Neurally Adjusted Ventilatory Assist (NAVA) Versus Conventional Biphasic Positive End Expiratory Pressure (BiPAP) Non-Invasive Respiratory Support in Infants Following Congenital Heart Surgery
Phase: NA
Conditions: Respiratory Failure
Sponsor: Children's Hospitals and Clinics of Minnesota

 
 
 
 
 
 
 
 
 
 
 
Neurally Adjusted Ventilatory Assist (NAVA) versus 
Conventional Biphasic Positive End Expiratory Pressure 
(BiPAP) Non-Invasive Respiratory Support in Infants 
Following Congenital Heart Surgery 
 
NCT # 03180385 
 
Document Date: 01/10/2018 
 
 
 
 
 
 
 
 
 
 
 
 

     McGuire, Gretchen 
                                                                                                                            
 
Version Date: 01/10/2018 
 
Research Protocol 
 
1. Study Team 
PI: Gretchen McGuire, RN, MSN, CPNP-AC 
Co-PI: Robert Horvath-Csongradi, MD 
Co-Is: Steve McDonald, RN, MSN, CPNP-AC 
            David Overman, MD 
            Frank Moga, MD 
            Robroy MacIver, MD, MPH 
            Charles Kauzlarich, RRT-NPS 
Study Coordinator(s): Mark Lo Galbo, MPH 
 
 
          Melissa Buescher, MPH 
 
2. Project Title 
Neurally Adjusted Ventilatory Assist (NAVA) versus Conventional Biphasic Positive End 
Expiratory Pressure (BiPAP) Non-Invasive Respiratory Support in Infants Following Congenital 
Heart Surgery 
 
3. Introduction 
Background/Significance 
Mechanical ventilation is often necessary in the care of critically ill pediatric patients, but is not 
without risk. Traditional and newly emerging modalities of respiratory support operate under the 
same goals: optimize gas exchange without causing lung damage or discomfort to the patient. 
However, it has been estimated that around 40% of mechanically-ventilated pediatric patients 
experience complications related to their respiratory support (1, 2). Complications can include but 
are not limited to atelectasis, post-extubation stridor, pneumothorax, tissue damage, ventilator-
associated pneumonia, tracheal edema, or chronic lung disease. 
 
Over the years, an increased understanding of how a child’s physiology interacts with a 
ventilation system has led to improved technologies. Whereas traditional ventilation modalities 
such as endotracheal intubation is invasive and can lead to tracheal damage with prolonged use 
(3), non-invasive ventilation (NIV) modalities avoid the risks associated with tracheal intubation. 
In addition, NIV can be used at an earlier stage compared to tracheal intubation, and facilitates 
gradual weaning when used intermittently (4). Two modalities that are widely used in intensive 
care units are continuous positive air pressure (CPAP) and bilevel positive air pressure (BiPAP). 
Both of these modalities operate using positive airway pressure to keep the trachea open. CPAP 
machines are set to deliver a continuous stream of air, while BiPAP machines offer a different 
level of pressure for inhalation versus exhalation. Collectively, use of these modalities and their 
benefits are well-documented, including improved gas exchange, decreased respiratory and heart 
rate, and decreased inspiratory work of breathing (5-8). Building on these strengths, neurally 
adjusted ventilator assist (NAVA) is emerging as an alternative form of the bi-level NIV with 
application in multiple settings. 
 
With NAVA support, delivery of positive pressure is based on the electrical activity of the 
diaphragm (Edi) via a nasogastric (NG) catheter that is placed on the phrenic nerve, which runs 
along the esophagus. This concordance between the Edi and NAVA lends itself to synchrony 
between the patient and ventilator, as well as respiratory support that is proportional to the neural 
effort of the patient (9). Synchronous ventilation support results in decreased neural drive and 

