Optimisation of Neonatal Ventilation - NAVA vs PAV
Phase: NA
Conditions: Bronchopulmonary Dysplasia
Sponsor: King's College London

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Optimisation of Neonatal Ventilation: Neurally Adjusted Ventilator Assist 
(NAVA) versus Proportional Assist ventilation (PAV) 
A randomised cross over study assessing the oxygenation index, thoracoabdominal asynchrony, 
work of breathing, and trigger delay on neurally adjusted ventilatory assist (NAVA) and 
proportional assist ventilation (PAV) 
Sponsor 
Sponsoring Organisation/s: King’s College London and King’s College Hospital NHS  
Name of Sponsor Representative: Keith Brennan, Director of Research Management & 
Director of Administration (Health Schools) 
Address: Room 1.8 Hodgkin Building, Guy's Campus, King's College London, LONDON, 
SE1 4UL. 
Tel: 020 7848 6960 
Email: keith.brennan@kcl.ac.uk 
 
Name of Sponsor Representative: Liba Stones , R&D Manager,  
Address: King’s College Hospital, 161 Denmark Hill, London, SE5 8EF,   
Tel: 020 3299 3841   
e-mail: liba.stones@nhs.net  
 
Chief Investigator  
Name: Professor Anne Greenough 
Address: 4th Floor Golden Jubilee Wing, King's College Hospital, Denmark Hill, SE5 
9RS 
Tel: 020 3299 3037 
Email: anne.greenough@kcl.ac.uk 
Name and address of Investigator(s) 
Name: Dr Katie Hunt  
Address: 4th Floor Golden Jubilee Wing, King's College Hospital, Denmark Hill, SE5 
9RS 
Tel: 02032998492 
Email: Katie.a.hunt@kcl.ac.uk 
 
Statistician 
Name: Professor Anne Greenough 
Address: 4th Floor Golden Jubilee Wing, King's College Hospital, Denmark Hill, SE5 
9RS 
Tel: 020 3299 3037 
Email: anne.greenough@kcl.ac.uk 
 
 
 
 
 
 

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2 Trial Objectives, Design and Statistics 
2.1. Trial Objectives 
2.2 Trial Design & Flowchart 
2.3 Trial Flowchart 
2.4 Trial Statistics 
3. Sample Size, Selection and Withdrawal of Subjects 
3.1 Inclusion 
3.2 Exclusion 
3.3 Criteria for Premature Withdrawal 
4. Study procedures 
4.1 Screening Procedures  
4.2 Randomisation Procedures 
4.3 Schedule of Treatment for each visit  
4.4 Follow up procedures 
4.5 Radiology assessments 
   4.6 End of Study Definition  
5.  Laboratories 
 
5.1 Central/local Laboratories 
 
5.2 Sample collection/labelling logging 
 
5.3 Sample analysis procedures 
 
5.4 Sample storage procedures 
 
5.5 data Recording/Reporting 
 
5.6 Sample receipt/chain of custody/Accountability 
 
5.7 Tissue Sample Transfer 
6. Assessment of Safety 
 
6.1 Ethics Reporting 
7. Trial Steering Committee 
8. Direct Access to Source Data and Documents 
9. Ethics & Regulatory Approvals 
10. Data Handling 
10.1 Case Report From 
10.2 Record retention and Archiving 
10.3 Compliance 
10.4 Clinical Governance issues 
10.4 Non Compliance 
11. Finance & Publication Policy 
 
 

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Study Synopsis 
 
Title   
 
Randomised crossover study of Neurally Adjusted Ventilator 
Assist (NAVA) versus Proportional Assist Ventilation  (PAV) 
(NAVA Vs PAV  1.0  15/08/2015) 
Protocol Short Title/Acronym  
Assessment of triggered ventilation – NAVA versus PAV 
Protocol Version number and Date  
NAVA Vs PAV 1.0 15/8/2015 
Study Phase if not mentioned in title  
 
