Non-invasive Respiratory Support in Preterm Infants
Non-invasive Respiratory Support in Preterm Infants
Lungs of babies born early are not fully developed and they often need a machine to help them
 breathe. The traditional approach to provide this support is with a breathing tube passed
 into the windpipe. However, we know that breathing tubes can cause injury to the fragile
 lungs of premature babies. Providing breathing support through nose-masks instead of
 breathing tubes (called nasal breathing support) is becoming popular, as it is gentler on
 developing lungs. Doctors, in trying to limit the use of support with a breathing tube, are
 using many different forms of nasal breathing support. The most common form is nasal
 continuous positive airway pressure (CPAP) which delivers a constant pressure and the baby
 breathes on his on her own. However, when this strategy is no longer able to support a
 premature baby's breathing, the best way to provide breathing support is not known. Some
 doctors use a strategy called "nasal intermittent positive airway pressure" (NIPPV) which
 gives the baby artificial breaths through the nose-mask. Others simply increase the pressure
 on nasal CPAP to higher than traditional levels. In the first study of its kind, we will
 compare these two strategies of nasal breathing support given to premature babies.
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.

 OBJECTIVES AND HYPOTHESIS:

 To determine the feasibility of the conduct of a larger and definitive trial comparing two
 NRS strategies (NIPPV vs. high NCPAP pressures) in preterm infants. Therefore to prepare for
 this a pilot trial is proposed. We hypothesize that the conduct of a definitive trial
 comparing these two NRS modes to assess clinical outcomes will be feasible.

 METHODS:

 Parents of all patients with gestational age < 29 weeks who do not meet any of the exclusion
 criteria will be approached for consent by the research assistant at the earliest
 opportunity. Consent will be sought within the first 72 hours. Subjects whose parents provide
 consent AFTER 72 days will still be eligible, as long as there is no administration of high
 NCPAP or NIPPV outside of randomization for greater than 4 continuous hours AFTER day 10 [240
 hours] of post-natal age . A subject for whom consent is obtained from the parents will be
 considered an "enrolled subject". The research assistant will be responsible for indicating
 this by placing a laminated card at the bedside, and informing both the medical and
 respiratory therapy teams.

 Enrolled subjects who meet NRS failure criteria despite NCPAP 8 cmH2O, or are being extubated
 from invasive mechanical ventilation with a mean airway pressure >/= 10 cmH2O will be
 eligible for randomization to either high CPAP > 8 cmH2O (experimental arm) or NIPPV (control
 arm). Once NRS failure criteria (indicated on bedside laminated card) and randomization
 eligibility is confirmed, the subject will be randomized using an electronic web-based secure
 platform (REDCap). An enrolled subject who gets randomized to one of the two arms will be
 considered a "randomized subject". A study initiation form will be completed by the research
 team within 24 hours of randomization, and a new laminated card indicating arm of
 randomization and extubation criteria will replace the enrollment card. This form will
 include demographic data about the subject, the NRS failure criteria that was met which led
 to randomization, and the suspected underlying pathophysiological mechanism for NRS failure.

 Guidelines for initiation and recommended increments of both high CPAP and NIPPV will be
 provided, with a view towards maintaining similar mean airway pressures between the two modes
 (which will also be placed at patient bedside in randomized subjects). Given the existing
 variability of practice in NRS application and lack of evidence-based guidelines, the
 strategies will NOT provide guidance with regards to day-to-day changes in settings or
 modalities, but rather provide only ceiling limits and maximum allowed pressures for each NRS
 mode. However, interfaces must be limited to either nasal masks or short bi-nasal prongs (RAM
 cannulas will not be allowed). However, ceiling limits and maximum allowed pressures for each
 NRS mode will be provided, as delineated below:

 -  High CPAP - Maximum PEEP: 15 cmH2O

 -  NIPPV - Maximum (set) PIP: 25 cmH2O; AND/OR Maximum (set) PEEP: 12 cmH2O; AND/OR Maximum
 (calculated) MAP: 15 cmH2O

 If NRS failure criteria are met despite escalating settings (with a strongly suggested - but
 not mandated - minimum MAP of 12 cmH2O) whether either randomized arm of high NCPAP or NIPPV,
 the clinician will have one of following three options:

 -  Intubation and endotracheal mechanical ventilation

 -  Escalation of settings within the randomized arm beyond the aforementioned ceiling limit
 - will still be considered failure of assigned mode

 -  Use of an alternate mode of NRS (NIV-NAVA or NIHFV) - but no crossover

 Of note, the maximum recommended settings for each NRS mode need not be reached before
 decision to intubate a subject, at the medical team's discretion. Furthermore, the NRS
 strategy corresponding to the randomization arm reflects use of NRS at any and all times
 after randomization until a randomized subject is discharged or transferred. The decision to
 wean down to traditional NCPAP levels from either arm will be at discretion of the medical
 team. Finally, subjects randomized to a particular strategy will NOT be allowed to cross-over
 to the other arm until the first intubation. Patients may be pulled out from the study
 protocol only at the discretion of the attending medical physician following the first
 intubation, and the reason must be discussed in advance with the PI (A.M.). A customized
 protocol violation form will then be completed by the attending physician, facilitated by the
 research assistant.

 Two major forms of protocol violations will be tracked prospectively (by research
 coordinator):

 1. Use of NIPPV or high CPAP in an enrolled patient outside of randomization. Such patients
 will not be included in any further analysis of clinical outcomes, but will count
 towards feasibility outcome.

