to Test the Hypothesis That NHFOV is More Effective Than nCPAP in the Treatment of Respiratory Distress Syndrome (RDS) in Verypreterm Neonates
Conditions
Keywords
nasal high frequency oscillation ventilation(NHFOV); nasal continuous positive airway pressure(NCPAP); preterm infants
Brief summary
This will be a prospective, multi-center, two-arms,parallel, randomized, controlled trial with a superiority design,conducted in China. The investigators conduct this multi-centre, randomized, controlled trial to test the hypothesis that NHFOV is more effective than nCPAP in the treatment of respiratory distress syndrome (RDS) in infants with a gestational age of less than 28 weeks when used as a primary noninvasive ventilation (NIV) mode.
Detailed description
Preterm infants are eligible to the study if they they match the following inclusion criteria: (1) Gestational age between 240/7 and 286/7 weeks; (2) diagnosis of RDS. The diagnosis of RDS will be based on clinical manifestations (tachypnea, nasal flaring and or grunting) and a fraction of inspired oxygen (FiO2) greater than 0.25 for target saturation of peripheral oxygen (SpO2) 89% to 94%;; (3) Age less than 2 hours; (4)Informed parental consent has been obtained. Neonates will be randomized and assigned either to nCPAP or NHFOV arms with a 1:1ratio, when patients fulfill all inclusion criteria. Randomization cannot be done earlier. Simple randomization will be done according to a computer-generated random number table and will be posted in a specific secured website 24/7 available. Twins will be allocated in the same treatment group. Infants randomized to one arm cannot crossover to the other or vice- versa during the study. For all the groups, if the fraction of inspired oxygen (FiO2) requirement is persistently higher than 0.30 per target SpO2 89-94% after starting the respiratory support, newborns receive Surfactant by LISA technique, administration of surfactant (Curosurf,Chiesi Pharmaceutics, Parma, Italy) 200 mg/kg. After the administration of surfactant, if FiO2 requirement is persistently \>0.4 to keep SpO2 89-94% or severe apnea episodes are present (defined as recurrent apnea with \>3 episodes/h associated with heart rate \<100/min or a single episode of apnea requiring bag and mask ventilation within a 24-hour period ) or at the blood gas (arterial or free-flowing capillary blood) PaCO2\>60 mmHg and potential of hydrogen (pH)\<7.20 obtained at least 1 hour after commencement of the assigned treatment, newborns are intubated and mechanically ventilated. For all the newborns enrolled in the study, arterial or free-flowing capillary blood gas is checked every 6-12 hours, a cerebral and cardiac ultrasound screening is performed within 24 hrs. Further controls follow the routine of the ward.
Interventions
PROCEDUREinfants receive primary non-invasive respiratory support by mean of nCPAP
neonates assigned to the nCPAP group will be started on a pressure of 6 cmH2O( adjust range:6-10 cmH2O) , with FiO2 (0.21-0.40)adjusted to target SpO2 from 89% to 94%. CPAP will be provided by either variable flow or continuous flow devices, as there is no clear evidence that one type of CPAP generator would be better than any other by pure CPAP system.
PROCEDUREinfants receive primary non-invasive respiratory support by mean of NHFOV
neonates assigned to NHFOV will be started with the following boundaries: a) Paw of 6 cmH2O (the range 6-10 cmH2O); b) frequency of 10 Hz (the range 8-12 Hz). c) Inspiratory time 50% (1:1). d) amplitude 15 cmH2O(the range 15-25 cmH2O) NHFOV will only be provided with piston/ membrane oscillators able to provide an active expiratory phase (that is, Acutronic FABIAN-III, SLE 5000, Loweinstein Med LEONI+, Sensormedics 3100A).
