nHFOV Versus Invasive Conventional Ventilation for Preterm Neonates With Respiratory Distress Syndrome

Study Overview
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Brief Summary
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Preterm neonates usually develop respiratory distress syndrome (RDS) for which they need respiratory support, which may be invasive and non-invasive depend on the availability and individual need. Non-invasive is relatively safe but non-invasive high frequency oscillatory ventilation (nHFOV) is not appropriately evaluated in neonates as primary support. So the investigators hypothesized that nHFOV is relatively safe and effective in comparison with invasive ventilation for preterm neonates with RDS.

Detailed Description
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Respiratory distress is a common morbidity in preterm neonates that requires respiratory support and surfactant replacement, if not adequately and timely managed may cause multi-organ dysfunction. Respiratory support can be delivered via both non-invasive (NIV) and invasive mode depending upon the availability of ventilators ,experience and comfort level of physician, and availability of department protocol. Non-invasive ventilation include CPAP (Continuous Positive Airway Pressure), NIPPV (Non-invasive Positive Pressure Ventilation) and nHFOV (Non-invasive High Frequency Oscillatory Ventilation). Non-invasive ventilation is currently the preferred mode of ventilation globally due to its safety profile, early weaning, less barotrauma, volume trauma and other complications. Literature review reveals reported comparison for some non-invasive modes of ventilation like CPAP and NIPPV versus conventional ventilation however other non-invasive modes such as nHFOV have still not been appropriately evaluated. nHFOV provides 60-1200 breath/minute with minimal tidal volume while keeping the lungs expanded with equal distribution of air in whole lung so less chances of barotrauma and volutrauma. Extra pressure which is not needed by the lung is dissipated through oral cavity and esophagus to the stomach. Few observational studies reported that extubation failure is better prevented with utilization of NHFOV. For preterm neonates with RDS nHFOV compared with nCPAP showed better results in term of short duration of intervention, less chances of failure, low incidence of intraventricular hemorrhage, and other respiratory complications were almost equal. A multicenter double, blinded, randomized controlled trial is under process for using non-invasive ventilation to prevent extubation failure. Another randomized controlled cross over trial performed in a small number of extreme preterm does showed better clearance of carbon dioxide with nHFOV compared with CPAP. Retrospective cohort study published recently evaluating the use of non-invasive ventilation (nCPAP, SNIPPV and nHFOV) for preterm neonates with RDS, showed satisfactory outcomes with nHFOV with fewer babies requiring invasive ventilation. A metanalysis of Randomized Controlled Trials of studies evaluating the use of nHFOV, nCPAP and biphasic CPAP; published recently showed nHFOV to be more effective as compared to other modes. The primary outcome of the RCT included in the meta analysis was decreased chances of intubation and better clearance of carbon dioxide. In this study investigators will include inborn preterm neonates with no antenatal, perinatal risk factor or anomalies that can affect the outcome. Those babies who developed respiratory distress syndrome at birth and does not need early invasive ventilation will be recruited in study. Study will be conducted in almost 10 centers in Pakistan and Russia, total 1200 babies will be included from all centers. After all teaching and training regarding management strategies and equipment utilization. Recruited participants will be further divided in two arms, one in intervention arm (nHFOV) and other is control arm (Invasive Conventional) ventilation. Outcome will be assessed for respiratory support, surfactant requirement, duration of respiratory support, response to therapy and complications related to respiratory support.

Official Title
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Effectiveness of Non-invasive High Frequency Oscillatory Ventilation (nHFOV) Versus Invasive Conventional Ventilation for Preterm Neonates With Respiratory Distress Syndrome

Conditions
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Respiratory Distress Syndrome in Premature Infant

Intervention / Treatment
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* Device: Non-invasive High Frequency Oscillatory Ventilation
* Device: Conventional Invasive Ventilation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inborn Preterm Neonates 26-34 weeks gestation admitted to NICU with diagnosis of RDS Babies who were initially started on High Flow Oxygen Therapy/nCPAP but unable to maintain saturation > 90% on fio2 of 40% in 1st 6 hours of life. Capillary PCO2 of > 70 or arterial PCO2 > 65 on two repeated sampling within 4 hours Neonates whose parents consented to participate. Exclusion Criteria: All preterm babies who are below < 26 weeks above the 34 weeks of gestation Preterm neonates (26-34 weeks) with diagnosis of RDS requiring endotracheal intubation within Labor room/Operation Theater or within 1st hour of life for respiratory support. Preterm Neonates with the gestational age of 26-34 weeks, diagnosed as congenital pneumonia or sepsis. Patient with poor respiratory drive due to any reason neurological or central causes Diaphragmatic hernia or any other thoracic anomaly Pleural effusion unilateral or bilateral Congenital cystic pulmonary malformation. Neonates with underlying cyanotic heart disease. Neonates with acynotic heart disease causing pulmonary edema Neonates with cleft lip and cleft palate or any other surgical condition.

