Pilot Cross-Over Trial of Neurally Adjusted Ventilatory Assist (NAVA) and Conventional Flow Triggered Mechanical Ventilation (CMV) in Severe Bronchopulmonary Dysplasia (sBPD)
Phase: NA
Conditions: Bronchopulmonary Dysplasia, Neurally Adjusted Ventilatory Assist, Mechanical Ventilation
Sponsor: Children's Hospital of Philadelphia

 
 
Official title: Pilot Cross-Over Trial of Neurally Adjusted Ventilatory Assist 
(NAVA) and Conventional Flow Triggered Mechanical Ventilation (CMV) in 
Severe Bronchopulmonary Dysplasia (sBPD) 
 
NCT number: NCT04821453 
 
Document date: 31August2022 
 
 

 
 
 
 
 
 
 
 
ii
Title: 
Pilot Cross-Over Trial of Neurally Adjusted Ventilatory Assist 
(NAVA) and Conventional Flow Triggered Mechanical 
Ventilation (CMV) in Severe Bronchopulmonary Dysplasia 
(sBPD) 
Short Title 
NAVA Crossover sBPD 
eIRB Number 
19-017175 
Protocol Date: 
2 June 2020 
Amendment 1 Date: 11February 2022 
Amendment 3 Date: 31August2022 
Amendment 2 Date:  03March2022 
Amendment 4 Date: 
 
Study Co-Principal Investigators  
Nadir Yehya, MD, MSCE 
The Children’s Hospital of Philadelphia 
Division of Pediatric Anesthesia and Critical Care 
Philadelphia, PA, 19104 
Phone 925-413-6501 
email: yehyan@chop.edu 
 

 
 
 
 
 
 
 
 
iii
TABLE OF CONTENTS 
Table of Contents ................................................................................................................... ii 
Abbreviations and Definitions of Terms............................................................................. iv 
Abstract .................................................................................................................................. v 
Protocol Synopsis .................................................................................................................. vi 
Table 1: Schedule of Study Procedures .............................................................................. ix 
Figure 1: Study Diagram ....................................................................................................... x 
1 
BACKGROUND INFORMATION AND RATIONALE ......................................................................... 1 
1.1 
INTRODUCTION ........................................................................................................................................ 1 
1.2 
NAME AND DESCRIPTION OF INVESTIGATIONAL PRODUCT OR INTERVENTION ........................................ 1 
1.3 
FINDINGS FROM NON-CLINICAL AND CLINICAL STUDIES ........................................................................ 2 
1.3.1 
Clinical Studies ................................................................................................................................ 2 
1.3.1.1 Clinical Studies in Adults ................................................................................................................ 2 
     1.3.1.2 CLINICAL STUDIES IN CHILDREN ........................................................................................................... 2 
1.4 
RELEVANT LITERATURE AND DATA ........................................................................................................ 3 
1.5 
COMPLIANCE STATEMENT ....................................................................................................................... 3 
2 
STUDY OBJECTIVES ................................................................................................................................ 3 
2.1 
PRIMARY OBJECTIVE (OR AIM) ................................................................................................................ 4 
2.2 
SECONDARY OBJECTIVES (OR AIM) ......................................................................................................... 4 
3 
INVESTIGATIONAL PLAN ...................................................................................................................... 4 
3.1 
GENERAL SCHEMA OF STUDY DESIGN ..................................................................................................... 4 
3.1.1 
Screening Phase .............................................................................................................................. 4 
3.1.2 
Study Observation Phase ................................................................................................................. 4 
3.1.3 
Study Treatment Phase (start of the study intervention) .................................................................. 5 
3.2 
ALLOCATION TO TREATMENT GROUPS AND BLINDING............................................................................ 5 
3.3 
STUDY DURATION, ENROLLMENT AND NUMBER OF SITES ...................................................................... 5 
3.3.1 
Duration of Study Participation ...................................................................................................... 5 
3.3.2 
Total Number of Study Sites/Total Number of Subjects Projected .................................................. 5 
3.4 
STUDY POPULATION ................................................................................................................................ 5 
3.4.1 
Inclusion Criteria ............................................................................................................................ 5 
3.4.2 
Exclusion Criteria............................................................................................................................ 6 
4 
STUDY PROCEDURES .............................................................................................................................. 6 
4.1 
SCREENING AND COMMENCEMENT OF STUDY .......................................................................................... 6 
4.2 
UNBLINDED VENTILATOR MODE CROSSOVER PHASE ................................................................................ 6 
4.3 
SUBJECT COMPLETION/WITHDRAWAL ..................................................................................................... 7 
5 
STUDY EVALUATIONS AND MEASUREMENTS................................................................................ 7 
5.1 
SCREENING AND MONITORING EVALUATIONS AND MEASUREMENTS ...................................................... 7 
5.1.1 
Medical Record Review ................................................................................................................... 7 
5.1.2 
Physical Examination ...................................................................................................................... 7 
5.1.3 
Vital Signs ........................................................................................................................................ 8 
5.1.4 
Laboratory Evaluations ................................................................................................................... 8 
5.1.5 
Ventilatory Parameters .................................................................................................................... 8 
5.2 
SAFETY EVALUATION ............................................................................................................................... 9 
6 
STATISTICAL CONSIDERATIONS ........................................................................................................ 9 
6.1 
PRIMARY OUTCOME ................................................................................................................................. 9 
6.2 
SECONDARY OUTCOME ............................................................................................................................ 9 
6.3 
STATISTICAL METHODS ......................................................................................................................... 10 

  
 
 
 
 
 
 
 
iv
6.3.1 
Analysis Plan ................................................................................................................................. 10 
6.4 
SAMPLE SIZE AND POWER ..................................................................................................................... 11 
6.5 
INTERIM ANALYSIS ................................................................................................................................ 11 
7 
SAFETY MANAGEMENT ....................................................................................................................... 11 
7.1 
CLINICAL ADVERSE EVENTS ................................................................................................................. 11 
7.2 
ADVERSE EVENT REPORTING ................................................................................................................ 11 
8 
STUDY ADMINISTRATION ................................................................................................................... 11 
8.1 
TREATMENT ASSIGNMENT METHODS .................................................................................................... 11 
8.1.1 
Randomization ............................................................................................................................... 11 
8.2 
DATA COLLECTION AND MANAGEMENT................................................................................................ 12 
8.3 
CONFIDENTIALITY ................................................................................................................................. 12 
8.4 
REGULATORY AND ETHICAL CONSIDERATIONS ..................................................................................... 12 
8.4.1 
Data and Safety Monitoring Plan .................................................................................................. 12 
8.4.2 
Risk Assessment ............................................................................................................................. 13 
8.4.3 
Potential Benefits of Trial Participation ....................................................................................... 14 
8.4.4 
Risk-Benefit Assessment ................................................................................................................ 14 
8.5 
RECRUITMENT STRATEGY ..................................................................................................................... 14 
8.6 
INFORMED CONSENT/ASSENT AND HIPAA AUTHORIZATION ................................................................ 14 
8.6.1 
Waiver of Assent ............................................................................................................................ 15 
9 
PUBLICATION ........................................................................................................................................ 15 
10 
REFERENCES ......................................................................................................................................... 15 
 

  
 
 
 
 
 
 
 
v
ABBREVIATIONS AND DEFINITIONS OF TERMS 
C 
 
Degrees centigrade 
AE 
 
Adverse event 
sBPD 
 
Severe Bronchopulmonary Dysplasia 
N/IICU 
 
Neonatal & Infant Intensive Care Unit 
PICU 
 
Pediatric Intensive Care Unit 
NAVA 
 
Neurally Adjusted Ventilatory Assist 
CMV 
 
Conventional flow triggered Mechanical Ventilation 
Edi 
 
Diaphragmatic Electrical Activity 
PEEP 
 
Positive End Expiratory Pressure 
PIP 
 
Peak Inspiratory Pressure 
cmH2O 
 
Centimeters of water 
Crs 
 
Compliance of the respiratory system 
Rrs 
 
Resistance of the respiratory system 
Hrs 
 
Hours 
ETT 
 
Endotracheal Tube 
Vt 
 
Tidal Volume 
RR 
 
Respiratory Rate 
HR 
 
Heart Rate 
BP 
 
Blood Pressure 
Tcom 
 
Transcutaneous Carbon Dioxide  
EtCO2 
 
End Tidal Carbon Dioxide 
MAP 
 
Mean airway pressure 
OSI 
 
Oxygen Saturation Index 
FiO2 
 
Fraction of Inspired Oxygen 
SpO2 
 
Oxygen Saturation Percent 
PSV 
 
Pressure Support Ventilation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
 
