Post-extubation using high nCPAP: are we ready for the change?

Extremely preterm born neonates <28 weeks gestational age (GA) are at increased risk of receiving mechanical ventilation (MV) soon after birth and this risk increases with decreasing GA. The harmful effects of MV on the developing lung have been clearly demonstrated by many investigators, leading to the development of strategies designed to not only limit the duration of postnatal MV, but also improve the transition to noninvasive mechanisms of respiratory support. Nonetheless, extubation failure remains a common issue in this preterm population and continues to be associated with an increased risk of mortality and morbidity (1). Thus, in recent years, the best predictors of extubation success and the optimal method(s) for post-extubation support have been rigorously evaluated. However, there is still no consensus regarding either of these. Nasal continuous positive airway pressure (nCPAP) and noninvasive intermittent positive pressure ventilation (NIPPV) are the two modalities most often used for post-extubation respiratory support in low GA neonates. In a meta-analysis that included 19 randomized control trials (RCTs) comparing nCPAP and NIPPV, it was suggested that NIPPV may be the superior modality in achieving successful extubation in neonates 28–32 weeks GA; however, the authors noted a paucity of data regarding neonates <28 weeks GA (2). Moreover, the post-extubation nCPAP level was limited to ≤8 cmH₂O, whereas the mean airway pressure in the NIPPV arm of the studies examined was higher.

Despite the routine use of nCPAP as the primary modality for respiratory support at birth or post-extubation, the optimal level of nCPAP for both purposes remain unclear (3). Concerns about the occurrence of pneumothorax with higher levels of nCPAP were raised in a RCT that applied a nCPAP of 8 cmH₂O at birth. Notably, these investigators also used a high threshold to administer surfactant therapy, i.e., nCPAP of 8 cmH₂O and FiO₂ ≥0.6 (4). It is well established that early surfactant administration not only mitigates the risk of pneumothorax, but also improves outcomes compared to late rescue surfactant in neonates intubated soon after birth (5). In a recent RCT evaluating early rescue (FiO₂ 0.3) with less invasive surfactant administration (LISA) it was observed that the rate of pneumothorax was decreased despite the use of higher levels of nCPAP, i.e., 5–8 cmH₂O (6). In our experience in a large Neonatal Intensive Care Unit the stepwise escalation of nCPAP (≤8 cmH₂O) along with timely surfactant administration resulted in a decreased occurrence of pneumothorax (7,8). However, there are limited data regarding the use of nCPAP ≥9 cmH₂O. Notably, the application of brief periods of elevated nCPAP at 8–13 cmH₂O in physiologic studies resulted in improved lung volume without increasing the risk of pneumothorax or significant changes in cardiac output compared to what many consider a “standard” levels of 5–6 cmH₂O in preterm neonates (9,10). To date, the use of higher nCPAP levels, i.e., 7–9 cmH₂O, for post extubation support has been reported in only one study (11). Therefore, evaluating the benefits of higher levels of nCPAP in neonates extubated after surfactant therapy is important.

The report by Kidman et al. (12) is a multicenter study performed in Australia. It begins to fill the knowledge gap regarding the use of higher nCPAP levels for the post-extubation respiratory support of neonates <28 weeks GA. In that study, neonates were extubated from conventional or high-frequency oscillatory ventilation with a pre-extubation mean airway pressure of <10 cmH₂O. However, extubation criteria and timing of extubation are not defined. The intervention arm utilized nCPAP levels of 9–11 cmH₂O whereas the control arm used the more conventional nCPAP levels of 6–8 cmH₂O. Neonates were extubated to an average nCPAP of 10 vs. 7 cmH₂O, respectively. The primary outcome was extubation failure, defined as the need for reintubation within 7 days after the first attempt to extubate or escalation of support above pre-specified levels. Unfortunately, the study was stopped after enrolling only 75% (139/185) of the desired neonates due to slow enrollment during the pandemic. There are no differences in the baseline characteristics, including GA, birth weight, postnatal age and weight at the time of extubation. The primary outcome, failed extubation, occurred less frequently in the high nCPAP or intervention arm (35%) compared to the control arm (57%), risk difference −21.7 [95% confidence interval (CI): −38.5% to −3.7%], number needed to treat 5 (95% CI: 3 to 27). It is important to note, however, that there was no benefit in the subgroup who were extremely low GA, i.e., 22–25 weeks GA (56% vs. 69%). Thus, the success of extubation with the higher nCPAP was basically derived from neonates 26–27 weeks GA and in whom post-extubation failure was 16% vs. 42%, respectively. Importantly, there were no differences in any of the secondary outcomes, i.e., pneumothorax, the duration of MV or nCPAP, mortality or the incidence of bronchopulmonary dysplasia. Overall, seven neonates required reintubation for acute decompensation and five died during the study period without any group differences in these adverse outcomes, reflecting the high-risk study population that was studied. As the authors claim, this is the largest study comparing “high” nCPAP vs. “conventional” nCPAP. It is also the first RCT to examine the effects of nCPAP levels >9 cmH₂O.

There are, however, limitations to the study. As the authors pointed out, the study enrolled only 75% of the planned sample size, potentially impacting the effect size. Although the extubation failure rate was lower in the high nCPAP group as a whole, the efficacy of the higher nCPAP actually occurred in the older GA group, 26–27 weeks GA, and there was no significant benefit in neonates <26 weeks GA. It is possible that early termination has negatively impacted this outcome.

The findings of the study by Kidman et al. (12) are consistent with the only other study comparing two levels of nCPAP for post-extubation respiratory support. In that study, Buzzella et al. (11) compared nCPAP levels of 4–6 and 7–9 cmH₂O in neonates 23–30 weeks GA (n=93). As in the current study, the higher nCPAP group had fewer extubation failures (defined as the need for intubation within 96 hours post-extubation) than the low nCPAP group (24% vs. 43%). In a recent multicenter study, Mukerji et al. (13) compared centers that self-selected the use of either nCPAP (5–12 cmH₂O) or NIPPV (PIP 12–24 cmH₂O, PEEP 5–10 cmH₂O and rate 20–40 breaths/minute) but they allowed cross over. They observed that nCPAP (n=843) was non-inferior to NIPPV (n=974) for reintubation in the first 7 days after birth (16.4% vs. 22.8%). Notably, these studies suggest that nCPAP is an acceptable modality for post-extubation respiratory support, particularly when a higher level of nCPAP (≥8 cmH₂O) is used along with NIPPV as a rescue modality.

In summary, extubation failure in extremely low GA neonates is fraught with significant complications, thus it is important to design and adopt strategies that optimize the success of post-extubation respiratory support. Kidman et al. (12) have shown that nCPAP of 9–11 cmH₂O is a safe and potentially effective modality for post-extubation support in preterm neonates delivered at ≤28 weeks GA. Although this conclusion is consistent with other studies that compared higher nCPAP with conventional levels of nCPAP, a larger RCT should be designed comparing “higher” nCPAP (9–11 cmH₂O) as an initial support strategy with NIPPV with equivalent mean airway pressure in order to prevent extubation failure and improve short- and long-term outcomes. We believe this should address any concerns that may exist.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Pediatrics. The article has undergone external peer review.

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-24-318/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-24-318/coif). V.K. reports that he has received grant support for ongoing investigator-initiated research through UT Southwestern Medical Center and participated in a scientific symposium at the Pediatric Academic Society meeting in Toronto, CA, sponsored by Chiesi Pharmaceuticals in 2024. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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