Sponsors
Jiangxi Maternal and Child Health Hospital
Children's Hospital of Chongqing Medical University
Guiyang Maternity and Child Health Care Hospital
The Second Hospital of Shandong University
Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region
Hunan Provincial Maternal and Child Health Care Hospital
Zhangzhou Affiliated Hospital of Fujian Medical University
Women and Children's Health Hospital of Yulin
Chongqing Three Gorges Central Hospital
Gansu Provincial Maternal and Child Health Care Hospital
The First People's Hospital of Yunnan
Chengdu Women's and Children's Central Hospital
Maternal and Children's Healthcare Hospital of Taian
People's Hospital of Xinjiang Uygur Autonomous Region
Quanzhou Children's Hospital
Chongqing West Hospital
Chongqing Medical Center for Women and Children
Xiamen Maternity & Child Care Hospital
Qujing Maternal and Child Health Hospital
Liuzhou Maternity and Child Healthcare Hospital
International Peace Maternity and Child Health Hospital
Jiulongpo No.1 People's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
0 Hours to 2 Hours
Healthy volunteers
No
Inclusion criteria
(1) Gestational age between 240/7 and 286/7 weeks; (2) diagnosis of RDS. The diagnosis of RDS will be based on clinical manifestations (tachypnea, nasal flaring and or grunting) and a fraction of inspired oxygen (FiO2) greater than 0.25 for target saturation of peripheral oxygen (SpO2) 89% to 94%；（3） Age less than 2 hours
Exclusion criteria
* Intubated forany reasons at birth * Major congenital malformations or known complex congenital heart disease * No parental consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Failure Within 72 Hours After Randomization 72 Hours After Randomization Need for Invasive Mechanical Ventilation | within 72 hrs from the beginning of the study mode | The respiratory support failure will be considered if one of the following occurs: (1) severe respiratory acidosis (defined as PaCO2 \>60mm Hg with pH\<7.2) for at least 1hour; (2) hypoxia refractory to study intervention (defined as SpO2 \<90%, with FiO2=0.4 and maximal pressures allowed in the study arm) for at least 1 hour after the administration of surfactant; (3) severe apnoea (defined as recurrent apnoea with \>3 episodes/hour associated with heart rate \<100/min or a single episode of apnoea requiring bag and mask ventilation) and (4) attending physician determined that urgent intubation is necessary. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Airleaks(Pneumothorax and/or Pneumomediastinum) Occurred During Noninvasive Respiratory Support | the first 4weeks of life or until NICU discharge, whichever comes first | the diagnosis a Chest XR |
Other
| Measure | Time frame | Description |
|---|---|---|
| Rate of Necrotizing Enterocolitis (NEC) ≥ 2nd Stage | the first 4weeks of life or until NICU discharge, whichever comes first | — |
| Rate of Intraventricular Hemorrhage ≥ 3nd Grade | the first 4weeks of life or until NICU discharge, whichever comes first | — |
| Rate of Thick Secretions Causing an Airway Obstruction | the first 4weeks of life or until NICU discharge, whichever comes first | — |
| In-hospital Mortality | through study completion, an average of 1 year | — |
| Rate of Nasal Trauma | the first 4weeks of life or until NICU discharge, whichever comes first | — |
| Rate of Bronchopulmonary Dysplasia | 36 weeks of postmenstrual age | defined according to the NICHD definition |
| Weekly Weight Gain | the first 4weeks of life or until NICU discharge, whichever comes first | in grams/d |
| Overall Duration of Non Invasive Respiratory Assistance | the first 4weeks of life or until NICU discharge, whichever comes first | — |
| Overall Duration of Hospitalisation | up to 2 years from birth | — |
| the Rate of Patent Doctus Arterious | through study completion, an average of 1 year | If a pharmaceutical or surgical treatment is required is considered. Small doctuses closing spontaneously during the first days of life are not included. |
| Composite Mortality/BPD Tality/BPD | through study completion, an average of 1 year | — |
| Rate of Retinopathy of Prematurity (ROP)≥ 2nd Stage | the first 4weeks of life or until NICU discharge, whichever comes first | — |
Countries
China
Participant flow
Recruitment details
From August, 2022, through August, 2024, a total of 20 centers screened 729 infants, of which 405 were eligible. We recruited 360 infants (180 in each group), to account for dropouts. Finally, 342 infants completed the trial (170 in NHFOV; 172 in NCPAP group.)