Is the study a Pilot?  
Yes 
Study Duration  
24 months 
Methodology 
 
 
Open randomised crossover study 
Sponsor name  
Mr Keith Brennan 
Chief Investigator  
Professor Anne Greenough 
REC number  
 
Medical condition or disease under 
investigation 
 
Evolving Bronchopulmonary Dysplasia 
Purpose of clinical trial  
Evaluation of two newer ventilator modes - NAVA and PAV - to 
determine which is more advantageous 
Primary objective  
In prematurely born infants (less than 32 weeks gestation) with 
evolving bronchopulmonary dysplasia, that is ventilated since 
birth and still ventilated at one week of age, NAVA compared to 
PAV will be associated with decreased oxygenation index. 
Secondary objective (s)  
NAVA compared to PAV will be associated with decreased work 
of breathing, lower thoracoabdominal asynchrony, and shorter 
trigger delay 
Number of Subjects/Patients  
18  
Trial Design   
Randomised cross over 
Endpoints  
Oxygenation Index, length of trigger delay, work of breathing, and 
thoraco-abdominal asynchrony 
Main Inclusion Criteria  
All prematurely born (<32/40) infants with evolving 
bronchopulmonary dysplasia ventilated since birth and still 
ventilated at one week of age. 
Statistical Methodology and Analysis  
Non-parametric statistics  
 
 
 
 
 
 
 

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Glossary of Terms and Abbreviations 
 
AE 
 
 
Adverse Event 
 
 
AR 
 
 
Adverse Reaction 
ASR 
 
 
Annual Safety Report 
CA 
 
 
Competent Authority 
CI 
 
 
Chief Investigator 
CRF 
 
 
Case Report Form 
CRO  
 
Contract Research Organisation 
DMC  
 
Data Monitoring Committee 
EC 
 
 
European Commission 
GAfREC 
Governance Arrangements for NHS Research Ethics Committees 
ICF 
 
 
Informed Consent Form 
ISRCTN 
 
International Standard Randomised Controlled Trial Number 
MA 
 
 
Marketing Authorisation 
MS 
 
 
Member State 
Main REC 
 
Main Research Ethics Committee 
NHS R&D 
 
National Health Service Research & Development   
PI 
 
 
Principle Investigator 
QA 
 
 
Quality Assurance 
QC 
 
 
Quality Control 
Participant 
 
An individual who takes part in a clinical trial 
RCT 
 
 
Randomised Controlled Trial 
REC 
 
 
Research Ethics Committee 
SAE 
 
 
Serious Adverse Event 
SDV 
 
 
Source Document Verification 
SOP 
 
 
Standard Operating Procedure  
SSA 
 
 
Site Specific Assessment 
TMG  
 
Trial Management Group 
TSC 
 
 
Trial Steering Committee 

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1. Introduction 
 
Despite improvements in survival rates of extremely preterm born infants, the incidence of 
bronchopulmonary dysplasia (BPD) remains unchanged over the last two decades. [1] As 
invasive ventilation is frequently necessary and indeed life saving, numerous ventilator 
strategies have been developed to reduce damage to the developing lung. Synchronisation of 
mechanical breaths with the patient’s respiratory effort offers the theoretical benefit of improving 
oxygenation and ventilation, requiring lower ventilator pressures, fewer air leaks and increased 
patient comfort.  
 
Conventional ventilation allows the clinician to set the inspiratory pressure or tidal volume 
delivered by the ventilator. The appropriateness of this target is then assessed via blood gas 
analysis and adjusted as necessary with changes in respiratory system mechanics and patient 
condition.  
 
Compared to continuous mandatory ventilation, triggered ventilation (assist control (ACV) and 
synchronized intermittent mandatory ventilation (SIMV) have been shown to reduce duration of 
mechanical ventilation, but not rates of BPD.[2]  
 
During ACV and SIMV, triggering is via either pressure or flow sensors which determine the 
initiation of inflation. In the neonatal population, with small tidal volumes, high respiratory rates 
and often significant leak from uncuffed endotracheal tubes, sensitive triggering can be 
challenging and hence, some of the benefits of triggered ventilation may not materialise. 
 
