31,35,36) of similar design and meta-analysis(1,4,37,38) from
various countries in the world have reported a significant reduction in
the need for mechanical ventilation in the LISA group. Most of
studies(22,31,35,36) which found significant difference in the need of
MV in 72 h used nCPAP as their primary respiratory support. Evidence
from literature shows that NIPPV facilates better deliver of presure in
the alveoli to overcome the airway clog and leaks during catheterisation
by a thin intra-tracheal catheter(39). Also NIPPV prevents
intubation(18). Both these factors may explain the lack of difference
between LISA and InSurE groups in the primary outcome in our study.

In our study, we used NIPPV as a primary mode of respiratory support
whereas the majority of the studies which found a significant difference
in the need for intubation in the first 72h used nCPAP as their primary
mode of ventilation(2,31,35,36). Evidence from the literature supports
that NIPPV as the primary mode of respiratory support reduces the need
for mechanical ventilation(18). Multiple studies(17,40) and
meta-analysis (40,41) suggest that NIPPV works better than CPAP in
reducing the need for mechanical ventilation. The possible mechanism
explained is the inclusion of PIP above PEEP, thereby delivering higher
MAP, improving alveolar recruitment, and thus reducing the work of
breathing(17,40--43). This can explain the lack of difference in the
primary outcome among both the groups in our study. Other notable Indian
research by Gupta et al.(29) and Pareek et al.(34) using NIPPV showed no
significant difference in the need for intubation within the first 72h.
Similar findings were seen in a recent trial from Turkey by Akcay et
al.(30)

The study population included preterm babies of a wider gestational age
range (28-36weeks) with a mean gestational age of 31.4 weeks. It is
comparable with other studies(29,34). Most of the studies have included
preterms below 34 weeks of gestation(27,28,30,32,35,36,44). It is
uncertain whether difference in the study groups affected key endpoints.
There were insignificant statistical difference in the duration of MV/
NIPPV or supplemental oxygen and the incidence of BPD between the
groups.This could be attributed to similar rate of mechanical
ventilation in both the groups. Similar findings were reported from
other studies(27--30,33,34). We found no significant difference in other
major complications such as IVH, NEC, ROP, hsPDA, pneumothorax, and LOS
between the groups. Similar results were reported from other
studies(27,29,30,34,44). Our study did not show any significant
difference between the groups in the need for a second dose of
surfactant, as did most of the studies of similar design(27,29,34,36).
Continuous NIPPV support along with LISA gives a better pressure
effect(45), potential reason for less surfactant retreatment in our
study. There was no substantial difference in the rate of adverse events
such as transient bradycardia/desaturation during the procedure(12\%
LISA \&14.6\% InSurE, p = 0.63), comparable with other
studies(27,29,36). In contrast, Olivier et al(46) and Mohamadizadeh et
al.(28) reported a statistically significant higher incidence of
desaturation/ bradycardia during the procedure, attributed to
premedication for sedation before the procedure or inadequate training.
Duration of hospital stay was also similar among the groups, comparable
to other studies(2,27,33). There was no statistically significant
difference in the survival outcome between the groups (RR: 1.06,
95\%CI:0.76-1.57 (37,47). Gestational age stratified subgroup analysis
was done for all primary and secondary outcomes and findings did not
differ from main results..

Generalizability of the study: this study can be replicated in tertiary
level nicu of many LMICs, provided NIPPV facility should be available

Strength of the study : Our study is among the very few RCTs that has
compared the efficacy of LISA with InSurE using NIPPV as a primary mode
of respiratory support, carried out in a large public hospital in LMIC.
This study has large sample size with bigger and wider gestational age
compared to other studies.

LIMITATION: This study has some limitations. As both the groups included
different procedures; hence healthcare workers could not be blinded, but
the study analysis was done by a statistician not involved in this
research study. Our null hypothesis for primary outcome was true however
the hypothesis for secondary outcome that LISA would be better in
reducing rates of bpd in babies reqiring surfacatant administration was
not true.This could be due to the fact that our study was not adequately
powered for evaluating rates of bpd in babys recieving surfactant
therapy.

CONCLUSION: To conclude, our study found LISA to be equally effective
and safe compared to InSurE, as a method for surfactant administration
in spontaneously breathing preterm neonates using NIPPV as a primary
mode of respiratory support. We found insignificant statistical
difference in the need for intubation within 72hours of birth between
the two groups. The study is among very few trials comparing LISA with
InSurE using NIPPV in preterms with a wide range of gestation between
28-36 weeks.

REFERENCES:

1. Wu X, Feng Z, Kong J, Lai Y, Jia C, Xu Z, et al. Efficacy and safety
of surfactant administration via thin catheter in preterm infants with
neonatal respiratory distress syndrome: A systematic review and
meta-analysis. Pediatr Pulmonol. 2021 Sep;56(9):3013--25.

2. Halim A, Shirazi H, Riaz S, Gul SS, Ali W. Less Invasive Surfactant
Administration in Preterm Infants with Respiratory Distress Syndrome. J
Coll Physicians Surg--Pak JCPSP. 2019 Mar;29(3):226--330.

3. Polin RA, Carlo WA, Committee on Fetus and Newborn, American Academy
of Pediatrics. Surfactant replacement therapy for preterm and term
neonates with respiratory distress. Pediatrics. 2014 Jan;133(1):156--63.

4. Panza R, Laforgia N, Bellos I, Pandita A. Systematic review found
that using thin catheters to deliver surfactant to preterm neonates was
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