Comparison of a Sustained Inflation to Shorter Inflation Breaths During Resuscitation at Delivery of Prematurely Born Infants
Phase: NA
Conditions: Premature Birth
Sponsor: King's College London

 
 
 
 
 
 
 
 
 
 
 
 
 
Neonatal resuscitation: comparing sustained inflations to standard practice 
 
NCT02967562 
 
11/1/18 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Protocol for: Neonatal resuscitation: comparing sustained inflations to 
standard practice 
A prospective randomised controlled trial assessing the efficacy of sustained 
inflations in neonatal resuscitation compared to repeated shorter inflation breaths 
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: 020 3299 4564 
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   
 
Neonatal resuscitation: comparing sustained inflations 
to repeated shorter inflation breaths 
Protocol Short Title/Acronym  
Neonatal Resuscitation: sustained inflation 
Protocol Version number and Date  
 4 11/1/18 
Study Phase if not mentioned in title  
 
Is the study a Pilot?  
No 
Study Duration  
12 months 
Methodology 
 
 
Randomised controlled trial 
Sponsor name  
Mr Keith Brennan/Ms Liba Stones 
Chief Investigator  
Professor Anne Greenough 
REC number  
16 LO 1718 
Medical condition or disease under 
investigation 
 
Need for resuscitation at delivery in babies born prematurely 
Purpose of clinical trial  
To assess whether 15 second inflations are more effective at 
stimulating spontaneous breathing than five shorter inflation 
breaths of 2-3 seconds. 
Primary objective  
To assess whether sustained inflations provoke active inflations 
sooner during resuscitation than repeated shorter inflation 
breaths 
Secondary objective (s)  
To assess whether sustained inflations improve tidal volume 
exchange and end tidal carbon dioxide levels compared to 
repeated shorter inflation breaths, and to collect data regarding 
any adverse outcomes. 
Number of Subjects/Patients  
 48 + 
Trial Design   
Randomised controlled trial 
Endpoints  
Equal distribution of gestational age between groups 
Main Inclusion Criteria  
Any baby born <34/40 requiring resuscitation at delivery 
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 
Around  10% of newborns  will require some form of assistance after delivery, with babies born 
more prematurely more likely to require resuscitation.1  
 
Current UK guidelines advise initial resuscitation with the delivery of five ‘inflation breaths’ 
lasting 2-3 seconds with peak inflation pressure of 30cmH2O (20-25cm H2O in premature 
neonates).2 Previous studies have shown that despite resuscitation training, clinicians in both 
simulated and real resuscitation scenarios do not deliver the recommended duration of inflation 
breaths3. This, combined with leaks around the facemask often being as large as 50% or 
greater, contributes to low expired tidal volumes during resuscitation, thus increasing the 
likelihood of hypoxia and delay in establishing effective respiration.  
 
The use of sustained inflations (up to 15 seconds), rather than intermittent shorter inflation 
breaths, has shown promising results, with reduction in the need for intubation, and the need for 
and duration of mechanical ventilation.4–7 Around 30% of units in Germany use sustained 
inflations as first line delivery room management, as do many other hospitals around the world.8 
Resuscitation guidelines from the USA, UK and Europe suggest that sustained inflations should 
be researched further.9,10  
 
Several studies have shown that for several lengths of inflation breaths, the expired tidal volume 
achieved is higher if the baby makes respiratory effort during the inflation (active inflation),3,11,12 
and that stimulation of spontaneous respiratory effort is a key part in establishing an FRC, 
enabling spontaneous breathing, and increasing the likelihood of successful resuscitation.  
 
To date, there are no studies directly comparing whether prolonged inflations are more 
successful at provoking an inspiration than other methods of resuscitation. We therefore aim to 
compare a 15 second sustained inflation to repeated shorter inflations to determine which is 
more effective. 
 
