A Trial Comparing Noninvasive Ventilation Strategies in Preterm Infants Following Extubation

NCT ID: NCT03181958

Last Updated: 2021-09-30

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

NA

Total Enrollment

1493 participants

Study Classification

INTERVENTIONAL

Study Start Date

2017-12-01

Study Completion Date

2021-06-30

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.

Conditions

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Intubated Infants Were Intend to Extubation Using Noninvasive Ventilation Strategies

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

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 Study Purpose

TREATMENT

Blinding Strategy

DOUBLE

Investigators Outcome Assessors
Blinding towards the caregivers is impossible and blinding towards the patients makes no sense. However, outcomes' assessors will be blinded, as endpoints will be recorded by investigators not involved in patients' care. An assessor per each participating NICU will be nominated. Moreover, investigators performing the final statistical analyses will be blinded to the treatment allocation, as data collected by assessors will be inserted in the dedicated website and the arms' allocation will be re-coded.

Study Groups

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NHFOV

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.

Group Type EXPERIMENTAL

NHFOV

Intervention Type DEVICE

Nasal high frequency oscillation ventilation (NHFOV) is used as the noninvasive supporting mode after extubation.

NCPAP

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.

Group Type ACTIVE_COMPARATOR

NCPAP

Intervention Type DEVICE

Nasal continuous positive airway pressure(NCPAP) is used as the noninvasive supporting mode after extubation.

NIPPV

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).

Group Type EXPERIMENTAL

NIPPV

Intervention Type DEVICE

Nasal intermittent positive pressure ventilation(NIPPV) is used as the noninvasive supporting mode after extubation.

Interventions

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NHFOV

Nasal high frequency oscillation ventilation (NHFOV) is used as the noninvasive supporting mode after extubation.

Intervention Type DEVICE

NCPAP

Nasal continuous positive airway pressure(NCPAP) is used as the noninvasive supporting mode after extubation.

Intervention Type DEVICE

NIPPV

Nasal intermittent positive pressure ventilation(NIPPV) is used as the noninvasive supporting mode after extubation.

Intervention Type DEVICE

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
Minimum Eligible Age

30 Minutes

Maximum Eligible Age

1 Month

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Children's Hospital of Chongqing Medical University

OTHER

Sponsor Role collaborator

Jiulongpo No.1 People's Hospital

OTHER

Sponsor Role collaborator

Chongqing Maternal and Child Health Hospital

OTHER

Sponsor Role collaborator

The First Affiliated Hospital of Anhui Medical University

OTHER

Sponsor Role collaborator

Children's Hospital of The Capital Institute of Pediatrics

OTHER

Sponsor Role collaborator

Peking University Third Hospital

OTHER

Sponsor Role collaborator

First Hospital of Tsinghua University

OTHER

Sponsor Role collaborator

Women and Children's Hospital, Branch of Chongqing Sanxia Central Hospital

OTHER

Sponsor Role collaborator

First Affiliated Hospital of Chongqing Medical University

OTHER

Sponsor Role collaborator

Quanzhou Children's Hospital

OTHER

Sponsor Role collaborator

Xiamen Maternity & Child Care Hospital

OTHER

Sponsor Role collaborator

Zhujiang Hospital

OTHER

Sponsor Role collaborator

Nanfang Hospital, Southern Medical University

OTHER

Sponsor Role collaborator

Guangdong Academy of Medical Science and General Hospital

OTHER

Sponsor Role collaborator

Guangdong Women and Children Hospital

OTHER

Sponsor Role collaborator

Women and Children's Health Hospital of Yulin

OTHER

Sponsor Role collaborator

Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region

OTHER

Sponsor Role collaborator

Second Affiliated Hospital of Guangzhou Medical University

OTHER

Sponsor Role collaborator

Guiyang Maternal and Child Health Care Hospital

OTHER

Sponsor Role collaborator

Zunyi First People's Hospital

INDUSTRY

Sponsor Role collaborator

Lanzhou University Second Hospital

OTHER

Sponsor Role collaborator

Gansu Provincial Maternal and Child Health Care Hospital

OTHER

Sponsor Role collaborator

LanZhou University

OTHER

Sponsor Role collaborator

First Affiliated Hospital of Harbin Medical University

OTHER

Sponsor Role collaborator

First Affiliated Hospital of Xinjiang Medical University

OTHER

Sponsor Role collaborator

Zhengzhou Children's Hospital, China

OTHER

Sponsor Role collaborator

Third Affiliated Hospital of Zhengzhou University

OTHER

Sponsor Role collaborator

the Maternal and Child Health Hospital of Hainan Province

OTHER

Sponsor Role collaborator

Bethune International Peace Hospital

OTHER

Sponsor Role collaborator

Union Hospital, Tongji Medical College, Huazhong University of Science and Technology

