A Trial Comparing Noninvasive Ventilation Strategies in Preterm Infants Following Extubation

Study Overview
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Brief Summary
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Respiratory distress syndrome (RDS) is the main cause of respiratory failure in preterm neonates, its incidence varying from 80% to 25% depending on gestational age.When optimal prenatal care is provided, the best approach to treat RDS, according to several recent trials,consists in providing continuous positive airway pressure (CPAP) from the first minutes of life using short binasal prongs or masks, followed by early selective surfactant administration for babies with worsening oxygenation and/or increasing work of breathing. Any effort should be done to minimize the time under invasive mechanical ventilation (IMV).Nonetheless, clinical trials have shown that a relevant proportion of preterm neonates fails this approach and eventually need IMV.The duration of IMV is a well known risk factor for the development of broncho-pulmonary dysplasia (BPD) - a condition associated with significant morbidity and mortality. To minimize the duration of IMV, various non invasive respiratory support modalities are available in neonatal intensive care units (NICU). CPAP is presently the most common technique used in this regard. However, a systematic review has shown that non-invasive positive pressure ventilation (NIPPV) reduces the need for IMV (within one week from extubation) more effectively than NCPAP, although it is not clear if NIPPV may reduce need for intubation longterm and it seems to have no effect on BPD and mortality. NIPPV main drawback is the lack of synchronization, which is difficult to be accurately achieved and is usually unavailable. A more recent alternative technique is non-invasive high frequency oscillatory ventilation (NHFOV) which consists on the application of a bias flow generating a continuous distending positive pressure with oscillations superimposed on spontaneous tidal breathing with no need for synchronization. The physiological, biological and clinical details about NHFOV have been described elsewhere. To date, there is only one small observational uncontrolled study about the use of NHFOV after extubation in preterm infants. Other relatively small case series or retrospective cohort studies suggested safety, feasibility and possible usefulness of NHFOV and have been reviewed elsewhere.The only randomized trial published so far compared NHFOV to biphasic CPAP,in babies failing CPAP and it has been criticized for methodological flaws and for not taking into account respiratory physiology.An European survey showed that, despite the absence of large randomized clinical trials, NHFOV is quite widely used, at least in some Countries and no major side effects are reported, although large data about NHFOV safety are lacking. This may be due to the relative NHFOV easiness of use but evidence-based and physiology-driven data are warranted about this technique.

Detailed Description
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NHFOV should theoretically provide the advantages of invasive high frequency oscillatory ventilation (no need for synchronization, high efficiency in CO2 removal, less volume/barotrauma) and nasal CPAP (non-invasive interface, oxygenation improvement by the increase in functional residual capacity through alveolar recruitment). NHFOV should allow to increase mean airway pressure (Paw) avoiding gas trapping and hypercarbia, thanks to the superimposed high frequency oscillations. Therefore, NHFOV is more likely to be beneficial for those neonates requiring high distending pressure to open up their lungs, such as babies at high risk of extubation failure due to severity of their lung disease. This may also be the case of extremely preterm, BPD-developing neonates who have increased airway resistances, while they are subjected to a deranged alveolarization and lung growth. Neonates presenting with respiratory acidosis may also benefit from NHFOV. Several animal and bench studies investigated the physiology and peculiarities of NHFOV and these data should be used to conduct a physiology-guided trial in order to avoid errors done in the early trials about invasive high frequency ventilation. This study will be the first large trial aiming to compare CPAP vs NIPPV vs NHFOV in preterm neonates after surfactant replacement and during their entire NICU stay, to reduce the total need of invasive ventilation. Since there is a lack of formal data regarding NHFOV safety, some safety outcomes will also be considered.Specific subgroup analysis will be conducted for pre-specified groups of patients who may most likely benefit from NHFOV, according to the above-described physiological characteristics.

Official Title
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Nasal High Frequency Oscillation Ventilation(NHFOV) vs. Nasal Continuous Positive Airway Pressure(NCPAP) vs Nasal Intermittent Positive Pressure Ventilation（NIPPV） as Post-extubation Respiratory Support in Preterm Infants With Respiratory Distress Syndrome:a Multicenter Randomized Controlled Trial

Conditions
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Intubated Infants Were Intend to Extubation Using Noninvasive Ventilation Strategies

Intervention / Treatment
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* Device: NHFOV
* Device: NCPAP
* Device: NIPPV


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: gestational age between 25+0 and 32+6 weeks; birth weight more than 600 g; supported with any type of endotracheal ventilation; Has not had first attempt at extubation(extubation readiness requires fulfilling of all the following criteria: a. Having received at least one loading dose of 20 mg/kg and 5 mg/kg daily maintenance dose of caffeine citrate; b. pH>7.20 PaCO2<=60 mmHg (these may be evaluated by arterialized capillary blood gas analysis or appropriately calibrated transcutaneous monitors. Venous blood gas values cannot be used); c. Paw <=7-8 cmH2O; d. FiO2<=0.30; e. sufficient spontaneous breathing effort, as per clinical evaluation).; Obtained parental consent. Informed consent will be obtained antenatally or upon neonatal intensive care unit admission.; Exclusion Criteria: major congenital anomalies or chromosomal abnormalities; Presence of neuromuscular disease; Upper respiratory tract abnormalities; ; need for surgery known before the first extubation; Grade IV-intraventricular haemorrhage (IVH) occurring before the first extubation congenital lung diseases or malformations or pulmonary hypoplasia

