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