Ages Eligible for Study
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Minimum Age: 1 Hour
Maximum Age: 6 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
Interventional Model Description: Randomization will be done via random allocation software 1.0.0. This software produces as its output a sequence of allocation based on selected type. Considering 2 groups with equal sample size, a simple random allocation list will be generated using block randomization. The list will be used to create Sequentially Numbered, Opaque, Sealed Envelopes (SNOSE) to assure allocation concealment. The process of randomization will be conducted by Indus Hospital Research Centre (IHRC) independently.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Non-invasive High Frequency Oscillatory Ventilation<br>Preterm babies (26-28 weeks) born with respiratory distress will be initially started on nCPAP with setting of flow 6-8 liter, PEEP 5-6, FiO2 21-40%. If fio2 requirefment more than 40%, surfactant will be given in first 2 hours of birth. If baby fails on CPAP then will be switched to nHFOV with below mentioned settings. Preterm born babies 28-34 weeks gestation with RDS, respiratory support will be started on Heated Humidified High Flow Oxygen therapy or nCPAP, if that fails then baby will be switched to NHFOV with frequency of 5-20 (300-1200 breathe/min), Amplitude of 1-10, flow1-17.5 liter/min, fiO2 21-100% and integrated pressure triggered sensitivity option. | Device: Non-invasive High Frequency Oscillatory Ventilation<br>* We are planning to use (Medin-CNO) for non-invasive ventilation. This machine has option to deliver NHFOV with frequency of 5-20 (300-1200 breathe/min), Amplitude of 1-10, flow1-17.5 liter/min, fiO2 21-100% and integrated pressure triggered sensitivity option.<br>* Other names: Conventional Invasive Ventilation;|
| Active Comparator: Conventional Invasive Ventilation<br>Preterm babies (26-28 weeks) born with respiratory distress will be initially started on nCPAP with setting of flow 6-8 liter, PEEP 5-6, FiO2 21-40%. If fio2 requirement more than 40%, surfactant will be given in first 2 hours of birth. If baby fails on CPAP then will be switched to nHFOV with below mentioned settings. Preterm born babies 28-34 weeks gestation with RDS, respiratory support will be started on Heated Humidified High Flow Oxygen therapy or nCPAP, if that fails then baby will be switched to invasive ventilation through endotracheal tube, mode will be selected as Synchronized Intermittent Mandatory ventilation (SIMV) with rate of 25-60 breath/min, flow of 8 liter, positive inspiratory pressure (PIP) of 14-25, Positive end expiratory pressure (PEEP) 4-5, fio2 of 21-40. | Device: Conventional Invasive Ventilation<br>* Invasive ventilation will be started following endotracheal intubation, mode will be selected as Synchronized Intermittent Mandatory ventilation (SIMV) with rate of 25-60 breath/min, flow of 8 liter, positive inspiratory pressure (PIP) of 14-25, Positive end expiratory pressure (PEEP) 4-5, fio2 of 21-40.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Respiratory Support Escalation | After starting with intervention or control group, baby will be monitored for further escalation of respiratory support like baby is Conventional Invasive Ventilation needs High frequency oscillatory ventilation. Baby started on NHFOV need invasive ventilation. | within first 24 hours of intervention | 
| Oxygen Requirement | With assigned intervention or comparator, baby will be monitored for oxygen requirement comparing with baseline oxygen demand or > 40% of fractional Inspiratory oxygen. | Within first 24 hours | 
| Weaning from Assigned respiratory support | Babies started on intervention or comparator will be monitored for weaning from respiratory support in hours after starting respiratory support. | within 1-2 weeks of respiratory support starting | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Surfactant Needed | Both groups will be compared for number of surfactant needed | within first 3 days of assignment | 
| Respiratory Support Duration | Both groups will be compared for respiratory support duration in hours | up to 2 weeks | 
| Complications related to respiratory support | Both groups will be compared for complication like pneumothorax, atelectasis, Collapse, pneumonia and bronchopulmonary dysplasia. | Within 1 week after respiratory support discontinuation | 
| Complication related to prematurity | both groups will be compared for complication of prematurity like intraventricular hemorage, Patent Ductus Arteriosus, Intraventricular Hemorrhage, necrotizing enterocollitis, and nosocomial infection | Within 1week | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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nHFOV, RDS, CPAP, Respiratory failure, Respiratory support