Nasal High Frequency Oscillatory Versus Synchronized Intermittent Positive Pressure Ventilation in Neonate Following Extubation: Randomized Controlled Crossover Study
Phase: NA
Conditions: High-Frequency Ventilation, Intermittent Positive-Pressure Ventilation, Newborn Morbidity, Noninvasive Ventilation
Sponsor: Prince of Songkla University

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Research Protocol (Full Proposal) 
Human Research Ethics Committee (HREC) 
Faculty of Medicine, Prince of Songkla University 
NCT04323397, Date 15 October 2019  
1. Title of the study  
Nasal High Frequency Oscillatory versus Synchronized Intermittent Positive Pressure 
Ventilation in Neonate following Extubation: Randomized Controlled Crossover Study  
2. Principal Investigator 
Name: Anucha Thatrimontrichai   
Position: Associate professor   
Affiliation: Division of Neonatology, Department of Pediatrics, Faculty of Medicine, 
Prince of Songkla University    
Telephone Number: +66 74451257 
Mobile Phone Number: +66 95 4300690 
E-mail: tanucha@medicine.psu.ac.th 
3. Sub-investigators and advisors 
Name 
Position/Affiliation 
E-mail address and phone 
number 
Responsibility in the 
project 
1. Kulthida 
Baingam 
Pediatric resident/ 
Department of 
Pediatrics, Faculty of 
Medicine, Prince of 
Songkla University    
Kulthida.b93@gmail.com  +66 
869559933 
designed the data 
collection instruments,
collected data, 
performed the initial 
analyses, drafted the 
initial manuscript 
(MS) and revised the 
MS. 
2. Manapat 
Phatigomet 
Neonatal fellow/ 
Department of 
Pediatrics, Faculty of 
Medicine, Prince of 
Songkla University    
manapatpang@gmail.com 
+66 869564774 
 
designed the data 
collection instruments,
collected data, 
performed the initial 
analyses, drafted the 
initial MS and revised 
the MS. 
3. Gunlawadee 
Maneenil 
Assistant professor/ 
Department of 
Pediatrics, Faculty of 
Medicine, Prince of 
Songkla University    
kookwadee@hotmail.com 
+66 980169491 
conceptualized the 
study, coordinated, 
supervised data 
collection, critically 
reviewed the 
manuscript, and 
approved the final MS 

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Name 
Position/Affiliation 
E-mail address and phone 
number 
Responsibility in the 
project 
4. Supaporn 
Dissaneevate 
Assistant professor/ 
Department of 
Pediatrics, Faculty of 
Medicine, Prince of 
Songkla University    
dsupapor@medicine.psu.ac.th 
+66 817887765 
conceptualized the 
study, coordinated, 
supervised data 
collection, critically 
reviewed the 
manuscript, and 
approved the final MS 
5. Waricha 
Janjindamai 
Associate professor/ 
Department of 
Pediatrics, Faculty of 
Medicine, Prince of 
Songkla University    
jwaricha@medicine.psu.ac.th 
+66 816788116 
conceptualized the 
study, coordinated, 
supervised data 
collection, critically 
reviewed the 
manuscript, and 
approved the final MS 
6. Sireepatch 
Cheamsanit 
Neonatal fellow/ 
Department of 
Pediatrics, Faculty of 
Medicine, Prince of 
Songkla University    
happiipc@gmail.com   
+66 846214237 
coordinated 
intervention 
 
4. Student support 
Check ✓  in ( ) that apply 
(  ) Not associated  
(✓) Undergrad./post grad. (indicate resident, fellow, master, PhD student)  
5. Keywords:  
High-Frequency Ventilation, Intermittent Positive-Pressure Ventilation, Newborn, 
Noninvasive Ventilation 
6. Background and rationale 
Non-invasive ventilation (NIV) in neonate has 4 main modes 
1. Nasal continuous positive airway pressure (nCPAP) 
2. Nasal biphasic CPAP (nBi-CPAP)  
3. Nasal intermittent positive pressure ventilation (nIPPV) or nasal synchronized IPPV 
(nSIPPV) 
4. Nasal high frequency oscillation (nHFO)  
 From meta-analyses, respiratory and extubation failure in n(S)IPPV and nHFO modes 
were lower than nCPAP. However, most studies were enrolled by primary support but few 
studies from post-extubation and high-heterogeneity.   
Knowledge gap  
The comparison of n(S)IPPV and nHFO is still limited in neonatal period. In 
ClinicalTrial.gov, there are 3 registry studies in Table 1.  

