Continuous positive airway pressure (CPAP) vs noninvasive positive pressure ventilation (NIPPV) vs noninvasive high frequency oscillation ventilation (NHFOV) as post-extubation support in preterm neonates: protocol for an assessor-blinded, multicenter, randomized controlled trial

Abstract

Background: Various noninvasive respiratory support modalities are available in neonatal critical care in order to minimize invasive ventilation. Continuous positive airway pressure (CPAP) is the more commonly used but noninvasive positive pressure ventilation (NIPPV) seems more efficacious in the early post-extubation phase, although it is not clear if NIPPV may influence longterm outcomes. A recently introduced alternative is noninvasive high frequency oscillatory ventilation (NHFOV) which might be especially useful in babies needing high constant distending pressure. Preterm neonates may receive these respiratory supports for several weeks. Nonetheless, no data are available for the longterm use of NIPPV and NHFOV; few data exist on NHFOV and clinical outcomes, although its safety and suitability are reported in a number of preliminary short-term studies.

Methods: We designed an assessor-blinded, multicenter, three-arms, parallel, pragmatic, randomized, controlled trial with a superiority design, investigating the use of CPAP vs NIPPV vs NHFOV during the whole stay in neonatal intensive care units in China. Since safety data will also be analyzed it may be considered a phase II/III trial. Moreover, subgroup analyses will be performed on patients according to prespecified criteria based on physiopathology traits: these subgroup analyses should be considered preliminary. At least 1440 neonates are supposed to be enrolled. The trial has been designed with the collaboration of international colleagues expert in NHFOV, who will also perform an interim analysis at the about 50% of the enrolment.

Discussion: The study is applying the best trial methodology to neonatal ventilation, a field where it is often difficult to do so for practical reasons. Nonetheless, ours is also a physiology-driven trial, since interventions are applied based on physiological perspective, in order to use ventilatory techniques at their best. The pragmatic design will increase generalizability of our results but subgroup analyses according to predefined physiopathological criteria are also previewed trying to have some advantages of an explanatory design. Since not all clinicians are well versed in all respiratory techniques, the training is pivotal. We intend to apply particular care to train the participating units: a specific 3-month period and several means have been dedicated to this end.

Trial registration: NCT03181958 (registered on June 9, 2017).

Keywords: Neonate; Non invasive high frequency oscillatory ventilation; Noninvasive respiratory ventilation.

Fig. 1

Neonatal Intensive Care Units participating to the trial. Different colors represent the number of NICU participating in each area

Fig. 2

Basic study design. Neonates will stay on the assigned intervention until the final weaning. No cross-over allowed. In case of intubation, when the baby will be extubated, he will receive again his original treatment according to randomization

Fig. 3

Current bronchopulmonary dysplasia definition [24]. The figure represents the algorithms to apply the definition only in babies ≤32 weeks’ gestation, as these are those enrolled in the trial

Fig. 4

Trial flow-chart according to SPIRIT guidelines [57]. Black squares indicate timepoints when the intervention will surely be provided, while grey squares indicate a time point (36 weeks’ postconceptional age) when the intervention may be provided unless it has been interrupted earlier. All assessments will be performed at the NICU discharge apart from the diagnosis of BPD (that requires evaluation of at 36 weeks’ postconceptional age [24]), safety outcomes and serious adverse events