Clinical trial NCT03181958: A Trial Comparing Noninvasive Ventilation Strategies in Preterm Infants Following Extubation
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Intubated Infants Were Intend to Extubation Using Noninvasive Ventilation Strategies
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
Lead sponsor: Daping Hospital and the Research Institute of Surgery of the Third Military Medical University
Sponsor class: OTHER
Collaborators: name: Children's Hospital of Chongqing Medical University
name: Jiulongpo No.1 People's Hospital
name: Chongqing Maternal and Child Health Hospital
name: The First Affiliated Hospital of Anhui Medical University
name: Children's Hospital of The Capital Institute of Pediatrics
name: Peking University Third Hospital
name: First Hospital of Tsinghua University
name: Women and Children's Hospital, Branch of Chongqing Sanxia Central Hospital
name: First Affiliated Hospital of Chongqing Medical University
name: Quanzhou Children's Hospital
name: Xiamen Maternity & Child Care Hospital
name: Zhujiang Hospital
name: Nanfang Hospital, Southern Medical University
name: Guangdong Academy of Medical Science and General Hospital
name: Guangdong Women and Children Hospital
name: Women and Children's Health Hospital of Yulin
name: Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region
name: Second Affiliated Hospital of Guangzhou Medical University
name: Guiyang Maternal and Child Health Care Hospital
name: Zunyi First People's Hospital
name: Lanzhou University Second Hospital
name: Gansu Provincial Maternal and Child Health Care Hospital
name: LanZhou University
name: First Affiliated Hospital of Harbin Medical University
name: First Affiliated Hospital of Xinjiang Medical University
name: Zhengzhou Children's Hospital, China
name: Third Affiliated Hospital of Zhengzhou University
name: the Maternal and Child Health Hospital of Hainan Province
name: Bethune International Peace Hospital
name: Wuhan Union Hospital, China
name: Children's Hospital of Nanjing Medical University
name: The First Hospital of Jilin University
name: Children's Hospital of Fudan University
name: Maternal and Children's Healthcare Hospital of Taian
name: The Second Hospital of Shandong University
name: Shanxi Provincial Maternity and Children's Hospital
name: Chengdu Women and Children's Center Hospital
name: The Affiliated Hospital Of Southwest Medical University
name: Affiliated Hospital of Southwest Medical University
name: Shenzhen People's Hospital, The Second Medical College of Jinan University
name: Tianjin Central Hospital of Gynecology Obstetrics
name: People's Hospital of Xinjiang Uygur Autonomous Region
name: Kunming Children's Hospital
name: The First People's Hospital of Yunnan
name: First Affiliated Hospital of Kunming Medical University
name: Yan'an Affiliated Hospital of Kunming Medical University
name: Women and Children's Health Hospital of Qujing
name: The People's Hospital of Dehong Autonomous Prefecture
name: The First People's Hospital of Yinchuan
name: The Children's Hospital of Zhejiang University School of Medicine
name: Women's Hospital School Of Medicine Zhejiang University
name: Beijing 302 Hospital
name: Hunan Children's Hospital
name: Women and Children Hospital of Qinghai Province
name: Jiangxi Province Children's Hospital
name: Inner Mongolia People's Hospital
name: Mianyang Central Hospital
name: People's Liberation Army No.202 Hospital
name: Ningbo Women & Children's Hospital
name: Shanghai Children's Medical Center
name: First Affiliated Hospital of Guangxi Medical University
name: Nanjing Medical University
name: Qinhuangdao Maternal and Child Health Care Hospital
name: Xuzhou Children Hospital
name: Catholic University of the Sacred Heart
name: The First Affiliated Hospital of Zhengzhou University
name: Xianyang Children's Hospital
First posted: 2017-06-09
Enrollment: 1493
Sex: ALL
Minimum age (years): 30
Maximum age (years): 1
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

Brief 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 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.

Eligibility criteria: 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

Primary outcomes:
measure: Duration of Invasive Mechanical Ventilation
timeFrame: up to 8 weeks
measure: Ventilator-free Days
timeFrame: up to 8 weeks
measure: Number of Babies With Reintubation
timeFrame: up to 8 weeks
Secondary outcomes:
measure: Number of Participants With Airleaks
timeFrame: up to 8 weeks
measure: Number of Participants With Bronchopulmonary Dysplasia(BPD)
timeFrame: at gestational age of 36 weeks or at discharge
measure: Number of Participants With Retinopathy of Prematurity> 2nd Stage
timeFrame: up to 8 weeks
measure: Number of Participants With Neonatal Necrotizing Enterocolitis≥ 2nd Stage
timeFrame: up to 8 weeks
measure: Number of Participants With Intraventricular Hemorrhage>2nd Grade
timeFrame: up to 8 weeks
measure: Number of Participants With Need for Postnatal Steroids
timeFrame: up to 8 weeks
measure: In-hospital Mortality
timeFrame: up to 8 weeks
measure: Composite Mortality/BPD
timeFrame: up to 8 weeks
measure: Weekly Weight Gain
timeFrame: during hospitalization for the first 4 weeks of life or until NICU discharge whichever came first, an average of 1 month
measure: Haemodynamically Significant Patent Ductus Arteriosus (PDA)
timeFrame: up to 8 weeks
Other outcomes:
Locations:
city: Chongqing
country: China
facility: Daping Hospital and the Research Institute of Surgery of the Third Military Medical University
state: Chongqing
Study officials:
affiliation: Daping Hospital and the Research Institute of Surgery of the Third Military Medical University
name: Shi Yuan, PhD,MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Zhu 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.
citation: Shi 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.