A Trial Comparing Noninvasive Ventilation Strategies in Preterm Infants Following Extubation

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.

Study Overview

• Status: Completed
• Conditions: Intubated Infants Were Intend to Extubation Using Noninvasive Ventilation Strategies
• Intervention / Treatment: Device: NHFOV; Device: NCPAP; Device: NIPPV

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 Type: Interventional
• Enrollment (Actual): 1493
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Chongqing
    • Chongqing, Chongqing, China, 400042
      • Daping Hospital and the Research Institute of Surgery of the Third Military Medical University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 1 year (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Device: NHFOV; Nasal high frequency oscillation ventilation (NHFOV) is used as the noninvasive supporting mode after extubation.
Active Comparator: 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.	Device: NCPAP; Nasal continuous positive airway pressure(NCPAP) is used as the noninvasive supporting mode after extubation.
Experimental: 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).	Device: NIPPV; Nasal intermittent positive pressure ventilation(NIPPV) is used as the noninvasive supporting mode after extubation.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Daping Hospital and the Research Institute of Surgery of the Third Military Medical University
• Collaborators: The First Affiliated Hospital of Anhui Medical University; LanZhou University; Beijing 302 Hospital; Peking University Third Hospital; Nanfang Hospital of Southern Medical University; The First Affiliated Hospital of Zhengzhou University; Children's Hospital of Fudan University; Shanghai Children's Medical Center; Zhujiang Hospital; The First Hospital of Jilin University; Women's Hospital School Of Medicine Zhejiang University; Wuhan Union Hospital, China; People's Hospital of Xinjiang Uygur Autonomous Region; The First Affiliated Hospital of Kunming Medical College; The Second Hospital of Shandong University; Nanjing Medical University; Second Affiliated Hospital of Guangzhou Medical University; First Affiliated Hospital of Xinjiang Medical University; Bethune International Peace Hospital; Kunming Children's Hospital; First Affiliated Hospital of Chongqing Medical University; First Affiliated Hospital of Harbin Medical University; Hunan Children's Hospital; Guangdong Women and Children Hospital; Xiamen Maternity & Child Care Hospital; Inner Mongolia People's Hospital; The Affiliated Hospital Of Southwest Medical University; The Children's Hospital of Zhejiang University School of Medicine; Jiangxi Province Children's Hospital; Mianyang Central Hospital; Zhengzhou Children's Hospital, China; Quanzhou Children's Hospital; Children's Hospital of Chongqing Medical University; Second Hospital of Lanzhou University; Tianjin Central Hospital of Gynecology Obstetrics; First Affiliated Hospital of Guangxi Medical University; The First People's Hospital of Yunnan; Shanxi Provincial Maternity and Children's Hospital; Yan'an Affiliated Hospital of Kunming Medical University; Children's Hospital of Nanjing Medical University; Third Affiliated Hospital of Zhengzhou University; Gansu Provincial Maternity and Child-Care Hospital; Zunyi First People's Hospital; Affiliated Hospital of Southwest Medical University; Chongqing Maternal and Child Health Hospital; First Hospital of Tsinghua University; Chengdu Women and Children's Center Hospital; Ningbo Women & Children's Hospital; Xianyang Children's Hospital; Jiulongpo No.1 People's Hospital; Children's Hospital of The Capital Institute of Pediatrics; Women and Children's Hospital, Branch of Chongqing Sanxia Central Hospital; Guangdong Academy of Medical Science and General Hospital; Women and Children's Health Hospital of Yulin; Women and Children Health Care Hospitalof GuangXi Zhuang Autonomous; Guiyang Maternal and Child Health Care Hospital; the Maternal and Child Health Hospital of Hainan Province; Maternal and Children's Healthcare Hospital of Taian; Shenzhen People's Hospital, The Second Medical College of Jinan University; Women and Children's Health Hospital of Qujing; The People's Hospital of Dehong Autonomous Prefecture; Yinchuan No 1 people's Hospital Affiliated of Ningxia Medical University; Women and Children Hospital of Qinghai Province; People's Liberation Army No.202 Hospital; Qinhuangdao Maternal and Child Health Care Hospital; Xuzhou Children Hospital; South Paris University Hospitals, Catholic University of the Sacred Heart
• Investigators: Principal Investigator: Shi Yuan, PhD,MD, Daping Hospital and the Research Institute of Surgery of the Third Military Medical University

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2017
• Primary Completion (Actual): May 31, 2021
• Study Completion (Actual): June 30, 2021

Study Registration Dates

• First Submitted: May 28, 2017
• First Submitted That Met QC Criteria: June 7, 2017
• First Posted (Actual): June 9, 2017

Study Record Updates

• Last Update Posted (Actual): September 30, 2021
• Last Update Submitted That Met QC Criteria: September 2, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: preterm infants; nasal high frequency oscillation ventilation(NHFOV); nasal continuous positive airway pressure(NCPAP); nasal intermittent positive pressure ventilation（NIPPV）; neonatal respiratory distress syndrome(NRDS)
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Respiratory Distress Syndrome
• Other Study ID Numbers: 201721

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Every researchers can obtain the IPD after the study completely.
• IPD Sharing Time Frame: At Oct-22,2017,Suzhou,PR.China.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No