Intubated Infants Were Intend to Extubation Using Noninvasive Ventilation StrategiesNCT03181958
A Trial Comparing Noninvasive Ventilation Strategies in Preterm Infants Following Extubation
A study testing NHFOV, NCPAP and NIPPV in people with Intubated Infants Were Intend to Extubation Using Noninvasive Ventilation Strategies, run by Daping Hospital and the Research Institute of Surgery of the Third Military Medical University at 1 site in China.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 30 minutes to 1 month
- Conditions the study is for
- Intubated Infants Were Intend to Extubation Using Noninvasive Ventilation Strategies
- What is being tested?
- NHFOV, NCPAP and NIPPV
- Type of treatment
- Medical device
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 1,493 participants
- Where
- 1 siteChina
- Study dates
- 1 Dec 2017to 30 Jun 2021
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 30 minutes to 1 month
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- 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.;
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
China1 site
Daping Hospital and the Research Institute of Surgery of the Third Military Medical University
Chongqing, Chongqing Municipality, 400042
About this study
Official title: 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
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.
Read the detailed description
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.
- Being tested
- NHFOV, NCPAP, NIPPV
- Keywords
- 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
- Medical subject headings
- Respiratory Distress Syndrome, Newborn
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
NHFOVDevice
Nasal high frequency oscillation ventilation (NHFOV) is used as the noninvasive supporting mode after extubation.
NCPAPDevice
Nasal continuous positive airway pressure(NCPAP) is used as the noninvasive supporting mode after extubation.
NIPPVDevice
Nasal intermittent positive pressure ventilation(NIPPV) is used as the noninvasive supporting mode after extubation.
| Study group | Role | What they receive |
|---|---|---|
| NHFOV | Experimental | 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. Receives: Device: NHFOV |
| NCPAP | Active comparator | 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. Receives: Device: NCPAP |
| NIPPV | Experimental | 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). Receives: Device: NIPPV |
What is being measured
The primary outcome is the main question the study is designed to answer.
Duration of Invasive Mechanical Ventilation
the total days of the baby supported with the ventilator
Measured: up to 8 weeks
Ventilator-free Days
non-invasive ventilation was need after extubation
Measured: up to 8 weeks
Number of Babies With Reintubation
the total numbers of the baby supported with ventilator
Measured: up to 8 weeks
Secondary outcomes (10)
Number of Participants With Airleaks
airleaks was diagnosed after extubation
Measured: 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
Measured: 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
Measured: up to 8 weeks
Number of Participants With Neonatal Necrotizing Enterocolitis≥ 2nd Stage
Neonatal necrotizing enterocolitis≥ 2nd stage was diagnosed after extubation
Measured: up to 8 weeks
Number of Participants With Intraventricular Hemorrhage>2nd Grade
Intraventricular hemorrhage>2nd grade was diagnosed after extubation
Measured: up to 8 weeks
Number of Participants With Need for Postnatal Steroids
steroids was used for chronic lung disease
Measured: up to 8 weeks
In-hospital Mortality
the baby died in hospital
Measured: up to 8 weeks
Composite Mortality/BPD
the baby was dead or diagnosed with BPD.
