Effect of Synchronized vs. Continuous High Flow Nasal Cannula Using Neurally Adjusted Ventilatory Assist on Work of Breathing in Infants With Bronchopulmonary Dysplasia
Phase: NA
Conditions: Bronchopulmonary Dysplasia
Sponsor: University of Arkansas

TITLE: 
Effect of Synchronized vs. Continuous High Flow 
Nasal Cannula using Neurally Adjusted Ventilatory 
Assist on Work of Breathing in Infants with 
Bronchopulmonary Dysplasia 
 
 
Principal Investigator: 
Sherry E. Courtney, MD 
 
 
Study Location: 
Arkansas Children’s Hospital 
1 Children’s Way 
Little Rock, AR 72202 
 
 
NCT #:  
NCT04274192 
 
 
Document Date:  
June 29th, 2021 

Study Title: 
Effect of Synchronized vs. Continuous High Flow Nasal Cannula using 
Neurally Adjusted Ventilatory Assist on Work of Breathing in Infants 
with Bronchopulmonary Dysplasia  
 
 
Principal  
 
Investigator:  
Sherry E. Courtney, MD 
 
Arkansas Children’s Hospital 
University of Arkansas for Medical Sciences 
1 Children’s Way  
Slot 512-5 
  
 
 
Little Rock, AR 72202 
  
 
 
Telephone: 501-364-1056 
Emails: SECourtney@uams.edu 
 
Sub-Investigator(s): David N. Matlock, MD 
Arkansas Children’s Hospital 
University of Arkansas for Medical Sciences 
4301 W. Markham St. 
Slot 512-5B 
Little Rock, AR 72205 
Telephone: 501-526-3580 
Email: DNMatlock@uams.edu 
 
 
                      
 
Medical Monitor: 
Robert E. Lyle, MD 
 
 
 
Arkansas Children’s Hospital  
 
 
 
University of Arkansas for Medical Sciences 
 
 
 
1 Children’s Way 
 
 
 
Slot 512-5 
 
 
 
Little Rock, AR 72202 
 
 
 
Telephone: 501-364-5678 
 
 
 
Email: LyleRobertE@uams.edu 
 
Study Location:  
Arkansas Children’s Hospital 
 
 
 
1 Children’s Way 
 
 
 
Little Rock, AR 72202 
 
Version Number: 
5 
 
Date:  
 
06/29/2021 
 
 
 
 

IRB# 239863                                                                                                                                                Protocol v 5                             
 
 
06/29/2021 
 
Title: Effect of Synchronized vs. Continuous High Flow Nasal Cannula using Neurally Adjusted Ventilatory          
           Assist on Work of Breathing in Infants with Bronchopulmonary Dysplasia  
PI: Sherry Courtney, MD 
  
 
 
2 
Table of Contents 
List of Frequently Used Abbreviations: ..................................................................................3 
Background and Rationale: ......................................................................................................4 
Innovation: ..................................................................................................................................6 
Hypothesis: .................................................................................................................................6 
Specific Aims: .............................................................................................................................6 
Investigational Device(s) ...........................................................................................................7 
Study Population: ......................................................................................................................7 
Study Design/Procedures: ........................................................................................................8 
Risks and Benefits: .................................................................................................................. 11 
Data Handling and Recordkeeping: ....................................................................................... 11 
Data Analysis: ........................................................................................................................... 12 
Adverse Event: ......................................................................................................................... 12 
Serious Adverse Event (SAEs): .............................................................................................. 13 
Unanticipated Adverse Device Effects (UADEs): ................................................................. 14 
Monitoring, Recording and Reporting of AEs: ..................................................................... 14 
Expedited Reporting of AE: .................................................................................................... 16 
Sponsor Reporting: ................................................................................................................. 16 
Deaths: ...................................................................................................................................... 17 
Monitoring: ................................................................................................................................ 17 
Protocol Deviations and Violations: ...................................................................................... 18 
Ethical Considerations: ........................................................................................................... 18 
Dissemination of Data: ............................................................................................................ 19 
References ................................................................................................................................ 20 
 

IRB# 239863                                                                                                                                                Protocol v 5                             
 
 
06/29/2021 
 
Title: Effect of Synchronized vs. Continuous High Flow Nasal Cannula using Neurally Adjusted Ventilatory          
           Assist on Work of Breathing in Infants with Bronchopulmonary Dysplasia  
PI: Sherry Courtney, MD 
  
 
 
3 
List of Frequently Used Abbreviations:  
• AE- Adverse Event  
• ACH- Arkansas Children’s Hospital 
• ACRI – Arkansas Children’s Research Institute 
• BPD- Bronchopulmonary Dysplasia 
• Edi- Electrical activity of the diaphragm 
• HFNC- High flow nasal cannula 
• FiO2- Fraction of inspired oxygen 
• GCP- Good clinical practice 
• ICH- International Conference on Harmonization 
• IRB- Institutional Board Review 
• LPM- liters per minute 
• NAVA- Neurally adjusted ventilatory assist 
• nCPAP- Nasal continuous positive airway pressure 
• NICU- Neonatal Intensive Care Unit  
• NIPPV- Nasal intermittent positive pressure ventilation 
• NIV- Non-invasive ventilation 
• PEEP- Positive end expiratory pressure 
• RAM- RAM Cannula   
• RIP- Respiratory inductance plethysmography  
• SAE- Serious adverse event 
• TCOM- Transcutaneous oximetry measurement  
• UADE- Unanticipated adverse event 
• UAMS- University of Arkansas for Medical Sciences 
• WOB- Work of breathing 
 