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Table 1 The studies were registered in ClinicalTrial.gov  
 
7. Objective(s) of the study 
Primary objective: To assess the pCO2 after 2 hours of nHFO compared with 2 hours of 
nSIPPV in crossover study. 
Secondary objective: To assess the reintubation rate within 7 days between non-invasive 
ventilations (nHFO vs nSIPPV) from the latter NIV mode in parallel study 
 
8. Study flow diagram and/or Conceptual framework 
 
 
 
 

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9. Literature review 
Mechanical ventilation was introduced to treat respiratory failure in preterm infants or sick 
neonates then improvements in survival.1,2 However, the complications from short or long 
term use of ventilation can result in unintended harm or burden (e.g., air leak syndrome, 
pneumonia, bronchopulmonary dysplasia, neurological injury, retinopathy of prematurity).3,4 
To reduce these risks, clinicians should aggressive extubated neonates as early as possible. 
Respiratory (focus on blood gas as well as partial pressure CO2 [pCO2]) or extubation (focus 
on clinical condition as well as reintubation) failure was worrisome in pediatrician and 
parents if the neonate was reintubated owing to complete recovery of lung disease or 
inadequate respiratory drive. 
Non-invasive ventilation (NIV) was supported for primary respiratory support (initial 
mode before endotracheal intubation) or post-extubation. Nasal continuous positive airway 
pressure (nCPAP) was familiar to NIV mode in neonatal respiratory support. Nowadays, the 
new NIV modalities are nasal intermittent synchronized positive pressure ventilation 
(nSIPPV) and nasal high frequency oscillation (nHFO).  
To increase the likelihood of nCPAP success, other new modalities of NIV may be 
interesting. From theory, nSIPPV and nHFO combines peak inspiratory pressure (PIP) with 
synchrony and high-frequency oscillations without synchrony above CPAP, respectively. 
From meta-analysis, nSIPPV and nHFO were statistically significant superior than nCPAP 
both respiratory and extubation failure in neonate (Table 2, Fig. 2-5).5,6   
The aim of our study was to investigate the efficacy of nHFOV and nSIPPV for CO2 
clearance and reintubation rate after extubated neonates. We hypothesized that nHFOV mode 
would improve CO2 clearance better than nSIPPV mode. 
 
 

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Table 2 Meta-analyses compared nIPPV, nSIPPV, nBi-CPAP, and nHFO to nCPAP 
Intervention 
Control 
 
Respiratory failure 
Reintubation within 7 
days 
Interventions to improve rates of successful extubation in preterm infants: a systematic review and meta-analysis. JAMA Pediatr 2017;171:165-74. 
n(S)IPPV or nBi-CPAP 
nCPAP 
RR (95%CI) 
.70 (.60, .81) 
.74 (.64, .85)  
• 9 RCTs (Fig. 1-2) 
RD (95%CI) 
-.13 (-.18, -.08) 
-.10 (-.15, -.05) 
NNT (95%CI) 
8 (5-13) 
10 (6-20) 
I2 
66% 
51% 
nSIPPV 
nCPAP 
RR (95%CI) 
.25 (.15, .41) 
 
• 5 RCTs (Fig. 1) 
RD (95%CI) 
-.33 (-.43, -.23) 
 
NNT (95%CI) 
4 (2-5) 
 
I2 
0% 
 
Noninvasive high-frequency oscillatory ventilation as respiratory support in preterm infants: a meta-analysis of randomized controlled trials. Respir 
Res 2019;20:58. 
nHFO 
nBi-CPAP or nCPAP 
 
 
 
• 5 RCTs (1 postextubation, 4 primary support) 
pCO2, WMD 95%CI), I2  
-4.61 (-7.94, -1.28), 67% 
 
ΔpCO2, WMD 95%CI), I2 
-4.89 (-8.36, -1.42), 70% 
 
• 7 RCTs (1 postextubation, 6 primary support) 
RR (95%CI), I2 
 
.50 (.36, .70), 0% 

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Fig. 2 Respiratory failure compared nSIPPV, nIPPV, mixed modes to nCPAP 
 
 
 
Fig. 3 Respiratory failure and reintubation compared n(S)IPPV to nCPAP 

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Fig. 4 pCO2 and ΔpCO2 between nHFO and nBi-CPAP or nCPAP 
 
