Noninvasive Ventilation for Preterm Neonates With Respiratory Distress Syndrome: a Multi-center Randomized Controlled Trial
Phase: NA
Conditions: Preterm Infants
Sponsor: Xingwang Zhu

1 
 
Noninvasive Ventilation for Preterm Neonates With 
Respiratory Distress Syndrome: a Multi-center Randomized 
Controlled Trial  
(NCT03099694) 
 13 July 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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STUDY PROTOCOL 
Noninvasive 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. For 
the Noninvasive High-Frequency Oscillatory Ventilation Study Group (NHFOV 
Study Group*). 
 
 
 
Abstract  
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 
decrease the incidence of bronchopulmonary dysplasia (BPD). The aim of this trial is 
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 born 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 noninvasive 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 
 
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prespecified secondary outcomes include days of hospitalization, days on noninvasive 
respiratory support, days on IMV, days on supplemental oxygen, mortality, need for 
surfactant, severe retinopathy of prematurity(ROP) requiring laser or surgery, patent 
ductus arteriosus needing ligation, bronchopulmonary dysplasia(BPD), occurrence of 
abdominal distention, air leaksyndromes, intraventricular hemorrhage (IVH ≥ grade 
3), necrotizing enterocolitis (NEC> II stage) and nasal trauma. Other secondary 
outcomes include Bayley Scales of Infant Development at 18-24 months of corrected 
age. 
 
Trial registration: ClinicalTrials.gov Identiﬁer: NCT03099694. 
 
Key words: Noninvasive high-frequency oscillatory ventilation; nasal continuous 
positive airway pressure; respiratory distress syndrome; preterm infants; surfactant; 
invasive mechanical ventilation 
 
 
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Background 
Respiratory distress syndrome (RDS) due to surfactant deficiency is the leading cause 
of respiratory failure in preterm infants [1]. Early noninvasive positive pressure 
ventilation has become a recommended strategy for respiratory management of 
preterm infants with RDS [2].In addition to nasal continuous positive airway pressure 
(NCPAP), various types of noninvasive ventilation(NIV) modes have been used in the 
treatment of RDS including heated, humidified, high-flow nasal cannula (HHFNC), 
biphasic NCPAP (BP-NCPAP) and nasal intermittent positive airway pressure(NIPPV) 
[3]. However, clinical trials have shown that 25 to 67%of very low birth weight 
preterm infants fail these NIV modes and require IMV [4-5]. To minimize the need of 
IMV, noninvasive high-frequency oscillatory ventilation (NHFOV) has been studied 
as a rescue treatment after failure of other NIV modes or following extubation from 
IMV during weaning phase [6]. However, to date, no studies have been published on 
the efficacy of NHFOV as a primary mode of respiratory support in preterm infants. 
In the present trial, we aim to compare the effect of NHFOV and NCPAP in preterm 
infants with RDS as a primary NIV mode. Our main hypothesis is that NHFOV is 
more effective in the treatment of preterm infants with RDS than NCPAP when used 
as a primary NIV mode. 
Trial Design 
Aim 
The primary aim of this trial is to compare the need for IMV during the first 7 days of 
life in infants randomized to NHFOV versus NCPAP. 
Study design 
 
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This will be a multi-center, prospective, randomized controlled trial conducted in 18 
tertiary neonatal intensive care units (NICUs) in China. The trial will be performed in 
accordance with prospective trial flow（Fig.1).  
Inclusion criteria:  
(1) Gestational age (GA) is from 26 weeks 0 days (26+0weeks) to 33 weeks 6 
days(33+0weeks) (estimated on the postmenstrual date and early gestation 
ultrasonographic findings); (2) diagnosis of RDS. The diagnosis of RDS will be based 
on clinical manifestations(tachypnea, nasal flaring and or grunting) and the typical 
X-ray picture of RDS (grain shadow, air bronchogram or white lung)-see appendix; (3) 
RDS Silverman score>5; (4) Age ＜12 hours; (5) informed parental consent has been 
obtained. 
Exclusion criteria 
(1) Resuscitation requiring early intubation according to the American Academy  
of Pediatrics guidelines for neonatal resuscitation [8]; (2)major congenital 
malformations or known complex congenital heart disease; (3)pulmonary hemorrhage 
or pneumothorax; (4) congenital lung diseases or malformations or pulmonary 
hypoplasia; 
Setting 
We plan to enroll preterm infants born between 26 and 34 weeks of gestational age 
from 18 tertiary NICUs in China. These 18 tertiary NICUs have more than 800 NICU 
beds and annual admissions of nearly 8,000 preterm infants with RDS each year. The 
first (XZ) and last authors (RR) take responsibility for the accuracy and completeness 
 