OTHER

Sponsor Role collaborator

Children's Hospital of Nanjing Medical University

OTHER

Sponsor Role collaborator

The First Hospital of Jilin University

OTHER

Sponsor Role collaborator

Children's Hospital of Fudan University

OTHER

Sponsor Role collaborator

Maternal and Children's Healthcare Hospital of Taian

OTHER

Sponsor Role collaborator

The Second Hospital of Shandong University

OTHER

Sponsor Role collaborator

Shanxi Provincial Maternity and Children's Hospital

OTHER

Sponsor Role collaborator

Chengdu Women and Children's Center Hospital

OTHER

Sponsor Role collaborator

The Affiliated Hospital Of Southwest Medical University

OTHER

Sponsor Role collaborator

Affiliated Hospital of Southwest Medical University

OTHER

Sponsor Role collaborator

Shenzhen People's Hospital, The Second Medical College of Jinan University

OTHER

Sponsor Role collaborator

Tianjin Central Hospital of Gynecology Obstetrics

OTHER

Sponsor Role collaborator

People's Hospital of Xinjiang Uygur Autonomous Region

OTHER

Sponsor Role collaborator

Kunming Children's Hospital

OTHER

Sponsor Role collaborator

The First People's Hospital of Yunnan

OTHER

Sponsor Role collaborator

First Affiliated Hospital of Kunming Medical University

OTHER

Sponsor Role collaborator

Yan'an Affiliated Hospital of Kunming Medical University

OTHER

Sponsor Role collaborator

Women and Children's Health Hospital of Qujing

OTHER

Sponsor Role collaborator

The People's Hospital of Dehong Autonomous Prefecture

OTHER

Sponsor Role collaborator

The First People's Hospital of Yinchuan

OTHER

Sponsor Role collaborator

The Children's Hospital of Zhejiang University School of Medicine

OTHER

Sponsor Role collaborator

Women's Hospital School Of Medicine Zhejiang University

OTHER

Sponsor Role collaborator

Beijing 302 Hospital

OTHER

Sponsor Role collaborator

Hunan Children's Hospital

OTHER_GOV

Sponsor Role collaborator

Women and Children Hospital of Qinghai Province

OTHER

Sponsor Role collaborator

Jiangxi Province Children's Hospital

OTHER

Sponsor Role collaborator

Inner Mongolia People's Hospital

OTHER

Sponsor Role collaborator

Mianyang Central Hospital

OTHER

Sponsor Role collaborator

People's Liberation Army No.202 Hospital

OTHER

Sponsor Role collaborator

Ningbo Women & Children's Hospital

OTHER

Sponsor Role collaborator

Shanghai Children's Medical Center

OTHER

Sponsor Role collaborator

First Affiliated Hospital of Guangxi Medical University

OTHER

Sponsor Role collaborator

Nanjing Medical University

OTHER

Sponsor Role collaborator

Qinhuangdao Maternal and Child Health Care Hospital

OTHER

Sponsor Role collaborator

Xuzhou Children Hospital

OTHER

Sponsor Role collaborator

Catholic University of the Sacred Heart

OTHER

Sponsor Role collaborator

The First Affiliated Hospital of Zhengzhou University

OTHER

Sponsor Role collaborator

Xianyang Children's Hospital

OTHER

Sponsor Role collaborator

Daping Hospital and the Research Institute of Surgery of the Third Military Medical University

OTHER

Sponsor Role lead

Responsible Party

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Ma Juan

director

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Shi Yuan, PhD,MD

Role: PRINCIPAL_INVESTIGATOR

Daping Hospital and the Research Institute of Surgery of the Third Military Medical University

Locations

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Daping Hospital and the Research Institute of Surgery of the Third Military Medical University

Chongqing, Chongqing Municipality, China

Site Status

Countries

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China

References

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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.

Reference Type DERIVED
PMID: 37399009 (View on PubMed)

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.

Reference Type DERIVED
PMID: 35467744 (View on PubMed)

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.

Reference Type DERIVED
PMID: 31349833 (View on PubMed)

Provided Documents

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Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

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201721

Identifier Type: -

Identifier Source: org_study_id

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