 
 
 
 
Fig. 5 Intubation between nHFO and nBi-CPAP or nCPAP 
 
 
 

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10. Research methodology  
10.1. Study design: Non-blinded prospective (pragmatic) randomized controlled cross-
over study 
10.2. Setting of the study/Trial site: Neonatal Intensive Care Unit (NICU), 
Songklanagarind Hospital 
10.3. Target population: NICU admitted neonate 
10.4. Study population: Ventilated neonate 
10.5. Inclusion criteria 
1.  Born in hospital and admit in NICU 
2.  The first endotracheal intubation and need NIV if extubation  
3.  Neonate has not been intervened from another RCT study 
10.6. Exclusion criteria 
1. Major congenital anomalies or chromosomal abnormalities 
2. Neuromuscular diseases 
3. Upper respiratory tract abnormalities 
4. Suspected congenital lung diseases or pulmonary hypoplasia 
5. Need for surgery known before the first extubation 
6. Grade IV intraventricular hemorrhage (IVH) occurring before the first extubation  
7. Palliative care 
8. Unplanned extubation 
9. Parents’ decision not to participate 
10.7. Participant withdrawal criteria  
1. Parents’ decision not to participate 
2. Reintubation during 4-hour cross-over study 
10.8. Study termination criteria  
Interim analysis every 6 months, study will stop when  
• 
Reintubation rate in nHFO more than 30% (2 time of 15% in Fig. 4)  
• 
Reintubation rate in nSIPPV more than 60% (2 time of 29% in Fig. 2)  
• 
Reintubation rate between nHFO and nSIPPV difference more than 30%  
10.9. Sample size calculation 

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10.10. Study procedure(s)/stage(s) 
This study was blocked and stratified randomization. Subjects were equally (1:1) 
randomized to one of the two treatment sequences (nHFOV–nSIPPV, nSIPPV–nHFOV). 
The allocation sequence was computer generated by box of four. The allocation concealment 
was ensured by using identical, opaque, sealed envelopes. An envelope was drawn by a 
dedicated nurse immediately after enrolment of the infant. The participants were stratified by 
gestational age and oxygen index (OI = mean airway pressure [MAP]*FiO2*100/PaO2). The 
participates were on the non-blinded and randomized NIV mode for 2 hours and blood gas 
was analyzed then switched to another NIV mode for 2 hours (cross-over) and blood gas was 
analyzed repeatedly. There was not a washout period between 2 NIV modes then the last 
NIV mode was on until no need NIV. We will register in ClinicalTrials.gov before start and 
enrollment of the participants.  
Extubation criteria: The ventilated neonate had a targeted oxygen saturation (SpO2 > 
90%) during on FiO2 < 0.4 and acceptable blood gas (pH > 7.25, PaCO2 < 60) with the 
respiratory setting of  
1. HFO: flow 6-10 L/min, frequency 10 Hz, MAP = “6-7 (preterm), 7-9 (term)” cmH2O, dP 
= 12-20, I:E = 1:1 
2. AC: flow 6-10 L/min, rate 30/minute, PIP 12-15 cmH2O, PEEP = 3 cmH2O  
Intervention nHFOV and nSIPPV were generated by neonatal ventilators (SLE6000 
infant ventilators, United Kingdom) using bi-nasal prongs (RAM cannula, NEOTECH®, 
USA) or the nasal mask of the same type for both ventilation modes. The size of the prongs 
was determined by the infant’s weight. The largest possible prongs were used, with a snug fit 
to avoid leakage. Pacifier for preterm and term neonate (Jollypop™, USA) was taken to 
avoid leakage from the mouth. The disposable ventilator circuit (Fisher & Paykel RT268™, 
Evaqua Dual Limb Infant Breathing Circuit Kit with Evaqua 2 Technology and Pressure 
Line, Flow > 4L/min, New Zealand) was used. The initial NIV setting was7  

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1. nHFO: flow 8-10 L/minute, frequency 10 Hz, MAP = “MAP (before extubation) + 2” or 
“8 (preterm), 10 (term)” cmH2O, dP = "2-3 times of MAP with visible chest oscillations" 
or 25-35 cmH2O, I:E = 1:1, FiO2 = “FiO2 (before extubation) + 0.1-0.2” keep targeted 
SpO2 90-94% 
 
2. nSIPPV: flow 8-10 L/minute, rate 60/minute, PIP = “PIP (before extubation) + 2-5” or 
“20 (preterm), 25 (term)” cmH2O, PEEP = 5 cmH2O, IT = 0.5 s, FiO2 = “FiO2 (before 
extubation) + 0.1-0.2” keep targeted SpO2 90-94%. The highest trigger sensitivity 
avoiding auto triggering was selected. 
 