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of the trial. 
Randomization 
To avoid the chance of having more infants in one group than another, block 
randomization will be applied, with a block size of 4. The envelopes are sealed, 
shuffled, and then numbered in sequential order from 1 to 4. A clinician who is not in 
the trial group will open the envelope and randomize patients. This procedure will be 
repeated for each group of four infants. Infants will be stratified according to 
260/7-276/7weeks, 280/7–296/7weeks, 300/7-316/7 weeks and 320/7–336/7weeks. Infants 
born from multiple gestations will be assigned by individual randomization. Infants 
randomized to one arm cannot crossover to the other or vice-versa during the study. 
Trial intervention 
Ventilators 
CPAP: CPAP will be provided by continuous flow devices(CNO Medin, Germany or 
Carefusion, USA) Bubble CPAP devices will not be used. 
NHFOV: NHFOV will be provided by two ventilators (CNO, Medin, Germany or SLE 
5000, UK). The Medin CNO ventilator produces high-frequency oscillations by ﬂow 
interruption with cyclic opening-closure of the end expiratory valve. Otherwise, The SLE 
5000 ventilator is a time-cycled, pressure-limited and continuous-flow neonatal ventilator.  
Before the beginning of the study all ventilators will be checked to ensure that there is no 
malfunction. 
Interfaces 
CPAP and NHFOV will be all administered through short, low-resistance binasal prongs, 
 
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since these are supposed to be the best in terms of resistive charge, leaks and/of comfort. Nasal 
prongs size will be chosen according to the nares’ diameter as the best fitting ones (the largest 
ones that fit the nares without blanching the surrounding tissues) and following manufacturer’s 
recommendations. Particular care (e.g.: pacifiers, positioning, nursing) will be applied to reduce 
leaks and improve patients’ comfort. These latters will be evaluated through a dedicated 30 min 
observation period when study intervention will be instigated.  
Ventilatory management  
The two different respiratory supports will be managed as follows:  
CPAP: 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 10 cmH2O. If this is not enough to 
maintain target oxygen saturation (SpO2) from 89% to 93% in preterm infants <30 
weeks GA and 90-94% in infants >30 weeks GA by pulse oximeter, FiO2 will be added 
up to 0.40. 
NHFOV: For Medin CNO, the initial NHFOV settings will be: mean airway  
pressure (MAP) of 6cmH2O(range 6-10cmH2O), frequency of 10 Hz(range  
6-12), The Medin CNO has ten grades of amplitude. grade 7th amplitude  
will be to start with( grade range 7th-10th). For SLE 5000, The initial settings  
will be: MAP of 6 cm H2O (range 6-10cmH2O); frequency of 10Hz (range  
6-12), inspiratory time 50% (1:1), oscillations of amplitude of 20 cm H2O(range  
20-35 cm H2O). It is not strictly necessary to have visible chest oscillations, as  
most of the CO2 elimination during NHFOV will occur in the upper airway  
dead space. Maximal allowed FiO2 will be 0.40 and SpO2 from 89% to 93% in  
 
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preterm infants <30 weeks GA and 90-94% in infants >30 weeks GA by pulse  
oximeter.  
Surfactant Therapy 
Surfactant (Poractant alfa, Chiesi Pharmaceuticals, Parma, Italy) at dose of 200 mg/ 
kg will be administered via INSURE method if infant presents with the following：
infants<26 week’s gestation when FiO2 requirement >0.30 and infants>26 week’s 
gestation when FiO2 requirement >0.40 [2]. Additional doses of surfactant may be 
given using INSURE technique at the discretion of the clinician.  
Caffeine Therapy 
Caffeine (Caffeine Citrate Injection. Chiesi Pharmaceuticals, Parma, Italy) will be 
administered when infants present with moderate apnea (defined as 3 or more 
episodes in 24 hours or a single episode requiring resuscitation and bag-mask 
ventilation). The initial loading dose is 20mg/kg, and the maintenance dose is 5mg/kg 
per day. 
Weaning from study interventions 
The criteria for weaning noninvasive respiratory will be: (1) minimal or no signs of 
respiratory distress (RDS Silverman score＜5) ; (2) NHFOV MAP or NCPAP 
pressure <6cmH2O and (3) FiO2<0.25 to achieve target SpO2. 
Criteria for intubation and IMV 
These will be as follows [10-11]: (1)severe respiratory acidosis (PaCO2>65 mmHg 
with pH<7.20);(2)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 
 