 
 
 
 
 
 
vi
ABSTRACT 
Context: 
Most research to date in neonatal lung disease has focused on BPD prevention. As a result, 
insufficient investigation has been performed to define optimal respiratory management 
strategies for infants and young children with established BPD. Thus, there is no robust 
evidence base to guide ventilator management to promote lung disease recovery and support 
neurodevelopment in this population. Neurally adjusted ventilatory assist (NAVA) is an 
alternative to conventional flow triggered ventilation that has shown promise for improving 
respiratory gas exchange, patient-ventilator interaction, and work of breathing in preterm 
neonates. The safety and efficacy of NAVA in infants and young children with established, 
severe BPD is uncertain. 
Objectives: 
To compare measures of pulmonary mechanics, respiratory gas exchange, and patient 
comfort between conventional flow triggered mechanical ventilation and NAVA among 
prematurely born infants and young children receiving invasive respiratory support for 
severe BPD. 
Study Design:  
Prospective, unblinded, pilot randomized cross-over trial of 2 modes of mechanical 
ventilation. 
Setting/Participants: 
The trial will take place in the N/IICU and PICU at CHOP and the PICU at Hasbro 
Children’s Hospital. Up to 25 patients will be enrolled in the study to produce up to 20 
children with evaluable trial data.  
Study Interventions and Measures:  
After informed consent, a NAVA catheter will be placed in all enrolled subjects and baseline 
data will be recorded for 24 hours. After this initial observation period, study participants 
will be randomized to either continue flow-triggered mechanical ventilation (CMV) (current 
standard of care) or begin mechanical ventilation with NAVA. This treatment period will 
last 5 days. After completing the first 5-day treatment period, subjects will crossover to the 
alternate mode of mechanical ventilation (CMV or NAVA) for a second, 5-day treatment 
period. The primary study outcome is the median daily, time-weighted oxygen saturation 
index ([mean airway pressure x FiO2]/SpO2). Additional measures of respiratory gas 
exchange, pulmonary mechanics, and patient comfort will also be recorded. The results of 
all study outcome measures will be compared between the 2 modes of mechanical 
ventilation with each study participant serving as his/her own control.   

 
 
 
 
 
 
 
 
 
 
vii
PROTOCOL SYNOPSE 
Study Title 
Pilot Cross-Over Trial of Neurally Adjusted Ventilatory Assist 
(NAVA) and Conventional Flow Triggered Mechanical Ventilation 
(CMV) in Severe Bronchopulmonary Dysplasia (sBPD) 
Funder 
Respiratory Therapy Department and Division of Neonatology and 
the American Respiratory Care Foundation 
Study Rationale 
Despite substantial advances in neonatal care, BPD rates are not 
improving. Most research efforts to date in neonatal lung disease 
focused on BPD prevention. As a result, insufficient investigation 
has been performed to define optimal respiratory management 
strategies for established BPD. Thus, there is no robust evidence 
base to guide ventilator management to promote lung disease 
recovering and support neurodevelopment in severe BPD. The 
pulmonary parenchyma in severe BPD is poorly suited for gas 
exchange. This in turn leads to patient-ventilator asynchrony, 
increased respiratory work, and patient discomfort. The NAVA 
mode of invasive mechanical ventilation is an emerging alternative 
to CMV that may provide better patient-ventilator interaction, gas 
exchange, and reduce work of breathing in sBPD. Although NAVA 
has shown utility in neonatal and pediatric intensive care patients, 
no randomized studies have explored this mode of ventilation in a 
cohort exclusively comprised of infants and young children with 
sBPD. The chronic, heterogeneous lung changes and high ventilator 
pressures used in sBPD distinguish this illness from other, acute 
respiratory processes encountered in the neonatal and pediatric 
intensive care units.  
Study Objective(s) 
Primary  
To determine whether invasive mechanical ventilation with NAVA, 
as compared to CMV, improves respiratory gas exchange in 
prematurely born infants and young children with sBPD.  
Secondary 
• 
Compare patient respiratory mechanics and cardiopulmonary 
stability between the two modes of ventilation 
• 
Compare patient comfort between the two modes of ventilation 
• 
Compare age and respiratory support at discharge 
Study Design 
 
Prospective, unblinded, randomized cross-over trial of 2 modes of 
mechanical ventilation 
Subject Population 
key criteria for Inclusion 
and Exclusion: 
Inclusion Criteria 
1. Gestational ages (GA) ≤ 32 weeks 
2. Current age between 36 weeks postmenstrual age (PMA) and 2 
years corrected age 

 
 
 
 
 
 
 
 
 
 
viii
3. Severe BPD (as per NIH consensus definition) diagnosed at 36 
weeks postmenstrual age 
4. Receiving invasive mechanical ventilation for ongoing lung 
disease  
5. Not expected to be ready for extubation within 10 days 
following enrollment 
6. Parental consent  
Exclusion Criteria 
1. Severe congenital anomalies 
2. Known diaphragmatic defect 
3. Current treatment with high frequency mechanical ventilation 
4. DNR Status or Futility of Care 
5. >10% leak around the endotracheal tube, 
6. Treatment with neuromuscular blockade within 72 hours prior 
to enrollment 
7. Acute respiratory instability defined as a ventilator rate 
increase >15 bpm, PEEP increase >2 cm/H2O, sustained, 
absolute FiO2 increase >20%, and/or prescribed increase in 
tidal volume >2 mL/kg within 24 hours prior to enrollment.  
Number of Subjects  
Up to 25 patients will be enrolled to produce 20 children with 
evaluable trial data. The N/IICU and the PICU at CHOP and the 
PICU at Hasbro Children’s Hospital will be the only sites for the 
trial. 
Study Duration 
Each subject’s participation will last until discharge. The active 
treatment phase of the study will last 11 days. Medical records will 
be reviewed until hospital discharge. 
The entire study is expected to last 24 months. 
Study Phases 
Screening 
 
 
24-hour Observation 
Period 
 
Study Treatment 
Period  
Participants will be identified by review of daily census logs in the 
participating ICU’s. Enrollment will be discussed with the patients’ 
primary physician before parents are approached for consent. 
 
 
Following informed consent, a NAVA catheter will be placed in all 
study subjects and baseline data will be recorded for 24 hours. 
 
