Noninvasive High Frequency Oscillatory Ventilation Versus Nasal Intermittent Mandatory Ventilation for Respiratory Distress Syndrome in Preterm Neonates

Treatment failure is defined as initiation of invasive mechanical ventilation due to any of the following: pH <7.20 with pCO₂ >60 mmHg on two blood gas measurements at least 30 minutes apart, SpO₂ <90% with FiO₂ >0.60 for at least 15 minutes on maximal noninvasive support; at least one apnea episode requiring bag mask ventilation; Silverman Anderson Score ≥7 on maximal noninvasive support; hemodynamic instability requiring inotropic support secondary to respiratory failure, or the physician's decision to intubate for clinical reasons with written justification. The number and proportion of neonates meeting the treatment failure criteria will be reported in each study arm.

Among enrolled neonates born at ≤32 weeks' gestation who survive to 36 weeks' PMA, BPD will be classified according to respiratory support at 36 weeks using Jensen et al. (2019): no BPD, no respiratory support; Grade 1, nasal cannula ≤2 L/min; Grade 2, nasal cannula >2 L/min or noninvasive positive-pressure support; and Grade 3, invasive mechanical ventilation. Respiratory status will be obtained from inpatient records, outpatient assessment, or telephone follow-up. Neonates who die before 36 weeks' PMA will be excluded from BPD ascertainment.

The proportion of enrolled neonates born at <32 weeks' gestation or with a birth weight <1,500 g who develop severe IVH will be reported for each study arm. Severe IVH is defined according to the Papile classification as Grade III, IVH occupying ≥50% of the ventricular area with ventricular dilatation, or Grade IV, IVH with periventricular echodensity consistent with periventricular hemorrhagic infarction. All routine and clinically indicated cranial ultrasounds obtained during the assessment period will be included and reported by a consultant radiologist blinded to treatment allocation.

The proportion of enrolled neonates born at <32 weeks' gestation or with a birth weight <1,500 g who develop treatment-requiring ROP in either eye will be reported for each study arm. Screening will be performed by a consultant ophthalmologist, and ROP will be classified according to ICROP3. Treatment-requiring ROP is defined as Type 1 ROP-Zone I ROP of any stage with plus disease, Zone I Stage 3 without plus disease, or Zone II Stage 2 or 3 with plus disease-aggressive ROP, or Stage 4 or 5 ROP. Treatment may include laser photocoagulation, intravitreal anti-VEGF therapy, or vitreoretinal surgery. Findings will be obtained from inpatient records and scheduled post-discharge ophthalmology follow-up.

The cumulative duration for which each participant receives noninvasive respiratory support after randomization will be recorded and reported in days, including the assigned nHFOV or NIMV intervention and any subsequent noninvasive positive pressure respiratory support. Heated humidified high flow nasal cannula and supplemental oxygen alone will not be included. The duration will be compared between the two study arms.

Among participants who require intubation and invasive mechanical ventilation after randomization, the cumulative duration of all invasive mechanical ventilation episodes will be recorded and reported in days. The duration will be compared between the nHFOV and NIMV study arms.

The cumulative duration for which each participant receives supplemental oxygen after randomization will be recorded and reported in days. This will include supplemental oxygen delivered through invasive mechanical ventilation, noninvasive respiratory support, heated humidified high-flow nasal cannula, low-flow nasal cannula, oxygen hood, or any other oxygen delivery device. The duration will be compared between the nHFOV and NIMV study arms.

The number and proportion of neonates who receive at least one dose of surfactant after randomization will be recorded and compared between the nHFOV and NIMV study arms.

The number and proportion of participants who develop a radiographically confirmed air leak syndrome including pneumothorax, pulmonary interstitial emphysema, or pneumomediastinum while receiving their assigned nHFOV or NIMV respiratory support will be recorded and compared between the study arms. Air leaks occurring after discontinuation of the assigned modality will not be included in this outcome.

The number and proportion of participants who develop Stage II or higher necrotizing enterocolitis according to the modified Bell criteria will be recorded and compared between the nHFOV and NIMV study arms. Suspected Stage I necrotizing enterocolitis will not be included in this outcome.

The number and proportion of participants diagnosed with a hemodynamically significant patent ductus arteriosus requiring medical treatment or surgical ligation, based on clinical and echocardiographic findings, will be recorded and compared between the nHFOV and NIMV study arms.

Nasal injury attributable to the assigned noninvasive respiratory interface will be assessed at least every 24 hours using the modified Fischer classification: Grade 0, no injury; Grade 1, erythema or discoloration without skin breakdown; Grade 2, superficial erosion or ulceration; and Grade 3, full-thickness tissue loss, necrosis, or cartilage damage. The highest grade recorded for each participant during the assessment period will be compared between the study arms.

The duration of hospitalization will be calculated in days from hospital admission until final hospital disposition, defined as discharge, transfer, leaving against medical advice, or death. The duration will be compared between the nHFOV and NIMV study arms.

The number and proportion of participants who die from any cause during hospitalization after randomization will be recorded and compared between the nHFOV and NIMV study arms. Final hospital disposition is defined as discharge, transfer to another unit or facility, leaving against medical advice, or death.