Pre-assignment details
45 Did not undergo randomization 25 Refused to participate 11 transferr out of the NICU before randomisation 9 major congenital malformations
Participants by arm
| Arm | Count |
|---|---|
| NCPAP infants receive primary non-invasive respiratory support by mean of nCPAP: neonates assigned to the nCPAP group will be started on a pressure of 6 cmH2O( adjust range:6-10 cmH2O) , with FiO2 (0.21-0.40)adjusted to target SpO2 from 89% to 94%. CPAP will be provided by either variable flow or continuous flow devices, as there is no clear evidence that one type of CPAP generator would be better than any other by pure CPAP system.
infants receive primary non-invasive respiratory support by mean of NHFOV: neonates assigned to NHFOV will be started with the following boundaries: a) Paw of 6 cmH2O (the range 6-10 cmH2O); b) frequency of 10 Hz (the range 8-12 Hz). c) Inspiratory time 50% (1:1). d) amplitude 15 cmH2O(the range 15-25 cmH2O) NHFOV will only be provided with piston/ membrane oscillators able to provide an active expiratory phase (that is, Acutronic FABIAN-III, SLE 5000, Loweinstein Med LEONI+, Sensormedics 3100A). | 172 |
| NHFOV infants receive primary non-invasive respiratory support by mean of nCPAP: neonates assigned to the nCPAP group will be started on a pressure of 6 cmH2O( adjust range:6-10 cmH2O) , with FiO2 (0.21-0.40)adjusted to target SpO2 from 89% to 94%. CPAP will be provided by either variable flow or continuous flow devices, as there is no clear evidence that one type of CPAP generator would be better than any other by pure CPAP system.
infants receive primary non-invasive respiratory support by mean of NHFOV: neonates assigned to NHFOV will be started with the following boundaries: a) Paw of 6 cmH2O (the range 6-10 cmH2O); b) frequency of 10 Hz (the range 8-12 Hz). c) Inspiratory time 50% (1:1). d) amplitude 15 cmH2O(the range 15-25 cmH2O) NHFOV will only be provided with piston/ membrane oscillators able to provide an active expiratory phase (that is, Acutronic FABIAN-III, SLE 5000, Loweinstein Med LEONI+, Sensormedics 3100A). | 170 |
| Total | 342 |
Baseline characteristics
| Characteristic | NCPAP | Total | NHFOV |
|---|---|---|---|
| Age, Categorical <=18 years | 172 Participants | 342 Participants | 170 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 1 hours STANDARD_DEVIATION 0.2 | 1 hours STANDARD_DEVIATION 0.2 | 1 hours STANDARD_DEVIATION 0.3 |
| Birth weight | 970 g STANDARD_DEVIATION 212 | 950 g STANDARD_DEVIATION 205 | 940 g STANDARD_DEVIATION 204 |
| Gestational age | 26.9 weeks STANDARD_DEVIATION 1.2 | 27.0 weeks STANDARD_DEVIATION 1 | 27.0 weeks STANDARD_DEVIATION 1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 172 Participants | 342 Participants | 170 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment China | 172 Participants | 342 Participants | 170 Participants |
| Sex: Female, Male Female | 68 Participants | 142 Participants | 74 Participants |
| Sex: Female, Male Male | 104 Participants | 200 Participants | 96 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 12 / 172 | 9 / 170 |
| other Total, other adverse events | 0 / 172 | 0 / 170 |
| serious Total, serious adverse events | 0 / 172 | 0 / 170 |
Outcome results
Primary
Treatment Failure Within 72 Hours After Randomization 72 Hours After Randomization Need for Invasive Mechanical Ventilation
The respiratory support failure will be considered if one of the following occurs: (1) severe respiratory acidosis (defined as PaCO2 \>60mm Hg with pH\<7.2) for at least 1hour; (2) hypoxia refractory to study intervention (defined as SpO2 \<90%, with FiO2=0.4 and maximal pressures allowed in the study arm) for at least 1 hour after the administration of surfactant; (3) severe apnoea (defined as recurrent apnoea with \>3 episodes/hour associated with heart rate \<100/min or a single episode of apnoea requiring bag and mask ventilation) and (4) attending physician determined that urgent intubation is necessary.