After the observation period, study participants will be randomized 
to continue CMV or initiate NAVA. After receiving the randomly 
assigned mode of mechanical ventilation for 5 days, subjects will 
crossover to the alternate mode of ventilation for a final 5-day 
treatment period.  
Efficacy Evaluations 
Comparisons of primary and secondary outcomes between the two 
modes of ventilation 

  
 
 
 
 
 
 
 
ix
Safety Evaluations 
Subject safety will be monitored by through assessment of adverse 
events, vital signs, physical examinations, and laboratory data by 
the medical and study teams as well as the independent data safety 
monitoring committee. 
All study investigators and a core group or respiratory therapists 
who will care for study infants will be provided training on the 
Servo I ventilator and the NAVA mode. Clinicians responsible for 
the care of study subjects receiving the NAVA mode of ventilation 
will be trained up to the current standard for their role, as is done for 
clinicians using clinically deployed ventilators. Guidelines for 
startup and continued management, including troubleshooting 
techniques of the NAVA mode, will be available for the medical 
teams and a study investigator will be on call 24/7. Individual 
subjects will be withdrawn from the study for safety if there is an 
absolute, sustained increase in FiO2 by 20% or if the pCO2/TcO2 
increase by 25 points above baseline or to a level greater than 90 
mm Hg, for more than 2 hours while on the NAVA mode. If this 
occurs, the patient will discontinue NAVA therapy and be 
transitioned to previous CMV settings. A study investigator will 
round daily with the clinical team and be available 24/7 for 
questions. 
The overall safety of the study will be assessed with interim safety 
analyses after the completion of every 5 patients (3 times total) and 
in the event of any serious safety events. 
Statistical and Analytic 
Plan 
Summarized values for the primary and secondary outcomes will be 
compared between the two treatment arms using paired statistical 
tests (e.g. Wilcoxon signed rank tests, paired t-tests) as appropriate, 
based on the data distribution. Linear mixed effects models will be 
used to explore longitudinal change in the study outcomes (as 
continuous measures) as a function of the treatment arm. 
DATA AND SAFETY 
MONITORING PLAN 
Clinical adverse events will be monitored throughout the study 
period. There will be monthly and as needed ad-hoc study 
investigator meetings to discuss and monitor trial data and safety. 
All data will be kept confidential in accordance with HIPPA and 
CHOP policies. An independent safety monitoring committee 
inclusive of physicians from each study site will be formed to 
review any adverse events, adjudicate relatedness to the study 
procedures, and recommend trial continuation or early closure.  

 
x  
 
 
 
 
 
 
 
TABLE 1: SCHEDULE OF STUDY PROCEDURES  
Study Phase 
Screening 
Unblinded Intervention 
 
 
Observation 
Phase 
1st Mode 
Phase 
2nd Mode 
Phase 
Observation 
Study Days 
 
1 
2-6 
7-11 
12-discharge 
Informed Consent 
X 
 
 
 
 
Review Inclusion/Exclusion Criteria 
X 
 
 
 
 
Demographics/Medical History 
X 
 
 
 
X 
Vital Signs 
X 
X 
X 
X 
 
Ventilator settings/measurements/OSI 
X 
X 
X 
X 
 
Placement of Tcom (if applicable) 
 
X 
 
 
 
Placement of NAVA catheter 
 
X 
 
X 
 
Randomization  
 
X 
 
 
 
Daily Asynchrony Index 
 
X 
X 
X 
 
Daily Salivary Cortisol Levels 
 
X 
X 
X 
 
Adverse Event Assessment 
 
X 
X 
X 
X* 
 
 
 
*We will monitor for targeted adverse events that may be related to the study procedures for 72 hours after completion of the 2nd mode phase. 
.

 
 xi 
  
 
 
 
FIGURE 1: STUDY DIAGRAM 
 
 
 
 
 

 
  
 
 
 
1
1 
BACKGROUND INFORMATION AND RATIONALE 
1.1 Introduction 
Bronchopulmonary dysplasia (BPD) is a leading pediatric cause of death and disability. 
BPD affects 50% of extremely preterm infants and is a strong predictor of life-long 
cardiopulmonary and neurodevelopmental impairment.1-4 Despite substantial advances in 
neonatal care, BPD rates are not improving. Most research efforts to date in neonatal lung 
disease focused on BPD prevention. As a result, insufficient investigation has been 
performed to define optimal respiratory management strategies for established BPD. This is 
of particular importance for the 5-10% of extremely preterm infants who require prolonged 
invasive respiratory support. For this population, that comprises an increasing number of the 
infants cared for in tertiary, referral centers, there is no robust evidence to guide ventilator 
management to promote lung disease recovery and support neurodevelopment.  
The pulmonary parenchyma in severe BPD (sBPD) is poorly suited for gas exchange. The 
lung architecture often consists of large, air-trapped cystic expansions that increase dead 
space with adjacent areas of focal lung collapse and interstitial fibrosis. Small airway 
malacia, which further contributes to air trapping, directly impairs the ability of most flow-
sensing ventilators to appropriately support patient-initiated breathing. This in turn leads to 
patient-ventilator asynchrony, increased respiratory work, and patient discomfort.5,6 In 
practice, clinicians often rely on frequent doses of narcotic sedatives to suppress patient 
respiratory effort and/or high positive end-expiratory pressures (PEEP) to overcome lung 
intrinsic PEEP and enable sufficient inspiratory air flow to trigger the ventilator.7 Patient-
ventilator asynchrony can exacerbate air trapping and impair the ability to wean ventilator 
settings, resulting in prolonged exposure to invasive mechanical ventilation.8 In infants, the 
ventilator is traditionally triggered when an alteration in flow in the ventilator circuit is 
sensed.  At times, infants are either unable to generate the required flow change to trigger 
the ventilator or the insufficient airflow results in a significant delay in breath delivery. 
Greater ability to identify and support patient triggered ventilation is expected to improve 
patient-ventilator synchrony, gas exchange, and comfort.  
1.2 Name and Description of Investigational Intervention 
The Maquet Servo I ventilator has a proprietary mode of ventilation approved for use in 
infants and children called Neurally Adjusted Ventilatory Assist (NAVA). This mode 
utilizes a breath trigger based on the electrical activity of the diaphragm (Edi) instead of a 
flow or pressure trigger used by traditional modes of conventional mechanical ventilation 
(CMV). NAVA utilizes a specialized nasogastric tube imbedded with four electrode sensors 
that detect Edi.  The Edi signal is used to trigger the ventilator and determine the level of 
inflationary support provided by the ventilator.  This allows the ventilator to match, breath 
to breath, the inspiratory time and respiratory rate of the patient.  The ventilator matches the 
support it provides based off the Edi level (i.e. higher Edi leads to more support provided).  
The peak inspiratory pressure is determined by both the ventilator pressure selected by the 
clinician and value termed the NAVA level. The NAVA level is calculated as the The 
maximum Edi detected minus the minimum Edi detected. PIP is calculated as the NAVA 
level plus the PEEP: [PIP = (Edimax – Edimin)+PEEP. The delivered PIP is determined for 
each individual breath according to these paremeters.9 Importantly, NAVA doesn’t simply 

 
  
 
 
 
2
replace flow-triggered technology used by standard conventional ventilators, but rather adds 
an additional means of detecting patient respiratory effort. NAVA works on the principal of 
“first serve first” in which the ventilator triggers each breath using either the neural trigger 
or the standard flow trigger, whichever it senses first.9 A key safety feature of the NAVA 
mode is mandated clinician input of back-up ventilator settings.  In the event that the patient 
stops breathing or the electrical diaphragm signal is lost, the ventilator will automatically 
switch from the NAVA mode to the mode and settings selected for back-up ventilation by 
the clinicians. These settings can be entered to match the infant’s settings employed on the 
Draeger ventilator. In this manner, NAVA ventilations adds to standard conventional 
mechanical ventilation with traditional ventilation as an ever-present safeguard.   
1.3 Findings from Non-Clinical and Clinical Studies  
1.3.1 Clinical Studies 
1.3.1.1 Clinical Studies in Adults 
Studies conducted in adults have demonstrated safety and efficacy of the neural trigger used 
in NAVA compared to the pneumatic trigger10 and in critically ill patients showed improved 
work of breathing11,12 and reduced asynchrony.13  These early studies, however, only 
assessed the use of NAVA for short time frames (e.g. up to 3 hours) and did not include 
patients with chronic lung disease.   
Spahija et al, explored the use of NAVA compared to pressure support ventilation (PSV) in 
subjects with COPD and saw improvement in patient-ventilator synchrony.14  This study, 
however, also utilized a short study time frame of only 10 minutes in each mode. Coisel et 
al, compared NAVA and PSV in subjects who underwent abdominal surgery and monitored 
each mode for 24 hours.15 As seen in other studies, they reported an increase in variability of 
the respiratory pattern, with NAVA mode, as well as increased oxygenation.  
1.3.1.2 Clinical Studies in Children 
Although NAVA has been studied in term and preterm infants and compared with CMV 
modes, a 2017 Cochrane review of NAVA in pre-term infants found only 1 valid trial with 
endpoints examining rates of BPD, other morbidities, and mortality.16,17  This single trial 
showed that NAVA was associated with lower PIPs compared with CMV in preterm infants 
with RDS, but did not show differences in mortality or morbidity.  A number of small cross-
over trials looked at NAVA in a range of patients, from premature infants at high risk of 
developing BPD to patients with established BPD.  In all of these previous studies, NAVA 
was shown to decrease the PIP. Studies have also demonstrated better patient ventilator 
synchrony and a decrease in work of breathing, FiO2 and PaCO2 with NAVA compared to 
CMV.16-20  
Observational and interventional trials have also been performed in the pediatric ICU.  
Comparison of PSV and NAVA in a multiple cross-over study in the post-operative cardiac 
surgical population showed an improvement in patient-ventilator synchrony and decreased 
peak inspiratory pressures21. Alander et al, compared the different types of conventional 
triggers (flow and pressure) with NAVA in both pediatric and neonatal patients22. Each 
trigger type was assessed for 10 minutes.  There was a significant difference in short-term 
patient-ventilator synchrony but no difference in oxygenation parameters. The interaction 

