Non-invasive Respiratory Support in Preterm Infants: a Multicentre Pilot Randomized Controlled Trial

BACKGROUND:

Bronchopulmonary dysplasia (BPD) is the most common morbidity of prematurity, and affects up to 40% of all preterm infants. It is independently associated with long term pulmonary and neurodevelopmental impairment, and confers a significant cost to society. Although development of BPD is multifactorial in nature, endotracheal mechanical ventilation (EMV) is known to be a significant contributor and strategies aimed at avoiding endotracheal mechanical ventilation may indeed reduce the incidence of bronchopulmonary dysplasia.

Use of non-invasive respiratory support (NRS) has increased over the last decades in an effort to minimize dependence on endotracheal ventilation and reduce BPD in preterm neonates. Nasal continuous positive airway pressure (NCPAP) remains the prototypical form of NRS and is most commonly utilized. Another commonly used modality is non-invasive positive pressure ventilation (NIPPV) though it is often relegated as a "rescue" NRS mode following failure of NCPAP. NIPPV mimics tidal breathing by delivering "breaths" through a nasal interface at regular intervals, and results in higher mean airway pressures compared to NCPAP. Despite the increase in use of NRS and evidence from clinical studies demonstrating effectiveness in reducing BPD,results at a population level have been rather disappointing, with a recent report from the United States actually showing an increasing trend in BPD.

In recent years, in an effort to further minimize dependence on endotracheal ventilation and BPD, some new strategies in NRS use are emerging. One of these approaches is the early use of NIPPV in place of NCPAP, rather than as a rescue mode after failure of NCPAP. Two recent Cochrane reviews have evaluated NIPPV as an alternative to NCPAP, and suggested superiority over NCPAP Based on these results, a number of NICUs have started utilizing NIPPV in place of NCPAP as the default NRS mode. However, there are a number of methodological limitations of studies that were included in these reviews. First, most studies did not allow for rescue use of NIPPV in the NCPAP arms, which is not representative of current clinical practice at most NICUs. Secondly, the mean airway pressures in NIPPV vs. NCPAP were vastly different, and the question remains whether it is truly the mechanism of NIPPV or simply higher mean airway pressure that leads to the superior outcomes reported. These limitations warrant consideration because most NIPPV use is not synchronized to patients' respiratory efforts, the optimal and safe peak pressures remain unknown.

An alternative approach that has emerged in recent years is the use of high end-expiratory pressures (defined as pressures > 8 cm H2O) on NCPAP. As of 2015, use of high NCPAP pressures had only been adopted at 5 out of 28 Canadian neonatal intensive care units (NICU), and McMaster Children's Hospital NICU is currently one of only few Canadian centres employing pressures > 12 cm H2O on NCPAP. The reasons for the lack of widespread use of high end-expiratory pressures on NCPAP are unknown, but may relate to the theoretical concerns of altered systemic hemodynamics including impaired cardiac venous return, decreased venous drainage of the cerebral circulation as well as the potential for air leak syndromes such as pneumothoraces. On the other hand, such high end-expiratory pressures are very commonly and safely used during endotracheal mechanical ventilation, as well as during NIPPV. As such, the selective use of high end-expiratory pressures on NCPAP non-invasively may be quite appropriate. However, the use of high end-expiratory pressures on NCPAP is currently based on very limited evidence, and whether adopting this strategy leads to a meaningful decline in the dependence on endotracheal ventilation and/or bronchopulmonary dysplasia remains unknown. In this study, we aim to comparatively evaluate use of NIPPV vs. high end-expiratory pressures (> 8 cmH2O) on NCPAP after failure of NCPAP use at traditional pressures (≤ 8 cmH2O) among preterm infants. This will be the first prospective clinical study to evaluate high end-expiratory pressures on NCPAP, and also the first to compare NIPPV and NCPAP at equivalent mean airway pressures. If high NCPAP is shown to be as effective and safe as NIPPV, it will lead to a significant advancement in the understanding of NRS and the respiratory management of extremely preterm neonates.