1.  
Aziz K, Chadwick M, Baker M, Andrews W. Ante- and intra-partum factors that predict 
increased need for neonatal resuscitation. Resuscitation. 2008;79(3):444-452. 
doi:10.1016/j.resuscitation.2008.08.004. 
2.  
(UK) RC. NLS Guidelines (Resuscitation council). resus.org.uk. 
3.  
Murthy V, Dattani N, Peacock JL, et al. The first five inflations during resuscitation of 
prematurely born infants. Arch Dis Child - Fetal Neonatal Ed. 2012;97(4):F249-F253. 
doi:10.1136/archdischild-2011-300117. 
4.  
te Pas AB, Walther FJ. A Randomized, Controlled Trial of Delivery-Room Respiratory 
Management in Very Preterm Infants. Pediatrics. 2007;120(2):322-329. 
doi:10.1542/peds.2007-0114. 
5.  
Grasso C, Sciacca P, Giacchi V, et al. Effects of Sustained Lung Inflation, a lung 
recruitment maneuver in primary acute respiratory distress syndrome, in respiratory and 
cerebral outcomes in preterm infants. Early Hum Dev. 2015;91(1):71-75. 
doi:10.1016/j.earlhumdev.2014.12.002. 
6.  
Lista G, Boni L, Scopesi F, et al. Sustained Lung Inflation at Birth for Preterm Infants: A 
Randomized Clinical Trial. Pediatrics. 2015;135(2):e457-e464. doi:10.1542/peds.2014-
1692. 
7.  
El-Chimi MS, Awad HA, El-Gammasy TM, El-Farghali OG, Sallam MT, Shinkar DM. 
Sustained vs. Intermittent Lung Inflation for Resuscitation of Preterm Infants: a 

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Randomized Controlled Trial. J Matern Neonatal Med. July 2016:1-21. 
doi:10.1080/14767058.2016.1210598. 
8.  
Fuchs H. German experience in the management of ELGAN infants. Acta Biomed. 
2015;86 Suppl 1:16-20. http://www.ncbi.nlm.nih.gov/pubmed/26135950. Accessed July 
21, 2016. 
9.  
Wyllie J, Ainsworth S. What is new in the European and UK neonatal resuscitation 
guidance? Arch Dis Child - Fetal Neonatal Ed. April 2016:fetalneonatal - 2015-309472. 
doi:10.1136/archdischild-2015-309472. 
10.  
Wyckoff MH, Aziz K, Escobedo MB, et al. Part 13: Neonatal Resuscitation: 2015 
American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and 
Emergency Cardiovascular Care. Circulation. 2015;132(18 Suppl 2):S543-S560. 
doi:10.1161/CIR.0000000000000267. 
11.  
Schilleman K, van der Pot CJMM, Hooper SB, Lopriore E, Walther FJ, te Pas AB. 
Evaluating Manual Inflations and Breathing during Mask Ventilation in Preterm Infants at 
Birth. J Pediatr. 2013;162(3):457-463. doi:10.1016/j.jpeds.2012.09.036. 
12.  
van Vonderen JJ, Hooper SB, Hummler HD, Lopriore E, te Pas AB. Effects of a 
Sustained Inflation in Preterm Infants at Birth. J Pediatr. 2014;165(5):903-908.e1. 
doi:10.1016/j.jpeds.2014.06.007. 
 
2 Trial Objectives, Design and Statistics 
2.1. Trial Objectives 
To assess whether a 15 second inflation are more effective at stimulating spontaneous 
breathing than five shorter breaths of 2-3 seconds, evidenced by a greater number of active 
inflations and superior tidal volume exchange and end tidal carbon dioxide levels. 
2.2 Trial Design & Flowchart 
Randomised controlled trial. 
 
 
 
 
 
 
 
 
 
 

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2.3 Trial Flowchart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.  Sample Size, Selection and Withdrawal of Subjects 
We have previously demonstrated that active compared to passive inflations during resuscitation at least 
double expiratory tidal volumes and end tidal CO2 levels.  (An active inflation is one where the baby 
makes inspiratory effort during a mechanical inflation.) During resuscitation with short inflations, all 
infants had an active inflation by 50 seconds, but the active inflation occurred earlier in those who 
received longer rather than shorter mechanical inflations. We therefore postulate that over the first minute 
of resuscitation the total expiratory tidal volume (minute volume) will be 25% higher in the prolonged 
inflation group. Randomisation of 40 infants will allow us to detect one standardised difference in the 
minute volume between the two groups with 90% power at the 5% level. The standard deviation in our 
previous cohort in minute volume was 71mls/min/kg, that is 25% of the maximum minute volume 
achieved in our previous cohort.   
Randomisation at delivery 
Analysis of traces 
Collection of follow up data 
Ongoing resuscitation as per normal 
procedures, clinicians present to decide re 
intubation, etc
Initial 
resuscitation 
with 5 inflation 
breaths of 2-3 
seconds 
Initial 
resuscitation 
with 15 second 
sustained 
inflation  
Respiratory function monitoring 
available, clinical team trained in 
its use 
Parents approached as soon as possible 
after resuscitation to inform regarding 
study and to obtain consent for data 
analysis 