 
  
 
 
 
3
between the patient and ventilator was investigated by Bordessoule, et al in ten infants. This 
study showed that 4.6% & 7.7% of patient efforts did not result in ventilator support during 
pressure control and PSV, respectively. There were no wasted efforts (non-supported patient 
initiated breaths) with NAVA23. Kallio et al, also showed an improvement in PIP and 
oxygenation with a reduction in need for sedative medication for non-surgical patients24.  In 
contrast, Duyndam, et al did not see a difference in comfort in relation to sedation needs or 
COMFORT scores.25 The currently available literature for the use of NAVA in children is 
limited to preterm infants with RDS with very little research concentrating on sBPD.  These 
studies are also limited to short time frames for comparisons lasting no longer than 12 hours 
and commonly comparing NAVA to PSV, a weaning mode of mechanical ventilation, and 
not to a ventilator mode providing moderate support.   
1.4 Relevant Literature and Data 
The NAVA mode of invasive mechanical ventilation is an emerging alternative to 
conventional pressure or flow triggered ventilation that may provide better patient-ventilator 
interaction, comfort, and gas exchange in severe BPD (sBPD).  There is only one study that 
looks specifically at NAVA use in infants with sBPD.  Lee et al performed a retrospective 
review of infants born prematurely that underwent tracheostomy and required mechanical 
ventilation for > 6 months.26 14 infants over a 6 year period met their definition of prolonged 
mechanical ventilation and only 9 were supported with NAVA.  In these nine infants, 
compared to the 5 infants supported with other modes, they saw a decreased use of sedation 
in children and fewer cyanotic events once patients were switched to the NAVA mode.  
Although no studies raised safety concerns with the use of NAVA in infants there are no 
prospective randomized controlled trials comparing NAVA to other modes on mechanical 
ventilation for safety and efficacy in sBPD. 
As part of our evaluation, we will compare daily salivary cortisol levels and median daily 
State Behavioral Scale (SBS) and Withdrawal Assessment Tool (WAT-1) between the two 
modes of ventilation to evaluate patient stress and comfort levels.  Salivary cortisol has been 
shown to increase in response to stress in both pre-term and term infants in multiple 
studies27 and stay elevated in response to persistent stress in multiple different disease 
processes28.  The well described adult diurnal pattern of cortisol release is absent in full term 
infants less than a month and begins to approximate the adult circadian rhythm in pre-term 
infants by 3-6 month, but may remain attenuated until age 428,29.  
1.5 Compliance Statement 
This study will be conducted in full accordance all applicable Children’s Hospital of 
Philadelphia Research Policies and Procedures and all applicable Federal and state laws and 
regulations including 45 CFR 46, CFR Parts 50, 54, 56, and 812. All episodes of 
noncompliance will be documented. 
The investigators will perform the study in accordance with this protocol, will obtain 
consent, and will report unanticipated problems involving risks to subjects or others in 
accordance with The Children’s Hospital of Philadelphia IRB Policies and Procedures and 
all federal requirements. Collection, recording, and reporting of data will be accurate and 
will ensure the privacy, health, and welfare of research subjects during and after the study.  

 
  
 
 
 
4
2 
STUDY OBJECTIVES 
The purpose of the study is to establish pilot data on the safety and efficacy of NAVA 
during invasive mechanical in infants and young children with established, severe BPD 
2.1 Primary Objective 
To determine whether invasive mechanical ventilation with NAVA, as compared to CMV, 
improves respiratory gas exchange in prematurely born infants and young children receiving 
invasive respiratory support for severe BPD.  
The primary study outcome is the median, time-weighted daily oxygen saturation index 
([mean airway pressure x FiO2]/SpO2). Secondary measures of respiratory gas exchange 
that will be evaluated are the daily median transcutaneous pCO2 levels (measured hourly) 
and the daily frequency of intermittent hypoxemic events (SpO2 < 80% for ≥ 10 seconds and 
less than 3 minutes) recorded by continuous SpO2 measurement.  
We hypothesize that NAVA compared with conventional mechanical ventilation will result in 
statistically significant reductions (p<0.05) in the median daily oxygen saturation index. 
2.2 Secondary Objectives 
To determine whether NAVA as compared to CMV, improves measures of pulmonary 
mechanics and patient comfort in prematurely born infants and young children receiving 
invasive respiratory support for severe BPD (see section 6.2 for a list of secondary study 
outcomes). 
3 
INVESTIGATIONAL PLAN 
3.1 General Schema of Study Design 
We propose a prospective, randomized cross-over trial comparing NAVA mechanical 
ventilation to CMV. After a 24-hour observation period to collected baseline Edi data, 
enrolled preterm infants and young children requiring invasive ventilation for sBPD will 
undergo two consecutive 5-day treatment periods, one while receiving CMV and the other 
while receiving NAVA (Figure 1). The treatment order will be determined by 
randomization. For each study site, the ventilator used for the observation phase and CMV 
phase of the study will be the standard flow triggered ventilator platform primarily used at 
each institution for routine clinical care. At CHOP, this is the Dräger V500 ventilator and at 
Hasboro, this is the Servo U ventilator. Edi will be continuously monitored, recorded, and 
displayed for all phases of this trial by the servo I or U ventilators, as it has the capability to 
monitor, record, and display these data while in standby mode. 
3.1.1 Screening Phase 
Potential subjects will be screened using daily census logs and the protocol inclusion and 
exclusion criteria. Male and female children born <32 weeks’ gestation, who are ≥36 weeks 
PMA and < 2 years of age at enrollment, and expected to continue receiving invasive 
mechanical ventilation for at least 11 days after enrollment will be eligible for the study.  

 
  
 
 
 
5
3.1.2 Study Observation Phase 
Prior to beginning the initial treatment phase, all subjects will undergo a 24-hour period of 
observation with an Edi catheter in place while receiving CMV as ordered by the primary 
medical team. This period will be used to establish baseline Edi (Edi peak and Edi min), 
positive inspiratory pressure (PIP), and transcutaneous pCO2 levels that will be employed in 
the study treatment phase.  
At the end of the 11-day treatment phase, a second observation phase will begin and will be 
limited to medical record review. This phase will continue until the child is discharged in 
order to ascertain age and respiratory support needs at discharge. 
3.1.3 Study Treatment Phase (start of the study intervention)  
Computer generated randomization by will be performed by the study team to determine the 
initial ventilator mode. The randomly assigned mode of ventilation will be initiated in 
accordance with accepted standardized ventilation practices for conventional mechanical 
ventilation by the BPD consult teams at each center.  These guidelines include a tidal 
volume of > 8 ml/kg and an inspiratory time sufficient to allow full inspiratory cycle as 
assessed by flow time scalars on the ventilator.  Data will be collected to fulfill the primary 
and secondary objectives.  After 5 days the subject will be switched to the second ventilator 
mode.  During each phase, the ventilator will be managed by the clinical team, but with 
close consultation from the study team and application of study guidelines for patient 
management. 
3.2 Allocation to Treatment Groups 
The initial mode of ventilation will be randomly assigned using a computer-generated 
sequence.  Investigators and clinicians will not be blinded to the ventilator mode as it is 
essential for medical management.  Every subject will be placed in both ventilator modes 
during the study to serve as their own controls. 
3.3 Study Duration, Enrollment and Number of Sites 
3.3.1 Duration of Study Participation 
The duration of the interventional phase of the study will be up to 11 days per subject, with 
1 day in observation, 5 days in the initial ventilator mode, and 5 days in the second 
ventilator mode. All subjects will be followed until discharge for safety and assessment of 
the postmenstrual age and respiratory support administered at discharge. 
3.3.2 Total Number of Study Sites/Total Number of Subjects Projected 
The study will be conducted in two intensive care units at CHOP (NI/ICU and PICU) and 
the PICU at Hasbro Children’s Hospital. 
Recruitment will stop when 20 subjects successfully complete the trial. It is expected that 
approximately 25 subjects will be enrolled to produce 20 evaluable subjects.  