Conventional ventilation allows the clinician to set the inspiratory pressure or tidal volume 
delivered by the ventilator. The appropriateness of this target is then assessed via blood gas 
analysis and adjusted as necessary with changes in respiratory system mechanics and patient 
condition.  
 
Recently, novel modes of ventilation have been introduced that aim to improve upon 
conventional ventilation. During both proportional assist ventilation (PAV) and neurally-adjusted 
ventilatory assist (NAVA), respiratory support is servo-controlled based on continuous input 
from the baby’s respiratory effort. Both aim to improve synchronization of the timing of the 
respiratory cycle and also to vary the level of support offered breath-to-breath in proportion to 
the respiratory effort of the patient.  
 
During proportional assist ventilation (PAV), the ventilator can vary inflation pressure in phase 
with both volume change and flow change in order to offload both elastic and resistive 
components of the work of breathing. We have previously shown that PAV, compared to ACV, 
reduces the oxygenation index and improves respiratory muscle strength in infants born 
prematurely who remain ventilated at or beyond one week of life [4,5]. 
 
Neurally adjusted ventilatory assist (NAVA) utilises the electrical activity of the diaphragm to 
trigger the ventilator. A modified nasogastric feeding tube with a series of electrodes allows 
monitoring of the diaphragmatic electromyogram (Edi). The waveform of the Edi is used to 
trigger and control ventilator support. We have recently shown that NAVA compared to ACV 
results in a lower oxygenation index in infants born prematurely who remain ventilated at or 
beyond one week of life. 

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Both PAV and NAVA have been shown to have advantages above conventional triggered 
ventilation in neonates, but they have not been compared to each other. Our aim is to determine 
whether NAVA or PAV is more effective in reducing oxygenation index, work of breathing, and 
thoracoabdominal asynchrony, and preserving respiratory muscle strength in prematurely born 
neonates with evolving or established BPD. 
 
 
References 
1. Costeloe K L, Hennessy E M, Haider S, Stacey F, Marlow N, Draper E S. Short term 
outcomes after extreme preterm birth in England: comparison of two birth cohorts in 1995 and 
2006 (the EPICure studies). BMJ 2012;345:e7976. 
2. Greenough A, Dimitriou G, Prendergast M, Milner A D. Synchronized mechanical ventilation 
for respiratory support in newborn infants. Cochrane Database of Systematic Reviews 
2008:CD000456. 
3. Beck J, Reilly M, Grasselli G, Mirabella L, Slutsky A S, Dunn M S, et al. Patientventilator 
interaction during neutrally adjusted ventilatory assist in low birth weight infants. Pediatr Res 
2009;65:6638.  
4. Proportional assist versus assist control ventilation. S Shetty, P Bhat, A Hickey, JL Peacock, 
AD Milner A Greenough. Accepted for publication in European Journal of Pediatrics – June 
2015. 
5. Bhat P, Patel DS, Hannam S, et al. Crossover study of proportional assist versus assist 
control ventilation. Arch Dis Child Fetal Neonatal Ed 2015;100:F353F38 
2 Trial Objectives, Design and Statistics 
2.1. Trial Objectives 
To compare NAVA and PAV in prematurely born infants (less than 32 weeks gestation) with 
evolving bronchopulmonary dysplasia, that is ventilated since birth and still ventilated at one 
week of age, measuring oxygenation index, work of breathing, respiratory muscle strength, and 
thoracoabdominal asynchrony.  
2.2 Trial Design & Flowchart 
Randomised crossover design - two hour epochs of NAVA versus PAV 
 
