The goal of this clinical trial is to learn if nasal high frequency oscillatory ventilation (nHFOV) works no worse than nasal intermittent mandatory ventilation (NIMV) as early breathing support. The study will include preterm babies born from 28 weeks through 36 weeks of gestation..All babies will have respiratory distress syndrome and need noninvasive breathing support within six hours of birth. Noninvasive support helps breathing through a nasal interface without placing a tube in the windpipe. The main questions it aims to answer are: Does nHFOV work no worse than NIMV in preventing the need for a breathing tube within 72 hours? What medical problems occur in babies receiving each type of breathing support? Researchers will compare nHFOV with NIMV. nHFOV uses rapid, small pressure waves. NIMV provides regular supported breaths. Both methods are routinely used at the study hospital. Babies will: Be assigned by chance to receive either nHFOV or NIMV Receive regular monitoring of breathing, oxygen levels, and medical condition Be assessed for the need for a breathing tube during the first 72 hours Be followed for complications of disease and assigned treatment during hospitalization and after discharge when required The study will also record breathing support duration, hospital stay, survival, chronic lung disease, severe bleeding in the brain, and eye disease related to prematurity. The findings may help doctors choose breathing support for preterm babies with respiratory distress syndrome.
Direct comparisons of nasal high frequency oscillatory ventilation (nHFOV) and nasal intermittent mandatory ventilation (NIMV) as primary respiratory support for preterm neonates with respiratory distress syndrome are limited, particularly in Pakistan and other lower middle income settings. Both methods are routinely used at Aga Khan University Hospital, but the choice between them currently depends mainly on the treating clinician's preference. This study is intended to provide local evidence that may guide a more standardized approach to early noninvasive respiratory support. This is a prospective, single center, open label, parallel group, non inferiority randomized controlled trial. A total of 158 neonates will be assigned in a 1:1 ratio using stratified permuted block randomization based on gestational age. Allocation will be concealed using sequentially numbered, opaque, sealed envelopes prepared by an independent biostatistician. Because the two ventilation modes use visibly different settings, treating clinicians and research personnel will not be blinded. Statistical analysis will remain blinded until completion of the primary analysis. The primary analysis will estimate the risk difference in treatment failure between the nHFOV and NIMV groups with a two-sided 95% confidence interval. nHFOV will be considered non-inferior if the upper limit of the confidence interval is below the prespecified absolute non-inferiority margin of 15 percentage points. Both intention to treat and per protocol analyses will be performed. An independent Data and Safety Monitoring Board will review safety data after approximately 25%, 50%, and 75% of planned enrollment.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
158
Noninvasive high frequency oscillatory ventilation will be delivered as primary respiratory support through a nasal interface using a RAM cannula or Infant Flow Generator and an nHFOV capable ventilator. Initial settings will include mean airway pressure of 10-12 cmH₂O, amplitude of 15-25 cmH₂O, frequency of 8-12 Hz, and an inspiratory to expiratory ratio of 1:1. Mean airway pressure may be increased by 1 cmH₂O to a maximum of 20 cmH₂O, and amplitude may be increased by 5 cmH₂O to a maximum of 35 cmH₂O. Settings will be adjusted according to clinical response to maintain SpO₂ between 90% and 95%.
Nasal intermittent mandatory ventilation will be delivered as primary respiratory support through a nasal interface using a RAM cannula or Infant Flow Generator and an NIMV capable ventilator. Initial settings will include PEEP of 8-12 cmH₂O, peak inspiratory pressure of 18-24 cmH₂O, inspiratory time of 0.5 seconds, and respiratory rate of 30 breaths per minute. The respiratory rate may be increased by 5 breaths per minute to a maximum of 50 breaths per minute based on PaCO₂. FiO₂ and other ventilator settings may be adjusted according to clinical response to maintain SpO₂ between 90% and 95%.
Aga Khan University Hospital, Karachi Stadium Road, P.O.Box 3500 Karachi 74800, Pakistan
Karachi, Sindh, Pakistan
Proportion of preterm neonates with treatment failure requiring invasive mechanical ventilation
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.
Time frame: Within 72 hours after randomization
Proportion of Eligible Neonates With Bronchopulmonary Dysplasia at 36 Weeks' Postmenstrual Age Description
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.
Time frame: At 36 weeks' postmenstrual age
Proportion of eligible neonates with severe intraventricular hemorrhage
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.
Time frame: From randomization until 44 weeks' postmenstrual age or final hospital disposition, whichever occurs first
Proportion of Eligible Neonates With Treatment-Requiring Retinopathy of Prematurity
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.
Time frame: From the first ROP screening examination until 44 weeks' postmenstrual age or discharge from ROP screening by the treating ophthalmologist, whichever occurs first
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