NHFOV vs NIPPV vs nCPAP in Preterm Infants With Respiratory Distress Syndrome

Study Overview
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Brief Summary
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This will be a prospective, multi-center, three-arms,parallel, randomized, controlled trial with a superiority design,conducted in China. The investigators conduct this multi-centre, randomized, controlled trial to test the hypothesis that NHFOV is more effective than nCPAP or NIPPV in the treatment of respiratory distress syndrome (RDS) in infants with a gestational age of less than 30 weeks or a birth weight of less than 1500g when used as a primary noninvasive ventilation (NIV) mode.

Detailed Description
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Preterm infants are eligible to the study if they they match the following inclusion criteria: (1) Gestational age (GA) less than 30 weeks or Birth weight less than 1500g; (2) They have a diagnose of RDS, and RDS Silverman score﹥5; (3) Informed parental consent has been obtained. Neonates will be randomized and assigned either to nCPAP, NIPPV or NHFOV arms with a 1:1:1 ratio, when patients fulfill all inclusion criteria. Randomization cannot be done earlier. Simple randomization will be done according to a computer-generated random number table and will be posted in a specific secured website 24/7 available. Twins will be allocated in the same treatment group. Infants randomized to one arm cannot crossover to the other or vice-versa during the study. For all the groups, if the fraction of inspired oxygen (FiO2) requirement is persistently higher than 0.35-0.40 per target SpO2 89-94% and/or dyspnoea defined by Silverman score > 6 after starting the respiratory support, newborns receive Surfactant by INSURE technique, involving endotracheal intubation by direct laryngoscopic vision, endotracheal administration of surfactant (Curosurf, Chiesi Pharmaceutics, Parma, Italy) 200 mg/kg and finally extubation. After the administration of surfactant, if FiO2 requirement is persistently >0.4 to keep SpO2 89-94% or severe apnea episodes are present (defined as recurrent apnea with >3 episodes/h associated with heart rate <100/min or a single episode of apnea requiring bag and mask ventilation within a 24-hour period ) or at the blood gas (arterial or free-flowing capillary blood) PaCO2>60 mmHg and potential of hydrogen (pH)<7.20 obtained at least 1 hour after commencement of the assigned treatment, newborns are intubated and mechanically ventilated. For all the newborns enrolled in the study, arterial or free-flowing capillary blood gas is checked every 6-12 hours, a cerebral and cardiac ultrasound screening is performed within 24 hrs. Further controls follow the routine of the ward. The study intervention (nCPAP, NIPPV or NHFOV) will be stopped when the above-described minimum parameters are reached and maintained for at least 48h with the following: (1) FiO2≤0.25; (2) Silverman score <3; (3)no apneas or bradycardia without spontaneous recovery.If a baby will desaturate (SpO2<85% with FiO2>25%) or has relevant dyspnea (Silverman≧3) or more than 3 apneas/d, the intervention (CPAP, NIPPV or NHFOV) will be restarted for at least 48h and then re-evaluated

Official Title
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NHFOV vs NIPPV vs nCPAP in Preterm Infants With Respiratory Distress Syndrome: A Multi-center, Prospective, Randomized, Controlled Clinical Superior Trial

Conditions
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Preterm Infant

Intervention / Treatment
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* Other: nCPAP
* Other: NIPPV
* Other: NHFOV


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Gestational age (GA) of less than 30 weeks or birth weight less than 1500g Clinical diagnose of RDS Parental consent Exclusion Criteria: Intubated for resuscitation or for other reasons at birth Major congenital malformations or known complex congenital heart disease No parental consent

Ages Eligible for Study
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Maximum Age: 12 Hours

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: nCPAP<br>neonates assigned to the nCPAP group will be started on a pressure of 6 cmH2O( adjust range:6-8 cmH2O) by pure CPAP system , with FiO2 (0.21～0.40)adjusted to target SpO2 from 89% to 94% | Other: nCPAP<br>* infants receive primary non-invasive respiratory support by mean of nCPAP<br>|
| Active Comparator: NIPPV<br>neonates assigned to the NIPPV group will be started with the following parameters: a) positive end-expiratory pressure (PEEP) of 4 cmH2O (can be raised in steps of 1 cmH2O to max 8 cmH2O, according to the oxygenation).b)Peak Inspiratory Pressure (PIP) of15 cmH2O (can be raised in steps of 1 cmH2O to max 25 cmH2O, according to oxygenation,PaCO2 levels and the chest expansion); maximal allowed FiO2 will be 0.40 and SpO2 targets will be 90-95%. c) inspiratory time (IT) will be 0.45 - 0.5 sec (according to clinicians'evaluation of leaks and the appearance of the pressure curve: a small pressure plateau is required and flow may be set accordingly) and rate will be started at30 bpm (can be raised in steps of 5 bpm to max 50 bpm, according to PaCO2 levels). | Other: NIPPV<br>* infants receive primary non-invasive respiratory support by mean of NIPPV<br>|
| Experimental: NHFOV<br>- neonates assigned to NHFOV will be started with the following boundaries, according to available physiological and mechanical data, as suggested elsewhere: a) Paw of 10 cmH2O (can be changed in steps of 1 cmH2O within the range range 5- 16cmH2O); Paw will be titrated (within the range) according to open lung strategy, performing alveolar recruitment. Maximal allowed FiO2 will be 0.40 and SpO2 targets will be 89%-94%. b) frequency of 10Hz(can be changed in steps of 1Hz within the range 8-15Hz). c)Inspiratory time 50% (1:1).[ d)amplitude 25 cmH2O(can be changed in steps of 5 cmH2O within the range 25-50 cmH2O); amplitude will be titrated according to PaCO2. | Other: NHFOV<br>* infants receive primary non-invasive respiratory support by mean of NHFOV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| treatment failure within 72 hours after randomization 72 hours after randomization | need for invasive mechanical ventilation | within 72 hours after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of airleaks(pneumothorax and/or pneumomediastinum) occurred during noninvasive respiratory support | determined by the treating clinician by the treating clinician | during noninvasive respiratory support | 
| Rate of bronchopulmonary dysplasia | defined according to the NICHD definition | 36 weeks of postmenstrual age | 
| Rate of retinopathy of prematurity (ROP) | ≥ 2nd stage | Within 6 months after birth | 
| Rate of necrotizing enterocolitis (NEC) | ≥ 2nd stage | through study completion, an average of 1 year | 
| Rate of intraventricular hemorrhage | ≥ 3nd grade | through study completion, an average of 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Preterm Infant, Respiratory distress syndrome, nasal continuous positive airway pressure, noninvasive intermittent positive airway pressure, noninvasive high-frequency oscillatory ventilation