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.
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