 
  
 
 
 
6
3.4 Study Population   
3.4.1 Inclusion Criteria 
1) Gestational ages (GA) ≤ 32 weeks 
2) Current age between 36 weeks postmenstrual age (PMA) and 2 years corrected age 
3) Severe BPD (as per NIH consensus definition) diagnosed at 36 weeks postmenstrual age  
4) Receiving invasive mechanical ventilation for ongoing lung disease  
5) Not expected to be ready for extubation within 11 days following enrollment 
6) Parental consent 
3.4.2 Exclusion Criteria 
1) Severe congenital anomalies 
2) Known diaphragmatic defect 
3) Current treatment with high frequency mechanical ventilation 
4) DNR Status or Futility of Care 
5) >10% leak around the artificial airway, 
6) Treatment with neuromuscular blockade within 72 hours prior to enrollment 
7) Acute respiratory instability defined as a ventilator rate increase > 15 bpm, PEEP 
increase > 2 cm/H2O, sustained FiO2 increase > 20%, and/or prescribed increase in tidal 
volume > 2 mL/kg within 24 hours prior to enrollment will be excluded.  
Subjects that do not meet all of the enrollment criteria may not be enrolled. Any violations 
of these criteria must be reported in accordance with IRB Policies and Procedures.  
4 
STUDY PROCEDURES 
4.1 Screening and Commencement of Study 
The following evaluation will be done prior to the study: 
• 
Informed Consent 
• 
Medical Record Review 
4.2 Unblinded Ventilator Mode Crossover Phase  
Observation phase and Ventilation Mode crossover phases will have the same study 
procedures performed on a daily basis or less frequently as indicated.   

 
  
 
 
 
7
• Placement of NAVA catheter. Catheter will be placed prior to the baseline 
monitoring phase and will be replaced before going into the 2nd ventilator mode on 
day 7 of the study. 
• Placement of transcutaneous CO2 monitor (Tcom) (if not already in use) will occur 
prior to the monitoring phase and remain throughout the 11 days of data collection. 
• Salivary cortisol samples will be collected three times per day using a swab placed in 
the patient’s mouth to collect pooled saliva. Samples will be collected at the same 
time each day and independently analyzed for cortisol values. The 3 cortisol values 
will be averaged for the 24 hour time frame.  
• Asynchrony index will be calculated as the number of asynchrony events divided by 
the sum of the ventilator cycles and ineffective efforts for 1 minute. This will be 
determined two ways: first by physical assessment by the respiratory therapist with 
their patient/ventilator assessments every four hours and second by assessment of 
time delay or complete miss of neural trigger compared to ventilator trigger from 
ventilator waveforms. 
• Download of data from the ventilators and clinical monitoring equipment as well as 
extraction of information from the electronic medical record will be done for data 
normally documented as part of routine clinical care. 
4.3 Subject Completion/Withdrawal 
Subjects may withdraw from the study at any time without prejudice to their care.  They 
may also be discontinued from the study at the discretion of the Investigator or attending 
physician to protect the subject for reasons of safety or for administrative reasons. If the 
withdrawal occurs during the NAVA mode phase of the trial, each site will return the 
subject to a ventilator platform that is routinely used at their site, selected at the discretion of 
the treating physician. It will be documented whether or not each subject completes the 
clinical study. If the Investigator becomes aware of any serious, related adverse events after 
the subject completes or withdraws from the study, they will be recorded in the source 
documents and on the CRF. Specific subject and study stopping rules are outlines in section 
5. 
5 
STUDY EVALUATIONS AND MEASUREMENTS 
5.1 Screening and Monitoring Evaluations and Measurements 
5.1.1 Medical Record Review 
• Date of birth 
• Gender 
• Race/Ethnicity 
• Current Dosing Weight 
• Gestational age 
• Corrected gestational age at entry into study 
• Corrected gestational age at discharge 
• Birth weight 

 
  
 
 
 
8
• Current medications 
• SBS and WAT-1 Score 
• Respiratory support required at discharge 
5.1.2 Physical Examination 
Cardiorespiratory assessment including respiratory rate, auscultation, symmetry, retractions, 
nasal flaring, and asynchrony index. 
5.1.3 Vital Signs 
Vital signs for the study will be recorded from the electronic medical record and continuous 
multiparameter clinical monitors.  Any vital signs seen outside the ranges considered 
clinically normal for each subject will be reported to the medical team as standard practice.  
All bedside care team members will be aware that the subject is enrolled in the study.  BP 
will be monitored using the standard automated device and cuff that is being used currently. 
HR, Pulse oximetry, Tcom will be monitored continuously as is the standard of care for 
ventilated children in the N/IICU and PICU.  
5.1.4 Laboratory Evaluations 
• Salivary cortisol samples will be collected three times per day using a swab placed in 
the patient’s mouth to collect pooled saliva. Samples will be collected at the same 
time each day and independently analyzed for cortisol values. The 3 cortisol values 
will be averaged for the 24 hour time frame. The samples will be labeled with study 
ID#, date and time of collection and stored at -20C prior to being shipped for 
analysis.   
• Samples will be shipped on dry ice to Salimetrics SalivaLab, Attn: Kelly Henning 
5962 La Place Court, Suite 275 Carlsbad, CA 92008. 
• Salivary Cortisol testing: Samples will be thawed to room temperature, vortexed, and 
then centrifuged for 15 minutes at approximately 3,000 RPM (1,500 x g) 
immediately before performing the assay. Samples will be tested for salivary cortisol 
using a high sensitivity enzyme immunoassay (Cat. No. 1-3002). Sample test volume 
is 25 μl of saliva per determination. The assay has a lower limit of sensitivity of 
0.007 μg/dL, a standard curve range from 0.012-3.0 μg/dL, and an average intra-
assay coefficient of variation of 4.60%, and an average inter-assay coefficient of 
variation 6.00%, which meets the manufacturers’ criteria for accuracy and 
repeatability in Salivary Bioscience, and exceeds the applicable NIH guidelines for 
Enhancing Reproducibility through Rigor and Transparency.  10% of the samples 
will be run in duplicate to report an intra-assay variability.   
• Blood gas values order by the medical team for clinical care will be documented and 
trended. 
5.1.5 Ventilatory Parameters 
The following parameters will be collected and trended from the ventilator: 
• FiO2 
• RR 

 
  
 
 