Protocol: 
1. Order of modes randomized for each baby using random number generator and sealed 
opaque envelopes 
2. Infant examined before commencement of study 
3. A dual pressure transducer catheter and catheter with Edi electrode array (similar in diameter 
to that of the infant’s feeding tube) inserted via the infant’s nose or mouth and secured in place 
4. Baseline settings noted  
5. Infant changed to ventilator for mode A (Stephanie or Maquet) with baseline settings 
6. Allow period of stabilisation on baseline settings on the new ventilator – 1 hour 
7. A blood gas performed and the compliance and resistance measurements noted (from 
ventilator screen) in the baseline mode 
8. Enter into mode A for 2 hours 
9. During last five minutes – measure 
a. PTPdi (Measure of the work of breathing) 
b. TAA (measure of asynchrony) 

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c. Blood gas measurement (CO2 levels and calculating the oxygenation index) 
10. Change to ventilator for mode B (Maquet or Stephanie) 
11. Allow period of stabilisation on original settings on the new ventilator - 1 hour  
12. Enter into mode B for 2 hours 
13. During last five minutes measure 
a. PTPdi 
b. TAA 
c. Blood gas measurement (CO2 levels and calculating the oxygenation index) 
14. During each epoch: The number and length of desaturations, respiratory rate, heart rate, 
mean airway pressure, the tidal volumes and the FiO2 utilised are noted every 10 min. 
FiO2 to maintain saturations 92-96%. 
 
Ventilator settings: 
NAVA level will be set so that the NAVA curve and pressure curves are matching. We will titrate 
NAVA level to aim for Edi between 5 and 15. 
PAV – previous studies have shown waveform abnormalities and oscillations with resistive 
unloading, therefore elastic unloading only will be used. Elastic unloading will initially be set at 
75% of full unloading, and then if the infant remains stable, increased after 10 minutes to 100% 
unloading. If pressure waveform abnormalities develop then the unloading will be reduced back 
to 75%. 
 
Assessments:  
 
Oxygenation Index will be calculated by blood gas analysis from an indwelling catheter or by 
heelprick at the end of the 2 hour period of each ventilator mode ie NAVA/PAV.  
 
The WOB will be assessed by the measurement of the transdiaphragmatic pressure time 
product (PTPdi). Transdiaphragmatic pressure (Pdi) will be obtained from measurements of 
oesophageal (Poes) and gastric (Pgas) pressures, measured using a dual-pressure transducer 
tipped catheter and associated amplifier (Gaeltec, Dunvegan, UK). Correct positioning of the 
gastric transducer will be confirmed by a positive pressure deflection during inspiration while the 
position of the oesophageal transducer determined by comparing Poes and airway pressure 
during an occluded inspiratory effort. Airflow will be measured using a pneumotachograph 
(Mercury F10L; GM Instruments, Kilwinning, UK) connected to a differential pressure transducer 
(MP45; Validyne Corporation, Northridge, California, USA). Airway pressure will be measured 
from a side port on the pneumotachograph using a second differential pressure transducer 
(MP45; Validyne Corporation). The PTPdi will be obtained by integration of Pdi with time for 
each breath and expressed per minute. The mean PTPdi will be calculated from the first set of 
20 consecutive breaths without artefact during the last five minutes of each period on NAVA and 
PAV modes. 
Thoracoabdominal asynchrony will be assessed using uncalibrated respiratory inductance 
plethysmography (Respitrace model 10.9230, Ambulatory Monitoring, New York, USA) in 
ACcoupled mode. Inductance coils embedded in two elastic bandages will be placed around the 
ribcage (RC) and midabdomen. TAA will then be determined from five consecutive, artefact-free 
breaths during the 5 min measurement period. For each breath, the RC and abdominal 
wall (AB) movements will be derived from the recording software. A Lissajous figure is plotted 
and asynchrony between RC and abdominal motion quantified. The phase angle will be 
determined by comparing the difference between inspiratory and expiratory abdominal positions 

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at midRC excursion (ABdiff) with the maximum abdominal excursion (ABmax). The phase angle 
φ is calculated as sin φ=ABdiff/ABmax. 
 
References 
6. Beardsmore CS, Helms P, Stocks J, et al. Improved esophageal balloon technique for use in 
infants. J Appl Physiol 1980;49: 735–42. 
7. Baydur A, Behrakis PK, Zin WA, et al. A simple method for assessing the validity of the 
esophageal balloon technique. Am Rev Respir Dis 1982;126: 788–91. 
 