IRB# 239863                                                                                                                                                Protocol v 5                             
 
 
06/29/2021 
 
Title: Effect of Synchronized vs. Continuous High Flow Nasal Cannula using Neurally Adjusted Ventilatory          
           Assist on Work of Breathing in Infants with Bronchopulmonary Dysplasia  
PI: Sherry Courtney, MD 
  
 
 
4 
Background and Rationale:  
 
Affecting between 10,000 and 15,000 infants in the United States each year, 
bronchopulmonary dysplasia (BPD) is a heterogeneous lung disease seen in formerly 
premature infants who continue to require ongoing respiratory support at 28 days of life 
or 36 weeks post menstrual age.1,2 BPD has been associated with an increased risk for 
life-long sequelae including asthma, chronic obstructive pulmonary disease, and 
cerebral palsy, making prevention and treatment of this disease of utmost importance.3-
5 Invasive mechanical ventilation has been identified as a major contributor to the 
development of BPD in premature neonates, leading to the emergence and more 
frequent use of various modes of non-invasive ventilation (NIV) for both treatment and 
prevention of BPD 6,7 Current forms of NIV include: nasal continuous positive airway 
pressure (nCPAP), nasal intermittent positive pressure ventilation (NIPPV), non-
invasive neurally adjusted ventilatory assist (NIV NAVA), and high flow nasal cannula 
(HFNC). Currently, the gold standard of NIV is nCPAP, which delivers a continuous 
positive distending pressure through nasal prongs and helps to maintain functional 
residual capacity within the lung.8 In nCPAP, airflow is delivered to maintain a set 
pressure. This differs from HFNC in which heated and humidified air is delivered at a set 
flow rate without maintaining a set pressure.9 HFNC supports infants by washing 
carbon dioxide out of the nasopharyngeal dead space, providing positive distending 
pressure, and reducing upper airway resistance.10,11  
HFNC is a form of NIV that is being used more frequently in infants with BPD. 
Reasons for this increasing use may include a lower incidence of nasal septal 
breakdown, reduced infant pain scores, improved parent-child bonding, and decreased 
abdominal distension.12-14 Osman et al performed an observational cross-over study 
and found lower premature infant pain profile scores as well as lower salivary cortisol 
levels in infants receiving HFNC vs. nCPAP.12 In another study by Klingenberg et al 
parents reported higher satisfaction with the treatment of their child when he or she was 
on HFNC rather than nCPAP. Contributing factors for this were increased ability of 
parents to interact with their child and the perception that their child was more 
comfortable on HFNC.13 NCPAP requires larger, tighter fitting nasal interfaces to 
ensure adequate pressure delivery, whereas HFNC relies on a high flow of gas and the 
presence of a leak between the patient’s nares and the interface to appropriately wash 
out the nasopharyngeal dead space.15 This leads to the decreased incidence of nasal 
septal breakdown seen with the use of HFNC.  
HFNC has been investigated and found in some studies to have similar efficacy 
to that of nCPAP in clinically stable preterm infants.11,16-18 A meta-analysis published 
in 2015 by Kotecha et al showed similar efficacy of HFNC when compared with other 

IRB# 239863                                                                                                                                                Protocol v 5                             
 
 
06/29/2021 
 
Title: Effect of Synchronized vs. Continuous High Flow Nasal Cannula using Neurally Adjusted Ventilatory          
           Assist on Work of Breathing in Infants with Bronchopulmonary Dysplasia  
PI: Sherry Courtney, MD 
  
 
 
5 
forms of NIV.11 Boumecid et al found no difference between tidal volume generation 
and thoraco-abdominal asynchrony between nCPAP and HFNC.16 Saslow et al also 
demonstrated similar efficacy between nCPAP and HFNC when comparing work of 
breathing (WOB) using respiratory inductance plethysmography (RIP) to estimate tidal 
volume.17 Another study evaluating WOB in twenty preterm neonates found statistically 
significant but clinically similar results when treated with HFNC vs. nCPAP.18  
Infants with BPD often have increased WOB which leads to prolonged ventilatory 
support, increased caloric needs, and prolonged hospitalization. WOB refers to the 
amount of energy expended to overcome the elastic and resistive forces of the 
respiratory system during ventilation.19 Clinical signs of increased WOB include nasal 
flaring, increased use of accessory muscles (retractions), and paradoxical movements 
of the rib cage and abdominal wall (thoracoabdominal asynchrony). The measurement 
of actual WOB is difficult, invasive, and not easily achieved in neonates receiving NIV, 
however it can be estimated. Swing electrical activity of the diaphragm (Edi) has been 
used to estimate WOB in neonates and is the difference between the resting tonic 
activity of the diaphragm (Edi min) and the peak activity of the diaphragm (Edi max) 
measured by the Edi catheter.20 Another tool to estimate WOB uses RIP bands to 
measure the timing of chest and abdominal wall movements. Based on these 
movements, a phase angle can be calculated, which is reflective of the degree of 
thoracoabdominal asynchrony. The greater the thoracoabdominal asynchrony, the 
greater the estimated WOB.21 A third method estimates WOB using the pressure-time 
product, which measures the work required for the subject to trigger a breath and is 
used when no leak is present.22  
Synchronization of non-invasive respiratory support provides more effective 
ventilation and reduces respiratory effort but is difficult to achieve with NIV.23 
Synchronization can, however, be achieved using NAVA, in which Edi is measured 
using an electrode-embedded oro/nasogastric tube called an Edi catheter.24 The Edi 
signal is then used to synchronize the rate, timing, and intensity of ventilatory support to 
the patient’s own respiratory effort.25 NAVA has been shown to have some advantages 
over unsynchronized respiratory support such as improved patient comfort and reduced 
WOB.26,27 Using pressure-time product, Jones et al showed that estimated WOB was 
reduced in neonatal piglets with lung disease when breaths were given in synchrony 
with the piglet’s respiratory effort using NIV NAVA as opposed to asynchronous delivery 
of breaths via NIPPV.27 A study done by Lee et al using swing Edi as an estimate for 
work of breathing found that NIV NAVA decreased WOB in fourteen preterm neonates 
when compared to unsynchronized NIV-pressure support.20 Synchronized HFNC is a 
novel method of NIV, which has not yet been studied in neonates with BPD. NIV NAVA, 