 
9
• Vt 
• MAP 
• PIP 
• PEEP 
• Dynamic Lung Compliance (Crs) 
• Dynamic Lung Resistance (Rrs) 
• NAVA level 
• Edi peak and min - measured from the Edi Catheter that will remain in place during 
the 11 days of data collection 
• Pressure waveform data  
5.2 Safety Evaluation 
Subject safety will be monitored by adverse events, vital signs, physical examinations, and 
laboratory data by the medical and study team as well as the independent safety monitoring 
committee.  
Clinicians responsible for the care of study subjects receiving the NAVA mode of 
ventilation will be trained up to the current standard for their role, as is done for clinicians 
using clinically deployed ventilators (as listed in section 8.4.2). Guidelines for startup and 
continued management, including troubleshooting techniques, of NAVA mode will be 
available for the medical teams and a study investigator will round with the clinical team 
daily to provide expertise on the device/mode as well as be on call for assistance 24/7. 
Individual subjects will be withdrawn from the study for safety if an absolute increase in 
FiO2 by 20% or if the pCO2/TcO2 increase by 25 points or greater than 90 mm Hg, which 
ever is achieved first, for more than 2 hours from baseline while on NAVA mode, The 
NAVA arm of the study will be discontinued and the patient will be transitioned to previous 
CMV settings. Study investigators will be available 24 hours day when a patient is on the 
trial. 
The overall safety of the study will be assessed with interim safety analysis after the 
completion of every 5 patients (3 times total) and upon any serious safety events occurring.  
6  
STATISTICAL CONSIDERATIONS 
6.1  Primary Outcome 
The mean daily oxygen saturation index ([mean airway pressure x FiO2]/SpO2) compared 
between NAVA and conventional mechanical ventilation will be the primary study outcome. 
Oxygen saturation index is a reliable surrogate measure for oxygenation index in children 
with moderate to severe lung disease that is used clinically and in research when arterial 
blood gas PaO2 levels are not routinely available. 
6.2  
Secondary Outcome 
The following secondary study outcomes will be compared between NAVA and 
conventional mechanical ventilation treatment periods. All outcome measures will be taken 

 
  
 
 
 
10
from nursing and respiratory therapy charting in the EPIC or downloaded directly from the 
machines.   
Measures of cardiorespiratory mechanics and stability:  
(1) Measures of respiratory mechanics: hourly mean PIP, MAP, tidal volume, respiratory 
rate, FiO2, Edi (peak and min), and NAVA level. The NAVA catheter will be in place for 
the entire study (24 hour baseline and both crossover groups) for a consistent Edi 
measurement for both treatment arms and all over measures are comparable across machines 
and modes of ventilation. 
(2) The daily number of intermittent (SpO2 < 80% for ≥ 10 seconds and less than 3 minutes) 
and prolonged (SpO2 < 80% for ≥ 60 seconds) hypoxemic events recorded by continuous 
pulse oximetry.  
(3) Median hourly transcutaneous pCO2 levels 
(4) Median daily Q4-6 hour OSI  
(5) Dynamic lung compliance.  
Patient Comfort and sedation exposure:  
(1) Median daily State Behavioral Scale (SBS) and Withdrawal Assessment Tool (WAT-1) 
scores. Both scoring systems are validated measures of subject comfort and sedation 
requirements used in the CHOP intensive care units.  
(2) Daily frequency and total daily dose (mg/kg) of sedation medications.  
(3) Mean daily asynchrony index calculated as the number of asynchrony events divided by 
the sum of the ventilator cycles and ineffective efforts. 
(4) Salivary cortisol will be collected three times per day and averaged by the respiratory 
therapist.  The daily average will be assessed and compared as a marker for patient stress on 
the different ventilator modes. 
Long Term Outcomes 
(1) Postmenstrual age at discharge 
(2) Respiratory support required at discharge 
 
6.3  Statistical Methods 
6.3.1 Analysis Plan  
Subject demographic and clinical characteristics will be summarized with standard 
descriptive statistics. Summarized values for the primary and secondary outcomes will be 
compared between the two treatment arms using paired statistical tests (Wilcoxon signed 
rank tests, paired t-tests) as appropriate based on the data distribution. Crossover treatment 
trials traditionally have a washout phase with no treatment in order to determine if all 
outcome measures are reflective of the current treatment and not remnants of the prior 
treatment.  Ventilation studies are not able to have a washout phase, as it is not possible to 
stop providing ventilator support for a set timeframe.  In addition, the timeframe needed for 

 
  
 
 
 
11
a washout is unknown for change in ventilation modes. For the primary analysis, all data 
will be included in the analysis.  As a secondary analysis we will selectively exclude the first 
4, 8, and 12 hours of data to determine what washout phase may make a difference in data 
analysis.  This timeframe will be considered a washout out phase to ensure all data collected 
for each mode of ventilation is related to this mode and not residual effect of the prior mode.  
Linear mixed effects models will be used to explore longitudinal change in the study 
outcomes (as continuous measures) as a function of the treatment arm. These models are 
well suited for repeated measurements in longitudinal studies and are capable of handling 
unbalanced data if present (e.g. due to drop-out). Random effects terms for both the intercept 
and slope will be evaluated to account for potential subject specific deviation from the 
cohort’s overall average baseline (intercept) and change over time (slope). Model fit will be 
assessed using the Akaike Information Criterion.  
6.4   Sample Size and Power 
We will enroll up to a total of 25 subjects to 
generate 20 subjects will have adequate evaluable 
data, during a proposed 24 month study period. 
The Table shows the number of patients required, 
with 80% power and α=0.05, to detect a range of 
within subject differences in mean oxygen 
saturation index (at various within subject 
standard deviation [SD] levels) between the two 
treatment periods. As shown, the proposed sample 
size of 20 subjects will provide sufficient power to detect a range of clinically meaningful 
differences in oxygen saturation indices with statistical significance.  
 
6.5    Interim Analysis 
Interim analysis for safety will be performed after every 5 subjects are completed to 
determine the safety and validity of the ventilator management guidelines by the safety 
monitoring committees at each site. 
7  SAFETY MANAGEMENT 
7.1 Clinical Adverse Events 
Clinical adverse events (AEs) will be monitored throughout the study.  
7.2 Adverse Event Reporting 
Study procedures that are greater than minimal risk are the use of the servo I ventilator and 
the NAVA mode at CHOP. While the servo ventilator is approved for clinical care at CHOP, 
the NAVA mode is not widely used and may be unfamiliar to some of the medical staff. 
Section 5.2 and 8.4.2 more explicitly discuss the risks and mitigation of these risks.  
Targeted adverse event monitoring will occur from study start to 72 hours after the 
intervention phase has concluded.  
Table. Minimal detectable difference in 
mean oxygen saturation index 
 
Detectable difference 
SD 
1 
1.5 
2 
3 
0.25 
4 
3 
3 
3 
0.5 
7 
5 
4 
3 
1 
18 
10 
7 
5 
1.5 
38 
18 
11 
7 
2 
65 
30 
18 
10 
3 
144 
65 
38 
18 

 
  
 
 
 
12
Although no SAEs are expected, if any unanticipated problems related to the research 
involving risks to subjects or others happen during the course of this study (including SAEs) 
they will be reported to the IRB in accordance with CHOP IRB SOP 408: Unanticipated 
Problems Involving Risks to Subjects. AEs that are not serious but that are notable and 
could involve risks to subjects will be summarized in narrative or other format and 
submitted to the IRB at the time of continuing review.  
8 
 STUDY ADMINISTRATION 
8.1 Treatment Assignment Methods 
8.1.1 Randomization 
Computer generated randomization will determine the initial mode of mechanical 
ventilation. There will be 1 randomization scheme for the entire study (to be used by both 
sites) to ensure equal allocation of each ventilation mode as the starting mode.  Investigators 
and clinicians will not be blinded to the mode of ventilation as this information is essential 
for patient management and is easily discovered. However, blinded data analysis will be 
performed.   
8.2 Data Collection and Management 
The information collected will be entered into the password protected computerized 
database REDCap and house on the CHOP server. Confidentiality will be ensured from 
abstraction through analysis by utilizing the HIPPA functions in REDCap. To ensure 
security, a copy of the data collected will be saved in a Research share drive on the CHOP 
server with only study team members having access. Data will be downloaded from the 
ventilators and monitoring devices and saved to the research share drive by study ID 
number.  All Identified data will be maintained and destroyed in compliance with CHOP 
Policy A-3-9. 
Saliva specimens transferred for analysis of cortisol levels will be done under material 
transfer and data use agreements.  Saliva specimens will only be marked with study ID 
number and day of sample.  No identifiable information will be transferred with the 
specimens. 
8.3 Confidentiality 
All data and records generated during this study will be kept confidential in accordance with 
Institutional policies and HIPAA on subject privacy and that the investigator and other site 
personnel will not use such data and records for any purpose other than conducting the 
study. 
No identifiable data will be used for future study without first obtaining IRB approval. The 
investigator will obtain a data use agreement between the provider (the PI) of the data and 
any recipient researchers (including others at CHOP) before sharing a limited dataset.  