     McGuire, Gretchen 
                                                                                                                            
 
Version Date: 01/10/2018 
improved comfort in intubated patients (10, 11). Prior research has examined the use of NAVA in 
different patient settings, most notably the PICU and NICU as summarized in Table 1. These 
studies suggest NAVA may contribute to decreased sedation needs (12), improved synchrony (10, 
13, 14), improved breath-to-breath mechanical variability (10), increased patient comfort (10), 
and reduction of wasted breathing efforts (13). In these populations, evidence supports the safety 
and feasibility of NAVA (12, 15). 
Table 1. Selected prior NAVA studies in the PICU or NICU 
While many studies have examined NAVA in the PICU and NICU, there is a paucity of research 
in the cardiovascular intensive care unit (CVICU) setting. PICU and NICU patients often are 
critically ill with diseased or malfunctioning lungs, but relatively healthy hearts. Conversely, 
CVICU patients have abnormal hearts with relatively healthy lungs. Given the implications for 
improved cardiopulmonary interactions (16), NAVA could be beneficial in the CVICU. The use 
of NAVA in the pediatric CVICU has been described in one article, which compared the use of 
cPAP versus NAVA in infants  <  5 kg following postoperative extubation. The 2015 randomized 
cross-over trial found that the synchronization rate using NAVA was 99.3% for all respiratory 
cycles, and EAdi measurements suggest that NAVA decreased the work required to breathe more 
quickly than nasal cPAP (17). This study focused on proximal measurements of NAVA 
effectiveness, but more research is needed to understand how NAVA affects the clinical course of 
CVICU patients. To the investigator’s knowledge, no studies to date have examined clinical 
outcomes in pediatric patients postoperatively in the CVICU. Understanding clinical outcomes 
following NAVA use could further inform use of the relatively new technology in this clinically 
complex patient population. 
 
NAVA has recently been adopted for non-invasive respiratory support in the Children’s Hospitals 
and Clinics of Minnesota CVICU, the cardiovascular care center (CVCC). Close to 10% of 
CVCC post-operative patients receive a form of bi-level NIV support, either NAVA or BiPAP. 
The frequency of NIV use in neonates (0 to 28 days of age) can be 30% or higher. We propose a 
randomized study to compare clinical outcomes following use of NAVA versus BiPAP in CVCC 
patients following cardiac surgery. Specifically, we will compare duration of NIV, duration of 
sedation, and hospital length of stay. 
 
Research Question 
Is the use of synchronized biphasic support with NAVA associated with shorter duration of non-
invasive respiratory support, less sedation requirements, and reduced hospital length of stay 
compared to conventional BiPAP? 
Reference 
Setting 
Design 
Intervention 
Results 
Kallio et 
al 2014 
PICU 
Randomized 
controlled trial 
Conventional ventilation (CV) 
or NAVA 
Ventilation duration: 3.3hrs NAVA and 6.6hrs 
CV (P=0.17); Sedation amount: 0.80units/hr 
NAVA and 2.23units/hr CV (P=0.03, excluding 
postoperative patients)  
Ducharme
-Crevier et 
al 2015 
PICU 
Non-
randomized, 
Crossover 
Conventional NIV (CNIV) 
[30mins], NAVA [60mins], 
CNIV [30mins] 
Asynchrony index: 8% NAVA and 27/32% 
CNIV (P=.05); Wasted efforts: 0% NAVA and 
12/6% CNIV (P<.01) 
De la 
Olivia et 
al 2012 
PICU 
Non-
randomized, 
Crossover  
Conventional PS ventilation 
[10mins], optimized PS 
[10mins], NAVA [10mins], 
optimized PS [10mins] 
Asynchrony index: 2.0% NAVA and 8.5/7.5% 
optimized PS (P=0.017/0.008); COMFORT 
score: 15 NAVA and 18/17.5 optimized PS 
(P=0.0125/0.039) 
Lee et al 
2015 
NICU 
Randomized, 
Crossover 
Conventional PS ventilation 
[5mins], NAVA [5mins] 
Trigger delay: 35.2ms NAVA and 294ms PS 
(p<0.001); Inspiratory time in excess: 32.3% 
NAVA and 294.6% PS (p=0.001) 

