Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000291785
Ethics application status
Approved
Date submitted
26/08/2021
Date registered
16/02/2022
Date last updated
16/02/2022
Date data sharing statement initially provided
16/02/2022
Date results provided
16/02/2022
Type of registration
Retrospectively registered

Titles & IDs
Public title
Efficacy of nasal high frequency oscillation ventilation (NHFOV) compared to noninvasive positive-pressure ventilation (NIPPV) in pre-terms with respiratory distress syndrome during the first 7 days of life
Scientific title
Efficacy of nasal high frequency oscillation ventilation (NHFOV) compared to noninvasive positive-pressure ventilation (NIPPV) in pre-terms with respiratory distress syndrome during the first 7 days of life
Secondary ID [1] 305131 0
none
Universal Trial Number (UTN)
none
Trial acronym
none
Linked study record
none

Health condition
Health condition(s) or problem(s) studied:
Respiratory Distress Syndrome 323368 0
Premature neonates 323369 0
Low birth weight 323370 0
Condition category
Condition code
Respiratory 320939 320939 0 0
Other respiratory disorders / diseases
Reproductive Health and Childbirth 321776 321776 0 0
Childbirth and postnatal care

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Premature neonates (Gestational age 27 wk -34wk) born with respiratory distress syndrome was assigned on intervention group within 6 hours of birth by an attending pediatric registrar not involved in the research in neonatl intensive care unit.
intervention group was provided nasal high frequency oscillation ventilation (NHFOV) by a high-frequency ventilator (Medin, Germany) via nasal mask. Initial settings were be a mean airway pressure of 6 cm H2O (range 6–10), which was equivalent to that for the NIPPV group and a frequency of 8 Hz (range 8-12).The amplitude produced by the Medin CNO device was adjusted between 1 and 10, and the initial setting for the amplitude was 7 (range 7–10).
An Oro-gastric tube was placed in the stomach to limit the abdominal distention and was intermittently aspirated during the study period in intervention group. Nasal mask as an interface was used in intervention group. Nasal mask that fits the nares without blanching the surrounding skin,based on the diameter of the nares (small , medium ,large size )as per manufacturer’s recommendations was used. Pacifiers was be used to reduce the air leaks from the mouth. Target oxygen saturation (SpO2) from 90 %to 94% in preterm neonates less 30weeks gestational age (GA) and more than 89 % to 94% in neonates more than 30 week gestational age by pulse oximeter.
Neonates with moderate to sever Respiratory Distress Syndrome was given Surfactant (curocef, Poractant alfa, Chiesi Pharmaceuticals, Parma, Italy), at a dose of 2.5ml/kg via the INSURE method (intubation, surfactant, and extubation) before initiation of intervention. In the INSURE technique, surfactant was administered via an endotracheal tube and after a brief period of positive pressure ventilation, patients was extubated via the assigned mode. Infants undergoing the INSURE method was not be considered as having received inasive mechanical ventilation (IMV). Second doses of surfactant 1.5ml/kg may be given using the INSURE technique with in 12 hours, if FiO2 requirement more than 0.40 to maintain target SpO2 (89% to 93%) for preterm with less than 30 week (90-94%) for more than 30week gestational age.
A caffeine citrate injection (Chiesi Pharmaceuticals, Parma, Italy) was be administered via intravenous site,when infants present with moderate apnea (defined as three or more episodes in 24 h or a single episode requiring resuscitation and bag and mask ventilation). The initial loading dose was 20 mg/kg, and the maintenance dose was 10mg/kg per day till completion of 34 week post-conception gestational age.