IRB# 239863                                                                                                                                                Protocol v 5                             
 
 
06/29/2021 
 
Title: Effect of Synchronized vs. Continuous High Flow Nasal Cannula using Neurally Adjusted Ventilatory          
           Assist on Work of Breathing in Infants with Bronchopulmonary Dysplasia  
PI: Sherry Courtney, MD 
  
 
 
6 
however, is a commonly used mode of support and can potentially be used in a fashion 
very similar to HFNC to achieve synchronized HFNC. The effect of this novel use of 
NAVA on WOB has not previously been investigated in infants with BPD.  
 
Innovation:  
The proposed study will compare WOB between continuous HFNC and HFNC 
synchronized using NAVA. To our knowledge, synchronization of HFNC has not been 
attempted. This study will investigate the feasibility of synchronized HFNC as well as its 
possible efficacy in decreasing WOB compared to continuous delivery of high flow. This 
study has special relevance to the care of infants with BPD who continue to require 
respiratory support. Though decreasing WOB in this population may lead to earlier 
weaning from respiratory support and earlier discharge from the hospital, the direct and 
immediate relevance of this trial is the potential for development of technology that can 
provide synchronized HFNC, should it be shown to decrease WOB.  
 
Hypothesis:  
WOB estimated using swing Edi will be less with the use of synchronized HFNC 
using NAVA compared to continuous HFNC in infants with BPD being treated with NIV.  
 
Specific Aims: 
 
1. The primary objective will be to investigate whether WOB estimated using swing Edi 
is improved with synchronized HFNC using NAVA over continuous HFNC.  
 
2. Secondary objectives will be to evaluate the effect of NAVA-synchronized vs. 
continuous HFNC on thoracoabdominal asynchrony (using RIP bands to calculate 
phase angle), uncalibrated tidal volume (using RIP bands), FiO2 requirement, neural 
respiratory rate, oxygen saturation, and transcutaneous O2 and CO2 levels.  
 
 
 
 

IRB# 239863                                                                                                                                                Protocol v 5                             
 
 
06/29/2021 
 
Title: Effect of Synchronized vs. Continuous High Flow Nasal Cannula using Neurally Adjusted Ventilatory          
           Assist on Work of Breathing in Infants with Bronchopulmonary Dysplasia  
PI: Sherry Courtney, MD 
  
 
 
7 
Investigational Device(s) 
 
• Pneumotachograph (Hans-Rudolph, Shawnee, KS, USA) will be inserted into 
the inspiratory limb of the ventilator circuit and flows will be recorded on the data 
acquisition system.  
• RAM cannula (RAM cannula, Neotech, Valencia, CA, USA) is intended to be 
used for preterm and term neonates, infants, and pediatric patients who require 
supplemental oxygen, respiratory support, or assistance in breathing in an 
ambulatory, hospital, or institutional environment. In this study it will be used to 
provide both continuous and NAVA-synchronized HFNC. 
• Servo-u ventilators and Servo Tracker Software (Maquet Critical Care, Solna, 
Sweden) is cleared (K15814). It is being used as intended and will provide 
monitoring of the subjects’ respiratory drive, to improve synchrony between the 
ventilator system and patient when the electrical signal to from the brain to the 
diaphragm is active.  
• NAVA-Edi catheter (Maquet Critical Care, Solna, Sweden) is cleared 
(K153688). It will be used to detect electrical signal from the diaphragm and will 
be used to calculate swing Edi (difference between the resting tonic activity of the 
diaphragm and the peak activity of the diaphragm) to be used as an estimate of 
WOB.  
• Transcutaneous monitor (TCM4, Radiometer, Brea, CA, USA) will be used to 
measure CO2 and O2 levels.  
• RIP bands (SleepSense, MFI Medical San Diego, CA) are cleared (K173868) 
and will be placed around the chest and abdomen to measure breathing 
movements and relative tidal volume.  
• Pulse oximeter probe (MasimoSET, Irvine, CA, USA) is cleared (K061204). It 
will be used to measure oxygen saturations and heart rate.  
• MP100 Biopac data acquisition (Biopac Systems Inc., Goleta, CA, USA) will be 
used to collect data from the monitoring devices.  
 