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requires bag and mask ventilation); (3)hypoxia (FiO2>0.5 with PaO2<50mmHg), 
severe respiratory distress（RDS Silverman score﹥7）;(4)pulmonary hemorrhage; 
(5) pneumothorax; (6) cardiopulmonary arrest needing chest compressions. 
Training 
Since not all clinicians are well versed in all respiratory techniques and, particularly, NHFOV is a 
relatively new technique, the training is capital for the trial success. The protocol will be diffused 
between participating centers at least 3 months before the study begins. One investigator (YS) will 
explain the study protocol in an in-person meeting with all investigators. During the two months’ 
period, clinicians will familiarize with the protocol and the respiratory techniques and the two 
co-principal investigators will be available to solve any doubt. A dedicated social media chat has 
been set to facilitate these exchanges. The trial is supposed to actually start in July 2017. 
Outcomes 
The primary outcome of this trial will be to determine the need for IMV in the first 7 days of life 
in preterm infants randomized to the two groups. Secondary outcomes include days of 
hospitalization, days on noninvasive ventilation, days on supplemental oxygen, predischarge 
mortality, surfactant doses, incidence of> stage III ROP and BPD, occurrences of abdominal 
distention, air leaks, IVH ≥ grade 3and NEC. Secondary outcomes also include Bayley Scales of 
Infant Development at 18-24 months of corrected age. BPD will be defined according to the 
National Institutes of Health consensus definition as mild, moderate and severe BPD [12], IVH 
classification according to Papile et al [13] and for NEC, Bell staging will be used [14]. 
Data collection 
Patient demographic data include: sex, birth weight, gestational age, Apgar scores, mode of 
 
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delivery, prenatal corticosteroid use, premature rupture of the membrane, RDS Silverman score 
and critical risk index for babies-II (CRIB-II) score. More details see in the appendixClinical 
data :Including the need for IMV, days of hospitalization, days on noninvasive respiratory support, 
days on supplemental oxygen, mortality, the need for surfactant, occurrences of abdominal 
distention, air leaks, IVH ≥ grade and NEC>stage II. More details see in the appendixFollow-up 
data: The incidence of BPD and ROP at a post-menstrual age of 36 weeks or at discharge, and 
Bayley Scales of Infant Development at 18-24 months of corrected age.  
Sample size calculation 
It is difficult to calculate a sample size for such a study, since it is the first to investigate NHFOV 
vs CPAP in primary support phase in preterm infants with RDS. There is only one preliminary 
study available about the primary outcome “need for IMV”.  This pilot study conducted by Zhu 
et al provides data about the primary outcome “need for IMV”. This trial showed the need for 
IMV was significantly lower in the NHFOV compared with the NCPAP group (24.3% vs. 56.4%, 
P<0.01). Considering an alfa-error of 0.05 and a power of 90%, 150 neonates should be enrolled 
in each arm (with a 1:1 design) to detect the same difference.  
Statistical methods 
Data will be analyzed using SPSS version 19 software. The statistical analyses 
include Student’s t-test for continuous data and compared proportions using 
Chi-squared test, and Fisher‘s exact test for categorical data. Predefined four 
subgroups 
are 
260/7-276/7weeks, 
280/7–296/7weeks, 
300/7-316/7 
weeks 
and 
320/7–336/7weeks, and subgroup analyses will be conducted for the primary outcome 
in the preterm infants. To further evaluate the effect of NHFOV on intubation within 
 