Time frame: within 72 hrs from the beginning of the study mode
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NCPAP | Treatment Failure Within 72 Hours After Randomization 72 Hours After Randomization Need for Invasive Mechanical Ventilation | 48 Participants |
| NHFOV | Treatment Failure Within 72 Hours After Randomization 72 Hours After Randomization Need for Invasive Mechanical Ventilation | 27 Participants |
Secondary
Rate of Airleaks(Pneumothorax and/or Pneumomediastinum) Occurred During Noninvasive Respiratory Support
the diagnosis a Chest XR
Time frame: the first 4weeks of life or until NICU discharge, whichever comes first
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NCPAP | Rate of Airleaks(Pneumothorax and/or Pneumomediastinum) Occurred During Noninvasive Respiratory Support | 4 Participants |
| NHFOV | Rate of Airleaks(Pneumothorax and/or Pneumomediastinum) Occurred During Noninvasive Respiratory Support | 1 Participants |
Other Pre-specified
Composite Mortality/BPD Tality/BPD
Time frame: through study completion, an average of 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NCPAP | Composite Mortality/BPD Tality/BPD | 89 Participants |
| NHFOV | Composite Mortality/BPD Tality/BPD | 74 Participants |
Other Pre-specified
In-hospital Mortality
Time frame: through study completion, an average of 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NCPAP | In-hospital Mortality | 12 Participants |
| NHFOV | In-hospital Mortality | 9 Participants |
Other Pre-specified
Overall Duration of Hospitalisation
Time frame: up to 2 years from birth
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NCPAP | Overall Duration of Hospitalisation | 57 days |
| NHFOV | Overall Duration of Hospitalisation | 55 days |
Other Pre-specified
Overall Duration of Non Invasive Respiratory Assistance
Time frame: the first 4weeks of life or until NICU discharge, whichever comes first
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NCPAP | Overall Duration of Non Invasive Respiratory Assistance | 27 days |
| NHFOV | Overall Duration of Non Invasive Respiratory Assistance | 24 days |
Other Pre-specified
Rate of Bronchopulmonary Dysplasia
defined according to the NICHD definition
Time frame: 36 weeks of postmenstrual age
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NCPAP | Rate of Bronchopulmonary Dysplasia | 77 Participants |
| NHFOV | Rate of Bronchopulmonary Dysplasia | 65 Participants |
Other Pre-specified
Rate of Intraventricular Hemorrhage ≥ 3nd Grade
Time frame: the first 4weeks of life or until NICU discharge, whichever comes first
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NCPAP | Rate of Intraventricular Hemorrhage ≥ 3nd Grade | 16 Participants |
| NHFOV | Rate of Intraventricular Hemorrhage ≥ 3nd Grade | 15 Participants |
Other Pre-specified
Rate of Nasal Trauma
Time frame: the first 4weeks of life or until NICU discharge, whichever comes first
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NCPAP | Rate of Nasal Trauma | 9 Participants |
| NHFOV | Rate of Nasal Trauma | 5 Participants |
Other Pre-specified
Rate of Necrotizing Enterocolitis (NEC) ≥ 2nd Stage
Time frame: the first 4weeks of life or until NICU discharge, whichever comes first
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NCPAP | Rate of Necrotizing Enterocolitis (NEC) ≥ 2nd Stage | 13 Participants |
| NHFOV | Rate of Necrotizing Enterocolitis (NEC) ≥ 2nd Stage | 23 Participants |
Other Pre-specified
Rate of Retinopathy of Prematurity (ROP)≥ 2nd Stage
Time frame: the first 4weeks of life or until NICU discharge, whichever comes first
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NCPAP | Rate of Retinopathy of Prematurity (ROP)≥ 2nd Stage | 39 Participants |
| NHFOV | Rate of Retinopathy of Prematurity (ROP)≥ 2nd Stage | 40 Participants |
Other Pre-specified
Rate of Thick Secretions Causing an Airway Obstruction
Time frame: the first 4weeks of life or until NICU discharge, whichever comes first
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NCPAP | Rate of Thick Secretions Causing an Airway Obstruction | 10 Participants |
| NHFOV | Rate of Thick Secretions Causing an Airway Obstruction | 12 Participants |
Other Pre-specified
the Rate of Patent Doctus Arterious
If a pharmaceutical or surgical treatment is required is considered. Small doctuses closing spontaneously during the first days of life are not included.
Time frame: through study completion, an average of 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| NCPAP | the Rate of Patent Doctus Arterious | 32 Participants |
| NHFOV | the Rate of Patent Doctus Arterious | 35 Participants |
Other Pre-specified
Weekly Weight Gain
in grams/d
Time frame: the first 4weeks of life or until NICU discharge, whichever comes first
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NCPAP | Weekly Weight Gain | 17 g/Kg/day | Standard Deviation 6 |
| NHFOV | Weekly Weight Gain | 16 g/Kg/day | Standard Deviation 7 |