 
Study Population: 
 
Up to thirty subjects at Arkansas Children’s Hospital (ACH) will be consented to 
retain twenty-four participants in the study. Inclusion criteria will include:  
• Chronological age greater than 28 days 
• Gestational age at birth less than 33 weeks as documented in the 
subjects’ initial history and physical  

IRB# 239863                                                                                                                                                Protocol v 5                             
 
 
06/29/2021 
 
Title: Effect of Synchronized vs. Continuous High Flow Nasal Cannula using Neurally Adjusted Ventilatory          
           Assist on Work of Breathing in Infants with Bronchopulmonary Dysplasia  
PI: Sherry Courtney, MD 
  
 
 
8 
• A diagnosis of BPD, defined for this study as having received 
supplemental oxygen for greater than or equal to 28 days from birth 
• Currently receiving NIV in the form of nCPAP, NIV NAVA, NIPPV, or 
HFNC  
 
Exclusion criteria will include:  
• Post-menstrual age (gestational age plus chronological age) of greater 
than 50 weeks 0 days 
• Oxygen requirement greater than 40% at the time of enrollment  
• Transcutaneous CO2 measurements > 80 
• Currently receiving invasive ventilation  
• Major congenital anomalies of the heart and/or lungs  
• Bilateral phrenic nerve palsy 
• Major gastrointestinal malformations, including gastroschisis, 
omphalocele, and congenital diaphragmatic hernia  
• Currently receiving treatment for pneumonia or suspected/confirmed 
sepsis 
 
Study Design/Procedures: 
 
Parental consent will be obtained prior to study. Synchronized HFNC is not an 
option on current HFNC devices, which provide only a constant flow of gas. NAVA 
devices only provide pressure measurements during NAVA in intubated patients, or 
NAVA using non-invasive nasal prongs (NIV NAVA). Nonetheless, many neonatal 
intensive care units (NICUs), including the ACH NICU, use nasal cannulas designed for 
low or high flow, but not approved for nasal CPAP, to attempt provision of nasal CPAP 
and NIV NAVA. For our study, we will use the cannula currently in use at ACH (RAM 
cannula, Neotech, Valencia, CA, USA) and as currently FDA approved, and set the 
NAVA ventilator so that it responds similarly to a HFNC. The RAM cannula will be used 
to provide both continuous and NAVA-synchronized HFNC.  
The provision of continuous HFNC with displayed flow rates and Edi signal will 
be done using the Servo ventilator and the recently developed HFNC software for this 
ventilator. To more accurately record flow rates, a pneumotachograph (unheated, 
calibrated, 0-10 liters per minute (LPM), Hans-Rudolph, Shawnee, KS, USA) will be 
inserted into the inspiratory limb of the ventilator circuit and flows will be recorded on the 
data acquisition system. The pneumotachograph will also be used to translate pressure 
settings into flow settings for the synchronized HFNC portion of the study.  
During NAVA-synchronized HFNC, the NIV NAVA mode will be set in such a way 
that synchronized HFNC will be provided. A minimal end-expiratory flow of 2 LPM will 
be provided using the positive end expiratory pressure (PEEP) setting in the NIV NAVA 

IRB# 239863                                                                                                                                                Protocol v 5                             
 
 
06/29/2021 
 
Title: Effect of Synchronized vs. Continuous High Flow Nasal Cannula using Neurally Adjusted Ventilatory          
           Assist on Work of Breathing in Infants with Bronchopulmonary Dysplasia  
PI: Sherry Courtney, MD 
  
 
 
9 
mode on the ventilator. The PEEP setting corresponding to 2 LPM via the 
pneumotachograph will be used. In order to deliver the desired peak flow rate with each 
neurally-triggered breath, a NAVA level of 15 cmH2O/μV will be set, then the maximum 
pressure setting that corresponds to the desired flow rate using the pneumotachograph 
will be used for the study. The subject will thus be provided with “synchronized HFNC”.  
This contrasts with the constant-flow trials when subjects will receive a constant 
and non-synchronized flow using the HFNC software on the ventilator.  
WOB for this study will be calculated by a computerized program utilizing a 
process which has been used in a previously published study.28 Edi signal analysis will 
also be performed by a specifically developed computer program.  
Prior to the study period each subject will have the following monitoring 
equipment placed (if not already present): Edi catheter, transcutaneous monitor (TCM4, 
Radiometer, Brea, CA, USA) to measure CO2 and O2 levels, pulse oximeter probe 
(MasimoSET, Irvine, CA, USA) to measure oxygen saturations and heart rate, and RIP 
bands (SleepSense, MFI Medical, San Diego, CA, USA) around the chest and abdomen 
to measure breathing movements and relative tidal volume.  
Each subject will be randomized on the day the study is to occur to begin with 
either NAVA-synchronized or continuous HFNC before crossing over to the other mode 
to serve as his/her own control. The same RAM cannula will be used in both study arms 
and will provide a leak of 60-80% as recommended by the product manual. The delivery 
of high flow during both synchronized and continuous HFNC will be given at two 
commonly provided levels of high flow: 6 LPM and 8 LPM, given in the same order in 
each mode (6 LPM then 8 LPM). Each subject will receive 15-minute trials of each 
mode-level combination, for a total of four trials performed in succession. During each 
trial, the first 10 minutes will be used for stabilization, and the last 5 minutes will be used 
for data collection, as has been done in previous trials.20, 27-28 There will be 
approximately one to two minutes between each trial to adjust ventilator settings. Thus, 
the mode-level combinations of the trials will be as follows: for subjects randomized to 
begin with synchronized support: synchronized-6 LPM, synchronized-8 LPM, 
unsynchronized-6 LPM, unsynchronized-8 LPM. For subjects randomized to begin with 
unsynchronized support: unsynchronized-6 LPM, unsynchronized-8 LPM, synchronized-
6 LPM, synchronized-8 LPM.  
 