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subgroup, the test of treatment-by-gestational age subgroup interaction will also be 
done using the paired binary logistic regression. For the preterm infants lost to 
follow-up, the missing values of the primary and secondary outcomes are replaced 
using multiple imputation.A P-value < 0.05 will be regarded as statistically 
significant. 
Data Safety Monitoring Board (DSMB):  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.  
Registration number 
The trial has been approved by the centralized ethics committee (The Ethics 
Committee of Daping Hospital, Research Institute of Surgery, Third Military Medical 
University) and registered at http://www.clinicaltrials.gov(ID: NCT03099694). 
Discussion 
In the past decades, several clinical trials have compared the effects between NHFOV 
and NCPAP in neonates as a rescue mode or during weaning from IMV. These trials 
demonstrated that NHFOV applied with nasopharyngeal tube are more beneficial than 
NCPAP in reducing CO2 levels [16-19]. Recently, two retrospective case series also 
reported NHFOV could be applied in preterm infants as a rescue treatment after the 
 
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failure of other noninvasive ventilation modes[15,20].However, there are some 
limitations in these trials: 1) small sample size; 2) lack of a prospective, randomized 
trial design; and 3) wide range of NHFOV parameters used in these trials. Given these 
limitations, a multi-center, prospective, randomized, controlled trial is necessary for 
better evaluation of NHFOV as a primary mode of noninvasive support. To our 
knowledge, this will be the first multi-center prospective randomized controlled trial 
for evaluation of NHFOV as a primary noninvasive mode in preterm infants with 
RDS in China or any other part of the world. Our trial may help contribute to establish 
guidelines for NHFOV in preterm infants with RDS to minimize the need for IMV, 
and to decrease significant pulmonary and non-pulmonary morbidities associated with 
IMV. 
Funding 
The trial is initiated and planned by the researchers and funded by Scientific Research 
Projects unit of Chongqing (Project- cstc2016shms-ztzx13001) 
Acknowledgement 
The authors would like to thank all families whose infants will participate in this trial, 
and staff providing patient care in all the participating sites.  
Conflict of Interest 
None of the authors have declared conflicts of interests to participate in this trial. 
APPENDIX 
A1. Diagnosis of RDS: 
Respiratory distress appearing within the first 24 h of life, with complete, sustained, 
andprompt response to surfactant or lung recruitment orboth; additional non-mandatory criteria are 
 
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lung imaging (chest X-rays or ultrasound, according to local policies) supporting the diagnosis or 
lamellar body counts≤30 000/mm³, or both 
A2. CLARIFICATIONS FOR EXCLUSION CRITERIA 
Some exclusion criteria are represented by congenital disorders: when a patient is affected by 
these disorders his biology and physiology are significantly changed and are not eligible for the 
study and will not be randomized. If the condition has been discovered/suspected after the 
randomization but before the study inclusion (that is, before extubation), they will not receive the 
study intervention and will not entry in the study. If one of these conditions is diagnosed after the 
inclusion in the study, the neonate will be excluded a posteriori. This is the case of neonates 
withmajor congenital anomalies, chromosomal abnormalities, neuromuscular diseases, congenital 
upper respiratory tract abnormalities and congenital lung diseases or malformations or hypoplasia. 
Examples of these conditions are: genetic syndromes, surfactant protein defects, congenital 
adenomatous pulmonary malformations, congenital diaphragmatic hernia or sequestration, 
congenital hypoventilation syndrome, pulmonary hypoplasia or any metabolic disease. 
A3. LIST OF STUDY DEFINITION 
- 
Gestational age (GA).GA is determined based on sure dates of last menstrual period 
or early ultrasound scan (within the first trimester). If a discrepancy of more than 2 
weeks exists, the early ultrasound scan will be chosen.  
- 
INSURE. Intubation –Surfactant-Extubation 
- 
Antenatal steroids. Antenatal steroid prophylaxis will be considered complete if 
two 12 mg-doses of betamethasone 24h apart and between 1 day and 7 days before 
the delivery had been given. 
- 
Clinical Risk Index for Babies (CRIB-II) score.42This is an estimator of the 
clinical severity at the NICU admission.CRIB-II score considers 4 variables: birth 
weight, GA, base excess within the 1sthour of life and temperature at 
 
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theadmission(see below). An online calculator is available at 
www.sfar.org/scores2/crib22.php 
 
- 
Premature rupture of the membrane. Premature rupture of the membrane will be 
considered complete if more than 18 hours. 
- 
Abdominal distention. Abdominal circumference (cm) at 48h and 96h after study 
intervention 
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