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 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 < 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 <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 <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).
Fig. 1 CONSORT flow chart