IRB# 239863                                                                                                                                                Protocol v 5                             
 
 
06/29/2021 
 
Title: Effect of Synchronized vs. Continuous High Flow Nasal Cannula using Neurally Adjusted Ventilatory          
           Assist on Work of Breathing in Infants with Bronchopulmonary Dysplasia  
PI: Sherry Courtney, MD 
  
 
 
10
 
 
 
The flows described in the NAVA-synchronized trials refer to the peak flow 
provided during inspiration. A baseline flow rate of 2 LPM will be provided expiration in 
these trials (using the PEEP setting corresponding to the appropriate flow rate). During 
the unsynchronized trials, the continuous high flow rate will be provided (as is common 
practice with the use of HFNC). During the NAVA-synchronized HFNC trials, the Edi 
trigger will be set to 0.5 microvolts, apnea time to 5 seconds, back up rate to 10 breaths 
per minute, and backup pressure settings will be set to provide an estimated peak flow 
of 6 or 8 LPM according to the designated trial (again, using the pressure setting 
corresponding to the appropriate flow rate).  
Servo-u ventilators and Servo Tracker Software (Maquet Critical Care, Solna, 
Sweden) will be used in order to track Edi signal. The MP100 Biopac data acquisition 
(Biopac Systems Inc., Goleta, CA, USA) will be used to collect data from the monitoring 
devices. HFNC will be delivered using appropriately sized RAM cannula to allow for air 
leak around the subject’s nares. Persistent (>20 seconds) bradycardia (less than 100 
beats per minutes), desaturation (<85%), or hypercarbia (transcutaneous CO2 >70) will 
result in cessation of the study.  
 
 
 
Unsynchronized HFNC 
(6 LPM)
Synchronized HFNC 
(6 LPM)
Synchronized HFNC
(8 LPM)
Unsynchronized HFNC
(6 LPM)
Unsynchronized HFNC 
(8 LPM)
Unsynchronized HFNC 
(8 LPM)
Synchronized HFNC 
(8 LPM)
Synchronized HFNC
(6 LPM)
Subjects randomized to begin 
with either unsynchronized 
HFNC or NAVA-synchronized 
HFNC
Figure 1. Flowchart depicting order of trials based on initial randomization. 

IRB# 239863                                                                                                                                                Protocol v 5                             
 
 
06/29/2021 
 
Title: Effect of Synchronized vs. Continuous High Flow Nasal Cannula using Neurally Adjusted Ventilatory          
           Assist on Work of Breathing in Infants with Bronchopulmonary Dysplasia  
PI: Sherry Courtney, MD 
  
 
 
11
Risks and Benefits: 
 
 
Infants often have gagging and may have vomiting when a gastric tube, such 
as the NAVA catheter, is removed or replaced. Rarely, patients could have a gastric 
tube go into a place besides the stomach or coil in the esophagus. We should be 
able to detect if this occurs using the placement screen on the ventilator because the 
NAVA catheter has electrodes on it that detect the electrical activity of the heart and 
diaphragm, which can be used to determine the location. In extremely low birth 
weight infants, transcutaneous monitors (TCOMs) can cause skin burning. These 
effects are not seen in larger infants like those included in this study. There is a small 
risk of loss of confidentiality inherent in all research. We will do everything possible to 
protect the subjects’ confidentiality. 
There may or may not be direct medical benefit to the subjects involved in this 
study. The subjects will have continuous carbon dioxide and oxygen monitoring 
during the study and if any subject has any problems we will be able to detect and 
respond to this quickly. If a subject shows apparent improvement while using 
particular HFNC settings, we may be able to suggest to the treatment team that these 
settings be continued or the current settings adjusted accordingly. If a subject was 
already performing well on NIV, there may or may not be an improvement during the 
study. Subjects performing well on NIV will still undergo the trials of settings and 
interfaces if enrolled in this study. If using synchronized HFNC improves WOB in the 
subjects included in this study, then we hope the information learned from this study 
will benefit other infants with BPD needing respiratory support in the future. 
 
Data Handling and Recordkeeping: 
 
The Principal Investigator will carefully monitor study procedures to protect the 
safety of research subjects, the quality of the data and the integrity of the study. Each 
subject will be assigned a unique identifying code or number. The key to the code will 
be kept in a locked file in a research office. Only the principal investigator and sub-
investigators will have access to the code and information that identifies the subject in 
the study. Demographic and clinical information, such as gestational age, date of birth, 
gender, race/ethnicity, pregnancy complications, and clinical diagnoses, will be obtained 
from the medical record and kept on a password protected computer. All data will be de-
identified after analysis is complete by destroying the code key. De-identified data will 
be maintained as per UAMS and ACRI policy (currently all data will be kept until the last 
subject is 21 years of age plus 2 years) and destroyed per institutional guidelines.  
 
 
 

IRB# 239863                                                                                                                                                Protocol v 5                             
 
 
06/29/2021 
 
Title: Effect of Synchronized vs. Continuous High Flow Nasal Cannula using Neurally Adjusted Ventilatory          
           Assist on Work of Breathing in Infants with Bronchopulmonary Dysplasia  
PI: Sherry Courtney, MD 
  
 
 
