Preterm Infants
Conditions
Keywords
NRDS, nHFOV, nCPAP, preterm infants
Brief summary
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．
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.
Interventions
NHFOV will be provided by a high frequency ventilator (CNO, Medin, Germany or SLE 5000, UK). NHFOV will be provided via binasal prongs.
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)
Sponsors
Guiyang Maternity and Child Health Care Hospital
Daping Hospital and the Research Institute of Surgery of the Third Military Medical University
Children's Hospital of Chongqing Medical University
Chongqing Maternal and Child Health Hospital
The Second Hospital of Shandong University
Yan'an Affiliated Hospital of Kunming Medical University
The Children's Hospital of Zhejiang University School of Medicine
Hunan Children's Hospital
Zhengzhou Children's Hospital, China
Chengdu Women's and Children's Central Hospital
The People's Hospital of Dehong Autonomous Prefecture
Kunming Children's Hospital
Chongqing Three Gorges Central Hospital
Shanxi Provincial Maternity and Children's Hospital
University of Southern California
Vilnius University
Children's Hospital of Fudan University
Guangdong Women and Children Hospital
Nanjing Children's Hospital
Xingwang Zhu
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 12 Hours
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Required Intubation | during the first 7 days after birth | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| the Incidence of Pneumothorax | during non-invasive ventilation, up to 7 days | the incidence of pneumothorax |
| the Incidence of Neonatal Necrotizing Enterocolitis(>Stage II) | during non-invasive ventilation, up to 7 days | 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 |
| the Incidence of Retinopathy of Prematurity (>Stage II) | at a post-menstrual age of 36 weeks or at discharge | 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. |
| The Score of Bayley Scales of Infant Development | 30 months | scores of Bayley Scales of Infant Development at 2 months old and 2 years old |
| the Incidence of Bronchopulmonary Dysplasia(BPD) | at a post-menstrual age of 36 weeks or at discharge | 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. |
| the Incidence of Intraventricular Hemorrhage (IVH, ≥ Grade Ⅲ) | first two months after birth | 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. |
| The Time of Non-invasive Ventilation | during non-invasive ventilation, up to 30 days | Hours |
| Length of Hospitalization | during hospitalization, up to 60 days | Days |
| Predischarge Mortality | during hospitalization, up to 60 days | — |
| Length of O2 Therapy | during hospitalization, up to 60 days | Days |
| Number of Participants With Thick Secretions Causing an Airway Obstruction | during non-invasive ventilation, up to 15 days | determined by the clinician |
| the Incidence of Abdominal Distention | during non-invasive ventilation, up to 7 days | Abdominal circumference increase 2 centimeter during non-invasive ventilation |
Countries
China
Participant flow
Recruitment details
From May, 2017, through July, 2018, a total of 18 centers screened 2509 infants, of which 1385 were eligible. We recruited 340 infants (170 in each group), to account for dropouts. Finally, 302 infants completed the trial (152 in NHFOV; 150 in NCPAP group.)
