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.