12
Data Analysis: 
 
The primary hypothesis is that WOB estimated by swing Edi will be less during 
synchronized HFNC compared to continuous HFNC. Statistical analysis will be 
performed in conjunction with the Arkansas Children’s Research Institute (ACRI)/ 
University of Arkansas for Medical Sciences (UAMS) Department of Pediatrics 
Biostatistics program. A randomization list of synchronized vs. continuous HFNC will be 
provided by the biostatistics team.  
Data collected will be checked for outliers and extreme values, as well as 
distributional assumptions of the parametric statistical tests. Paired sample t-test will be 
used to compare the primary and secondary outcomes, as well as safety data, under 
the two NIV methods when such assumptions are met. When necessary, multivariate 
analysis that may be more powerful in the presence of high correlation between the 
outcomes will be conducted for both primary and secondary outcomes. When significant 
deviation from assumptions is encountered, nonparametric alternatives such as 
Wilcoxon signed-rank test will be used. Statistical analyses will be performed using SAS 
(Version 9.4, SAS Institute, Cary, NC, USA) statistical software.  
Sample size and power calculation:  
We plan to recruit twenty-four neonates being treated for BPD with NIV. Based 
on the previous study conducted by Lee et al, using swing Edi to estimate WOB with 
NIPPV vs NIV NAVA, a 20% reduction in the primary outcome is expected.20 A sample 
size of twenty-four subjects achieves 81% power to detect a 20% change in the primary 
outcome. This sample size is based on a two-sided alpha of 0.05. Randomized subjects 
that do not complete the study will be replaced and will not be included in data analysis.  
Potential reasons for withdrawal from the study include:  
• Serious adverse effects believed to be related to the investigational device 
• Intolerable side effects of the study procedures 
• Investigator believes it is in the best interest of the subject to discontinue 
study participation 
• Parents request withdrawal from the study 
Adverse Event: 
An adverse event (AE) is any medical occurrence that develops or worsens in severity 
during the course of the study, whether or not it has a causal relationship to the study 
treatment. Concurrent illnesses or injuries should be regarded as AEs. Abnormal results 
of diagnostic procedures, including abnormal laboratory values, are considered AEs if 
the abnormality: 

IRB# 239863                                                                                                                                                Protocol v 5                             
 
 
06/29/2021 
 
Title: Effect of Synchronized vs. Continuous High Flow Nasal Cannula using Neurally Adjusted Ventilatory          
           Assist on Work of Breathing in Infants with Bronchopulmonary Dysplasia  
PI: Sherry Courtney, MD 
  
 
 
13
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
 
Serious Adverse Event (SAEs): 
An adverse event is “serious” if it involves considerable detriment or harm to one or 
more persons (who may or may not be subjects), or requires intervention to prevent one 
or more persons from experiencing considerable detriment or harm. SAEs include 
• death 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• Important medical events are those that may not be immediately life threatening 
but are clearly of major clinical significance. They may jeopardize the subject and 
may require intervention to prevent one of the other serious outcomes noted 
above. For example, drug overdose or abuse, a seizure that did not result in in-
patient hospitalization or intensive treatment of bronchospasm in an emergency 
department would typically be considered serious. 
An investigator should immediately report to the Sponsor ANY serious adverse 
event, whether or not considered device related, including those listed in the protocol 
or device manual, along with an assessment of whether there is a reasonable 
possibility that the device caused the event. 
Although an event may be considered ‘Serious’ based on previous criteria and 
should be reported to ORRA immediately, not all SAEs meet Expedited Reporting 
criteria. 
To avoid confusion, as the terms “serious” and “severe” are not synonymous, the 
following clarification is given: The term “severe” is often used to describe the 

IRB# 239863                                                                                                                                                Protocol v 5                             
 
 
06/29/2021 
 
Title: Effect of Synchronized vs. Continuous High Flow Nasal Cannula using Neurally Adjusted Ventilatory          
           Assist on Work of Breathing in Infants with Bronchopulmonary Dysplasia  
PI: Sherry Courtney, MD 
  
 
 
14
intensity (severity) of a specific event (as in mild, moderate or severe myocardial 
infarction); the event itself, however, may be of relatively minor medical significance 
(such as severe headache). This is not the same as “serious,” which is based on 
subject/event outcome or action usually associated with events that pose a threat to 
a subject’s life or functioning. Seriousness (not severity) serves as a guide for 
defining regulatory reporting obligations. [ICH-E2A(II)(B)] 
 
Related: 
An event is “related” if more likely than not it was caused by the research activity. 
Unexpected: 
An event is “unexpected” when its specificity, nature, severity or incidence is not 
accurately reflected in the consent form, protocol, or investigator’s brochure previously 
reviewed and approved by the IRB. Examples include a lower rate of response to 
treatment or a side effect that is more severe than initially expected. 
Study Period: 
All Adverse Events (AE) will be recorded by the Investigator from the time the consent is 
signed through the end of the last use of the study device. All AEs will be recorded on 
the AE log. All relevant historical medical conditions that are known/diagnosed prior to 
the use of the study device are to be recorded as medical history.  
Unanticipated Adverse Device Effects (UADEs): 
An unanticipated adverse device effect is defined as “any serious adverse effect on 
health or safety, or any life-threatening problem, or death caused by, or associated with, 
a device; if that effect, problem, or death was not previously identified in nature, 
severity, or degree of incidence in the investigational plan, or application (including 
supplementary application), or any other unanticipated serious problem associated with 
a device that relates to the rights, safety, or welfare of subjects.”  
Monitoring, Recording and Reporting of AEs: 
All Adverse Events (AE) will be recorded by the Investigator from the time of consent 
through the end of the last use of the device.  All AEs will be recorded on the AE 
log.  Assessments may include monitoring the subjects’ clinical symptoms; laboratory, 
pathological, radiological, or surgical findings; physical examination; or other 
appropriate tests and procedures. If a laboratory abnormality is one component of a 
diagnosis or syndrome, then only the diagnosis or syndrome should be recorded as an 

IRB# 239863                                                                                                                                                Protocol v 5                             
 
 
06/29/2021 
 
Title: Effect of Synchronized vs. Continuous High Flow Nasal Cannula using Neurally Adjusted Ventilatory          
           Assist on Work of Breathing in Infants with Bronchopulmonary Dysplasia  
PI: Sherry Courtney, MD 
  
 
 
15
AE. If the laboratory abnormality was not a part of a diagnosis or syndrome, then the 
laboratory abnormality should be recorded as the AE. 
 