2.3 Trial Flowchart 
Patient 
information 
and 
informed 
consent 
 
Physical 
examination 
 
  
Baseline 
1 hour 
Mode A 
2 hours 
Baseline 
1 hour 
Mode B 
2 hours 
Oxygenation 
Index 
  
 
 x 
 
PTPdi 
 x 
 
 x 
 
TAA 
 x 
 
 x 
 
Adverse 
events 
  
 
  
 
 
2.4 Trial Statistics 
Recruitment of 18 infants will allow detection of a difference in the results of OI and the 
physiological assessments between the two groups equivalent to one standard deviation in the 
results with 80% power and 5% significance.  
3.  Sample Size, Selection and Withdrawal of Subjects 
 
Power calculation as stated in 2.4 requires the recruitment of 18 infants to participate in the 
study. 
 
Inclusion Criteria 
• 
Infants born at less than 32 weeks completed gestation who remain ventilator dependent 
one week after birth. 
 
Exclusion Criteria 
• 
Complex congenital cardiac abnormalities 

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• 
Infants on neuro-muscular blockade 
• 
Contraindication to nasogastric/orogastric tube insertion. 
 
Criteria for Premature Withdrawal 
• 
Parental Request 
4.   Study procedures 
Informed Consent Procedures 
 
Participants will be identified from the daily admission list and the clinical research fellow will 
approach parents. Parents will be provided with both verbal and written information, allowing at 
least 24 hours for consideration prior to entry into study. 
 
The clinical fellow will provide a full explanation of the study to the parents. They will highlight 
that the parents may choose not to allow their infant to be entered into the study and withdraw 
their child from the study at any time without compromising the child’s care. 
 
As the study involves hospital in-patients, consent will also be obtained from the consultant of 
the patient. 
 
4.1 Screening Procedures  
There are no study specific screening procedures prior to entry into the study. Eligible infants 
will be examined by the clinical fellow prior to undertaking physiological measurements in order 
to ensure they are in a stable condition. 
 
4.2 Randomisation Procedures  
Patients will be randomised using a sequential opaque-sealed envelope system, the contents 
having been determined by random number table generation.  
 
4.3 Schedule of Treatment for each visit  
The initial visit with the parents/carers of eligible infants will be primarily to provide information 
regarding the study, with a follow up meeting at least 24 hours later to ensure they have 
sufficient time to process the information and provide informed consent. 
 
The physiological measurements of each study participant will be performed on a single 
occasion, lasting approximately 6 hours. It is unlikely that repeat study measurements will need 
to be taken and if required, the reasons will be explained to parents prior to taking place. 
 
4.4 Follow up Procedures 
There are no specific study procedures for follow up of the participating infants.  
 
4.5 Radiology Assessments (not applicable)  
 
4.6 End of Study Definition 
 
Following completion of the physiological measurements and analysis of the results of  
the required number of infants, the REC will be informed that the study has been completed. 

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5. Laboratories (not applicable) 
6. Assessment of Safety  
 
All measurements are carried out whilst the patient is ventilated and closely monitored as part of 
routine clinical care. There have been no adverse effects or additional discomfort associated 
with previous studies which have used the same physiological assessments and similar study 
design. Infants will be fully examined to ensure clinical stability prior to undertaking 
measurements. 
 
6.1 Ethics Reporting 
 
Reports of related and unexpected serious adverse events will be submitted to the Main REC 
within 15 days of the chief investigator becoming aware of the event, using the NRES template. 
The parents will be informed of any events as soon as possible and be provided with an 
opportunity to meet with clinical and research team. The results of any reports or investigations 
relating to the events will also be communicated to the parents in writing. 
7. Trial Steering Committee (not applicable) 
8. Ethics & Regulatory Approvals 
We will submit via IRAS for HRA and NHS REC approval. 
9. Data Handling 
Confidentiality  
 
Analysis of the data will take place at King’s College Hospital and is to be undertaken by a 
clinical research fellow and by Professor Greenough, the principal investigator.  
 
