NHFOV vs. NCPAP as a Primary Treatment to Neonatal Respiratory Distress Syndrome(NRDS)

Noninvasive Ventilation for Preterm Neonates With Respiratory Distress Syndrome: a Multi-center Randomized Controlled Trial

The investigators compared advantages and disadvantages of two forms of noninvasive respiratory support -noninvasive high-frequency oscillatory ventilation (nHFOV) or nasal continuous positive airway pressure (nCPAP) -as a primary mode of ventilation in premature infants with RDS．

Study Overview

• Status: Completed
• Conditions: Preterm Infants
• Intervention / Treatment: Procedure: nasal continuous positive airway pressure (nCPAP); Procedure: noninvasive high-frequency ventilation (nHFOV)

Detailed Description

Background: Invasive mechanical ventilation is associated with development of adverse pulmonary and non-pulmonary outcomes in very low birth weight infants. Various modes of non-invasive respiratory support are being increasingly used to minimize the incidence of bronchopulmonary dysplasia (BPD). The aim of this trials to compare the effect of noninvasive high-frequency oscillatory ventilation (NHFOV) and nasal continuous positive airway pressure (NCPAP) in preterm infants with respiratory distress syndrome (RDS) as a primary noninvasive ventilation support mode.

Methods/Design:In this multicenter, randomized, controlled trial, 300 preterm infants at gestational age (GA) less than 34 weeks with a diagnosis of RDS will be randomized to NHFOV or NCPAP as a primary mode of non-invasive respiratory support. Study will be conducted in 18 tertiary neonatal intensive care units in China.

The primary outcome is the need for invasive mechanical ventilation (IMV)during the first 7 days after enrollment in preterm infants randomized to the two groups. The secondary outcomes include days of hospitalization, days on noninvasive respiratory support, days on IMV, days on supplemental oxygen, mortality, need for surfactant, incidence of retinopathy of prematurity(ROP) and bronchopulmonary dysplasia(BPD), occurrence of abdominal distention, air leaks, intraventricular hemorrhage (IVH ≥ grade 3) and necrotizing enterocolitis (NEC> II stage). Other secondary outcomes include scores of Bayley Scales of Infant Development at 2 months and 2 years of corrected age.

• Study Type: Interventional
• Enrollment (Actual): 340
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Chongqing
    • Chongqing, Chongqing, China, 400000
      • Xingwang Zhu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 3 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

(1)Gestational age (GA) is from 26 to 34 weeks; (2) diagnosis of RDS. The diagnosis of RDS will be based on clinical manifestations (tachypnea, nasal flaring and or grunting) and chest X-ray findings; (3) RDS Silverman score>5; (4) informed parental consent has been obtained.

Exclusion criteria

(1) severe RDS requiring early intubation according to the American Academy of Pediatrics guidelines for neonatal resuscitation7; (2)major congenital malformations or complex congenital heart disease; (3) group B hemolytic streptococcus pneumonia, septicemia, pneumothorax, pulmonary hemorrhage; (4) cardiopulmonary arrest needing prolonged resuscitation; (5) transferred out of the NICUs without treatment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: nCPAP; nasal continuous positive airway pressure (nCPAP) - as a primary mode of ventilation in premature infants with RDS	Procedure: nasal continuous positive airway pressure (nCPAP); Infants assigned to the NCPAP group will be started on a pressure of 6 cmH2O (range: 6-8 cmH2O) by CPAP system (CNO Medin, Germany, Carefusion, USA)
Experimental: nHFOV; noninvasive high-frequency ventilation (nHFOV) as a primary mode of ventilation in premature infants with RDS	Procedure: noninvasive high-frequency ventilation (nHFOV); NHFOV will be provided by a high frequency ventilator (CNO, Medin, Germany or SLE 5000, UK). NHFOV will be provided via binasal prongs.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Required Intubation	The criteria for endotracheal mechanical ventilation were as follows: severe respiratory acidosis (PaCO2 > 60 mmHg with pH<7.20), severe apnea and bradycardia (defined as recurrent apnea with > 3 episodes per hour associated with heart rate < 100/min, a single episode of apnea that required bag and mask ventilation), hypoxia (FiO2>0.5 with PaO2<50mmHg), severe respiratory distress, neonatal pulmonary hemorrhage, and cardiopulmonary arrest without effective resuscitation needing continued ventilation and rescue	during the first 7 days after birth