Any medical condition that is present at the time that the subject is screened will be 
considered as baseline and not reported as an AE. However, if the study subject’s 
condition deteriorates or exacerbates at any time during the study, it will be recorded as 
an AE. Pre-existing conditions should be recorded as adverse events only if the 
frequency, intensity, or the character of the condition worsens during the study. 
The clinical course of each event should be followed until resolution, stabilization, or 
until it has been determined that the study treatment or participation is not the 
cause.  SAEs that are still ongoing at the end of the study period must be followed for 
up to 30 days to determine the final outcome.  Any SAE that occurs after the study 
period and is considered to be possibly related to the study treatment or study 
participation should be recorded and reported immediately to the Sponsor. 
AE data collection and reporting, which are required as part of every study, are done to 
ensure the safety of subjects enrolled in the studies and those who will enroll in future 
protocols.  AEs are to be reported in a routine fashion at scheduled times during the 
trial, such as with the annual continuing review to the IRB.  Certain AEs must be 
reported in an expedited fashion to allow for timelier monitoring of subject safety and 
care.  
The reporting of these events depends on the characteristics of the event: 
1. Seriousness (grading of event) 
2.  Relatedness to study therapy (An event is “related” if more likely than not it was 
caused by the research activity) 
3. Expectedness 
Steps to Determine if the Event Requires Expedited Reporting: 
1. Determine whether the adverse event is related to the investigational 
device.  Attribution categories are as follows: 
▪ Unrelated 
▪ Unlikely 
▪ Possible 

IRB# 239863                                                                                                                                                Protocol v 5                             
 
 
06/29/2021 
 
Title: Effect of Synchronized vs. Continuous High Flow Nasal Cannula using Neurally Adjusted Ventilatory          
           Assist on Work of Breathing in Infants with Bronchopulmonary Dysplasia  
PI: Sherry Courtney, MD 
  
 
 
16
▪ Probable 
▪ Definite 
     2. Determine expectedness of event.  Expected events are those previously 
identified resulting from administration of the device.  An adverse event is considered 
unexpected when the type or severity of the event is not listed in: 
• Protocol 
• Device manual 
• Consent form 
Note: This includes all events that occur within 30 days of the last use of the protocol 
treatment or device.  Any event occurring more than 30 days after the last use of the 
device that is possibly, probably, or definitely attributable to the investigational device 
must be reported according to the instructions above. 
Expedited Reporting of AE: 
Institutional Review Board Reporting 
Only adverse events meeting the UPIRTSO (Unanticipated Problem Involving Risks 
to Subjects or Others) will need to be reported to the UAMS IRB within the required 
10-day allotment of being notified of the event. UPIRTSO requires that an 
unanticipated problem meet the following qualifications: a) unanticipated or 
unexpected; b) related to the research; and c) involves new or increased risk to the 
subject(s).  All other adverse events should be recorded and reported to the UAMS 
IRB at continuing review. 
 
Sponsor Reporting: 
The Sponsor will be promptly notified of all potential UADEs by the investigator/study 
staff using the FDA MedWatch 3500A. 
The Sponsor will evaluate all potential UADEs and report these evaluations to FDA 
in accordance with 21CFR812.  
All other serious adverse events not expeditiously reported to FDA will be reported 
to the Sponsor in the Annual Progress Report and the IRB at continuing review. 

IRB# 239863                                                                                                                                                Protocol v 5                             
 
 
06/29/2021 
 
Title: Effect of Synchronized vs. Continuous High Flow Nasal Cannula using Neurally Adjusted Ventilatory          
           Assist on Work of Breathing in Infants with Bronchopulmonary Dysplasia  
PI: Sherry Courtney, MD 
  
 
 
17
Deaths that are related to research will be reported to the Sponsor immediately upon 
notification of the Investigator.  A death due to a terminal condition of the research 
participant would be considered anticipated and not related to the research.   
THE SPONSOR WILL REPORT DEATHS TO FDA IN ACCORDANCE WITH 
21CFR812. 
Deaths: 
The investigator will notify the Sponsor as soon as possible, preferably within 24 
hours but in no event later than 48 hours, of learning of a subject’s death, regardless 
of whether the death is related or unrelated to the investigational device. The 
investigator will attempt to determine, as conclusively as possible, whether or not the 
death is related to the device. The cause of death and the investigator’s discussion 
regarding whether or not the death was device-related will be described in a written 
report. 
Deaths that are related to research will be reported to the Sponsor immediately upon 
notification of the investigator. A death due to a terminal condition of the research 
subject would be considered anticipated if not related to the research.  
THE SPONSOR WILL REPORT DEATHS TO FDA IN ACCORDANCE WITH 
21CFR812. 
 