Each patient will be assigned a unique patient identifier, under which patient data will be 
anonymously stored on a password protected computer. All paper copies containing patient 
identifiable data will be kept in a locked filing cabinet until the patients are 16 years of age.   
Only the principal investigator and research fellow involved in the study will have access to the 
data, the principal investigator will act as custodian  
 
Case Report Form 
 
Elements included in each case report form (CRF): 
-Unique patient identifier 
-Date of parental consent 
-Eligibility criteria checklist 
-Date of measurements 
-Record of clinical examination 
-Study template documenting the order of volume targets as per randomisation and PTPdi 
results 
-Any adverse events noted during measurements 
 
Completion of the CRF will be the responsibility of the clinical research fellow. 
 
Record Retention and Archiving 

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Records will be held in a locked filing cabinet located within the research office based at the 
neonatal unit of Kings College Hospital. Access is limited to the clinical research fellow and 
Chief Investigator.  
 
Compliance 
The CI will ensure that the trial is conducted in compliance with the principles of the Declaration 
of Helsinki (1996), and in accordance with all applicable regulatory requirements including but 
not limited to the Research Governance Framework, Trust and Research Office policies and 
procedures and any subsequent amendments. 
 
Clinical Governance Issues 
 
-Audit and Inspection 
Accurate records of all research activity including copies of the consent forms and completed 
case report forms will be safely stored and audited for compliance if requested. 
 
-Non-Compliance        
 
The sponsor will maintain a log of the non-compliances to ascertain if there are any trends 
developing which to be escalated. The sponsor will assess the non-compliances and action a 
timeframe in which they need to be dealt with. Each action will be given a different timeframe 
dependant on the severity. If the actions are not dealt with accordingly, the R&D Office will 
agree an appropriate action, including an on-site audit. 
 
10. Finance and Publication Policy 
 
Consumables for this study have been funded by the National Institute for Health Research 
(NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and 
King's College London. The clinical research fellow salary is funded by Professor Greenough’s 
NIHR Senior Investigator grant.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 1 – Information with regards to Safety Reporting in Non-CTIMP Research 
 
Who 
When 
How 
To Whom 
SAE 
Chief 
Investigator 
-Report to Sponsor 
within 24 hours of 
learning of the event 
 
-Report to the MREC 
within 15 days of 
learning of the event 
 
SAE Report form for Non-
CTIMPs, available from 
NRES website. 
Sponsor and 
MREC 
Urgent Safety 
Measures  
Chief 
Investigator  
Contact the Sponsor 
and MREC 
Immediately 
 
Within 3 days  
By phone 
 
 
 
 
Substantial amendment 
form giving notice in 
writing setting out the 
reasons for the urgent 
safety measures and the 
plan for future action. 
Main REC and 
Sponsor  
 
 
 
Main REC with a 
copy also sent to 
the sponsor. The 
MREC will 
acknowledge this 
within 30 days of 
receipt.  
Progress 
Reports  
Chief 
Investigator  
Annually ( starting 12 
months after the date 
of favourable opinion) 
Annual Progress Report 
Form (non-CTIMPs) 
available from the NRES 
website 
Main REC 
Declaration of 
the 
conclusion or 
early 
termination of 
the study 
Chief 
Investigator  
Within 90 days 
(conclusion) 
 
Within 15 days (early 
termination) 
 
The end of study 
should be defined in 
the protocol 
End of Study Declaration 
form available from the 
NRES website 
Main REC with a 
copy to be sent to 
the sponsor  
Summary of 
final Report  
Chief 
Investigator 
Within one year of 
conclusion of the 
Research 
No Standard Format 
However, the following 
Information should be 
included:- 
Where the study has met 
its objectives, the main 
findings and 
arrangements for 
publication or 
dissemination including 
feedback to participants 
Main REC with a 
copy to be sent to 
the sponsor