The monitoring after extubation was vital signs, clinical manifestations, respiratory 
distress, and umbilical arterial blood gas. The first blood gas before extubation was routine 
obtained. After randomization, the initial NIV was started then blood gas was obtained after 2 
hours. The participant was switched to another NIV and blood gas was obtained after 2 hours. 
The participant was continued with the last NIV mode until the NIV was stopped. The 
participant was excluded if severe respiratory failure with reintubation during 4 hours after 
intervention. The parameters were adjusted or titrated according to patient tolerance and 
disappeared respiratory distress, the intervention went on until 4 hours. The NIV was stopped to 
“room air, oxygen box, low or high flow cannula” when  
1. nHFO: MAP = 5-6 cmH2O, dP = 10-15 
2. nSIPPV: PIP/PEEP = 10-12/3-5 cmH2O 
Criteria for extubation failure or reintubation were as follows:  
1. Cardiorespiratory arrest or any type of pulmonary hemorrhage 
2. Persistent low blood pressure without response to volume expander and vasoactive 
agents 
3. Stupor or persistent drowsiness after initial correction and care 
4. Severe respiratory distress  
5. Two hours of respiratory acidosis with PaCO2 > 70 mmHg and pH < 7.2 
6. Two hours of hypoxia with PO2 < 50 mmHg with FiO2 > 0.6, and maximal pressures 
given (MAP 20 and PIP 25 cmH2O in the nHFOV and nSIPPV group, respectively) 
7. Apnea occurring three or more times per hour and a heart rate less than 100/min or apnea 
with required bag-and-mask ventilation. 
8. Severe post extubation stridor  
In case of extubation failure, the study period was ended prematurely for the respective 
infant, pCO2 was measured by blood gas analysis and a mode of ventilation was chosen as 

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deemed appropriate by the attending staff. In general, infants were treated with intravenous 
aminophylline then oral caffeine base and were supported before and after the study.  
10.11. Study instrument(s) and outcome measurement(s) 
The ventilator modes for nSIPPV and nHFO are SLE 6000 (United Kingdom). Nasal mask 
for interface. Blood gas and electrolytes analyzer ABL800 BASIC (Radiometer Medical 
ApS™, Denmark). 
10.12. Data collection methodology 
Participant’s data and blood gas’s result will be recorded in record form.   
10.13. Data management 
EpiData entry is used for data entry and data documentation. The data will be safe and 
private collected; moreover, only principal investigator and recorder will access. 
10.14. Statistical analysis  
Descriptive part: Mean (SD), Median ± IQR 
Analytic part: Continuous outcome 
1. Carry-over effect = Independent t-test comparing intraindividual sums of measurements 
from both periods. 
2. Treatment effect = Independent t-test comparing intraindividual differences of 
measurements of nHFOV versus nSIPPV from both periods. 
3. Dependent t-test  
Regression analysis  
 Category (reintubation): logistic regression  
 Time to event (reintubation): Cox’s proportion model 
Intention-to-treat analysis was applied in case of treatment failure. 
p < .05 was considered significant 
Subgroup analysis was performed 
 
11. Ethical consideration 
11.1. Possible risks/effects in the study, including preventive and alleviation 
measures 
Both interventions, the participants were obtained the blood samples before and after 
intervention via arterial line to minimize pain from phlebotomy.  
 
 
The volume of blood sample was 0.4 mL including before and after tests. The 
maximum allowable blood draw volumes were shown in Figure 6. 
 