Measured: 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
Measured: 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
Measured: up to 8 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Jun 2017
- Study start1 Dec 2017
- Primary completion31 May 2021
- Study completion30 Jun 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Intubated Infants Were Intend to Extubation Using Noninvasive Ventilation StrategiesStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- 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 blind
- Who is masked
- Investigator, Outcomes assessor
- Enrolment
- 1,493 participants (actual)
Sponsor and investigators
- Lead sponsor
- Daping Hospital and the Research Institute of Surgery of the Third Military Medical University
- Sponsor type
- University, hospital or other
- Collaborators
- Children's Hospital of Chongqing Medical University, Jiulongpo No.1 People's Hospital, Chongqing Maternal and Child Health Hospital, The First Affiliated Hospital of Anhui Medical University, Children's Hospital of The Capital Institute of Pediatrics, Peking University Third Hospital, First Hospital of Tsinghua University, Women and Children's Hospital, Branch of Chongqing Sanxia Central Hospital, First Affiliated Hospital of Chongqing Medical University, Quanzhou Children's Hospital, Xiamen Maternity & Child Care Hospital, Zhujiang Hospital, Nanfang Hospital, Southern Medical University, Guangdong Academy of Medical Science and General Hospital, Guangdong Women and Children Hospital, Women and Children's Health Hospital of Yulin, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Second Affiliated Hospital of Guangzhou Medical University, Guiyang Maternal and Child Health Care Hospital, Zunyi First People's Hospital, Lanzhou University Second Hospital, Gansu Provincial Maternal and Child Health Care Hospital, LanZhou University, First Affiliated Hospital of Harbin Medical University, First Affiliated Hospital of Xinjiang Medical University, Zhengzhou Children's Hospital, China, Third Affiliated Hospital of Zhengzhou University, the Maternal and Child Health Hospital of Hainan Province, Bethune International Peace Hospital, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Children's Hospital of Nanjing Medical University, The First Hospital of Jilin University, Children's Hospital of Fudan University, Maternal and Children's Healthcare Hospital of Taian, The Second Hospital of Shandong University, Shanxi Provincial Maternity and Children's Hospital, Chengdu Women and Children's Center Hospital, The Affiliated Hospital Of Southwest Medical University, Affiliated Hospital of Southwest Medical University, Shenzhen People's Hospital, The Second Medical College of Jinan University, Tianjin Central Hospital of Gynecology Obstetrics, People's Hospital of Xinjiang Uygur Autonomous Region, Kunming Children's Hospital, The First People's Hospital of Yunnan, First Affiliated Hospital of Kunming Medical University, Yan'an Affiliated Hospital of Kunming Medical University, Women and Children's Health Hospital of Qujing, The People's Hospital of Dehong Autonomous Prefecture, The First People's Hospital of Yinchuan, The Children's Hospital of Zhejiang University School of Medicine, Women's Hospital School Of Medicine Zhejiang University, Beijing 302 Hospital, Hunan Children's Hospital, Women and Children Hospital of Qinghai Province, Jiangxi Province Children's Hospital, Inner Mongolia People's Hospital, Mianyang Central Hospital, People's Liberation Army No.202 Hospital, Ningbo Women & Children's Hospital, Shanghai Children's Medical Center, First Affiliated Hospital of Guangxi Medical University, Nanjing Medical University, Qinhuangdao Maternal and Child Health Care Hospital, Xuzhou Children Hospital, Catholic University of the Sacred Heart, The First Affiliated Hospital of Zhengzhou University, Xianyang Children's Hospital
- Responsible party
- Principal investigator, Ma Juan, Daping Hospital and the Research Institute of Surgery of the Third Military Medical University
- Investigators
- Shi Yuan, PhD,MD, Principal investigator, Daping Hospital and the Research Institute of Surgery of the Third Military Medical University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03181958
- Sponsor's protocol ID
- 201721
- Status last verified
- Sep 2021
- First submitted
- 28 May 2017
- Last updated
- 30 Sep 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Every researchers can obtain the IPD after the study completely.
Publications
Zhu X, Li F, Shi Y, Feng Z, De Luca D; Nasal Oscillation Post-Extubation (NASONE) Study Group. Effectiveness of Nasal Continuous Positive Airway Pressure vs Nasal Intermittent Positive Pressure Ventilation vs Noninvasive High-Frequency Oscillatory Ventilation as Support After Extubation of Neonates Born Extremely Preterm or With More Severe Respiratory Failure: A Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open. 2023 Jul 3;6(7):e2321644. doi: 10.1001/jamanetworkopen.2023.21644.
PubMed 37399009Zhu X, Qi H, Feng Z, Shi Y, De Luca D; Nasal Oscillation Post-Extubation (NASONE) Study Group. Noninvasive High-Frequency Oscillatory Ventilation vs Nasal Continuous Positive Airway Pressure vs Nasal Intermittent Positive Pressure Ventilation as Postextubation Support for Preterm Neonates in China: A Randomized Clinical Trial. JAMA Pediatr. 2022 Jun 1;176(6):551-559. doi: 10.1001/jamapediatrics.2022.0710.