     McGuire, Gretchen 
                                                                                                                            
 
Version Date: 01/10/2018 
 
4. Study Design and Methodology 
Aim 1: To assess whether the use of neurally adjusted ventilator assist (NAVA) is associated 
with a shorter duration of non-invasive respiratory support compared to conventional BiPAP. 
Aim 2: To assess whether the use of neurally adjusted ventilator assist (NAVA) is associated 
with less sedation requirements compared to conventional BiPAP. 
Aim 3: To assess whether the use of neurally adjusted ventilatory assist is associated with 
reduced hospital length of stay compared to conventional BiPAP. 
Hypothesis: Synchronized biphasic support with NAVA will be associated with shorter duration 
of non-invasive respiratory support, less sedation requirements, and reduced hospital length of 
stay. 
 
Overview/Scope 
Study Design 
This will be a prospective randomized study comparing outcomes of pediatric patients who are 
treated with NAVA versus BiPAP respiratory support following cardiac surgery. Subjects will 
include pediatric CVCC patients who undergo cardiac surgery from October 2016 through 
October 2017 and who are up to 12 months of age. As patients recover from cardiac surgery, they 
are extubated and may require further respiratory support. If so, they receive CPAP support and 
then are transitioned to one of two modalities: either NAVA or BiPAP support. Both modalities 
are routinely used in the Children’s CVCC, and the investigators will compare if one modality 
produces more favorable outcomes than the other. Following CPAP, enrolled subjects will be 
randomized to receive either NAVA or BiPAP, and their remaining clinical course will follow 
standard care. Specific measures following initiation of respiratory support will be collected, in 
addition to characteristics of the operative procedure and patient diagnoses. The study aims to 
compare duration of respiratory support, sedation requirements, and hospital length of stay 
between the two modalities.  
 
Time Frame/Duration 
This study will be conducted over an 18-month period to allow for subject enrollment, data 
collection, analysis, and manuscript preparation. 
Activity 
 
 Month 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
IRB approval 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Recruitment/enrollment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data collection/ chart abstraction 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

     McGuire, Gretchen 
                                                                                                                            
 
Version Date: 01/10/2018 
Analysis 
Sample Size 
We will enroll all consecutive patients who are eligible for inclusion in the 12-month enrollment period 
and consent to participation, up to 40 patients. An interim analysis will be performed after 20 patients are 
enrolled to assess means and variance of the primary outcomes, and reassess sample size. 
Analytic Approach 
Exploratory analysis methods will be used to describe the enrolled patient population, including mean and 
standard deviation for continuous variables such as length of hospital stay, sedation needs, and intubation 
as well as frequency and percentage for categorical variables such as STAT score and type of non-
invasive PPV.  
 
For the continuous outcomes of interest (duration of non-invasive respiratory support, length of hospital 
stay and sedation needs), either a two-sample t-test or non-parametric Mann-Whitney U test will be used 
to compare those patients who received NAVA or BiPAP. For categorical variables, either a chi-square 
test or Fischer’s exact test will be used to compare the two groups. Additional regression analysis will 
adjust for procedure severity. 
 
Statistical significance will be defined as p < 0.05. 
 
5.  Subjects 
Subjects 
We plan to enroll 40 subjects 0 to 12 months of age at time of cardiac surgery over a 1 year period. 
Identification of Subjects, Recruitment, and Enrollment  
Potential subjects will be identified by monitoring the cardiovascular surgery schedule, and eligibility will 
be confirmed by the provider. Patients who meet all of the inclusion criteria and none of the exclusion 
criteria will be approached for consent by study staff. Not all cardiac patients receive NIV support 
postoperatively, and the decision to provide NIV support is not made by the provider until after the 
surgery. This will happen either while the patient is intubated, or immediately following extubation. 
Written informed consent will be sought from parents/guardians. Assent will not be sought in this young 
patient population. Patients who enroll will be assigned a unique study ID. A log of enrolled subjects will 
be maintained, and will only be accessible by approved study staff. The target enrollment is 40 patients. 
Inclusion Criteria:  
 