Figure 6 Maximum allowable blood draw volumes 

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11.2. Describe the process/system for assuring confidentiality and the privacy of the 
research participants/communities 
The record form was unidentifiable enrolled patients; therefore, name or hospital number 
would not be filled in the record form. The data would be kept in secret files and only 
principal investigators and recorders could access to these data during recruitment of the 
participants, during data collection, during transcription, and data analysis, and dissemination 
of research results. 
11.3. Benefits of the study for participants and the community/country including 
how findings of the study use for strengthening community. 
The result of this study may be the choice of post-extubation via nSIPPV and nHFO (head 
to head comparison) 
11.4. Informed consent process: Process/method of invitation the participants to 
participate in the research, such as personal contact, referral from other(s), 
brochure, and announcement, etc.  
The parents of intubated neonates without exclusion criteria would be pursued to enrolled 
in this study by the dedicated nurse. The parents would receive informative documents with 
explaining the entire data about 30 to 60 minutes or until the parent were crystal clear about 
the study detail by the nurse. If the parents allowed the patients to enroll in the study, they 
would sign the signature in the informed consent’s document.  
11.5. Procedure specifying for research participant withdrawal from the study 
If enrolled participant met the withdrawal criteria, the participant was withdrawal and not 
replaced. The subjects withdrawn were followed-up as routine care.  
11.6. Clearly indicate person(s) responsible for payment for treatment of 
complications and adverse effects 
None 
11.7. Compensation for research participant 
 Yes, please provide detail: 
 
 
 
 
 
 
 
_ No, please provide reasons: there was pragmatic trial and routine preterm care.  
11.8. Does the study involve biological specimen collection? If yes, also explain how 
the investigator manages the leftover specimen. 
None 
11.9. Research project with special ethical consideration (if applicable) 
 
 
This study involved in vulnerable subjects.  
12. Limitation(s) and barrier(s) of the study (If applicable) and plans for mitigation 
This study involved in vulnerable subjects, so the enrolled participants may not reach to 
targeted numbers of the calculated sample size. We need to closed monitor and progress to the 
REC every 6 months. If slow rate of enrollment may extend the duration or terminate of the 
study. 
13. Time schedule of the study 
Duration of the study: 3 years 10 months  
14. Budget detail of the study 
 Funded by:                                                                 Budget amount:  
 

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_ Expecting funded from: Research Grants, Faculty of Medicine, Prince of Songkla University  
 
Budget amount: 450,000 Baht 
 Private fund                                                             Budget amount:  
 
15. Expected outcomes of the study 
- Paper was published in database ISI at least 1 paper  
- For resident training of pediatric certification  
16. References 
1. 
Murdock AI, Linsao L, Reid MM, Sutton MD, Tilak KS, Ulan OA, et al. Mechanical 
ventilation in the respiratory distress syndrome: a controlled trial. Arch Dis Child 
1970;45:624-33. 
2. 
Reid DH, Tunstall ME, Mitchell RG. A controlled trial of artificial respiration in the 
respiratory-distress syndrome of the newborn. Lancet 1967;1:532-3. 
3. 
Thatrimontrichai A, Rujeerapaiboon N, Janjindamai W, Dissaneevate S, Maneenil G, 
Kritsaneepaiboon S, et al. Outcomes and risk factors of ventilator-associated 
pneumonia in neonates. World J Pediatr 2017;13:328-34. 
4. 
Thatrimontrichai A, Janjindamai W, Dissaneevate S, Maneenil G, Kritsaneepaiboon S. 
Risk factors and outcomes of ventilator-associated pneumonia from a neonatal 
intensive care unit, Thailand. Southeast Asian J Trop Med Public Health 2019;50:537-
45. 
5. 
Ferguson KN, Roberts CT, Manley BJ, Davis PG. Interventions to improve rates of 
successful extubation in preterm infants: a systematic review and meta-analysis. 
JAMA Pediatr 2017;171:165-74. 
6. 
Klotz D, Schneider H, Schumann S, Mayer B, Fuchs H. Non-invasive high-frequency 
oscillatory ventilation in preterm infants: a randomised controlled cross-over trial. 
Arch Dis Child Fetal Neonatal Ed 2018;103:F1-F5. 
7. 
De Luca D, Dell'Orto V. Non-invasive high-frequency oscillatory ventilation in 
neonates: review of physiology, biology and clinical data. Arch Dis Child Fetal 
Neonatal Ed 2016;101:F565-F70. 
 
 
Researcher certification 
The principal investigator (and advisor) listed and signed below, will make certain that  
x The study processes will be strictly conducted following the proposal that has been 
approved by the office of Human Research Ethics Unit and in accordance with all 
principles of health-related research involving human.  
x The study processes will be conducted in accordance with the Standard Operational 
Procedures (SOP) of the of Human Research Ethics Unit including report of protocol 
amendment, progression, serious adverse event, deviation, and final summary.  
 
 
 
 
 
(Anucha Thatrimontrichai) 
Date 15 October 2019 
Principal Investigator