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At reaching the prespecified sample size we have a two week discrepancy in gestational age 
between the two groups, and therefore we will continue to recruit to the study until this is 
balanced. We anticipate that around 60 infants will be required but this will be reviewed after 
every 4 babies to be recruited. 
Inclusion Criteria 
Infants born less than 34 weeks of gestation requiring resuscitation at delivery. 
 
Exclusion Criteria 
Major congenital abnormalities 
 
Criteria for Premature Withdrawal 
Withdrawal of parental consent 
 
4.   Study procedures 
Informed Consent Procedures 
Preterm delivery may often occur without significant prior warning. When women are  in preterm 
labour, it may be inappropriate to approach them regarding research at this potentially 
distressing time, particularly as this may be very close to the point of delivery.  
We therefore intend to conduct this study as emergency research without prior informed 
consent, and will approach parents as soon as is practical after delivery to explain the research 
and to gain consent for analysis of resuscitation data and collection of further data. 
Information will be displayed on the antenatal wards regarding research without prior consent 
and contact details if any parents wish to discuss this. 
 
4.1 Screening Procedures  
There are no study specific screening procedures prior to entry into the study.  
 
4.2 Randomisation Procedures  
A random number generator will be used and allocations concealed in sealed opaque 
envelopes, opened immediately when it is deemed that resuscitation is required. 
 
4.3 Schedule of Events for each visit  
Infants randomised to the routine care group will receive resuscitation as per NLS protocols, 
with the addition of respiratory function monitoring. Infants randomised to the sustained inflation 
group will receive a 15 second sustained inflation at 25cmH2O in place of the five inflation 
breaths and this will be repeated in situations where, under normal circumstances, the five 
inflation breaths would be repeated (e.g. no chest rise seen.) The decision to initially resuscitate 
via facemask or to immediately intubate will be taken on usual clinical grounds, as will any 
subsequent decisions to intubate, perform chest compressions, or deliver medications. 
Resuscitation will otherwise proceed as per normal practice and, as above, the decision to 
intubate etc will be taken on normal clinical grounds by the team performing the resuscitation. 
  
 
4.4 Follow up Procedures 
Data regarding rates of pneumothorax, patent ductus arteriosus, intraventricular haemorrhage, 
need for mechanical ventilation in the first 72 hours of life, and mortality will be recorded.  
 

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4.5 Radiology Assessments (not applicable)  
Not applicable 
 
4.6 End of Study Definition 
 
Following completion of the measurements and analysis of the results of the required number of 
infants, the REC will be informed that the study has been completed. 
5. Laboratories (not applicable) 
6. Assessment of Safety  
Some studies have shown small, non-significant trends towards increased incidence of 
pneumothorax and intraventricular haemorrhage with sustained inflations. Another trial has 
shown a reduction in the incidence of air leak with sustained inflation, and animal studies have 
demonstrated improved stabilisation of cerebral blood flow with sustained inflation. Meta-
analysis of four trials has shown an increase in the occurrence of patent ductus arteriosus 
requiring treatment, but these trials were heterogenous in terms of the oxygen concentration 
used and length and pressure of sustained inflation. Sustained inflations have not previously 
been compared to five shorter inflation breaths lasting 2-3 seconds. Sustained inflations are 
used as a routine standard of care in many hospitals worldwide. 
 
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 
8. Ethics & Regulatory Approvals 
We will make an application via IRAS for HRA and NHS REC review and approval. 
 
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 chief 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 25 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 

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-Eligibility criteria checklist 
-Date of resuscitation 
-Any adverse events noted  
 
Completion of the CRF will be the responsibility of the clinical research fellow. 
 
Record Retention and Archiving 
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 
 
 
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 
Main REC and 
Sponsor  
 
 
 
Main REC with a 

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form giving notice in 
writing setting out the 
reasons for the urgent 
safety measures and the 
plan for future action. 
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