 
  
 
 
 
13
8.4 Regulatory and Ethical Considerations 
8.4.1 Data and Safety Monitoring Plan 
Clinical adverse events will be monitored throughout the study period. There will be 
monthly and as needed ad-hoc meetings among the study investigators to discuss and 
monitor data and safety. All data will be kept confidential in accordance with HIPPA and 
CHOP policies. An independent safety monitoring committee (DSMC) will be formed to 
review any adverse events that occur and determine if they are related to the study or the 
natural course of this critical illness. The DSMC will have a representative make up of 3 
physicians represented by each specialty involved with these patients (neonatologist, 
pediatric intensivist, and pediatric pulmonologist). The DSMC will meet as needed to 
discuss patient specific concerns as well review data at the planned interim analysis after 
every 5 patients. 
CHOP PI will monitor and review the study progress, subject safety, and the accuracy and 
security of the emerging data at CHOP, and will report any adverse events in accordance 
with the FDA regulations and IRB policies. 
8.4.2 Risk Assessment 
The risks in this study associated with passing a second tube into the esophagus (the NAVA 
catheter) for research purposes is minimal, with a low probability of associated harm. The 
risk of inserting this tube for research purposes is no greater than inserting a feeding tube or 
temperature catheter. The insertion of these devices for clinical purposes is performed by 
nursing staff and is done frequently in the NI/ICU and PICU for almost every patient. The 
risk of esophageal perforation from the catheter used for Edi measurements is the same as 
that for routine insertion of feeding tubes done at the bedside and is extremely rare. The 
treatment for this complication consists of withdrawal of the tube and a course of antibiotics 
as the perforation heals naturally. 
The proper positioning of the NAVA catheter will be confirmed with a positioning 
identification software on the Servo I ventilator. There will be continuous monitoring of 
vital signs throughout the study in accordance with unit standards. A respiratory therapist 
specially trained in NAVA mode will care for the study patient 24 hours a day and a study 
physician will be available for consultation throughout the study to ensure safety and 
comfort of the patient and consultation for any ventilator adjustments. NAVA is an FDA 
approved mode of ventilation for subjects currently available and used commonly in 
children with other disease processes routinely at other hospitals. This mode is commonly 
used at other hospitals for sBPD and other diseases; however, the efficacy of its use 
compared to conventional ventilation has not been adequately studied. 
To measure the transcutaneous CO2, a probe is placed on the skin in a fleshy area of the 
body and it heats the skin.  Often times a temporary red mark is left when the probe is 
removed and there is a small chance of burning of the skin if the probe is left in place for too 
long. For this reason, nursing and respiratory therapy staff routinely rotate the position of the 
probe. 

 
  
 
 
 
14
For CHOP site only (as Hasboro site already used Servo U ventilators and the NAVA 
mode): There is a risk to the introduction of a less familiar mode of ventilation that is not 
widely used at CHOP. Lack of knowledge and expertise by the clinical team on the use of 
this mode can lead to decompensation in the respiratory status of the patient (i.e. reduction 
in SpO2, increase in CO2, increased heart rate, increase in work of breathing, and cardio 
respiratory arrest, and death). The risk of use of this mode is the same as the use of any of 
the modes of ventilation that are not widely used but on the multitude of ventilation devices 
available at CHOP. Each ventilator has approximately 12 modes of ventilation that can be 
used with only about 4 or 5 that are widely used. As an example, The Drager V500 
ventilator, the primary ventilator platform at CHOP, has 14 modes and only 6 of them are 
commonly used in all ICU’s. To assist in minimizing this risk to subjects, all clinical staff 
members that will care for these subjects will be trained on the use of the Servo I ventilator 
in accordance with the standards of ventilator training for their role.  The current standard 
for each roll is:  
• Nursing – in-servicing and hands on training limited to modes, reading of settings 
and monitoring parameters, adjustment of FiO2, and alarm silence 
• Physicians/FLC’s – in-servicing on modes, reading of setting and monitoring 
parameters, and ordering 
• Respiratory Therapists – in-servicing on modes, ventilator functionality, patient set-
up, setting of parameters and alarms, reading of monitoring parameters, 
troubleshooting, and cleaning completed with competency check off  
Only trained and certified respiratory therapists will be assigned to care for patient on study 
24/7. Guidelines for escalation and de-escalation of care will be available at the bedside of 
all subjects. A study investigator will provide a physical assessment of the subject and round 
daily with the clinical team to provide expertise on the mode of ventilation as well as be 
available 24/7 for questions.  Additionally, when the subject is in the NAVA mode arm of 
the study, the Drager ventilator will remain in the patient room and be ready for immediate 
use if needed.  The medical team will always have the option for safety or preference 
reasons to transition the subjects back to the standard Draeger ventilator used for routine 
clinical care. An additional safety feature of the NAVA mode is the mandated input of back-
up ventilation settings as described in section 1.2 of the protocol.  
Collection of salivary cortisol presents no more than minimal risk as it is less invasive than 
the mouth care these children receive on a daily basis 
8.4.3 Potential Benefits of Trial Participation 
There are no direct benefits to the subject for participating in the study. There are benefits 
for future patients with BPD to assist with determining the most effective ventilatory 
strategies for children with sBPD.  
8.4.4 Risk-Benefit Assessment 
The risk of participation in the study is a slight increase over minimal risk.  The participants 
will be closely monitored for any potential adverse effects of the different ventilation mode 
by clinicians with experience using the servo ventilator and NAVA at other institutions.  The 
children will not receive any direct benefit, however this study will assist us in gaining a 

 
  
 
 
 
15
better understanding of what role, if any, NAVA can play in the treatment of children with 
severe BPD in the future.    
8.5 Recruitment Strategy 
All subjects will be recruited from the CHOP N/IICU and PICU and Hasboro Children’s 
Hospital PICU. Unit census documents will be reviewed weekly to identify possible 
subjects. For subjects likely to be eligible, attending and respiratory therapist records will be 
further reviewed to assess for eligibility (only the number of subjects screened for eligibility 
and no specific subject level data will be recorded prior to informed consent). The 
Investigator or a designated study team member will confirm eligibility with the potential 
subject’s attending physician and request permission to approach the parent(s) or 
guardian(s). If appropriate, the parent(s) or guardian(s) of eligible subjects will be 
approached and details of the study will be discussed. If interested, the parent(s) or 
guardian(s) will be invited to participate. Study personnel will then review the information 
in the consent form, answer any questions, and obtain informed consent. Only 2 participants 
will be allowed in the trial at the same time due to the number of Servo I ventilators 
available or use. 
8.6 Informed Consent/Assent and HIPAA Authorization 
After determining eligibility and obtaining permission from the attending physician, a study 
team member will contact a potential participant’s parent(s) or guardian(s) to obtain 
informed consent and HIPAA authorization. The consent discussion will be conducted in the 
NICU in a private setting (e.g. at the bedside, in a private meeting room) where possible, or 
via telephone or video conference. A study team member will describe the goals and 
procedures involved in the study. Parent(s) or guardian(s) will be provided the opportunity 
to ask questions about the study and to discuss the study with their family, friends, and/or 
other medical professionals. Before any study procedures take place, the consent form must 
be signed by a legally acceptable surrogate and the investigator-designated research 
professional obtaining the consent. The consent form will be signed in paper copy form or 
electronically in REDCap. The parents will be permitted to take as much time as they need 
to make a decision. The investigators will be available to answer any questions or concerns 
about the study and to ensure that the parent/guardian signing the consent document 
comprehends the nature of the study, the study procedures and the risks and benefits of 
participation. Entry into the study will not be coerced. Study procedures will not proceed 
without documentation of consent. Also, HIPAA Authorization will be included as a 
combined consent-authorization document. The Part 11 compliant version of REDCAP 
eConsent will be used for consenting.  
Parents/guardians with limited English proficiency will utilize a consent process that 
includes verbal consent conversation with a translator of their primary language and the use 
of one of the approved short forms. LEP subjects with a short form available in their 
preferred language may provide consent in person. The study PI is familiar with the IRB 
stipulations related to this process for obtaining consent. The ORC job aid process for 
consenting will be followed. 