Postoperative cardiac surgery patients admitted to the CVCC  
 
Recommended for NIV respiratory support following extubation, per provider discretion 
 
0-12 months of age 
 
Exclusion Criteria:  
 
Tracheostomy in place at time of cardiac surgery 
 
Chronic lung disease 
 
Pre-operative non-invasive respiratory support 
 
6.  Study Procedures 
Data Requirements 
The data elements will be collected by the research study staff from the subject’s electronic medical 
record. These will include: 
Manuscript preparation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

     McGuire, Gretchen 
                                                                                                                            
 
Version Date: 01/10/2018 
 
Demographic Data (name, date of birth, age at admission, admission date/time, cardiac diagnosis, 
comorbidities) 
 
Operative Data (surgeon, date of procedure, intubation/extubation date/time, date/time returned to 
CVCC) 
 
Adverse Event Information (description of event and day post-cardiac surgery that the event(s) 
took place) 
 
Medication Data (daily amounts of dexmedetomidine, fentanyl (total fentanyl and boluses of pca 
fentanyl), midazolam, morphine, lorazepam for up to 14 days postoperatively, date/time patient is 
on/off the above medications) 
 
Post-Operative Respiratory Support Data (type of non-invasive respiratory support used, 
date/time on off CPAP, date/time on/off biPAP/NAVA) 
 
Pain and Sedation Score Data (daily FLACC/SBS scores for up to 14 days postoperatively) 
 
Discharge Data (discharge date/time, length of hospital stay, survival at discharge, date/time of 
death [if applicable], cause of death [if applicable]) 
 
Visit Schedule  
Eligible patients will be recruited during their admission to the CVCC. Upon enrollment, patients will be 
randomized to receive either NAVA or BiPAP. What respiratory modality the patient will receive will be 
determined by drawing a slip of paper from a sealed envelope. Following randomization and provision of 
respiratory support, patient care will be per standard care. Patient data will be only collected for the 
reference admission period. There will be no follow-up visits or activities required of the patient for this 
study following enrollment. 
 
Drug/Device, Handling, Storage (If Applicable) 
All devices in this study are currently used and stored in the CVCC. They will continue to be used as per 
CVCC SOPs. 
 
7. Risks/Benefits 
 
Potential Risks 
Subjects will be randomized to respiratory support treatments that are already incorporated into standard 
care. The potential risks from these treatments are no more than those experienced as part of standard 
care. There is a risk associated with privacy of personal health information, and there is a risk of breach of 
confidentiality. 
 
Methods to Minimize Risks 
Both NAVA and BiPAP are non-invasive modalities that are safely used in standard care. Providers will 
follow SOPs for the use of NAVA and BiPAP support to minimize risks. If complications occur, standard 
care will be provided and patients will be treated accordingly. Electronic data will be stored on secure 
password-protected computers in limited access files, in a locked office suite. Any paper records will be 
stored in locked cabinets that only approved study staff have access to. This is a single-site study, and no 
identifiable patient data will be shared outside of the IRB-approved study staff. Any results from the 
study will be published in aggregate form, preventing any individual patient’s data from being identified.  
 
Potential Benefits 
The subjects will not gain added benefit directly from this study, since the treatments provided will be 
consistent with standard care. This study will contribute to understanding how outcomes may vary with 
different modalities of respiratory support in this patient population.  
 
Adverse Events 

     McGuire, Gretchen 
                                                                                                                            
 
Version Date: 01/10/2018 
The research staff will document any adverse events that occur in the admission period for enrolled 
patients following provision of NAVA or BiPAP. Enrolled patients will be monitored in the CVCC, and 
standard care will be provided. Any unanticipated problems involving risks to the subjects or other 
(UPIRTSOs) will be reported to the IRB within 10 days. 
 