Monitoring: 
Clinical site monitoring will be conducted by the UAMS Office of Research 
Regulatory Affairs to ensure that the rights and well-being of trial subjects are 
protected, that the reported trial data are accurate, complete, and verifiable, and that 
the conduct of the trial is in compliance with the currently approved 
protocol/amendment(s), ICH GCP, and applicable regulatory requirements. 
Monitoring specialists from the UAMS Office of Research Regulatory Affairs will 
conduct periodic on-site, comprehensive monitoring as determined by a protocol 
specific monitoring plan, which will be provided by the Monitoring Unit of ORRA. 
A medical monitor has been identified and will serve as an independent, non-biased 
decision maker regarding protocol changes, evaluation of adverse events, and 
enrollment of subjects not meeting protocol requirements. The medical monitor will 

IRB# 239863                                                                                                                                                Protocol v 5                             
 
 
06/29/2021 
 
Title: Effect of Synchronized vs. Continuous High Flow Nasal Cannula using Neurally Adjusted Ventilatory          
           Assist on Work of Breathing in Infants with Bronchopulmonary Dysplasia  
PI: Sherry Courtney, MD 
  
 
 
18
monitor reports of SAEs in real time to ensure good clinical practice and to identify 
safety concerns quickly. He may also suggest protocol modifications to prevent the 
occurrence of particular AEs and may serve as a resource to the clinical 
investigators for advice about management of SAEs, but will not be involved in other 
aspects of the trial. Meetings may be held with the primary investigators and the 
monitor on a quarterly basis to ensure the trial is being safely and efficiently run.  
 
Protocol Deviations and Violations:  
A Protocol Deviation is any unintentional change, divergence, or departure from the 
study design or procedures defined in the protocol. A Protocol Violation is an event 
clearly occurring outside the approved research protocol that is considered serious 
non-compliance and often may affect the rights, safety and/or welfare of subjects. 
Protocol Deviations/ Violations will be tracked and compiled in a Protocol Deviation 
Log. Deviations that potentially cause concern for the subject’s health, safety, or 
rights will be reported to the Sponsor as soon as possible for guidance on reporting 
and any corrective actions that may be needed.  
If an emergency occurs that requires a deviation from the protocol in order to protect 
the welfare of a subject, the PI will attempt to contact the IRB prospectively if time 
allows. If circumstances do not allow, the IRB will be notified as soon as possible.  
If the protocol deviation does not represent a significant alteration in the approved 
protocol and/or does not affect the rights, safety or welfare of the subject, it will be 
reported to the UAMS IRB at the time of Continuing Review. If the protocol deviation/ 
violation represents a significant alteration in the approved protocol and/or if it 
affects the rights, safety or welfare of the subject, it must be reported to the Sponsor 
and the UAMS IRB immediately.  
  
Ethical Considerations: 
This study will be conducted in accordance with all applicable government 
regulations and University of Arkansas for Medical Sciences research policies and 
procedures. This protocol and any amendments will be submitted and approved by 
the UAMS Institutional Review Board (IRB) to conduct the study. The formal consent 
of each subject, using the IRB-approved consent form, will be obtained from the 

IRB# 239863                                                                                                                                                Protocol v 5                             
 
 
06/29/2021 
 
Title: Effect of Synchronized vs. Continuous High Flow Nasal Cannula using Neurally Adjusted Ventilatory          
           Assist on Work of Breathing in Infants with Bronchopulmonary Dysplasia  
PI: Sherry Courtney, MD 
  
 
 
19
parent(s) before that subject is submitted to any study procedure. All parents will be 
provided a consent form describing this study and providing sufficient information in 
language suitable for them to make an informed decision about participation in this 
study. The person obtaining consent will thoroughly explain each element of the 
document and outline the risks and benefits, alternate treatment(s), and 
requirements of the study. The consent process will take place in a quiet and private 
room or by phone, and parents of potential subjects may take as much time as 
needed to make a decision about their participation. Phone consent will be obtained 
with a witness and consent will be faxed, e-mailed, or otherwise transmitted to 
parent(s) who will then transmit it back to the Arkansas Children’s Hospital Neonatal 
ICU. The person conducting the consent process will then sign the form, and a 
signed copy of this form will be given/sent to the mother or father/LAR.  Phone 
consent will only be obtained in the event that the parents are unable to be present 
in the NICU.  
Participation privacy will be maintained and questions regarding participation will be 
answered. No coercion or undue influence will be used in the consent process. This 
consent form must be signed by the parent and the individual obtaining the consent. 
A copy of the signed consent will be given to the parent, and the informed consent 
process will be documented in each subject’s research record.  No research-related 
activities will be performed until the signed consent form is obtained by study 
personnel. 
 
Dissemination of Data: 
Results of this study may be used for presentations, posters, or publications. The 
publications will not contain any identifiable information that could be linked to a 
subject. The study will be listed on Clinicaltrials.gov in accordance with FDA 
requirements.   
 

IRB# 239863                                                                                                                                                Protocol v 5                             
 
 
06/29/2021 
 
Title: Effect of Synchronized vs. Continuous High Flow Nasal Cannula using Neurally Adjusted Ventilatory          
           Assist on Work of Breathing in Infants with Bronchopulmonary Dysplasia  
PI: Sherry Courtney, MD 
  
 
 
20
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IRB# 239863                                                                                                                                                Protocol v 5                             
 
 
06/29/2021 
 
Title: Effect of Synchronized vs. Continuous High Flow Nasal Cannula using Neurally Adjusted Ventilatory          
           Assist on Work of Breathing in Infants with Bronchopulmonary Dysplasia  
PI: Sherry Courtney, MD 
  
 
 
21
12. Osman M, Elsharkawy A, Abdel-Hardy H. Assessment of pain during application 
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Respir Rev 2009;10:75-80.  
 

IRB# 239863                                                                                                                                                Protocol v 5                             
 
 
06/29/2021 
 
Title: Effect of Synchronized vs. Continuous High Flow Nasal Cannula using Neurally Adjusted Ventilatory          
           Assist on Work of Breathing in Infants with Bronchopulmonary Dysplasia  
PI: Sherry Courtney, MD 
  
 
 
22
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