PubMed 35467744Shi Y, De Luca D; NASal OscillatioN post-Extubation (NASONE) study group. Continuous positive airway pressure (CPAP) vs noninvasive positive pressure ventilation (NIPPV) vs noninvasive high frequency oscillation ventilation (NHFOV) as post-extubation support in preterm neonates: protocol for an assessor-blinded, multicenter, randomized controlled trial. BMC Pediatr. 2019 Jul 26;19(1):256. doi: 10.1186/s12887-019-1625-1.
PubMed 31349833
Study at a glance
From the registry record, last updated by the sponsor on 30 Sep 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT03181958
- Acronym / sponsor ID
- 201721
- Keywords
- 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
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 1,493 participants (actual)
- Lead sponsor
- Daping Hospital and the Research Institute of Surgery of the Third Military Medical UniversityUniversity, hospital or other
- Collaborators
- Children's Hospital of Chongqing Medical University, Jiulongpo No.1 People's Hospital, Chongqing Maternal and Child Health Hospital, The First Affiliated Hospital of Anhui Medical University, Children's Hospital of The Capital Institute of Pediatrics, Peking University Third Hospital, First Hospital of Tsinghua University, Women and Children's Hospital, Branch of Chongqing Sanxia Central Hospital, First Affiliated Hospital of Chongqing Medical University, Quanzhou Children's Hospital, Xiamen Maternity & Child Care Hospital, Zhujiang Hospital, Nanfang Hospital, Southern Medical University, Guangdong Academy of Medical Science and General Hospital, Guangdong Women and Children Hospital, Women and Children's Health Hospital of Yulin, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Second Affiliated Hospital of Guangzhou Medical University, Guiyang Maternal and Child Health Care Hospital, Zunyi First People's Hospital, Lanzhou University Second Hospital, Gansu Provincial Maternal and Child Health Care Hospital, LanZhou University, First Affiliated Hospital of Harbin Medical University, First Affiliated Hospital of Xinjiang Medical University, Zhengzhou Children's Hospital, China, Third Affiliated Hospital of Zhengzhou University, the Maternal and Child Health Hospital of Hainan Province, Bethune International Peace Hospital, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Children's Hospital of Nanjing Medical University, The First Hospital of Jilin University, Children's Hospital of Fudan University, Maternal and Children's Healthcare Hospital of Taian, The Second Hospital of Shandong University, Shanxi Provincial Maternity and Children's Hospital, Chengdu Women and Children's Center Hospital, The Affiliated Hospital Of Southwest Medical University, Affiliated Hospital of Southwest Medical University, Shenzhen People's Hospital, The Second Medical College of Jinan University, Tianjin Central Hospital of Gynecology Obstetrics, People's Hospital of Xinjiang Uygur Autonomous Region, Kunming Children's Hospital, The First People's Hospital of Yunnan, First Affiliated Hospital of Kunming Medical University, Yan'an Affiliated Hospital of Kunming Medical University, Women and Children's Health Hospital of Qujing, The People's Hospital of Dehong Autonomous Prefecture, The First People's Hospital of Yinchuan, The Children's Hospital of Zhejiang University School of Medicine, Women's Hospital School Of Medicine Zhejiang University, Beijing 302 Hospital, Hunan Children's Hospital, Women and Children Hospital of Qinghai Province, Jiangxi Province Children's Hospital, Inner Mongolia People's Hospital, Mianyang Central Hospital, People's Liberation Army No.202 Hospital, Ningbo Women & Children's Hospital, Shanghai Children's Medical Center, First Affiliated Hospital of Guangxi Medical University, Nanjing Medical University, Qinhuangdao Maternal and Child Health Care Hospital, Xuzhou Children Hospital, Catholic University of the Sacred Heart, The First Affiliated Hospital of Zhengzhou University, Xianyang Children's Hospital
- Study start
- 1 Dec 2017 (actual)
- Primary completion
- 31 May 2021 (actual)
- Study completion
- 30 Jun 2021 (actual)
- First posted
- 9 Jun 2017 (actual)
- Results
- Posted 30 Sep 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (investigator, outcomes assessor)
- Number of arms
- 3
- 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.