 2. A patient with protocol violation related to cross-over; such a patient will be treated
 as intention-to-treat for clinical outcomes, but a set of sensitivity analyses excluding
 such patients (i.e. those that underwent protocol violation) will be conducted (see
 section below on Sensitivity Analyses).

 Assessment of cerebral and renal regional perfusion will be performed using near-infrared
 spectroscopy (NIRS) for all subjects (at the primary study site only) at time of
 randomization. At the time an enrolled subject meets NRS failure criteria, the NIRS leads
 will be placed and recording will be initiated. Perfusion will be assessed immediately prior
 to and continuously for up to 7 days post-randomization (or intubation if sooner that 7
 days). This will be conducted by the research assistant during office hours and the
 respiratory therapist at night.

 At the end of the study period, relevant demographic data and outcome variables for all
 randomized subjects will be extracted from the local Canadian Neonatal Network (CNN) database
 (or other equivalent local database) and from patient charts/electronic records by the
 research coordinator using a customized data collection form.

 DATA ANALYSIS, STATISTICS AND SAMPLE SIZE CALCULATIONS

 All randomized patients will be analyzed using intention-to-treat principle. Mean (SD) or
 Median (IQR) will be reported for continuous variables depending on normality of data, and
 percentages will be reported for categorical variables. T-test (or Wilcoxon rank sum test for
 non-normally distributed variables) and Chi-square test (or Fisher's exact test as
 appropriate) will be used to compare continuous and categorical variables, respectively. All
 analyses will be performed using SAS version 9.4.

 Subgroup analyses (for relevant secondary outcomes) will be performed based on the following
 variables:

 1. Indication for randomization [categorized broadly into: (a) Escalation from NCPAP due to
 Apneas; (b) Escalation from NCPAP due to all other causes; and (c) Post-extubation]

 2. Post-randomization respiratory management reflecting the initial alteration from
 assigned NRS mode [categorized broadly into: (a) Wean down to traditional NCPAP; (b)
 Escalation to alternate NRS mode (including escalation within assigned NRS mode beyond
 maximum allowed settings); or (c) Intubation]

 Sensitivity analyses (for secondary outcomes) based on the following variables:

 1. Protocol violations due to crossover to alternate rescue NRS arm under study - analysis
 of all secondary outcomes will be conducted after excluding such patients.

 a. Protocol violations due to crossover will be categorized into (i) within 7 days of
 randomization and (ii) after 7 days of randomization - exclusion of patients for this
 sensitivity analysis will be based on (i) and (ii) or (ii) only depending on which
 outcome is being analysed.

 2. Excluding patients for whom a minimum MAP of 12 cmH2O on rescue NRS was NOT utilized
 prior to NRS failure.

 3. Excluding patients for whom the post-randomization NRS failure criteria were due to need
 for intubation related to non-respiratory pathology (including but not limited to
 clinical deterioration due to sepsis)

 Regression analyses: No regression analyses are planned a-priori for this pilot trial.

 Regional perfusion data using NIRS (from participant data at primary study site only) will be
 compared within each randomization arm (immediately prior to and 2 hours post-randomization)
 as well as between the two randomization arms 2 hours-post randomization using paired t-test
 and unpaired t-tests, respectively.

 A convenience sample of 100 subjects (40 at the lead institution and 20 per site at the other
 3 centres) will be chosen for the purposes of this pilot trial. Analysis of secondary
 outcomes from this pilot study will help inform the design and sample size for a definitive
 trial comparing high CPAP and NIPPV. The feasibility outcome goals were used to determine the
 sample size, based on methods described by Thabane et al.

 DATA SAFETY AND MONITORING BOARD (DSMB): A DSMB will perform two reviews - one following the
 transition of the first phase of the study (30 randomized patients) and prior to commencement
 of the second phase, with a second review occurring after 40 patients have been randomized
 (70 total) in the second phase.

 Appendix: NRS • FiO2 >50% or rise in FiO2 >20% in ≤12 hours

 -  High CO2 with pH <7.20 (respiratory acidosis) on arterial or capillary blood gas

 -  Increased work of breathing (with RR >80 bpm)

 o Modified DOWNES' score to be completed in real time to objectively describe components
 of increased work of breathing

 -  Apnea/Desaturation/Bradycardia spells (>1 requiring bagging or >4/hour requiring
 moderate stimulation x 4 hours)

 -  Need for intubation related to non-respiratory pathology including but not limited to
 necrotizing enterocolitis, septic deterioration and hemodynamically significant ductus
 arteriosus where none of the above failure criteria are applicable [this option only
 applicable to post-randomization NRS failure] Failure Criteria
Inclusion Criteria: All preterm neonates with gestational age < 29 weeks with a
 chronological age of at least 72 hours admitted to one of four participating NICUs
 (McMaster Children's Hospital, Stollery Children's Hospital, BC Women and Children's
 Hospital, and Women and Infants' Hospital of Rhode Island); whose families have consented
 to study participation; and who do not meet any of the following exclusion criteria:

 1. Major upper airway malformation (cleft lip/palate, severe micro-retrognathia,
 congenital tracheal stenosis or vascular ring, and neck mass/cystic hygroma)

 2. Major (non-airway) congenital abnormality not-yet repaired (congenital diaphragmatic
 hernia, abdominal wall defect, and tracheo-esophgeal fistulas)

 3. Suspected or confirmed chromosomal/genetic abnormality

 4. Administration of high NCPAP or NIPPV outside of randomization for greater than 4
 continuous hours AFTER day 10 [240 hours] of post-natal age.