High-Frequency Oscillation Ventilation Versus Conventional Mechanical Ventilation in Very Preterm Infants With Perinatal Acute Respiratory Distress Syndrome: Multicenters Randomized Controlled, Superiority Trial (HFOV for ARDS)

Bronchopulmonary dysplasia (BPD) is a complex disorder and remains the most common complication in very preterm infants. Its incidence is increased with gestational age from 95.5% among infants born at 22 weeks' gestation to 22.2% among those born at 29 weeks' gestation. BPD is associated with the increased risks of delayed neurodevelopment and pulmonary impairment. High incidences of BPD and morbidities indicate inadequacy of current management guidelines of BPD.3 Caffeine reduces the development of BPD by lowering the duration of intubation.4 How to further reduce the risk of BPD and the duration of invasive ventilation remain the key focus for neonatologists.

Study Overview

• Status: Recruiting
• Conditions: Acute Respiratory Distress Syndrome; Preterm; High Frequency Oscillatory Ventilation; Conventional Mechanical Ventilation
• Intervention / Treatment: Device: HFOV; Device: CMV

Detailed Description

Before 2017, the management guideline of pediatric and adult acute respiratory distress syndrome (ARDS) exclude perinatal triggers-induced ARDS. Moreover, there is insufficient evidence to recommend high-frequency oscillatory ventilation (HFOV) or conventional mechanical ventilation (CMV) as the preferred fist-line therapy in pediatric and adult ARDS. In contrast, HFOV may benefit preterm baboons with acute pulmonary dysfunction-typically due to respiratory distress syndrome (RDS)-by using low tidal volume, supra-physiologically higher respiratory rate, and lower peak inspiratory pressure to enhance oxygenation and gas exchange. The team also reported that use of HFOV is associated with a modest reduction referring to BPD. However, European consensus guideline of RDS only recommend HFOV being a reasonable alternative to CMV when high pressure is needed to achieve adequate lung inflation. Because randomized controlled trials in humans have yielded inconsistent findings.

These differences between animal models-where RDS was induced and treated with surfactant alone-and clinical scenarios, where preterm birth often involved complex etiologies requiring both surfactant and antibiotics for placental insufficiency or intrauterine infection, may be the diagnosis of RDS and ARDS or the mixture of RDS and ARDS. Such findings highlighted the lack of robust evidence for optimizing ventilation strategies in preterm infants born <32 weeks with perinatal ARDS, and the need for well-designed multi-center randomized controlled trials in this high-risk population.

• Study Type: Interventional
• Enrollment (Estimated): 400
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Chongqing Municipality
    • Chongqing, Chongqing Municipality, China, 400042
      • Recruiting
      • Children's Hospital of Chongqing Medical University
      • Contact: Shi Yuan, PhD,MD; Phone Number: 86 13508300283; Email: petshi530@vip.163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 minute to 12 hours (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria

1. GA was between 24+0 and 31+6 weeks.
2. Preterm neonates were admitted to NICU within 1 hours after birth, diagnosed with perinatal ARDS using Montreux guidelines and stable supported by CMV.
3. Stabilization for 2 hours before randomization: FiO2 0.40, mean airway pressure (MAP) 10-14 cmH2O, ≤ 40 bpm of respiratory rate, 90%-94% of SpO2, pH > 7.20, PaCO2 60 mmHg, tidal volume of 5 ml/kg and > 35% of hematocrit (these may be evaluated by arterial blood gas analysis).

Exclusion criteria

Neonates were not included if any of the following criteria were met:

1. Parents or guardians' decision not to participate.
2. Major congenital anomalies or chromosomal abnormalities
3. Need for surgery or more than grade 2nd of IVH before randomization.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: high frenquency oscillation ventilation (HFOV); HFOV + volume guarantee (VG) as the intervention group HFOV was provided only with piston or membrane oscillators capable of delivering true oscillatory pressure with an active expiratory phase (i.e., Acutronic FABIAN-III, SLE 5000, Löwenstein Med LEONI+, or Sensormedics 3100A). Other machines offering high frequency ventilation were excluded. The lung recruitment maneuver was performed as previously described,15 and lung volume was assessed by chest radiography or lung ultrasound, targeting the right diaphragm at the level of 8th-9th rib (or 7th-8th rib in case of air leak). Crossover between HFOV and CMV This study allowed infants who failed to respond to their assigned ventilation mode to receive a trial of the alternate mode. Crossover criteria for HFOV-assigned neonates included failure for 3 hours to maintain SpO2 ≥ 50% despite FiO2 of 1.0, PaCO2 > 60 mmHg for 3 hours, or signs of ventilator-induced cardiac output reduction. Non-responders to HFOV were switched to CMV.	Device: HFOV; HFOV + volume guarantee (VG) as the intervention group HFOV was provided only with piston or membrane oscillators capable of delivering true oscillatory pressure with an active expiratory phase (i.e., Acutronic FABIAN-III, SLE 5000, Löwenstein Med LEONI+, or Sensormedics 3100A). Other machines offering high frequency ventilation were excluded. The lung recruitment maneuver was performed as previously described, and lung volume was assessed by chest radiography or lung ultrasound, targeting the right diaphragm at the level of 8th-9th rib (or 7th-8th rib in case of air leak). Crossover between HFOV and CMV This study allowed infants who failed to respond to their assigned ventilation mode to receive a trial of the alternate mode. Crossover criteria for HFOV-assigned neonates included failure for 3 hours to maintain SpO2 ≥ 50% despite FiO2 of 1.0, PaCO2 > 60 mmHg for 3 hours, or signs of ventilator-induced cardiac output reduction. Non-responders to HFOV were switched to CMV.
Active Comparator: conventional mechanical ventilation (CMV); CMV was delivered by time-cycled, pressure-limited ventilators. Only pressure regulated volume control (PRVC) will be provided by any type of neonatal ventilator. Crossover criteria for CMV-assigned neonates included failure for 3 hours to maintain SpO2 ≥ 50% despite FiO2 of 1.0, PaCO2 > 60 mmHg for 3 hours, or requiring > 30 cm H2O PIP to sustain ventilation. Non-responders to CMV were switched to HFOV. in both groups, ventilator settings were adjusted at the discretion of the attending clinician to maintain a SpO2 between 90%-94%, a PaO2 between 50 and 80 mm Hg and a PaCO2 between 35 and 60 mm Hg and a pH between 7.20 and 7.45. PO2 and PCO2 levels were monitored using arterial blood gas analysis and/or transcutaneous monitoring.	Device: CMV; CMV as the standard group CMV was delivered by time-cycled, pressure-limited ventilators. Only pressure regulated volume control (PRVC) will be provided by any type of neonatal ventilator. Crossover criteria for CMV-assigned neonates included failure for 3 hours to maintain SpO2 ≥ 50% despite FiO2 of 1.0, PaCO2 > 60 mmHg for 3 hours, or requiring > 30 cm H2O PIP to sustain ventilation. Non-responders to CMV were switched to HFOV. Ventilator settings were adjusted at the discretion of the attending clinician to maintain a SpO2 between 90%-94%, a PaO2 between 50 and 80 mm Hg and a PaCO2 between 35 and 60 mm Hg and a pH between 7.20 and 7.45. PO2 and PCO2 levels were monitored using arterial blood gas analysis and/or transcutaneous monitoring in both groups.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the incidence of bronchopulmonary dysplasia(BPD)	BPD is defined according to the 2019 diagnostic criteria. For infants discharged before 36 weeks' GA, BPD severity was assessed based on respiratory support at the time of discharge. Infants receiving no supplemental respiratory support were divided into no BPD, those treated with nasal cannula (≤ 2 L/min) as grade 1 BPD, those treated with nasal cannula (> 2 L/min) or noninvasive positive airway pressure as grade 2 BPD and those treated with invasive mechanical ventilation as grade 3 BPD.	36 weeks' gestational age

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
duration of invasive ventilation	duration of invasive ventilation for HFOV or CMV	36 weeks' gestational age
mortality	the included neonates were diagnosed with death	36 weeks' gestational age or before discharge
air leak (pneumothorax and/or pneumomediastinum) occurred	the included neonates were diagnosed with air leak	36 weeks' gestational age or before discharge
the incidence of hemodynamically significant patent ductus arteriosus (hsPDA)	the included neonates were diagnosed with hsPDA.	36 weeks' gestational age or before discharge
the incidence of retinopathy of prematurity(ROP)> 2nd grades	ROP was categorized according to the International Classification of Retinopathy of Prematurity, revised in 2005	36 weeks' gestational age or before discharge
the incidence of necrotizing enterocolitis(NEC)≥2nd stages	the development of NEC, specifically focusing on cases classified as Bell's stage ≥2, according to the modified Bell's staging criteria for NEC.	36 weeks' gestational age or before discharge
intraventricular hemorrhage(IVH)>2nd grade	IVH with grades 1-4 were defined by Papile et al	36 weeks' gestational age or before discharge

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; 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; People's Hospital of Xinjiang Uygur Autonomous Region; 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; 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; Affiliated Hospital of Southwest Medical University; Chongqing Maternal and Child Health Hospital; First Hospital of Tsinghua University; The First People's Hospital of Zunyi; Chengdu Women and Children's Center Hospital; Lanzhou University Second Hospital; Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region; 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; 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; Women and Children Hospital of Qinghai Province; People's Liberation Army No.202 Hospital; Qinhuangdao Maternal and Child Health Care Hospital; Xuzhou Children Hospital; First Affiliated Hospital of Kunming Medical University; The First People's Hospital of Yinchuan; Nanfang Hospital, Southern Medical University; Gansu Provincial Maternal and Child Health Care Hospital; Union Hospital, Tongji Medical College, Huazhong University of Science and Technology

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2025
• Primary Completion (Estimated): June 30, 2028
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: November 7, 2018
• First Submitted That Met QC Criteria: November 7, 2018
• First Posted (Actual): November 9, 2018

Study Record Updates

• Last Update Posted (Estimated): October 6, 2025
• Last Update Submitted That Met QC Criteria: September 30, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Respiratory Tract Diseases; Lung Diseases; Respiration Disorders; Premature Birth; Respiratory Distress Syndrome
• Other Study ID Numbers: HFOV for perinatal ARDS; CSTB2024NSCQ-MSX0158 (Other Identifier: Natural Science Foundation of Chongqing)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No