Stopping Rules and Data Safety Monitoring Plan 
The research interventions are both consistent with the standard of care for the study population. No 
stopping rules are planned. 
 
8. Administrative Procedures 
Patient Confidentiality 
All study data will be stored on a secure password-protected computer in the locked research office. 
Patient study files will be stored in a locked cabinet within the research office. Subjects will be given a 
unique study ID number when entered into the RedCap study database. 
 
Data Management 
Data will be collected on paper documents and will be securely stored in a locked cabined within the 
research office. Only the research study team will have access to these paper documents. Once the data 
has been collected on the source documents, the data will be entered into a study-specific RedCap 
database, which is a secure network that is password-protected. All of the study data will be securely 
stored for up to 3 years or completion of the study and all subsequent publications and presentations of 
the study results. 
 
9. References 
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Complications of mechanical ventilation in the pediatric population. Pediatric pulmonology. 
2011;46(5):452-7. doi: 10.1002/ppul.21389. PubMed PMID: 21194139. 
2. Kendirli T, Kavaz A, Yalaki Z, Ozturk Hismi B, Derelli E, Ince E. Mechanical ventilation in 
children. The Turkish journal of pediatrics. 2006;48(4):323-7. PubMed PMID: 17290566. 
3. Pacheco-Lopez PC, Berkow LC, Hillel AT, Akst LM. Complications of airway management. 
Respiratory care. 2014;59(6):1006-19; discussion 19-21. doi: 10.4187/respcare.02884. PubMed 
PMID: 24891204. 
4. British Thoracic Society Standards of Care C. Non-invasive ventilation in acute respiratory 
failure. Thorax. 2002;57(3):192-211. PubMed PMID: 11867822; PubMed Central PMCID: 
PMC1746282. 
5. Bersten AD, Holt AW, Vedig AE, Skowronski GA, Baggoley CJ. Treatment of severe 
cardiogenic pulmonary edema with continuous positive airway pressure delivered by face mask. 
The New England journal of medicine. 1991;325(26):1825-30. doi: 
10.1056/NEJM199112263252601. PubMed PMID: 1961221. 
6. Chadda K, Annane D, Hart N, Gajdos P, Raphael JC, Lofaso F. Cardiac and respiratory effects 
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7. Ho KM, Wong K. A comparison of continuous and bi-level positive airway pressure non-
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PMCID: PMC1550921. 

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8. L'Her E, Duquesne F, Girou E, de Rosiere XD, Le Conte P, Renault S, Allamy JP, Boles JM. 
Noninvasive continuous positive airway pressure in elderly cardiogenic pulmonary edema 
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10. de la Oliva P, Schuffelmann C, Gomez-Zamora A, Villar J, Kacmarek RM. Asynchrony, 
neural drive, ventilatory variability and COMFORT: NAVA versus pressure support in pediatric 
patients. A non-randomized cross-over trial. Intensive care medicine. 2012;38(5):838-46. doi: 
10.1007/s00134-012-2535-y. PubMed PMID: 22481227. 
11. Gilstrap D, MacIntyre N. Patient-ventilator interactions. Implications for clinical 
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12. Kallio M, Peltoniemi O, Anttila E, Pokka T, Kontiokari T. Neurally adjusted ventilatory 
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study. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the 
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10.1097/PCC.0b013e3181b0655e. PubMed PMID: 19593241. 
16. Rimensberger PC, Heulitt MJ, Meliones J, Pons M, Bronicki RA. Mechanical ventilation in 
the pediatric cardiac intensive care unit: the essentials. World journal for pediatric & congenital 
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17. Houtekie L, Moerman D, Bourleau A, Reychler G, Detaille T, Derycke E, Clement de Clety 
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10. Appendix 
Appendix 1: The Society of Thoracic Surgeons- European Association for Cardiothoracic Surgery 
Congenital Heart Surgery Mortality Categories (STAT Mortality Categories) 
Appendix 2:  Pain and Sedation Scales 
Appendix 3: Study Schema 
Appendix 4: Data Collection Forms