Pre-assignment details
1045 Did not undergo randomization * 663 Refused to participate * 382 NHFOV devices not available
Participants by arm
| Arm | Count |
|---|---|
| nCPAP infants receive primary non-invasive respiratory support by mean of nCPAP | 150 |
| nHFOV infants receive primary non-invasive respiratory support by mean of NIPPV | 152 |
| Total | 302 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 9 | 5 |
| Overall Study | Withdrawal by Subject | 11 | 13 |
Baseline characteristics
| Characteristic | nCPAP | nHFOV | Total |
|---|---|---|---|
| Age, Continuous | 30.9 Weeks STANDARD_DEVIATION 1.8 | 30.6 Weeks STANDARD_DEVIATION 1.7 | 30.7 Weeks STANDARD_DEVIATION 1.7 |
| Antenatal steroids | 101 Participants | 105 Participants | 206 Participants |
| Birth Weight | 1582 g STANDARD_DEVIATION 343 | 1564 g STANDARD_DEVIATION 367 | 1572 g STANDARD_DEVIATION 351 |
| Cesarean delivery | 81 Participants | 89 Participants | 170 Participants |
| Gestational diabetes mellitus | 10 Participants | 10 Participants | 20 Participants |
| Multiple birth | 57 Participants | 36 Participants | 93 Participants |
| Premature rupture of membranes>18h | 61 Participants | 59 Participants | 120 Participants |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Sex: Female, Male Female | 71 Participants | 61 Participants | 132 Participants |
| Sex: Female, Male Male | 79 Participants | 91 Participants | 170 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 6 / 152 | 4 / 150 |
| other Total, other adverse events | 0 / 152 | 0 / 150 |
| serious Total, serious adverse events | 0 / 152 | 0 / 150 |
Outcome results
Primary
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
Time frame: during the first 7 days after birth
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| nCPAP | Number of Participants Who Required Intubation | 26 Participants |
| nHFOV | Number of Participants Who Required Intubation | 15 Participants |
Secondary
Length of Hospitalization
Days
Time frame: during hospitalization, up to 60 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| nCPAP | Length of Hospitalization | 29.0 days |
| nHFOV | Length of Hospitalization | 31.0 days |
Secondary
Length of O2 Therapy
Days
Time frame: during hospitalization, up to 60 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| nCPAP | Length of O2 Therapy | 7.0 days |
| nHFOV | Length of O2 Therapy | 8.0 days |
Secondary
Number of Participants With Thick Secretions Causing an Airway Obstruction
determined by the clinician
Time frame: during non-invasive ventilation, up to 15 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| nCPAP | Number of Participants With Thick Secretions Causing an Airway Obstruction | 8 Participants |
| nHFOV | Number of Participants With Thick Secretions Causing an Airway Obstruction | 21 Participants |
Secondary
Predischarge Mortality
Time frame: during hospitalization, up to 60 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| nCPAP | Predischarge Mortality | 4 Participants |
| nHFOV | Predischarge Mortality | 6 Participants |
Secondary
the Incidence of Abdominal Distention
Abdominal circumference increase 2 centimeter during non-invasive ventilation
Time frame: during non-invasive ventilation, up to 7 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| nCPAP | the Incidence of Abdominal Distention | 19 Participants |
| nHFOV | the Incidence of Abdominal Distention | 26 Participants |
Secondary
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.
Time frame: at a post-menstrual age of 36 weeks or at discharge
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| nCPAP | the Incidence of Bronchopulmonary Dysplasia(BPD) | 15 Participants |
| nHFOV | the Incidence of Bronchopulmonary Dysplasia(BPD) | 17 Participants |
Secondary
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.
Time frame: first two months after birth
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| nCPAP | the Incidence of Intraventricular Hemorrhage (IVH, ≥ Grade Ⅲ) | 2 Participants |
| nHFOV | the Incidence of Intraventricular Hemorrhage (IVH, ≥ Grade Ⅲ) | 4 Participants |
Secondary
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
Time frame: during non-invasive ventilation, up to 7 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| nCPAP | the Incidence of Neonatal Necrotizing Enterocolitis(>Stage II) | 7 Participants |
| nHFOV | the Incidence of Neonatal Necrotizing Enterocolitis(>Stage II) | 11 Participants |
Secondary
the Incidence of Pneumothorax
the incidence of pneumothorax
Time frame: during non-invasive ventilation, up to 7 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| nCPAP | the Incidence of Pneumothorax | 1 Participants |
| nHFOV | the Incidence of Pneumothorax | 3 Participants |
Secondary
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.
Time frame: at a post-menstrual age of 36 weeks or at discharge
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| nCPAP | the Incidence of Retinopathy of Prematurity (>Stage II) | 9 Participants |
| nHFOV | the Incidence of Retinopathy of Prematurity (>Stage II) | 7 Participants |
Secondary
The Score of Bayley Scales of Infant Development
scores of Bayley Scales of Infant Development at 2 months old and 2 years old
Time frame: 30 months
Secondary
The Time of Non-invasive Ventilation
Hours
Time frame: during non-invasive ventilation, up to 30 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| nCPAP | The Time of Non-invasive Ventilation | 81.0 hours |
| nHFOV | The Time of Non-invasive Ventilation | 78.5 hours |