Discussion  
This network meta-analysis included data of 3994 preterm babies from 34 studies to evaluate the efficacy of different NRS modalities as primary support for RDS. Clear differences between NRS modes were found. NIPPV reduced the risk of MV when compared to both CPAP and HFNC. Also, both NIPPV and BiPAP were associated with lesser treatment failure in comparison to CPAP and HFNC. Ranking probabilities indicate that NIPPV might be the most appropriate primary modality of NRS in preterm neonates with RDS.
The findings of this network meta-analysis are similar to Lemyre et al’s with NIPPV being superior to CPAP in preventing treatment failure as well as MV9. The relative risk reduction for both the primary outcomes were much larger than that reported by Lemyre et al. with narrower credible intervals. Reasons for this could be that this network meta-analysis had included more recently published studies and also that the modalities BiPAP and NIPPV were evaluated as separate interventions. Also, this was a network meta-analysis where apart from the direct synthesis, the indirect evidence also contributed towards the overall effect estimate. It is evident from the included studies that the peak inspiratory pressure (PIP) and hence the mean airway pressure (MAP) that was delivered with NIPPV was much higher than the positive end expiratory pressure (PEEP) generated with CPAP41-53. This might be one of the reasons for NIPPV being more effective than CPAP. The fact that the incidence of air leak as well as that of the combined outcome of BPD or mortality was much lesser with NIPPV when compared to CPAP might suggest that the use of a relatively higher MAP with NIPPV was not deleterious.
The results of this NMA were similar to those by Fleeman et al. and Hong et al. with HFNC being equally efficacious as CPAP as a primary mode of respiratory support in neonates with RDS7,8. It should be noted that most of the studies that had compared HFNC with CPAP had enrolled neonates of gestational ages of more than 28 weeks. Hence, these findings are not generalisable to the more immature neonates. The meta-regression also showed a trend of HFNC being less efficacious at lesser gestational ages compared to other NRS modalities. However, the results were imprecise making it difficult to draw reasonable conclusions.
Both NIPPV and BiPAP were equally efficacious in preventing treatment failure and mechanical ventilation. Most of the evidence that contributed to this comparison was indirect and there was only a single RCT that had compared these two interventions56. Millar et al. in their a priori planned non-randomised comparison of neonates randomised to the NIPPV arm of the NIPPV trial (a large RCT comparing NIPPV/BiPAP versus CPAP as primary as well as post extubation respiratory support ) had reported similar findings with no differences in the incidence of re-intubation between NIPPV and BiPAP groups in the first week after randomisation in the primary respiratory support group57. Similar to the BiPAP versus NIPPV comparison, there was paucity of direct evidence for studies evaluating HFNC versus NIPPV where only two RCTs contributed to the direct evidence54,55. These reiterate the need for further RCTs comparing these interventions.
The analysis of secondary outcomes reveal that both BiPAP and CPAP were associated with an increased risk of air leak and mortality when compared to NIPPV. Also, the risk of mortality or BPD was higher in CPAP compared with NIPPV. Isayama et al. in their network meta-analysis of different invasive and non-invasive modalities along with different methods of surfactant administration in preterm neonates with RDS had found no differences in the incidence of air leak, mortality or BPD between CPAP and NIPPV10. This discrepancy between this network meta-analysis and Isayama et al.’s might be due to the fact that this network meta-analysis had included only non-invasive modalities of respiratory support and had excluded neonates requiring invasive MV. Also, more recent studies that were published after Isayama et al’s meta-analysis were included in the present analysis39,40,51-53. It should be noted that the network assessing the outcome mortality was inconsistent. In a scenario where inconsistency has been detected for an outcome in a network meta-analysis, the network estimates are not reliable and any changes in the included studies to address the inconsistency becomes a post hoc analysis58.
The increased risk of air leak with BiPAP when compared to NIPPV could be explained by the different mechanism of flows used by these two interventions59.While NIPPV uses a fixed flow using a ventilator, BiPAP is a variable flow device. Some of the BiPAP studies have used very high Pressure high of upto 15 cm H2O which might require a very high gas flow rate60. Also, the inspiratory times are typically higher in BiPAP compared to NIPPV which might result in the alveoli being exposed to higher pressures for a longer period of time as well as increasing the risk gas trapping, especially when higher respiratory rates are used. The risk of mortality or BPD was higher in CPAP compared with NIPPV in this network meta-analysis. This was not seen in the Isayama et al’s network meta-analysis. This might be due to the differences in the inclusion criteria between the two meta-analyses as specified above. Also, the quality of evidence for most of the secondary outcomes of this network meta-analysis were low to very low and hence should be interpreted with caution.