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Predischarge Mortality		during hospitalization, up to 60 days
Length of Hospitalization	Days	during hospitalization, up to 60 days
the Incidence of Intraventricular Hemorrhage (IVH, ≥ Grade Ⅲ)	The criteria for intraventricular hemorrhage (IVH, ≥ grade Ⅲ): intraventricular hemorrhage with ventricular dilatation and intraventricular hemorrhage with paren- ehymal hemorrhage. Intraventricular hemorrhage (≥ grade Ⅲ) is worse outcome.	first two months after birth
the Incidence of Pneumothorax	the incidence of pneumothorax	during non-invasive ventilation, up to 7 days
the Incidence of Neonatal Necrotizing Enterocolitis(>Stage II)	The criteria for neonatal necrotizing enterocolitis(>stage II): Unequivocal malfunction of the gastrointestinal tract is demonstrated clinically and by radiographic evaluation. Other disorders such as malrotation and volvulus and Hirschsprung's disease must be excluded. Neonatal necrotizing enterocolitis(>stage II) is worse outcome	during non-invasive ventilation, up to 7 days
the Incidence of Retinopathy of Prematurity (>Stage II)	The criteria for Retinopathy of prematurity (>Stage II); extraretinal fibrovascular proliferation neovascularization extends from ridge into the vitreous. Retinopathy of prematurity (>Stage II) is worse outcome.	at a post-menstrual age of 36 weeks or at discharge
The Score of Bayley Scales of Infant Development	scores of Bayley Scales of Infant Development at 2 months old and 2 years old	30 months
the Incidence of Bronchopulmonary Dysplasia(BPD)	BPD was defined according to the National Institutes of Health consensus definition: Need for O2 supplementation(FiO2>0.21) for at least 28 days after birth. BPD is worse outcome.	at a post-menstrual age of 36 weeks or at discharge
the Incidence of Abdominal Distention	Abdominal circumference increase 2 centimeter during non-invasive ventilation	during non-invasive ventilation, up to 7 days
The Time of Non-invasive Ventilation	Hours	during non-invasive ventilation, up to 30 days
Length of O2 Therapy	Days	during hospitalization, up to 60 days
Number of Participants With Thick Secretions Causing an Airway Obstruction	determined by the clinician	during non-invasive ventilation, up to 15 days

Collaborators and Investigators

• Sponsor: Xingwang Zhu
• Collaborators: University of Southern California; Children's Hospital of Fudan University; The Second Hospital of Shandong University; Daping Hospital and the Research Institute of Surgery of the Third Military Medical University; Chengdu Women's and Children's Central Hospital; Kunming Children's Hospital; Hunan Children's Hospital; Guangdong Women and Children Hospital; The Children's Hospital of Zhejiang University School of Medicine; Nanjing Children's Hospital; Zhengzhou Children's Hospital, China; Vilnius University; Children's Hospital of Chongqing Medical University; Shanxi Provincial Maternity and Children's Hospital; Yan'an Affiliated Hospital of Kunming Medical University; Chongqing Maternal and Child Health Hospital; Chongqing Three Gorges Central Hospital; The People's Hospital of Dehong Autonomous Prefecture; Guiyang Maternity and Child Health Care Hospital
• Investigators: Study Director: Shi Yuan, PhD, Third Military Medical University

Publications and helpful links

General Publications

• Zhu X, Feng Z, Liu C, Shi L, Shi Y, Ramanathan R; NHFOV study group. Nasal High-Frequency Oscillatory Ventilation in Preterm Infants with Moderate Respiratory Distress Syndrome: A Multicenter Randomized Clinical Trial. Neonatology. 2021;118(3):325-331. doi: 10.1159/000515226. Epub 2021 Apr 7.
• Zhu XW, Shi Y, Shi LP, Liu L, Xue J, Ramanathan R; NHFOV Study Group. Non-invasive high-frequency oscillatory ventilation versus nasal continuous positive airway pressure in preterm infants with respiratory distress syndrome: Study protocol for a multi-center prospective randomized controlled trial. Trials. 2018 Jun 14;19(1):319. doi: 10.1186/s13063-018-2673-9.

Study record dates

Study Major Dates

• Study Start (Actual): April 27, 2017
• Primary Completion (Actual): July 28, 2018
• Study Completion (Actual): July 28, 2018

Study Registration Dates

• First Submitted: November 17, 2016
• First Submitted That Met QC Criteria: April 3, 2017
• First Posted (Actual): April 4, 2017

Study Record Updates

• Last Update Posted (Actual): March 2, 2021
• Last Update Submitted That Met QC Criteria: February 8, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: preterm infants; nCPAP; NRDS; nHFOV
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Infant, Newborn, Diseases; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Infant, Premature, Diseases; Premature Birth; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn
• Other Study ID Numbers: Jiulongpo People's Hospital

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Dr. Kris Sekar, Professor of Pediatrics, Oklahoma University Medical Center, Oklahoma, Dr. Jatinder Bhatia, Professor of Pediatrics, Medical College of Georgia, Georgia Health Sciences University, Augusta, Georgia, and Dr. Rowena Cayabyab, MD., MPH (Biostatistics and Epidemiology) Assistant Professor of Pediatrics, Keck School of Medicine of the University of Southern California, Los Angeles, California will serve as DSMB members. Dr. Cayabyab will also serve as consultant for statistical analysis.

Drug and device information, study documents

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