 
  
 
 
 
16
8.6.1 Waiver of Assent 
Assent is to be waived under 45 CFR 46.408, as the capability of all of the children is so 
limited that they cannot reasonably be consulted. 
 
9 
PUBLICATION 
The study investigators plan to publish the findings of this study in a peer-reviewed 
journal. Any results shared at conferences or in papers will not contain identifiable 
patient information. 
 
10 REFERENCES 
1. Jensen EA, Schmidt B. Epidemiology of bronchopulmonary dysplasia. Birth Defects 
Res A Clin Mol Teratol 2014;100(3):145-157. 
2. Fawke J, Lum S, Kirkby J, et al. Lung function and respiratory symptoms at 11 years in 
children born extremely preterm: The epicure study. Am J Respir Crit Care Med 
2010;15(182):237-245. 
3. Murray CJL, Atkinson C, Bhalla K, et al. The state of us health, 1990-2010: Burden of 
diseases, injuries, and risk factors. JAMA 2013;310(6):591-608. 
4. Murray C, Lopez A. Measuring the global burden of disease. N Engl J Med 
2013;369(5):448-457. 
5. Rosan RC. Hyaline membrane disease and a related spectrum of neonatal 
pneumopathies. Perspect Pediatr Pathol 1975;2:15-60. 
6. Stocker JT. Pathologic features of long-standing "healed" bronchopulmonary dysplasia: 
a study of 28 3- to 40-month-old infants. Hum Pathol Sep 1986;17(9):943-961. 
7. Napolitano N, Jalal K, McDonough JM, et al. Identifying and treating intrinsic PEEP in 
infants with severe bronchopulmonary dysplasia. Pediatric Pulm March 2019; Epub 
ahead of print. 
8. Thille AW, Rodriguez P, Cabello B, Lellouche F, Brochard L. Patient-ventilator 
asynchrony during assisted mechanical ventilation.  Intensive care med 2006;32:1515-
1522. 
9. Sinderby C, Navalesi P, Beck J, Skrobik Y, Comtois N, Friberg S, Gottfried SB, 
Lindstrom L. Neural control of mechanical ventilation in respiratory failure. Nat Med 
1999;5:1499-1436. 
10. Sinderby C, Beck J, Spahija J, de Marchie M, Lacroix J, Navalesi P, Slutsky AS. 
Inspiratory muscle unloading by neutrally adjusted ventilatory assist during maximal 
inspiratory efforts in healthy subjects. CHEST 2007;131:711-717. 
11. Brander L, Leong-Poi H, Beck J, Brunt F, Hutchinson SJ, Slutsky AS, Sinderby C. 
Titration and implementation of neutrally adjusted ventilatory assist in critically ill 
patients. CHEST 2009;135:695-703. 
12. Schmidt M, Demoule A, Cracco C, Gharbi A, Fiamma MN, Straus C, Dugut A, 
Gottfried SB, Similowski T. Neurally adjusted ventilatory assist increases respiratory 
variability and complexity in acute respiratory failure. Anesthesiology 2010;112(3):670-
681. 

 
  
 
 
 
17
13. Colombo D, Cammarota G, Bergamaschi V, De Lucia M, Della Corte F, Navalesi P. 
Physiologic response to varying levels of pressure support and neutrally adjusted 
ventialtory assist in patient with acute respiratory failure.  Intensive care med 
2008;34:2010-1018. 
14. Spahija J, de Marchie M, Albert M, Bellemare P, Delisle S, Beck J, Sinderby C. 
Patient-ventilator interaction during pressure support ventilation and neutrally adjusted 
ventilatory assist. Crit care med 2010;38(2):518-526. 
15. Coisel Y, Chanques G, Jung B, Constantin JM, Capdevila X, Matecki S, Grasso S, 
Jaber S. Neurally adjusted ventilatory assist in critically ill postoperative patients: a 
crossover randomized study. Anesthesiology 2010;113:925-935. 
16. Rosser TE, Hunt KA, Shetty S, Greenough A. Neurally adjusted ventilatory assist 
compared to other forms of triggered ventilation for neonatal respiratory support. 
Cochrane Database of Systematic Reviews, 2017. 
17. Kallio M, Koskela U, Peltoniemi O, Kontiokari T, Suo-Palosaari M, Saarela T. 
Neurally adjusted ventilatory assist (NAVA) in preterm newborn infants with 
respiratory distress syndrome – a randomized controlled trial. Euro J Ped 
2016;175(9):1175-1183. 
18. Rosterman, JL, Pallotto EK, Truog WE, Escobar H, Meinert KA, Holmes A, Dai H, 
Manimtim WM. The impact of neutrally adjusted ventilatory assist mode on respiratory 
severity score and energy expenditure in infants: a randomized crossover trial. J 
Perinatology 2017;38(1):59-63. 
19. Shetty S, Hunt K, Peacock J, Ali K, Greenough A. Crossover study of assist control 
ventilation and neutrally adjusted ventilatory assist. Euro J Pediatr 2017;176(4):509-
513. 
20. Lee J, Kim HS, Jung YH, Shin SH, Choi CW, Kim EK, Kim BI, Choi JH. Non-invasive 
neutrally adjusted ventilatory assist in preterm infants: a randomized phase II crossover 
trial. Arch Dis Child Fetal Neonatal Ed 2015;100(6):F507-513. 
21. Bengtsson JA, Edberg KE. Neurally adjusted ventilatory assist in children: A 
observational study. Pediatr Crit Care Med 2010;11(2):253-257. 
22. Alander M, Peltoniemi O, Pokka T, Kontiokari T. Comparison of pressure-, flow-, and 
NAVA-triggering in pediatric and neonatal ventilatory care. Ped Pulm 2012;47:76-83. 
23. Bordessoule A, Emeriaud G, Morneau S, Jouvet P, Neck J. Neurally adjusted 
ventilatory assist improves patient-ventilator interaction in infants as compared with 
conventional ventilation. Ped research 2012;72(2):194-202. 
24. Kallio M, Peltoniemi O, Anttila E, Pokka T, Kontiokari T. Neurally adjusted ventilatory 
assist (NAVA) in pediatric intensive care – a randomized controlled trial. Ped Pulm 
2015;50:55-62. 
25. Duyndam A, Bol BSP, Kroon A, Tibboel D, Ista E. Neurally adjusted ventilatory assist: 
assessing the comfort and feasibility of use in neonates and children. Nursing in Crit 
Care 2012;18(2):86-92. 
26. Lee J, Kim HS, Jung YH, Choi CW, Jun YH. Neurally adjusted ventilatory assist for 
infants under prolonged ventilation. Pediatrics International 2017;59(5):540-544. 
27. Morelius E, He H-G, Shorey S. Salivary cortisol reactivity in preterm infants in 
neonatal intensive care: an integrative review. Int J of Environ Res Pub Health 
2016;13(3):337-351. 

 
  
 
 
 
18
28. Jessop DS, Turner-Cobb JM. Measurement and meaning of salivary cortisol: a focus on 
health and disease in children. Stress 2009;11(1):1-14. 
29. Gunnar MR, Donzella B. Social regulation of the cortisol levels in early human 
development. Psychoneuroendocrinology 2002;21(1-2):199-220.