Ages Eligible for Study
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Minimum Age: 30 Minutes
Maximum Age: 1 Month

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
Interventional Model Description: When the neonate had fulfilled the extubation criteria, extubation will took place with a gentle intratracheal suction. Upper airways will then be suctioned and intervention will be started immediately as follows: Ventilators CPAP: CPAP will be provided by either variable flow or continuous flow devices, as there is no evidence that one type of CPAP generator would be better than any other. NIPPV: NIPPV will be provided by any type of neonatal ventilator. Synchronization will not be applied, as many currently marketed neonatal ventilators usually do not provide it for NIPPV. NHFOV: NHFOV will only be provided with piston/membrane oscillators able to provide a real oscillatory pressure with active expiratory phase (that is, Acutronic FABIAN-III, SLE 5000, Loweinstein Med LEONI+, Sensormedics 3100A). Other machines providing high frequency ventilations will not be used. Importantly, the randomization should be done within one hour from the extubation to avoid bias.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NHFOV<br>neonates assigned to NHFOV will be started with the following boundaries: 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, similar to what is done in endotracheal high frequency oscillatory ventilation targeting a FiO2≤25-30%. Maximal allowed FiO2 will be 0.40 and SpO2 targets will be 90%-95%. b) frequency of 10Hz(can be changed in steps of 1Hz within the range 8-12Hz). 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. | Device: NHFOV<br>* Nasal high frequency oscillation ventilation (NHFOV) is used as the noninvasive supporting mode after extubation.<br>|
| Active Comparator: NCPAP<br>Neonates assigned to the CPAP group were initiated on a pressure of 5 cmH2O. CPAP can be raised in steps of 1 cmH2O up to 8 cmH2O. If this is not enough to maintain SpO2 between 90% and 95%, FiO2 will be added up to 0.40. | Device: NCPAP<br>* Nasal continuous positive airway pressure(NCPAP) is used as the noninvasive supporting mode after extubation.<br>|
| Experimental: 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) of 15 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 at 30 bpm (can be raised in steps of 5 bpm to max 50 bpm, according to PaCO2 levels). | Device: NIPPV<br>* Nasal intermittent positive pressure ventilation(NIPPV) is used as the noninvasive supporting mode after extubation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Invasive Mechanical Ventilation | the total days of the baby supported with the ventilator | up to 8 weeks | 
| Ventilator-free Days | non-invasive ventilation was need after extubation | up to 8 weeks | 
| Number of Babies With Reintubation | the total numbers of the baby supported with ventilator | up to 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Airleaks | airleaks was diagnosed after extubation | up to 8 weeks | 
| Number of Participants With Bronchopulmonary Dysplasia(BPD) | Bronchopulmonary dysplasia was defined, according to National Institutes of Health (NIH) criteria, by the receipt of any form of positive-airway-pressure support or a requirement for supplemental oxygen at 36 weeks. A requirement for supplemental oxygen at 36 weeks was defined as an FiO2 of 0.30 or more or | at gestational age of 36 weeks or at discharge | 
| Number of Participants With Retinopathy of Prematurity> 2nd Stage | Retinopathy of prematurity> 2nd stage was diagnosed after extubation | up to 8 weeks | 
| Number of Participants With Neonatal Necrotizing Enterocolitis≥ 2nd Stage | Neonatal necrotizing enterocolitis≥ 2nd stage was diagnosed after extubation | up to 8 weeks | 
| Number of Participants With Intraventricular Hemorrhage>2nd Grade | Intraventricular hemorrhage>2nd grade was diagnosed after extubation | up to 8 weeks | 
| Number of Participants With Need for Postnatal Steroids | steroids was used for chronic lung disease | up to 8 weeks | 
| In-hospital Mortality | the baby died in hospital | up to 8 weeks | 
| Composite Mortality/BPD | the baby was dead or diagnosed with BPD. | up to 8 weeks | 
| Weekly Weight Gain | Weekly weight gain (in grams/day) for the first 4 weeks of life or until NICU discharge, whichever comes first | during hospitalization for the first 4 weeks of life or until NICU discharge whichever came first, an average of 1 month | 
| Haemodynamically Significant Patent Ductus Arteriosus (PDA) | hemodynamically significant patent ductus arteriosus (PDA), defined according to local NICU protocols | up to 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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nasal high frequency oscillation ventilation(NHFOV), nasal continuous positive airway pressure(NCPAP), nasal intermittent positive pressure ventilation（NIPPV）, neonatal respiratory distress syndrome(NRDS), preterm infants