| Arm | Type | Receives |
|---|---|---|
| NHFOV | Experimental | Device: NHFOVneonates 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. |
| NCPAP | Active comparator | Device: NCPAPNeonates 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. |
| NIPPV | Experimental | Device: NIPPVneonates 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). |
Who may qualify
- Ages
- 30 minutes to 1 month
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (5 listed)
- 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.;
Key exclusion criteria (6 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| NHFOVNasal high frequency oscillation ventilation (NHFOV) is used as the noninvasive supporting mode after extubation. | Device | NHFOV |
| NCPAPNasal continuous positive airway pressure(NCPAP) is used as the noninvasive supporting mode after extubation. | Device | NCPAP |
| NIPPVNasal intermittent positive pressure ventilation(NIPPV) is used as the noninvasive supporting mode after extubation. | Device | NIPPV |
Primary outcome
Duration of Invasive Mechanical Ventilation
Time frame: up to 8 weeks
the total days of the baby supported with the ventilator
Ventilator-free Days
Time frame: up to 8 weeks
non-invasive ventilation was need after extubation
Number of Babies With Reintubation
Time frame: up to 8 weeks
the total numbers of the baby supported with ventilator
10 secondary outcomes
Number of Participants With Airleaks
Time frame: up to 8 weeks
Number of Participants With Bronchopulmonary Dysplasia(BPD)
Time frame: at gestational age of 36 weeks or at discharge
Number of Participants With Retinopathy of Prematurity> 2nd Stage
Time frame: up to 8 weeks
Number of Participants With Neonatal Necrotizing Enterocolitis≥ 2nd Stage
Time frame: up to 8 weeks
Number of Participants With Intraventricular Hemorrhage>2nd Grade
Time frame: up to 8 weeks
Number of Participants With Need for Postnatal Steroids
Time frame: up to 8 weeks
In-hospital Mortality
Time frame: up to 8 weeks
Composite Mortality/BPD
Time frame: up to 8 weeks
Weekly Weight Gain
Time frame: 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)
Time frame: up to 8 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Sep 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 37399009Zhu X, Li F, Shi Y, Feng Z, De Luca D; Nasal Oscillation Post-Extubation (NASONE) Study Group. Effectiveness of Nasal Continuous Positive Airway Pressure vs Nasal Intermittent Positive Pressure Ventilation vs Noninvasive High-Frequency Oscillatory Ventilation as Support After Extubation of Neonates Born Extremely Preterm or With More Severe Respiratory Failure: A Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open. 2023 Jul 3;6(7):e2321644. doi: 10.1001/jamanetworkopen.2023.21644.
- Derived from this study: PubMed 35467744Zhu X, Qi H, Feng Z, Shi Y, De Luca D; Nasal Oscillation Post-Extubation (NASONE) Study Group. Noninvasive High-Frequency Oscillatory Ventilation vs Nasal Continuous Positive Airway Pressure vs Nasal Intermittent Positive Pressure Ventilation as Postextubation Support for Preterm Neonates in China: A Randomized Clinical Trial. JAMA Pediatr. 2022 Jun 1;176(6):551-559. doi: 10.1001/jamapediatrics.2022.0710.
- Derived from this study: PubMed 31349833Shi Y, De Luca D; NASal OscillatioN post-Extubation (NASONE) study group. Continuous positive airway pressure (CPAP) vs noninvasive positive pressure ventilation (NIPPV) vs noninvasive high frequency oscillation ventilation (NHFOV) as post-extubation support in preterm neonates: protocol for an assessor-blinded, multicenter, randomized controlled trial. BMC Pediatr. 2019 Jul 26;19(1):256. doi: 10.1186/s12887-019-1625-1.
- Individual participant dataSharing planned: Yes. Every researchers can obtain the IPD after the study completely.
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Shi Yuan, PhD,MD principal investigator
Daping Hospital and the Research Institute of Surgery of the Third Military Medical University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing NHFOV, NCPAP and NIPPV in people with Intubated Infants Were Intend to Extubation Using Noninvasive Ventilation Strategies, run by Daping Hospital and the Research Institute of Surgery of the Third Military Medical University at 1 site in China.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 30 Sep 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in China. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 30 Sep 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Duration of Invasive Mechanical Ventilation (time frame: up to 8 weeks). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03181958, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Sep 2021.