If baby was failed on intervention group then neonate was intubated as follows.
The criteria for intubation and invasive mechanical ventilation (IMV) was : severe respiratory acidosis (PaCO2 more than 65 mmHg with pH <7.20), severe apnea and bradycardia (defined as recurrent apnea with more than 3 episodes per hour associated with heart rate less than 100/min or a single episode of apnea that requires bag and mask ventilation), hypoxemia (FiO2 more than 0.5 with PaO2 less than 50 mmHg from an arterial blood gas sample), severe respiratory distress, pulmonary hemorrhage, and cardiopulmonary arrest needing chest compressions.
The criteria for weaning from intervention was: (1) minimal or no signs of respiratory distress, (2) mean airway pressure pressure less than 6 cm H2O, and (3) FiO2 less than 0.25 to achieve target oxygen saturation ( SpO2).
Intervention code [1] 321541 0
Treatment: Devices
Comparator / control treatment
Premature neonates Gestational age (GA 27 wk-34wk)born with respiratory distress was assigned to control group with in 6 hours of birth by attending pediatric registrar in neonatal intensive care unit.

Neonates assigned to the control group were started with the following parameters: a) positive end expiratory pressure (PEEP) of 6cmH2O (can be raised in steps of 1 cmH2O to max 8 cmH2O, according to the oxygenation). b) Peak Inspiratory Pressure (PIP) of 15 cmH2O (can be raised in steps of 1 cmH2O to max 25 cmH2O, according to oxygenation, PaCO2 levels and the chest expansion); fraction of inspired oxygen(FiO2 ) was adjusted to maintain target oxygen saturation (SpO2 )from 89% to 93% in preterm infants less than 30 weeks gestational age ( GA) and from 90 to 94% in infants more than 30 weeks gesatational age ( GA) by pulse oximeter. c) inspiratory time (IT) was 0.40s (according to clinicians’ evaluation of leaks and the appearance of the pressure curve: a small pressure plateau is required and flow may be set accordingly) and rate was started at 40 bpm (can be raised in steps of 5 bpm to max 60 bpm, according to PaCO2 levels) via NIPPV (CNO Medin, Germany).
An Oro-gastric tube was placed in the stomach to limit the abdominal distention and was periodically aspirated during the study period to control group. Nasal mask as an interface was used in control group. Nasal mask that fits the nares without blanching the surrounding skin,based on the diameter of the nares (small , medium ,large size )as per manufacturer’s recommendations was used. Pacifiers was be used to reduce the air leaks from the mouth. Target oxygen saturation (SpO2) from 90 %to 94% in preterm neonates less 30weeks gestational age (GA) and more than 89 % to 94% in neonates more than 30 week gestational age (GA) by pulse oximeter.
Neonates with moderate to sever Respiratory Distress Syndrome was given Surfactant curocef (Poractant alfa, Chiesi Pharmaceuticals, Parma, Italy), at a dose of 2.5ml/kg via the INSURE method (intubation, surfactant, and extubation) before initiation of NIPPV. In the INSURE technique, surfactant was administered via an endotracheal tube and after a brief period of positive pressure ventilation, patients was extubated via the assigned mode. Infants undergoing the INSURE method was not considered as having received invasive mechanical ventilation (IMV). Second doses of surfactant 1.5ml/kg may be given using the INSURE technique within 12 hours, if FiO2 requirement more than 0.40 to maintain target oxygen saturation ( SpO2 89% to 93%) for preterm with less than 30 week (90-94%) for more than 30week gestational age.
A caffeine citrate injection (Chiesi Pharmaceuticals, Parma, Italy) was administered via intravenous site when infants present with moderate apnea (defined as three or more episodes in 24 h or a single episode requiring resuscitation and bag and mask ventilation). The initial loading dose was 20 mg/kg, and the maintenance dose was 10mg/kg per day till complition of postconception gestational age 34 week.
The criteria for intubation and invasive mechanical ventilation was as follows: severe respiratory acidosis (PaCO2 more than 65 mmHg with pH less than 7.20), severe apnea and bradycardia (defined as recurrent apnea with more than 3 episodes per hour associated with heart rate less than 100/min or a single episode of apnea that requires bag and mask ventilation), hypoxemia (FiO2 more than 0.5 with PaO2 less than 50 mmHg from an arterial blood gas sample), severe respiratory distress, pulmonary hemorrhage, and cardiopulmonary arrest needing chest compressions.
The criteria for weaning for control group was: (1) minimal or no signs of respiratory distress, (2) mean airway pressure less than 6 cm H2O, and (3) fraction inspired oxygen (FiO2 less than 0.25) to achieve target oxygen saturation (SpO2).
Control group
Active

Outcomes
Primary outcome [1] 328721 0
Requirement for invasive mechanical ventilation during first 7 days of life in neonate with respiratory distress syndrome randomized in intervention and control groups.
Requirement for invasive mechanical ventilation was accessed by following composite outcome,
severe respiratory acidosis (PaCO2 > 65 mmHg with pH < 7.20),
severe apnea and bradycardia
hypoxemia (FiO2 > 0.5 with PaO2 < 50 mmHg from an arterial blood gas sample),
severe respiratory distress
pulmonary hemorrhage, and cardiopulmonary arrest needing chest compressions.
Respiratory acidosis was accessed by arterial ABGs ,
Apnea and bradycardia was accessed on clinical examination and by oxygen and heart rate monitor.
Sever respiratory distress,pul heamorrhage and cardiopulmonary arrest was accessed by clinical examination.
Timepoint [1] 328721 0
first 7 days of life after birth.
Secondary outcome [1] 400122 0
Number of days of hospitalization was accessed by accessing patients medical records.
Timepoint [1] 400122 0
during first 7 days of life after birth
Secondary outcome [2] 402880 0
days of supplementary oxygen was accessed by accessing patient medical records.
Timepoint [2] 402880 0
during first 7 days of life after birth
Secondary outcome [3] 402881 0
days of non-invasive ventilation was accessed by patients medical records.
Timepoint [3] 402881 0
during first 7 days of life after birth
Secondary outcome [4] 402882 0
mean airway pressure was accessed by accessing patients medical records.
Timepoint [4] 402882 0
during first 7 days of life after birth
Secondary outcome [5] 402883 0
Use of surfactant via INSURE technique was given to neonates moderate -sever respiratory distress accessed by clinically examination .
Second doses of surfactant was given, if requirement of FiO2 was more than 40% ,to keep oxygen saturation 89-93% in < 30 week gestational age, 90-94% in > 30 week gestational age.
Oxygen saturation was accessed clinically by oxygen monitor.
Timepoint [5] 402883 0
during first three days of life
Secondary outcome [6] 402884 0
Mortality was accessed by accessing patient medical records.
Timepoint [6] 402884 0
from birth till hospital stay.
Secondary outcome [7] 402885 0
Abdominal distention was accessed by accessing patients medical records.
Timepoint [7] 402885 0
during first 7 days of life after birth
Secondary outcome [8] 402886 0
Air leak was accessed by Xray chest finding, mentioned in patients medical record.
Timepoint [8] 402886 0
during first 7 days of life after birth
Secondary outcome [9] 402887 0
Necrotizing Enterocolitis was accessed by Bell staging clinical criteria , mentioned in patients medical record.
Timepoint [9] 402887 0
during first 7 days of life after birth
Secondary outcome [10] 402888 0
Retinopathy of prematurity was accessed by ophthalmologist for detail eye exam.
Timepoint [10] 402888 0
All neonates born at less than 30 week gestational age or wt less than 1.5 kg at birth, neonates with gestational age more than 3o weeks and birth weight more than 1.5 kg at birth with moderate to sever respiratory distress syndrome, will be accessed at 4- 6 weeks after birth.
Secondary outcome [11] 402889 0
Bronchopulmunary dysplasia was accessed by need of oxygen supplement , mentioned in patients medical records
Timepoint [11] 402889 0
during first 7 days of life after birth
Secondary outcome [12] 402890 0
Patentductus arteiosus was accessed by Electrocardiograph findings.
Timepoint [12] 402890 0
during first 7 days of life after birth
Secondary outcome [13] 402891 0
Intraventricular Hemorrhage was accessed by Ultrasound brain finding of the patient.
Timepoint [13] 402891 0
during first 7 days of life after birth
Secondary outcome [14] 402892 0
Spontaneous Intestinal Perforation was accessed by clinical exam and Xray abdomen ,mentioned in patients medical record.
Timepoint [14] 402892 0
during first 7 days of life after birth

Eligibility
Key inclusion criteria
Neonates with these following criteria fulfilled was included in the study.
1.Gestational age 27 week and 34week (estimated on postmenstrual date and early gestational ultasonographic findings).
Neonates with respiratory distress syndrome ( RDS) will be based on clinical manifestations ( tachypnea ,nasal flaring, and or grunting) or respiratory distress syndrome (RDS) Silverman score >5.
2. Moderate –severe respiratory distress syndrome ( RDS) is based on arterial to alveolar PO2 (a/A PO2) ratio and Silverman score within the first hour of life (a/A PO2 ratio . 0.30 or Silverman score >6)
Minimum age
1 Hours
Maximum age
6 Hours
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Any baby intubated for resuscitation or for other reasons.
2. birth weight less than 600gm,
3. Major congenital malformations such as cystic adenomatous malformations, sequestration, diaphragmatic hernia) or pulmonary hypoplasia , or known complex congenital heart disease.
4. Pulmonary hemorrhage.
5. Grade 4 intraventricular hemorrhage.
6. Cardiopulmonary arrest needing prolonged resuscitation.
7. Transferred out of the NICU before randomization.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Neonates with inclusion criteria were allocated to intervention or control group after birth with in 6 hours ,after opening of sealed envelopes, not before.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Sample size was drawn from the software OpenEpi Version 3 by taking 95% confidence interval and 5% margin of error. For Randomized control trial study was cited (reference study Noninvasive high-frequency oscillatory ventilation versus nasal continuous positive airway pressure in preterm infants with moderate-severe respiratory distress syndrome: A preliminary report). The required sample size was found to be 48. 24(experimental group) and 24 (control group).
Data was analyzed using SPSS version 19. The statistical analyses include Student’s t-test for continuous data. Proportions was compared using a chi-squared test. Fisher‘s exact test was used for categorical data.P < 0.05 was regarded as statistically significant.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
1/01/2021
Date of last participant enrolment
Anticipated
Actual
20/08/2021
Date of last data collection
Anticipated
Actual
27/08/2021
Sample size
Target
48
Accrual to date
Final
48
Recruitment outside Australia
Country [1] 24059 0
Pakistan
State/province [1] 24059 0
SINDH/KARACHI

Funding & Sponsors
Funding source category [1] 309523 0
Hospital
Name [1] 309523 0
PNS Sifa Hospital
Country [1] 309523 0
Pakistan
Primary sponsor type
Hospital
Name
PNS Shifa Hospital
Address
PNS Shifa Hospital
Main Korangi Road, defense phase II, Karachi.
Country
Pakistan
Secondary sponsor category [1] 310505 0
Individual
Name [1] 310505 0
Dr Shahid Mahmud
Address [1] 310505 0

PNS Shifa Hospital
Main Korangi Road, defence phase II, Karachi.
Country [1] 310505 0
Pakistan

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309304 0
Ethical Committe PNS Shifa Hospital Karachi
Ethics committee address [1] 309304 0
Ethics committee country [1] 309304 0
Pakistan
Date submitted for ethics approval [1] 309304 0
01/12/2020
Approval date [1] 309304 0
01/01/2021
Ethics approval number [1] 309304 0
ERC/2021/PAED/52

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 113698 0
Dr Rida Ali
Address 113698 0
PNS Shifa Hospital
Main Korangi Road, defence phase I,Karachi .
Country 113698 0
Pakistan
Phone 113698 0
+00922148506543
Fax 113698 0
Email 113698 0
[email protected]
Contact person for public queries
Name 113699 0
Rida Ali
Address 113699 0
PNS Shifa Hospital

Main Korangi Road, dfence phase 2, Karachi.
Country 113699 0
Pakistan
Phone 113699 0
+00922148506543
Fax 113699 0
Email 113699 0
[email protected]
Contact person for scientific queries
Name 113700 0
Rida Ali
Address 113700 0
PNS Shifa Hospital
Main Korangi Road, defence phase II,Karachi,
Country 113700 0
Pakistan
Phone 113700 0
+00922148506543
Fax 113700 0
Email 113700 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.